Handbook of Disease Burdens and Quality of Life Measures

Part 1
1 Instruments and Methodological

Aspects
1.1 Instruments Used in the
Assessment of Disease Impact
1 The International Classification
of Functioning, Disability and
Health: A Tool to Classify and
Measure Functioning
G. Stucki . N. Kostanjsek . A. Cieza
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2 The ICF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1 The ICF in the Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.2 The ICF in the WHO and the UN Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.3 Development of the ICF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.4 Up-Date and Revision Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.5 The Structure of the ICF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.6 Validity of the ICF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.6.1 Exhaustiveness or Width . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.6.2 Precision or Depth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.6.3 ICF Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3 Implementation of the ICF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4 ICF-based Classification and Measurement of Functioning . . . . . . . . . . . . . . . . . . . . . . 18

4.1 ICF Categories: Building Blocks and Reference Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4.2 ICF-based Practical Tools: ICF Checklist and ICF Core Sets . . . . . . . . . . . . . . . . . . . . . . . 19
4.2.1 ICF Checklist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.2.2 ICF Core Sets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.3 Mapping the World of Measures to the ICF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4.3.1 Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4.3.2 Linkage Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4.4 ICF-based Measurement of Functioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
4.4.1 Measuring a Single ICF Category . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
4.5 Measuring Across ICF Categories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
# Springer Science+Business Media LLC 2010 (USA)

4 1 The International Classification of Functioning, Disability and Health
Abstract: The endorsement of the > International Classification of Functioning, Disability and
Health (ICF) by the 54th World Health Assembly in May 2001 mirrors an important shift in the
priorities by the > World Health Organization (WHO). Although WHO has traditionally
focused on infection control and mortality reduction WHO now also emphasizes the importance
of reducing the burden associated with non-fatal health conditions. WHO has developed the ICF
to provide a unified, international and standardized language for describing and classifying health
and health-related domains and hence to provide a common framework for health outcome
measurement. With the approval of the ICF the WHO member states are now called upon to
implement the ICF in the health, education, labour and social sector. The ICF has found
immediate interest in the health sciences with currently more than 600 ICF related publications
reflecting the interest, relevance, and impact of its application in health research worldwide.
The > ICF categories are the discrete, meaningful, universally shared and understood
elements which allow users to comprehensively classify and measure > functioning, > disabil-
ity and health of individuals and populations. They are thus the building blocks for the
construction of ICF-based practical tools such as the > ICF Checklist and the > ICF Core Sets as
well as clinical measurement instruments such as the ICF Core Set Indices and self-reported
measurement instruments such as the World Health Organization Disability Assessment
Schedule II (WHODAS II).
While ICF-based practical tools such as the ICF Core Sets allow the classification of
functioning states, clinical and self-reported measurement instruments allow the measurement
and hence the estimation of functioning status or aspects of it in relation to specific purposes.
Vice versa, the ICF categories serve as meaningful and universal reference units for reporting
and communicating results of measurements of aspects of functioning made with any
measurement instrument from the infinite universe of measurement instruments including
health-status measures or health-related quality of life measures.
List of Abbreviations: CAT, Computer Adaptive Testing; CTS, Classification, Terminology
and Standards; DAR, Disability and > Rehabilitation; DIMDI, Deutsches Institut für Medizi-
nische Dokumentation und Information; FDRG, Functioning and Disability Reference Group;
ICD, > International Classification of Diseases; ICF, International Classification of Function-
ing, Disability and Health; ICF-CY, International Classification of Functioning, Disability and
Health for Children and Youth; ICIDH, > International Classification of Impairment,
Disabilities and Handicaps; ICIDH-2, International Classification of Impairment, Disabilities
and Handicaps-2; ILO, International Labour Organization; ISPRM, International Society of
Physical and Rehabilitation Medicine; NACC, North American Collaboration Center; NHP,
Nottingham health profile; OMERACT, Outcome Measures in Theumatoid Arthritis Clinical
Trials; SF-36, Medical Outcomes Study 36-item short-form health survey; SNOMED, System-
ized Nomenclature of Medicine; UN, United Nations; UNCESCO, United Nations Education-
al, Scientific and Cultural Organization; UNSTAT, United Nations Statistics Division; VAS,
Visual Analog Scale; WHA, World Health Assembly; WHO FIC CC Network, World Health
Organization Network of the Collaboration Centers for the Family of International Classifica-
tions; WHO, World Health Organization; WHODAS II, World Health Organization Disability
Assessment Schedule II
1 Introduction
Functioning is the lived experience of people (Bickenbach et al., 1999). It is a universal human
experience (Bickenbach et al., 1999), in which body, person and society are intertwined (WHO,
The International Classification of Functioning, Disability and Health 1 5
2001). Over the life span people may experience a variation in the level of functioning associated
with congenital disorders, injuries, acute and chronic health conditions and ageing. The experi-
ence of a limitation of functioning or disability thus is part of the human condition (Bickenbach
et al., 1999). According to estimates of the World Health Organization (WHO) at least 10% of
the world’s population experience disability. This figure is increasing as a result of population
growth, medical advances and the ageing process, but also due to malnutrition, war, violence,
road-traffic, domestic and occupational injuries and other causes often related to poverty.
With the International Classification of Functioning, Disability and Health (ICF)
approved by the 54th World Health Assembly in 2001 (WHO, 2001), the WHO provides for
the first time a universal and internationally accepted framework and classification (Stucki,
2005a). The ICF is a promising starting point for the integrative understanding of functioning,
disability and health and the overcoming of Cartesian dualism of body and mind as well as
both sociological and biomedical reductionism (Imrie, 2004). The objective of this chapter is
to introduce the reader to the ICF. In the first section we review the history and development
of the ICF and describe its structure and validity. In the second section we illustrate how to use
the ICF for the classification and measurement of functioning. Finally, we discuss the current
state of the implementation and application of the ICF.
2 The ICF
2.1 The ICF in the Historical Perspective
Clinicians have relied on classifications for the diagnosis of health conditions for over 100
years. The International Classification of Diseases (ICD) was first published as a classification
of causes of death in 1898 (Hetzel, 1997). In the meantime the International Classification of
Diseases is undergoing its 11th revision. The ICD was initially used for actuarial reasons to
document death. It was later adopted for epidemiology and by public health to monitor health
and interventions. Lately it was used for clinical purposes mainly driven by the need to classify
diagnoses in the context of reimbursement systems including diagnostic related groups.
By contrast, the first classification of disability, the International Classification of Im-
pairment, Disabilities and Handicaps (ICIDH) was published in 1976 and released for trial
purposes in 1980 only. The ICIDH together with models of the Institute of Medicine (Pope
and Tarlov, 1991) which are based on Nagi’s model (Nagi, 1965) and the Quebec model
(Fougeyrollas et al., 1998) have provided the basis for definitions of > rehabilitation (Stucki
et al., 2007a), the development of rehabilitation practice and research (Stucki et al., 2007a),
and legislation and policy-making (Stucki, 2005a). The ICIDH model represented a real
breakthrough in that the WHO recognized that the > medical model and its associated
International Classification of Diseases did not address non-fatal health outcomes. Particularly
in Europe, there was considerable interest in the application of the ICIDH as a unifying
framework for classifying the consequences of disease during the last 20 years of the twentieth
century. E.g. the Council of Europe launched its Recommendation No. R (92) 6 on ‘‘a coherent
policy for people with disabilities’’ based on the ICIDH and the Quebec model.
However, the ICIDH, which was never approved by the World Health Assembly as an
official WHO classification, did not find worldwide acceptance (Bickenbach et al., 1999). It
was criticized by the disability community over time for the use of negative terminology, such
as handicap, and for not explicitly recognizing the role of the environment in its model. In the
publication of the second edition of the ICIDH in 1993, WHO thus expressed its intention to
embark in the development of a successor classification.
2.2 The ICF in the WHO and the UN Perspective
The endorsement of the ICF by the 54th World Health Assembly (WHA) in May 2001 mirrors
an important shift in the priorities by the WHO. Although WHO has traditionally focused on
infection control and mortality reduction WHO now also emphasizes the importance of
reducing the burden associated with non-fatal health conditions. Recognizing the importance
of functioning and disability as a major public health issue both in the developed and in the
developing world, WHO has developed the ICF to provide a unified, international and
standardized language for describing and classifying health and health-related domains and
hence to provide a common framework for health outcome measurement. The ICF thus
complements indicators that have traditionally focused on deaths and diseases. To comple-
ment mortality or diagnostic data on morbidity and diseases is important since they alone do
not adequately capture health outcomes of individuals and populations (e.g., diagnosis alone
does not explain what patients can do, what their prognosis is, what they need, and what
treatment costs) (Üstün et al., 2004).
The ICF, which is now coordinated by WHO’s ‘‘Classification, Terminology and Standards
(CTS)’’ team serves as reference framework throughout WHO. Most importantly, the ICF is the
reference framework of the Disabilities and Rehabilitation Team (DAR) under the Department of
Violence and Injury Prevention and Disability. The WHA resolution 58.23 on ‘‘Disability,
including prevention, management and rehabilitation’’ approved in May 2005 by the 58th
World Health Assembly and coordinated by the DAR team thus recalls the ICF as its framework
(Stucki et al., 2007a). As requested by the resolution, the WHO is currently developing a world
report on disability and rehabilitation whose structure is based on the ICF framework.
While the ICF has been developed by WHO, the specialty agency responsible for health
within the United Nations (UN) system, the ICF has been accepted as one of the United
Nations social classifications (WHO, 2001). It thus now serves as reference framework for the
UN and its other specialty agencies including the United Nations Statistics Division
(UNSTAT), the United Nations Educational, Scientific and Cultural Organization (UNESCO)
and the International Labour Organization (ILO).
Although the ICF is not explicitly mentioned, the understanding of functioning as a
universal experience according to the ICF framework is the basis for the characterization of
disability in the UN Convention on the Rights of Persons with Disabilities approved on
13 December 2006 at the United Nations Headquarters in New York. While the convention
does not establish new human rights, it does define the obligations on states to promote,
protect and ensure the rights of persons with disabilities. Most importantly, it sets out the
many steps that states must take to create an enabling environment so that persons with
disabilities can enjoy inclusion and equal > participation in society.
2.3 Development of the ICF
Coordinated by WHO’s secretariat for mental health and later by the secretariat responsible
for classifications and terminology, the ICF was developed in a worldwide collaborative
process through the Network of Collaboration Centers for the Family of International
Classifications, especially the NACC, the North American Collaboration Center. After three
preliminary drafts and extensive international field testing including linguistic and cultural
applicability research, the successor classification which was first tentatively named ICIDH-2,
the International Classification of Functioning, Disability and Health (ICF) was finalized in
2000 (WHO, 2001). The ICF for Children and Youth, the ICF-CY, was finalized and officially
launched in 2007. Until March 2008 the ICF has been translated in several languages.
The ICF not only addresses Western concepts but has worldwide cultural applicability. The
ICF follows the principle of a universal as opposed to a minority model. Accordingly, it covers
the entire life span. It is integrative and not merely medical or social. Similarly, it addresses
human functioning and not merely disability. It is multi-dimensional and interactive and
rejects the linear linkage between health condition and functioning. It is also etiologically
neutral which means functioning is understood descriptively and not caused by diagnosis. It
adopts the parity approach which does not recognize an inherent distinction or asymmetry
between mental and physical functioning.
These principles address many of the criticisms of previous conceptual frameworks and
integrate concepts established during the development of the Nagi model (Nagi, 1965) and the
Institute of Medicine model of 1991 (Pope and Tarlov, 1991). Most importantly, the inclusion
of environmental and personal factors together with the health condition reflects the integra-
tion of the two main conceptual paradigms that had been used previously to understand and
explain functioning and disability, that is, the medical model and the > social model.
The medical model views disability as a problem of the person caused directly by the
disease, trauma or other health conditions and calls for individual medical care provided by
health professionals. The treatment and management of disability aim at cure and target
aspects intrinsic to the person, i.e. the body and its capacities, in order to achieve individual
adjustment and behaviour change (Lemert, 1972).
By contrast, the social model views disability as the result of social, cultural, and environ-
mental barriers that permeate society. Thus, the management of disability requires social
action, since it is the collective responsibility of society at large to make the environmental
modifications necessary for the full participation of people with disabilities in all areas of
social life (DeJong, 1993; Dixon et al., 2007). The ICF and its framework achieve a synthesis,
thereby providing a coherent view of different perspectives of health (Bickenbach et al., 1999).
2.4 Up-Date and Revision Process
The ICF published in 2001 is a first version. Similar to the ICD it will undergo up-dates and
ultimately a revision process. The up-date is prepared by WHO’s CTS team in collaboration
with the relevant committees and the ‘‘Functioning and Disability Reference Group’’ (FDRG)
of the Network of the Collaboration Centers for the Family of International Classifications
(WHO FIC CC Network).
The up-date will include information obtained in a wide range of testing and validation
studies conducted in collaboration with FDRG and in the scientific community. Currently,
FDRG is exploring the possibility and methodological approaches to develop a classification of
personal factors. In the future the ICF may evolve in a classification which is based on an
ontological approach similar to the approach taken by SNOMED (Systemized Nomenclature
of Medicine) (Stucki and Grimby, 2004).
2.5 The Structure of the ICF
As shown in > Figure 1-1, the ICF consists of three key components. In short, the first
component, > body functions and structures, refers to physiologic functions and anatomic
. Figure 1-1
The model of functioning and disability on which the ICF is based. Functioning is an umbrella
term for body functions and structures, activities and participation. Disability is an umbrella term
for impaired body functions and activities limitation in activities and restriction in participation
parts, respectively; loss or deviations from normal body functions and structures are referred
to as impairments. The second component, > activities, refers to task execution by the
individual. ‘‘Activity limitations’’ are thus difficulties the individual may have in executing
activities (Stucki, 2005a). The third component, > participation, refers to involvement in life
situations. ‘‘Participation restrictions’’ are thus problems the individual may experience with
such involvement (Stucki, 2005a). These three components are summarized under the um-
brella terms > functioning and disability. They are related to and may interact with the health
condition (e.g., disorder or disease) and personal and environmental factors.
The components of body functions and structures, activities and participation, and
environmental factors are classified based on ICF categories. It is conceivable, that a list of
personal factors will be developed over the next years. The ICF contains a total of 1,424
meaningful and discrete or mutually exclusive categories. Taken together the ICF categories
are cumulative exhaustive and hence cover the whole spectrum of the human experience. The
categories are organized within a hierarchically nested structure with up to four different levels
as shown in > Figure 1-2. The ICF categories are denoted by unique alphanumeric codes with
which it is possible to classify functioning and disability, both on the individual and popula-
tion level.
An example of the hierarchically nested structure is as follow: ‘‘b1 Mental functions’’ (first/
chapter level); ‘‘b130 Energy and drive functions’’ (second level); and ‘‘b1301 Motivation’’
(third level). Based on the hierarchically nested structure of the ICF categories, a higher-level
category shares the attributes of the lower-level categories to which it belongs. In our example
the use of a higher numbered level category (b1301 Motivation) automatically implies that
the lower numbered level category is applicable (b130 Energy and drive functions).
. Figure 1-2
The structure of the ICF and the distribution of the ICF’s 1,424 categories across its four
components and four levels of hierarchy
Because the ICF categories are always accompanied by a short definition and inclusions
and exclusions the information on aspects of functioning can be reported unambiguously.
Examples of ICF categories, with their definitions, inclusions and exclusions are shown in
> Table 1-1.
2.6 Validity of the ICF
A wide range of studies across world regions and user perspectives have been examined and
have provided empirical and theoretical evidence supporting different aspects of the validity of
the ICF framework. They include exhaustiveness or width, and precision or depth of the
classification.
2.6.1 Exhaustiveness or Width
A classification needs to be exhaustive by its very nature. In relation to the ICF and its
categories, exhaustiveness refers to the coverage of the complete spectrum of health and
health-related domains that make up the human experience of functioning and disability,
and the complete spectrum of environmental factors that influence that experience of func-
tioning and disability. Exhaustiveness is thus closely related to the concept of width, which
refers to the number of distinct health and health-related domains at the same level of
specification included in the classification. Based on results of published studies, the ICF
appears to fulfil the formal criteria of exhaustiveness, especially in relation to the bandwidth
of covered domains. In this respect, the results of the studies conducted in the context of the
ICF Core Set development (Cieza et al., 2004a; Stucki and Grimby, 2004; Grill et al., 2005a)
(> Table 1-2) can be considered ‘‘proof of concept.’’
To the surprise of many clinicians and scientists involved, the ICF has been shown to be a
highly comprehensive classification covering virtually all aspects of the patient experience.
More specifically, the ICF has covered the spectrum of problems encountered in people with
a wide range of conditions and along the continuum of care. Ongoing validation studies
. Table 1-1
Examples of ICF categories with their corresponding code, title, definition and inclusion and
exclusion criteria
Codea and title, definition, inclusions and exclusions

b130 Energy and drive functions
General mental functions of physiological and psychological mechanisms that cause the individual
to move towards satisfying specific needs and general goals in a persistent manner
Inclusions: functions of energy level, motivation, appetite, craving (including craving for substances
that can be abused), and impulse control
Exclusions: consciousness functions (b110); temperament and personality functions (b126); sleep
functions (b134); psychomotor functions (b147); emotional functions (b152)
b280 Sensation of pain
Sensation of unpleasant feeling indicating potential or actual damage to some body structure
Inclusions: sensations of generalized or localized pain, in one or more body part, pain in a dermatome,
stabbing pain, burning pain, dull pain, aching pain; impairments such as myalgia, analgesia and
hyperalgesia
s730 Structure of upper extremity
d450 Walking
Moving along a surface on foot, step by step, so that one foot is always on the ground, such as
when strolling, sauntering, walking forwards, backwards, or sideways
Inclusions: walking short or long distances; walking on different surfaces; walking around obstacles
Exclusions: transferring oneself (d420); moving around (d455)
d920 Recreation and leisure
Engaging in any form of play, recreational or leisure activity, such as informal or organized play and
sports, programmes of physical fitness, relaxation, amusement or diversion, going to art galleries,
museums, cinemas or theatres; engaging in crafts or hobbies, reading for enjoyment, playing
musical instruments; sightseeing, tourism and traveling for pleasure
Inclusions: play, sports, arts and culture, crafts, hobbies and socializing
Exclusions: riding animals for transportation (d480); remunerative and non-remunerative work (d850
and d855); religion and spirituality (d930); political life and citizenship (d950)
e1101 Drugs
Any natural or human-made object or substance gathered, processed or manufactured for
medicinal purposes, such as allopathic and naturopathic medication
a
The letter b of the ICF refers to body functions, s to body structures, d to activities and participation domains, and
e to environmental factors
for the ICF Core Sets from the patient and health professional perspectives (> Table 1-2) have
shown that the ICF broadly covers patient problems and aspects of functioning treated by
occupational therapists, physiotherapists and psychologists e.g. in patients with rheumatoid
arthritis. The results also show that health professionals from different professions differ
greatly in their intervention goals, reflecting the importance of validating the ICF from the
perspective of many different health professions.
. Table 1-2
The ICF Core Set development
Protocol Consensus
paper Preparatory phase conference Validation phase
Patient Expert perspective Patient Expert perspective Economic
perspective perspective perspective
ICF Core Set ICF data Literature Delphi Focus groups Linking Delphi Nursing
collection review method or patient method resources
interviews
Acute Grill et al., Grill et al., Grill et al., Mueller
context 2005a 2005b 2005c et al., 2008
Neurological Grill et al., Grill et al., Grill et al., Ewert et al.,
conditions 2005a 2005b 2005c 2005
Musculoskeletal Grill et al., Grill et al., Grill et al., Stoll et al.,
conditions 2005a 2005b 2005c 2005
Cardiopulmonary Grill et al., Grill et al., Grill et al., Scheuringer
conditions 2005a 2005b 2005c et al., 2005a
Early Grill et al., Scheuringer Grill et al.,
post- 2005a et al., 2005b 2006;
acute Mueller
context et al., 2008
Neurological Grill et al., Grill et al., Scheuringer Stier-Jarmer Grill et al.,
conditions 2005a 2005d et al., 2005b et al., 2005 2006;
Mueller
et al., 2008
The International Classification of Functioning, Disability and Health
Musculoskeletal Grill et al., Scheuringer Boldt et al., Grill et al.,

conditions 2005a et al., 2005b 2005 2006;
Mueller
et al., 2008
1
11
12
. Table 1-2 (continued) 1
Protocol Consensus
paper Preparatory phase conference Validation phase
Cardiopulmonary Grill et al., Scheuringer Wildner Grill et al.,
conditions 2005a et al., 2005b et al., 2005 2006;
Mueller
et al., 2008
Geriatric patients Grill et al., Grill et al., Scheuringer Grill et al., Grill et al.,
2005a 2005e et al., 2005b 2005f 2006;
Mueller
et al., 2008
Long Cieza et al., Ewert et al., Weigl et al.,
term 2004a 2004 2004
context
Chronic Cieza et al., Ewert et al., Brockow Weigl et al., Cieza et al.,
widespread pain 2004a 2004 et al., 2004a 2004 2004b
Low back pain Cieza et al., Ewert et al., Brockow Weigl et al., Cieza et al.,
2004a 2004 et al., 2004a 2004 2004c
Osteoarthritis Cieza et al., Ewert et al., Brockow Weigl et al., Dreinhöfer
2004a 2004 et al., 2004a 2004 et al., 2004
Osteoporosis Cieza et al., Ewert et al., Brockow Weigl et al., Cieza et al.,
2004a 2004 et al., 2004a 2004 2004d
Rheumatoid Cieza et al., Ewert et al., Brockow Weigl et al., Stucki et al., Coenen et al., Kirchberger
arthritis 2004a 2004 et al., 2004a 2004 2004a 2006; Stamm et al., 2007
et al., 2005
Chronic ischemic Cieza et al., Ewert et al., Cieza et al., Weigl et al., Cieza et al.,
heart disease 2004a 2004 2004e 2004 2004e
Diabetes Cieza et al., Ewert et al., Wolff et al., Weigl et al., Ruof et al.,
2004a 2004 2004 2004 2004
Obesity Cieza et al., Ewert et al., Wolff et al., Weigl et al., Stucki et al.,
2004a 2004 2004 2004 2004b
Obstructive Cieza et al., Ewert et al., Wolff et al., Weigl et al., Stucki et al.,
pulmonary 2004a 2004 2004 2004 2004c
diseases
Depression Cieza et al., Ewert et al., Brockow Weigl et al., Cieza et al.,
2004a 2004 et al., 2004b 2004 2004f
Breast cancer Cieza et al., Ewert et al., Brockow Weigl et al., Brach et al.,
2004a 2004 et al., 2004c 2004 2004
Stroke Cieza et al., Ewert et al., Geyh et al., Weigl et al., Geyh et al.,
2004a 2004 2004a 2004 2004b
Psoriasis and Stamm
psoriatic arthrits et al., 2007
Ankylosing van Echteld i.p. i.p. i.p.
spondylitis et al., 2006
Spinal cord injury Biering- i.p. i.p. i.p. i.p.
Sorensen
et al., 2006
Systemic lupus Aringer i.p. i.p. i.p. i.p.
erythematosus et al., 2006
Multiple sclerosis Kesselring i.p. i.p. i.p. i.p.
et al., 2008
Head and neck Tschiesner i.p. i.p. i.p. i.p.
cancer et al., 2007
Bipolar disorders Vieta et al., i.p. i.p. i.p. i.p.
2007
The first rows of the table show the phases of the development of the ICF Core Sets. The numbers in the cells refer to the publications reporting on the results of the different
phases for the corresponding health conditions. The abbreviation i.p. means in progress. Empty cells means that the corresponding study has not been performed
1
13
Further proof to the comprehensiveness of the ICF is the finding that items of a wide range
of measurement instruments (> Table 1-3) can be mapped to the ICF. Most importantly, the
ICF broadly represents the contents of health-related quality of life measures.
2.6.2 Precision or Depth
The second consideration for a classification is its depth or precision. Depth or precision can
be defined as the number of distinct levels of specification differentiated within a health or
health-related domain. Ultimately, the proposal, as presented to the World Health Assembly in
2001, was arbitrary. However, there were guiding principles. Most importantly, the level of
specification of ICF categories was established in relation to the human experience of people
across a wide range of health conditions, along the continuum of care, along the life span and
across the WHO regions. Since the ICF categories are intended to be discrete and meaningful
elements, they reflect the intuitive level or the level of informed ‘‘lay experts’’ but not the level
of ‘‘professional experts’’ in a specific area.
Few studies have so far explicitly addressed this issue. A study that linked health-related
quality of life measures to the ICF found that items with different content are linked to the same
ICF category (Cieza and Stucki, 2005a). This can be seen as an indication that the ICF does not
differentiate these categories adequately. One example is the category b152, Emotional func-
tions. In a review of the items of the SF-36 (Medical Outcomes Study 36-Item Short-Form
Health Survey) and the NHP (Nottingham Health Profile), different items of these instruments
were linked to the same ICF category b152, even though they referred to different emotions.
Based on this and other results, the most common emotional functions that could be specified in
a future version of the ICF are: sadness, happiness, anxiety, and anger (Cieza and Stucki, 2005a).
2.6.3 ICF Framework
Jette has rightly argued that for ‘‘scientific investigation, a crucial aspect of any conceptual
framework is its internal coherence and its ability to differentiate among concepts and
categories within the framework (Kaplan, 1964). Without empirical differentiation, concep-
tual frameworks cannot be investigated and validated. One of the common criticisms of the
original ICIDH was that it was difficult to ascertain the boundaries between the basic concepts,
each lacked the clarity and distinctness necessary for useful empirical testing (Grimby et al.,
1988; Dijkers et al., 2000; Gray and Hendershot, 2000; Johnston and Pollard, 2001). Thus,
for the ICF to be useful as a framework for research, it is critical that the classification is clear
about the phenomena it classifies with distinct and measurable definitions of each dimension.
Without distinct and measurable dimensions, researchers will have trouble using the ICF for
hypothesis development, study design and measurement construction’’ (Jette et al., 2003).
Currently, only few published studies have empirically investigated the components of the
ICF (Jette et al., 2003). A most important question with regard to the components of the ICF
framework is the differentiation of activities and participation (Field and Jette, 2007), and, the
differentiation between capacity and performance. In the development process of the ICF no clear
distinction between the activities and participation component could be made in relation to
specified sets of ICF categories. In the first version of the ICF, WHO thus suggest the further
investigation of this issue and offers four possibilities to differentiate between these components.
A first empirical study exploring the issue found, that there are distinct concepts conforming to
the two ICF components activities and participation (Jette et al., 2003).
. Table 1-3
Mapping of measurement instruments to the ICF
Context Health condition Reference Measurements/instruments

Early post-
acute context
Neurological conditions, Musculoskeletal Grill et al., Functional Independence Measure (FIM), Functional Assessment Measure
conditions, Cardiopulmonary conditions, 2006 (FAM); Barthel Index (BI)
Geriatric patients
Long term
context
Obesity Stucki Bariatric Analysis and Reporting Outcome System (BAROS); Bariatric Quality
et al., of Life Index (BQL); Lite, Impact of Weight on Quality of Life Questionnaire
2006 (IWQOL); LEWIN-TAG Questionnaire (LEWIN-TAG); Obesity Adjustment
Survey-Short Form (OAS-SF); Obesity-Related Coping Questionnaire (OCQ);
Obesity-Related Distress Questionnaire (ODQ); Obesity Eating Problems
Scale (OE); Obesity-Related Problems Scale (OP); Obesity-Related Well-being
Questionnaire (ORWELL); Short-Specific Quality of Life Scale (OSQOL);
Obesity and Weight-Loss Quality of Life (OWLQOL); Weight-Related
Symptom Measure (WRSM)
Osteoarthritis Stamm Health Assessment Questionnaire (HAQ); Australian/Canadian Osteoarthritis
et al., Hand Index (AUSCAN); Cochin scale; Functional Index of Hand OA (FIHOA);
2006b Score for Assessment and Qualification of Chronic Rheumatoid Affections of
the Hands questionnaire (SACRAH); Arthritis Impact Measurement 2 Short
Form questionnaire (AIMS2-SF)
Osteoarthritis Weigl Western Ontario and McMaster Universities (WOMAC) and Lequesne-
et al., Algofunctional Indices

2003
Low back pain Sigl et al., North American Spine Society Lumbar Spine Outcome Assessment
2006 Instrument (NASS); Oswestry Low Back Disability Questionnaire (ODI);
Roland-Morris Disability Questionnaire (RMQ)
1
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16
1
. Table 1-3 (continued)
Context Health condition Reference Measurements/instruments

Osteoporosis Borchers Quality of Life Questionnaire of the European Foundation for Osteoporosis
et al., (QUALEFFO-41); Osteoporosis Assessment Questionnaire (OPAQ 2.0);
2005 Osteoporosis Assessment Questionnaire Short Version (OPAQ-SV)
Stroke Geyh Stroke Impact Scale (SIS); Stroke-Specific Quality of Life Scale (SSQOL); Stroke
et al., and Aphasia Quality of Life Scale (SAQOL-39); Quality of Life Index – Stroke
2007 Version (QLI-SV); Stroke-Adapted Sickness Impact Profile-30 (SA-SIP30);
Burden of Stroke Scale (BOSS); Quality of Life Instrument for Young
Hemorrhagic Stroke Patients (HSQuale)
Ankylosing spondylitis Sigl et al., Bath Ankylosing Functional Index (BASFI); Dougados Functional Index (DFI);
2005 Health Assessment Questionnaire modified for the spondylarthropathies
HAQ-S); Revised Leeds Disability Questionnaire (RLDQ)
Chronic obstructive pulmonary diseases Stucki St. George’s Respiratory Questionnaire (SGRQ); Chronic Respiratory
et al., Questionnaire, Standardized Version (CRQ-SAS); Pulmonary Functional
2007 Status & Dyspnea Questionnaire, Modified Version (PFSDQM); Pulmonary
Functional Status Scale (PFSS); Breathing Problems Questionnaire (BPQ);
Seattle Obstructive Lung Disease Questionnaire (SOLDQ); Quality of Life for
Respiratory Illness Questionnaire (QOLRIQ); Airway Questionnaires 20 (AQ20);
London Chest Activity of Daily Living Scale (LCADL); Maugeri Foundation
Respiratory Failure Questionnaire (MRF28); Clinical COPD Questionnaire
(CCQ)
Generic
Different conditions Cieza and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36);
Stucki Nottingham Health Profile (NHP); Quality of Life Index (QLI); World Health
2005 Organization Quality of Life Scale (WHOQOL-BREF); World Health
Organisation Disability Assessment Shedule II (WHODASII); European Quality
of Life Instrument (EQ-5D)
Different conditions Geyh Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36);
et al., Reintegration to Normal Living Index (RNL); Sickness Impact Profile (SIP);
2007 European Quality of Life Instrument (EQ-5D); LHS London Handicap Scale
(LHS); Nottingham Health Profile (NHP); Dartmouth COOP Charts (COOP);
15-Dimensional Measure of Health Related Quality of Life Test (15-D);
Assessment of Life Habits (LIFE-H); Assessment of Quality of Life (AQoL); Craig
Handicap Assessment and Reporting Technique (CHART); Health Utilities
Index Mark II (HUI II); Health Status Questionnaire (HSQ); Lancashire Quality
of Life Profile (LQLP); Quality of Life Index (QLI); World Health Organization
Quality of Life Scale (WHOQOL)
Occupational
context
Different conditions Stamm Canadian Occupational Performance Measure (COPM); Assessment of Motor
et al., and Process Skills (AMPS); Sequential Occupational Dexterity Assessment
2004 (SODA); Jebsen Taylor Hand Function Test (JT-HF); Moberg Picking Up Test
(MPUT); Button Test (Button); Functional Dexterity Test (FDT)
The fourth column shows the instruments which that have been linked to the ICF and from which a content comparison has been performed. The results have been reported in the
paper referenced in the third column
1
17
Another approach to study the validity of the ICF framework is its reflection from the
perspective of theoretical or professional models in relation to functioning. e.g. occupational
therapy models which focus on occupations and activities of daily living in the context of the
environment which can be expected to be closely related to the ICF. In a paper exploring the link
of conceptual occupational therapy models to the ICF, the majority of the concepts from three
conceptual occupational therapy models could be linked to the ICF (Stamm et al., 2006a). The
ICF also proved to be useful as a framework for comparing the similarities and differences of the
three conceptual occupational therapy models. The findings of the study also demonstrated that
there are strong conceptual connections between the ICF and occupational therapy models,
which encourage occupational therapists to use the ICF in their practice (Stamm et al., 2006a).
3 Implementation of the ICF
With the approval of the ICF the WHO member states are now called upon to implement the
ICF in the health, education, labour and social sector. The implementation of the ICF is
coordinated by the Network of the Collaboration Centers for the Family of International
Classifications (WHO FIC CC Network) and its Functioning and Disability Reference Group
(FDRG) in which members of WHO and members of WHO Collaborating Centers from all
WHO world regions are represented. The mandate of FDRG is to promote the use of the ICF
and improve international comparability of functioning and disability data by establishing
standardised procedures and implementation guidelines for different applications of the ICF.
The ICF has also found immediate interest in the health sciences and particularly rehabili-
tation (Stucki et al., 2002; Stucki, 2005a). By 2008 there have been over 600 ICF related
publications reflecting the interest, relevance, and impact of its application in health research
worldwide.
The ICF itself has become the focus of interest of scholars worldwide. It has e.g. been
critically discussed in a number of papers in recent reports by the Institute of Medicine on the
future of disability in America (Field and Jette, 2007). Closely ICF related applications include
the use of the ICF for the classification and measurement of functioning as presented in the
previous section. It is important to recall that the ICF is relevant for all medical disciplines and
allied professional groups. In physiotherapy and occupational therapy, many curricula are now
already based on or have integrated the ICF (Allan et al., 2006). Also, following reports on the
application of the ICF in rehabilitation (Steiner et al., 2002; Stucki et al., 2002; Rentsch et al.,
2003; Cieza and Stucki, 2006a), there are now also reports on the application of the ICF in other
medical specialties in which rehabilitation is a major health strategy including psychiatry and
rheumatology (Cieza and Stucki, 2006a). OMERACT (Outcome Measures in Rheumatoid
Arthritis Clinical Trials), an international group committed to the standardization of outcome
measures in rheumatology now uses the ICF as their reference framework (Stucki et al., 2007b).
4 ICF-based Classification and Measurement of Functioning
4.1 ICF Categories: Building Blocks and Reference Units
The ICF categories are the discrete, meaningful, universally shared and understood elements
which allow users to comprehensively classify and measure functioning of individuals and
populations. They are thus the building blocks for the construction of ICF-based practical
tools such as the ICF Checklist (WHO, 2003) and the ICF Core Sets (Cieza et al., 2004a; Stucki
and Grimby, 2004; Grill et al., 2005a; Stucki et al., 2005b) as well as clinical measurement
instruments such as the ICF Core Set Index currently under development for Ankylosing
Spondylitis (Cieza and Stucki, 2008) and self-reported measurement instruments such as the
WHODAS-II (Epping-Jordan and Üstün, 2000).
While ICF-based practical tools such as the ICF Core Sets allow the classification of
functioning states, clinical and self-reported measurement instruments allow the measure-
ment and hence the estimation of functioning status or aspects of it in relation to specific
purposes. Vice versa, the ICF categories serve as meaningful and universal reference units
for reporting and communicating results of measurements of aspects of functioning made
with any measurement instrument from the infinite universe of measurement instruments
(Stucki, 2005a).
In this context it is important to recall the difference between the mutually exclusive and
discrete elements of a classification such as the ICF categories versus measurement items or
simply items e.g. of self-reported health status measures. As meaningful and universally shared
elements, ICF categories represent constructs while items as indicators of constructs are used to
estimate the variation in a construct, e.g. an ICF category. As shown in a following paragraph,
there are e.g. many items used in a wide range of self-reported health status measures which
can serve as indicators to estimate the level of the ICF category b130 Energy and drive functions
(Cieza et al., 2008b) (> Figure 1-3).
4.2 ICF-based Practical Tools: ICF Checklist and ICF Core Sets
To implement the ICF in clinical medicine, service provision and policy, practical tools need to
be developed (Stucki et al., 2002). In this context it is important to recall that the ICF has been
developed as a reference classification and is not intended to be a practical tool. To address the
needs of prospective users, the FDRG of the WHO FIC CC Network collaborates with
international organizations in official relation with WHO including ISPRM and a wide
range of partners in the development of ICF-based practical tools including the ICF Core Sets.
The main challenge to the application of the ICF is the size of the classification system with
its 1,424 categories. Dr. Üstün, the leader of WHO’s CTS team has pointed out that ‘‘a clinician
cannot easily take the main volume of the ICF and consistently apply it to his or her patients. In
daily practice, clinicians will only need a fraction of the categories found in the ICF.’’ Therefore,
‘‘to be useful, practical ICF-based tools need to be tailored to the need of the prospective users
without forgoing the information needed for health statistics and health reporting.’’
4.2.1 ICF Checklist
The ICF Checklist is a 12-page, ‘‘short’’ version of the ICF with 125 second-level categories.
All information from written records, primary respondent, other informants, and direct
observation can be used (http://www3.who.int/icf/checklist/icf-checklist.pdf). It takes around
1h to complete but may take much longer in patients with multiple impairments, activity
limitations, and participation restrictions. It has been applied in a wide range of surveys and in
studies in the process of developing ICF Core Sets (> Table 1-2).
. Figure 1-3
Rasch scale for measurement items mapped to the ICF category b130 Energy and drive. The x- and
the y-axes represent the ICF category interval scale of the continuum energy and drive, with
values ranging from 0 to 100. Not all values from 0 to 100 are represented on the y-axis because
of space constraints. The 16-items in order of difficulty from the easiest item (bottom) to the
most difficult item (top) are presented on the y-axis. The value corresponding to the position of
the items is presented next to them. The position of the thresholds of the response options of the
items are represented by the bars in the diagram. The different grey tones represent the
different response options for each individual item. The vertical arrows represent the position of
each of the response options of the ICF Qualifier. RAQoL rheumatoid arthritis quality of life
questionnaire; HAQ the health assessment questionnaire; SF-36 the medical outcomes study
short form 36; EQ-5D the European Quality of Life instrument; MFI the multidimensional fatigue
inventory; CES-D the Center for Epidemiological Studies Depression Scale
4.2.2 ICF Core Sets
4.2.2.1 The ICF Core Set Project

The goal of the ICF Core Set project is to systematically develop parsimonious and hence
practical sets of ICF categories for clinical practice, service provision and research and
to link the ICF to health conditions as coded with the ICD (Stucki and Grimby, 2004;
Stucki et al., 2005b). The ICF Core Sets serve first as practical tools for the documentation
of functioning and second as international reference standards for the reporting of functioning
(Stucki, 2005a) irrespective of which measurement instruments were used. They are also the
starting point for the development of clinical and self-reported measurement instruments
(Grill and Stucki, 2008; Cieza and Stucki, 2008a; Cieza et al., 2008c).
The ICF Core Set Project is a joint project of the ICF Research Branch of the WHO FIC CC
Germany (DIMDI = Deutsches Institut für Medizinische Dokumentation und Information) at
the Institute for Health and Rehabilitation Sciences at the Ludwig-Maximilian-University in
Munich, Germany (http://www.ICF-research-branch.org), together with WHO’s CTS team,
the International Society of Physical Medicine an Rehabilitation (ISPRM) and a large number
of partner organizations and associated institutions as well as committed clinicians and
scientists (Stucki and Grimby, 2004; Stucki et al., 2005b).
4.2.2.2 Conceptual Approach

The conceptual approach for the development of the ICF Core Sets was derived from two
perspectives: (1) the perspective of people who share the experience of the same condition (e.g.
multiple sclerosis) or condition group (e.g. neurological conditions) and (2) the perspective of
the health service context along the continuum of care and the life span.
4.2.2.3 ICF Core Sets for the Acute Hospital and (Early) Post-acute Rehabilitation Facilities
The ICF Core Sets for the acute hospital including the ICF Core Sets for neurological, cardio-
pulmonary and musculoskeletal conditions are intended for use by physicians, nurses, thera-
pists and other health professionals not specialized in rehabilitation care provision (Grill et al.,
2005a; Stucki et al., 2005b). By contrast, the ICF Core Sets for (early) post-acute rehabilitation
facilities including the ICF Core Sets for neurological, cardiopulmonary and musculoskeletal
conditions as well as the ICF Core Set for geriatric patients are intended for use by physicians,
nurses, therapists and other health professionals specialized in rehabilitation or geriatric care
provision (Grill et al., 2005a; Stucki et al., 2005b). The use of the term early indicates the
‘‘early’’ part of rehabilitation where patients have both, medical needs requiring hospital care,
and rehabilitation needs.
4.2.2.4 ICF Core Sets for Chronic Conditions

The ICF Core Sets for chronic conditions are intended for use in the community (Cieza et al.,
2004a; Stucki and Grimby, 2004). For each chronic health condition, both a Brief ICF Core Set
and a Comprehensive ICF Core Set have been developed. While the ICF Core Sets serve as
practical tools for single encounters, minimum data sets for the reporting of clinical and
epidemiological studies and health statistics, the Comprehensive ICF Core Sets are intended for
use in multidisciplinary settings.
4.2.2.5 Generic ICF Core Set

While the condition and context-oriented ICF Core Sets are useful when classifying function-
ing for patients with specific health problems in specific health care situations, a parsimonious
set of categories is needed to be able to assess and compare functioning across conditions and
> contextual factors. The Generic ICF Core Set is currently being developed in an iterative
process involving a number of criteria and methodological approaches. A first study in this
process examined the explanatory power of determined ICF categories in relation to external
standards across the 12 chronic conditions for which condition-specific ICF Core Sets have
already been developed (Cieza et al., 2006b). The categories identified as candidate categories
from this study are shown in > Table 1-4.
. Table 1-4
ICF categories identified as candidate ICF categories for the Generic ICF Core Set (Cieza et al.,
2006b)
ICF component Candidate ICF categories for generic ICF Core Sets
Body functions b130 Energy and drive functions
b152 Emotional functions
b230 Vestibular functions
b280 Sensation of pain
b730 Muscle power functions
Activities and participation d450 Walking
d620 Acquisition of goods and services
d640 Doing housework
d660 Assisting others
d850 Remunerative employment
d920 Recreation and leisure
Environmental factors e450 Individual attitudes of health professionals
e580 Health services, systems and policies
. Figure 1-4
Illustration of the process to develop ICF Core Sets
4.2.2.6 Development Process

While there are some singularities in the process of developing ICF Core Sets in relation to the
context for which they are being developed, the development as illustrated in > Figure 1-4
involves an international consensus process based on evidence gathered in a preparatory phase
and an international testing and validation phase in the six WHO world regions (Africa, the
Americas, the Eastern Mediterranean, Europe, South-East Asian, and the Western Pacific)
(Cieza et al., 2004a).
The preparatory phase consists of: (1) an empirical data collection, based on the
ICF, reflecting the perspective and the situation of the patient (2) an expert survey using the
Delphi method, (3) a systematic review on outcomes used in observational and experimental
clinical studies, which also represents the view of experts. Additionally, for ICF Core Sets now in
the preparatory phase (4) a qualitative study using focus group or patient interviews, repre-
senting the view of patients complement the methods. The results of the preparatory studies
are presented at a consensus conference. They represent the starting point for a structured
decision-making and consensus process in which clinicians and health professionals, experts
in the field for which the specific ICF Core Set is to be developed, participate. Finally, the ICF
Core Sets are tested and validated in an international effort in a wide range of contexts.
4.3 Mapping the World of Measures to the ICF
4.3.1 Applications
Since the ICF is the universal and standardized language to describe and report function-
ing and health, users need to be able to map the world of measures to the ICF. The qualitative
> mapping of measurement instruments to the ICF relies on linkage rules (Cieza et al.,
2005b). The quantitative mapping relies on transformations using the Rasch-model (Cieza
et al., 2008b).
Qualitative mapping is applied for the content comparison of measurement instruments
e.g. when studying their comparative content validity. The ICF-based comparison of measure-
ment instruments can therefore assist researchers and clinicians to identify and select a most
suited measurement instrument for a specified purpose. ICF-based comparisons also enable
researchers to ensure that all ICF categories of a suitable ICF Core Set are covered by candidate
measurement instruments and hence to report functioning according to international stan-
dards (Stucki, 2005a) as described in the last section of this chapter. > Table 1-3 lists studies
which have compared most widely used measurement instruments for specified health con-
ditions as well as a comparison of generic health status measures.
Qualitative in combination with quantitative mapping is used for the identification of items
addressing the construct covered by a specified ICF category and the construction of Rasch
scales to estimate the level of functioning for this category. As we will describe in more detail in
the following paragraph this involves the identification of items from measurement instru-
ments which address the construct of a specified ICF category within their scope. Another
example of qualitative combined with quantitative mapping is the transformation of infor-
mation from electronic records (Mayo et al., 2004).
4.3.2 Linkage Methodology
The linking methodology consists of two main steps. The first step refers to the identification
of concepts within the health-related information to be translated to the ICF. The second step
refers to linking those concepts to the ICF.
4.3.3.1 Step one, Identification of Concepts

The first step, the identification of concepts, varies slightly depending on the origin of the
information that is to be translated. In health-status questionnaires, the concepts refer to the
different contents addressed in each of its items. A single item may contain more than one
concept. For example, item 8 of the SF-36 ‘‘During the past four weeks, how much did pain
interfere with your normal work (including both work outside the home and housework)’’
contains three different concepts ‘‘pain,’’ ‘‘work outside the home,’’ and ‘‘housework.’’
In qualitative data collection with open-ended questions in focus groups, patient inter-
views or e-mail surveys, the process of identification of concepts is similar to the process
followed with questionnaires. However, while in questionnaires the concepts are identified
within items, in qualitative data the concepts are identified within ‘‘meaning units.’’ A
meaning unit is defined as a specific unit of text of either a few words or a few sentences
with a common theme (Karlsson, 1993). A meaning unit division does not follow linguistic
grammatical rules. Rather, the text is divided wherever the researcher discerns a shift in
meaning (Kvale, 1996). > Table 1-5 presents an example of meaning units identified in an
extract of the information collected in a focus group.
When linking clinical assessments, concepts refer to the aims with which a clinical assess-
ment was performed. For example, when pulse rate is assessed to measure ‘‘exercise tolerance,’’
this aim is considered the meaningful concept of the clinical assessment ‘‘heart rate.’’ However,
when pulse rate is assessed to measure ‘‘heart rate’’ and ‘‘heart rhythm’’ these two aims are
considered the meaningful concepts addressed in the same clinical assessment ‘‘heart rate.’’
4.3.3.2 Step Two, Linking of Concepts to the ICF

When linking clinical interventions, the concepts also refer to the aims with which an
intervention was applied. For example, nurses mobilize their patients with different aims,
for example, ‘‘mobility improvement’’ or ‘‘prevention of skin ulcer.’’ Thus, ‘‘mobility improve-
ment’’ or ‘‘prevention of skin ulcer’’ is identified as concept for the intervention ‘‘mobiliza-
tion’’ depending on the aim with which the intervention was performed.
After the concepts have been identified, the second step involves the linking of those
concepts to the ICF according to ten rules (Cieza et al., 2005b). The most relevant and obvious
rule states that concepts must be linked to the ICF category or categories which most precisely
represent them. An example of the linkage of concepts to the ICF is shown in > Table 1-5.
Both steps of the linking methodology should always be performed by two trained health
professionals independently of each other. Thus, after the second step, two independent results
of the linking process exist. These results are compared. The reliability of the linking process is
evaluated by calculating kappa coefficients (Cohen, 1960) and nonparametric bootstrapped
confidence intervals (Efron, 1982) based on the two independent linking results in order to
indicate the degree of agreement between the two health professionals. Disagreement regard-
ing the ICF categories selected during the linking process is resolved by structured discussion
and an informed decision by a third expert. The result of applying the linking methodology is
a list of ICF categories that is equivalent in content to the original health-related information.
4.4 ICF-based Measurement of Functioning
4.4.1 Measuring a Single ICF Category
WHO prosposes the so-called generic qualifier scale that goes from 0 (no problem) to 4
(complete problem) to rate the magnitude or the severity of the problem in each of the ICF
categories (> Table 1-6). Considering the > ICF Qualifier, there are, in principle, two
. Table 1-5
Illustration of the linkage procedure (Cieza and Stucki, 2008a) with parts of a conversation
recorded during a focus group interview. The information has been divided into meaning units,
concepts have been identified within the meaning units and they have been linked to ICF
categories
Transcription divided according to meaning Identified

ID units concepts ICF categories
Question by researcher: If you think about your
body and mind, what does not work the way it
is supposed to?
2 My nails break more. I used to have long, – Breaking nails b860 Functions of nails
strong nails, but now they break easily. Also,
my thumbnails split quickly
– Thumbnails split b860 Functions of nails
2 My hands; they are not painful but I have no – No power in b7300 Power of isolated
power. Things often drop hands muscles and muscle
groups
– Things drop d440 Fine hand use
1 For the past couple of years I’ve noticed that – Nails are not b860 Functions of nail
my nails are not strong strong
3 I have always had bad nails. That’s why I can’t – Hair falling out b850 Functions of hair
judge whether they’ve become worse. But my due to medication
hair has been falling out. Could be due to the
medication. It’s hard to say. It’s awful
e1101 Drugs
4 I haven’t lost any hair, but I stopped dyeing it. – Stopping dyeing d5202 Caring for hair
I thought that, since I already have to take hair
such strong medication, I should do without
hair dye and let the natural color grow in
again
– Strong e1101 Drugs
medication (+)
without hair loss
[. . . .]
approaches to measure a specified ICF category, i.e. to quantify the extent of variation therein.
The first is to use the ICF Qualifier as a rating scale ranging from 0–4. The second is to use
information obtained with a clinical test or a patient-oriented instrument and to transform this
information into the ICF Qualifier taking into account the percentage values provided by WHO.
4.4.4.1 Direct Coding of the ICF Qualifier
With this approach a physician or health professional integrates all accessible and suitable
information from the patient’s history, clinical and technical exams to code a specified category
according to established coding guidelines (Reed et al., 2005). To ensure quality in a specific
setting, it is advisable to regularly assess the reliability of coding (Grill et al., 2007).
> Figure 1-5 shows a simple and informative graphical approach to assess the inter-observer
. Table 1-6
ICF Qualifier with percentage values provided by the WHO
ICF Qualifiera Percentage of problem

0 – NO problem (none, absent, negligible,. . .) 0–4
1 – MILD problem (slight, low,. . .) 5–24
2 – MODERATE problem (medium, fair. . .) 25–49
3 – SEVERE problem (high, extreme,. . .) 50–95
4 – COMPLETE problem (total,. . .) 96–100
a
‘‘Having a problem may mean an impairment, a limitation, a restriction or a barrier, depending on the construct,’’
i.e. depending on whether we are classifying body functions and structures (impairments), activity and participa-
tion (limitations or restrictions) or environmental factors (barriers or facilitators)
reliability of ICF Qualifier codes (Grill et al., 2007). The rating of certain ICF categories may
be facilitated by complementary instructions provided in addition to the descriptions of
the ICF categories as provided in the ICF reference material. > Table 1-7 shows an additional
instruction developed by the American Psychological Association (2007) (APA, 2007) for the
ICF category b130 Energy and drive functions for which the original description in the ICF
reference material is shown in > Table 1-6. Similar instructions have been developed by the
American Psychological Association for a large number of ICF categories (APA, 2007).
4.4.4.2 Transformation of Information Obtained with a Clinical Test or a Patient-oriented

Instrument
With the second approach, the ICF Qualifier serves as a reference scale. The results from a
clinical test or a patient-oriented measurement instrument are transformed into the ICF
Qualifier.
For many ICF categories there are suitable clinical tests which include standardized expert
and technical examinations or patient-oriented measurement instruments which include pa-
tient and proxy-reported, self-administered or interview-administered questionnaires which
are routinely used in clinical practice or for research purposes. In this case, information
already available can be transformed to report the results in the standard language of the ICF.
Since the ICF Qualifier is a rating scale for which WHO has provided percentage values as a
reference (> Table 1-6), transformation to the ICF Qualifier is straightforward in the case of
interval-scaled clinical tests or patient-oriented instruments, which comprehensively and
uniquely cover the content of a respective ICF category. For example, the Visual Analog
Scale (VAS) to assess pain can be used to address the ICF category b280 Sensation of pain.
The values of VAS-Pain can be transformed into an ICF Qualifier in a straightforward manner,
since it represents a 100 millimeter (mm) interval scale marked as ‘‘no pain’’ at one end and as
‘‘worst pain’’ at the other (Kvale, 1996). Considering the percentage values of the ICF Qualifier
in > Table 1-6, a person marking a level of pain between 0 (zero) and 4 mm would receive the
qualifier 0 in the ICF category b280 Sensation of pain, between 5 and 24 mm the Qualifier 1,
between 25 and 49 mm the Qualifier 2, between 50 and 95 mm the Qualifier 3, and between 96
and 100 mm the Qualifier 4.
In the case where there are no readily available clinical tests or patient-oriented instru-
ments with interval-scale properties that can be used to assess a specified ICF category one
. Figure 1-5
Bangdiwala observer agreement chart for the ICF category d430. The chart is a square whose
edges are determined by sample size. The edges of the black squares show the number of
patients who got identical ratings from both observers. The large bright rectangle shows the
maximum possible agreement, given the marginal totals. Partial agreement is showed by
including a weighted contribution from off-diagonal cells, here represented by hatching. One
observer’s ratings would differ systematically from the other observer’s ratings if all black
squares were above or below the diagonal
may consider the construction of an ICF category interval scale using parts of clinical test
batteries or selected items of patient-oriented measurement instruments that cover a specified
ICF category. > Figure 1-3 illustrates the construction of an interval reference scale using
the Rasch model to estimate the level of functioning for b130 Energy and drive functions (Cieza
et al., 2008b). Sixteen of the 19 items linked from three instruments did fit the Rasch model
and could be integrated in an ICF category interval scale. Based on this principle, clinicians
can estimate the level of b130 Energy and drive functions by adding the responses to the 16
items. In clinical practice, one would obviously need only a subset of possibly five items to
reliably estimate the level of functioning in b130 Energy and drive functions. Alternatively one
may increase efficiency by using computer adaptive testing (CAT). Whatever method is used,
the obtained raw scores can then be transformed into the ICF Qualifier which serves as a
reference scale.
A major advantage of the second approach is that the original format of the items used to
construct the ICF category interval scale remains unchanged. Thus, it is possible to use the
information provided by items within the context of their original instruments and, at
the same time, within the context of the ICF. This application can be extremely useful, given
the increasing use of the ICF and the ICF Qualifier as references when documenting and
reporting functioning and disability (Jette, 2006).
. Table 1-7
Additional instructions for ICF categories illustrated with the example b130 Energy and drive
functions
b130: Energy and drive functions

General mental functions of physiological and psychological mechanisms that cause the individual
to move towards satisfying specific needs and general goals in a persistent manner
Inclusions: functions of energy level, motivation, appetite, craving (including craving for
substances that can be abused), and impulse control
Exclusions: consciousness functions (b110); temperament and personality functions (b126); sleep
functions (b134); psychomotor functions (b147); emotional functions (b152)
Additional Information
This code includes general behavioral tendencies including Energy level b1300 and Motivation
b1301 to move toward goals. It also includes the constructs of Appetite b1302 and Craving b1303,
which may be general tendencies or relate to specific substances or behaviors (e.g., psychoactive
substances, food, gambling). In addition, this code includes Impulse control b1304, which may refer
to impulses in general or relate to more specific impulses to engage in particular behaviors. This
code and its subcodes should be used only to refer to characteristics or behaviors that are
consistent or occur frequently over time, not to single behaviors or transitory states
These codes may be useful in a variety of settings. Motivation, craving, and impulse control are
often a part of motivational assessment in relation to substance abuse treatment or other
treatments that have the goal of reducing, avoiding, or abstaining from particular behaviors (e.g.,
substance use, overeating, gambling). In such cases, impairments related to these factors may be a
part of the disorder. Energy level and motivation may also be important in cases of CNS injury or
disease (e.g., stroke), where concerns related to ‘‘lack of initiation’’ or ‘‘mental fatigue’’ may be
present, and in patients with psychological disorders such as depression and bipolar disorder.
Impairments in impulse control are by definition a part of substance abuse and impulse-control
disorders, and may also be a central part of a variety of other psychological disorders including
attention deficit hyperactivity disorder, conduct disorder, and bipolar disorder
Generally, Energy level b1300 and Motivation b1301 should be reserved for cases in which abnormal
levels or significant changes in energy level and motivation occur as a direct result of a disorder,
disease process, or injury, or as an effect of treatment (e.g., decreased energy level is a side effect of
some medications)
Motivation is considered to be particularly important in relation to the success of treatment for
many health conditions. However, caution should be exercised in assigning this code. Body
functions are meant to be coded with the ICF to the extent that impairments are attributable to a
health condition or health-related state, which will not be to the extent that high or low motivation
is a general personality characteristic of the individual. This is not to say that it will not be highly
relevant to treatment, only that it would correspond more closely in this case to what the ICF
identifies as Personal Factors rather than to Body Functions. In addition, Motivation b1301 should
not be used to describe an individual’s motivation to comply with a specific treatment, such as
physical therapy in rehabilitation programs. Finally, lack of motivation may be used by health care
personnel or others in the patient’s social environment as a pejorative explanation for a patient’s
lack of progress in treatment, one that attributes the problem to the patient. It is important not to
attribute lack of motivation to patients who are physically or mentally unable to perform particular
tasks or actions or who are not receiving the most appropriate treatments to help them progress
Case Examples
Following a stroke, a 67-year-old woman has difficulty selecting or getting started on projects, and
often complains of feeling ‘‘too tired’’ and ‘‘mentally worn out’’
A 45-year-old man with an alcohol abuse disorder refuses all attempts at treatment, indicating that
although he recognizes the negative consequences of substance use in his life, he is not willing to
stop drinking
Other codes within this section
b1300: Energy level
b1301: Motivation
b1302: Appetite
b1303: Craving
b1304: Impulse control
b1308: Energy and drive functions, other specified
b1309: Energy and drive functions, unspecified
4.5 Measuring Across ICF Categories
4.5.1 Self-reported ICF-based Measurement Instruments

Based on the ICF, WHO has developed the > WHO Disability Assessment Schedule Version II
(WHODAS II) (Pösl et al., 2007), a generic self-administered questionnaire used in adults
>18 years of age which covers the ICF components activity and participation. It includes
six domains: understanding and communicating, getting around, self care, getting along with
others, household and work activities, and participation in society. It has been developed cross-
culturally and is applicable across the spectrum of cultural and educational backgrounds. In
addition to self-report, an interviewer and proxy version is available. The time to complete the
questionnaire for the 12-item version takes approximately 5 min and for the 36-item version
about 20 min.
The first study applying the WHODAS II in rehabilitation using a German version
demonstrated that it is a useful instrument for measuring functioning and disability in
patients with musculoskeletal diseases, internal diseases, stroke, breast cancer and depressive
disorder (Pösl et al., 2007). The results of this study also support the reliability, validity,
dimensionality, and responsiveness of the WHODAS II. However, for the domain household
and work activities, a clear distinction between work activities versus household activities was
apparent in musculoskeletal and internal conditions (Pösl et al., 2007). Therefore, one may in
the future consider the separate scoring and reporting of these sub-domains.
For specific conditions and/or settings one may want to use a specific measurement instru-
ment. A suitable starting point for the development for such measurement instruments are
the ICF Core Sets. The ICF Research Branch of the WHO FIC CC Germany at the University
of Munich is thus cooperating with and supporting research groups in the process to develop
self-reported questionnaires based on the ICF Core Sets (www.icf-research-branch.org).
4.5.2 ICF-based Clinical Measurement Instruments

Clinician’s ratings of the ICF Qualifier (> Table 1-6) across a number of ICF categories,
e.g. across the categories of an ICF Core Set, can be reported in the form of a categorical
profile. A categorical profile across a valid set of ICF categories such as an ICF Core
Set provides an estimation of a persons functioning state. The functioning state is the
central information for clinicians when planning and reporting the results of a health
. Table 1-8 30
1
ICF-based assessment and evaluation including goal setting and goal achievement in a patient after Spinal Cord Injury. The functioning states at the start
of rehabilitation and after 4 weeks are shown as categorical profiles based on expert ratings of the ICF Qualifier
ICF Qualifier range from 0 = no problem in the components of body functions (b), body structures (s), activity and participation (d) and from 4 = complete barrier to +4 = complete
facillitator in the environmental factors. In personal factors, the sign + and - indicates to what extent a determined personal factor has a positive or negative influence on the
individuals functioning. The symbol ü indicates that the treatment goals with their goal values have been achieved and the symbol - that they were not achieved
care intervention. > Table 1-8 shows the example of functioning states at the start and the end
of a rehabilitation program.
The aggregation of information obtained from a categorical profile using the Rasch model
results in a summary score (Grill and Stucki, 2008; Cieza and Stucki, 2008a). In the case of
aggregation of information across a valid set of categories such an ICF Core Set, the summary
score provides an estimation of a persons functioning status. If using an electronic clinical
chart, the creation of a score from a categorical profile created based on an ICF Core Set does
not require additional work. Functioning status information provides clinicians with an
intuitive, overall understanding of a patient’s general level of functioning. It can be used by
clinicians, service program providers and payers e.g. for the assignment of patients to suitable
health service programs, to monitor and manage persons functioning along the continuum of
care and across service program providers, to evaluate service programs, to predict resources
and hence costs and to derive payment schemes.
The principle of how to develop one- or multi-dimensional clinical measurement instru-
ments based on clinicians ratings of ICF Core Sets has been recently demonstrated (Grill and
Stucki, 2008; Cieza and Stucki, 2008a). It could also be demonstrated how to apply such scores
across countries by adjusting for differential item function. It is thus possible to compare
functioning status information across countries and world regions.
4.5 Conclusion
The ICF has become the universal and unifying framework for functioning, disability and
health. As international standards, the ICF Core Sets are the practical tools for the classification
and description of patients functioning states. They are the reference for the reporting of
measurements made with a wide range of validated measurement instruments and they serve
as starting point for the development of clinical measures or ICF Core Indices as well as self-
reported instruments.
Summary Points
The ICF is a multipurpose classification designed to serve various disciplines and different
sectors. The ICF is the international classification for health and health-related states.
The ICF offers a conceptual framework for information that is applicable to personal
health care, including prevention, health promotion, and many other fields. Its framework
is the bio-psycho-social model of functioning and disability. The ICF achieve a synthesis,
thereby providing a coherent view of different perspectives of health.
The components of body functions and structures, activities and participation, and
environmental factors are classified based on 1,425 ICF categories. The categories are
organized within a hierarchically nested structure with up to four different levels and are
denoted by unique alphanumeric codes.
The WHO provides with the ICF for the first time a universal and internationally accepted
framework and classification. It is a promising starting point for the integrative under-
standing of functioning, disability and health and the overcoming of Cartesian dualism of
body and mind as well as both sociological and biomedical reductionism.
Implementation of the ICF includes e.g. its use as a screening tool for referral to rehabili-
tation services and for the rehabilitation management in rehabilitation facilities. Parallel to
the official implementation activities the ICF has found immediate interest in the health
sciences, particularly rehabilitation as well as in different scholars worldwide.
The objectives of ICF Core Sets are to be a parsimonious and hence practical selection of
ICF categories for clinical practice, service provision and research and to link the ICF to the
International Classification of Diseases.
Acknowledgments
The authors would like to thank Prof. Jerome Bickenbach and Dr. Somnath Chatterij from
WHO for the inspiring discussions of the ICF and related concepts and Dr. Thomas Ewert,
Gisela Immich and Susanne Stucki for their help in the preparation of the manuscript.
References
Allan CM, Campbell WN, Guptill CA, Stephenson FF, Cieza A, Ewert T, Üstün TB, Chatterji S, Kostanjsek N,
Campbell KE. (2006). J Interprofessional Care. 20: Stucki G. (2004a). J Rehabil Med. 44: 9–11.
235–245. Cieza A, Stucki G, Weigl M, Kullmann L, Stoll T, Kamen
APA, American Pschological Association. (2007). Proce- L, Kostanjsek N, Walsh N. (2004b). J Rehabil Med
dural Manual and Guide for Standardized Applica- Suppl. 44: 63–68.
tion of the International Classification of Cieza A, Stucki G, Weigl M, Disler P, Jäckel W, van der
Functioning, Disability and Health (ICF), Field Linden S, Kostanjsek N, de Bie R. (2004c). J Rehabil
Trial Version from http://icf.apa.org Med Suppl. 44: 69–74.
Aringer M, Stamm TA, Pisetsky DS, Yarboro CH, Cieza Cieza A, Schwarzkopf SR, Sigl T, Stucki G, Melvin J, Stoll
A, Smolen JS, Stucki G. (2006). Lupus. 15: 248–253. T, Woolf A, Kostanjsek N, Walsh N. (2004d). J
Bickenbach JE, Chatterji S, Badley EM, Üstün TB. (1999). Rehabil Med Suppl. 44: 81–86.
Soc Sci Med. 48: 1173–1187. Cieza A, Stucki A, Geyh S, Berteanu M, Quittan M,
Biering-Sorensen F, Scheuringer M, Baumberger M, Simon A, Kostanjsek N, Stucki G, Walsh N.
Charlifue SW, Post MW, Montero F, Kostanjsek N, (2004e). J Rehabil Med Suppl. 44: 94–99.
Stucki G. (2006). Spinal Cord. 44: 541–546. Cieza A, Chatterji S, Andersen C, Cantista P, Herceg M,
Boldt C, Brach M, Grill E, Berthou A, Meister K, Melvin J, Stucki G, de Bie R. (2004f). J Rehabil Med
Scheuringer M, Stucki G. (2005). Disabil Rehabil. Suppl. 44: 128–134.
27: 431–436. Cieza A, Geyh S, Chatterji S, Kostanjsek N, Ustun BT,
Brach M, Cieza A, Stucki G, Füssl M, Cole A, Ellerin BE, Stucki G. (2006b). BMC Med Res Methodol. 6: 36.
Fialka-Moser V, Kostanjsek N, Melvin J. (2004). Cieza A, Geyh S, Chatterji S, Kostanjsek N, Üstün TB,
J Rehabil Med Suppl. 44: 121–127. Stucki G. (2005b). J Rehabil Med. 37: 212–218.
Brockow T, Cieza A, Kuhlow H, Sigl T, Franke T, Cieza A, Hilfiker R, Boonen A, Chatterji S, Konstanjsek N,
Harder M, Stucki G. (2004a). J Rehab Med Suppl. Üstün TB, Stucki G. (2008b). Clin J Epidemiol.
44: 30–36. in press.
Brockow T, Wohlfahrt K, Hillert A, Geyh S, Weigl M, Cieza A, Hilfiker R, Chatterji S, Konstanjsek N, Üstün
Franke T, Resch KL, Cieza A. (2004b). J Rehab Med TB, Stucki G. (2008c). Clin J Epidemiol. in revision.
Suppl. 44: 49–55. Cieza A, Stucki G. (2005a). Qual Life Res. 14: 1225–1237.
Brockow T, Duddeck K, Geyh S, Schwarzkopf SR, Weigl Cieza A, Stucki G. (2006a). In: Bartlett SJ, Bingham CO,
M, Franke T, Brach M. (2004c). J Rehab Med Suppl. Maricic MJ, Iversen MD, Ruffing V (eds.) Clinical
44: 43–48. Care in the Rheumatic Diseases. Amer College of
Borchers M, Cieza A, Sigl T, Kollerits B, Kostanjsek N, Rheumatology, Atlanta, pp. 79–87.
Stucki G. (2005). Clin Rheumatol. 24: 139–144. Cieza A, Hilfiker R, Boonen A, van der Heijde D, Braun J,
Coenen M, Cieza A, Stamm TA, Amann E, Kollerits B, Stucki G. (2008). Disabil Rehabil. 12: 1–10. [Epub
Stucki G. (2006). Arthritis Res Ther. 8: R84. ahead of print]
Cohen J. (1960). Educ Psychol Meas. 20: 37–46. Hetzel AM. (1997). History and Organization of the Vital
DeJong G. (1993). Arch Phys Med Rehabil. 74: Statistics System. National Center for Health Statis-
1017–1024. tics, Hyattsville.
Dijkers MP, Whiteneck G, El-Jaroudi R. (2000). Arch Imrie R. (2004). Soc Health Illn. 26: 287–305.
Phys Med Rehabil. 81: S63–S80. Jette AM. (2006). Phys Ther. 86: 726–734.
Dixon D, Pollard B, Johnston M. (2007). Pain. 130: Jette AM, Haley SM, Kooyoomjian JT. (2003). J Rehabil
249–253. Med. 35: 145–149.
Dreinhöfer K, Stucki G, Ewert T, Huber E, Ebenbichler G, Johnston M, Pollard B. (2001). Soc Sci Med. 53:
Gutenbrunner CH, Kostanjsek N, Cieza A. (2004). 1261–1273.
J Rehabil Med Suppl. 44: 75–80. Kaplan A. (1964). The Conduct of Inquiry: Methodology
Efron B. (1982). The Jackknife, the Bootstrap, and Other for Behavioral Science. Chandler, San Francisco.
Resampling Plans. Society for Industrial and Karlsson G. (1993). Psychological Qualitative Research
Applied Mathematics, Philadelphia. from a Phenomenological Perspective. Almqvist and
Epping-Jordan JA, Üstün TB. (2000). WHO Mental Wiksell International, Stockholm.
Health Bull. 6: 5–6. Kesselring J, Coenen M, Cieza A, Thompson A,
Ewert T, Grill E, Bartholomeyczik S, Finger M, Mokrusch Kostanjsek N, Stucki G. (2008). Mult Scler. 14:
T, Kostanjsek N, Stucki G. (2005). Disabil Rehabil. 252–254.
27: 367–373. Kirchberger I, Glaessel A, Stucki G, Cieza A. (2007). Phys
Ewert T, Fuessl M, Cieza A, Andersen C, Chatterji S, Ther. 87: 368–384.
Kostanjsek N, Stucki G. (2004). J Rehab Med Kvale S. (1996). Interviews: An Introduction to
Suppl. 44: 22–29. Qualitative Research Interviewing. Sage, Thousand
Field ML, Jette AM. (2007). The Future of Disability in Oaks.
America. National Academy. Washington DC. Lemert EM. (1972). Human Deviance, Social
Fougeyrollas P, Noreau L, Bergeron H, Cloutier R, Problems, and Social Control. Prentice-Hall,
Dion SA, St-Michel G. (1998). Int J Rehabil Res. Englewood Cliffs.
21: 127–141. Mayo NE, Poissant L, Ahmed S, Finch L, Higgins J,
Gray DB, Hendershot GE. (2000). Arch Phys Med Reha- Salbach NM, Soicher J, Jaglal S. (2004). Am Med
bil. 81: S10–S14. Inform Assoc. 11: 514–522.
Geyh S, Kurt T, Brockow T, Cieza A, Ewert T, Omar Z, Mueller M, Boldt C, Grill E, Strobl R, Stucki G. (2008).
Resch KL. (2004a). J Rehab Med Suppl. 44: 56–62. BMC Nurs. 7: 3.
Geyh S, Cieza A, Schouten J, Dickson H, Frommelt P, Nagi SZ. (1965). Some Conceptual Issues in Disability
Omar Z, Kostanjsek N, Ring H, Stucki G. (2004b). and Rehabilitation. American Sociological Associa-
J Rehabil Med Suppl. 44: 135–141. tion, Washington DC.
Geyh S, Cieza A, Kollerits B, Grimby G, Stucki G. (2007). Pope AMP, Tarlov AR. (1991). Disability in America:
Qual Life Res. 16: 833–851. Toward a National Agenda for Prevention. National
Grill E, Ewert T, Chatterji S, Kostanjsek N, Stucki G. Academy, Washington DC.
(2005a). Disabil Rehabil. 27: 361–366. Pösl M, Cieza A, Stucki G. (2007). Qual Life Res. 16:
Grill E, Huber EO, Stucki G, Herceq M, Fialka-Moser V, 1521–1531.
Quittan M. (2005b). Disabil Rehabil. 27: 447–458. Reed GM, Lux JB, Bufka LF, Trask C, Peterson DB, Stark
Grill E, Quittan M, Huber OE, Boldt C, Stucki G. S, Threats TT, Jacobson JW, Hawley JA. (2005).
(2005c). Disabil Rehabil. 27: 437–445. Rehabil Psychol. 50: 122–131.
Grill E, Lipp B, Boldt C, Stucki G, Koenig E. (2005d). Rentsch H, Bucher P, Dommen N, Wolf C, Hefti H, Fluri
Disabil Rehabil. 27: 459–465. E, Wenger U, Wälti C, Boyer I. (2003). Disabil Reha-
Grill E, Stucki G, Boldt C, Joisten S, Swoboda W. (2005e). bil. 25: 411–421.
Disabil Rehabil. 27: 467–473. Ruof J, Cieza A, Wolff B, Angst F, Ergeletzis D, Omar Z,
Grill E, Hermes R, Swoboda W, Uzarewicz C, Kostanjsek N, Stucki G. (2004). J Rehabil Med
Kostanjsek N, Stucki G. (2005f). Disabil Rehabil. Suppl. 44: 100–106.
27: 411–417. Scheuringer M, Stucki G, Huber EO, Brach M,
Grill E, Stucki G, Scheuringer M, Melvin J. (2006). Am J Schwarzkopf SR, Kostanjsek N, Stoll T. (2005a).
Phys Med Rehabil. 85: 640–649. Disabil Rehabil. 27: 405–410.
Grill E, Mansmann U, Cieza A, Stucki G. (2007). J Reha- Scheuringer M, Grill E, Boldt C, Muellner P, Mittrach R,
bil Med. 39: 71–76. Stucki G. (2005b). Disabil Rehabil. 27: 419–429.
Grill E, Stucki G. (2008). Clin J Epidemiol. Jul 9 [Epub Sigl T, Cieza A, Brockow T, Chatterji S, Kostanjsek N,
ahead of print] Stucki G. (2006). J Clin Pain. 22: 147–153.
Grimby G, Finnstam J, Jette A. (1988). Scand J Rehabil Sigl T, Cieza A, van der Heijde D, Stucki G. (2005). Ann
Med. 20: 93–98. Rheum Dis. 64: 1576–1618.
Stamm T, Cieza A, Machold KP, Smolen JS, Stucki G. Stucki G, Ewert T, Cieza A. (2002). Disabil Rehabil. 24:
(2004). Arthritis Rheum. 51: 917–924. 932–938.
Stamm T, Cieza A, Coenen M, Machold KP, Nell VP, Stucki G, Grimby G. (2004). J Rehabil Med. 44: 5–6.
Smolen JS, Stucki G. (2005). Arthritis Rheum. 53: Stucki G, Üstün TB, Melvin J. (2005b). Disabil Rehabil.
431–439. 27: 349–352.
Stamm T, Cieza A, Machold K, Smolen JS, Stucki G. Stucki A, Stucki G, Cieza A, Schuurmans M, Kostanjsek
(2006a). Austr Occup Ther J. 53: 9–17. N, Ruof J. (2007). Respir Med. 101: 1113–1122.
Stamm T, Geyh S, Cieza A, Machold K, Kollerits B, Tschiesner U, Cieza A, Rogers SN, Piccirillo J, Funk G,
Kloppenburg M, Smolen J, Stucki G. (2006b). Rheu- Stucki G, Berghaus A. (2007). Eur Arch Otorhino-
matology. 45: 1534–1541. laryngol. 264: 1215–1222.
Stamm TA, Nell V, Mathis M, Coenen M, Aletaha D, Üstün TB, Chatterji S, Kostanjsek N. (2004). J Rehabil
Cieza A, Stucki G, Taylor W, Smolen JS, Machold Med. 44: 7–8.
KP. (2007). Arthritis Rheum. 57: 487–494. Weigl M, Cieza A, Andersen C, Kollerits B, Amann E,
Steiner WA, Ryser L, Huber E, Uebelhart D, Aeschlimann Stucki G. (2004). J Rehab Med Suppl. 44: 12–21.
A, Stucki G. (2002). Phys Ther. 82: 1098–1107. Weigl M, Cieza A, Harder M, Geyh S, Amann E,
Stier-Jarmer M, Grill E, Ewert T, Bartholomeyczik S, Kostanjsek N, Stucki G. (2003). Osteoarthritis
Finger M, Mokrusch T, Kostanjsek N, Stucki G. Cartilage. 11: 519–523.
(2005). Disabil Rehabil. 27: 389–395. WHO (World Health Organization). (2001). Interna-
Stoll T, Brach M, Huber EO, Scheuringer M, tional Classification of Functioning, Disability and
Schwarzkopf SR, Kostanjsek N, Stucki G. (2005). Health: ICF. WHO, Geneva.
Disabil Rehabil. 27: 381–387. WHO (World Health Organization). (2003). ICF Check-
Stucki G. (2005a). Am J Phys Med Rehabil. 84: 733–740. list. Version 2.1a, Clinician Form for International
Stucki A, Borchers M, Stucki G, Cieza A, Amann E, Classification of Functioning, Disability and Health
Ruof J. (2006). Int J Obes. 30: 1791–1799. from http://www3.who.int/icf/checklist/icf-checklist.
Stucki G, Cieza A, Geyh S, Battistella L, Lloyd J, pdf
Symmons S, Kostanjsek N, Schouten J. (2004a). J Wildner M, Quittan M, Portenier L, Wilke S, Boldt C,
Rehabil Med Suppl. 44: 87–93. Stucki G, Kostanjsek N, Grill E. (2005). Disabil
Stucki A, Daansen P, Fuessl M, Cieza A, Huber E, Rehabil. 27: 397–404.
Atkinson R, Kostanjsek N, Stucki G, Ruof J. Wolff B, Cieza A, Parentin A, Rauch A, Sigl T, Brockow T,
(2004b). J Rehabil Med Suppl. 44: 107–113. Stucki A. (2004). J Rehab Med Suppl. 44: 37–42.
Stucki A, Stoll T, Cieza A, Weigl M, Giardini A, Wever D, van Echteld I, Cieza A, Boonen A, Stucki G, Zochling J,
Kostanjsek N, Stucki G. (2004c). J Rehabil Med Braun J, van der Heijde D. (2006). J Rheumatol. 33:
Suppl. 44: 114–120. 2475–2483.
Stucki G, Boonen A, Tugwell P, Cieza A, Boers M. Vieta E, Cieza A, Stucki G, Chatterji S, Nieto M, Sanchez-
(2007b). J Rheumatol. 34: 600–606. Moreno J, Jaeger J, Grunze H, Ayuso-Mateos JL.
Stucki G, Cieza A, Melvin J. (2007a). J Rehabil Med. 39: (2007). Bipolar Disord. 9: 16–24.
279–285.
2 The Keele Assessment of
Participation
R. Wilkie
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2 Developing a Conceptual Model of Participation Restriction . . . . . . . . . . . . . . . . . . . . 39
3 Developing an Instrument and Measurement Model to

Measure Participation Restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.1 Item Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.2 Number of Items . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.3 Scoring of Each Item . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.4 Instrument Score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4 Psychometric Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
5 Pre-Testing Interview Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

5.1 Cognitive Interviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
5.2 Qualitative Interviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
6 Further Development of Instrument . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
7 Pilot Questionnaire Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

7.1 Pilot Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
7.1.1 Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
7.1.2 Validity of the Four Filter Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
7.1.3 Discriminant Validity (Conceptual Discrimination – Does
Frequency Matter?) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
7.1.4 Repeatability of the KAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
7.1.5 Validity of the KAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
7.1.6 Convergent Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
7.1.7 Discriminant Validity (Item Discrimination) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
7.2 Pilot Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
7.2.1 Validity of the Four Filter Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
7.2.2 Discriminant Validity (Conceptual Discrimination) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
7.2.3 Repeatability of the KAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
7.2.4 Convergent and Discriminant Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

36 2 The Keele Assessment of Participation
8 Overview of Psychometric Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

8.1 Discriminant Validity (Item Discrimination) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
9 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
The Keele Assessment of Participation 2 37
Abstract: The World Health Organization has proposed > participation restriction to reflect
the societal consequences of health conditions. Participation restriction can be multiply
determined and represents the outcome of an individual’s ongoing interaction with their
environment and with society; it emphasizes the independent causal role of environmental
factors in determining functioning and refers to what is actually performed by the individual
in real life situations. It is appealing concept for those interested in older populations and the
impact of chronic diseases because even when health conditions and activity limitations
persist, there may still be potential to maintain participation. Despite its importance, partici-
pation restriction is inconsistently represented or absent from the content of many health
status instruments and has not been clearly measured in population studies.
This chapter describes the development of the Keele Assessment of Participation (KAP),
a self-complete instrument designed to provide estimates of > person-perceived participation
restriction in population-based surveys. It specifies a > conceptual model of participation
restriction (based on the individual’s perception of > performance of tasks), outlines how the
instrument was developed (with the aim of being short and simple for application in epidemio-
logical studies) and how its scale scores were decided (to allow differentiation between large
groups in the population). It also describes, and reports the results of the > pre-pilot studies and
pilot studies designed to investigate its measurement properties. The KAP performed adequately
in > validity and > reliability tests and can be considered as an instrument that is likely to detect
and provide sensible estimates of participation restriction in postal surveys.
List of Abbreviations: 95% CI, 95% confidence intervals; ICF, international classification of
functioning, disability and health; IPA, impact on participation and autonomy; k, > kappa;
kw , weighted kappa; KAP, keele assessment of participation; n, number; Norstop, North
Staffordshire osteoarthritis project; RNL, reintegration to normal living; WHO, World Health
Organization
1 Introduction
The World Health Organization (WHO) have endorsed the International Classification of
Functioning, Disability and Health (ICF) (> Figure 2‐1) as a framework to describe the health
state of a person at a particular point in time (World Health Organization, 2001). The
framework provides a basis for understanding and studying health-related functioning and
the consequences of health conditions. It incorporates the > biopsychosocial model, a synthe-
sis of the medical and social approaches, and emphasizes the multi-dimensional nature of
health-related functioning and consequences through interplay of the body, the person and
broader social and environmental factors. Focusing on the consequences of health conditions
will enhance the understanding of their impact in the general population and of their health
and policy implications (Ebrahim, 1997).
The ICF has three levels of negative consequences of health conditions: anatomical/
physiological level – impairment (e.g., pain, high blood pressure); individual level – activity
limitation (e.g., difficulty picking up objects); societal level – participation restriction (e.g.,
difficulty getting around or with work) (World Health Organization, 2001). Each level is
distinct and the WHO advocates data to be collected independently for each level to explore
the associations and causal links between them. Participation restriction is an appealing
concept for those interested in older populations and the impact of chronic diseases because
. Figure 2‐1
The International Classification of Functioning, Disability and Health International Classification
of Functioning, Disability and Health (WHO, 2001). The ICF framework organizes information into
two parts: (1) functioning and disability and (2) contextual factors. Functioning and disability
serve as umbrella terms for normal and abnormal functioning at body, individual and societal
levels. Functioning refers to body structure and function, activities and participation. Disability
refers to impairment, activity limitation and participation restriction. Environmental and
personal factors may influence all three levels of functioning
even when health conditions and activity limitations persist, there may still be the potential
to maintain participation (Harwood et al., 1998). For example, people with knee pain and
difficulty standing for long periods continue to work and socialize with friends. There is a
growing interest and acknowledgement of the influence of environmental factors on function-
ing, which may explain the gap between individual capacity and performance in activities of
daily life (Grimby and Smedby, 2001; Verbrugge, 1994) (e.g., people may be able to walk on a
treadmill, but find walking in a town centre difficult due to uneven pavements and obstacles).
Social, economic and political factors are increasingly recognized as contributors to health
(Simeonsson et al., 2000). The social context shapes the impact of a health condition on a
person’s life and may be more concerning to individuals than impairments and activity
limitations. For example, being unable to maintain relationships with friends may be an
equal source of suffering as the experience of pain itself.
Population-based studies have tended to focus on impairment and activity limitation and
we know least about participation restriction, which cannot be inferred from these (World
Health Organization, 2001). Information on participation restriction is highly fragmented and
has been measured inconsistently with researchers using different terminology and different
conceptual models. There are no published instruments based exclusively on the concept of
participation restriction despite it being argued as a principal component of health-related
quality of life (Fransen et al., 2002; Wilkie et al., 2004). Most health measurement instruments
do not separate participation restriction from activity limitation (Chapireau and Colvez, 1998;
Weigl et al., 2003). The latter measures only an individual’s capacity to execute a task
regardless of the specific context of their situation and social surroundings. To exclusively
measure the occurrence of participation restriction in population samples a new instrument
was required.
This chapter consists of two sections. The first describes the development of the Keele
Assessment of Participation (KAP). This instrument was developed by the author and
colleagues (Dr George Peat, Dr Elaine Thomas, Dr Helen Hooper, Professor Peter Croft) as
part of the North Staffordshire Osteoarthritis Project (Norstop), a general investigation of the
health of older people, which is based in the Arthritis Research campaign National Primary
Care Centre, Keele University, United Kingdom. One of the key objectives of Norstop was to
enhance the epidemiology of the consequences of health conditions in community-dwelling
adults. There was a perceived need to investigate participation restriction to provide a fuller
account of the impact of health conditions in the community. The KAP was developed
specifically for population based postal surveys and prior to the Norstop survey, the challenges
for measurement were how to develop the concept, operationalize and quantify participation
restriction; the KAP was developed as a self-complete instrument to provide estimates of
person-perceived participation restriction in population-based surveys. The approach may
miss some specific details and distinctiveness of participation restriction in individuals, since it
cannot be specific for all and may not capture relevant information for clinical or rehabilita-
tion purposes. This section includes
Development of a conceptual model of participation restriction
Instrument construction
Proposal of a > measurement model
The second section describes the > psychometric testing of the instrument for its ability to
measure participation restriction in population studies. This chapter draws heavily on
a shorter account which is published in peer review journal (Wilkie et al., 2005) and on a
PhD (Wilkie R, A study of participation restriction and joint pain in community-dwelling
older adults, Keele University, 2006).
2 Developing a Conceptual Model of Participation Restriction
The WHO defines participation restriction as ‘‘problems an individual may experience in

involvement in life situations’’ (World Health Organization, 2001). This description is broad
and is intended to provide a basis for tailoring and developing to meet specific uses (Stucki
et al., 2002). Hence, the first stage in developing an instrument to measure participation
restriction was to propose a conceptual model. The following propositions were made to
direct instrument development:
i. Participation restriction is a performance-based, context-dependent, phenomenon
Performance is about what people do. It is therefore about functioning in an indivi-
dual’s real-life environment: the ‘‘lived experience’’ that will be influenced by facilitators
and barriers in the environment (World Health Organization, 2001). Indeed at one point
in their guidelines the WHO declares performance as the only qualifier that they regard as
appropriate for measuring participation restriction. In characterizing participation restric-
tion by performance, instrument scores can be interpreted as restrictions in the perfor-
mance of everyday tasks that involve interaction with the environment and society. For
example, taking children to play in the park or working as a shop assistant.
ii. Participation restriction is most meaningfully understood as a person-perceived phenomenon
requiring the judgment of the individual
The WHO defines participation restriction from a > societal perspective if there is
difference between observed functioning and what would be expected of an individual who
did not have the same or similar health condition, or would be regarded as normal
functioning for someone of that age, sex and culture (World Health Organization,
2001). Although useful for epidemiological studies in which application of a defined
standard can allow comparison between different groups, studies of handicap found it
difficult to define what was ‘‘normal’’ because of the variability of individual roles and
needs (Carr, 1999; Harwood et al., 1998). The same problem arises for participation
restriction. Comparing individuals with a reference standard of what is proposed as
normal for society or study population, may be based on an erroneous assumption that
participation restriction occurs when individuals deviate from ‘‘norms.’’ Instead it is better
to view normality as an individually defined concept. An alternative approach to measur-
ing participation restriction is to allow individuals themselves to judge whether or not
their participation is maintained or falls below what they expect. The experience of
participation restriction is specific to each person due to the variability of roles and
influencing factors (Carr, 1996; Ueda and Okawa, 2003). That judgment may still reflect
perceived societal norms but is also likely to depend on the different roles that individuals
fulfill, their standards, needs, aspirations, and expectations. Environmental and personal
factors would still be expected to influence participation restriction measured from this
perspective.
iii. Participation restriction is not a fixed state but may be experienced intermittently within a
given time period
Participation restriction is a dynamic concept. The nature of ongoing interaction of the
individual with the physical, social and psychological environment will not be static but is
likely to change with time and setting. Factors particular to the individual, and facilitators
and barriers to participation will vary. For example, the symptoms of joint pain and the
presence of someone to assist participation may change with time and setting. The key
dimensions of participation restriction are how and when performance in life situations
occurs.
iv. There are an infinite number of life situations that can be organized under the WHO domains
for the measurement of participation restriction; domains are conceptually mutually exclusive
The WHO offers nine domains as a method of organizing the infinite number of life
situations where participation restriction can occur. Each domain is a practical, meaning-
ful set of actions, tasks and life situations. They are conceptually different and mutually
exclusive, suggesting that each form of participation restriction may be determined by a
unique group of factors. The absence of a single concept of participation restriction is
implicit in the four alternative methods for allocating domains and sub-domains to either
participation or activity limitation in the ICF (World Health Organization, 2001). Criteria
(i.e., does the functional task involve interaction with factors external to the individual
(e.g., type of environment, the assistance of others, use of aids) or a non-standardized
environment (e.g., public park) were applied to each item in the nine domains to identify
which domains measured participation restriction. Six domains were identified as relating
to participation restriction; namely mobility, self-care, domestic life, interpersonal inter-
action, major life and community, social and civic life (> Table 2‐1). The nature and extent
of participation restriction will be considered at domain level, which requires responders
to make an ‘‘internal calculation’’ of performance in a number of functional activities of a
particular domain.
. Table 2-1
A priori designation of ICF domains and subdomains to activity limitation or participation
restriction
ICF Domain Activity limitation Participation restriction

1. Learning and applying knowledge ●
2. General tasks and demands ●
3. Communication ●
4. Mobility ●a ●b
5. Self-care ● c
●d
6. Domestic life ●
7. Interpersonal interaction ●
8. Major life ●
9. Community, social, and civic life ●
Each task within the nine domains were reviewed for whether they captured activity limitation or participation
restriction. In domains 1 to 3 all tasks were deemed to measure activity limitation. In domains 4 and 5 some
items were deemed to capture activity limitation and others captured participation restriction. In domains
6 to 9 all tasks were deemed to measure participation restriction
a
Mobility subdomains: Changing and maintaining body position (4.10–4.19); Walking (4.50)
b
Mobility subdomains: Transferring oneself (4.20); Carrying, moving and handling objects (4.30–4.49); Moving
around (4.55–4.69); Moving around using equipment (4.70–4.89)
c
Self-care subdomains: Eating (5.50); Drinking (5.60)
d
Self-care subdomains: Washing oneself (5.10); Caring for body parts (5.20); Toileting (5.30); Dressing (5.40);
Looking after one’s health (5.70)
v. Participation restriction across multiple domains is summative with restriction in more

domains indicating greater participation restriction.
Prior to any empirical testing, each item is considered to be equal. Increasing numbers
of domains where participation restriction occurs indicates more aspects of life in which
participation restriction is experienced.
3 Developing an Instrument and Measurement Model to

Measure Participation Restriction
The instrument and measurement model were designed to be consistent with the specified
conceptual model of participation restriction (i.e., performance in life situations as perceived by
the individual). Where possible, empirical evidence was used to inform choices in the develop-
ment of the questionnaire and measurement model. Items were designed to be short, specific
and consistent to enhance response and completion rates (McColl et al., 2001). Questionnaire
development drew on previously published recommendations on item wording and response
formats (McColl et al., 2001; Moser and Kalton, 1971; Sudman and Bradburn, 1974). The
measurement model outlining issues of scaling and scoring of this measure was developed with
particular attention to the needs of an epidemiological study of participation restriction in
population studies.
3.1 Item Development
The phrase ‘‘I have’’ was used to measure performance. The phrase ‘‘I wanted’’ was used to
indicate individual perception and judgment, and the phrase ‘‘as and when I wanted’’ was used
to denote how and when participation restriction tasks were performed. The term ‘‘restric-
tion’’ was avoided to maintain the neutral language that characterizes the ICF. The items
contained a recall period set at 4 weeks, which was considered to be a convenient time unit for
participants to refer to, with the aim of preventing recall bias due to memory failure and
‘‘telescoping’’ (Abramson and Abramson, 1999).
Each item was ‘‘closed’’ and invited responses on an adjective ordinal scale. A non-
overlapping five point adjectival ordinal scale was devised, to capture the dynamic nature of
participation restriction and comprehensively presented proportions of time. Adjectives for
response categories were chosen to facilitate consistent interpretation between responders
(e.g., All the time, Most of the time ….. None of the time).
3.2 Number of Items
Items were designed to measure domains in a way that requires responders to make an aggregate
judgment on the basis of the life situations within the domain that are relevant and meaningful
to them. Domain titles were reviewed for their clarity and whether they represented a collection
of similar functions for responders to interpret and relate to when responding. Three domains
(mobility, domestic life and major life) were broken down to present a more interpretable set of
tasks. This resulted in a total of 11 items (> Table 2‐2). The items were presented in the
measurement instrument in the same order as the ICF domains.
3.3 Scoring of Each Item
Individual item scoring was based on a pragmatic assumption of when participation restriction
occurs. The adjectival ordinal scale of each item is dichotomized to indicate participation and
participation restriction (i.e., 0-0-1-1-1) (> Figure 2‐2). The scale was dichotomized on the
basis of a plausible boundary between participation and participation restriction. Participa-
tion that occurs ‘‘as and when you want’’ only some of the time or less is regarded as restricted.
3.4 Instrument Score
A simple conceptual and arithmetical approach was taken to scoring which makes no
assumptions about individual items in terms of their importance, other than that they are
all equally contributing to the score (Streiner and Norman, 2003). The instrument score is a
simple count of the number of items of restriction indicated by each responder, up to a total of
eleven. Increasing numbers of items with participation restriction indicate more aspects of life
where individuals perceive their performance to be restricted. This approach does not consider
the potential weighting of the total score towards domains with more than one item (e.g.,
there are three items for domestic life and one for self-care).
. Table 2-2
KAP items measuring participation restriction in ICF domains
ICF domains KAP items

a
4. Mobility Mobility within the home (Item 1)
4.1–4.29 Changing and maintaining body parts Mobility outside the home (Item 2)
4.3–4.49 Carrying, moving and handling body parts
4.5–4.69 Walking and moving
4.7–4.99 Moving around using transport
5. Self-Care Self-Care (Item 3)
5.1–5.29 Washing, caring for body parts
5.3–5.69 Toileting, Dressing
5.7–5.99 Looking after one’s health
6. Domestic Lifea Looking after the home (Item 4)
6.1–6.29 Acquisition of resources Looking after things (Item 5)
6.3–6.49 Household tasks Looking after dependants (Item 6)
6.5–6.99 Caring for household objects and others
7. Interpersonal interaction Interpersonal interaction (Item 7)
7.1–7.29 General interpersonal interaction
7.3–7.99 Personal interpersonal relationships
8. Major Life
8.6–8.79 Economic life Managing money (Item 8)
8.4–8.59 Work and employment Work (Item 9)
8.1–8.39 Education Education (Item 10)
9. Community, Social and Civic life Social Life (Item 11)
9.1–9.19 Community life
9.2–9.29 Recreation and leisure
9.3–9.99 Religion and spirituality
a
For mobility and domestic life aspects of the main sub-domains feature in the two and three items, respectively,
designed to measure these domains. KAP items were designed to measure domains in a way that requires
responders to make an aggregate judgment on the basis of the life situations within the domain that are relevant
and meaningful to them. Domain titles were reviewed for their clarity and whether they represented a collection
of similar functions for responders to interpret and relate to when responding. Three domains (mobility,
domestic life and major life) were broken down to present a more interpretable set of tasks. This resulted in a
total of 11 items
Estimates of prevalence can be produced for:

Participation restriction in each of the 11 different aspects of life (i.e., the proportion of
responders in each aspect of life who do not participate ‘‘as and when they want,’’ ‘‘some of
the time or less.’’
Participation restriction in at least one item (i.e., the proportion of responders who
indicate that they perceive their performance in at least one item/aspect of life to be
restricted ‘‘as and when they want’’ at least ‘‘some of the time’’). Participation restriction in
multiple aspects of life (1–3, 4–6, 7–11 areas) could also be calculated – i.e., a simple count
of the number of items in which restriction occurs.
. Figure 2‐2
Scale scoring and dichotomy for KAP items. Individual item scoring was based on a pragmatic
assumption of when participation restriction occurs. The adjectival ordinal scale of each item is
dichotomized to indicate participation and participation restriction (i.e., 0-0-1-1-1). The scale was
dichotomized on the basis of a plausible boundary between participation and participation
restriction. Participation that occurs ‘‘as and when you want’’ only some of the time or less is
regarded as restricted
4 Psychometric Testing
To examine the ability of the Keele Assessment of Participation to measure person-perceived

participation restriction in population studies, and to inform the interpretation of scores, the
instrument was examined against the relevant review criteria proposed by the Scientific Advisory
Committee of the Medical Outcomes Trust (Lohr et al., 1996) in pre-pilot and pilot studies.
A number of methods were included to specifically examine each attribute (> Figure 2‐3).
5 Pre-Testing Interview Stage

The objectives of the cognitive and qualitative interviews were to examine face > validity,
> content validity and > responder burden.
5.1 Cognitive Interviews
Two separate purposive convenience samples of individuals aged 50 years and over were
selected for > cognitive interviews to represent older people with a range of participation
restriction. One sample consisted of patients receiving treatment for a range of conditions on a
rheumatology ward (n = 8) and the other sample consisted of healthy volunteers with no joint or
current health problems (n = 3). Participants completed the draft instrument and were observed
for any difficulties encountered during this process, which was timed. Semi-structured inter-
views asked questions related to face validity, responder burden and content validity.
All participants in the cognitive interviews reported the questions to be easy to understand
and complete, and relevant for the assessment of tasks of daily life. The mean time for
completion was 3 min (range: 2–4) with no difficulties observed. No additional domains
were suggested for inclusion.
. Figure 2‐3
Flowchart of the methods for examining the measurement properties of the Keele Assessment of
Participation. Pre-pilot and pilot studies for the main study were used to examine the
psychometric properties of the KAP. This figure sets out what was examined at each stage
5.2 Qualitative Interviews
Qualitative interviews were conducted in a separate sample of participants (n = 4), purposively

sampled from a rheumatology ward to represent a range of experiences of health conditions and of
past or present functional restrictions, to generate narrative accounts of the impact and experience
of living with these. The interviewer was provided with the World Health Organization definition
of the domains covered by the questionnaire. From these, stem questions for the interview were
generated, which allowed the participants to respond openly about their experiences in relation to
each domain. Participants were then invited to complete the KAP and were asked if the question-
naire covered all areas of life and if any additional questions should be included.
The interviews were tape-recorded and transcribed, and anonymous data analyzed focusing
on face and content validity. Face validity was assessed from participants’ views as they
completed the questionnaire, and their opinions gathered on the relevance of the KAP to their
problems and on whether it did reflect their restrictions. To examine content validity, interview
transcriptions were analyzed for descriptions of functional restrictions. These were then com-
pared to the answers provided by the same participant in filling out their KAP questionnaire.
The participants found the items to be relevant, allowed them to convey the problems they
were having, and were presented in an acceptable way. All functional restrictions discussed in
the interviews could be mapped to a domain of the KAP. However the number of functional
restrictions discussed in the interviews differed from the number indicated in the KAP: higher
at interview for three participants, higher on the questionnaire for the fourth. Reasons for the
discrepancies were identified by examining the interview transcripts. For example, participant
1 reported being unable to climb steps or stairs, but did not record restriction of mobility
within the home on the KAP because she used a stair lift.
6 Further Development of Instrument
In both interview studies, a number of participants expressed that for four domains (looking
after dependents, work, education and social activities) they either chose not to participate
in them or that the items were not relevant. Filter questions, with responses ‘‘yes’’/‘‘no,’’
were added to these items to indicate if responders had, for example, dependents to look
after, or if they chose to participate in work, education or social activities. If responders
indicated ‘‘yes,’’ they would be asked to complete the relevant participation item. If they
indicated ‘‘no’’ they would be asked to go to the next question and were scored as not having
participation restriction for that item. The modified instrument (> Figure 2‐4) with filter
questions was included in the ‘‘Pilot questionnaire stage’’ to assess the KAP’s repeatability
and validity.
7 Pilot Questionnaire Stage
In addition to investigating how the instrument would perform in a population survey, the
objectives of the pilot study were to examine repeatability and > construct validity.
7.1 Pilot Methods
The KAP was included in a survey instrument mailed to a random sample of 1,461 adults aged
50 years and over drawn from the registered population of one general practice belonging to
the North Staffordshire Primary Care Research Consortium.
7.1.1 Performance
To measure the performance of the KAP in a population survey, completion rates and missing data
were calculated as proportions of the total number of responders. The distributions of responses
for each KAP item and the number of restricted items were calculated for all responders.
7.1.2 Validity of the Four Filter Questions
Filter items were added to the instrument to identify people who could not be restricted
because they did not participate in that area of life. To assess that this assumption was
correct, each filter question was matched with a frequency question. For each filter
question the proportion of those responding that they did not choose to participate in
that particular area of life and also indicated that the frequency of participation was ‘‘no
days’’ in the corresponding frequency question was calculated. This was taken as an indi-
cation of those correctly classified as not having participation restriction in each filter
question.
. Figure 2‐4
Keele Assessment of Participation. This is the Keele Assessment of Participation (KAP), an 11 item
self-complete instrument designed to measure person-perceived participation. The KAP can be
considered as an instrument that is likely to detect and provide sensible estimates of
participation restriction in postal surveys of a population of adults aged 50 and over
7.1.3 Discriminant Validity (Conceptual Discrimination – Does

Frequency Matter?)
KAP items were developed to capture the individual’s perspective of their participation and this
viewpoint may be independent of how often or how many times someone participates in an area
of life. Additional items were included in the questionnaire that assessed the same dimensions as
the KAP but from a frequency perspective, i.e., ‘‘On how many days in the past month have you
been out for a walk’’ with response options ‘‘All days’’ to ‘‘No days.’’ There were 23 pairs of
corresponding items. Responses to KAP items were compared with the corresponding frequency
items in order to establish whether the KAP measured participation restriction differently to a
normative population standard (i.e., from a societal perspective). For each frequency item,
restriction was defined as reporting participation less frequently than the modal value for the
whole sample. Actual agreement for each corresponding pair (%) was calculated.
Responders to the questionnaire, who gave permission for further contact, were randomly
designated to two groups and sent further questionnaires, each group addressing a separate
issue: (1) the repeatability of the KAP, and (2) validity of the KAP compared to items
measuring participation derived from other instruments.
7.1.4 Repeatability of the KAP
Responses to the first and second completion of the KAP were compared for both the main
and filter questions. Repeatability was calculated by actual agreement (% of responders with
agreement) and agreement beyond chance (kappa (k) for dichotomous variables; linearly
weighted kappa [kw] for analysis of the five response options) and described using cut-offs
suggested by Landis & Koch (Landis and Koch, 1977). The difference in the prevalence of any
participation restriction between the first and second mailings was calculated with 95%
confidence intervals (using Confidence Interval Analysis for Windows) to determine if there
was a systematic difference in prevalence between the two mailings. Repeatability was assessed
for (1) the original five response options for each item, (2) the dichotomized response for each
item, and (3) the categories of ‘‘None’’ and ‘‘Any’’ participation restriction.
7.1.5 Validity of the KAP
The Impact on Participation and Autonomy (IPA) (Cardol et al., 2001) and the Reintegration to
Normal Living (RNL) (Wood-Dauphinee et al., 1988) were used to examine convergent and
discriminant validity when compared to the KAP. The IPA was developed as a self-complete
questionnaire focusing on perceived and experienced participation restriction, and has been
administered previously as a postal questionnaire. The RNL assesses global function and
measures both the patients’ perceptions of their own capabilities and objective indicators of
physical, social, and psychologic performance. It was developed as a tool to monitor progress
during the rehabilitation process and to predict future outcomes, and has recently been used in
a postal survey (Harker et al., 2002). They were chosen as they were known to contain specific
items that measure participation restriction. The response scales of the IPA and the RNL were
dichotomized a priori to indicate participation restriction for comparison with the KAP.
Responses of seven or below on the visual analogue scale of RNL items and ‘‘moderate,’’
‘‘poor’’ or ‘‘very poor’’ on the IPA item scale were considered to measure participation
restriction and correspond to the KAP dichotomy.
7.1.6 Convergent Validity
Items from the RNL and IPA were matched to similar items on the KAP, based on domain
content. For example, the self-care items of the RNL and the IPA were compared with the self-
care item of the KAP. There were ten pairs of items from the RNL and the KAP and 24 pairs
from the IPA and the KAP for analysis. Actual agreement (%) for each corresponding pair
between KAP and RNL, and KAP and IPA, was calculated.
7.1.7 Discriminant Validity (Item Discrimination)
Discrimination was investigated by comparing KAP items with RNL and IPA items from non-
corresponding domains to establish the ability of KAP items to measure participation restriction
specific to one domain. For example, the KAP item for mobility within the home was compared
with IPA and RNL items which captured every other domain. This produced 60 pairs of non-
corresponding items between KAP and RNL, allowing seven KAP items to be examined, and 160
between KAP and IPA, allowing eight KAP items to be examined. Agreement for non-
corresponding pairs was calculated and compared with the levels of agreement for corresponding
pairs. If KAP items measured participation restriction specific to one domain, the agreement for
the corresponding pairs would be higher than for the non-corresponding pairs.
7.2 Pilot Results
A total of 1,117 completed questionnaires were received (adjusted response rate 71.7%). The
mean completion of KAP items was 98.2% (range: 97.0–99.5%). The distribution of participation
restriction for individual KAP items ranged from 4% (work) to 18% (mobility outside the home)
(> Table 2‐3). Fifty three percent of responders had no restriction at all (> Figure 2‐5).
7.2.1 Validity of the Four Filter Questions
The proportion of responders who indicated ‘‘no’’ in a filter question and also indicated that
they did not participate in the corresponding task (or frequency item) ranged from 64% (‘‘Do
you have any relatives, or other people who depend on you?’’) to 98% (‘‘Do you choose to take
part in education or training?’’) (> Table 2‐4).
7.2.2 Discriminant Validity (Conceptual Discrimination)
There was no clear association between person-perceived participation restriction and the
frequency with which people participated in these domains. Mean percentage agreement,
where responders indicated participation or participation restriction in both matched items
for 23 matched pairs, was 47.6% (range: 24–87%). Three pairs of corresponding items had
moderately high observed agreement (mobility within the home (87%), education (79%) and
looking after dependents (71%)). The lowest observed agreement was for pairs of items
referring to looking after the home (24%).
. Table 2‐3
Prevalence of participation restriction in each of the 11 areas of life
Area of life Prevalence of restriction (%)

Mobility within the home 9
Mobility outside the home 18
Self-care 6
Looking after the home 11
Looking after belongings 10
Looking after dependants 14
Interpersonal interaction 10
Managing money 12
Work 4
Education 4
Social activities 14
The prevalence of restriction in each domain is described as the proportion of the total population. The prevalence
of restriction was highest for mobility outside the home (18%) and lowest for work and education (4% for each)
7.2.3 Repeatability of the KAP
Out of a possible 314, 196 completed repeat questionnaires were received (adjusted response
of 62.4%).
For the four filter questions, the mean observed agreement was 87.5% (range: 84–92%)
and chance-corrected agreement ranged from moderate (‘‘Do you have any relatives, or other
people, who depend on you?’’ k = 0.54; 95% CI: 0.41, 0.67) to substantial (‘‘Do you choose to
take part in paid or voluntary work?’’ k = 0.70; 95% CI: 0.57, 0.83).
The mean observed agreement for the five response options to each participation item was
75.1% (range: 68–83%) and chance-corrected agreement ranged from slight (kw = 0.34; 95%
CI: 0.09, 0.59) to moderate (kw = 0.64; 95% CI: 0.54, 0.74) (> Table 2‐5).
Better repeatability was seen for the dichotomized response (mean agreement = 90.4%;
range: 85.3–94.4%) (> Table 2‐5) with chance-corrected agreement ranging from slight
(k = 0.20, 95% CI: 0.04, 0.44) to substantial (k = 0.71; 95% CI: 0.57, 0.85). The actual
agreement for the categories of ‘‘None’’ and ‘‘Any’’ restriction was 71.6% and chance corrected
agreement gave a kappa of 0.42 (95% CI: 0.27, 0.57).
There was a systematic difference in the prevalence of ‘‘Any’’ participation restriction between
the first and second administrations with the prevalence for the first mailing higher than for the
second (46.7% cf 37.3%; % difference: 9.4; 95% confidence interval: 1.4%, 17.3%).
7.2.4 Convergent and Discriminant Validity
Analysis was performed for 102 responders who completed both KAP and RNL and for a
separate 104 responders who completed KAP and IPA.
. Figure 2‐5
Distribution of the number of restricted items. Multi-domain scores are calculated only for
responders who have completed all 11 items. The distribution of the number of items where
restriction was indicated was examined to determine the ability of the KAP to explain the full range
of amounts of participation restriction in the general population. Responders indicated restrictions
in a varying number of items. A ceiling effect was observed with over half of the responders
indicating that they were not restricted in any items. The majority of those with restrictions indicated
1–3 restrictions, with a small minority indicating restriction in a substantial number of aspects of life.
The distribution of the number of restrictions is similar to that expected for a general population
sample (i.e., mostly consisting of people who do not suffer from health conditions or functional
restrictions)
Mean percentage agreement for the ten pairs of corresponding items (convergent validity)
between KAP and RNL was 79.3% (range: 72–84%). Mean percentage agreement for 23 pairs
of corresponding items between KAP and IPA was 87.7% (range: 74–97%).
Mean agreement for 60 pairs of non-corresponding items (discriminant validity) between
the KAP and the RNL was 76.0% (range: 57–89%). The mean agreement for 160 pairs of non-
corresponding items between the KAP and the IPA was 82.8% (range: 66–97%).
. Table 2‐4
The number of responders who gave a negative answer to the filter question and the number
and proportion of those responders who indicated that they do not participate in the
matched task
Total no. No. (%) indicating no days of

Filter item stating ‘‘no’’ participation in that area
Do you
6. have any relatives or other people 726 467a (64)
who depend on you?
9. choose to take part in paid or 710 552b (78)
voluntary work
10. choose to take part in education 900 878c (98)
11. choose to take part in social activities 331 253d (77)
331 307e (93)
To examine the validity of the filter questions the number and proportion of responders who said that they choose
not to participate in an area of life and did not participate is in the right hand column. The highest level of
agreement occurred for education: 878 of 900 (98%) responders indicated that they did not choose to take part in
education and did not participate in work or training activities. The lowest level of agreement was for looking after
dependents; 467 of 726 (64%) responders indicated that they did not have any dependants and did not look after
others. Key for superscript: Denotes the number of people who indicated in the past month their frequency was no
days in the comparable tasks of
a
looking after others
b
going out to work
c
go on an education or training course
d
go to a club, church or social event
e
play a sport
8 Overview of Psychometric Testing
Although performed with small samples and with limited analyses, the pre-pilot tests sug-
gested that the KAP had sufficient levels of face and content validity; all items were considered
acceptable and relevant and no additional domains had appeared which were not already
covered by the KAP.
The fact that each KAP item requires an overall judgment on a number of tasks was
illuminated by the finding that participants reported some specific functional restrictions
without indicating participation restriction in the corresponding item because the restriction
was not considered important or severe enough to influence participation.
The minimal responder burden and high completion rates support the potential useful-
ness of KAP for epidemiological research. The frequency distribution of restricted items
indicated a wide range of participation restriction in the general population, but also high-
lighted a ceiling effect with over half of the responders having no restricted items at all.
The filter questions were included to establish when responders could not be restricted because
they chose not to participate in those items. The a priori assumption for the filter questions
(people who choose not to participate in a domain would not take part in such tasks and therefore
could not be ‘‘restricted’’) was confirmed on analysis for most responders. There were, however,
. Table 2‐5
Test retest repeatability for the main component of KAP items
Prevalence of Dichotomized categories

participation (participation/
restriction participation restriction) Five response options
Observed Observed
Baseline Repeat agreement Kappa score agreement Kappa score k
No. (%) No. (%) No. (%) k (95%CI) No. (%) (95%CI)
Mobility 24 (12.3%) 19 (9.7%) 184 (94.4) 0.71 (0.57,0.85) 154 (79.0) 0.63 (0.53,0.73)
within the
home
Mobility 39 (20.0%) 37 (19.0%) 177 (90.8) 0.71 133 (68.2) 0.64 (0.54,0.74)
outside the (0.57,0.85)
home
Self care 11 (5.6%) 9 (4.6%) 183 (93.9) 0.37 160 (82.1) 0.45 (0.33,0.55)
(0.23,0.51)
Looking after 21 (11.1%) 14 (7.4%) 167 (88.8) 0.34 136 (72.0) 0.46 (0.35,0.57)
the home (0.20,0.48)
Looking after 11 (5.8%) 9 (4.7%) 176 (92.6) 0.26 148 (77.9) 0.42 (0.30,0.54)
belongings (0.12,0.40)
Looking after 4 (2.1%) 4 (2.1%) 36 (92.3) 0.36 27 (69.2) 0.34 (0.09,0.59)
dependants (0.05,0.67)
Interpersonal 23 (12.0%) 20 (10.5%) 176 (92.2) 0.61 138 (71.9) 0.51 (0.41,0.61)
interaction (0.46,0.74)
Managing 29 (15.3%) 19 (10.0%) 162 (85.3) 0.34 149 (78.0) 0.37 (0.25,0.49)
money (0.19,0.47)
Work 11 (5.8%) 4 (2.1%) 50 (88.3) 0.20 46 (76.7) 0.39 (0.20, 0.58)
( 0.04,0.44)
Education 7 (3.7%) 6 (3.2%) 21 (87.5) 0.59 20 (83.3) 0.56 (0.22, 0.90)
(0.19,0.99)
Social 24 (12.8%) 22 (11.7%) 110 (88.7) 0.54 86 (68.8) 0.52 (0.39, 0.65)
activities (0.36,0.72)
The reliability of each KAP item was examined using the test-retest method of repeatability and summarized using
actual agreement and agreement beyond chance (Kappa). It is difficult to interpret the levels of chance-corrected
agreement for individual items due to the effects of low prevalence. For example, the mean level of
actual agreement for the dichotomous classification of items was 90.4% (range: 85.3–94.4%), and the range
of levels of chance-corrected agreement was 0.20 (slight) to 0.71 (substantial (Landis and Koch, 1977)). The
prevalence of participation restriction for some items was so low (e.g., 4% for work) that the possible agreement
above chance can only be small due to a high expected agreement. In these cases it is difficult even to achieve
moderate kappa values. However levels of actual agreement were good. As expected agreement levels were
higher for the dichotomy of participation/participation restriction than for individual response options. k kappa;
kw linearly weighted kappa; CI confidence interval
some responders who stated they did not have dependents or chose not to take part in work,
education or social activities, but who also indicated that they did participate in a related frequency
task and could therefore potentially be restricted. This occurred more so for those who did not
have dependents but who looked after others on at least a few days. This questions the ability of this
filter question to include those who are involved in looking after relatives or others as part of a
caring role within domestic life and indicates a need for re-phrasing.
It also suggests that capturing the ‘‘choice’’ to participate is difficult, and highlights the
difficulty in capturing functioning in aspects of life such as work. Participation restriction may
be under-estimated as a result, however the size of any error is likely to be modest, and most
responders were consistent (at least 64% for each item).
The study of discriminant validity confirmed that the individuals’ perception does not
simply reflect the frequency of participation restriction. There was a relatively high observed
agreement within some of the matched pairs, suggesting that participation frequency may be
more influential on the perception of participation restriction for some tasks than others.
The analysis did not consider the effects of age and gender on the matched pairs, where
frequency may have a greater bearing on perceived restriction for items for some age groups or
for men or women. However, in general the results support the conceptual distinction between
a person-perceived participation restriction and a restriction indicated by less frequent
participation measured against a normal population standard. The latter would result in a
proportion of individuals who perceive no participation restriction, being classed as restricted.
Conversely, frequent performance of certain tasks does not mean that individuals will inevita-
bly perceive themselves as not being restricted in that domain.
Person-perceived participation restriction as measured by KAP was not completely stable
over time. There were 71.6% of responders who consistently indicated participation (‘‘none’’)
or participation restriction (‘‘any’’) on the two occasions separated by 4 weeks. The levels of
actual agreement for the filter questions and the dichotomous classification of participation
restriction were also reasonably high.
Other levels of repeatability were influenced by measurement characteristics (low preva-
lence for some items (e.g., work 4%)) and by systematic differences in the prevalence of
participation restriction between the questionnaire mailings both of which will tend to reduce
levels of agreement and kappa scores (Hoehler, 2000). The systematic differences suggest that
perceived participation restriction can vary over short periods of time.
This may be attributable to the instability of the person’s perceived participation restric-
tion and the possibility that their perception at one time point may be influenced by that at
another. In this study, reassessment of perceived participation may have led to a more
optimistic conclusion and resulted in a reduced prevalence of participation restriction. It
may also be that more of the group as a whole were experiencing unusually high restriction on
the first occasion, but regressed to their normal level by the second time point. The use of early
responders who may have returned their questionnaires quickly perhaps due to the perceived
relevance of the questionnaire, may have given rise to this.
The KAP had high levels of agreement with items from the Reintegration to Normal Living
Index and the Impact of Participation and Autonomy, two instruments that consist of a high
proportion of items which measure person-perceived participation restriction and can be
considered to measure a similar concept. This suggests that person-perceived participation
restriction is being measured by KAP items.
The levels of agreement were higher than the those reported by McDowell & Newell
(McDowell and Newell, 1996) who reviewed a large number of health outcome measures
and found that tests of convergent validity generally demonstrate low levels of agreement
typically falling between 0.40 and 0.60. The interview content demonstrated that participants
considered expectations, aspirations, needs and contextual factors, such as the presence of
carers and the availability of mobility aids, when rating perceived participation. This is
consistent with the conceptual model for the KAP.
8.1 Discriminant Validity (Item Discrimination)
Evidence of responders discriminating between aspects of life was obtained during the cognitive
and qualitative interviews. However these abstract distinctions were not demonstrated empiri-
cally by the study of item discrimination, since agreement between corresponding items on the
different scales was little different to that between non-corresponding items.
This suggests that participation restriction may not occur specifically in individual aspects
of life, but may overlap into different aspects of life with patterns of co-occurrence. Although
the hypothesis of discordance was flawed, the study suggests that the same characteristics that
influence participation restriction in one aspect of life also influence participation restriction
in others. This apparent lack of discrimination should not affect the use of the KAP or the
inclusion in it of questions about different aspects of life.
9 Conclusions
The KAP was developed to specifically measure participation restriction in population
surveys. The rationale has been presented for measuring participation restriction from the
perspective of the individual and with reference to the performance of tasks. The instrument is
intended to measure participation restriction comprehensively and consists of eleven items,
each representing a different aspect of life. The measurement model of the KAP allows
prevalence estimates of participation restriction in any, multiple, and each different aspect
of life. It was designed to be a short and simple questionnaire for application in epidemiologi-
cal studies and to describe, and discriminate between large groups in the population. This
approach may miss some specific details and distinctiveness of participation restriction in
individuals, since it cannot be specific for all and may not capture relevant information for
clinical or rehabilitation purposes.
The pilot studies have tested a number of attributes that are traditionally considered when
reviewing the quality of health outcome instruments. The KAP has performed adequately
in validity and reliability tests and can be considered as an instrument that is likely to detect
and provide sensible estimates of participation restriction in postal surveys of a population
of adults aged 50 and over.
Summary Points
Participation restriction is an appealing concept for those interested in older populations

and the impact of chronic diseases because even when health conditions and activity
limitations persist, there may still be the potential to maintain participation.
Population-based studies have tended to focus on impairment and activity limitation and
we know least about participation restriction, which cannot be inferred from these.
Participation restriction is a performance-based, context-dependent, phenomenon, most

meaningfully understood when perceived by individuals, which requires their own judgment.
The Keele Assessment of Participation was developed as a self-complete instrument to
provide estimates of person-perceived participation restriction in population-based
surveys. It consists of 11 items that comprehensively capture participation as proposed
by the World Health organization in the International Classification of Functioning.
The Keele Assessment of Participation performed adequately in validity and reliability
tests and can be considered as an instrument that is likely to detect and provide sensible
estimates of participation restriction in postal surveys of a population of adults aged 50
and over.
Acknowledgements
The study in which this work was undertaken was supported financially by a Program Grant
awarded by the Medical Research Council, UK (grant code: G9900220) and by funding secured
from the North Staffordshire Primary Care R&D Consortium for NHS service support costs.
The author would like to thank Dr George Peat, Dr Elaine Thomas, Dr Helen Hooper and
Professor Peter Croft for their input in developing the KAP. Also the administrative and health
informatics staff at Keele University’s Primary Care Sciences Research Centre and the doctors,
staff and patients of the participating general practice and the rheumatology wards of the
Haywood Hospital, North Staffordshire.
References
Abramson ZH, Abramson JH. (1999). Survey Methods in Landis JR, Koch GG. (1977). Biometrics. 33: 159–174.
Community Medicine: Epidemiological Research, Lohr KN, Aaronson NK, Alonso J, Burnam MA, Patrick
Programme Evaluation, Clinical Trials. Churchill DL, Perrin EB, Roberts JS. (1996). Clin Ther. 18:
Livingstone, Edinburgh. 979–992.
Cardol M, de Haan RJ, de Jong BA, van den Bos GAM, de McColl E, Jacoby A, Thomas L, Soutter J, Banford C,
Groot IJM. (2001). Arch Phys Med Rehabil. 82: Steen N, Thomas R, Harvey E, Garratt A, Bond J.
210–216. (2001). Health Technol Assess. 5(31): 43–101.
Carr AJ. (1996). Br J Rheumatol. 35: 921–932. McDowell I, Newell C. (1996). Measuring Health. A
Carr AJ. (1999). Osteoarthritis Cartilage. 7: 230–238. Guide to Rating Scales and Questionnaires, 2nd ed.
Chapireau F, Colvez A. (1998). Soc Sci Med. 47: 59–66. Oxford University Press, Oxford.
Ebrahim S. (1997). J Epidemiol Commun Health. 51: Moser CA, Kalton G. (1971). Survey Methods in Social
469–471. Investigation, 2nd ed. Dartmouth Publishing, Alder-
Fransen J, Uebelhart D, Stucki G, Langenegger T, shot.
Seitz M, Michel BA. (2002). Ann Rheum Dis. 61: Simeonsson RJ, Lollar D, Hollowell J, Adams M. (2000).
225–231. J Clin Epi. 53: 113–124.
Grimby G. Smedby B. (2001). J Rehabil Med. 33: Streiner DL, Norman GR. (2003). Health Measure-
193–194. ment Scales: A Practical Guide to Their Develop-
Harker WF, Dawson DR, Boschen KA, Stuss DT. (2002). ment and Use, 3rd ed. Oxford University Press,
Int J Rehabil Res. 25: 93–102. Oxford.
Harwood RH, Prince M, Mann A, Ebrahim S. (1998). Int Stucki G, Cieza A, Ewert T, Kostanjsek N, Chatterji S,
J Epidemiol. 27: 261–268. Bedirhan Ustun T. (2002). Disabil Rehabil. 24:
Hoehler FK. (2000). J Clin Epidemiol. 53: 499–503. 281–282.
Sudman S, Bradburn N. (1974). Response Effects in Wilkie R, Peat G, Thomas E, Hooper H, Croft PR.
Surveys: A Review and Synthesis. Aldine, Chicago. (2005). Qual Life Res. 14: 1889–1899.
Ueda S, Okawa Y. (2003). Disabil Rehabil. 25: 596–601. Wood-Dauphinee SL, Opzoomer MA, Williams JI,
Verbrugge LM, Jette A. (1994). Soc Sci Med. 38: 1–14. Marchand B, Spitzer WO. (1988). Arch Phys Med
Weigl M, Cieza A, Harder M, Geyh S, Amann E, Rehabil. 69: 583–590.
Kostanjsk N, Stucki G. (2003). Osteoarthritis World Health Organization. (2001). International Clas-
Cartilage. 11(7): 519–523. sification of Functioning, Disability and Health.
Wilkie R, Peat G, Thomas E, Croft PR. (2004). Arthritis World Health Organization, Geneva.
Rheum. 51: 755–762.
3 The Global Person Generated
Index
F. Martin . L. Camfield . D. Ruta
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
1.1 Overview of Quality of Life Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
1.2 The Importance of Different Areas of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
1.3 Individualized Measures of Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
2 The Patient Generated Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

2.1 Uses of the PGI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
3 The Global Person Generated Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

3.1 Development of the Pilot Instrument . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
3.2 Sampling and Data Collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
3.3 Quantitative Validation: Content Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.4 Quantitative Validation: Criterion Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.5 Quantitative Validation: Construct Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.6 Qualitative Validation: Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.7 Qualitative Validation: Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4 Conclusions Regarding the Usage of PGI and GPGI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

4.1 Comparing Scores Between Individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.2 Weighting QOL Scores by Importance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.3 Advantages of the Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
4.4 Disadvantages of the Measures’ Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

60 3 The Global Person Generated Index
Abstract: The entry briefly describes the value of > individualized quality of life measures
and the philosophy behind them and outlines the main measures in this field. It then
focuses on the > Patient Generated Index (PGI) (Ruta et al., 1994) and explains its purpose
and methodology. Three different forms of administration are explored and its use in a
variety of healthcare settings is described. Finally, its psychometric properties are summar-
ized. The > Global Person Generated Index (GPGI) (Ruta et al., 2004a) is then introduced,
which is an open-ended measure with a simple method of administration, appropriate for
use in developing countries. The piloting and administration of the GPGI in three develop-
ing country settings is described in detail to illustrate the challenges of measuring quality of
life in these contexts. The validation process is described, focusing particularly on the
innovative technique of > qualitative validation, which used semi-structured interviews
collected on the same occasion to assess the accuracy with which the measure captured
the respondent’s world view. Some response errors were identified, which required addi-
tional administrator training, and the value of a brief accompanying interview are discussed.
The measure’s advantages are summarized, namely that is flexible and person-centered,
relatively quick to administer, generates new information, works across cultures, and
provides a direct measure of the gap theory of quality of life (Calman, 1984). The entry
concludes that the common criticism of individualized measures that respondents are not
rating the same dimensions evaporates when we consider that respondents are rating the
results of their judgments of what is important to quality of life: these judgments are
directly comparable (Parducci, 1995, p. 29). Therefore they provide a valid measure of
people’s perceptions of the quality of their life as a whole across time.
List of Abbreviations: ADDQOL, Audit of Diabetes Dependent QOL; GPGI, Global Person
Generated Index; MacDQOL, individualized measure of the impact of macular degeneration
on quality of life; PGI, Patient Generated Index; QOL, quality of life; SEIQOL, > Schedule for
Evaluation of Individual Quality of Life; SPSS, Statistical Package for the Social Sciences
(quantitative data analysis software); SWLS, Satisfaction with Life Scale; WeD, Wellbeing in
Developing Countries ESRC Research Group (see http://www.welldev.org.uk/)
1 Introduction
1.1 Overview of Quality of Life Measures
Most measures of quality of life (QOL) take the form of questionnaires where items are
generated by reviews of the literature, consultation with ‘‘experts,’’ and qualitative research and
are rated using Likert scales (e.g., the MOS 36-item Short-Form Health Survey (SF-36), Ware
and Sherbourne, 1992). These approaches assume that every item is of relevance to every
individual, and further that each item is of equal importance to the respondent, as items are
rarely weighted. Items are chosen for inclusion in QOL measures based on an analysis of how
they contribute statistically to a model of QOL (e.g., the Personal Wellbeing Index (PWI),
International Wellbeing Group, 2006; World Health Organization Quality of Life Measure
(WHOQOL), Skevington, 1999). This assumes that following statistical procedures will ensure
the inclusion of items that are important to everyone. However, the degree to which items are
equally important to everyone must be considered.
The Global Person Generated Index 3 61
1.2 The Importance of Different Areas of Life
The idea that the importance of different aspects of life varies both across and within
individual life courses and cultures is highly intuitive and supporting evidence exists. Indeed,
the rationale for developing disease, condition, population, or country-specific QOL measures
is that different aspects of life are relevant and important and require different item content
(e.g., Tovbin et al., 2003). For example, even within a sample of ‘‘healthy’’ adults in the UK,
there were differences by age in the areas participants nominated as important to their life:
older participants mentioned health more often than younger participants, whilst mentioning
money was more common in the younger (Bowling, 1995). Furthermore, not all of the life
areas nominated were covered by commonly used QOL scales, e.g., SF-36 does not explicitly
cover sleep, financial management, material welfare, sexual functioning, communication,
education, independence or religion (ibid).
Differences in importance are also seen in relation to health. For example, Weitzenkamp
et al. (2000) suggested that participants with spinal cord injuries ranked components of QOL
in a different way to non-injured participants, placing greater emphasis on relationships with
relatives, learning, creative expression, reading and other sedentary leisure activities. While the
study’s conclusions are limited by the fact that the participants with spinal cord injuries were
British, while the non-disabled participants were American, this illustrates another important
area of difference. Further support comes from Hensel et al. (2002) who found that people
with intellectual disabilities rated five out of eight domains of the same measure as signifi-
cantly more important than non-disabled participants. This would not be expected if one
believes in the universality of importance ratings. Here, importance is shown to be variable
and must therefore be measured.
Differing importance of the different facets has implications for the accuracy of the overall
measurement of quality of life. For example, one person may rate their physical health as low,
but not important, whereas another person may rate it equally low, but very important, so its
absence may have a more negative impact on their quality of life. Importance is therefore a
central issue in accurate measurement of quality of life. An area that is poorly rated, but not
seen as important may have a different effect on QOL from a poorly rated area that is highly
important (see Ferrans and Frisch, 2004). This suggests the importance of some degree of
individualization in assessing the true impact of a shortfall in a particular life domain on a
person’s quality of life.
1.3 Individualized Measures of Quality of Life
The underlying philosophy of the individualized approach to measuring QOL has been
outlined. Some measures take a partial approach to individualization where respondents
rate common items, but are able to exclude irrelevant items by scoring some areas as ‘‘not
applicable.’’ An extension of this approach allows weighting of the remaining items by
importance, e.g., the ‘‘Audit of Diabetes Dependent QOL’’ or ‘‘ADDQOL’’ (Bradley et al.,
1999) and the measure of the impact of macular disease on QOL (‘‘MacDQOL,’’ Mitchell and
Bradley, 2004). Fully individualized measures of QOL, where the respondent nominates,
scores and weights all elements of the rating include the ‘‘Schedule for the Evaluation of
Individual Quality of Life’’ or ‘‘SEIQOL’’ (McGee et al., 1991; O’Boyle, 1995) and the ‘‘Patient
Generated Index’’ or ‘‘PGI’’ (Ruta et al., 1994). Both instruments ask respondents to nominate
personally important areas of life (step one in the PGI), to indicate their current satisfaction
with these areas (step two), and to rate their importance (step three). Importance rating is
carried out by allocating a limited number of points, which encourages respondents to
indicate priorities within the domains. The SEIQOL appears to have never been used without
an accompanying interview, partly due to the complexity of its scoring system. However, the
PGI has been used in postal and self-report studies (Lindblad et al., 2002; Tully and Cantrill,
2002). Furthermore, unlike the SEIQOL, the PGI was originally designed to focus on the
impact of a specific health condition on QOL.
2 The Patient Generated Index
The ‘‘Patient Generated Index’’ or ‘‘PGI’’ has three steps, as shown in > Figure 3-1. In the first
step respondents are asked to nominate up to five important areas of their life affected by the
specified health condition (e.g., ‘‘your arthritis’’). The second step asks respondents to rate
each nominated area on a scale of 0–10 (previous versions used 0–60 or 0–100, but 0–10 was
considered more accessible and psychometrically credible, see Cummins and Gullone, 2000).
. Figure 3-1
The Patient Generated Index – the measure (*see Martin et al. (2007) for a review of the different
versions of this measure)
The lowest scale point is anchored with the statement ‘‘the worst you can imagine’’ and highest
point is anchored with the statement ‘‘exactly as you would like to be.’’ In some versions,
participants are also asked to rate a sixth area, meant to represent ‘‘all other areas of life not
already mentioned.’’ In later versions of the PGI both a sixth and seventh area are used to
differentiate between ‘‘other health-related areas’’ not already nominated and ‘‘other non-
health related areas.’’ In the third and final step, respondents are asked to spend points
(different versions have a different number of points to spend) to indicate the relative
importance of each life area for overall QOL. The scores from step two are multiplied by the
step three weights. This weighted score is then multiplied by the proportion of points allocated
to each area. This is then summed to generate a single index score, reported as a percentage.
When used longitudinally, three formats of administration are possible. In the ‘‘blind’’
format, the areas previously nominated as important in PGI stage one (i.e., at baseline) are not
made available to the respondent. In the ‘‘open’’ format, the areas nominated previously are
shown to the respondent; in both blind and open formats respondents can add, remove or
substitute important areas of life. While changes in areas nominated over time are overt and
explicit in the ‘‘open’’ format, these could also be due to forgetting or misremembering
previous areas in the ‘‘blind’’ format. Conversely, in the ‘‘closed’’ format the areas nominated
previously are rated a second time with no option for change.
2.1 Uses of the PGI
The PGI has been adapted to different contexts and respondents, for example, older adults
(Dempster and Donnelly, 2000), new mothers (Symon et al., 2003) and in a community
nursing setting (Griffiths et al., 2000). The structure of the measure also evolved as step two
changed from 0 to 100 to an 11 point scale, and methods for step three ranged from spending
£100 to between 12 and 60 points (Martin et al., 2007). The PGI has also been used across a
wide range of clinical conditions, from lower limb amputees (Callaghan and Condie, 2003)
to atopic dermatitis (Herd et al., 1997). More recently, the PGI was used to assess ‘‘> response
shift’’ (Sprangers and Schwartz, 1999), namely a change in the meaning of one’s evaluation of a
construct as a result of a change in one’s internal standards of measurement, a change in one’s
values, or a change in one’s definition of the construct (Ahmed et al., 2005). A full review of the
measure’s psychometric properties is given by Martin et al. (2007), which shows that whilst
validity and reliability for group comparisons appear sound, responsiveness to change is
complex. The PGI continues to be used in a variety of contexts, with appropriate adaptation,
and most recently, a non-health related version of the measure has been developed to establish
whether Calman’s (1984) definition of QOL as the gap between expectations and experience
applies outside healthcare.
3 The Global Person Generated Index
The ‘‘Global Person Generated Index’’ or ‘‘GPGI’’ is then an extension of the PGI, which
moves the focus from health and healthcare settings to encompass a more holistic under-
standing of quality of life (Ruta et al., 2004b). It was designed to combine the open-endedness
of the SEIQOL (McGee et al., 1991) with a simple administration method appropriate to
developing country contexts. This will enable its use as project planning or evaluation tool,
although there are some issues to address, as described in the final section. > Figure 3-2 shows
64
3
. Figure 3-2
The Global Person Generated Index (the psychometric properties of this scale continue to be researched. The psychometric properties of the English
version of this scale are yet to be investigated)
The Global Person Generated Index
the current English version. The GPGI was piloted and administered in Bangladesh, Thailand,
and Ethiopia during the first phase of the exploratory quality of life work conducted by the
Wellbeing in Developing Countries (WeD) ESRC Research Group (see Camfield and Ruta,
2007; Jongudomkarn and Camfield, 2006; Ruta et al., 2004b, 2006) and has subsequently been
further developed by WeD affiliated researchers working in these countries.
3.1 Development of the Pilot Instrument
WeD fieldworkers in each of the three countries were given a free hand to interpret and
translate a culturally relevant version of the GPGI. This included translations of: instructions
to nominate important life areas; the wording and construction of Likert statements and
scales; and the method of ‘‘spending’’ points. Back and re-translation methods were used.
A purposive sample of 36 (17 female, 19 male) respondents was identified by local fieldworkers
in seven towns and villages. A qualitative content analysis was undertaken to explore the
elicited life areas, and the validity of rating and weighting methods. Although a range of life
areas were generated, with similarities and differences observed between countries, economic
‘‘development’’ focused areas were frequently mentioned in all field sites.
In Bangladesh, an alternative form of wording for step two was introduced. In Bangla the
words ‘‘good’’ (bhalo) and ‘‘bad’’ (kharap) are vague descriptors. Therefore a seven point
scale was constructed around the notions of satisfaction (shontushtho) and dissatisfaction
(oshontushtho). In Ethiopia it was difficult to find a word equating with ‘‘important’’ in the
context of the GPGI. Eventually the word ‘‘wesagn,’’ literally meaning crucial or needed, was
used. It was also decided to give respondents ten ten-cent pieces and to ask them to place the
coins in the boxes on the questionnaire when ‘‘spending’’ points in step three of the GPGI.
In Thailand, three methods were tried for step two: moons (pie-charts, originally depicted as
full-empty, later light-dark), smiley faces (happy-sad) and numbers (labeled from good to
bad), however, after mixed results it was agreed that any method could be used, if it was
sufficiently well explained. In Thailand three methods were also tried for step three: spending
Thai Baht, placing stones and making tallies. The coins were the most successful as they could
be explained in terms of shopping in the market or ‘‘making merit’’ (donating to a Buddhist
shrine). The stones were the least successful as people didn’t know how to value them.
Following the pre-pilot analysis, a final questionnaire wording was agreed for the pilot
instrument in each country. All countries decided to reduce the original 10 point scale used
in step two to a seven point (i.e., a 0–6) scale, and to use the method of spending ten coins to
assign importance weights in step three.
3.2 Sampling and Data Collection
The GPGI was administered as part of WeD’s exploratory research into Quality of Life, which
took place in rural, peri-urban, and urban sites in Bangladesh, Ethiopia, and Thailand. The
fieldwork involved semi-structured interviews, which were used to interpret and validate the
GPGI, focus group discussions, and the piloting of other measures, such as the ‘‘Satisfaction
with Life Scale’’ (Diener et al., 1985). In Ethiopia, it was carried out by local researchers,
the majority of whom had spent at least 1 year attached to the site, which enabled them to
build a good rapport with the inhabitants. The researchers received full training in the
methods used, and the majority had also participated in the GPGI piloting. As the GPGI was
interview-administered, the response rate was 100%, with the exception of Bangladesh where
four female respondents (two of whom were illiterate) chose only to respond to the semi-
structured interviews. 242 GPGIs were administered during the main fieldwork (120 in
Ethiopia, 102 in Thailand, and 22 in Bangladesh), using a purposive sample to capture
differences in age, socio-economic status and religion, as well as location.
3.3 Quantitative Validation: Content Validity
Content validity, that is the extent to which a measure assesses content relevant to the
underlying construct, was assessed in two ways. First, a frequency analysis was undertaken
of the areas mentioned in respondents’ GPGI questionnaires in step 1. This analysis was
undertaken separately for each of the three countries. Three commonly mentioned areas
emerged:
1. Indicators of material well-being, which included income, assets, crops, property, land,
livestock, job, debts and agriculture
2. Health, including health of the family and
3. Family or Children, which included children’s education
Therefore a second method of assessing content validity involved correlating respondents’
ratings on a 0–6 scale as mentioned in step two of the GPGI, with scores derived from the
semi-structured interviews (described in full in Camfield 4 Ruta, 2007). Material well-being
as indicated in the semi-structured interview shows a moderate but statistically significant
correlation (0.286) with material well-being as indicated in step two of the GPGI. Interest-
ingly the material well-being score from the semi-structured interview shows a higher
correlation with family/children (0.395) as indicated in the GPGI. The health score as
indicated on the semi-structured interview shows a strong and statistically significant
correlation (0.584) with health as measured by the GPGI. The family/children score on
the semi-structured interview shows a moderate and significant correlation (0.361) with
family/children as indicated in the GPGI. As with the score for material well-being, the
family/children score from the semi-structured interviews shows a moderate but significant
correlation (0.232) with the material well-being score as indicated on the GPGI.
3.4 Quantitative Validation: Criterion Validity
Assessing criterion validity (i.e., the extent to which a new measure correlates with established
measures of the concept under study) is problematic in the absence of a gold standard measure
of individual quality of life in developing countries (Cummins, 2007). However in Ethiopia it
was possible to correlate GPGI scores with scores on the five items of the Satisfaction with Life
Scale (SWLS), an established measure of a related concept. The GPGI shows weak to moderate
but statistically significant correlations with four items ranging from 0.202 to 0.351. No
correlation is observed between the GPGI and the item ‘‘I would change nothing in my life.’’
The SWLS item that is conceptually closest to the GPGI, ‘‘My life is close to my ideal,’’ shows
the strongest correlation.
3.5 Quantitative Validation: Construct Validity
Construct validity has been defined as ‘‘the extent to which a new measure is related to specified
variables in accordance with an established theory or hypothetical construct’’ (Streiner
and Norman, 1995). Two of the authors have recently proposed a general theory that both defines
individual quality of life and explains its relationship to key causal determinants (Ruta et al., 2006).
According to the theory, indicators of material well-being and indicators of health demonstrate
a positive linear relationship with individual quality of life until a certain level is reached –
described here as the ‘‘basic capability threshold.’’ Beyond this basic capability threshold,
further marginal increases in levels of material well-being and health will give rise to rapidly
diminishing marginal increases in quality of life. Accordingly the following validity hypotheses
were tested:
1. GPGI scores show a positive linear or curvilinear relationship with material well-being and
health scores (including health of family members) derived from semi-structured inter-
views
Yes, slight curvilinearity at higher levels
2. Poor respondents in Bangladesh and Southern Thailand have lower quality of life scores
than rich respondents
Yes (55.7% vs. 65.4%, p < 0.01)
3. Rural respondents from Ethiopia have a lower quality of life than urban respondents
Yes (55.9% vs. 65.1%, p < 0.05)
Further construct validity tests of the relationship between GPGI Index scores and other
respondent characteristics such as education were conducted; for example, there was a
significant difference in GPGI scores between respondents who had completed further or
higher education and everyone else (67.8% vs. 58%, p < 0.05).
SPSS stepwise regression was used with specified independent variables to model the
relationship between the GPGI and the variables identified above. This demonstrated that
only material wellbeing (as indicated in respondents’ semi structured interviews) and ‘‘country’’
remained in the model. Together they were able to explain over 21% of the variation in
respondents’ GPGI scores.
Of 40 respondents explicitly mentioning religion as an important area in their GPGI,
34 were from Ethiopia. We were therefore able to test the hypothesis that Ethiopians who
mentioned religion in their GPGI (n = 34) had higher quality of life scores than Ethiopians not
mentioning religion in their GPGI (n = 82). While those mentioning religion had a slightly
higher mean score (61.9% vs. 59.2%), this was not significant.
3.6 Qualitative Validation: Method
The qualitative validation used the data from the semi-structured interviews to explore
content validity, aiming to establish whether (1) the area nominated in the GPGI appeared
as an area of importance in the semi-structured interview; (2) whether the way the area was
discussed in the semi-structured interview suggested that the appropriate number of points
had been allocated to indicate its importance; (3) whether the respondent’s satisfaction with
this area appeared to be adequately represented by their GPGI score; (4) whether there were
areas in the semi-structured interview that appeared to be even more important to the
respondent, but were not nominated in the GPGI; and (5) whether the overall picture given by
the semi-structured interview of the extent to which the respondent’s reality met their
expectations corresponded with the total score given in the GPGI.
Any problems with scoring or spending points were also noted (e.g., where the number of
points spent failed to add up to ten), although these may have been due to administrator
rather than respondent error. For example, some administrators appear to have asked respon-
dents to rank the areas, rather than spend points, as this a method commonly used in
participatory research.
3.7 Qualitative Validation: Results
In the Ethiopian sample, a content analysis of 21 responses to the three steps of the GPGI, and
comparison with the content of semi-structured interviews, revealed a close correspondence
between the two sources for eight respondents (four female and four male, aged from 19 to
76 years). In each case, the life areas nominated in the GPGI were mentioned several times in
the corresponding semi-structured interview and few if any additional areas were emphasized
within the semi-structured interview that did not appear in the GPGI. There appeared to be a
good match between the extent to which respondents felt their reality met their expectations
for each GPGI nominated area, as measured in step two of the GPGI, and the content of the
semi-structured interview. The relative importance attached to each GPGI nominated life area,
as indicated in the points spent in step three of the GPGI, was also consistent with the
interview content. A further 16 responses were content analyzed for Thailand, and another
16 for Bangladesh, sampled according to gender, type of site, region (Thailand), and age
(Bangladesh). In Thailand only five responses showed close correspondence, although the
majority of discrepancies were minor. The picture was slightly better in Bangladesh where nine
respondents showed close correspondence.
The majority of the Ethiopian sample (13 of 21 respondents) did not show the same degree
of consistency between the content of the GPGI and the semi-structured interview. Analysis
suggested three broad levels of inconsistency: errors in GPGI completion that appear to arise
from a basic lack of comprehension on the part of respondents or interviewers; minor
inconsistencies between one GPGI nominated area and the GPGI; and major inconsistencies
where discrepancies were identified between two or more life areas, or where the semi-
structured interview raised questions about the validity of a respondent’s overall quality of
life index score as measured by the GPGI.
The exercise generated responses consistent with those collected in participatory research
in developing countries, particularly studies that focus on people’s conceptions of wellbeing
or poverty (e.g., Narayan et al., 2000). The most mentioned area across the three countries
in the WeD sample (n = 242) was Health, however, this was partly due to its popularity in
Ethiopia which accounted for 62% of the responses. The second was Money, assets, which was
also the main priority in Thailand, accounting for 17% of the responses (78% item frequency).
Children was the third most mentioned area, and featured in every country’s ‘‘top five,’’ with
Bangladesh also prioritizing Children’s education/future. The fourth was Home, which was very
important in Thailand (11.5% of respondents), and fairly important in Ethiopia (5.5%). Fifth
and sixth most mentioned areas were Employment and Family. Both of these areas were
important in Thailand (to 9.8 and 9.3% of respondents respectively), with Employment
also important in Ethiopia (third priority, 6.9% of respondents) and Family in Bangladesh
(second priority, 7.4% of respondents). Where the GPGI is less successful is in capturing areas
that are abstract, or personal, and thus difficult to capture in a few words, e.g., ‘‘own boredom
and lack of fulfillment.’’ It also fails to represent potentially shameful areas such as debt or
mental health problems, and is slightly biased towards the normative, i.e., areas that are
universally acknowledged as important, rather than areas that are ‘‘just’’ important to the
respondent.
4 Conclusions Regarding the Usage of PGI and GPGI
The conclusions concerning the PGI and GPGI measures are broken down into four areas: the
issue of whether individuals’ scores can be compared; the challenges posed by weighting areas
of life by their perceived importance; the advantages of the measures; and the disadvantages.
It must be made clear at this point that the psychometric properties of the ‘‘Global Patient
Generated Index’’ require further investigation and that the English version has not yet been
validated.
4.1 Comparing Scores Between Individuals
The most common criticism of individualized scores is that inter-individual comparisons are
impossible if respondents are not all rating the same items. Parducci responds to this in his
discussion of the different nature of pleasant experiences where he acknowledges that while a
cold drink on a hot day is dissimilar to a reciprocated love, both are the result of a
‘‘pleasantness judgment’’ and therefore comparable to some extent (Parducci, 1995, p. 29).
In the same way, if one respondent to the PGI chooses to evaluate ‘‘my health,’’ ‘‘having a high
income’’ and ‘‘being fashionable,’’ they are making a judgment about the state of the areas that
are important to their QOL, which is comparable to another respondent’s evaluations. This is
true even if the content is as different as ‘‘coping with their feelings of grief,’’ ‘‘having a nice
home’’ and ‘‘staying in touch with their friends’’ as the overall evaluation is of the state of the
areas that are important to QOL. Whether the lack of a comparison of ratings on the same
domains is a problem depends upon the purpose of the QOL measure. If the ratings of cancer
patients of their psychological and physical health are to be compared to the ratings of healthy
patients on these domains, then clearly an individualized approach presents difficulties.
However, if the interest is in global perceptions of quality of life, perhaps over time, then an
individualized approach provides the necessary data.
4.2 Weighting QOL Scores by Importance
Whilst weighting QOL scores by the perceived importance of the area has been criticized on
statistical grounds (e.g., Trauer and MacKinnon, 2001), comparisons of weighted and un-
weighted QOL scores on the ‘‘PGI’’ suggests that there is no evidence that weighting adversely
affects reliability (Ruta et al., 1994). PGI scores derived solely from the ‘‘satisfaction’’ ratings
(ratings of the current state of important areas of life compared to the participant’s ideal state)
achieved a test-retest correlation of 0.75 (p < 0.001) and the importance weighted index scores
achieved 0.70 (p < 0.001), in both cases using respondents indicating no change in health
status over time. Similar results have been reported elsewhere, with a slight (although probably
non-significant) increase in reliability when the > weighted scores were used (Macduff and
Russell, 1998). As such, weighting by importance cannot be seen as a weakness of the measure
in statistical terms.
4.3 Advantages of the Measures
The advantages of the recent expansion of the PGI into the GPGI, and the extension of its use to
developing countries, are firstly that people like it. Both respondents and researchers enjoyed
using the measure (e.g., Bevan et al., 2003) and praised the fact that it was flexible and person-
centered and in many ways resembled the participatory methods more commonly used in
development research (White and Pettit, 2005). Secondly, the measure can produce genuinely
new information, especially if it is then used as the basis for further discussion (e.g., by asking
respondents to reflect on GPGI areas and scores provided on a previous occasion). Thirdly,
it provides a direct operationalisation of the popular gap theory of quality of life (Calman,
1984), which is experiencing a renaissance due to a growing interest in social comparison and
adaptation on the part of economists. Fourthly, it works well cross-culturally, if sensitively
translated and carefully piloted. It has also been with used with a more representative sample of
the population than is normally the case for cross-cultural validation. Finally, even with the
addition of an appraisal schedule or brief contextual interview, it is quicker to administer than a
semi-structured interview, albeit more time-consuming than a conventional measure.
4.4 Disadvantages of the Measures’ Approach
The PGI and GPGI have some disadvantages, although arguably many of these apply to all
attempts to capture people’s quality of life, whether quantitative or qualitative. Firstly, even
categories as apparently straightforward as family are difficult to interpret accurately without
an accompanying interview or appraisal schedule and for this reason it can appear to only elicit
normative responses. Secondly, the measure is sensitive to framing and context; for example,
the translation of important as ‘‘crucial’’ or ‘‘needed’’ in the Ethiopian pilot and the fact that
much research in Ethiopia is conducted by Non-Governmental Organizations elicited what the
team ironically called ‘‘development-related quality of life’’ (Bevan et al., 2003). Thirdly, even
rating satisfaction proved challenging for some respondents. Therefore administration requires
skilled and patient interviewers as the method of allotting points to indicate importance is
difficult to explain, especially to older and less educated respondents. The standard sample for
psychometric validation world-wide is psychology undergraduates; as such the challenges of
using QOL measures with other populations are rarely seen during measurement validation.
However, QOL measures are now being used with different populations for different purposes –
necessitating their validation with these groups. Nonetheless, the GPGI proved popular and
effective when used in developing country contexts and provides a means of evaluating
development interventions. It raises a further question as to whether a new model of validation
should be considered that expands conventional understandings of validity to foreground the
accuracy with which the measure has represented the respondent’s world view.
Summary Points
Individualized measures assume that quality of life is determined by the gap between
people’s expectations and experiences.
As ‘‘universal’’ items are not equally valued, individualized measures ask respondents to
nominate the areas they consider important and assess their performance against their own
standards.
The PGI has been used in a range of healthcare settings and proved valid and reliable for
group comparisons (Martin et al., 2007).
It was developed into a measure of general quality of life, the GPGI, which has been
successfully translated into more than five world languages.
References
Ahmed SM, Mayo NE, Wood-Dauphinee S, Hanley JA, Griffiths R, Jayasuriya R, Maitlandv H. (2000). Aust N Z J
Cohen SR. (2005). Qual Life Res. 14: 2247–2257. Public Health. 24(5): 529–535.
Bevan P, Kebede K, Pankhurst A. (2003). A Report on a Hensel E, Rose J, Kroese BS, Banks-Smith J. (2002).
Very Informal Pilot of the Person Generated Index J Intellect Disabil Res. 46(2): 95–107.
of Quality of Life in Ethiopia (unpublished report Herd RM, Tidman MJ, Ruta D, Hunter JAA. (1997). Br J
for the ‘‘Wellbeing in Developing Countries Dermatol. 136: 502–507.
Research Group’’ at the University of Bath, UK). International Wellbeing Group. (2006). Personal Well-
Bowling A. (1995). Soc Sci Med. 41(10): 1447–1462. being Index, 4th ed. Australian Centre on Quality
Bradley C, Todd C, Gorton T, Symonds E, Martin A. of Life, Deakin University, Melbourne (http://
(1999). Qual Life Res. 8: 79–91. www.deakin.edu.au/research/acQOL/instruments/
Callaghan BG, Condie ME. (2003). Clin Rehabil. wellbeing_index.htm.).
17: 858–864. Jongudomkarn D, Camfield L. (2006). Soc Indic Res.
Calman K. (1984). J Med Ethics. 10: 124–127. 78: 489–529.
Camfield L, Ruta D. (2007). ‘‘Translation in Not Enough": Lindblad AK, Ring L, Glimelius B, Hansson MG. (2002).
Using the Global Person Generated Index (GPGI) Acta Oncologica. 41(6): 507–516.
to Assess Individual Quality of Life in Bangladesh, Macduff C, Russell E. (1998). Qual Life Res. 7: 761-769.
Thailand, and Ethiopia. Quality of Life Research, 16 Martin F, Camfield L, Rodham K, Kliempt P, Ruta D.
(6): 1039–1051. (2007). Qual Life Res. 16(4): 705–715.
Cummins RA. (1995). Soc Indic Res. 35: 179–200. McGee H, et al. (1991). Psychol Med. 21: 749–759.
Cummins RA, Gullone E. (2000). Why we should not use Mitchell J, Bradley C. (2004). Qual Life Res. 13:
5-point Likert scales: The case for subjective quality 1163–1175.
of life measurement. In Proceedings of the Second Narayan DR, Chambers R, Shah MK, Petesch P. (2000).
International Conference on Quality of Life in Voices of the Poor: Crying out for Change.
Cities. National University of Singapore, Singapore, Oxford University Press for the World Bank,
pp. 74–93. New York.
Dempster M, Donnelly M. (2000). Qual Life Res. O’Boyle A, Browne J, Hickey A, et al. (1995). SEIQOL
9: 369–375. Administration Manual. Department of Psychology,
Diener E, Emmons RA, Larsen RJ, Griffin. (1985). J Pers Royal College of Surgeons of Ireland, Dublin.
Assess. 49(1): 71–75. Parducci A. (1995). Happiness, Pleasure, and Judgment:
Ferrans CE, Frisch M. (2004). The Importance of Impor- The Contextual Theory and Its Applications. Lawr-
tance: Why Weight Life Satisfaction. Paper Pre- ence Erlbaum Associates, Hove.
sented at the Advancing Quality of Life in a Ruta D, Camfield L, Donaldson C. (2006). Sen and the
Turbulent World, International Society for Quality Art of Quality of Life Maintenance: Towards a
of Life Studies, Philadelphia, PA. Working Definition of Quality of Life. Wellbeing in
Developing Countries (WeD) Research Group Streiner D, Norman G. (1995). Health Measurement
Working Paper. Available at: http://www.bath.ac. Scales: A Practical Guide to Their Development
uk/econ-dev/wellbeing/research/workingpaperpdf/ and Use. Oxford University Press, Oxford.
wed12.pdf. Symon A, MacKay A, Ruta D. (2003). J Adv Nurs. 42(1):
Ruta DA, Camfield L, Martin F. (2004a). Qual Life Res. 21–29.
13: 1545. Tovbin D, Gidron Y, Jean T, Granovsky R, Schnieder A.
Ruta D, Garratt AM, Leng M, Russell IT, MacDonald LM. (2003). Qual Life Res. 12: 709–717.
(1994). Med Care. 32(11): 1109–1126. Trauer T, MacKinnon A. (2004). Qual Life Res. 10(7):
Ruta D, Martin F, Camfield L, Devine J, Bevan P. (2004b). 579–585.
Assessing Individual Quality of Life in Developing Tully MP, Cantrill JA. (2002). J Health Serv Res Policy.
Countries: Piloting a Global PGI in Ethiopia and 7(2): 81–89.
Bangladesh. Paper presented at the International Ware JE, Sherbourne CD. (1992). Med Care. 30: 473–483.
Society for Quality of Life Research: Harmonizing Weitzenkamp DA, Gerhart KA, Charlifue SW, Glass CA,
International Health-Related Quality of Life Whiteneck GG. (2000). Br J Health Psychol. 5:
(HRQOL) Research, Hong Kong. 57–69.
Skevington SM, Bradshaw J, Saxena S. (1999). Soc Sci White S, Pettit J. (2005). Participatory approaches and the
Med. 48: 473–487. measurement of human wellbeing. In: McGillivray M
Sprangers MA, Schwartz CE. (1999). Soc Sci Med. 48: (ed.) Measuring Human Wellbeing. WIDER/Oxford
1507–1515. University Press, Oxford, UK.
4 The Total Illness Burden
Index
S. Greenfield . J. Billimek . S. H. Kaplan
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
2 Structure and Scoring of the TIBI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

2.1 Constructing the Dimensions of the TIBI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
2.2 Computing Raw Dimension Scores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
2.3 The Global Severity of Illness Measure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3 The Predictive Ability of the TIBI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

74 4 The Total Illness Burden Index
Abstract: The Total Illness Burden Index is a comprehensive summary measure of case mix or
> severity of illness that aggregates all of the patients’ conditions, problems, and diseases,
weighting them by their severity. The TIBI offers advantages over other methods of case mix
measurement because it (1) is based on clinical information beyond the simple presence or
absence of specific diagnoses, (2) is scored using a psychometric approach that avoids reliance
on any single variable, (3) predicts health related quality of life and mortality events five or
more years in the future, (4) is feasible, utilizing patient report over administrative data while
requiring less than 15 minutes to complete, and (5) can be adapted based on the clinical
context to assess > comorbidity with respect to a selected index condition, or to assess total
morbidity from all of the patient’s conditions.
These features allow the measure to be applied in clinical settings among patients facing
real-time treatment decisions and for risk adjustment in research on a wide range of medical
outcomes.
List of Abbreviations: ANOVA, analysis of variance; APACHE II, Acute Physiology and
Chronic Health Evaluation II; CP, cardiopulmonary; HRQOL, health-related quality of life;
SF-36, Medical Outcomes Study Short Form, a measure of health-related quality of life; TIBI,
Total Illness Burden Index; TIBI-CaP, Prostate cancer version of the Total Illness Burden Index
1 Introduction
The Total Illness Burden Index (Greenfield et al., 1995; Litwin; et al., 2007) is a comprehensive
summary measure of severity of illness that aggregates all of the patients’ conditions, pro-
blems, and diseases, weighting them by their severity. The instrument is a reliable predictor of
health-related quality of life (HRQOL) (Greenfield et al., 1995; Litwin; et al., 2007) and
mortality (Greenfield et al., 1995; Litwin et al., 2007) that can be used both in clinical practice,
primarily office-based practice, and in medical outcomes research.
The definitions of severity of illness, appropriate data sources for its determination, and
the analytic methods for assembling severity of illness measures used in health outcomes
research have varied widely (Iezzoni, 2003). ‘‘case mix’’, ‘‘patient mix’’, ‘‘disease severity
assessment’’, ‘‘risk adjustment’’ and ‘‘comorbidity assessment’’ all have been used to describe
measures that array patients on a continuum of extent of total disease burden. Most of these
measures have been developed to assess differences in utilization of health care services, or
differences in mortality (Fortin et al., 2006; Hudon et al., 2005; Perkins et al., 2004; Tooth
et al., 2008). Most are based on physician-reported diagnosis from claims databases or
from medical records, and include only selected major diseases or conditions (Crabtree
et al., 2000).
Several diagnosis-based measures have been developed for reimbursement purposes in
outpatient settings (Charlson et al., 1987; Pearte et al., 2006; Perkins et al., 2004), but these
measures often do not represent the severity and therefore the prognosis of the condition, and
further, are often not readily available at the time of decision-making. Summary measures of
patient-reported HRQOL have been shown to predict mortality but are based on variables
with which clinicians are less comfortable than the review of systems variables that they
routinely collect (Min et al., 2007; Saliba et al., 2001). Most available measures of comorbid-
ities are only available after treatment and have been used primarily to adjust group differences
(Charlson et al., 1987; Greenfield et al., 1993).
The Total Illness Burden Index 4 75
In response to these shortcomings, the TIBI was developed as a patient-reported measure

of comorbidity based on items akin to the traditional review of systems that patients regularly
respond to when queried by their physicians. The instrument represents an approach to case
mix or severity of illness measurement that is unique in five major ways.
First, the TIBI is based on clinical information (symptoms and events) beyond diagnosis,
addresses not only the presence but the severity of the patient’s conditions, independent of the
many specific diagnoses a patient may have. In this regard, it closer to the APACHE II (Knaus
et al., 1985) than to diagnosis-based instruments; however, in contrast to APACHE, it does not
rely on a small number of non-specific variables, such as hemoglobin, representing end stage
systemic breakdown. Second, it is scored and summarized using a psychometric approach that
avoids reliance on any single variable, because single variables are inherently unreliable. It is
constructed to reflect empirical confirmation of clinically defined scales, with special attention
to analytic techniques that compensate for missing data, unreliability of clinical information,
and interactions between variables. Third, it is aimed not at a short term time span, such as
one month or one year, but on the more distant future, three to five years or longer. Fourth,
the measure is feasible, although more time consuming and expensive than those indexes
derived from administrative data, and the data can be collected in an office practice, without
access to information that needs to be gathered from the medical record or administrative data
sources. Fifth, it is flexible in its use. Dimensions of illness can be added or removed based on
the context. In addition, although it is most often used to measure comorbidity in relation to
an index condition, when that index condition is included among the dimensions, it becomes
a measure of total morbidity, or ‘‘> multimorbidity’’.
In this chapter, we describe the structure and scoring of the TIBI, and provide data to
support its reliability and validity. Then we will return to the characteristics described above so
that a user may be able to compare instruments and approaches.
2 Structure and Scoring of the TIBI
The TIBI was developed as a battery of over 100 items reflecting illness severity for 15
‘‘dimensions’’, or sets of diseases or conditions, grouped by body system to assess comorbidity
in type 2 diabetes patients (Greenfield et al., 1995). From this initial battery, we can modify the
instrument to fit the clinical context, as we have done, for example, to assess for prostate
cancer 11 dimensions of comorbidity with 84 patient reported items (Litwin et al., 2007; Stier
et al., 1999). Below, we describe how the dimensions were (1) constructed, (2) scored and
(3) aggregated to compute a global severity of illness score.
2.1 Constructing the Dimensions of the TIBI
Construction of the TIBI began with physicians, working independently, specifying the
relevant variables (mostly symptoms, with some diagnoses) that should be included in a
questionnaire to reflect the most common diseases, disease manifestations, or conditions
within each body system that would be likely to affect patients’ functional outcomes or
mortality over the next 3–5 years. Item content was revised based on physician consensus
and on survey research principles. Each dimension was then scored on a clinical basis,
and modified after the data were collected. For example, the items for chronic lung disease
include: orthopnea requiring extra pillows, frequency of shortness of breath while performing
various activities, amount of cough and volume of sputum production, and numbers of
episodes of bronchitis and flu in the past 6 months.
For different uses, we have added, deleted, or combined dimensions to fit the medical
context. However, the items reflecting the traditional review of systems variables, within each
dimension, are stable and basic to the predictive accuracy of the instrument. First, dimensions
reflecting the index disease should be deleted so that the instrument only includes true
comorbid conditions. Second, dimensions reflecting previously unmeasured comorbidities
(e.g., conditions that were the index disease in prior versions) can be added. Finally, the
instrument can be shortened by deleting whole dimensions based on clinical input, low
relevance, or poor scaling with outcome variables of interest, or by aggregating dimensions
for which the symptoms overlap, when supported by data analysis. In any given situation,
deletion or modification of dimensions could be justified by using analyses which removed a
dimension and then recalculated the explained variance in one or more key dependent
variables with and without that dimension.
As an example, we modified the original TIBI to produce a version measuring 11 dimen-
sions of comorbidity in prostate cancer patients. This version, called the TIBI-CaP was created
by adding and deleting selected items to represent prostate cancer as the index condition based
on results from a pilot study (Stier et al., 1999). Changes in the constituent dimensions of the
two versions are outlined in > Table 4-1.
Renal disease and genitourinary problems were dropped from the TIBI-CaP because they
were closely related to the index condition of prostate cancer. Diabetes, on the other hand,
which was the index condition in the original TIBI was now added as a possible comorbid
condition in the TIBI-CaP. A dimension for other cancers, excluding prostate, was also added
. Table 4-1
Individual Body System Disease Measures of the original TIBI and the TIBI-CaP
The Original TIBI (type 2 diabetes) TIBI-CaP (prostate cancer)

Hearing problems Hearing problems
Eye and vision conditions Eye and vision conditions
Hypertension Hypertension
Foot disease Foot disease
Atherosclerotic heart disease Atherosclerotic heart disease
Stroke and neurological disease Stroke and neurological disease
Arthritis Arthritis
Renal disease Other cancers (excluding prostate)
Genitourinary problems Diabetes
Chronic lung disease Cardiopulmonary disease
Congestive heart failure
Gastrointestinal autonomic neuropathy Gastrointestinal conditions
Lower gastrointestinal disease
Upper gastrointestinal disease
Nonspecific bowel disease
because cancers frequently spread to multiple body systems. Because shortness of breath was a
symptom shared by chronic lung disease and congestive heart failure, these two dimensions
were combined to form a single dimension called cardiopulmonary disease. Similarly, items
from gastrointestinal autonomic neuropathy, lower gastrointestinal disease, upper gastroin-
testinal disease and nonspecific bowel disease were combined into a single dimension of
gastrointestinal conditions.
In addition to allowing researchers to define comorbidity in the most clinically relevant
way in terms of an index condition, the ability to modify the instrument improves its
feasibility by allowing unneeded items and dimensions to be pared away. It is usually estimated
in survey research that a person can respond to about six items per minute, so that it takes 12
or so minutes for a patient to complete the TIBI-CaP. Because prior analyses have shown that
each of the dimensions in the versions studied so far has correlates closely to various
dimensions of HRQOL measured with the Medical Outcomes Study Short Form 36 (SF-36;
Stewart et al., 1988), it may be hard to reduce the instrument to less than 50 or so items and
retain its strong predictive capacity.
2.2 Computing Raw Dimension Scores
Physicians, working as a group, classified patient responses across items within each question
(i.e., disease manifestations, symptoms) into multiple ordinal scale points reflecting severity
levels. The scoring system for the cardiopulmonary (CP) dimension of the TIBI-CaP is
presented in > Table 4-2 as an example.
The CP dimension score can increase by one point if a patient has ever been told by a
physician that they have had one or more of the following conditions: emphysema, chronic
bronchitis, or asthma. An additional one to three points can be added based on the frequency
of any of the following symptoms: pneumonia, bronchitis (for which the patient took
antibiotics) or flu (with coughing). Another point is added if the patient uses extra pillows
at night because of breathing problems. One or two additional points can be added based on
the reported volume of sputum coughed up in a typical day. A report of frequent wheezing
adds another point to the CP score. And finally, the frequency and causes of shortness of
breath can be interpreted to add another one, three or five points to the CP score. Using this
scoring scheme, a patient’s CP dimension score can range between zero and thirteen.
For CP and the other dimensions, there were multiple ways to reach each level, thus
minimizing misclassification due to missing or unreliable responses. Using this technique,
physicians created clinically defined severity scales using diagnoses and symptoms for each of
the different diseases or conditions, considered separately.
2.3 The Global Severity of Illness Measure
We then constructed a composite, global, or summary measure by aggregating the individual

dimensions of the TIBI into a single score. First, clinicians ranked each disease or condition
grouped by body system as having minimal, moderate, or severe impact on functional out-
comes in an ambulatory population. For the TIBI-CaP, those diseases or conditions clinically
defined as having minimal negative impact on functional outcomes in prostate cancer patients
. Table 4-2
Computing the raw score for the Cardiopulmonary (CP) Dimension of the TIBI-CaP
included vision, hearing loss, diabetes, and hypertension. Diseases or conditions classified as
having moderate negative impact on functional outcomes included foot disease and arthritis.
Other cancers, GI conditions, atherosclerotic heart disease and cardiopulmonary disease were
classified as having the greatest negative impact on functional outcomes.
In order to weight the dimensions differentially, those considered to have the greatest
clinical impact on illness burden were stratified, based on clinical judgement, into 4 severity
levels (0–3 points), those with intermediate impact into 3 severity levels (0–2 points), and
those with the least impact into 2 severity levels (0–1). The raw dimension scores were then
recoded into these severity levels using clinically defined cutpoints.
The severity level cutpoints for each dimension were then validated using analysis of
variance (ANOVA) to compare scores on the Physical Functioning and Role Physical subscales
of the SF-36 across the severity levels of each dimension. For every dimension of the original
TIBI and the TIBI-CaP, patients falling into higher levels of severity reported worse HRQOL at
the time the TIBI was administered. This same association between severity levels and HRQOL
persisted for patients completing the SF-36 six months after completing the TIBI-CaP
(> Table 4-3). In addition to validating the clinically defined cutpoints for the severity levels,
these analyses support the modular structure of the instrument because each dimension
independently predicts HRQOL.
The severity levels for all the dimensions were summed to create the global score for the
TIBI. The TIBI-CaP global score, for example, could theoretically range from 0 to 23, but the
actual scores measured in our sample ranged from 0–18 with a mean of 3.5 (SD=2.6) and a
median of 3.
The amount of missing data was small – no items had more than 10% missing, and 78 of
the 84 items had less than 4% missing. For those dimensions with 1 or more items missing, the
dimension score was computed on the completed items based on the scoring rules. For
presentation purposes, we collapse the global TIBI scores into five levels with 3-point intervals
from least severe (scores of 0–2) to most severe (scores of > 12).
. Table 4-3
SF-36 Health-related quality of life scale scores at 6-month follow up by severity levels of the
dimensions of the TIBI-CaP, mean (SD)*
Physical Functioning Role Physical

TIBI-CaP Dimension Points N Mean (SD) Mean (SD)
Cardiopulmonary
0 1961 86 (18) 80 (34)
1 490 72 (25) 58 (42)
2 291 62 (28) 48 (43)
3 66 50 (31) 30 (40)
Atherosclerotic heart disease
0 1312 83 (22) 78 (36)
1 1439 79 (23) 71 (39)
2 162 68 (28) 49 (44)
3 87 57 (28) 35 (39)
Stroke/neurologic
0 2606 81 (23) 74 (38)
1 221 75 (25) 62 (43)
2 120 65 (28) 51 (44)
3 23 41 (24) 27 (39)
GI conditions
0 2321 83 (22) 76 (37)
1 454 72 (26) 60 (42)
2 105 64 (29) 42 (43)
3 30 60 (29) 33 (43)
Other cancer
0 2559 81 (23) 74 (38)
1 241 75 (23) 61 (42)
2 95 70 (27) 50 (44)
3 34 60 (31) 45 (46)
Arthritis/joints
0 1689 86 (20) 81 (34)
1 1191 73 (25) 61 (42)
2 94 54 (30) 35 (42)
Feet
0 2390 83 (21) 76 (36)
1 309 72 (24) 58 (43)
2 209 55 (29) 39 (42)
Eyes/Vision
0 1743 84 (21) 78 (36)
1 1230 73 (26) 63 (42)

TIBI-CaP Dimension Points N Mean (SD) Mean (SD)
Hearing
0 1510 84 (22) 79 (35)
1 1458 75 (25) 64 (42)
Hypertension
0 2773 80 (23) 73 (39)
1 227 70 (27) 57 (43)
Diabetes
0 2516 81 (22) 74 (38)
1 445 70 (27) 58 (43)
*p<.0001 for all dimensions in table
Even though we originally developed and tested these measures among patients with type
2 diabetes, the inclusiveness of the multiple body system approach makes it generalizable to
most outpatient groups. Though the selection and weighting of each of the disease dimensions
may change for different study diseases, the integrity of this approach for generalized applica-
tion would not alter the item content and scoring of the individual disease severity measures.
3 The Predictive Ability of the TIBI
The TIBI has been used in a number of studies (Hayward et al., 1997; Hofer et al., 1999;
Nicolucci et al., 2000) as covariates for adjustment of outcomes. In four studies, it has been
tested for its capability of predicting various outcomes including HRQOL, cardiovascular
events and mortality (Greenfield et al., 1995, 2008; Litwin et al., 2007; Stier et al., 1999). In the
original validation study, the TIBI was shown to be associated with HRQOL as measured by
the SF-36. The diminution in physical functioning, which tracks best with disease (Stewart
et al., 1988), was large for each increasing level of severity on the global TIBI measure, and
statistically significant, usually at least a third or greater of a standard deviation. The Stier et al.
(1999) study confirmed these results in a study of patients with prostate cancer. In both of
these studies, the data on HRQOL was collected at the same time as the TIBI, in the same
questionnaire.
As was observed with the individual dimensions, the global TIBI-CaP score also predicts
HRQOL longitudinally (Litwin et al., 2007). Among the 2,607 men who completed the health
status questionnaire 6 months following the administration of TIBI-CaP, as the aggregate
TIBI-CaP level increased, mean scores in both physical functioning and role-physical limita-
tions worsened (> Table 4-4). Each increasing category of the aggregate TIBI-CaP had a
correspondent statistically significant decrease in levels of physical function and role-physical
scores compared to the adjacent category.
With TIBI-CaP treated as a continuous variable, we examined its contribution to variation
in the subdimensions of the SF-36, compared with sociodemographic characteristics
alone (> Table 4-5). A model including the TIBI as a covariate alongside sociodemographic
. Table 4-4
SF-36 Health-related quality of life scale scores at 6-month follow up by severity levels of
TIBI-CaP, mean (SD)*

TIBI-CaP Global Score n Mean (SD) Mean (SD)
0–2 1074 91 (13) 89 (25)
3–5 1026 80 (21) 71 (38)
6–8 378 65 (26) 47 (42)
9–11 94 51 (27) 31 (39)
12+ 33 35 (18) 10 (23)
ANOVA p-value and group differences <0.0001* <0.0001*
*Tukey standardized range test for multiple comparisons reveal that all means across all TIBI categories are
different from each other
. Table 4-5
Relationship between TIBI-CaP, sociodemographic characteristics and SF-36 subdimensions
(n=2607)}
SF-36 Physical function SF-36 Role physical

Regression model Variables R2 F-value& R2 F-value
1 Age, education, income, 0.16 N/A 0.11 N/A
race/ethncity
2 Age, education, income, 0.35 756.2* 0.28 585.4*
race/ethnicity, TIBI-CaP
*p<.001
}
Table entries are variance explained (R2) in each of the SF-36 subdimensions separately by variables listed in
regression models 1 and 2
&
Values from F-tests comparing model 2 to model 1
characteristics model explained significantly more variation in both HRQOL measures than a
model including sociodemographic characteristics alone.
The study by Litwin et al. (2007) also demonstrated the ability the TIBI to predict future
mortality. Of the 2,894 participants followed for 3.5 years after administration of TIBI-CaP
questionnaire, 135 died from causes other than prostate cancer (median 1.4 years, range
18 days to 38 months). Of these 135, over 60% died from cardiovascular or pulmonary
disease, or from other cancers and infections; the remainder died from a wide variety of
causes. These patients constituted the group of interest when making treatment decisions.
Twenty-six patients died of prostate cancer or its complications and were therefore censored at
their time of death. In the Cox proportionate hazards models (> Table 4-6), TIBI-CaP was
significantly related to mortality, after controlling for age, education, income and race/
ethnicity (hazard ratio 13.1, 95% (C1 = 6.3–27.4). Men with global TIBI-CaP scores of 12
or higher were 13 times more likely than those with scores of 0–2 to die in this period of causes
other than prostate cancer.
> Figure 4-1 shows the Kaplan-Meier survival graph for the men who died of non-prostate
cancer causes. By 3.5 years, 56% (95% CI: 12–85%) of those with a global TIBI-CaP score of 12
or higher had survived compared with 95% of those with a score of 0–2 (p<0.0001). These
mortality rates were not due to cardiac disease and other cancers alone.
A similar pattern of results was found in diabetes patients in the most recent study, to be
presented at the national ADA meeting in San Francisco in June 2008 (Greenfield et al., 2008).
. Table 4-6
Mortality rates and hazard ratios for aggregate TIBI-CaP1 (n=2984)
TIBI-Cap score§ n N of deaths& 3.5 yr survival (%) (95% CI)# Hazard ratio¥ (95% CI)
0–2 1177 24 95.1 (85.5–98.4) –§§
3–5 1133 48 90.4 (80.8–95.3) 1.6 (1.0–2.7)
6–8 427 38 89.8 (83.3–93.9) 3.1 (1.8–5.2)
9–11 114 14 84.3 (67.0–93.0) 4.7 (2.4–9.1)
≥12 43 11 56.1 (12.1–85.4) 13.1 (6.3–27.4)
§
Scores range from least severe (0–2) to most severe (12+) aggregate co-morbidities
&
Deaths due to a cause other than prostate cancer
#
Calculated using life table analysis. Median follow-up time for survivors was 2.7 years
¥
Calculated using Cox proportional hazards model adjusting for age, education, income, and race/ethnicity
§§
Reference group for comparisons
. Figure 4-1
That study, being prepared for publication, shows that TIBI at baseline predicts new cardio-
vascular events and mortality 5 years later, after controlling for hemoglobin A1c, blood
pressure, and cholesterol, in addition to age, gender and socioeconomic status.
4 Conclusions
Accurate assessment of comorbidity is crucial to the selection and evaluation of therapy in
patients with chronic disease. The TIBI has been used as a feasible and systematic method for
assessing prognosis, taking into account a broad representation of the individual’s medical
conditions and their severity. Because this instrument is self-reported, it can be applied in
clinical settings among patients facing real-time treatment decisions. It can be scored from
data that are collected from patients at the time of the office visit, rather than often incomplete
and post hoc medical records or claims data, and made available to clinicians at the time of
treatment decisions.
The TIBI can make the traditionally implicit process of estimating the impact of comor-
bidity explicit. It is based on symptoms, such as graded levels of shortness of breath, that have
prognostic value independent of the exact underlying diagnosis. The aggregation of severity
across conditions is unique to this measure. A patient with shortness of breath while at rest, for
example, a productive cough, and a recent hospital visit for lung problems, is likely to have a
severe respiratory disease, regardless of the specific underlying diagnosis. This approach also
relies on historical information, such as myocardial infarction, which patients can remember
accurately. The combination of variables overcomes the potential unreliability of patient
report of any one symptom or event. The modular nature of the instrument allows dimensions
to be added, removed or modified based on the index condition and the intended use of
the data.
The TIBI measures the extent of total illness severity of a patient, defined primarily in
terms of the health outcomes of death and/or poor quality of life over the five or more year
period following initial measurement. It has been also used for other outcomes such as
utilization of services, and for shorter periods of time such as one year, but it is designed
and has been tested for identifying those patients who will experience poor health or die over
the next several years. The instrument is patient-reported, thus negating the need for chart
review or collecting administrative data from multiple sources in office practice. It is feasible,
taking between 10–12 minutes to complete, and does not rely on diagnosis or on single
variables. It can be shortened or lengthened depending on the context, and it can represent
comorbidity for an index condition, or total multimorbidity when the index condition is not
removed. It has shown to be highly accurate in its predictive capability, showing almost no
deaths in the lowest category to over 50% mortality in the highest, with good separation of the
middle groups. There is no other instrument that combines these features.
Summary Points
The TIBI (Total Illness Burden Index) measures the extent of total illness severity of a
patient, either as comorbidity with respect to an index disease excluded from the instru-
ment, or as ‘‘multimorbidity’’ including all diseases.
The instrument typically requires less than 15 minutes to administer and collects data on
the presence and severity of symptoms and events across body systems and disease types,
or ‘‘dimensions’’ of illness.
The modular nature of the instrument allows dimensions to be added, removed or
modified based on the index condition and the intended use of the data.
Both the individual dimension scores, and the global measure of total severity of illness
across all body symptoms predict health-related quality of life, cardiovascular events and
mortality.
The relationship between TIBI scores and patient outcomes is independent of sociodemo-
graphic characteristics.
The TIBI predicts patient outcomes cross-sectionally and longitudinally, at least out to five
years in the future.
The instrument may be applied in clinical settings to tailor treatment in real time, or for
risk adjustment in research on a wide range of medical outcomes.
References
Charlson ME, Pompei P, Ales KL, MacKenzie CR. (1987). Knaus WA, Draper EA, Wagner DP, Zimmerman JE.
J Chronic Dis. 40: 373–83. (1985). Crit Care Med. 13: 818–829.
Crabtree HL, CS; G, AJ; H, JE; OC, JB. (2000). J Am Litwin MS, Greenfield S, Elkin EP, Lubeck DP, Broering
Geriatr Soc. 48: 1674–1678. JM, Kaplan SH. (2007). Cancer 109: 1777–1783.
Fortin M, Bravo G, Hudon C, Lapointe L, Almirall J, Min LC, Wenger NS, Fung C, Chang JT, Ganz DA,
Dubois M-F, Vanasse A. (2006). Qual Life Res Higashi T, Kamberg CJ, MacLean CH, Roth CP,
15: 83. Solomon DH, Young RT, Reuben DB. (2007). Med
Greenfield S, Apolone G, McNeil BJ, Cleary PD. (1993). Care. 45: 480–488.
Med Care. 31(2): 141–154. Nicolucci A, Ciccarone E, Consoli A, Di Martino G,
Greenfield S, Nicolucci A, Pelligrini F, Billimek J, Kaplan La Penna G, Latorre A, Pandolfi A, Vitacolonna E,
SH, Preventing Cardiovascular Disease: Identifica- Capani F. (2000). Diabetes Nutr Metab 13: 276–283.
tion of Co-Morbidity Subgroups who may not Pearte CA, Furberg CD, O’Meara ES, Psaty BM, Kuller L,
Benefit from Aggressive Diabetes Management. Powe NR, Manolio T. (2006). Circulation 113:
68th Scientific Sessions of the American Diabetes 2177–2185.
Association, San Francisco, CA, 2008. Perkins AJ, Kroenke K, Unutzer U, Katon W, Williams
Greenfield S, Sullivan L, Dukes KA, Silliman R, JW, Jr., Hope C, Callahan CM. (2004). J Clin
D’Agostino R, Kaplan SH. (1995). Med Care. 33: Epidemiol 57: 1040–1048.
AS47–AS55. Saliba D, Elliott M, Rubenstein LZ, Solomon DH, Young
Hayward RA, Manning WG, Kaplan SH, Wagner EH, RT, Kamberg CJ, Carol Roth RN, MacLean CH,
Greenfield S. (1997). JAMA. 26; (20): 1663–1669. Shekelle PG, Sloss EM, Wenger NS. (2001). J Am
Hofer TP, Hayward RA, Greenfield S, Wagner EH, Geriatr Soc 49: 1691–1699.
Kaplan SH, Manning WG. (1999). JAMA. 281: Stewart AL, Hays RD, Ware JE Jr. (1988). Med Care. 26:
2098–2105. 724–735.
Hudon C, Fortin M, Vanasse A. (2005). Journal of Stier DM, Greenfield S, Lubeck DP, Dukes KA, Flanders
Clinical Epidemiology 58: 603. SC, Henning JM, Weir J, Kaplan SH. (1999). Urology
Iezzoni LI. (2003). Getting Started and Defining Terms. 54: 424–429.
In: Iezzoni L. (ed.) Risk Adjustment. Health Admin- Tooth L, Hockey R, Byles J, Dobson A. (2008). J Clin
istration Press, Chicago, IL, p. 17–32. Epidemiol 61: 151–159.
5 The EQ-5D Health-Related
Quality of Life Questionnaire
N. Gusi . P. R. Olivares . R. Rajendram
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
2 Definitions and Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
3 Use of EQ-5D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
4 Description of a Sample Population Using the EQ-5D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

4.1 The Descriptive System as a Health Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
4.2 The EQ VAS as a Measure of Overall Self-Rated Health Status . . . . . . . . . . . . . . . . . . . . . . 94
4.3 The Descriptive System as a Weighted Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
5 Recent Developments in EQ-5D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

5.1 The Five Level Version of the EQ-5D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
5.2 The Version of EQ-5D for Children (EQ-5D-Y) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

88 5 The EQ-5D Health-Related Quality of Life Questionnaire
Abstract: Assessment of health care requires measurement and monitoring of health. The
EuroQOL five dimensions > questionnaire (> EQ-5D) is one of the most commonly used
generic questionnaires to measure health-related > quality of life (HRQOL). The conceptual
basis of the EQ-5D is the holistic view of health, which includes the medical definition, as well
as the fundamental importance of independent physical, emotional and social functioning. The
concept of health in EQ-5D also encompasses both positive aspects (well-being) and negative
aspects (illness). The EQ-5D is short, easy to use and flexible. It has been used successfully in
several different settings (scientific trials, health policies, pharmacoeconomics, clinics, etc.). It
consists of a questionnaire and a > visual analogue scale (EQ-VAS). The EQ-VAS is a self-rated
health status using a VAS. The EQ-VAS records the subject’s perceptions of their own current
overall health and can be used to monitor changes with time. The self-assessment questionnaire
is self-reported description of the subject’s current health in 5 dimensions i.e., mobility, self-
care, usual activities, pain/discomfort and anxiety/depression. The subject is asked to grade
their own current level of function in each dimension into one of three degrees of disability
(severe, moderate or none). The combination of these with the conditions ‘‘death’’ and
‘‘unconscious’’ enables description of 245 different health states. Each health state can be ranked
and transformed a single score called the utility. The utility score is an expression of the Quality
Adjusted Life Years (QALY) and is commonly used to make evidence-based decisions in analyses
of cost-effectiveness. Therefore, the EQ-5D can be used for health outcomes studies and eco-
nomic analyses. The EQ-5D was initially developed for adults; a new version has recently been
developed for children aged 8–18 years old (> EQ-5D-Y).
List of Abbreviations: CF-EQ-5D, child friendly euroQOL five dimensions questionnaire;
EQ-5D, euroQOL five dimensions questionnaire; EQ-5D-Y, euroQOL five dimensions
questionnaire for young; HRQOL, health related quality of life; NICE, National Institute of
Clinical Excellence; QALY, quality adjusted life years; SF-6D, 6-item short form health survey
questionnaire; TTO, time-trade-Of; VAS, visual analogue scale
1 Introduction
Assessment of health care requires measurement and monitoring of health. However, health-
related quality of life (HRQOL) is an abstract, subjective concept that is difficult to measure.
Several questionnaires are available but these instruments are usually long, complex and
disease-specific limiting their usefulness and comparability. Simple devices including a basic
common core are needed to facilitate comparison of health care outcomes.
The EuroQOL five dimension questionnaire (EQ-5D) is a simple self-administered instru-
ment that assesses HRQOL. It assesses function in five socially relevant domains:
1. Mobility
2. Self-care
3. Usual activities
4. Pain-discomfort
5. Anxiety-depression
It is accompanied by a Visual Analogue Scale (VAS) on which the subject is asked to provide a
self-assessment of their own health in a range from 0 (worst imaginable health state) to 100
(best imaginable health state).
The EQ-5D Health-Related Quality of Life Questionnaire 5 89
The origins of the EQ-5D date back to May 1987 when the EuroQOL Group first met to
consider the development of a standardized non-disease-specific instrument for describing and
valuing HRQOL (EuroQOL Group, 1990). The Group originally consisted of a network of 23
multilingual, multidisciplinary researchers from five European countries (the UK, Finland, the
Netherlands, Norway and Sweden). The aim of this group was to develop a tool that provided
a simple, generic measure of HRQOL for clinical or economic analyses that enabled interna-
tional comparisons.
Their initial objectives and the outcomes of their meetings were described in their first
publication (EuroQOL Group, 1990). The EQ-5D was initially developed simultaneously in
Dutch, English, Finnish, Norwegian and Swedish. It is now widely used and has been validated
in many other countries and has been translated into most major languages.
For several years the term ‘‘EuroQOL’’ was synonymous with the instrument because the
EuroQOL Group developed it. However, because the current version of the ‘‘EuroQOL
Instrument’’ assesses five dimensions of function in adults it was actually called EQ-5D. To
avoid confusion the term EQ-5D should be used when referring to this instrument.
The EQ-5D is one of the most commonly used standardized HRQOL questionnaires
available today and has been used to measure the cost-effectiveness of therapies for many
diseases. It is short, flexible, easy to use and can generate a single total score based on socially
relevant measures of HRQOL. This score is known as the utility score. The importance and
popularity of the EQ-5D are demonstrated by the fact that over 1,000 scientific papers listed in
the ISI Web of KnowledgeTM refer to the EQ-5D and the utility score.
The (EuroQOL Group, 1990) initially developed an instrument that assessed six dimen-
sions of function EQ-6D; (EuroQOL Group, 1990) and at one stage the addition of a seventh
dimension was even suggested. The assessments of the sixth and seventh domains (social
relationships and energy-tiredness) made little contribution to the assessment of health status
and so were removed (Williams, 2005). The recent suggestion to add a new cognitive dimen-
sion was also rejected because the current version of the EQ-5D can adequately assess HRQOL
in populations with cognitive impairments (Wolfs et al., 2007).
Recently, the need to develop a self-administered tool to measure the HRQOL in children
and adolescents prompted adaptation of the EQ-5D. The EuroQOL Group has developed and
validated the EuroQOL five dimensions questionnaire for young people (EQ-5D-Y). This is a
new version of the EQ-5D for use in populations of children and adolescents aged 8–18 years
old. The first results have been presented at recent EuroQOL Scientific Meetings and several
research papers are currently in press and publication is expected during the second half of
2008 (Gusi et al., 2009; Wille et al., 2006).
2 Definitions and Concepts

To administer a questionnaire appropriately and interpret the results correctly it is crucial to
understand the concepts underlying its development. The specific-validity and conceptual
basis of questionnaires are reflected in the definitions of the concepts and words included in it.
The child-friendly task force of the EuroQOL Group recently presented a revised version of the
concepts and definitions included in the standard adult version of the EQ-5D. These defini-
tions were adapted to children and adolescents (Wille et al., 2006). These concepts and
definitions are available on the EuroQOL web site (www.euroQOL.org).
EQ-5D manages eight main concepts:

The subject’s health state at the time of assessment
The best and worst imaginable health states
The five dimensions of EQ-5D
The EQ-5D is a generic instrument intended for use by different health professionals. The
conceptual basis of the EQ-5D is therefore a holistic view of health, which includes the medical
definition, as well as the fundamental importance of independent physical, emotional and
social functioning. For example, the worst imaginable health state, in terms of capacity for
independent function, is that which prevents an acceptable level of function in all aspects of
life. The concept of health in EQ-5D also encompasses both positive aspects (well-being) and
negative aspects (illness).
Subjects are asked to grade their own level of function or disability in each dimension on
the specific day that the questionnaire is administered into one of three levels;
No problems, no disability (level 1)
Some problems, moderate disability (level 2)
A lot of problems, severe disability (level 3)
The levels of function in the mobility dimension, for example, are classified as:
level 1 – able to walk easily, both inside and out, unaided
level 2 – able to walk with difficulty/require some assistance (sticks, crutch, analgesia)
level 3 – extremely difficult to walk inside or out/confined to bed or chair
These difficulties may be due to a chronic condition (e.g., confined to bed because of terminal
cancer) or acute illness (e.g., confined to bed because of flu).
Similarly, the other dimensions refer to independence in daily personal care and usual
activities rather than skills that can be learnt (e.g., the ability of children to dress themselves).
The pain/discomfort dimension refers to physical injury or discomfort (ache, breathlessness,
itching, palpitations, tiredness, ringing in the ears, etc.). Psychological or mental sufferings are
assessed in the fifth dimension (anxiety/depression). This is related to a broad concept of
psychological disturbance covering clinical depression and anxiety, feeling gloomy, dejected,
down, sad, or unhappy, etc.
3 Use of EQ-5D
The EQ-5D is intended to be self-completed and has been used in postal surveys, clinics and face-
to-face interviews (Szende and Williams, 2004). For practical reasons postal surveys using EQ-5D
have been used in large population studies whilst face-to-face interviews are used with inpatients,
the elderly and the illiterate or to increase the accuracy of responses. Proxy versions (> proxy
questionnaire) have also been used to obtain information from the caregivers of subjects who
could not complete the questionnaire themselves (e.g., coma, dementia, young children, etc.
(Hung et al., 2007; Jonsson et al., 2006; Matza et al., 2005; Sach and Barton, 2007).
The EQ-5D includes five questions related to the five dimensions that are measured. The
level of function in each dimension is classified into one of three degrees of disability, reflecting
no disability (level 1), moderate disability (level 2) and severe disability (level 3). The
yuxtaposition of the responses to the five questions generates a 5-digit descriptor ranging
from 11111 for perfect health to 33333 for the worst possible state. This descriptor represents a
unique heath state. The patient’s health state can therefore be classified into any one of 243
theoretically possible health states. The states of ‘‘unconscious’’ and ‘‘dead’’ were added in
order to obtain a value set or ‘‘tariff’’ for evaluation of the EQ-5D generated health states. So
there are in fact 245 possible health states or EQ-Index.
The subjects are asked to rate their own health on a vertical 20 cm visual analogue scale
(EQ-VAS) included with the EQ-5D. The scale ranges from 0 (worst imaginable health state)
up to 100 (best imaginable health state). The inclusion of this scale essentially allows numeri-
cal assessment of the patient’s perception of their own general health and HRQOL using a self-
completed instrument that could be conducted by postal survey (Brooks, 1996). The EQ-VAS
is an economical and practical addition to the EQ-5D that provides a general and unique
insight into patients’ subjective perception of their own overall current health. It can also be
used like a barometer to monitor changes in HRQOL over time.
The EQ-VAS values obtained from large population surveys were used to obtain the
reference values related to the 245 possible health states in different countries. This set
of reference values is labeled the VAS tariff. The reference values for the EQ-5D scores obtained
in various countries can be found in Measuring self-reported population health: An internation-
al perspective based on EQ-5D (Szende and Williams, 2004).
With the availability of more time and research funds, the value sets were redefined using
the Time Trade-Off (TTO) and Standard-Gamble (SG) methods which reflect the social
acceptability of having various health states. Time Trade-Off is most commonly used. The
book EQ-5D Value Sets: Inventory, Comparative Review and User Guide (Szende et al., 2007)
provides comparative reviews of the TTO and VAS value sets, a guide for users of EQ-5D value
sets and inventories of TTO and VAS evaluation surveys.
The application of TTO to EQ-5D results usually reflects the preference of having one health
state over another during the next 4 or 10 years. The mathematical combination of these
preferences gives a total score that links each health state with time. This total score ranges
from 1 (fully functional quality of life) to 0 (death) but also allows negative scores (worse than
death). This score is called utility is linked to the quality-adjusted life years (QALYs) and it is
very useful for economic analyses and pharmacoeconomics (Devlin and Williams, 1999).
To date, over 250 scientific papers have used the utility score in economic analyses (cost-
utility analyses) to describe the health of a population, effects of interventions, cost-effectiveness
analyses or make decisions etc. The use of EQ-5D in economics analyses (Betegon and Badia,
2006) is increasing. It is recommended by well-recognised guidelines of institutions such as the
National Institute of Clinical Excellence (NICE) in the United Kingdom and the Washington
Panel on Cost-Effectiveness in Health and Medicine in the United States.
4 Description of a Sample Population Using the EQ-5D

This section illustrates how to use EQ-5D data to describe a sample using data from the
‘‘Exercise looks after you’’ program funded by public Regional Government of Extremadura in
Spain (Gusi et al., 2007). This program recruited people over 55 years old with various
different diseases detected by the primary care team, including for example obesity, diabetes
or moderate depression. Thus this data is not representative of the general population.
There are several ways to present the data obtained with the EQ-5D but for simplicity we
will use the same subdivisions used in the EQ-5D user guide (Oppe et al., 2007):
1. The descriptive system as a health profile

2. The EQ VAS as a measure of overall self-rated health status
3. The descriptive system as a weighted index
4.1 The Descriptive System as a Health Profile
A simple way to describe a population using the EQ-5D is with a frequency table of the health
states obtained. > Table 5-1 is an example of a frequency table of the health states obtained
using the EQ-5D. Health states with a frequency under 10 have been removed because of the
large number of different states obtained (80).
. Table 5-1
Frequency of EuroQOL 5-Dimension questionnaire (EQ-5D) Health states obtained in a sample
from the Exercise Looks After You program
Q-5D health states n %

11111 360 26.3
11112 93 6.8
11113 12 0.9
11121 237 17.3
11122 133 9.7
11123 33 2.4
11131 40 2.9
11132 37 2.7
11133 26 1.9
11211 11 0.8
11221 14 1.0
11222 22 1.6
21111 22 1.6
21121 55 4.0
21122 45 3.3
21131 12 0.9
21132 16 1.2
21133 10 0.7
21222 14 1.0
21232 12 0.9
22232 11 0.8
Others 156 11.3
Total 1,368 99.8
Missing 3 0.2
These data are from the Exercise Looks After You program and include elderly people with multiple diseases
. Table 5-2
EuroQOL 5-Dimension questionnaire (EQ-5D) levels of disability obtained in the sample from the Exercise Looks After You program (n = 1,371). Reported
by age and sex
Age groups
51–60 61–70 71–80 +80 Total
EQ-5D Dimension Sex M (n = 8) F (n = 60) M (n = 83) F (n = 552) M (n = 96) F (n = 465) M (n = 29) F (n = 76) M (n = 216) F (n = 1,153)
Mobility Level 1 87.5 75.0 78.3 81.3 89.6 73.3 82.8 81.6 84.3 77.8
Level 2 12.5 25.0 21.7 18.3 10.4 26.5 17.2 18.4 15.7 22.0
Level 3 0 0 0 4.0 0 2.0 0 0 0 0.3
Self-care Level 1 100 83.3 90.4 94.6 96.9 91.8 86.2 88.2 93.1 92.4
Level 2 0 16.7 8.4 5.4 3.1 7.8 13.8 11.8 6.5 7.4
Level 3 0 0 1.2 0 0 0.4 0 0 0.5 0.2
Usual activities Level 1 87.5 90.9 89.2 87.5 96.9 84.7 86.2 65.8 92.1 85.1
Level 2 12.5 8.3 9.6 11.6 3.1 14.4 13.8 30.3 7.4 13.8
Level 3 0 1.7 1.2 0.9 0 0.9 0 3.9 0.5 1.1
Pain/discomfort Level 1 75.0 36.7 50.6 36.8 50.5 35.6 55.2 32.9 52.1 36.0
Level 2 25.0 48.3 38.6 45.3 43.2 47.0 31.0 51.3 39.1 46.5
Level 3 0 15.0 10.8 17.6 6.3 17.5 13.8 15.8 8.8 17.3
Anxiety/depression Level 1 37.5 46.7 72.3 54.9 74.0 58.7 75.9 61.8 72.2 56.5
Level 2 37.5 40.0 20.5 35.7 22.9 30.8 17.2 32.9 21.8 33.7
Level 3 25.0 13.3 7.2 9.4 3.1 10.5 6.9 5.3 6.0 9.8
The EQ-5D Health-Related Quality of Life Questionnaire
These data are from the Exercise Looks After You program and include elderly people with multiple diseases. Women report higher levels of disability than men. Reported levels of
disability do not increase with the age because of the specific characteristics of this population. M males; F females; values expressed in %
5
93
The descriptive system is usually used with a frequency table presenting the proportion of
answers obtained in each dimension by levels or using dichotomized information structuring
the answers by dimension. An example of a frequency table can be seen in > Table 5-2. In this
example the table has been expanded to show the information by demographic groupings (age
and sex). An example of dichotomized information can be seen in > Figure 5-1, where the data
is structured by percentage of reported problems by dimension and sex.
4.2 The EQ VAS as a Measure of Overall Self-Rated Health Status
The data should be presented as a measure of the central tendency with a measure of
dispersion (e.g., mean and standard deviation or median with 25th and 75th percentiles).
This information can be divided by age subgroups, sex, illness, etc. > Figure 5-2 is an example
of this.
Normally the score decreases with the age and men have higher scores than women. In this
sample men had higher scores than women but the scores did not decrease with the age.
4.3 The Descriptive System as a Weighted Index
The EQ-5D index can be presented in the same format as the VAS with a measure of central
tendency and a measure of dispersion. For more precise valuation, a specific value set should
be used for data from a specific country. These examples have used the Spanish value set (Badia
et al., 1999; Badia et al., 2001b). > Figure 5-3 shows the VAS value set for the ‘‘Exercise looks
. Figure 5-1
EuroQOL 5-Dimensions questionnaire (EQ-5D) levels of reported problems in each dimension
by sex. These data are from the Exercise Looks After You program and include people with
multiple diseases so are not representative of the general population. Women reported higher
levels of disability in all dimensions. Values are expressed as a percentage of reported problems
. Figure 5-2
Visual Analogue Scale (VAS) scores from the EuroQOL 5-Dimensions questionnaire (EQ-5D) by
age and sex. These data are from the Exercise Looks After You program and include people
with multiple diseases so are not representative of the general population. Males report lower
(better) scores than females. Values expressed as mean ± standard deviation
after you’’ population and > Figure 5-4 shows the TTO value set. > Figure 5-5 shows the
hypothetical effect of a treatment on health status (these data are fictitious and for illustration
purposes only).
5 Recent Developments in EQ-5D

The EuroQOL foundation recently conducted several new surveys for the further development
of the EQ-5D questionnaire. Some of these surveys were used to evaluate a five level version of
the EQ-5D and the new version of the EQ-5D for children (EQ-5D-Y).
5.1 The Five Level Version of the EQ-5D
Although the EQ-5D has good psychometric properties and is able to detect small changes
in chronic diseases (Campbell et al., 2006; Gusi et al., 2006), there are only 243 possible
health states. This is considered a disadvantage in comparison to other instruments like the
Health Utilities Index Mark 2 & Mark 3, and the Short Form 6D (SF-6D) which have 24,000,
972,000 and 18,000 possible health states respectively (Janssen et al., 2008).
. Figure 5-3
EurQOL 5-Dimensions questionnaire (EQ-5D) value set based in the Visual Analogue Scale (VAS)
by age and sex. These data are from the Exercise Looks After You program and include
people with multiple diseases so are not representative of the general population. Men reported
lower (better) scores than women. Values expressed as mean
If the severity levels in each domain of the EQ-5D were expanded from 3 to 5, the number
of possible health states would increase to 3,125. This would increase the descriptive capacity
of the EQ-5D significantly. This would improve its ability to detect small changes in health
states. Nevertheless, the currently available three level version is easy to use, functions well and
provides the utility score.
Some authors have performed preliminary research on the psychometric characteristics of
a five level version of EQ-5D. (Janssen et al., 2008; Pickard et al., 2007a; Pickard et al., 2007b)
and the compatibility of the utility scores obtained from the three and five level versions. Kind
(2007) suggested some factors which need to be considered in the development of a new five
level EQ-5D. Kind indicated that ‘‘the task of establishing value sets for EQ-5D health states is
an essential complementary exercise.’’ To expand the value sets for a 5 level version would take
time and the currently available, standardized three level version would be a useful reference.
For further discussion of the advantages and disadvantages of varying the number of severity
levels of the EQ-5D see Van Agt and Bonsel (2005).
5.2 The Version of EQ-5D for Children (EQ-5D-Y)
The EQ-5D was developed for use in adults. Although this instrument has been used by some
researchers to study the HRQOL in children (Badia et al., 2001a; Polinder et al., 2005;
. Figure 5-4
EurQOL 5-Dimensions questionnaire (EQ-5D) value set based in the Time Trade Off (TTO) by age
and sex EQ-5D TTO value set by age and sex. These data are from the Exercise Looks After
You program and include people with multiple diseases so are not representative of the general
population. Men reported lower (better) scores than women. Values expressed as mean
Stolk et al., 2000), children under 16 years of age may have difficulty understanding the
questionnaire and VAS. As a reuslt, Hennessy and Kind (2002) developed an experimental version
of the EQ-5D for use with children. In 2006 the EuroQOL Group designated an international Task
force with the objective to develop a specific international version of EQ-5D for young children &
adolescents (8–18 years old). The version was initially named the Child Friendly EQ-5D (CF-EQ-
5D) but the name was later changed to the EQ-5D for Young (EQ-5D-Y). The development of this
international version of the EQ-5D for the young required the cooperation of a multinational team
who tested versions in five different languages (English, German, Italian, Spanish and Swedish).
The EQ-5D-Y was initially produced in English. This English version was the starting point for the
versions in other languages. This ensured the > conceptual equivalence of each version and
enables international comparisons. The EQ-5D-Y classifies subjects into one of three levels of
function (severe disability, moderate disability or no disability) in five dimensions:
1. Walking about
2. Look-after myself
3. Doing usual activities
4. Having pain or discomfort
5. Feeling worried, sad or unhappy
The research papers presenting the validity and characteristic proprieties of the different
language versions of the EQ-5D-Y will be published soon. For example a paper presenting
the validity of the Spanish version is currently in press and due to be published in late 2008.
. Figure 5-5
EuroQOL 5-Dimensions questionnaire (EQ-5D) value set based on Time Trade Off (TTO) before
and after a hypothetical treatment. Values expressed as mean. The data show the effect of
the treatment in the quality of life. The control group and intervention group increase their
scores, however the treatment group scores are higher after treatment, so the treatment is
effective. This data are fictitious and for illustration purposes only
Parental proxy-versions to measure the HRQOL in children under 8 years old are currently
being developed.
Summary Points
The EuroQOL Group developed the EQ-5D, one of the most widely used generic ques-
tionnaires to measure HRQOL.
The EQ-5D is characterized by its ease of use, brevity and flexibility in different settings
(trials, health policies, pharmacoeconomics, clinics, etc.).
The EQ-5D is a generic instrument intended for use by different health professionals. Thus
its conceptual basis incorporates the holistic nature of HRQOL which includes the medical
interpretation as well as physical, emotional and social functioning.
The concept of health in EQ-5D includes both negative aspects (illness) and positive
aspects (well-being). Most of the concepts relate to the ability to function independently.
EQ-5D classifies subjects into one of three levels of function in five dimensions: mobility,
self-care, usual activities, pain/discomfort and anxiety/depression. The combination of
scores for question (11111–33333) plus the states of death and unconscious offers a
descriptive system with up to 245 different possible health states.
Each health state could be transformed and ranked in a single score (utility) which is
thought to correlate with Quality of Life Adjusted-Years (QALY).
EQ-5D was developed for adults and the EQ-5D-Y has been recently developed for
children and adolescents aged 8–18 years old.
Well recognized institutions including NICE in the UK recommend the use of EQ-5D for
monitoring HRQOL and in economic analyses.
References
Badia X, Garcia-Hernandez G, Cobos N, Lopez-David C, Matza LS, Secnik K, Mannix S, Sallee FR. (2005).
Nocea G, Roset M. (2001a). Med Clin (Barc). 116: Pharmacoeconomics. 23: 777–790.
565–572. Oppe M, Rabin R, & De Charro F. (2007). EQ-5D User
Badia X, Roset M, Herdman M, Kind P. (2001b). Med Guide version 1.0. EuroQOL Group.
Decis Making. 21: 7–16. Pickard AS, De Leon MC, Kohlmann T, Cella D,
Badia X, Roset M, Montserrat S, Herdman M, Segura A. Rosenbloom S. (2007a). Med Care. 45: 259–263.
(1999). Med Clin (Barc). 112 (Suppl. 1): 79–85. Pickard AS, Kohlmann T, Janssen MF, Bonsel G,
Betegon L, Badia X. (2006). In: Badia X (ed.) Review of Rosenbloom S, Cella D. (2007b). Med Care. 45:
the use of the EQ-5D in cost-utility analysis. Paper 812–819.
Presented at the 23rd Scientific Plenary Meeting Polinder S, Meerding WJ, Toet H, Mulder S, Essink-Bot
of the EuroQOL Group. Health Economics & ML, Van Beeck EF. (2005). Pediatrics. 116: e810–817.
Outcomes Research IMS Health, Barcelona. Sach TH, Barton GR. (2007). Int J Pediatr Otorhinolar-
Brooks R. (1996). Health Policy. 37: 53–72. yngol. 71: 435–445.
Campbell H, Rivero-Arias O, Johnston K, Gray A, Stolk EA, Busschbach JJ, Vogels T. (2000). Qual Life Res.
Fairbank J, Frost H. (2006). Spine. 31: 815–822. 9: 29–38.
Devlin N, Williams A. (1999). N. Z. Med J. 112: 68–71. Szende A, Oppe M, Devlin N. (2007). EQ-5D Value Sets:
EuroQOL Group. (1990). Health Policy. 16: 199–208. Inventory, Comparative Review and User Guide.
Gusi N, Badia X, Herdman M, Olivares PR. (2009). Aten Springer, Berlin.
Primaria. (in press). Szende A, Williams A (ed.). (2004). Measuring Self-
Gusi N, Herrera E, Davila M, Campon JC. (2007). De- Reported Population Health: An International
velopment of the socio-sanitary program ‘‘exercise Perspective Based on EQ-5D. SpringMed Publishing
looks after you’’: phase I for elderly. Paper Presented Ltd, Budapest, Hungary.
at the Third Annual Meeting of HEPA Europe, Graz Van Agt H, Bonsel G. (2005). In: Kind P, Brooks R,
(Austria). Rabin R (ed.) EQ-5D Concepts and Methods: A
Gusi N, Tomas-Carus P, Hakkinen A, Hakkinen K, Ortega- Developmental History. Springer, Berlin.
Alonso A. (2006). Arthritis Rheum. 55: 66–73. Wille N, Rabens-Sieberer U, Bonsel G, Burstrom K,
Hennessy S, Kind P. (2002). Measuring health status in Cavrini G, Egmar AC, Greiner W, Gusi N,
children:developing and testing a child friendly ver- Herdmann M, Jelsma J, Kind P, Krabbe-Lugner A,
sion of EQ-5D. Paper Presented at the EuroQOL Scalone L. (2006). Establishing definitions of the
Plenary Meeting. University of New York, New York. concepts included in CF-EQ-5D: a revision of the
Hung SY, Pickard AS, Witt WP, Lambert BL. (2007). definition of EQ-5D concepts for adults. In: Badia X
J Clin Epidemiol. 60: 963–970. (ed.) Paper Presented at the 23rd Scientific Plenary
Janssen MF, Birnie E, Bonsel GJ. (2008). Qual Life Res. Meeting of the EuroQOL Group. Health Economics
17(3): 463–473. & Outcomes Research IMS Health, Barcelona.
Jonsson L, Andreasen N, Kilander L, Soininen H, Williams A. (2005). In: Kind P, Brooks R, Rabin R (eds.)
Waldemar G, NygaardH, Winblad B, Jonhagen ME, EQ-5D Concepts and Methods. Springer, Dor-
Hallikainen M, Wimo A. (2006). Alzheimer Dis drecht, Netherlands.
Assoc Disord. 20: 49–55. Wolfs CA, Dirksen CD, Kessels A, Willems DC, Verhey FR,
Kind P. (2007). Med Care. 45: 809–811. Severens JL. (2007). Health Qual Life Outcomes. 5: 33.
6 The University of Washington
Quality of Life Scale
S. N. Rogers . D. Lowe
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
2 Historical Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
3 Questionnaire Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

3.1 Version 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
3.2 Version 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
3.3 Version 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.4 Version 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.5 Translations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
4 Scoring and Presenting the UW-QOLv4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

4.1 Presenting Domain Scores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
4.2 Presenting Global Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
4.3 Presenting the Importance Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
4.4 Presentation of Composite Scores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5 Features of the UW-QOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

5.1 Feasible and Acceptable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
5.2 Face and Content Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.3 Construct Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.4 Responsiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
5.5 Interpretability, Clinical Effect and Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
5.6 Stability of UWQOL for Longer-Term Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
5.7 Normative Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
5.8 Composite Scores and Factor Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6 Comparison of Domains with Other Questionnaires . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

6.1 Clinically Meaningful Cut-Offs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
7 Resume of Published Peer Review Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
8 Version 5 of the UW-QOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

102 6 The University of Washington Quality of Life Scale
Abstract: The need for validated head and neck specific cancer health-related quality of life
(HRQOL) questionnaires has long been recognised. One of the first to be published was the
University of Washington quality of life scale (UW-QOL) in 1993. The current version 4 covers
12 domains - pain, appearance, activity, recreation, swallowing, chewing, speech, shoulder
function, taste, saliva, mood and anxiety. Each question is scaled from 0 (worst) to 100 (best)
according to the hierarchy of response. The UW-QOL also contains three global questions, one
as a five-point Likert scale asking about HRQOL compared to the month before the cancer,
and the other two as a six-point Likert scale, one asking about health-related and the other
asking about overall quality of life during ‘the past 7 days’. It also has a question asking about
the importance of domains and an option for free-text comment.
The lack of any copyright agreements and its simplicity in scoring makes using the UW-
QOL questionnaire easy to use. It has been translated into numerous languages. The ques-
tionnaire has face and content validity and there is considerable evidence to support the
construct validity of its domains. Our work indicates the UW-QOL to be sensitive to changes
in patient characteristics and to changes over time. The identification of suitable cut-offs in
domain scores adds to the interpretability of the UW-QOL in a routine clinic setting to help
screen patients with particular problems. The UW-QOL displays stability in patients beyond
one year from treatment and shows expected differences in regard to normative values. Factor
analyses indicate that two composite scores – physical function and social function – are
logical, each being a simple average of 6 domain scores. Further work is necessary to develop a
better understanding of these composite scores, which have the potential of being used to
assess clinical effect in treatment evaluation studies and to develop sample size calculations.
List of Abbreviations: BDI, Beck Depression Inventory; CES-D, Centre for Epidemiology
Studies Depression Scale; DAS-24, Derriford Appearance Scale; EORTC, European Organisa-
tion for Research and Treatment of Cancer; EQ-5D, EuroQolEQ-5D; FACT, Functional
Assessment of Cancer Therapy; FEES, Fibreoptic Endoscopic Evaluation of Swallowing;
HADS, Hospital Anxiety and Depression Scale; HRQOL, Health-Related Quality of Life;
IMRT, Intensity Modulated Radiotherapy; LORQ, Liverpool Oraql Rehabilitation Question-
naire; MDADI, M.D.Anderson Dysphagia Inventory; NDII, Neck Dissection Impairment
Index; SDQ, Shoulder Disability Questionnaire; SF-36, medical outcomes study 36-item
Short-Form health survey; SIP, Sickness Impact Profile; SWAL-QOL, Swallowing Quality of
Life measure; TOM, Therapy Outcome Measures; UWQOL, University of Washington Quality
of Life scale; VAS, Visual Analogue Scale; VHI, Voice Handicap Index; V-RQOL, Voice Related
Quality of Life; XeQOLS, Xerostomia- related Quality of Life Questionnaire
1 Introduction
The University of Washington quality of life (UWQOL) scale is one of the more commonly
used questionnaires in head and neck cancer. This is probably in part due to its simplicity and
suitablity for routine use in a busy clinical setting.This chapter will deal with aspects of
historical background, questionnaire development (versions 1, 2, 3 and 4), translations,
scoring and presentation (domain, global, importance and composite scores), feasibility and
acceptability, face and content validity, construct validity, responsiveness, stability, normative
data, composite scores and factor analysis, comparison of domains with other questionnaires,
summary of its use as reported in peer review journals and finally a comment about possible
The University of Washington Quality of Life Scale 6 103
further modifications if there were to be a version 5. Validation of the UW-QOLv4 as a clinical

outcomes measure is an ongoing process, as is finding the most suitable way of using it to
enhance multidisciplinary team decision making and patient care.
2 Historical Background
The need for validated head and neck specific cancer health-related quality of life (HRQOL)
questionnaires was recognised many years ago (Rogers et al., 2008). One of the first to be
published was the UW-QOL in 1993 (Hassan and Weymuller, 1993) and it now holds an
established place in the reporting of patient derived outcomes following head and neck cancer
(Rogers et al., 2008). There is of course no ‘gold standard’ questionnaire and each has it own
merits and weaknesses (Ringash and Bezjak, 2001, Rogers et al., 2008). Perhaps one of the
most appealing features of the UW-QOL is its simplicity. In the original description, Hassan
and Weymuller (1993) stated that the advantages of the head and neck questionnaire are that
(1) it is brief and self-administered, (2) it is multifactorial, allowing sufficient detail to identify
subtle change, (3) it provides questions specific to head and neck cancer, and (4) it allows no
input from the health provider, thus reflecting the QOL as indicated by the patient. There are
many barriers to HRQOL collection in a head and neck setting (Rogers et al., 2008) so the
UW-QOL has clinical relevance as it easy for both patient and clinician to use. Its application
in routine clinical practice can be facilitated by touchscreen computerised technology (Rogers
et al., 2008). It is important to include HRQOL as an outcome parameter (Rogers et al., 2008)
and also as a means of helping to identify patients doing badly who otherwise can easily go
unrecognised (Rogers et al., 2008). The terminology and scoring is an important issue and the
UW-QOL uses terms and cut-offs that are easily recognised and hence it gives clinically useful
information suitable for healthcare professional, patient and carers alike (Rogers et al., 2008).
The conciseness of the UW-QOL means that it can anchor a Unit’s evaluation of itself over
time. Because the core questionnaire is brief it is possible to add other questionnaires as
required without compromising response rates or causing the patient excessive questionnaire
burden and fatigue. Additional validated measures such as for depression, xerostomia, swal-
lowing or shoulder function can be asked concurrently to audit or test a particular issue.
3 Questionnaire Development
There have been four versions of the UW-QOL since it was first published in 1993.
The modifications to the questionnaire are shown in > Table 6-1.
3.1 Version 1
The first version of the UW-QOL comprised of 9 domains (pain, appearance, activity, recrea-
tion, swallowing, chewing, speech, shoulder, employment). It was compared to two established
equality of life evaluation tools, the Karnofsky scale and the Sickness Impact Profile (SIP)
(Hassan and Weymuller, 1993). Using the SIP as a gold standard, the UW QOL scale demon-
strated an average criterion validity of 0.849, whereas the Karnofsky average criterion validity
was 0.826. The UW-QOL questionnaire scored >0.90 on reliability coefficients versus 0.80 for
. Table 6-1
Summary of development of the UW-QOL
Domain Version 1 Version 2 Version 3 Version 4

Pain X X X X
Appearance X X X X
Activity X X X X
Recreation X X X X
Swallowing X X X X
Chewing X X X X
Speech X X X X
Shoulder X X X X
Taste X X
Saliva X X
Mood X
Anxiety X
Employment X X
Global QOL items X X X
Free text X X X
Importance rating X X X
the Karnofsky and 0.87 for the SIP scale. The UW QOL scale faired better than the Karnofsky
and the SIP scale in detecting change (responsiveness). It was the face and construct validity
that appealed to authors when looking for a head and neck measure at a time when there was a
paucity of specific questionnaires available. Questionnaire content was also important as the
UW-QOL included a question about shoulder function, missing on other questionnaires but
important to a surgical head and neck oncologist. The lack of any copyright agreements and its
simplicity in scoring made using the UW-QOL questionnaire quite straightforward. The
authors thought that the questionnaire had potential to be a standard way of capturing a
patient’s perspective in a busy routine clinical setting and that could be used in national audit.
3.2 Version 2
In version 2 (Deleyiannis et al., 1997) each of the 9 original domains was followed by an
importance-rating scale. Also three new single item ‘quality of life’ questions were added
(> Table 6-1). These amendments were useful as they brought in the concepts of importance
and global measures of quality of life. Importance has been shown to be helpful as there is a
wide variation between patients (Rogers et al., 2008). Both pre- and post-treatment there was a
general lack of correlation between importance-rating and domain scores. At all time points,
patients tended to rate speech, chewing and swallowing as more important than the other
UW-QOL domains. The inclusion of importance with domain score gives a way of identifying
patients with problems who might benefit from intervention. Prior to the addition of the three
general quality of life questions it was shown that a composite score of UW-QOL domains
correlated well with global questions in other questionnaires (Rogers et al., 2008). Another
new feature of the UW-QOL was the freetext element. Freetext allows the questionnaire to
record other issues of importance to the patient and in so doing provides a better overall
questionnaire experience for the patient. Freetext also gives the multidisciplinary team a better
insight into the concerns of the patient and can be used to promote a holistic approach. We
found that around 61% of patients make a comment at some time, predominantly head and
neck (39%) and medical (35%) (Rogers et al., 2008), and about one-third of all questionnaires
have some freetext added. The analysis of freetext has shown that the UW-QOL has patient
approval, however there are one or two items that could be changed (as is discussed in section
vii) such as the addition of too much saliva to the saliva domain.
3.3 Version 3
In version 3 (Weymuller et al., 2000, 2001) two new domains (taste, saliva) were added and the
employment domain dropped (> Table 6-1). Rather than asking patients to rank the impor-
tance of each individual domain, version 3 asked patients to indicate which three domains had
been most important to them in the last seven days. This resulted in a 10-item instrument
(UW-QOL-R) with an overall internal consistency score of 0.85.
3.4 Version 4
Health-related quality of life refers to the physical, emotional, and social impact of diseases
and their treatments on patients. Version 3 did not include an emotional domain and hence
two new domains (anxiety and mood) styled in a similar fashion to the existing questionnaire
were added (Rogers et al., 2008). The new domains correlated significantly with the emotional
functioning domains from the EORTC C30 and with the pain and appearance domains of
UW-QOL. There were also significant correlations between the ‘‘global quality of life’’ item
and the two new domains.
3.5 Translations
The UW-QOL has been translated into several different languages (> Table 6-2) (Andrade et al.,
2006, Lovell et al., 2005, Omoro et al., 2006, Thone et al., 2003, Vartanian et al., 2004,
Vartanian et al., 2006b, Wang et al., 2002). Such papers also compare the UW-QOL with
other validated measures, for example the Medical Outcomes Study 36-Item Short-Form
Health Survey (SF-36) and a Hospital Anxiety and Depression Scale (HADS) (Vartanian
et al., 2006b).
4 Scoring and Presenting the UW-QOLv4
The scoring of the UW-QOLv4 is based on the earlier scoring of the questionnaire.
(Deleyiannis and Weymuller, 1996, Deleyiannis et al., 1997) and shown in > Table 6-3.
The UW-QOL has domains and general questions based upon discrete ordinal responses.
Scoring is scaled so that a score of 0 represents the worst possible response, and a score of 100
represents the best possible response. Scoring is scaled in equal stages from 0 to 100 to reflect
. Table 6-2
Translations of the UW-QOL (as currently known to the authors)
America
Asia and Africa
Chinese (both simplified and traditional)
Dutch
English
Europe
French
German
Greek
Hindi
Italian
Japanese
Malay
Marathi
Norwegian
Portuguese
Spanish
Swahili
Turkish
www.headandneckcancer.co.uk
the number of possible responses. Thus the pain domain has five possible responses which are
scored as 0, 25, 50, 75 and 100. The global question asking about overall QOL has six possible
responses, which are scored as 0, 20, 40, 60, 80 and 100.
The UW-QOL also has a question asking about which three domain issues were the most
important during the past seven days. A column for each domain should be created in the
dataset with each column being scored either as ‘1’ if that domain is chosen as important,
otherwise scored as ‘0’.
We illustrate next how the UW-QOL data can be presented in a compact form suitable for
peer review journals. The actual data used here comes from our use of the UW-QOL
questionnaire since 1995, version 4 since 2000, by patients with oral/oro-pharyngeal SCC
cancer whose primary treatment was by surgery with or without adjuvant radiotherapy. These
data from 550 patients were selected so as to give the QOL response closest to 12 months after
surgery, median 16 months, inter-quartile range 12–25 months.
4.1 Presenting Domain Scores
For each domain the > Table 6-4 gives the number of patients with each score, the mean
scores, Standard Error (SE) of mean scores, and the percentage of patients selecting the best
possible response (100). Though the data are quite clearly skewed towards the higher and
better scores no notable ‘floor’ or ‘ceiling’ effects are observed (> Table 6-4). Note that the
. Table 6-3
Scoring of the UW-QOLv4
University of Washington Quality of Life Questionnaire (UW-QOL v4)

This questionnaire asks about your health and quality of life over the past seven days. Please answer
all of the questions by ticking one box for each question.
1. Pain. (Tick one box: ☐)
☐ I have no pain. (100)
☐ There is mild pain not needing medication. (75)
☐ I have moderate pain - requires regular medication (e.g. paracetamol). (50)
☐ I have severe pain controlled only by prescription medicine (e.g. morphine). (25)
☐ I have severe pain, not controlled by medication. (0)
2. Appearance. (Tick one box: ☐)
☐ There is no change in my appearance. (100)
☐ The change in my appearance is minor. (75)
☐ My appearance bothers me but I remain active. (50)
☐ I feel significantly disfigured and limit my activities due to my appearance. (25)
☐ I cannot be with people due to my appearance. (0)
3. Activity. (Tick one box: ☐)
☐ I am as active as I have ever been. (100)
☐ There are times when I can’t keep up my old pace, but not often. (75)
☐ I am often tired and have slowed down my activities although I still get out (50)
☐ I don’t go out because I don’t have the strength. (25)
☐ I am usually in bed or chair and don’t leave home. (0)
4. Recreation. (Tick one box: ☐)
☐ There are no limitations to recreation at home or away from home. (100)
☐ There are a few things I can’t do but I still get out and enjoy life. (75)
☐ There are many times when I wish I could get out more, but I’m not up to it. (50)
☐ There are severe limitations to what I can do, mostly I stay at home and watch TV (25)
☐ I can’t do anything enjoyable. (0)
5. Swallowing. (Tick one box: ☐)
☐ I can swallow as well as ever. (100)
☐ I cannot swallow certain solid foods. (70)
☐ I can only swallow liquid food. (30)
☐ I cannot swallow because it "goes down the wrong way" and chokes me. (0)
6. Chewing. (Tick one box: ☐)
☐ I can chew as well as ever. (100)
☐ I can eat soft solids but cannot chew some foods. (50)
☐ I cannot even chew soft solids. (0)

7. Speech. (Tick one box: ☐)
☐ My speech is the same as always. (100)
☐ I have difficulty saying some words but I can be understood over the phone. (70)
☐ Only my family and friends can understand me. (30)
☐ I cannot be understood. (0)
8. Shoulder. (Tick one box: ☐)
☐ I have no problem with my shoulder. (100)
☐ My shoulder is stiff but it has not affected my activity or strength. (70)
☐ Pain or weakness in my shoulder has caused me to change my work/hobbies. (30)
☐ I cannot work or do my hobbies due to problems with my shoulder. (0)
9. Taste. (Tick one box: ☐)
☐ I can taste food normally. (100)
☐ I can taste most foods normally. (70)
☐ I can taste some foods. (30)
☐ I cannot taste any foods. (0)
10. Saliva. (Tick one box: ☐)
☐ My saliva is of normal consistency. (100)
☐ I have less saliva than normal, but it is enough. (70)
☐ I have too little saliva. (30)
☐ I have no saliva. (0)
11. Mood. (Tick one box: ☐)
☐ My mood is excellent and unaffected by my cancer. (100)
☐ My mood is generally good and only occasionally affected by my cancer. (75)
☐ I am neither in a good mood nor depressed about my cancer. (50)
☐ I am somewhat depressed about my cancer. (25)
☐ I am extremely depressed about my cancer. (0)
12. Anxiety. (Tick one box: ☐)
☐ I am not anxious about my cancer. (100)
☐ I am a little anxious about my cancer. (70)
☐ I am anxious about my cancer. (30)
☐ I am very anxious about my cancer. (0)
Which issues have been the most important to you during the past 7 days?
Tick ☐ up to 3 boxes.
☐ Pain
☐ Swallowing
☐ Taste
☐ Appearance
☐ Chewing
☐ Saliva

☐ Activity
☐ Speech
☐ Mood
☐ Recreation
☐ Shoulder
☐ Anxiety
General Questions
Compared to the month before you developed cancer, how would you rate your health-related
quality of life? (Tick one box: ☐)
☐ Much better (100)
☐ Somewhat better (75)
☐ About the same (50)
☐ Somewhat worse (25)
☐ Much worse (0)
In general, would you say your health-related quality of life during the past 7 days has been: (Tick
one box: ☐)
☐ Outstanding (100)
☐ Very good (80)
☐ Good (60)
☐ Fair (40)
☐ Poor (20)
☐ Very poor (0)
Overall quality of life includes not only physical and mental health, but also many other factors,
such as family, friends, spirituality, or personal leisure activities that are important to your
enjoyment of life. Considering everything in your life that contributes to your personal well-being,
rate your overall quality of life during the past 7 days. (Tick one box: ☐)
☐ Outstanding (100)
☐ Very good (80)
☐ Good (60)
☐ Fair (40)
☐ Poor (20)
☐ Very poor (0)
Please describe any other issues (medical or nonmedical) that are important to your quality of life and have not
been adequately addressed by our questions (you may attach additional sheets if needed)
standard deviation measures the scatter of raw data scores symmetrically about a mean and is
less useful with ordered categorical data with few categories. Standard error measures the
precision of the mean, and mean +/2 SE is the approximate 95% confidence interval for the
mean. Having few categories renders the median to be an insensitive measure and we therefore
do not recommend it to summarise UW-QOL domain scores.
4.2 Presenting Global Questions
The UW-QOL asks three global questions, one about how patients feel relative to before they
developed their cancer, one about their health-related QOL and one about their overall QOL.
These can also be scaled from 0 to 100 to enable ease of presentation of all key results using the
same scale. No notable ‘floor’ or ‘ceiling’ effects can be observed (> Table 6-5).
. Table 6-4
Presentation of UW-QOL domain results
UW-QoL Scores
UW-QOL N 0 25 30 50 70 75 100 Mean SE % Best Scores
Pain 545 6 31 107 131 270 79 1 50
Appearance 545 3 31 105 260 146 74 1 27
Activity 545 16 25 185 154 165 70 1 30
Recreation 547 10 47 116 210 164 72 1 30
Swallowing 544 25 58 194 267 77 1 49
Chewing 548 81 276 191 60 1 35
Speech 538 3 41 290 204 78 1 38
Shoulder 531 32 55 103 341 81 1 64
Taste* 365 20 69 96 180 73 2 49
Saliva* 360 24 66 88 182 73 2 51
Mood* 357 7 45 28 120 157 76 1 44
Anxiety* 354 18 46 142 148 74 2 42
*These were not in the earliest versions of the UW-QOL but were added later, hence fewer patients
. Table 6-5
Presentation of UW-QOL global results
UW-QOL Scores
% Best
UW-QOL N 0 20 25 40 50 60 75 80 100 Mean SE Scores*
A. Health-related QOL 343 25 58 139 55 66 56 2 76
compared to month before
had cancer
B. Health-related QOL 306 8 17 63 115 87 16 60 1 71
during the past 7 days
C. Overall QOL during the 306 2 14 64 105 105 16 63 1 74
past 7 days
*BEST SCORES: A: % scoring 50, 75 or 100; B & C: % scoring 60, 80 or 100
KEY to ratings:
A: (0) Much worse (25) Somewhat worse (50) About the same (75) Somewhat better (100) Much better
B: (0) V Poor (20) Poor (40) Fair (60) Good (80) V Good (100) Outstanding
C: (0) V Poor (20) Poor (40) Fair (60) Good (80) V Good (100) Outstanding
4.3 Presenting the Importance Question
The UW-QOL asks about which three domain issues were the most important during the past
seven days. Patients can choose up to three domains. Very occasionally patients may choose
more than three and when this occurs we suggest you score all those they have chosen as ‘1’
and all those not chosen as ‘0’.
Results can be presented as % of patients choosing each domain. The domains can also
be ranked in order. The five main concerns chosen at about 1–2 years after surgery were
saliva, swallowing, chewing, speech and appearance. These patients chose a mean of 2.3
domains (> Table 6-6).
4.4 Presentation of Composite Scores
An overall composite score (a simple average of UW-QOL domain scores) has not been
recommended for use since version 4 because as more domains have been added it became
less interpretable. However, more recent work applying factor analysis to the QOL data (see
later section), has suggested two composite scores, one for ‘physical function’ and another for
‘social–emotional function’. The physical function score is computed as the simple average of
6 domain scores – those of chewing, swallowing, speech, taste, saliva and appearance.
The social–emotional function is also computed as the simple average of 6 domain scores –
those of anxiety, mood, pain, activity, recreation and shoulder function. Missing data for the
UW-QOL is rare but to accommodate this it is suggested that the composite scores only be
computed if there are at least four component domain scores available. Further details of this
work will be given later. This section explains how to score and present the results.
These composite scores can be regarded as numerical for the purpose of presentation. The
overall median (Inter-Quartile Range) physical function score for patients at 1–2 years was 74
. Table 6-6
Presentation of UW-QOL importance
N of N of patients choosing the % of patients choosing the Rank

UW-QOL patients domain domain order
Pain 358 46 13 10
Appearance 358 76 21 5
Activity 358 67 19 6
Recreation 358 32 9 12
Swallowing 358 94 26 2
Chewing 358 89 25 3
Speech 357 87 24 4
Shoulder 358 37 10 11
Taste 358 56 16 9
Saliva 358 102 28 1
Mood 358 66 18 7
Anxiety 358 62 17 8
. Figure 6-1
Box-plot representation of the UW-QOL physical function composite score
(59 to 91) whilst that for social function was 80 (61 to 94). No notable ‘floor’ or ‘ceiling’ effects
can be observed. A box-plot graphical representation is also appropriate, as illustrated for
physical function below (> Figure 6-1). The patients are grouped according to key clinical
characteristics. Note that each box incorporates 50% of the data (i.e., that between the 25th
and the 75th percentiles) and is therefore the graphical equivalent of the Inter-Quartile Range.
One quarter of scores will lie at the bottom of or below the box and one quarter will lie at the
top of or above the box. The thick black line within each box represents the median score.
Individual patient ‘outlier’ scores are marked separately with a ‘circle’. The best set of physical
function scores were for those patients with less advanced oral cancer tumours and not
requiring free-flap surgery nor adjuvant radiotherapy (> Figure 6-1).
5 Features of the UW-QOL
5.1 Feasible and Acceptable
Instruments for routine use in clinical care need to be brief and simple to use. Too brief and
they lack content and precision; too complex and they reduce response rates and require
programming skills to process. The ideal is for a well-defined questionnaire that can be applied
and interpreted easily and for which there is no great burden of labour. Our experience of the
UW-QOL is that it is a practical, feasible and acceptable questionnaire, suitable for routine use
as it takes at most ten minutes for patients to complete, and the data processing is relatively
straightforward. Postal response rates are typically two-thirds to three-quarters of those
targeted and missing data rates are very low (1–3% amongst domains). For each domain
patients are required to choose one from only a few discrete hierarchical options and though
the distribution of responses is typically skewed there are no notable ‘floor’ or ‘ceiling’ effects
(seen if over 95% of responses go to one option only).
5.2 Face and Content Validity
Many of our published papers provide evidence in supporting the validity of the domains
and global questions of the UW-QOL. A valid instrument will measure what it is supposed
to measure and will not measure what it is not supposed to measure. It is our belief that the
UW-QOL version 4 has good ‘face’ and ‘content’ validity. ‘Face validity’ is a loose basic
concept and indicates that the questions have face value to the profession and to the patient.
Content validity is slightly more precise and indicates that the questions adequately cover the
breadth or content of what is meant to be included. It can apply to the breadth amongst
domains and of the detail within a domain. Our belief arises from verbal exchanges between
patient and consultant, from focus group work, from administering patients to respond via
touch-screen and from hundreds of written responses to the free-text question on the UW-
QOL that asks patients to describe any other important issues not covered by the main
questions.
5.3 Construct Validity
Construct validity is particularly relevant because there are no gold standards against which
to compare. Therefore we became involved in various studies collecting concurrent evidence
from other more detailed and established questionnaires to support the inference that the
UW-QOL has meaning. We have been able to demonstrate positive correlations where
expected between UW-QOL domains conceptually linked with the concurrent measures
and have demonstrated lesser correlations involving the other UW-QOL domains. Where
concurrent measures have established definitions of ‘case-ness’ (Rogers et al., 2008) we have
assessed sensitivity and the positive predictive value of the UW-QOL. In the absence of case-
ness in concurrent measures we have assessed the extent to which the UW-QOL domains
identify the more severely affected patients. We have also stratified our analysis of UW-QOL
domain and concurrent data by clinical characteristics of patients to see if the same clinical
differences exist for both measures. On the whole we have been surprised at the ability of
the UW-QOL domains, given the limited number of distinctions made within each scale, to
reflect the key essence of the more detailed questionnaires. We accept that the UW-QOL has
less precision than the alternative battery of detailed questionnaires but believe that as it
seems able to flag a high proportion of problem cases, and is simple and quick to
administer, it is well suited as a quick screening tool in routine clinics, as well as having
potential for use in clinical research.
5.4 Responsiveness
To use a QOL scale as an outcome variable to evaluate treatment efficacy requires evidence that
it can react or respond to real changes in a patient’s condition. Our work on the changes in the
UW-QOL after treatment, and between different clinical groups of patients, adds to the
evidence supporting the responsiveness or sensitivity of the UW-QOL to changes in patient
characteristics and to changes over time.
5.5 Interpretability, Clinical Effect and Sample Size
Researchers have quite a good handle on what constitutes a meaningful change in biochemical
measures and other well-used scales but lack experience in using QOL scales in everyday
practice. Interpretability is to do with clinical meaning and if we want to use the UW-QOL
scale as an outcome measure we need to know what constitutes a small but relevant clinical
change over time. One possible way to interpret and compare change is through what are
known as effect sizes (Kazis et al., 1989) with an effect size in this context being the mean
change in score between two time points divided by the standard deviation at the first time
point, an effect size of 0.20 being ‘small’, 0.50 ‘moderate’ and 0.80 ‘large’.
However the problem with UW-QOL domains and global scales is that they are not
numerical, have at most six discrete options and a skewed response. On the other hand the
new composite ‘Physical Function’ and ‘Social–emotional Function’ scores are numerical and
not particularly skewed and these offer the prospect of being used to assess clinical effect in
treatment evaluation studies and being used to develop sample size calculations. More
validation work is necessary to establish these composite scores.
An alternative to effect size is to categorise domain scores into binary measures from which
the % with the best score of 100, or the % below a certain cut-off score can be derived. We have
worked with the UW-QOL to identify suitable cut-offs in domain scores to help find patients
with more serious problems (Rogers et al., 2008) but there is a lack of evidence as to what
might constitute a meaningful change in these measures. Having suitable cut-off values does
however add to the interpretability of the UW-QOL in a routine clinic setting in helping to
screen patients with particular problems.
5.6 Stability of UWQOL for Longer-Term Survivors
Our longitudinal work indicates that changes in patient condition are most often seen within
the first few months after treatment and our cross-sectional work suggests stability after 1 year.
However, we have not yet investigated within-patient change using the UW-QOL beyond one
year. The analyses that follow are akin to ‘test-retest’ reliability and are unique to this chapter
and they describe the within-patient agreement between one annual survey and the next.
The data comes from version 4 of the UW-QOL questionnaire in annual surveys since
2000, from the cohort of MFU patients treated since 1992. There were 79 patients responding
in both 2000 and 2001, 63 in 2001 & 2002, 115 in 2002 & 2003, 150 in 2003 & 2004, 169 in
2004 & 2005, 173 in 2005 & 2006 and 202 in 2006 & 2007. The median time from surgery
increased from 24 months in 2000 to 53 months in 2006. In all 951 pairs of questionnaires
were analysed for agreement, 89% (851) being returned by patients at least 12 months after
surgery. Agreement was measured by the kappa coefficient weighted by applying standard
weights according to the number of categories in error. Kappa values (k) of 0.41–0.60 indicate
‘moderate’ agreement, 0.61–0.80 ‘good’ agreement and over 0.80 ‘very good’ agreement.
In summary, for survivors beyond one year (median 50 months) the 12 UW-QOL domains
and 2 global QOL items show moderate to good agreement from one annual survey to the next
(> Table 6-7). Domain importance was considerably less stable. Strongest agreement was for
swallowing (k = 0.73), chewing (k = 0.70) and saliva (k = 0.70) scores. The overall kappa
statistics are confirmed by narrow ranges from each separate set of paired surveys (2000 &
2001, 2001 & 2002 etc). There was moderate agreement for the global questions about health-
related (k = 0.50) and overall (k = 0.51) QOL. Less agreement (range for overall k: 0.26–0.49)
was seen for stating a domain issue as important and for the global question comparing to
before cancer had developed. There was also less agreement, as expected, across the UW-QOL
for patients first responding before 12 months (median 7 months). There was no evidence
found (from McNemars or McNemar-Bowker’s tests as appropriate at p < 0.01) for any score
to show a systematic improvement or deterioration between surveys.
5.7 Normative Data
Age and gender reference data for the UW0QOLv4 have been collected from 372 patients
attending general dental practices (Rogers et al., 2008). Oral and oropharyngeal patients
compared to the normative data showed that at baseline the key differences were anxiety,
pain, swallowing, chewing, and mood. At one year there were big differences in all domains
with deterioration in the oral cancer group. The difference was least notable in pain, shoulder,
mood and anxiety. Also the UW-QOL was compared with other questionnaires with estab-
lished reference data such as the Medical Outcomes Short Form 36 (Rogers et al., 2008) and
the EuroQol EQ-5D (Rogers et al., 2008). Compared to the UK population survey of 1993
using the EQ-5D, oral and oropharyngeal patients under 60 years of age fared significantly
worse than expected for their age. The mean (SE) VAS values of 74 (1) were at levels expected
for the most elderly (80 + years) of UK residents.
5.8 Composite Scores and Factor Analysis
The multi-dimensionality of the UW-QOL means that to obtain an overall feel of the UW-
QOL profile we have to trade off results from one domain against another. Some researchers
would prefer a single global index, though the difficulty with this is the loss of sensitivity to
subtle and perhaps important changes. There is no single clinical, physiological or biochemical
measure of health and no logical reason for imagining that any single value could possibly
summarise health-related QOL. Nevertheless in our early publications we did report a
composite score that was a simple average of domain scores. The positive correlation amongst
domain scores helped to justify the use of this composite score and to help establish it we
published a paper (Rogers et al., 2008) that demonstrated that it was able to discriminate in a
very noticeable way across all EORTC and SF-36 domains except for emotional function
(EORTC) and mental health (SF-36). As the UW-QOL has developed to include more
domains, including mood and anxiety, we moved away from reporting an overall score
believing it to be less interpretable.
Unique to this chapter we have revisited our pool of 2728 UW-QOL responses since 1995
to use factor analysis to investigate whether composite scores may be possible. These data
. Table 6-7
Within-patient agreement in UW-QOL responses between one annual survey and the next
Patients first
responding
<12months after
Patients responding at least 12 months after surgery surgery
Range of kappa statistic Overall Kappa
amongst the 7 paired Overall Kappa (results (results from 7
surveys (2000 & 2001, 2001 from 7 paired surveys paired surveys
& 2002 etc) combined) combined)
DOMAIN
Pain 0.58–0.70 0.63 0.48
Appearance 0.52–0.62 0.58 0.48
Activity 0.53–0.71 0.61 0.49
Recreation 0.57–0.71 0.62 0.42
Swallowing 0.70–0.81 0.73 0.49
Chewing 0.66–0.74 0.70 0.51
Speech 0.62–0.69 0.66 0.53
Shoulder 0.58–0.85 0.64 0.41
Taste 0.57–0.68 0.63 0.46
Saliva 0.61–0.78 0.70 0.46
Mood 0.46–0.61 0.52 0.38
Anxiety 0.38–0.63 0.55 0.48
IMPORTANCE
Pain 0.26–0.46 0.36 0.26
Appearance 0.26–0.45 0.40 0.38
Activity 0.15–0.52 0.35 0.09
Recreation 0.07–0.49 0.26 -0.06
Swallowing 0.41–0.60 0.46 0.36
Chewing 0.17–0.49 0.38 0.21
Speech 0.18–0.46 0.35 0.24
Shoulder 0.39–0.69 0.49 0.41
Taste 0.00–0.40 0.29 0.15
Saliva 0.38–0.55 0.45 0.36
Mood 0.16–0.37 0.28 0.22
Anxiety 0.13–0.45 0.31 0.30
GLOBAL
Compared to 0.29–0.44 0.37 0.37
month before
cancer
Health related 0.44–0.58 0.50 0.41
QOL
Overall QOL 0.47–0.60 0.51 0.36
come from our 1992–2007 cohort of patients with oral/oro-pharyngeal SCC cancer treated
primarily by surgery with or without adjuvant radiotherapy. First we analysed data for 550
patients with QOL responses closest to 12 months following surgery (median 16 months,
inter-quartile range 12–25 months) and second for all 2,728 responses (a mixed bag of data
comprising multiple responses from the same patient and data ranging from just before
operation to 15 years after surgery). We ran factor analyses using Maximum Likelihood
estimation and Promax oblique rotation. For both analyses the inspection of scree slopes
indicated a two factor solution explaining 58% and 56% of total variation respectively
with a very clear elbow in the plot with the first two factors lying above a straight line joining
factors 3 to 12. Each factor comprised six domains and correlations between all domain
scores were positive.
Factor 1 is interpreted as ‘physical function’ and comprises chewing, swallowing, speech,
taste, saliva and appearance. Factor 2 is interpreted as ‘social–emotional function’ and
comprises anxiety, mood, pain, activity, recreation and shoulder function. The factor 1 and
2 loadings for appearance were quite similar but were higher for factor 1 and do indicate that
appearance somehow straddles between physical and social–emotional function with slightly
more physical than social–emotional function. We computed physical and social function
scores as a simple average of their component domain scores. The next two figures show
variation in physical (> Figure 6-2) and social (> Figure 6-3) function scores over time, from
. Figure 6-2
Variation in UW-QOL physical function composite scores over time
. Figure 6-3
Variation in UW-QOL social–emotional function composite scores over time
before operation up to seven years after operation, the time frames being chosen to minimise
the possibility of multiple responses per patient within each time frame. Each bar includes a
different patient mix. The data clearly show the effect of treatment on physical function, with
similar levels of deficit reported from about one year. The effect of treatment on social–
emotional function is less pronounced and levels of function beyond 12 months are compara-
ble to before the operation.
These observations do of course mask the more subtle changes that can be observed from a
full profile of results and our conclusion is that these physical and social–emotional function
scores have a part to play in the presentation of results of the UW-QOL but in addition to and
not instead of the full profile of domain results. Clearly we need to do further work to develop
a better understanding of these composite scores and we expect to publish further clinical
validation work in the near future.
6 Comparison of Domains with Other Questionnaires
Initially the UW-QOL was compared with the Medical Outcomes Short Form 36. (Rogers
et al., 2008). By using the SF36 it was possible to compare the impact of surgery for oral cancer
on quality of life to normative reference data and hence put the disease and the affect of
treatment into a broader context. The same year Rogers et al. published a paper comparing the
UW-QOL to a well-validated European general cancer and head and neck specific cancer
questionnaire, EORTC QOQ-C33 and EORTC Head and Neck 35. Also (D’Antonio et al.,
1996) compared the UW-QOL with the Functional Assessment of Cancer Therapy (FACT).
More recently as head and neck cancer function specific questionnaires have emerged the
individual domains of the UW-QOLv4 have been compared with these (> Table 6-8). Corre-
lations have been strong. > Figures 6-4–6-7 illustrate the strong correlations seen between
saliva and xerostomia scale (XeQOLS), shoulder function and Neck Dissection Index (NDII),
appearance and Derriford scale (DAS-24), and between overall QOL and the EQ-5D visual
analogue scale.
Activity and recreation. The physical domain is common to many HRQOL questionnaires.
The UW-QOL activity and recreation domains have been compared to similar domains in
several other questionnaires such as the SF-36 (Rogers et al., 2008) SF-12 (Vilaseca et al.,
2006), EQ-5D (Rogers et al., 2008) On each occasion a strong relationship existed between
UW-QOL and these other measures in the appropriate domains. Rogers et al showed that
there are strong correlations between the five dimensional classification of the EQ-5D (mobil-
ity, self-care, usual activities, pain/discomfort and anxiety/depression) and appropriate
domains in the UW-QOLv4 (pain, activity, recreation, anxiety and mood).
Appearance. The appearance domain of the UW-QOLv4 has been compared with the
Derriford Appearance Scale (DAS24) (Rogers et al., 2008). There was strong correlation
between the UWQOL appearance domain and the DAS24 score (> Figure 6-6). A score of
<75 in the appearance domain is associated with distress and this cut off could act as a trigger
on an individual patient basis in out-patients for further evaluation with a view to offering
support and intervention.
. Table 6-8
Other head and neck cancer function specific questionnaires and measures that have been
compared with individual domains of the UW-QOL
UW-QOL Concurrent measure

Pain EORTC, EQ-5D, SF36
Appearance Derriford (DAS-24)
Activity EQ-5D
Recreation EQ-5D
Swallowing MDADI, SWAL-QOL
Chewing LORQ, EORTC, Mouth opening
Speech V-RQOL, VHI
Shoulder NDII, SDQ, physiotherapy range of movement
Taste EORTC
Saliva Xerostomia scale (XeQoLS), LORQ, EORTC
Mood HAD, CES-D, EORTC, EQ-5D
Anxiety HAD, EORTC, EQ-5D, SF36
Overall QOL SF36, EQ-5D, EORTC
HRQOL SF36, EQ-5D, EORTC
. Figure 6-4
Correlation between UW-QOL saliva and xerostomia scale (XeQOLS)
. Figure 6-5
Correlation between UW-QOL shoulder function and Neck Dissection Index (NDII)
. Figure 6-6
Correlation seen between UW-QOL appearance and Derriford scale (DAS-24)
. Figure 6-7
Correlation between UW-QOL overall QOL and the EQ-5D visual analogue scale
Chewing. The chewing domain has been compared with the Liverpool Oral Rehabilitation
Questionnaire (Rogers et al., 2008). There were significant correlations (P < 0.001) between
items in the LORQ and those in the UW-QOL and EORTC HN questionnaires.
The amount of mouth opening (trismus) is significantly associated with the UWQOL
chewing domain and more weakly with UWQOL overall quality of life question
(Rogers et al., 2008).
Emotion (mood and anxiety). These domains of the UW-QOL have been compared with
CES-D and HADS (Rogers et al., 2008), Beck Depression Inventory (BDI) (D’Antonio et al.,
1998), and the emotional functioning domains from the EORTC C30 (Rogers et al., 2008) and
strong relationships were found.
Global quality of life. In addition to earlier work on a composite UW-QOL score and its
relation to quality of life (Rogers et al., 2008), the global quality of life questions have been
explored in some detail.There were strong correlations between UW-QOL global measures
and EQ-5D VAS (> Figure 6-7). As with the EQ-5D VAS patient age was not correlated with
either the health-related UW-QOL item or with the overall UW-QOL item. The strongest
correlations between clinical demographic factors and both global items were regarding
tumour size, type of surgery and radiotherapy, again as found with the EQ-5D VAS.
Pain. Pain is a frequent component to HRQOL evaluation. The UW-QOL pain domain has
been shown to have strong correlation with the pain domain in other measures such as SF-36
(Rogers et al., 2008), SF-12 (Vilaseca et al., 2006), EQ-5D (Rogers et al., 2008), LORQ (Rogers
et al., 2008), EORTC C30 and H&N35 (Rogers et al., 2008).
Saliva. The UW-QOL saliva domain has been compared with the Xerostomia- Related
Quality of Life Questionnaire (XeQOLS). This work, yet to be published, showed a strong
correlation between the UWQOL saliva domain and the XeQOLS (> Figure 6-4). The strong
association was present across all of the four attributes of the XeQOLS namely physical,
personal/psychological, pain/discomfort, and social function.
Shoulder. There have been several studies specifically reporting shoulder dysfunction
using the UW-QOL both from a clinician-rated objective assessment and comparison
with other validated questionnaires (Rogers et al., 2008) Although the UW-QOL shoulder
domain is limited to one of four responses, when compared with the neck dissection
impairment index (NDII), and the shoulder disability questionnaire (SDQ) it performed
very well (> Figure 6-5).
Speech. Speech is a key outcome following head and neck cancer. Radford and co-workers
(Rogers et al., 2008) showed that there was significant correlation between UW-QOL speech
and Therapy Outcome Measures (TOM) laryngectomy, voice, phonology and dysarthria
subscales. Thomas et al (Rogers et al., 2008) compared the speech domain of the UW-QOL
with the Voice Handicap Index (VHI) and Voice related Quality of Life (VRQOL). In addition
the scores were compared with objective testing; GRBAS rating, speech intelligibility and
dysarthria rating. There were strong correlations and clear demarcations between UW-QOL
scores of 30, 70 and 100 on the voice questionnaires.
Swallowing. Swallowing is a key outcome parameter. Radford and co-workers (Rogers
et al., 2008) showed correlations between UW-QOL swallowing and Therapy Outcome
Measures (TOM) dysphagia. It has also been compared with the M. D. Anderson Dysphagia
Inventory (MDADI) and the SWALQOL together with an objective evaluation (Fibreoptic
Endoscopic Evaluation of Swallowing- FEES) (Rogers et al., 2008) with strong correlations
reported between the UW-QOL swallowing domain and the other measures. Percutaneous
Endoscopic Gastrostomy feeding (PEG) has an important role in providing nutritional
support in selected patients. Rogers et al., 2008 using a PEG specific questionnaire showed that
the UW-QOL swallowing domain strongly related to the continued need for a PEG tube in
long-term survivors.
Taste. The taste domain of the UW-QOL has been compared favourably with the EORTC
H&N taste question (Rogers et al., 2008).
6.1 Clinically Meaningful Cut-Offs
The comparison of the UW-QOL domains with other specific domain questionnaires has
allowed us to bring forward the concept that the UW-QOLv4 is an appropriate screening tool
in a busy clinical setting. It has been possible to postulate cut-offs that identify clinical distress
and could trigger intervention (Rogers et al., 2008). The algorithm is based on the UW-QOL
score and whether the patient considers this as important. The > Table 6-9 shows what we
consider as our trigger criteria for each domain and also shows considerable variation in the
percentage of patients selected at around 2 years from surgery according to key clinical patient
characteristics.
7 Resume of Published Peer Review Studies
There is a lot of information concerning quality of life outcomes following head and neck
cancer Rogers et al., 2008). The UW-QOL has help to inform clinicians and healthcare
professions on the multidisciplinary team regarding patient based outcomes and has helped
shape treatment protocols. In the section below papers from the literature that have reported
the UW-QOL to help inform outcome following treatment and evaluate treatment will be
briefly summarised. This will give an indication of the range of clinical settings the question-
naire has been used in.
Access. The UW-QOL has been used to help evaluate the best way of getting to a tumour to
facilitate as removal. In a comparison of aesthetic, functional and patient subjective outcomes
following lip-split mandibulotomy and mandibular lingual releasing access procedures the lip-
split mandibulotomy group reported significantly better speech, swallowing and chewing
(Rogers et al., 2008).
Base of tongue. Base of tongue cancer is a site that tends to confers a lot of problems in
terms of function and HRQOL following treatment. Using the UW-QOL as an outcome
measure surgical resection can offer good functional and overall QOL results for advanced
tumours when combined with reconstruction (Winter et al., 2004).
Chemoradiation. Chemoradiation (organ preservation) has recently become a strategy of
choice for certain H&N tumours. The UW-QOL has been used to report HRQOL following
chemoradiation and compare ‘organ preservation’ to surgery (LoTempio et al., 2005, Mowry
et al., 2006a, b).
Comorbidity. No significant association was found between comorbidity and pretreatment
UW-QOL scores, (Gourin et al., 2005) although it has been reported that American Society of
Anesthesiologists’ (ASA), which is often recorded as part of preoperative assessment, reflects
both survival and UW-QOL scores (Rogers et al., 2008).
Coping. The UW-QOL has been used in studies exploring issues such as coping style,
fighting spirit, level of social support and satisfaction with that support (Hassanein et al., 2001,
Hassanein et al., 2005) and in addition personality (Fang et al., 2004).
124
6
. Table 6-9
Trigger rates for patients at around 2 years from surgery (median 29, inter-quartile range23–45 months), by main clinical characteristics
Early Early Early Late Late

Oral Oral Oral Oral Oral
No flap Flap Flap Flap Flap
No RT No RT RT No RT RT Oropharynx
Trigger criteriaa % of N ¼ 101 % of N ¼ 82 % of N ¼ 42 % of N = 46 % of N = 57 % of N = 46
Pain 0, 25, 50 + IMP 8 16 5 11 20 13
Appearance 0, 25, 50 + IMP 2 11 10 15 29 13
Activity 0, 25, 50 + IMP 9 15 8 15 18 17
Recreation 0, 25, 50 + IMP 5 5 3 20 16 13
Swallowing 0, 30 4 8 10 9 35 35
Chewing 0 4 4 12 11 39 24
Speech 0, 30 4 7 10 11 24 11
The University of Washington Quality of Life Scale
Shoulder 0, 30 + IMP 8 17 15 9 15 11
Taste 0, 30 + IMP 6 6 14 9 30 13
Saliva 0, 30 + IMP 7 4 32 9 30 37
Mood 0, 25, 50 + IMP 13 13 22 9 20 11
Anxiety 0 or 30 15 9 20 14 24 22
One or more domains triggered 42 51 64 52 81 70
Three or more domains triggered 13 17 21 17 42 35
a
This is the trigger criteria preferred by the authors
For example with pain a scores of 0 alone, or 25 alone, or 50 plus the patient marking this as (IMP) would trigger the algorithm
Each patient is represented only the once; the closest to 24 months (but after 15months) was selected for analysis
Deprivation. The issue of deprivation (Rogers et al., 2008) and socioeconomic factors
(Vartanian et al., 2006a) have been evaluated in the context of the UW-QOL. Deprivation is
associated with poorer scores and additional rehabilitation social support should be consid-
ered for this vunerable group.
Donor site and free tissue transfer. Parts of the body are used to reconstuct the defect
following the removal of the cancer. The radial forearm free flap is the work horse in
reconstruction. The outcome of this donor site has been assessed (Smith et al., 2006).
The UW-QOL was used to help assess function in a paper comparing two bone flaps,
the fibula (leg) and deep circumflex laic (hip) (Rogers et al., 2008). Markkanen-Leppanen
et al., 2006 used the UW-QOL to report outcome following surgery for large carcinoma in
the oral cavity, oral pharynx, or hypopharynx with free-flap surgery with or without
radiotherapy.
Dysphagia (difficulty swallowing). Dysphagia is a significant morbidity of head-and-neck
cancer treatment, and the severity of dysphagia correlated with a compromised QOL as
reflected in the UW-QOL (Nguyen et al., 2005). Papers exploring the association with
swallowing specific questionnaires and the swallowing domain of the UW-QOL also reflect
the importance of swallowing as an outcome measure.
Laryngeal cancer. Loughran et al. (2005) has used the UW-QOL to compare outcomes and
voice following endoscopic resection or radiotherapy for early glottic cancer. Campbell et al.
(2004) used the UW-QOL in an evaluation of swallowing function and weight change and
HRQOL. The UW-QOL has also been used to report HRQOL following total laryngectomy
(Kazi et al., 2007, Vilaseca et al., 2006, Zhang et al., 2002), following partical laryngec-
tomy (Vigili et al., 2002) and to compare partial laryngectomy to total laryngectomy
(Wang et al., 2002).
Length of hospital admission. Length of stay is potentially a useful indicator of HRQOL as
measured by the UW-QOL because it is linked by tumour size, however, the relationship is
confounded by age, which tends to influence length of stay more than health related quality of
life (Rogers et al., 2008).
Long-term outcomes. As cure rates for head and neck cancer improve so the HRQOL of
survivors is an important consideration. There are at least three papers that have specifically
explored this area using the UW-QOL (Campbell et al., 2000, Rogers et al., 2008, Vartanian
et al., 2004).
Mandibular (Lower jaw) resection. Mandibular resection has an important influence on
HRQOL. The UW-QOL has been used to help quantify this from the patient perspective
(Petruzzelli et al., 2003, Rogers et al., 2008, Young et al., 2007).
Nasopharyngeal (back of the nose). The UW-QOL has been used to assess outcome in
nasopharyngeal cancer (Lovell et al., 2005, Talmi et al., 2002). Dry mouth, chewing, and ear
problems were of major concern with the majority of patients.
Neck dissection (clearance of the drainage lymph glands). Neck dissection is a common
surgical procedure in the management of head and neck cancer. The UW-QOL has helped
put the function deficit into a patient perspective and perhaps has helped lead to a less
radical approach and hence a better HRQOL outcome following this operation (Kuntz and
Weymuller 1999, Rogers et al., 2008).
Oral and Oropharyngeal. There has been a considerable amount of interest in the outcome
of oral and oropharyngeal cancer using the UW-QOL as a predictor of outcome and for
comparing surgical techniques (Klozar et al., 2001, Rogers et al., 2008).
Oral rehabilitation. Oral rehabilitation is an important aspect of maintaining HRQOL.

The UW-QOL has been used to explore this area (Rogers et al., 2008).
Palliative surgery. Smucler and Mazanek (2004) reported the effect of the combination of
laser excision and interstitial hyperthermia in palliative therapy of head and neck tumours in
the advanced stage of the disease.
Parotidectomy. The quality of life following parotidectomy for malignant and benign
disease has been published using the UW-QOL (Nitzan et al., 2004).
Photodynamic therapy. The UW-QOL has helped to show that patients with advanced
cancer of the head and neck, who have exhausted other treatment options, can achieve
significant clinical benefit and improvement in quality of life by using this laser based
treatment (D’Cruz et al., 2004).
Prosthetic voice restoration. Speech after laryngectomy is a key area of HRQOL
outcome and the UW-QOL has helped to inform practice (Gerwin and Culton 2005,
Kazi et al., 2006).
Radiotherapy. There have been recent innovations aimed at reducing the radiation dose to
the parotid glands. The technique is called intensity modulated radiotherapy (IMRT) and has
been shown to reduce the side effect of dry mouth (Scrimger et al., 2007).
Submandibular salivary gland transfer. Submandibular salivary gland transfer has a
potential role of in reducing or preventing dry mouth (xerostomia) in selected head
and neck patients receiving chemoradiotherapy (Al-Qahtani et al., 2006, Jha et al., 2000, Jha
et al., 2003).
Trauma (facial). Sen and co-workers (Rogers et al., 2008) used a modification of the
UW-QOL to assess outcome following maxillofacial trauma.
8 Version 5 of the UW-QOL
It seems appropriate to end this chapter by posing the question, is there a need for a version 5
of the UW-QOL? There is a natural reticence to modify a questionnaire that was first
published in 1993 with the most recent version (the addition of two extra domains in
version 4) published more than five years ago. Changing the questionnaire means that its
reporting is difficult to compare. There is no single pressing concern that argues directly for a
version 5. Possible changes to existing domains would be to consider building in the fact that
some patients report they have too much saliva, and also to add extra precision to the
chewing domain by increasing the number of responses from the current three levels. One
additional domain that might be added is that of intimacy. What could also be built in is an
indication of how much of the domain responses are related to comorbidity and how much to
the cancer. This apportioning may be impossible for the patient to judge in which case it might
help just to know whether or not the response was entirely due to something else other than
the cancer.
Summary Points
UW-QOL was first published in 1993
It has undergone three revisions with UW-QOLv4 being published in 2002
It is a simple questionnaire suitable for routine clinical practice

It has been used in many different head and neck cohorts
It is one of the commonest reported validated head and neck questionnaires
It does not have a copyright
It has been translated into numerous languages
When compared to other specific functional questionnaires the single items correlate
It is an ideal screening tool in routine head and neck cancer practice
References
Al-Qahtani K, Hier MP, Sultanum K, Black MJ. (2006). Kazis LE, Anderson JJ, Meehan RF. (1989). Med Care. 27:
Oral Surg Oral Med Oral Path Oral Rad Endo. 101: S178–189.
753–756. Kazi R, Kiverniti E, Prasad V, Venkitaraman R,
Andrade FP, Antunes JL, Durazzo MD. (2006). Braz Oral Nutting CM, Clarke P, Rhys-Evans P, Harrington
Res. 20: 290–296. KJ. (2006). Clin Otolaryng. 31: 511–517.
Campbell BH, Marbella A, Layde PM. (2000). Laryngol- Kazi R, De Cordova J, Kanagalingam J, Venkitaraman R,
ogy. 110: 895–906. Nutting CM, Clarke P, Rhys-Evans P, Harrington KJ.
Campbell BH, Spinelli K, Marbella AM, Myers KB, (2007). J Otolaryngol 69(2): 100–106.
Kuhn JC, Layde PM. (2004). Otolaryngology. 130: Klozar J, Lischkeova B, Betka J. (2001). Eur Arch
1100–1103. Otolaryngol. 258(10): 546–551.
D’Antonio LL, Zimmerman GJ, Cella DF, Long SA. Kuntz AL, Weymuller EA Jr. (1999). Laryngology. 109(8):
(1996). Otolaryngol Head Neck Surg. 122: 482–487. 1334–1338.
D’Antonio LL, Long SA, Zimmerman GJ, Peterman AH, LoTempio MM, Wang KH, Sadeghi A, Delacure MD,
Petti GH, Chonkich GD. (1998). Laryngology. 108: Juillard GF, Wang MB. (2005). Otolaryngol Head
806–811. Neck Surg. 132(6): 948–953.
D’Cruz AK, Robinson MH, Biel MA. (2004). Head Neck. Loughran S, Calder N, MacGregor FB, Carding P,
26: 232–240. MacKenzie K. (2005). Clin Otolaryngol. 30(1):42–47.
Deleyiannis FW-B Weymuller EA. (1996). Quality of life Lovell SJ, Wong HB, Loh KS, Ngo RY, Wilson JA. (2005).
in patients with head and neck cancer In: Myers EN, Head Neck. 27(10): 864–872.
Suen JY (ed.) Cancer of the Head and Neck, 3rd ed. Markkanen-Leppanen M, Makitie AA, Haapanen ML,
Saunders Company, pp. 904–916. Suominen E, Asko-Seljavaara S. (2006). Head
Deleyiannis FW-B, Weymuller EA, Coltrera MD. (1997). Neck. 28(3): 210–216.
Head Neck 19: 466–473. Mowry SE, Ho A, Lotempio MM, Sadeghi A, Blackwell
Fang WQ, Chen XY, Guan CH, Chen JF, Wang JB. (2004). KE, Wang MB. (2006a). Laryngology. 116(9):
Chin J Otolaryngol. 39(4): 227–231. 1589–1593.
Gerwin JM, Culton GL. (2005). Otolaryngol Head Neck Mowry SE, LoTempio MM, Sadeghi A, Wang KH,
Surg. 133(5): 685–688. Wang MB. (2006b). Otolaryngol Head Neck Surg.
Gourin CG, McAfee WJ, Neyman KM, Howington JW, 135(4): 565–570.
Podolsky RH, Terris DJ. (2005). Laryngology 115(8): Nguyen NP, Frank C, Moltz CC, Vos P, Smith HJ,
1371–1375. Karlsson U, Dutta S, Midyett A, Barloon J, Sallah
Hassan SJ, Weymuller EA Jr. (1993). Head Neck. 15(6): S. (2005). Int J Rad Oncol Biol Phys. 61(3): 772–778.
485–496. Nitzan D, Kronenberg J, Horowitz Z, Wolf M, Bedrin L,
Hassanein KA, Musgrove BT, Bradbury E. (2001). Brit J Chaushu G, Talmi YP. (2004). Plastic Recon Surg.
Oral Maxfax. 39(5): 340–345. 114(5): 1060–1067.
Hassanein KA, Musgrove BT, Bradbury E. (2005). J Cra- Omoro SA, Fann JR, Weymuller EA, Macharia IM,
nio Maxfax Surg. 33(6): 404–409. Yueh B. (2006). Int J Psychiatr Med. 36(3): 367–381.
Jha N, Seikaly H, McGaw T, Coulter L. (2000). Int J Rad Petruzzelli GJ, Knight FK, Vandevender D, Clark JI,
Onc. 46(1): 7–11. Emami B. (2003). Otolaryng Head Neck Surg.
Jha N, Seikaly H, Harris J, Williams D, Liu R, McGaw T, 129(6): 713–719.
Hofmann H, Robinson D, Hanson J, Barnaby P. Ringash J, Bezjak A. (2001). Head Neck. 23: 201–213.
(2003). Rad Onc 66(3): 283–289. Rogers et al. (2008). www.headandneckcancer.co.uk.
Scrimger R, Kanji A, Parliament M, Warkentin H, Vigili MG, Colacci AC, Magrini M, Cerro P, Marzetti A.
Field C, Jha N, Hanson J. (2007). Am J Clin Oncol (2002). Eur Arch Otolaryngol. 259(1): 11–16.
30(3): 271–277. Vilaseca I, Chen AY, Backscheider AG. (2006). Head Neck
Smith GI, Yeo D, Clark J, Choy ET, Gao K, Oates J, 28(4): 313–320.
O’Brien CJ. (2006). Br J Oral Maxfax Surg. 44(3): Wang G, Ji W, Pan Z, Guo X. (2002). Chung-Hua Chung
187–192. Liu Tsa Chih. Chin J Oncol. 24(1): 53–56.
Smucler R, Mazanek J. (2004). Lasers Surg Med. 34(1): Weymuller EA, Yueh B, Deleyiannis FWB, Kuntz AL,
12–17. Alsarraf R, Coltrera MD. (2000). Arch Otolaryngol
Talmi YP, Horowitz Z, Bedrin L, Wolf M, Chaushu G, Head Neck Surg. 126: 329–335.
Kronenberg J, Pfeffer MR. (2002). Cancer. 94(4): Weymuller EA Jr. Alsarraf R, Yueh B, Deleyiannis FW,
1012–1017. Coltrera MD. (2001). Arch Otolaryngol Head Neck
Thone M, Karengera D, Siciliano S, Reychler H. (2003). Surg. 127(5): 489–493.
Revue de Stomatologie et de Chirurgie Maxillo- Winter SC, Cassell O, Corbridge RJ, Goodacre T,
Faciale. 104(1): 19–24. Cox GJ. (2004). Clin Otolaryngol Allied Sci. 29(3):
Vartanian JG, Carvalho AL, Yueh B, Priante AV, de Melo 274–278.
RL, Correia LM, Kohler HF, Toyota J, Kowalski IS, Young CW, Pogrel MA, Schmidt BL. (2007). J Oral Max-
Kowalski LP. (2004). Arch. Otolaryngol Head Neck fax Surg. 65(4): 706–712.
Surg. 130(10): 1209–1213. Zhang L, Luan X, Pan X, Xie G, Xu F, Liu D, Lei D.
Vartanian JG, Carvalho AL, Toyota J, Kowalski IS, (2002). [Chinese] Chung Hua Erh Pi Yen Hou Ko
Kowalski LP. (2006a). Arch Otolaryngol Head Tsa Chih - Chin J Otolaryngol. 37(1): 11–14.
Neck Surg. 132(1): 32–35.
Vartanian JG, Carvalho AL, Yueh B, Furia CL, Toyota J,
McDowell JA. (2006b). Head Neck Surg. 28(12):
1115–1121.
7 Comparison of Three Quality
of Life Questionnaires in
Urinary Incontinence
Ja Hyeon Ku . Seung-June Oh
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
2 Types of Urinary Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
3 Limitations of Objective Tests on Urinary Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . 131
4 Generic QOL Questionnaires on Urinary Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

4.1 Advantages and Disadvantages of Generic QOL Questionnaires . . . . . . . . . . . . . . . . . . . . 132
4.2 Use of Generic QOL Questionnaires in Urinary Incontinence . . . . . . . . . . . . . . . . . . . . . . 132
5 Three Disease-Specific QOL Questionnaires in Urinary Incontinence . . . . . . . . . . . . 133

5.1 The BFLUTS Questionnaire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
5.2 The I-QOL Questionnaire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
5.3 The KHQ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
6 Comparisons Between the Three QOL Questionnaires in

Urinary Incontinence Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
6.1 Correlations Between the Three QOL Questionnaires . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
6.2 Minimal Clinically Importance Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
6.3 Recommendations for Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

130 7 Comparison of Three Quality of Life Questionnaires in Urinary Incontinence
Abstract: Urinary incontinence is not life-threatening, but loss of urinary control can affect
the social, psychological, domestic, occupational, physical, and the sexual aspects of patients’
lives. A number of reliable, valid instruments are available for assessing the impact of urinary
incontinence on quality of life (QOL). Of these many questionnaires, we selected three,
namely, the Bristol Female Lower Urinary Tract Symptoms (BFLUTS) questionnaire, the
Incontinence Quality of Life (I-QOL) questionnaire, and the King’s Health Questionnaire
(KHQ), and compared the results obtained. These questionnaires have been developed
primarily to assess urinary incontinence in women and the impact that urinary incontinence
has on aspects of everyday QOL. In the present study, when BFLUTS and I-QOL were
compared, the “BFLUTS-IS” and “BFLUTS-QOL” domains were found to correlate inversely
with only two and three domains in the I-QOL, respectively. When BFLUTS and the KHQ
were compared, the scores of the “BFLUTS-IS” and “BFLUTS-QOL” domains were found to
correlate with six domains in the KHQ questionnaire, but these correlations were low to
moderate, with correlation coefficients that ranged from 0.412 to 0.649. When I-QOL and the
KHQ were compared, “Role limitations” and “Emotional problems” domains in the KHQ
were found to correlate with all domains in the I-QOL. Moreover, significant negative
correlations were noted between the “Severity measures” domain in the KHQ and all domains
in the I-QOL; however, correlations were low to moderate (range: –0.384 to –0.650). Other
domains in the three questionnaires showed no correlation with each other. Since a plethora of
measurement instruments are available that vary in scope and content, subjective QOL results
of urinary incontinence using specific-condition QOL questionnaires may differ. Therefore,
before deciding on an instrument, the content on the instrument’s items should be thoroughly
reviewed to ensure that a particular aspect of QOL does not need additional assessment.
List of Abbreviations: BFLUTS, Bristol female lower urinary tract symptoms; BFLUTS-FS,
BFLUTS filling symptoms; BFLUTS-IS, BFLUTS incontinence symptoms; BFLUTS-QOL,
BFLUTS quality of life; BFLUTS-sex, BFLUTS sexual function; BFLUTS-VS, BFLUTS voiding
symptoms; I-QOL, incontinence quality of life; KHQ, King’s health questionnaire; QOL,
quality of life; SF-36, medical outcomes study short form-36
1 Introduction
Urinary incontinence is defined by the International Continence Society as “a complaint of

any involuntary leakage of urine” (Abrams et al., 2002), and is a common problem that affects
around 20–30% of the adult population (Sandvik et al., 1993; Thomas et al., 1980). Although
urinary incontinence is not life-threatening, loss of urinary control can affect the social,
psychological, domestic, occupational, physical, and the sexual aspects of patients’ lives
(Thomas et al., 1980). Assessments of incontinence severity have been the mainstay of
investigations on the burden imposed by this condition, but it is now recognized that
psychosocial adjustment to illness is as important as the status of the physical disease.
Therefore, it is essential that health care evaluations focus on this concern by incorporating
some measure of abstract subjective feelings or quality of life (QOL). However, it is difficult to
appreciate the extent to which troublesome incontinence symptoms disrupt daily life.
Generic measures of health status have proven useful for comparing general and specific
populations, estimating the relative burdens of different diseases, differentiating the health
benefits produced by a wide range of different treatments, and screening individual patients
Comparison of Three Quality of Life Questionnaires in Urinary Incontinence 7 131
(Manocchia et al., 1998). However, although generic QOL instruments can be used for
such assessments, they may not be sensitive enough to detect the characteristics of urinary
incontinence.
Thus, several disease-specific QOL instruments have been developed to provide detailed
information on how urinary incontinence affects patients’ lives. The Bristol Female Lower
Urinary Tract Symptoms (BFLUTS) questionnaire has good psychometric > validity and
reliability (Jackson et al., 1996). Using data from a large, randomized clinical trial that assessed
treatments for women with urinary incontinence, Wagner et al. (1996) demonstrated that the
Incontinence Quality of Life (I-QOL) questionnaire has good > internal consistency,
> reproducibility, and validity. Moreover, the King’s Health Questionnaire (KHQ) is a valid
and reliable instrument for assessing QOL in women with voiding symptoms, including
urinary incontinence (Kelleher et al., 1997). Nevertheless, no questionnaire is generally
accepted for the assessment of urinary incontinence. Based on the results of a previous
study (Oh and Ku, 2007), we focused on the impact of urinary incontinence on QOL using
three disease-specific QOL instruments and compared the results obtained.
2 Types of Urinary Incontinence
Urinary incontinence may be classified as stress urinary incontinence (involuntary leakage

during effort or exertion, or during sneezing or coughing), urge urinary incontinence (invol-
untary leakage accompanied by or immediately preceded by urgency), or mixed incontinence
(a combination of stress and urge urinary incontinence) (Abrams et al., 2002). Since the
underlying pathophysiologies of stress and urge urinary incontinence differ (i.e., stress urinary
incontinence is attributable to urethral hypermobility or sphincter weakness and urge urinary
incontinence results from detrusor overactivity) the symptomatic presentations of stress and
urge urinary incontinence differ. Thus, incontinence types may affect QOL differentially,
i.e., urge urinary incontinence has been reported to have a greater impact on QOL than stress
urinary incontinence (Robinson et al., 1998; Wyman et al., 1987). Nevertheless, regardless
of type, incontinence has been shown to have a detrimental impact on patient health-
related QOL.
3 Limitations of Objective Tests on Urinary Incontinence
The principle aim of objective tests is to reproduce a patient’s symptoms and to provide a
pathophysiological explanation. Several investigators have demonstrated that low maximal
urethral closure pressure and low Valsalva leak point pressure values are associated with
a higher grade of incontinence severity (Bump et al., 1997; Nitti and Combs, 1996).
However, objective diagnostic tests, which are usually pad and/or urodynamic tests, may
not take into account patients’ perceptions of their problems. Moreover, several authors have
found that symptom scores and QOL measures are not correlated with urodynamic measures
that they inadequately predict urodynamic outcome (FitzGerald and Brubaker, 2002; Swift
and Ostergard, 1995). Nager et al. (2001) found insignificant correlations between urody-
namic parameters and pad loss or QOL measures, and a poor correlation was found between
the subjective degrees of the bothersomenesses of symptoms and objective measures of degree
of urinary incontinence (Ryhammer et al., 1995; Wyman et al., 1987). Moreover, Oh and
Ku (2007) found a poor correlation between QOL questionnaire findings and objective test
results. Several studies have suggested that the impact of urinary incontinence is not solely a
function of its severity, but that it also depends on abilities of individuals to cope (Lenderking
et al., 1996). Moreover, an individual’s perception of continence status and the reporting of
leakage episodes have been reported to be modulated by differences in personality characteristics
(Frazer et al., 1989). These findings support the notion that since objective clinical measures do
not reflect the patient’s view, QOL measures should be included in clinical practice.
4 Generic QOL Questionnaires on Urinary Incontinence
Two broad categories of QOL questionnaires exist. Generic QOL questionnaires have been
developed for use in a wide range of clinical populations, whereas disease-specific QOL
questionnaires include items directly related to a specific medical condition.
4.1 Advantages and Disadvantages of Generic QOL Questionnaires
Generic measures of health-related QOL are recommended for assessing the general quality of
healthcare, and are used to monitor health in large populations, and this form of assessment
may be preferred in research covering the full adult age spectrum. However, although generic
outcome instruments are designed for use in any population, their validity and reliability
vis-à-vis a particular disease should be verified to ensure their appropriateness. Furthermore,
the abilities of generic instruments to assess QOL in impairment-specific populations are
likely to depend on group characteristics, and these instruments may be more susceptible to
factors other than disease severity and reflect wider aspects of daily life.
4.2 Use of Generic QOL Questionnaires in Urinary Incontinence
To date, several studies have used generic health questionnaires to evaluate the impact of
urinary incontinence on health-related QOL. The Sickness Impact Profile developed by
Hunskaar and Vinsnes (1991) revealed that urge symptoms are associated with greater QOL
impairment than the symptoms of stress urinary incontinence. Grimby et al. (1993) used the
Nottingham Health Profile Questionnaire to assess QOL and found that women suffering
from urge or mixed urinary incontinence reported emotional disturbances more so than
continent women. Simeonova et al. (1999) assessed QOL using a visual analogue scale and
found that women with urge or mixed urinary incontinence reported a lower QOL than those
with stress urinary incontinence. In fact, the majority of studies carried out over the past
decade indicate that urge urinary incontinence has a greater impact on health-related
QOL than stress urinary incontinence (Grimby et al., 1993; Hunskaar and Vinsnes, 1991;
Lenderking et al., 1996; Sandvik et al., 1993; Simeonova et al., 1999). However, Ho-Yin et al.
(2003) found that a generic questionnaire (the Medical Outcomes Study Short Form-36
[SF-36]) was unable to detect a significant difference between the QOL measurements of
women suffering from genuine stress urinary incontinence and detrusor instability.
The effect of stress urinary incontinence in women on QOL is a controversial issue.
Women with stress urinary incontinence have reported an inferior QOL than continent
women in some studies (Simeonove et al., 1999), whereas other studies have concluded
that stress urinary incontinence does not significantly affect QOL (Grimby et al., 1993).
Oh and Ku (2006) were unable to confirm the hypothesis that women suffering from stress
urinary incontinence have an inferior QOL using the generic SF-36 questionnaire. However,
the poor content validities of generic health scales for urinary incontinence would make
them less sensitive to disease-specific changes, which makes them unsuitable for assessing
treatment efficacy.
5 Three Disease-Specific QOL Questionnaires in Urinary

Incontinence
A large number of studies have been undertaken with a view toward developing a valid disease-
specific QOL instrument for use in clinical trials. However, no generally accepted symptom
questionnaire is currently available for the assessment of urinary incontinence. Furthermore,
questionnaires vary widely, depending on their intended purposes and target populations.
Nevertheless, tools are available for differentiating stress and urge urinary incontinence, for
quantifying urinary symptom severities, for assessing urinary symptom severities and impacts
of symptoms, and for measuring treatment outcomes.
The KHQ, I-QOL and BFLUTS questionnaires were developed primarily to assess
urinary incontinence and its impacts on aspects of QOL. These questionnaires have been
determined to be reliable and valid for use in incontinent women, and the International
Consultation on Incontinence recommended that these three questionnaires are suitable for
use in urinary incontinence (Donovan et al., 2002). However, these questionnaires have their
own particularities, and thus, instruments are invariably chosen based on the population
under consideration.
5.1 The BFLUTS Questionnaire
The BFLUTS questionnaire has eight items related to urinary incontinence, four of which
were designed specifically to quantify urinary leakage (Jackson et al., 1996) (> Table 7-1).
Twelve items address other symptoms; four are associated with the storage phase and eight
with the voiding phase. Nine items address other aspects of QOL and four items address sexual
function. The format of BFLUTS is similar to that of the International Continence Society
male questionnaire developed for the International Continence Society Benign Prostatic
Hyperplasia study (Donovan et al., 1996). Although it is biased towards assessing urinary
incontinence, the BFLUTS instrument was intended to cover all symptoms pertaining to
female lower urinary tract dysfunction (Jackson et al., 1996). Thus, unlike the majority of
other questionnaires, BFLUTS also includes questions on a range of troublesome symptoms
that are not commonly included in other questionnaires.
Recently, Brookes et al. (2004) described the development and validation of a scored
form based on the BFLUTS questionnaire. Three domains were identified to assess
symptoms: incontinence (five items, BFLUTS-IS); voiding (three items, BFLUTS-VS);
and filling (four items, BFLUTS-FS); with additional subscales for sexual function (two
items, BFLUTS-sex) and QOL (five items, BFLUTS-QOL). All scales have simple addi-
tive scores.
. Table 7-1
Items of urinary symptoms, sexual matters, and quality of life in the BFLUTS questionnaire and its
scored form
BFLUTS items Scored form

Urinary questions
“During the day, how many times do you urinate on average? BFLUTS-FS
During the night, how many times do you get up to urinate, on average? BFLUTS-FS
Do you have to rush to the toilet to urinate? BFLUTS-FS
Does urine leak before you can get to the toilet? BFLUTS-IS
Do you have pain in your bladder? BFLUTS-FS
How often do leak urine? BFLUTS-IS
Does urine leak when you are physically active, exert yourself, cough or sneeze? BFLUTS-IS
Do you ever leak urine for no obvious reason and without feeling that you want BFLUTS-IS
to go?
How much urinary leakage occurs?
Is there a delay before you can start to urinate? BFLUTS-VS
Do you have to strain to urinate? BFLUTS-VS
Do you stop and start more than once while you urinate? BFLUTS-VS
Do you leak urine when you are asleep? BFLUTS-IS
Would you say that the strength of your urinary stream is. . .
Have you ever blocked up completely so that you could not urinate at all and had
to have a catheter to drain the bladder?
Do you have a burning feeling when you urinate?
How often do you feel that your bladder has not emptied completely after you
have urinated?
Can you stop the flow of urine if you try while you are urinating?
How often do you pass urine during the day?
Sexual questions
Do you have pain or discomfort because of a dry vagina?
To what extent do you feel that your sex life has been spoilt by your urinary BFLUTS-sex
symptoms?
Do you have pain when you have sexual intercourse?
Do you leak urine when you have sexual intercourse? BFLUTS-sex
Quality of life
Do you have to change your underclothes or wear protection because of your
leakage?
How many times a day do you change the above items because of leakage?
Do you need to change your outer clothing during the day because of BFLUTS-QOL
urine leakage?
Do you cut down on the amount of fluid you drink so that your urinary symptoms BFLUTS-QOL
improve, and you can do the tings that you want to do?
To what extent have your urinary symptoms affected your ability to perform daily BFLUTS-QOL
tasks (e.g., cleaning, DIY, lifting objects)?
Comparison of Three Quality of Life Questionnaires in Urinary Incontinence

7 135
BFLUTS items Scored form

Do you avoid places and situations where you know a toilet is not nearby (e.g., BFLUTS-QOL
shopping, traveling, theater, church)?
Do your urinary symptoms interfere with physical activity (e.g., walking, dancing,
swimming)?
Overall, how much do your urinary symptoms interfere with your social life (going
out, meeting friends and so on)?
Overall, how much do your urinary symptoms interfere with your life? BFLUTS-QOL
How long have you had urinary symptoms that bother you?
If you had to spend the rest of your life with your urinary symptoms as they are
now, how would you feel?
The BFLUTS questionnaire contains items relating to urinary incontinence (eight items), symptoms associated with
the storage phase (four items) and the voiding phase (eight items), sexual function (four items), and quality
of life (nine items). The scored form of the BFLUTS questionnaire contains five domains; incontinence (five
items, BFLUTS-IS), voiding (three items, BFLUTS-VS), filling (four items, BFLUTS-FS), sexual function (two items,
BFLUTS-sex), and QOL (five items, BFLUTS-QOL). BFLUTS Bristol female lower urinary tract symptoms; BFLUTS-IS
BFLUTS incontinence symptoms; BFLUTS-VS BFLUTS voiding symptoms; BFLUTS-FS BFLUTS filling symptoms;
BFLUTS-sex BFLUTS sexual function; BFLUTS-QOL BFLUTS quality of life. Source: Jackson et al. (1996), printed with
permission; Brookes et al. (2004), printed with permission
5.2 The I-QOL Questionnaire
This disease-specific, 22-item I-QOL instrument includes questions that evaluate the distress
and impact of urinary incontinence in three domains: avoidance and limiting behavior (eight
items), social embarrassment (five items) and psychosocial impact (nine items) (> Table 7-2).
For example, the I-QOL includes questions such as “I worry about coughing and sneezing”
(Item 2 in avoidance and limiting behavior), “I worry about being embarrassed or humiliated
because of my incontinence” (Item 14 in social embarrassment) and “My incontinence makes
me feel likr I’m not a healthy person” (Item 15 in psychosocial impact). These item scores are
summed and then transformed to a 0–100 scale, where a higher score represents a better QOL
(Patrick et al., 1999; Wagner et al., 1996). The I-QOL questionnaire has been used to evaluate
the effect of different therapies on women with urinary incontinence (Almeida et al., 2004;
Bump et al., 2003; Vandoninck et al., 2003).
The I-QOL questionnaire is a highly targeted condition-specific questionnaire that assesses
the impact and distress of specific incontinence symptoms. The potential advantage of the I-QOL
over previous measures is its applicability to patients over a range of ages and with varying types
and severities of urinary incontinence. The I-QOL is capable of discriminating between different
levels of perceived severity, the frequencies of incontinent episodes, and stress test pad weights.
Because this instrument was developed on the basis that its items should be meaningful to those
with urinary incontinence, I-QOL scores are not significantly affected by demographic variables.
5.3 The KHQ
The KHQ is a 21-item, condition-specific instrument designed to assess QOL, and has been
shown to be a valid and reliable psychometric questionnaire (Kelleher et al., 1997)
. Table 7-2
Items and domains of I-QOL questionnaire
Items Domains
I worry about not being able to get to the toilet on time Avoidance and limiting
behavior
I worry about coughing and sneezing Avoidance and limiting
behavior
I have to be careful about standing up after sitting down Avoidance and limiting
behavior
I worry where the toilets are in new places Avoidance and limiting
behavior
I feel depressed Psychosocial impacts
I don’t feel free to leave my home for long periods of time Psychosocial impacts
I feel frustrated because my UI prevents me from doing what I want Psychosocial impacts
I worry about others smelling urine on me Social embarrassment
Incontinence is always on my mind Psychosocial impacts
It’s important for me to make frequent trips to the toilet Avoidance and limiting
behavior
Because of my incontinence, it is important to plan every detail in Avoidance and limiting
advance behavior
I worry about my incontinence getting worse as I grow older Social embarrassment
I have a hard time getting a good night’s sleep Avoidance and limiting
behavior
I worry about being embarrassed or humiliated be cause of my Social embarrassment
incontinence
My incontinence makes me feel like I’m not a healthy person Psychosocial impacts
My UI makes me feel helpless Psychosocial impacts
I get less enjoyment out of life because of my UI Psychosocial impacts
I worry about wetting myself Social embarrassment
I feel like I have no control over my bladder Social embarrassment
I have to watch what I drink Avoidance and limiting
behavior
My UI limits my choice of clothing Psychosocial impacts
I worry about having sex Psychosocial impacts
The I-QOL instrument contains 22 questions that evaluate both the distress and impact of urinary incontinence,
i.e., avoidance and limiting behavior (eight items), social embarrassment (five items), and psychosocial
impact (nine items). I-QOL incontinence quality of life; UI urinary incontinence. Source: Patrick et al. (1999), printed
with permission
(> Table 7-3), and in women with voiding symptoms, including stress urinary incontinence
and an overactive bladder (Bidmead et al., 2001; Kelleher et al., 1997; Uemura and Homma,
2004). The KHQ contains seven multi-domains, i.e., role limitations, physical limitations,
social limitations, personal relationships, emotional problems, sleep/energy disturbances, and
. Table 7-3
Items and domains of KHQ
Items Domains
How would you describe your health at the present? General health
perception
How much do you think your bladder problem affects your life? Impact on life
Does your bladder problem affect your household tasks? (cleaning, Role limitations
shopping etc)
Does your bladder problem affect your job, or your normal daily activities Role limitations
outside the home?
Does your bladder problem affect your physical activities (e.g., going for a Physical limitations
walk, running, sport, gym etc)?
Does your bladder problem affect your ability to travel? Physical limitations
Does your bladder problem limit your social life? Social limitations
Does your bladder problem limit your ability to see and visit friends? Social limitations
Does your bladder problem affect your family life? Social limitations
Does your bladder problem affect your relationship with your partner? Personal
relationships
Does your bladder problem affect your sex life? Personal
relationships
Does your bladder problem make you feel depressed? Emotional problems
Does your bladder problem make you feel anxious or nervous? Emotional problems
Does your bladder problem make you feel bad about yourself? Emotional problems
Does your bladder problem affect your sleep? Sleep/energy
disturbances
Does your bladder problem make you feel worn out and tired ? Sleep/energy
disturbances
Wear pads to keep dry? Severity measures
Be careful how much fluid you drink? Severity measures
Change your underclothes because they get wet? Severity measures
Worry in case you smell? Severity measures
Get embarrassed because of your bladder problem? Severity measures
The KHQ has 21 items that assess quality of life and contains seven domains, i.e., role limitations, physical
limitations, social limitations, personal relationships, emotional problems, sleep/energy disturbances, severity
measures, general health perceptions, and impact on life. KHQ: King’s Health Questionnaire. Source: Kelleher
et al. (1997), printed with permission
severity measures, and two single-item domains: general health perceptions and impact on
life. The scoring algorithm used has been described (Kelleher et al., 1997). Possible KHQ scores
range from zero (best health perception) to 100 (worst health perception).
An abridged version of the KHQ has also been developed and validated in Japan (Homma
and Uemura, 2004). Instead of the 16 items grouped into eight domains in the KHQ, this
edited version consists of six items grouped into two domains (daily life limitations and
mental health).
6 Comparisons Between the Three QOL Questionnaires in

Urinary Incontinence Patients
6.1 Correlations Between the Three QOL Questionnaires
Oh and Ku (2007) assessed 28 patients with stress urinary incontinence. When BFLUTS
and I-QOL were compared, the “BFLUTS-IS” domain was found to be inversely correlated
with the following domains in the I-QOL; the “Psychological impact” domain (r ¼ 0.441),
the “Social embarrassment” domain (r ¼ 0.456) and “Total sum” (r ¼ 0.488). Significant
negative correlations were also noted between the “BFLUTSQOL” domain and IQOL
“Avoidance behaviors” (r ¼ 0.649), “Psychological impact” (r ¼ 0.438), and “Social
embarrassment” domains (r ¼ 0.600) and IQOL “Total sum” (r ¼ 0.637). The other
three domains of BFLUTS were not found to correlate with any domain in the IQOL
(> Table 7-4).
When BFLUTS and KHQ were compared, the “BFLUTS-FS,” “BFLUTS-VS,” and
“BFLUTS-sex” domains were not found to be correlated with most KHQ domains. However,
the scores of the “BFLUTS-IS” and “BFLUTS-QOL” domains were correlated with those
of six domains in the KHQ questionnaire, but correlations were low to moderate with
correlation coefficients that ranged from 0.412 to 0.649. Highest correlation was found
between the “BFLUTS-QOL” domain and the KHQ “Emotional problems” domain (r ¼ 0.649)
(> Table 7-5).
When the I-QOL and KHQ were compared, the “Role limitations” and “Emotional
problems” domains in the KHQ were found to be correlated with all domains in the I-QOL.
Statistically significant negative correlations were also noted between the “Severity mea-
sures” domain in the KHQ and all domains in the I-QOL. However, correlations were low to
moderate (range: –0.384 to –0.650). Highest correlation was found between the “Social
. Table 7-4
Correlation coefficients between the BFLUTS and I-QOL
BFLUTS
Filling Voiding Incontinence Sexual Quality of
I-QOL symptoms symptoms symptoms function life
Avoidance 0.359 0.024 0.318 0.045 0.649**
behaviors
Psychological 0.131 0.007 0.441* 0.145 0.438*
impacts
Social 0.196 0.121 0.456* 0.005 0.600**
embarrassment
Total 0.293 0.014 0.488** 0.141 0.637**
“BFLUTS incontinence symptoms” domain was found to correlate inversely with the I-QOL “Psychological impact”
domain (r ¼ 0.441), “Social embarrassment” domain (r ¼ 0.456) and “Total sum” (r ¼ 0.488), and the “BFLUTS
quality of life” domain correlated with inversely with I-QOL “Avoidance behaviors” domain (r ¼ 0.649), “Psycho-
logical impact” domain (r ¼ 0.438), “Social embarrassment” domain (r ¼ 0.600) and “Total sum” (r ¼ 0.637).
The other three domains in BFLUTS did not correlate with any domain in the I-QOL. BFLUTS Bristol female
lower urinary tract symptoms; I-QOL incontinence quality of life. Source: Oh and Ku (2007), printed with permission
*
p < 0.05, **p < 0.01
. Table 7-5
Correlation coefficients between the BFLUTS and KHQ
KHQ
General Impact Role Physical Social Personal Emotional Sleep/energy Severity
BFLUTS health on life limitations limitations limitations relationships problems disturbances measures
Filling symptoms 0.400a 0.219 0.038 0.082 0.277 0.098 0.306 0.365 0.082
Voiding 0.231 0.198 0.309 0.512b 0.266 0.031 0.058 0.323 0.012
symptoms
Incontinence 0.412a 0.320 0.599b 0.530b 0.562b 0.172 0.505b 0.229 0.599b
symptoms
Sexual function 0.200 0.048 0.074 0.007 0.358 0.495b 0.071 0.361 0.178
a b b b b
Quality of life 0.544 0.230 0.615 0.235 0.540 0.247 0.649 0.558 0.539b
“BFLUTS filling symptoms,” “BFLUTS voiding symptoms,” and “BFLUTS sexual function” domains did not correlate with most domains in the KHQ questionnaire. Scores for “BFLUTS
incontinence symptoms” and “BFLUTS quality of life” domains were found to correlate with six domains in the KHQ questionnaire. BFLUTS Bristol Female Lower Urinary Tract
Symptoms; KHQ: King’s Health Questionnaire. Source: Oh and Ku (2007), printed with permission
a
p < 0.05, bp < 0.01
Comparison of Three Quality of Life Questionnaires in Urinary Incontinence
7
139
. Table 7-6
Correlation coefficients between the I-QOL and KHQ
I-QOL
Avoidance Psychological Social
KHQ behaviors impacts embarrassment Total
General health 0.304 0.063 0.147 0.196
Impact on life 0.209 0.471* 0.342 0.319
Role limitations 0.384 *
0.554 **
0.612 **
0.532**
Physical limitations 0.341 0.491 **
0.447 *
0.461*
Social limitations 0.260 0.388 *
0.417 *
0.397*
Personal relationships 0.072 0.029 0.074 0.019
Emotional problems 0.495** 0.611** 0.650** 0.639**
Sleep/energy 0.457* 0.344 0.341 0.464*
disturbances
Severity measures 0.499** 0.455* 0.570** 0.545**
“Role limitations,” “Emotional problems” and “Severity measures” domains in the KHQ correlated with all domains
in the I-QOL, but “General health” and “Personal relationships” domains in the KHQ were not significantly
correlates with any domain in the I-QOL. I-QOL incontinence quality of life; KHQ King’s Health Questionnaire.
Source: Oh and Ku (2007), printed with permission
*
p < 0.05, **p < 0.01
embarrassment” domain in the I-QOL and the “Emotional problems” domain in the KHQ
(r ¼ 0.650). “General health” and “Personal relationships” domains in the KHQ were not
found to be significantly correlated with any domain in the I-QOL (> Table 7-6).
6.2 Minimal Clinically Importance Change
In a study that used data from two clinical trials on tolterodine in overactive bladder, Kelleher
et al. (2004) used > anchor-based approach and > distribution-based approach to calculate
minimally important differences for the KHQ. They found that a KHQ change of 5 points
indicated a clinically important difference in health-related QOL. In a randomized, double-
blind, placebo-controlled study on an oxybutynin transdermal patch, a reduction of three
times per week was found to be the minimum important change in incontinence frequency
among Japanese patients with an overactive bladder (Homma and Koyama, 2006). However,
the KHQ requires further testing before it can be used in men with incontinence symptoms
other than an overactive bladder (Symonds, 2003).
Recently, in a study using data from two randomized, placebo-controlled duloxetine
studies, Yalcin et al. (2006) proposed 2.5 points as a reasonable guide for an I-QOL
> between-treatment minimal clinically importance change and 6.3 points as a > within-
treatment minimal clinically importance change. However, the I-QOL needs further testing
before use in incontinent men (Symonds, 2003).
However, further research is needed to establish clinically relevant and interpretable cut-
off points for BFLUTS scores (Brookes et al., 2004). Hence, the BFLUTS requires appropriate
whole instrument testing, including testing of the health-related QOL and sexual functioning
items (Symonds, 2003).
6.3 Recommendations for Use
Based on assessments of validity, reliability, responsiveness, utility, and frequency of use, Ross
et al. (2006) recommended that some questionnaires, including the I-QOL, be viewed as first
choice QOL measures in trials on incontinence treatments.
Naughton et al. (2004) identified 1,300 published articles relating to symptoms of urinary
incontinence, effects on QOL, and outcomes assessments of incontinence treatments,
evaluated the instruments used using priori criteria and graded for quality. To be highly
recommended (grade A), an instrument was required to have supportive published data that
provided evidence of its reliability, validity, and responsiveness to change. For a grade B
recommendation, an instrument was required to have published data that provided evidence
of its reliability and validity and of its relevance to individuals with urinary incontinence.
Questionnaires must have reached at least grade B to be recommended for use. For assessing
symptoms of urinary incontinence, the KHQ was highly recommended (grade A), BFLUTS
was also recommended (grade B), but the I-QOL was not. For assessing bothersomeness in
persons with incontinence, only BFLUTS was recommended (grade B), and for assessing the
effect of incontinence on QOL, the I-QOL and the KHQ were highly recommended (grade A),
whereas BFLUTS was not recommended.
Recently, Reid et al. (2007) undertook a psychometric validation of three questionnaires,
including BFLUTS and KHQ, to assess surgical outcomes of stress urinary incontinence. They
found that the all three questionnaires had limitations when used as outcome measures. These
findings suggest that when instruments are used in different populations their psychometric
properties may change.
7 Conclusions
Health-related QOL is partly a reflection of an individual’s ability to cope and adapt to a new
life situation. The effect of physical disability or illness cannot be understood without taking
into consideration the specific areas of functioning affected by an individual’s physical
condition and those aspects of QOL that are of particular importance to an individual.
Subjective QOL results on urinary incontinence using specific-condition QOL questionnaires
may differ because of the many measurement instruments available that vary in scope and
content. However, this does not imply that several disease-specific QOL instruments should be
used simultaneously to evaluate patients with urinary incontinence. Rather, it means that
before deciding on an instrument, the content on the instrument’s items should be thoroughly
reviewed to ensure that a particular aspect of QOL does not need additional assessment.
Summary Points
Urinary incontinence is a common problem and may affect patient QOL.
Urge urinary incontinence has a greater impact on QOL than stress urinary incontinence.
Since objective clinical measures do not reflect the patient’s viewpoint, QOL measures
should be included in clinical practice.
Because generic health scales have poor content validity for urinary incontinence, they
may be unsuitable for assessing treatment efficacy.
BFLUTS includes a number of other troublesome symptoms that are not commonly
included in other questionnaires, in addition to a range of incontinence symptoms.
However, BFLUTS requires appropriate whole instrument testing, including of its
health-related QOL and sexual functioning items.
The potential advantage of the I-QOL over previous measures is its applicability to
patients over a range of ages and with varying types and severities of urinary incontinence.
The I-QOL is highly recommended for assessing the effect of incontinence on QOL, but it
needs further testing before use in incontinent men.
KHQ is highly recommended for assessing symptoms of urinary incontinence and their
effects on QOL. However, the KHQ requires further testing in men with incontinence
symptoms other than an overactive bladder.
Subjective QOL results in women with urinary incontinence using specific-condition QOL
questionnaires can differ because the many measurement instruments available in scope
and content.
References
Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Hunskaar S, Vinsnes A. (1991). J Am Geriatr Soc. 39:
Ulmsten U, van Kerrebroeck P, Victor A, Wein A. 378–382.
(2002). Neurourol Urodyn. 21: 167–178. Jackson S, Donovan J, Brookes S, Eckford S, Swithinbank
Almeida FG, Bruschini H, Srougi M. (2004). J Urol. 171: L, Abrams P. (1996). Br J Urol. 77: 805–812.
1571–1574. Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. (1997).
Bidmead J, Cardozo LD, McLellan A, Khullar V, Kelleher Br J Obstet Gynaecol. 104: 1374–1379.
CJ. (2001). BJOG. 108: 408–413. Kelleher CJ, Pleil AM, Reese PR, Burgess SM, Brodish
Brookes ST, Donovan JL, Wright M, Jackson S, Abrams P. PH. (2004). Br J Obstet Gynaecol. 111: 605–612.
(2004). Am J Obstet Gynecol 191: 73–82. Lenderking WR, Nackley JF, Anderson RB, Testa MA.
Bump RC, Coates KW, Cundiff GW, Harris RL, Weidner (1996). Pharmacoeconomics. 9: 11–23.
AC. (1997). Am J Obstet Gynecol. 177: 303–310. Manocchia M, Bayliss MS, Connor J. (1998). SF-36
Bump RC, Norton PA, Zinner NR, Yalcin I. (2003). Health Survey Annotated Bibliography: Second
Duloxetine Urinary Incontinence Study Group Edition (1988–1996). The Health Assessment Lab,
Obstet Gynecol. 102: 76–83. New England Medical Center, Boston, MA.
Donovan JL, Abrams P, Peters TJ, Kay HE, Reynard J, Nager CW, Schulz JA, Stanton SL, Monga A. (2001). Int
Chapple C, De La Rosette JJ, Kondo A. (1996). Br J Urogynecol J. 12: 395–400.
Urol. 77: 554–562. Naughton MJ, Donovan J, Badia X, Corcos J, Gotoh M,
Donovan JL, Badia X, Corcos J, Gotoh M, Kelleher C, Kelleher C, Lukacs B, Shaw C. (2004). Gastroenter-
Naughton M. (2002). In: Abrams P, Cardozo L, ology. 126(Suppl 1): S114–S123.
Khoury S, Wein A (eds.) Incontinence. Health Pub- Nitti VW, Combs AJ. (1996). J Urol. 155: 281–285.
lication Ltd, Plymouth, UK, pp. 267–316. Oh SJ, Ku JH. (2006). Qual Life Res. 15: 493–501.
FitzGerald MP, Brubaker L. (2002). Neurourol Urodyn. Oh SJ, Ku JH. (2007). Scand J Urol Nephrol. 41: 66–71.
21: 30–35. Patrick DL, Martin ML, Bushnell DM, Yalcin I,
Frazer MI, Haylen BT, Sutherst JR. (1989). Br J Urol. 63: Wagner TH, Buesching DP. (1999). Urology. 53:
14–15. 71–76.
Grimby A, Milsom I, Molander U, Wiklund I, Ekelund P. Reid FM, Smith ARB, Dunn G. (2007). Neurourol
(1993). Age Ageing 22: 82–89. Urodyn. 26L: 123–128.
Homma Y, Koyama N. (2006). Neurourol Urodyn. 25: Robinson D, Pearce KF, Preisser JS, Dugan E, Suggs PK,
228–235. Cohen SJ. (1998). Obstet Gynecol. 91: 224–228.
Homma Y, Uemura S. (2004). BJU Int. 93: 1009–1013. Ross S, Soroka D, Karanhalios A, Glazener CMA,
Ho-Yin PL, Man-Wah P, Shing-Kai Yip. (2003). Acta Hay-Smith EJ, Drutz HP. (2006). Int Urogynecol J.
Obstet Gynecol Scand. 82: 275–279. 17: 272–285.
Ryhammer AM, Djurhuus JC, Laurberg S, Hermann AP. Uemura S, Homma Y. (2004). Neurourol. Urodyn. 23:
(1995). Neurourol Urodyn. 14: 456–457. 94–100.
Sandvik H, Kveine E, Hunskaar S. (1993). Scand J Caring Vandoninck V, Van Balken MR, Finazzi Agro E, Petta F,
Sci. 7: 53–56. Caltagirone C, Heesakkers JP, Kiemenev LA,
Simeonova Z, Milsom I, Kullendorff AM, Molander U, Debruyne FM, Bemelmans BL. (2003). Neurourol
Bengtsson C. (1999). Acta Obstet Gynecol Scand. Urodyn. 22: 17–23.
78: 546–551. Wagner TH, Patrick DL, Bavendam TG, Martin ML,
Swift SE, Ostergard DR. (1995). Obstet Gynecol. 85: Buesching DP. (1996). Urology. 47: 67–71.
704–708. Wyman JF, Harkins SW, Choi SC, Taylor JR, Fantl JA.
Symonds T. (2003). Eur Urol. 43: 219–225. (1987). Obstet Gynecol. 70: 378–381.
Thomas TM, Plymat KR, Blannin J, Meade TW. (1980). Yalcin I, Patrick DL, Summers K, Kinchen K, Bump RC.
Br Med J. 281: 1243–1245. (2006). Urology. 67: 1304–1308.
8 Overview of Instruments
Used to Assess Quality of
Life in Dentistry
C. McGrath . S. N. Rogers
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
2 Use of Generic Health-Related Quality of Life Measures in Dentistry . . . . . . . . . . . . . 147
3 Oral Health-Related Quality of Life Measures in Dentistry . . . . . . . . . . . . . . . . . . . . . . . . 149
4 Condition Specific Oral Health-Related Quality of Life

Measures in Dentistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
5 Assessing the Impact of Oral Health on the Quality of Life of Children . . . . . . . . . . . 154
6 Uses and Future Directions of Health-Related Quality of Life

Measures in Dentistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

146 8 Overview of Instruments Used to Assess Quality of Life in Dentistry
Abstract: In recent times there has been an explosion of interest in assessing the impact of
> oral health status on quality of life (QOL) and in assessing the impact of oral health care
services and initiatives to QOL within dentistry. This has following developments within other
fields of medicine as well as the understanding that oral health is not equated with the absence
of oral disease. Clinical oral health status measures have provided little insight into the
physical, social and psychological consequences of oral health are of little use in assessing
the impact of oral health on QOL. Attempts have been made to use generic health-related
quality of life (HQOL) measures which have been used in other fields within medicine to
compare the impact on different oral health states on QOL. However, for the most part generic
HQOL have not been useful in assessing subtle difference in oral health states or changes to
oral health following oral health care interventions except in relation to more severe oral
diseases, such as oral cancer. This has led to the development of what are termed generic oral
health related quality of life (OHQOL) measures to assess the impact of the range of oral
diseases and conditions to QOL. A plethora of OHQOL measures exist and they have generally
been more useful in describing the impact of different oral health states to QOL. In assessing
the impact of specific oral health states condition specific HQOL have been developed and
these have proved useful in describing the impact of specific condition and treatment
initiatives on QOL. In many situations the preference of condition specific measure relative
to generic HQOL and OHQOL has not been established. More recently advances have been in
assessing the impact of oral health on QOL of children which has proved challenging. For the
most part attention has focused on developing generic child OHQOL measures. Despite the
availability of QOL measure within dentistry there has been little use in clinical practice and
limited determination of the effects of different oral health care intervention to QOL. Use and
future directions of research of QOL measures within dentistry are provided.
List of Abbreviations: CHQ, child health questionnaire; COIDP, child oral impact on daily
performance measure; COIHP, child oral health impact profile; CPQ, child perception ques-
tionnaire; DIDL, dental impact on daily living; DIP, dental impact profile; ECOHIS, early
childhood oral health impact scale; EORTC: HN, European Organization for Research and
Treatment of Cancer head and neck questionnaire; EuroQOL, European quality of life mea-
sure; FIS, family impact scale; GOHAI, geriatric oral health assessment index; HQOL, health-
related quality of life; LORQ, Liverpool oral rehabilitation questionnaire; LSI, Liverpool sicca
index; MCOHQOL, Michigan child oral health-related quality of life scale; MPDS, Manchester
orofacial pain disability; OHIP, oral health impact profile; OHQOL, oral health-related quality
of life; OH-QOL UK, United Kingdom oral health-related quality of life measure; OIDP, oral
impacts on daily performances; OQLQ, orthognathic quality of life questionnaire; PedsQL,
paediatric quality of life inventory; PPQ, parental perception questionnaire; QOL, quality
of life; SF12, (health survey) short form 12; SF36, (health survey) short form 36; SIDS,
social impacts of dental diseases; SIP, sickness impact profile; SOHSI, subjective oral health
status indicator; UWQOL, University of Washington quality of life questionnaire; XeQOLS,
xerostomia- related quality of life questionnaire; XI, xerostomia inventory
1 Introduction
This value and use of socio-dental indicator to assess the impact of oral health status on
quality of life (QOL) and to assess changes to QOL following oral health care interventions
Overview of Instruments Used to Assess Quality of Life in Dentistry 8 147
has been advocated since the 1970s (McGrath and Newsome, 2007). This followed the
considerable development and widespread use of health status measures (Health-related
Quality of Life (HQOL) measures) in medicine on the basis that the extension of people’s
life spans and the enhancement of their QOL are two central goals of health care systems. It has
long been recognized that clinical “objective” oral health status measures, fail to measure the
consequences of oral diseases and conditions and thus provide little insight into the likely
physical, social and psychological effects of oral health.
The prevailing concept of oral health has evolved from a narrowly reductive perspective,
where oral health was equated with the absence of oral disease to a multi dimensional concept
and thus the need to incorporate HQOL measures in the assessment of oral health (Locker,
1998). Moreover, there is a growing consensus that oral health states (aside from oral cancer)
are rarely if ever life threatening and thus the effects of oral ill health and the consequences of
oral health care are largely related to QOL. This has resulted in paradigm shift within dentistry
to patient/ client centered assessments and a rapid expansion in the use of HQOL measures to
assess oral health needs, describe treatment consequences and in evaluating the outcomes from
oral health care interventions (Buck and Newton, 2001).
2 Use of Generic Health-Related Quality of Life Measures in

Dentistry
The use of generic HQOL measures in assessing the impact of oral health status on life quality
has obvious advantages in that many of these measures have already undergone rigorous
psychometric analysis (Reisine, 1996). Moreover, their use in dentistry has the potential to be a
useful mechanism for comparing the impact of oral health with other health conditions, and
in that way provide a useful tool to describe their relative importance to people’s lives, and also
possibly play a role in prioritizing oral health care within health care systems. However, others
argue that generic health related quality of life instruments have very limited use in the
assessment of the impact of oral health on life quality because they are insufficiently sensitive
to measure the more subtle psychosocial impacts of oral problems. Moreover, in one commu-
nity-base study, oral health represented a dimension of health separate from other health
measures and should arguably be seen as a separate construct (Dolan et al., 1991). In contrast,
others have described oral health as part of the broader condition of general health and thus
the role of generic health-related quality of life measures in dentistry. Commonly employed
generic health related quality of life instruments used in dentistry are listed in > Table 8-1.
One generic HQOL measure the Sickness Impact Profile (SIP) has received particular
attention for being of use in assessing the impact of oral health on life quality (Bergner et al., 1976).
. Table 8-1
Examples of generic health-related quality of life measures used in dentistry
References Name of measure

Bergner et al. (1976) Sickness Impact Profile (SIP)
Ware and Sherbourne (1992) Medical Outcome Survey short form (SF36)
EuroQOL Group (1990) European Quality of Life measure (EuroQOL)
The psychometric properties of the SIP in a wide variety of settings are well documented.
In one study population chosen to validate SIP use in relation to oral health, a small convenient
non-random group of 152 patients from private dental practices, comprising of 48 > tempro-
mandibular joint dysfunction (TMD) patients, 33 patients with > periodontal disease, 23 denture
patients and 48 recall patients (> recall dental patients) were chosen (Reisine et al., 1989). The
construct validity of the measure was assessed through relating the domain scores of SIP to the four
patient groups. The hypothesis was that recall patients would have the lowest impact scores.
The findings indicated that TMD patients experienced a high degree of impact, in particular
the domains of well-being, social functioning and symptoms were affected, whereas, recall
patients experienced low impact, thus supporting its construct validity. That aside, the principal
investigators raised concerns about its sensitivity in relation to less extreme oral health problems
and in relation to clinical oral health status such as > dental caries status (number of decayed,
missing or filled teeth). Likewise, the sensitivity of the instrument in relation to changes with
dental treatment and disease has been questioned.
Another generic HQOL of life measure also reputed for its psychometric properties, the
Medical Outcome Survey short form SF36 (Ware and Sherbourne, 1992), was utilized in a
study to compare its performance with an oral health specific quality of life measure among a
group of adults seeking prosthetic care at a UK dental hospital (Allen et al., 1999). It was
concluded that a generic oral health related quality of life (OHQOL) measure demonstrated
better discriminate and construct validity properties compared with the generic HQOL
measure. Furthermore, the SF36 has been reported to be of limited use in determining changes
to quality of life following oral implant therapy (Allen and McMillan, 2003). In studies
comparing different measurement approaches to assessing the impact dentofacial deformity
on QOL it was concluded that the SF36 was unable to distinguish difference in HQOL between
those with and without dentofacial deformities and thus it has limited use in dentofacial
deformities research or practice (Cunningham et al., 2002). A study evaluating the perfor-
mance of SF12 in the oral surgery setting (in response to > dento-alveolar surgery) reported
that whilst SF-12 may have use in describing the consequences of dento-alveolar surgery it had
little value in assessing the need for dento-alveolar surgery or in assessing the outcome from
dento-alveolar surgery (McGrath et al., 2003).
The EuroQOL was developed by an international research group set up in 1987 to develop
a standardized, non-specific instrument for describing and valuing HQOL (EuroQOL, 1991).
The EuroQOL EQ-5D provides both a compact descriptive profile and a single index value
that can be used in the clinical and economic evaluation of health care. It consist of in two-
parts, part 1 is a self-reported description using a five dimensional classification of mobility,
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has three
statements organized hierarchically according to severity and the patient is asked to tick the
statement that best describes how they feel “today.” A total of 243 possible health states are
defined in this way and each heath state may be converted to a “utility health index” score
using tables of values in the EQ-5D user guide and for which the maximum score of 1 indicates
the best health state. Part 2 is a self-rated valuation using a visual analogue scale thermometer
in which patients’ rate how good or bad their own health is “today.” The best state they could
imagine would score 100 and the worst stage imaginable would score 0. The use of EQ-5D
among oral and oral pharyngeal cancer suffers has proved useful in understanding how these
cancers impact on life quality (Rogers et al., 1996). In addition, EQ-5D proved useful in
distinguishing different periodontal health states and thus has potential for describing the
burden of different oral disease on QOL (Brennan et al., 2007). Moreover, the EuroQOL is
reported to have comparable discriminant validity as a generic OHQOL measure (Brennan

and Spencer, 2005).
Various other generic HQOL status measures including assessments of pain, anxiety and
depression, life satisfaction, adjustment and coping, coherence and social functioning have
been used in dental research (McGrath and Newsome, 2007). However, it is beyond the scope
of this chapter to describe these in specific detail since the research focus has been on aspect of
QOL per se rather than a comprehensive assessment of the impact of oral diseases and
conditions to life quality. Thus far the value and use of generic HQOL measures in dentistry
is unclear as there are concerns about their ability to distinguish between different oral states
and to measure subtle changes in oral health. Moreover, in many cases they perform less well
than oral health specific measure at assessing the impact of oral health on quality of life.
3 Oral Health-Related Quality of Life Measures in Dentistry
Since the 1980s a plethora of generic oral health-related quality of life (OHQOL) measures
have been developed to asses the impact of oral health status on life quality (Allen, 2003),
> Table 8-2. Increasingly these measures have been employed in oral health research as they
are valuable tools in describing the physical, social and psychological consequences of oral
health states. These measures differ in the their underlying theoretical frameworks (some
having none); the dimensions of oral health which they assess (most assesses only the burden
of oral disease and deformities); the degree to which they capture the physical, social and
psychological aspects of oral health (some focus primarily on symptoms and the physical
domain); the number and type of items they contain, as well as differences in scoring methods:
difference in response categories and methods of scoring, and some use “weighting” system to
provide different weighting for different oral heath experiences (McGrath and Newsome,
2007). It is outside the scope of this chapter to describe all the measures in detail except and
so attention will be placed on oral health-related quality of life measures commonly use in
dental research and practice and for whom their psychometric properties have been more
comprehensively assessed.
. Table 8-2
Examples of currently available generic oral health-related quality of life measures

Cushing et al. (1986) Social Impacts of Dental Diseases (SIDS)
Atchison and Dolan (1990) Geriatric Oral Health Assessment Index (GOHAI)
Strauss and Hunt (1993) Dental Impact Profile (DIP)
Slade and Spencer (1994) Oral Health Impact Profile (OHIP)
Locker and Miller (1994) Subjective Oral Health Status Indicators (SOHSI)
Leao and Sheiham (1996) Dental Impact on Daily Living (DIDL)
Adulyanon and Sheiham (1997) Oral Impacts on Daily Performances (OIDP)
McGrath and Bedi (2001) United Kingdom Oral health-related Quality of Life mesure
(OH-QOL UK)
Perhaps the most sophisticated and most widely used measure has been the Oral Health
Impact Profile: OHIP (Slade and Spencer, 1994). The underlying theoretical framework for
OHIP is based on Locker’s adaptation of the World Health Organization’s classification of
Impairments, Disabilities and Handicaps for measuring oral health (Locker, 1998). This places
functional disorders relating to oral health and their social consequences in a hierarchy of
outcomes and thus provides a clearer insight into the multidimensional nature of oral health.
OHIP is a 49 item measure, with statements divided into seven theoretical domains, namely
functional limitation, pain, psychological discomfort, physical disability, psychological dis-
ability, social disability and, handicap. A Likert response format (0 = never, 1 = hardly ever,
2 = occasionally, 3 = fairly often, 4 = very often) is used to score the frequency of a problem
encountered as a result of oral ill health. Frequency of impacts is calculated by summing the
reported negative impacts (i.e., fairly often or very often) across the 49 statements. In addition,
the measure allows assessment of perceived severity of each impact, as a weighting method
(set-weights) for each statement has been derived using the Thurstone’s paired comparison
technique. However, research has questioned the value of the using the weights despite its
intuitive appeal (Allen and Locker, 1997). It is unclear as to whether this reflects the known
limitation of weighting where there is a large number of items or indeed the particular method
of deriving weights which are set weights and thus may not have universal applicability. The
validity and reliability of OHIP has been evaluated in a wide range of settings and there is a
general consensus that it demonstrates acceptable psychometric properties to support its use
in oral health research. Numerous short form measure of OHIP have been developed in an
attempt to reduce its number of item which in turn reduces burden on its administration and
also to make it more sensitive to specific oral health states using various statistical methods
(Allen and Locker, 2002; Slade, 1997; Wong et al., 2007). The short form OHIP-14 consisting
of 14 items covering the similar seven theoretical domains as OHIP and which is scored in a
similar manner has proved popular (Slade, 1997). However, there are concerns that a key
reason of its widespread use has not been because of suitability for use in all scenarios but
rather it has been frequently chosen because of the shorter number of items it contains
compared to OHIP (Allen and Locker, 2002; Wong et al., 2007).
Another commonly used measure is the General Oral Health Assessment Index: (GOHAI)
formally known as the Geriatric Oral Health Assessment Index (Atchison and Dolan, 1990). It
was developed in an attempt to estimate the degree of psychosocial impact associated with oral
diseases in older populations. The items relate to physical function (eating, speaking and
swallowing), psychological discomfort (worry, self-consciousness, social interaction) and
symptoms (pain, discomfort). Three of the items reflect an assessment of the positive
dimension of oral health (“ability to swallow comfortably,” how “pleased they are with their
looks” and “being free of discomfort”). Each item can be scored on a Likert scale, in some
studies a six point scale has been used with responses ranging from “always” experiencing the
effect (score of 5) to “never” experiencing the effect (score 0). Subsequently a five and three
point scale has been used in other studies (Atchison, 1997). Before calculating final scores, the
responses to nine of the items (the negative impacts of oral health) are reversed, in other words
those who respond to “never” score 5, thus allowing a higher final score to represent more
positive oral health. Final scores are calculated by summing responses on the Likert scales since
it is constructed a single scale of the impact of oral health on life quality. When the six-point
scale is used scores range from 0 to 60. The index is not weighted and thus does not provide an
assessment of the severity of events. It is reported to have somewhat more preferable qualities
than OHIP-14 for use among older and/or frail study populations (Locker et al., 2002a,b).
The Oral Impacts on Daily Performance (OIDP) measure was developed to provide an
alternative socio-dental indicator which focused on measuring the serious impacts of oral
health (Adulyanon and Sheiham, 1997). Its theoretical basis similar to OHIP’s but focused on
the disabling and handicap impact of oral diseases and conditions. Items were selected from
various socio-medical and > socio-dental indicators utilizing comparison tables of disability
indices. Originally nine items relating to physical, psychological and social performances were
selected but after pilot testing one item was excluded. The eight items include eating and
enjoyment of food, speaking and pronouncing clearly, cleaning teeth, sleeping and relaxing,
smiling; laughing and showing teeth without embarrassment, maintain usual emotional state
without being irritable, carrying out major work or social role and enjoying contact with
people. The items are scored according to frequency and severity. Frequency scores can
be classified according to whether the impact is “regular” (those never affected in the past
6 months score 0, less than once a month score 1, once or twice a month score 2, once or twice
a week score 3, 3–4 times a week score 4, every or nearly every day score 5). Frequency of effects
can also be classified by “spell” patterns, which relates to the length of time people experience
impacts (if the duration was for 0 days then the score is 0, for up to 5 days in total the score is 1,
for up to 15 days in total the score is 2, for up to 30 days the score is 3, for up to 3 months the
score is 4, for over 3 months in total the score is 5). Thus for example a person who twice
experienced impacts on eating during the past 6 months for 5 days in total should receive a
score of 2 according to period/ spell basis, rather than score of 1 according to regular/ periodic
basis. The severity of the impact is also scored from 0 to 5, five representing “very severe” and
0 representing “none.” A total OIDP score can be calculated by multiplying the frequency of
the impact score with the severity score. This then can be divided by the maximum possible
score (200) to provide a proportional score. However, improvement by multiplying frequency
and severity score is of questionable value, given the performance of the frequency scoring on
its own (Adulyanon and Sheiham, 1997). The instrument has been shown to have acceptable
psychometric properties for use in oral health service research although the reported preva-
lence of oral health impacts are relative low compared to when other measures of oral health
related quality of life presumably because ultimate impacts are rare in most study populations.
It is recommended that the preferable method of administration for OIDP is by interview
rather than questionnaire based (Robinson et al., 2001). OHIP-14 is reported to perform
better than OIDP when compared in different settings (Robinson et al., 2003).
The United Kingdom Oral Health-related Quality of Life measure (OHQOL-UK) was
developed based on the revised World Health Organization’s conceptual model of health,
which reflects both positive (functioning) and negative (disabling) aspects of health status
(WHO, 2001). The selection of “items” (questions) for inclusion in the measure was based on
the UK public’s perception (a national survey) of the most important ways in which oral
health (McGrath and Bedi, 2002). This measure consists of 16-items covering three domains:
physical, social and psychological effects. Two forms of OHQOL-UK exist. In the weighted
form respondents are asked to rate “what effect, if any, does the condition of your teeth, gums,
mouth and/or denture have on your (1 of 16 key areas)?”: Good, none or bad; and then asked
to rate “How would you rate the impact of this effect on your overall quality of life?”: None,
little, moderate, great or extreme. Summing up responses from individual questions can
produces overall OHQOL-UK(W)ß scores ranging from 16 (all bad effects of extreme impact)
to 144 (all good effects of extreme impact). An alternative simpler unweighted version exists
whereby subjects are asked to rate “What effect does your teeth, gums, mouth and/or false
teeth have on each of the 16 key areas?”: “Very bad (score 1), bad (score 2), none (score 3),
good (score 4) or very good (score 5).” Summing up responses from each of the 16-items can
produce overall OHQOL-UKß scores ranging from 16 to 80. Domain scores can also be
calculated for both the weighted and unweighted version of OHQOL-UK. The instrument has
been shown to have acceptable psychometric properties in terms of reliability and validity in
both clinical and epidemiological studies (McGrath and Bedi, 2001, 2003).
4 Condition Specific Oral Health-Related Quality of Life

Measures in Dentistry
There are a whole range of oral diseases and conditions which affect oral health and thus
describing the effect of a particular disease/ condition on QOL has been challenging. To this
end a range of condition specific HQOL measures have been developed. The most commonly
employed measures in dentistry are outlined in > Table 8-3. This has many potential advantages
since the measures capture specifically the subtle difference in different oral health status and
. Table 8-3
Examples of condition specific health-related quality of life measure used in dentistry

Bjordel et al. (1994) European Organisation for Research and Treatment of Cancer
Head and Neck questionnaire (EORTC: HN)
Thomson et al. (1999) The Xerostomia Inventory (XI)
Henson et al. (2001) The Xerostomia- Related Quality of Life Questionnaire (XeQOLS)
Rogers et al. (2002) University of Washington Quality of life questionnaire (UWQOL)
Cunnigham et al. (2002) The Orthognathic Quality of Life Questionnaire (OQLQ)
Field et al. (2003) The Liverpool Sicca Index (LSI)
Pace-Balzan et al. (2004) The Liverpool Oral Rehabilitation Questionnaire (LORQ)
Aggarwal et al. (2005) Manchester Orofacial Pain Disability (MPDS)
moreover the subtle changes that different treatment modalities can bring about to a specific oral
health status. However, using conditions specific measures limits comparisons to be made across
different health status (as well as different oral health states) and makes it difficult to compare
the contribution of different oral health care initiatives and therapies to life quality.
One particular area where condition specific HQOL measures have been widely use is with
respect to oral cancers. These in part reflects the rather different and severe influences oral cancers
or cancers of the head and neck, have on QOL compared to the more common oral diseases and
conditions. Moreover, within cancer research the use of condition specific cancer measures has
been widely used. The European Organization for Research and Treatment of Cancer (EORTC)
questionnaire has a specific module to be used in HQOL assessments in head -and neck cancer
patients. EORTC head and neck (Bjordal et al., 1994) consists of 35 questions about symptoms
and side-effects of treatment, and most of these are scored on a four-point response scale
from 1 (not at all) to 4 (very much). The first 18 questions ask about symptoms such as pain,
swallowing, taste, and appearance whilst the next 12 questions ask about functions such as
eating, talking, social contact and sexuality. The last five “yes/no” questions are about analgesia,
supplemental feeding and weight. Another commonly used measure with respect to head and
neck cancer has been the University of Washington Quality of life questionnaire (Rogers et al.,
2002). The current versions (version 4.0) covers 12 domains – pain, appearance, activity,
recreation, swallowing, chewing, speech, shoulder function, taste, saliva, mood and anxiety.
Each question is scaled from 0 (worst) to 100 (best) according to the hierarchy of response.
There are also two global questions, each a six-point Likert scale, one asking about health-related
and the other asking about overall quality of life during “the past 7 days.”
The Liverpool Oral Rehabilitation Questionnaire (LORQ) is a health-related quality of life
instrument assessing the impact of oral rehabilitation on patients’ HQOL following treatment
for oral cancer (Pace-Balzan et al., 2004). Various revisions of the measure have been made;
version 3, LORQv3 consists of 40 items divided into 2 primary sections, the first relating
to oral function, oro-facial appearance and social interaction, and the second section
relating to prostheses and patient denture/prosthetic satisfaction. Items refer to problems
or symptoms experienced during the previous week and are rated on a 1–4 Likert scale, from
“never” (1) to “always” (4). The LORQv3 has also been used with patients attending
general dental practices for routine dental care, patients attending the oral rehabilitation
clinic, and in a department of prosthodontics (Pace-Balzan et al., 2008).
Another area in which use of condition specific HQOL measures is common relates
to > dento-facial deformities. The Orthognathic Quality of Life Questionnaire – OQLQ
(Cunningham et al., 2002) consists of twenty-two items contributing to four domains: facial
aesthetics, oral function, awareness of dentofacial aesthetics and social aspects of dentofacial
deformity and each items is rated on a 4 point scale. The measure has proved more useful than
generic HQOL and generic OHQOL measures in describing the effects of dento-facial
deformities to life quality (Lee et al., 2008). Other patient centered measures of the combined
orthodontic and orthognathic treatment have been developed but less wieldy used.
In assessing the impact of orofacial pain on QOL the Manchester Orofacial Pain Disability
(MPDS) scale has been developed (Aggarwal et al., 2005). MPODS consist of 32-items of two
constructs – physical and psychosocial disabilities. Disability scores have been shown to be
higher pain intensity, pain duration and were greater amongst subjects who had sought a
health care consultation. Acceptable levels of internal reliability have been reported.
To assess the impact of xerostomia (dry-mouth) on life quality various measures have been
developed. The Xerostomia Inventory consists of 11 items and an additional 4-items can be
used in assessing Burning Mouth Syndrome (Thomson et al., 1999). The Xerostomia-related
Quality of Life Questionnaire (XeQOLS) consists of 15 items covering four domains pain/
discomfort, physical functioning, personal/psychological functioning and social functioning
(Henson et al., 2001). A measure to assess sicca-related symptoms in patients with primary
Sjögren’s syndrome consists of 28 items across five domains has also been developed (Field
et al., 2003). Further validation of all measures is required.
In other disciplines of dentistry the development of condition specific HQOL measures
continue to emerge. It is beyond the scope of this chapter to describe them all in detail but to
mention that for the most part the performances of these condition specific measure relative
to other established condition specific measure or compared to generic HQOL or generic
OHQOL measures has not be adequately assessed. In the end a plethora of patient centered
measured are available but there is little evidence as to which measures are preferable to use in
specific situations and this has ultimately led to much confusion within the field. This is not to
deny that developing new measure can make a contribution to how different oral condition
and their management impact QOL. However, there should be a clear rational behind the
development of new measures, their performance should be evaluated and compared with
existing measures if they are likely to have any added potential benefit in research and practice.
5 Assessing the Impact of Oral Health on the Quality of

Life of Children
Assessing the impact of oral health on QOL of children is a somewhat more complex issue
because childhood is a period of immense changes both physical and cognitive (McGrath
et al., 2004). It is only in relatively recently times that assessments of HQOL have been
conducted among child populations. For the most part it has been deemed necessary to
develop child specific measures and for specific age groups of children because of obvious
linguistic and cognitive difference between adults and children and among children of
different ages. A list of commonly used generic HQOL and Generic OHQOL measures for
assessing the impact of oral health on QOL of children is shown in > Table 8-4.
. Table 8-4
Examples of health-related quality of life measure used in dentistry among children

Landgraf et al. (1998) Child Health Questionnaire (CHQ)
Varni et al. (1999) Pediatric Quality of Life Inventory (PedsQL)
Jokovic et al. (2002) Child Perception Questionnaire (CPQ)
Locker et al. (2002a,b) Family Impact Scale (FIS)
Locker et al. (2003) Parental Perception Questionnaire (PPQ)
Filstrup et al. (2003) Michigan Child Oral Health related Quality of Life Scale
(MCOHQOL)
Gherunpong et al. (2004) Child Oral Impacts on Daily Performances (C-OIDP)
Broder and Wilson-Genderson Child Oral Health Impact (COHIP) measure
(2007)
Pahel et al. (2007) Early Childhood Oral Health Impact Scale (ECOHIS)
In terms of generic HQOL measures the most popular measures have been the Child Health
Questionnaire (CHQ). This instrument is comprised of scales specifically developed for
children and adolescents 5 years of age and older. The CHQ assesses a child’s physical,
emotional, and social well-being from the perspective of a parent or guardian (the 50 item
CHQ-PF50 and the 28 item PF-28 (short form) or, in some instances, the child directly (the
87 item CHQ-CF87, for children 10 years of age and older). All CHQ forms yield a 14-concept
health status and well-being concepts as well as reliable and valid summary (physical and
psychosocial health) scores. Areas measured include: general health, physical functioning,
limitations in schoolwork and activities with friends, behavior, mental health, emotional or
time impact on the parent, family cohesion, change in health, bodily pain or discomfort, self-
esteem and limitations in family activities (Landgraf et al., 1998). CHQ has been employed
within dentistry (the 87 item CHQ-CF87 form) in assessing the impact of tempromandibular
joint dysfunction (TMD) on the life quality of children (Jedel et al., 2007). Child patients with
TMD pain more than once a week reported significantly lower scores in CHQ-CF87 when
compared with a control group.
Another popular measure has been the Pediatric Quality of Life Inventory (PedsQL) (Varni
et al., 1999). Its measurement model is a modular approach to measuring HQOL in children
and adolescents. It consists of a 23-item generic core and it has four scales: physical functioning,
emotional functioning, social functioning and school functioning. Three summary scores
can be derived: total scale score, physical health summary score and psychosocial scale.
Different forms of the measure exist for use among children of different ages from 2 to 18.
It has been tested in dentistry but preliminary investigations have questioned its value in
assessing the impact of early childhood caries on quality of life (Lee et al., 2008).
Generic Child OHQOL measures have also been developed (> Table 8-4). The most
popular being the Child Oral Health-related Quality of Life measure (COHQOL) comprising
the Child Perception Questionnaire (CPQ), the Parental Perception Questionnaire (PPQ) and
the Family Impact Scale (FIS) life (Jokovic et al., 2002, 2003; Locker et al., 2002a,b). CPQ
assesses children’s own perceptions of the impact of their oral and oro-facial conditions on
their OHQOL (Jokovic et al., 2002). There are several forms of the CPQ: CPQ8–10 and CPQ11–14.
CPQ8–10 is used among children aged 8–10, and CPQ11–14 is used for children aged 11–14.
CPQ11–14 consists of 37 items covering four domains: oral symptom (6 items), functional
limitation (9 items), emotional well being (9 items) and social well being (13 items). Each item
of the CPQ is scored on a 5-point Likert scale to rate the frequency of occurrence of a
particular event. The respond options are “never” = 0, “once or twice” = 1, “sometimes” = 2,
“often” = 3, “everyday or almost every” = 4. Scores are calculated by summating respond code
of each domain. The possible score of CPQ can range from 0 to 148. A high score represent a
poor oral health related quality of life. It has been shown to exhibit acceptable psychometric
properties. For younger children a 25 item CPQ8–10 exist covering four domains: oral
symptom (5 items), functional limitation (5 items), emotional well being (5 items) and social
well being (10 items). Each item of the CPQ8–10 is scored on a 5-point Likert scale to rate the
frequency of occurrence of a particular event in the previous 4 weeks in relation to child’s oral
condition (Jokovic et al., 2006). The response options can range from “never” (score 0) to “every
day or almost every day” (score 4), same with the CPQ11–14. Scores are calculated by summating
respond code of each domain. The possible score of CPQ8–10 can range from 0 to 100.
A high score represent a poor oral health related quality of life. An analogous questionnaire
to elicit parental perceptions of the impact of their children’s oral health on the life quality
of their children exists (PPQ). PPQ consists of 31 items covering the similar four domain of
CPQ and has been shown to have appropriate validity and reliability (Jokovic et al., 2003). An
additional scale the FIS consist of 14 items covering four domains of family life: parental/
family activity (5 items), parental emotions (4 items), family conflict (4 items) and financial
burden (1 item) which is scored similar to CPQ and PPQ and too has demonstrated acceptable
psychometric properties (Locker et al., 2002a,b).
Another generic OHQOL measure for use among children is a child version of OIDP the
Child Oral Impacts on Daily Performances (C-OIDP). C-OIDP was developed through modify-
ing the wordings, changing the sequence of questions, simplifying the severity and frequency
ratings and shortening the recall period as well as using the pictures to assess ratings of
performances (Gherunpong et al., 2004). The authors advocated that the Child-OIDP specifies
the different clinical causes of each oral impact and the treatment need. Children are asked to
assess oral impacts on 8 daily performances in the past 3 months. If a child reports an impact on
any performance, the frequency and severity of impact on their daily life are scored on a 4-point
Likert scale which ranges from 0 to 3. The score of each performance is obtained by multiplying
severity and frequency score. Thus, a score of each performance can range from 0 to 9. The overall
impact score is obtained by summing the scores of 8 performances divided by 72 (the possible
maximum score) and multiplied by 100. The other method of reporting the severity of oral
impact is to use the “intensity” and “extent” of impacts. The “intensity” refers to the most severe
impacts on any of the 8 performances or the highest performance score. It is classified into six
levels: none, very little, little, moderate, severe and very severe. The “extent” refers to the number
of performances with impact (PWI) affecting a child’s quality of life over the past 3 months. It can
range from 0 to 8 PWI. “Intensity” and “extent” of impacts are more straightforward and use a
single score. C-OIDP has been reported to exhibit acceptable psychometric properties.
A more recent developed in assessing Child OHQOL has been the Child Oral Health
Impact (COHIP) measure (Broder and Wilson-Genderson, 2007). COHIP consists of 34 items
forming five conceptually distinct subscales: oral health, functional well-being, social/emotional
well-being, school environment and self-image (positive feelings). Responses are recorded for an
event occurring in the past 3-months being: “never” = 0, “almost never” = 1, “sometimes” = 2,
“fairly often” = 3, and “almost all of the time” = 4. Scoring of the 28 negatively-worded items
are reversed. Higher COHIP scores reflect more positive OHRQOL while lower scores reflect
lower OHRQOL. Additionally there were two items regarding treatment expectations and one
global health perception item used for clinical studies only. COHIP is reported to exhibit
excelled reliability and validity (Broder and Wilson-Genderson, 2007).
A less commonly used generic measure is the Michigan Child Oral Health related Quality of
Life Scale: MCOHQOL (Filstrup et al., 2003) consist of a Child and parental/proxy version for
use among children aged 4–16. It consists of 7-itmes covering three domains: pain/discomfort,
functioning and psychology. Its psychometric properties are reported to be acceptable.
For use among younger children the Early Childhood Oral Health Impact Scale (ECOHIS)
has been developed (Pahel et al., 2007). COHIS was developed from an item pool of 45 items
and resulted in a final 13-item measure with two scales: Child Impact (9 items) and Family
impact (4 items). The developers have suggested that because of the infrequent nature of oral
health problems and the young age of children being considered, the parent was asked to
consider the child’s entire life span when responding to the questions. Response categories for
the ECOHIS were coded: 0 = never; 1 = hardly ever; 2 = occasionally; 3 = often; 4 = very often;
5 = don’t know. ECOHIS scores are calculated as a simple sum of the response codes for the
child and family sections separately, after recoding all “Don’t know” responses to missing. The
measure has demonstrated acceptable reliability and validity in other settings (Li et al., 2008).
As assessments of the impact of oral health on the life quality of children is a relatively
recent initiative the use of condition specific measure has yet to emerge.
6 Uses and Future Directions of Health-Related Quality of Life

Measures in Dentistry
Quality of life is a dynamic concept because an individual’s perceptions of health and health-
related quality of life can change over time. Great advances have been made from theoretical
standpoints as to how oral health may impact on life quality. Nevertheless for the more part
there has been a tendency to focus only on the negative impact oral health on life quality – the
burden of oral health despite the evolution towards positive health (WHO, 2001). Failure to
include positive dimension may underestimate the importance of oral health to people lives,
underestimate the psychosocial impact of oral health, and the improvements to life quality
brought about by oral health care interventions (McGrath and Newsome, 2007). Furthermore,
there is need to explicitly test how clinical and non clinical variables direct and mediated
linkages within the theoretical models of health related quality of life (Baker et al., 2007).
Increasingly we live and work in multi-ethnic, multi-cultural and multi-linguistic envir-
onments. It is acknowledged that measures of health related quality of life developed in
western English-speaking settings have severe limitations for use in different environments.
Thus, there is a need to adapt (or develop new) health-related quality of life measures because
of language and cultural differences. Furthermore to establish whether instrument developed
in one setting and employed in a different setting exhibit consistent findings in the different
settings. Within dentistry much research that has derived different language forms of com-
monly use health related quality of life measures (McGrath and Newsome, 2007). Regrettably
these measures for the most part these have been direct translations with little (if any)
consideration to ethnic and cultural issues. What is required is a more rigorous approach to
trans and cross cultural health related quality of life research.
There is little doubt that quality of life data is better obtained from self-reporting than
from a proxy as it is more reliable and reduces the possibility of bias from an observers’
subjective internal standards in some instances. Nevertheless, in certain situations language
barriers, problems with memory and cognitive development often limits the use of self-report
data. For example children are in a sense “moving targets” because childhood is a period with
immense changes in psychosocial awareness, and because the children’s dental and facial
features change rapidly (McGrath et al., 2003). Thus it is widely accepted; particularly
among young children that reliance on proxy report is a more practical and possibly desirable
approach. In addition, among old and frail elderly particularly where they suffer from a
medical upset that impedes their cognitive ability then caregivers may be a useful alternative
in eliciting information about their health related quality of life. What is important to address
is whether proxy ratings are alternative or complimentary sources of information and as to
who is an appropriate proxy in the assessment process.
A significant barrier to their use of health related quality of life measure both in population
and clinical studies has been the large number of items in many measures currently available
(Allen, 2003). Various methods exist to derive short from measures based on expert approach as
well as numerous statistical approaches (including factor analysis and item impact processes).
Already advances have been made to derive briefer measures for the more commonly employed
measures and they have been shown to offer similar (albeit reduced in many cases) validity and
reliability (Allen and Locker, 2002; Slade, 1997; Wong et al., 2007). Unfortunately, whilst the
short from measures were derived for a specific entity there ahs been a tendency to use the
briefer measures even when the indented use is different to that which the short from measures
was intended to be used for. Moreover, while shorter versions have an intuitive appeal, the
content validity and reliability of the instruments tends to decrease as items are omitted.
Disappointingly there has been a paucity of use of health-related quality of life measures in
the clinic setting despite their potential use in assessing needs, prioritizing care and evaluating
outcomes for clinical “objective” clinical measure have severe limitations (Rogers et al., 1999;
Pace-Balzan et al., 2007; McGrath and Newsome, 2007). Perhaps with the explosion of interest
in health related quality of life research briefer (reduced number of items) measures will
emerge based on sound theoretical models with acceptable validity and reliability to screen
oral health needs and becomes useful tools which are sensitive and responsive to oral health
care interventions.
Summary Points
There has been considerable interest in assessing the impact of oral health on QOL and the
effects of oral health care intervention on improving QOL in recent decades.
Generic HQOL used in other disciplines of medicine have been used within dentistry but
have proven for the most part ineffective except for the more severe forms of oral diseases
such as oral cancer.
A number of generic OHQOL measures have been developed and several of them have
proved popular in use as their validity.
There is a move towards the use of condition specific HQOL measures within dentistry.
However, for the most part the value of condition specific HQOL over generic HQOL and
OHQOL has not been established.
In recent times advancements have been made in assessing the impact of oral health status
on QOL of children using age specific generic HQOL and OHQOL measures.
There has been limited use of QOL measures in dental practice or in assessing outcomes
from oral health care interventions.
References
Adulyanon S, Sheiham A. (1997). In: Slade DG (ed.) Buck D, Newton JT. (2001). Community Dent Oral
Measuring Oral Health and Quality of Life. Univer- Epidemiol. 29(1): 2–8.
sity of North Carolina, Chapel Hill. Cunningham SJ, Garratt AM, Hunt NP. (2002). Commu-
Aggarwal VR, Lunt M, Zakrzewska JM, Macfarlane GJ, nity Dent Oral Epidemiol. 30(2): 81–90.
Macfarlane TV. (2005). Community Dent Oral Dolan TA, Gooch BR, Bourque LB. (1991). Community
Epidemiol. 33(2): 141–149. Dent Oral Epidemiol. 19: 1–8.
Allen PF. (2003). Health Qual Life Outcomes. 1: 40–43. EuroQOL Group. (1990). The Health Policy. 16(3):
Allen PF, Locker D. (1997). Community Dent Health. 199–208.
14(3): 133–138. Field EA, Rostron JL, Longman LP, Bowman SJ, Lowe D,
Allen PF, Locker D. (2002). Int J Prosthodont. 15(5): Rogers SN. (2003). J Oral Pathol Med. 32(3):
446–450. 154–162.
Allen PF, McMillan AS. (2003). Clin Oral Implants Res. Filstrup SL, Briskie D, da Fonseca M, Lawrence L,
14(2): 173–179. Wandera A, Inglehart MR. (2003). Pediatr Dent. 25
Allen PF, McMillan AS, Walshaw D, Locker D. (1999). (5): 431–440.
Community Dent Oral Epidemiol. 27(5): 344–352. Gherunpong S, Tsakos G, Sheiham A. (2004). Commu-
Atchison KA, Dolan TA. (1990). J Dent Educ. 54(11): nity Dent Health. 21(2): 161–169.
680–687. Henson BS, Inglehart MR, Eisbruch A, Ship JA. (2001).
Baker SR, Pankhurst CL, Robinson PG. (2007). Qual Life Oral Oncol. 37(1): 84–93.
Res. 16(2): 297–308. Jedel E, Carlsson J, Stener-Victorin E. (2007). Eur J Pain.
Bergner M, Bobbitt RA, Pollard WE, Martin DP, 11(5): 557–563.
Gilson BS. (1976). Med Care. 14(1): 57–67. John MT, Patrick DL, Slade GD. (2002). Eur J Oral Sci.
Bjordal K, Ahlner-Elmqvist M, Tollesson E, Jensen AB, 110(6): 425–433.
Razavi D, Maher EJ, Kaasa S. (1994). Acta Oncol. 33 Jokovic A, Locker D, Guyatt G. (2006). Health Qual Life
(8): 879–885. Outcomes. 4: 4–6.
Brennan DS, Spencer AJ. (2005). Community Dent Jokovic A, Locker D, Stephens M, Kenny D, Tompson B,
Health. 22(1): 11–18. Guyatt G. (2002). J Dent Res. 81(7): 459–463.
Brennan DS, Spencer AJ, Roberts-Thomson KF. (2007). Jokovic A, Locker D, Stephens M, Kenny D,
J Dent Res. 86(8): 713–717. Tompson B, Guyatt G. (2003). J Public Health
Broder HL, Wilson-Genderson M. (2007) Community Dent. 63(2): 67–72.
Dent Oral Epidemiol. 35 (Suppl. 1): 20–31. Kressin NR. (1996). J Dent Educ. 60(6): 501–507.
Landgraf JM, Maunsell E, Speechley KN, Bullinger M, Pahel BT, Rozier RG, Slade GD. (2007). Health Qual Life
Campbell S, Abetz L, Ware JE. (1998). Qual Life Res. Outcomes. 1(5): 6–8.
7(5): 433–445. Reisine S. (1996). J Dent Educ. 60(6): 488–493.
Larsson P, List T, Lundström I, Marcusson A, Ohrbach R. Reisine ST, Fertig J, Weber J, Leder S. (1989). Community
(2004). Acta Odontol Scand. 62(3): 147–152. Dent Oral Epidemiol. 17(1): 7–10.
Lee S, McGrath C, Samman N. (2008). J Oral Maxillofac Robinson PG, Gibson B, Khan FA, Birnbaum W. (2001).
Surg. 66(6): 1194–1199. Community Dent Health. 18(3): 144–149.
Li S, Veronneau J, Allison PJ. (2008). Health Qual Life Robinson PG, Gibson B, Khan FA, Birnbaum W.
Outcomes. 1(6): 9–11. (2003). Community Dent Oral Epidemiol. 31(2):
Locker D. (1998). Community Dent Health. 5(1): 3–18. 90–99.
Locker D, Jokovic A, Stephens M, Kenny D, Tompson B, Rogers SN, Gwanne S, Lowe D, Humphris G, Yueh B,
Guyatt G. (2002a). Community Dent Oral Epide- Weymuller EA Jr. (2002). Head Neck. 24(6):
miol. 30(6): 438–448. 521–529.
Locker D, Matear D, Stephens M, Jokovic A. (2002b). Rogers SN, Miller RD, Ali K, Minhas AB, Williams HF,
Community Dent Health. 19(2): 90–97. Lowe D. (2006). Int J Oral Maxillofac Surg. 35(10):
McGrath C, Bedi R. (2001). Community Dent Health. 913–919.
18(3): 138–143. Slade GD. (1997). Community Dent Oral Epidemiol.
McGrath C, Bedi R. (2002). Community Dent Health. 25(4): 284–290.
19(4): 211–214. Slade GD, Spencer AJ. (1994). Community Dent Health.
McGrath C, Bedi R. (2003). J Public Health Dent. 63(2): 11(1): 3–11.
73–77. Thomson WM, Chalmers JM, Spencer AJ, Williams SM.
McGrath C, Broder H, Wilson-Genderson M. (2004). (1999). Community Dent Health. 16(1): 12–17.
Community Dent Oral Epidemiol. 32(2): 81–85. Varni JW, Seid M, Rode CA. (1999). Med Care. 37(2):
McGrath C, Comfort MB, Lo EC, Luo Y. (2003). J Oral 126–139.
Maxillofac Surg. 61(7): 759–763. Ware JE, Sherbourne CD. (1992). Med Care. 30(6):
McGrath C, Newsome PR. (2007). Dent Update. 34(1): 473–448.
41–42. Wong AH, Cheung CS, McGrath C. (2007). Community
Pace-Balzan A, Butterworth CJ, Dawson LJ, Lowe D, Dent Oral Epidemiol. 35(1): 64–72.
Rogers SN. (2008). J Prosthet Dent. 99(3): 233–242. World Health Organisation. (2001). International Classi-
Pace-Balzan A, Cawood JI, Howell R, Lowe D, Rogers SN. fication of Functioning, Disabilities and Health.
(2004). J Oral Rehabil. 31(6): 609–617. World Health Organisation, Geneva.
9 SQOR-V: A Patient Reported
Outcome Specifically
Dedicated to Chronic
Venous Disorders
J.-J. Guex . S. E. Zimmet . S. Boussetta . C. Taieb
1 Introduction: Chronic Venous Disorders (CVD), Definition . . . . . . . . . . . . . . . . . . . . . . 162
2 Specificities of Chronic Venous Disorders (CVDs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
3 Why Is QOL So Important for CVD Assessment? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
4 Validation of the SQOR-V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
5 Use of the SQOR-V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

5.1 Calculation of the SQOR-V Questionnaire Score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
5.2 Managing Missing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

162 9 SQOR-V: A Patient Reported Outcome Specifically Dedicated to Chronic Venous Disorders
Abstract: Chronic venous disorders (> CVD) are recognized on a number of clinical signs of
variable severity, from telangiectasias to skin ulceration of the lower legs. Their symptomatology
is highly variable as well. Evaluation of the global severity of the disease remains difficult, except
when considering late stages and complications, which represent only a vary small group of
patients. No biological or instrumental marker exists which could be correlated to improvement
or worsening whether spontaneous or after treatment. All these characteristics of CVD explain why
Patient Reported Outcome (> PRO) are becoming a popular part of phlebological research.
The SQOR-V is a validated PRO designed for Chronic Venous Disorders (CVD). It allows a
relevant and sensitive assessment of clinical features and quality of life of patients at all stages of
Chronic Venous Disorders (CVD). It can be used in epidemiological and clinical trials. It is
sensitive enough to assess CVD at early stages of the disease.
Using the SQOR-V in clinical trials is possible for any kind of treatment for CVD:
drugs, compression, surgery, or endovenous ablation. It adds a composite global assessment
complementary to hemodynamic measurements.
The SQOR-V can be used freely; provided it is applied according to its construction rules
and that its authors are informed of the intended use. More studies are needed to validate
versions in more languages and to better refine its practical use.
List of Abbreviations: CVD, chronic venous disorders; QOL, quality of life; PRO, patient
reported outcome
1 Introduction: Chronic Venous Disorders (CVD), Definition
CVD stands now for disorders when it previously stood for diseases. This term includes all mani-
festations related to a chronic impairment of the venous function, i.e., the return of blood to the
heart. It can be caused by blood reflux (valvular incompetence), outflow obstruction, vein wall
compliance reduction, venous wall cells dysfunction, and probably other mechanisms. Venous
abnormalities can affect superficial, deep and perforating venous networks. CVD can be congenital,
primary or secondary (=acquired, especially post-thrombotic). Chronic venous Insufficiency (CVI)
refers to severe stages where tissular decompensation occurs, especially at skin or sub-cutaneous level.
2 Specificities of Chronic Venous Disorders (CVDs)
Clinical presentation of Chronic Venous Disorders (CVD) is extremely variable and no

straight correlation can be observed between signs, and/or symptoms, and/or hemodynamic
anomalies. Very large varicose veins can be completely painless for years – until occurrence of
complications – when some patients experience early severe symptoms while lacking any
visibly dilated vein (varicose veins are a sign of chronic venous disease).
From the patient’s point of view, CVD can impair many different aspects of their life. CVD
can be responsible for pain and various discomforts, poor cosmetic aspect, complications such as
thrombosis or ulcers, reduction of social activities, and can be considered as a threat for their
health, especially in case of severe family history of CVD (ulcers, superficial thrombo-phlebitis).
From the instrumental point of view, the assessment of CVD is possible by Level 2 (noninva-
sive) investigations such as Duplex scanning (detecting and describing anatomic and hemodynamic
abnormalities) or plethysmograms (evaluating functional impairment through dynamic limb
volume measurement). However, due to the lack of correlation with clinical findings, no single
method is sufficient or reliable enough to estimate the actual severity of the disease.
SQOR-V: A Patient Reported Outcome Specifically Dedicated to Chronic Venous Disorders 9 163
Finally, CVD are fortunately almost always non lethal and the incidence of severe events
(ulcers, hemorrhage, pulmonary emboli, amputation) is delayed and limited, evaluation
based on these outcomes is only possible in late (and less frequent) cases.
Therefore, unlike many other diseases (for example arterial diseases where the ankle/
brachial index provides a simple method of assessment) there is no simple outcome usable
to assess worsening or improvement of CVD, spontaneously or after treatment.
Establishing the success of a CVD treatment has proven difficult since patient’s satisfaction
may not be correlated with the improvement of hemodynamic or appearance. The only sure
thing is that if the patient is not satisfied by the results, it means that the treatment has
failed. Other types of failures are also possible, some of which are not detected by the patient
(and/or the physician), and may sometimes lead to an early recurrence.
In order to refine clinical evaluation, venous clinical severity score (> VCSS) and venous
disability score (VDS) have been associated to the CEAP Classification (Eklöf, 2006). All are
assessed by the physician and not by the patient; though used in several studies, they are still
under revision and not appropriate for early stages of the disease.
3 Why Is QOL So Important for CVD Assessment?

Recently, like in many other medical fields (e.g., Haibel et al., 2004), more studies have used
Patient Reported Outcomes (PRO) to assess some aspects of the severity of the disease (Guex
et al., 2005, 2007).
Currently used QOL scales are:
either generic: like SF 12 (Ware et al., 1996) and SF 36 (Ware and Sherbourne, 1992)
or specific:
Of venous symptoms and signs like the Edinburgh (Smith et al., 1999), CIVIQ
(Launois et al., 1996) and > VEINES-QOL (Kahn et al., 2006) questionnaires
Of daytime sleepiness like the > EPWORTH questionnaire (Miletin and Hanly, 2003)
Or of depression like the > CES-D (Fuhrer and Rouillon, 1989)
Generic and specific questionnaires are generally scored in opposite ways: the higher the value
of the generic questionnaire score, the better the health status, and conversely; the higher the
value of the specific score the worst the QOL (> Figure 9-1).
CVD can be described using the CEAP classification (Eklof, 2006; Porter and Moneta,
1995). The CEAP uses four descriptors (the four letters of the acronym: C (clinical), E
(etiology), A (anatomy), P (pathophysiology). Each descriptor is delineated by a figure
and/or a letter as indicated in > Table 9-1. In fact, CEAP is now the international standard
for description of CVD. For example, a patient with uncomplicated symptomatic primary
varicose veins of the great saphenous territory will be classified [C2s, Ep, As, PR2,3], and a
patient with a painful post thrombotic (popliteal incompetence) active ulcer will be classified
[C6s, Es, Ad, PR14]. However, CEAP classification is not an evaluation tool; it only describes
the type of CVD, and does not evaluate its severity.
Focusing the evaluation of CVD on clinical features, including all known patients’
complaints, through a composite, sound and understandable PRO is the most logical option.
However, especially when evaluating efficacy of treatments, anatomical and hemodynamic
modifications (suppression of veins, correction of reflux, improvement of outflow, etc. . .)
must also be measured and reported. But the clinical appraisal, as reported by patients, should
be the predominant method of assessing therapeutic success or failure.
. Figure 9-1
Variation of QOL score: difference between specific and generic questionnaires
We have developed the SQOR-V after long discussions among vein experts (Guex et al.,
2007) and careful analysis of existing venous PRO, to which we acknowledge precedence and
value. However, certain QOL questionnaires are not without cost, and we wanted to improve
both the relevance of the questions and simplicity of the survey.
The SQOR-V may be used without charge.
4 Validation of the SQOR-V
Field testing and validation of the SQOR-V PRO were carried out in France (in French) and
have been reported (Guex et al., 2007). Languages for which we have obtained a cultural and
linguistic validation (at proof review time, more in progress): French, English, Czech, Spanish
(Spain and Argentina), Italian, Afrikaans, South African English.
Two hundred and two questionnaires were analyzed after a first application and 152 after a
second (test-retest). The Cronbach’s alpha coefficient was calculated at 0.96 and the structural
analysis demonstrated excellent internal and structural coherence. Reproducibility has been
verified by test-retest with a correlation of 0.80 on the global score. Clinical validity and convergent
validity were established by comparison with symptoms, and with two PRO: SF12 and CES D
(Fuhrer and Rouillon, 1989; Ware et al., 1996).
Unlike severity scores like the VCSS, SQOR-V is able to demonstrate a satisfactory
sensitivity between lower classes of the CEAP, with mean values of 38.89, 42.24, and 48.71
for classes C1, C2 and C3 respectively.
5 Use of the SQOR-V
Like other QOL questionnaires, the SQOR-V is auto administered and patients are left alone
for answering questions. Questions must not be discussed with the physician. Minimal
. Table 9-1
Outline of CEAP classification of chronic venous disorders
C Clinical signs 0: No sign of venous disease

1: Reticular veins and telangiectases
2: Varicose veins
3: Edema
4: Skin changes
4a: Eczema, pigmentation
4b: Lipodermatosclerosis, ‘‘atrophie blanche’’
5: Healed ulcer
6: Active ulcer
C Clinical symptoms A: Asymptomatic
S: Symptomatic
E Etiology P: Primary
S: Secondary
C: Congenital
N: No venous etiology identified
A Anatomy S: Superficial
D: Deep
P: Perforating veins
N: No venous location identified
P Pathophysiology R: Reflux (with # s indicating pathologic
segment(s))
O: Obstruction
RO: Reflux and obstruction
N: No venous pathophysiology identifiable
Nomenclature of diseased vein segments: Superficial: 1. Telangiectases & reticular veins; 2. Great saphenous vein
above knee; 3. Great saphenous vein below knee; 4. Small saphenous vein; 5. Non saphenous veins. Deep: 6.
Inferior vena cava; 7. Common iliac vein; 8. Internal iliac vein; 9. External iliac vein; 10. Pelvic veins; 11. Common
femoral vein; 12. Deep femoral vein; 13. Femoral vein; 14. Popliteal vein; 15. Deep leg veins; 16. Muscular veins.
Perforating Veins: 17. Thigh; 18. Leg. For example, a patient with uncomplicated symptomatic primary varicose
veins of the great saphenous territory will be classified [C2s, Ep, As, PR2,3], and a patient with a painful post
thrombotic (popliteal incompetence) active ulcer will be classified [C6s, Es, Ad, PR14]
interaction provides better reliability. If questions are not understood it is better to leave the
item blank (see ‘‘missing data’’ below) rather than completed with the physician’s or staff ’s
help. The usual duration for questionnaire completion is less than 10 min.
5.1 Calculation of the SQOR-V Questionnaire Score
The SQOR-V questionnaire (Specific Quality of Life and Outcome Response – Venous)
scoring comprises 45 items (> Figures 9-2 and > 9-3). Each of these items is rated from
1 to 5 (1 = None to 5 = Extremely). This questionnaire has been developed to explore five
. Figure 9-2
Questionnaire in French
. Figure 9-2 (continued)

broad dimensions affected by venous insufficiency, and each of the 45 items covers only one
dimension:
Discomfort – annoyance – pain: 22 items
Appearance – aesthetic aspect: 3 items
Risk – threat to health: 4 items
Restriction in movements – activities: 12 items
Emotional problems: 4 items
The relationship between the items and the dimension that they represent is summarized in
> Tables 9-2 and > 9-3.
We have adopted a method of ‘‘normalization’’ by bringing each dimension back to 20, in
order to facilitate interpretation of the dimension scores.
The total score is then the sum of the values shown for each dimension. This total score
will thus have a maximum of 100. Therefore, each dimension has the same impact on the
global score, which serves to clarify the impact of each dimension.
In order to refine the interpretation of the score and to make its usage more specific, we
have created two impacts resulting from the five dimensions. One is a psychosomatic compo-
nent and the other a physical component:
Physical impact: resulting from the sum of the scores of the dimensions ‘‘discomfort,’’
‘‘restriction in movement’’ and ‘‘risk,’’ with a total score of 100.
Psychosomatic impact: resulting from the sum of the scores of the dimensions ‘‘appear-
ance’’ and ‘‘emotional problems,’’ with a total score of 100.
The total score as well as the two impacts can thus vary from 20 to 100. The higher the score,
the worse the quality of life. A reduction in the score or scores reflects an improvement in the
quality of life.
. Figure 9-3
Questionnaire in English

5.2 Managing Missing Data
In order to avoid considerable loss of data, we have used a system for replacing missing
information. This involves giving each missing dimension value the average value of this
dimension obtained from the other patients in the study.
Important Statement
" The authors allow the USE of the SQOR-V provided it is used with the above mentioned protocol
and provided it is used in validated languages. Such validations are encouraged.
Before constructing their studies, potential SQOR-V users are required to inform
SQOR-V authors of their purpose and methodology. After completing their study, they should
communicate their results and indicate where and when their study will be published or presented.
. Table 9-2
Items, dimensions, impacts in the SQOR-V, in French
Numéro
item Items Dimension Valeur Impact
1 Gêne global (jambe Gauche) Inconfort 1–5 Physique
2 Douleur (jambe Gauche) Inconfort 1–5 Physique
3 Lourdeur (jambe Gauche) Inconfort 1–5 Physique
4 Démangeaisons (jambe Gauche) Inconfort 1–5 Physique
5 Crampes nocturnes (jambe Gauche) Inconfort 1–5 Physique
6 Gonflement (jambe Gauche) Inconfort 1–5 Physique
7 Sensation de chaleur (jambe Gauche) Inconfort 1–5 Physique
8 Picotements (jambe Gauche) Inconfort 1–5 Physique
9 Elancements (jambe Gauche) Inconfort 1–5 Physique
10 Jambes sans repos (jambe Gauche) Inconfort 1–5 Physique
11 Aggravation avec la chaleur (jambe Inconfort 1–5 Physique
Gauche)
12 Gêne global (jambe Droite) Inconfort 1–5 Physique
13 Douleur (jambe Droite) Inconfort 1–5 Physique
14 Lourdeur (jambe Droite) Inconfort 1–5 Physique
15 Démangeaisons (jambe Droite) Inconfort 1–5 Physique
16 Crampes nocturnes (jambe Droite) Inconfort 1–5 Physique
17 Gonflement (jambe Droite) Inconfort 1–5 Physique
18 Sensation de chaleur (jambe Droite) Inconfort 1–5 Physique
19 Picotements (jambe Droite) Inconfort 1–5 Physique
20 Elancements (jambe Droite) Inconfort 1–5 Physique
21 Jambes sans repos (jambe Droite) Inconfort 1–5 Physique
22 Aggravation avec la chaleur (jambe Droite) Inconfort 1–5 Physique
23 Apparence global de la jambe droite Apparence 1–5 Psychosomatique
affectée par les problèmes veineux
24 Apparence global de la jambe gauche Apparence 1–5 Psychosomatique
affectée par les problèmes veineux
25 Problèmes veineux conditionnent le choix Apparence 1–5 Psychosomatique
des vêtements
26 Problèmes veineux conditionnent le choix Restriction des 1–5 Physique
de vos activités mouvements
27 Restriction globale Restriction des 1–5 Physique
mouvements
28 Activités professionnelles Restriction des 1–5 Physique
mouvements
29 A la maison Restriction des 1–5 Physique
mouvements
SQOR-V: A Patient Reported Outcome Specifically Dedicated to Chronic Venous Disorders

9 173
Numéro
item Items Dimension Valeur Impact
30 Activités de loisirs ou sportives Restriction des 1–5 Physique
mouvements
31 Station debout prolongée Restriction des 1–5 Physique
mouvements
32 Position assise prolongée Restriction des 1–5 Physique
mouvements
33 Lors de la marche Restriction des 1–5 Physique
mouvements
34 Utilisation de la marche Restriction des 1–5 Physique
mouvements
35 Au cours du sommeil Restriction des 1–5 Physique
mouvements
36 Activités sociales Restriction des 1–5 Physique
mouvements
37 Relations intimes ou sexuelles Restriction des 1–5 Physique
mouvements
38 Problèmes veineux vous inquiètent-ils? Menace – 1–5 Physique
Risque
39 Aggravation de la maladie veineuse vous Menace – 1–5 Physique
inquiètent-elle? Risque
40 Complication de la maladie veineuse vous Menace – 1–5 Physique
inquiètent-elle? Risque
41 Le fait qu’un de vos proche souffre de Menace – 1–5 Physique
maladie veineuse vous inquiètent-il? Risque
42 Conséquences émotionnelles globales Problèmes 1–5 Psychosomatique
émotionnels
43 A cause de mon problème veineux, je suis Problèmes 1–5 Psychosomatique
à cran émotionnels
44 A cause de mon problème veineux, je suis Problèmes 1–5 Psychosomatique
irritable émotionnels
45 A cause de mon problème veineux, Problèmes 1–5 Psychosomatique
impression d’être un fardeau pour les émotionnels
autres
6 Conclusion
Use of SQOR-V in studies of CVD is simple, fast and reliable. It brings a sound and sensitive
assessment of patients’ clinical features and QOL, even in patients with early (limited)
symptoms and signs, which increases the relevance and utility for both epidemiologic
(descriptive), and comparative studies (see > Figure 9-4).
. Table 9-3
Items, dimensions, impacts in the SQOR-V, in English (suggested wording)
Item
number Items Dimension Value Impact
1 Overall discomfort (left leg) Discomfort 1–5 Physical
2 Pain (left leg) Discomfort 1–5 Physical
3 Heaviness (left leg) Discomfort 1–5 Physical
4 Itching (left leg) Discomfort 1–5 Physical
5 Night cramps (left leg) Discomfort 1–5 Physical
6 Swelling (left leg) Discomfort 1–5 Physical
7 Warm or burning sensation (left leg) Discomfort 1–5 Physical
8 Tingling (left leg) Discomfort 1–5 Physical
9 Stinging or stabbing sensation (left leg) Discomfort 1–5 Physical
10 Restless legs (left leg) Discomfort 1–5 Physical
11 Worse with heat (left leg) Discomfort 1–5 Physical
12 Overall discomfort (right leg) Discomfort 1–5 Physical
13 Pain (right leg) Discomfort 1–5 Physical
14 Heaviness (right leg) Discomfort 1–5 Physical
15 Itching (right leg) Discomfort 1–5 Physical
16 Night cramps (right leg) Discomfort 1–5 Physical
17 Swelling (right leg) Discomfort 1–5 Physical
18 Warm or burning sensation (right leg) Discomfort 1–5 Physical
19 Tingling (right leg) Discomfort 1–5 Physical
20 Stinging or stabbing sensation (right leg) Discomfort 1–5 Physical
21 Restless legs (right leg) Discomfort 1–5 Physical
22 Worse with heat (right leg) Discomfort 1–5 Physical
23 Overall appearance of your right leg affected Appearance 1–5 Psychosomatic
by vein problems
24 Overall appearance of your left leg affected by Appearance 1–5 Psychosomatic
vein problems
25 Vein problems impacting clothing chosse Appearance 1–5 Psychosomatic
26 Vein problems impacting activities chosse Restriction in 1–5 Physical
movements
27 Overall restriction Restriction in 1–5 Physical
movements
28 At work Restriction in 1–5 Physical
movements
29 At home Restriction in 1–5 Physical
movements
30 Sport or leisure activities Restriction in 1–5 Physical
movements
SQOR-V: A Patient Reported Outcome Specifically Dedicated to Chronic Venous Disorders

9 175
Item
number Items Dimension Value Impact
31 Prolonged standing Restriction in 1–5 Physical
movements
32 Prolonged sitting Restriction in 1–5 Physical
movements
33 When walking Restriction in 1–5 Physical
movements
34 When using stairs Restriction in 1–5 Physical
movements
35 During sleep Restriction in 1–5 Physical
movements
36 Social activities Restriction in 1–5 Physical
movements
37 Intimate or sexual relations Restriction in 1–5 Physical
movements
38 Overall, do your vein problems worry you? Risk – threat to 1–5 Physical
health
39 Does the possible worsening of your vein Risk – threat to 1–5 Physical
disease worry you? health
40 Does the possibility of your condition causing Risk – threat to 1–5 Physical
complications worry you? health
41 Does it worry you that someone related to you Risk – threat to 1–5 Physical
suffers from vein disease? health
42 Overall emotional consequences Emotional 1–5 Psychosomatic
problems
43 Because of my vein problems, I am on edge Emotional 1–5 Psychosomatic
problems
44 Because of my vein problems, I am irritable Emotional 1–5 Psychosomatic
problems
45 Because of my vein problems, I feel like I am a Emotional 1–5 Psychosomatic
burden to others problems
Summary Points
The classification of CVD (CEAP classification) provides a detailed and relevant descrip-
tion but is not intended to serve as an evaluation tool.
Evaluation of CVD severity at early stages is mostly clinical and robust outcomes, such as
skin changes and ulcers appear only late. Evaluation through a PRO allows a more precise
assessment.
Severity scores proposed in CVD are not quality of life questionnaires, nor PRO. They are
physician reported and specific of late, severe stages of the disease. They are appropriate for
Chronic Venous Insufficiency.
. Figure 9-4
Example of use of the SQOR-V (experimental study, not published yet). Variation of SQOR-V
value according to Body Mass Index (BMI) in the general population (776 persons): (Higher
SQOR-V global score means worse status)
SQOR-V provides with a multidimensional evaluation which needs to be associated to

instrumental assessments of hemodynamic abnormalities (plethysmography, duplex ultra-
sound).
Evaluation of treatments cannot rely only on hemodynamic appraisal, even if they are
absolutely necessary.
References
Eklöf B. (2006). Classifying venous disease In: Bergan JJ Launois R, Reboul-Marty J, Henry B. (1996). Qual Life
(ed.) The Vein Book. Elsevier, San Diego. Res. 5(6): 539–554.
Fuhrer R, Rouillon F. (1989). Psychiatrie et Psychobiolo- Miletin MS, Hanly PJ. (2003). Sleep Med. 4(3):195–199.
gie. 4:163–166. Porter JP, Moneta GM. (1995). J Vasc Surg. 21:635–645.
Guex JJ, Myon E, Didier L, Nguyen Le C, Taieb C. (2005). Smith JJ, Garratt AM, Guest M, Greenhalgh RM, Davies
Int Angiol. 24: 258–264. AH. (1999). J Vasc Surg. 30(4): 710–719.
Guex JJ, Zimmet SE, Boussetta S, Nguyen Le C, Taieb C. Ware JE Jr, Kosinski M, Keller SD. (1996). Med Care. 34:
(2007). J Mal Vasc. 32: 135–147. 220–233.
Haibel H, Niewerth M, Brandt J, Rudwaleit M, Listing J, Ware JE Jr, Sherbourne CD. (1992). Med Care. 30(6):
Sieper J, et al. (2004). Z Rheumatol. 63(5): 393–401. 473–483.
Kahn S, Lamping D, Ducruet T, Arsenault L, Miron M,
Roussin A, et al. (2006). J Clin Epidemiol. 59:
1049–1056.
10 The Uniscale Assessment of
Quality of Life: Applications
to Oncology
E. Ballatori . F. Roila . B. Ruggeri . A. A. Bruno . S. Tiberti . F. di Orio
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
2 Problems with the use of Psychometric Questionnaires . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
3 The Uniscale Assessment of Quality of Life: An Italian Experience . . . . . . . . . . . . . . . . 183
4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

180 10 The Uniscale Assessment of Quality of Life: Applications to Oncology
Abstract: The measurement of quality of life (QOL) is an important challenge in clinical

research, not only because QOL is one of the two main endpoints of effectiveness of
treatments, the other being overall survival, but also for taking clinical decisions shared with
the patient. Today, QOL is generally assessed using psychometric questionnaires; nevertheless,
these latter suffer from several shortcomings that often lead to unreliable results.
About 14 years ago, the Italian Group for the Evaluation of Outcomes in Oncology (IGEO)
planned a research program articulated in two phases. In the first phase, > domains of QOL
and problems connected with it were defined performing a content analysis of the interviews
of 248 Italian cancer patients, based on four areas related to the foundations of quality of life.
The domains/problems referred by the patients were submitted to a large population of more
than 6,000 Italian cancer patients so as to assign a frequency to the relevance of each domain
and to the presence/absence of each problem. In this study, a uniscale evaluation of QOL,
using a Visual Analogue Scale (> VAS), was also obtained. The rating of each patient was
classified in ‘‘bad QOL’’ and ‘‘good QOL,’’ if the chosen point fell in the 0–30 or 70–100
interval, respectively; the other scores (30–70 interval) were not considered.
The relationship between the uniscale assessment of QOL and the presence of each
problem was investigated. The impact of each problem, adjusted for the presence of the others,
and for the patient’s characteristics, was detected by a unifactorial analysis using logistic
additive models, where ‘‘good’’ and ‘‘bad’’ QOL were in turn considered as dependent
variables. Thirteen of 19 problems were significant, and this confirms the external validity of
the uniscale assessment of QOL.
AVAS can be considered a reference point in multidimensional QOL scales and should still
be regarded as a useful and synthetic tool to investigate phenomena related to the patient’s
QOL. In this perspective, more research on the psychometric properties of this instrument, in
the context of the assessment of QOL, is still needed.
List of Abbreviations: CRF, Case Record Form; > HRQL, Health-Related Quality of Life;
IGEO, Italian Group for the Evaluation of Outcomes in Oncology; > KPS, Karnofsky Perfor-
mance Status; > LP, Linear Predictor; NED, No Evidence of Disease; NHS, National Health
System; OR, > Odds Ratio; QOL, Quality of Life; RR, > Relative Risk; SD, Standard Deviation;
VAS, Visual Analogue Scale
1 Introduction
One of the most useful working definitions of quality of life is that reported by David Cella
(Cella and Tulsky, 1990): ‘‘Quality of life refers to patients’ appraisal of and satisfaction with
their current level of functioning as compared to what they perceive to be possible or ideal.’’ In
fact, this dynamic definition incorporates the patient’s strategies of coping with changed
health conditions due to the progression of disease. Moreover, it makes clear that Health-
Related Quality of Life (HRQL) is the goal of the evaluation.
HRQL can be considered as an important endpoint in several clinical trials in oncology,
especially when therapies giving a similar survival rate are compared, or when the survival
rates are expected to be different but the treatment that assures the longest survival is the same
that offers the worst HRQL. Its importance is not only in evaluating the effectiveness of
alternative medical interventions (HRQL is one of the two efficacy endpoints in comparative
clinical trials, the other being overall survival), but also in screening individual patients for
The Uniscale Assessment of Quality of Life: Applications to Oncology 10 181
possible psycho-social intervention, in monitoring the quality of care (Aaronson, 1990), and
in making clinical decisions shared with the patient.
Regardless of the type of instrument used, in assessing HRQL there are some points on
which there is general agreement (Aaronson, 1990):
1. Self-assessment, because of the subjectivity of HRQL.
2. HRQL should be measured using a tool able to give quantitative responses; these measure-
ments should be obtained repeatedly, so as to evaluate the variations of HRQL when a
patient’s health condition changes.
3. HRQL has a multidimensional framework. A review of literature suggests that HRQL
encompasses at least the following components (or domains, or dimension): physical
functioning status, disease symptoms and treatment side effects, psychological status,
social functioning (Aaronson, 1990).
The HRQL of cancer patients is today generally assessed using a psychometric questionnaire
able to explore each of several domains by means of one or more items. When the patient
repeatedly fills it out, the level of each domain at any time and their modification during
follow-up can be evaluated.
A great number of papers on the evaluation of HRQL of cancer patients have been published
during the last 30 years, but the majority of them were concerned with the > reliability and
validity of the measurement instrument (Ballatori, 2001). More than 600 different quality of
life questionnaires have been validated; the reasons for this are mainly the following:
1. The complexity of the problem.
2. The lack of a generally accepted theory.
3. The difficulties to obtain results that are useful in daily clinical practice.
Another tool able to measure HRQL is the uniscale assessment, widely used in early studies
(Coates et al., 1990; Hiratsuka and Kida, 1993). Generally it consists in a 100-mm Visual
Analogue Scale (VAS) where the patient reports his/her response to the following question:
‘‘How would you rate your quality of life today?’’ (Aaronson, 1990). The VAS for the
evaluation of HRQL mainly presents two shortcomings: (1) an unsatisfactory reproducibility,
and (2) giving a global measure, it yields only a summary score, insufficient to understand the
reasons for its variations.
On the other hand, serious problems arise when using a psychometric questionnaire; they are
discussed in the next section. Aims of this article are to obtain a further proof of validity of the
uniscale assessment of HRQL and to stimulate a discussion on future perspectives.
2 Problems with the use of Psychometric Questionnaires
Different problems arise both in measuring HRQL and evaluating the results of an assessment
of HRQL in cancer patients. They involve the patient, questionnaire, setting of administration,
and their interactions.
1. Selection effects: A questionnaire should be self-administered by the patient. In our
experience, about 12% of cancer patients, who gave their informed consent to participate
in the study, did not fill out the basal questionnaire (IGEO, 1999a). Patients who refuse to
fill out the HRQL questionnaire cannot be considered randomly selected from the
experimental group. In fact, this percentage increases with age and stage of disease, and is
particularly high in patients with low performance status and a low educational level
(IGEO, 1999a). Furthermore, in longitudinal studies, the percentage of patients who do
not fill out the HRQL questionnaire greatly increases during the follow-up, often with
disease progression. For instance, one study (Kemmler et al., 1999) indicated that, in the
sixth evaluation, about 4 months after the beginning of the trial, the percentages of
responses were 36% and 42% in the two arms of treatment involved, respectively; about
60% of patients were not evaluated. In this latter case, a selection bias can occur, being the
presence of dropouts frequently correlated with disease progression.
2. Items: Psychometric questionnaires are designed to evaluate both the levels of each
domain and their modifications during the follow-up; therefore, the same questionnaire
is used in repeated assessments. In this way it is implicitly assumed that the same domains
and the same items continue to be the most important even when disease is in progression.
For instance, in the early stage of disease, limitations in doing household jobs (an item
which often explores the domain ‘‘social role’’) might be perceived as important, but
probably the concerns are different when the disease becomes disseminated. The use of the
same questionnaire during the follow-up seems to be in contradiction to Cella’s definition
of quality of life (see Introduction section), and may lead to a lack of > responsiveness.
3. Geographic differences: Domains may not be independent of the country where the
evaluation is carried out. The ways of life (i.e., the patient’s family could play a different
role in the management of the cancer patient) as well as the mean educational level may be
different in various countries. Moreover, different social and National Health Systems
(NHS) could cause the patient to assign a different importance to the same domain (i.e.,
economic conditions may be more or less important depending on whether the cost of
the disease is completely supported by the NHS or is totally or partially charged to the
patient). In conclusion, in some countries domains different from those explored in a
questionnaire produced and validated in another country may be the most important.
4. Scoring: The score of each multi-item domain is obtained by calculating a simple mean. In
this way, a weight system is implicitly assumed: all items are equally important. The choice
of another weight system could highlight the different importance of the items in explor-
ing the same domain. The score of each multi-item can be affected by the choice of the
weights to assign to each item, but there is no agreement on how to obtain the best weight
system.
5. Setting: A patient’s answers could be affected by both the time and place in which the
questionnaire is filled out. Perhaps a patient waiting to receive chemotherapy might give
answers different from those that he/she would give after hearing reassuring news about
his/her disease. Unfortunately, experimental studies on these aspects are lacking.
Furthermore, comparisons between scores of the same domain obtained using different HRQL
questionnaires should be avoided. Even when the same patient fills out two questionnaires,
correlation between the scores referring to the same domain is generally poor (Kemmler
et al., 1999).
Many of the above-mentioned problems affecting psychometric questionnaires may be over-
come by using a simpler, single item overall measurement of HRQL such as the uniscale.
Because the selection effects are at least in part due to the length and complexity of a multi-
item questionnaire, perhaps a simpler tool might lead to greater patient compliance. Then,
problems described in points (2–4) would automatically be overcome.
The price to be paid consists in (1) more research on this old tool, and (2) the lack of
analyticity, i.e., the impossibility to detect what the domains are that have induced a variation
in a patient’s quality of life.
In the next section, an Italian experience of the external validity of the uniscale is
described, highlighting how easy it is for cancer patients to fill out the VAS.
3 The Uniscale Assessment of Quality of Life: An Italian

Experience
Starting from the awareness that the available QOL instruments reflect more a medical
perspective, rather than a patient’s perspective, the Italian Group for the Evaluation of Out-
comes in oncology (IGEO) planned a study on the foundations of QOL from the patient’s
point of view.
In the first phase, Italian cancer patients were interviewed to give an empirical content
to the concept of QOL as well as to define what domains and problems were involved in
their idea of QOL. A large sample of cancer patients, equally distributed among different
types and stages of disease, and geographic areas, was selected. They were asked to give
articulated answers to four questions:
1. What does the term ‘‘quality of life’’ mean to you?
2. In your opinion, what contributes to a good quality of life?
3. What contributes to a poor or bad quality of life?
4. Tell me what physical or psychological symptoms or problems influence your quality
of life.
In addition, patients were asked to maintain a diary on ‘‘everything (positive and negative)
changed in their quality of life by the illness or its treatment.’’
A study sample of 288 cancer patients with an equal distribution of the following character-
istics was planned:
1. Place of residence (96 patients living in North, Center, and South, respectively) and for
each place of residence, by
2. Primary cancer site (12 patients with cancer of the breast, lung, gastrointestinal, female
genital organs, male genital organs, urinary system, head and neck tumor, and others,
respectively), and for each cancer site, by
3. Stage of disease (six patients in follow-up with no evidence of disease or undergoing
adjuvant chemotherapy, and six patients undergoing therapy for advanced disease or
palliative care for each cancer site, respectively).
The seven participating centers were asked to identify the patients with the requested char-
acteristics.
The patients’ answers were transcribed, and the transcript was submitted to a content analysis
by a team including a psychologist, a nurse, and a physician (Costantini et al., 2000).
Two hundred and forty eight patients were enrolled (86.1% of the 288 planned patients).
Their characteristics are shown in > Table 10-1.
Overall, a list of symptoms and 43 contents were identified, 19 problems, and 24 domains.
In the second phase, an evaluation of the relevance of each domain and of the presence
of each problem in a very large population of Italian cancer patients was carried out, so as
. Table 10-1
Socio-economic and clinical characteristics of the 248 interviewed patients
Characteristics No. (%)

Geographic area
North 76 (30.6)
Center 88 (35.5)
South 84 (33.9)
Age
Mean sd* 53.2±14.7
Gender
Male 140 (56.7)
Female 107 (43.3)
NR 1
Education (years)
5 79 (33.9)
6–8 75 (32.2)
9–13 62 (26.6)
>13 17 (7.3)
NR 15
Living status
Alone 17 (7.8)
1 relative 55 (25.2)
146 (67.0)
NR 30
Cancer site
Breast 36 (14.5)
Lung – pleura 34 (13.7)
Gastrointestinal 33 (13.3)
Female genital organs 25 (10.1)
Male genital organs 22 (8.9)
Urinary system 36 (14.5)
Head and neck 35 (14.1)
Others 27 (10.9)
Stage of disease
NED+ or adjuvant chemotherapy 120 (40.4)
Advanced or palliative care 128 (51.6)
*sd = standard deviation; NR = Not reported (excluded in calculating the percentages)
+
NED = No evidence of disease
In planning the sample, patients were balanced with respect to both geographic area and cancer site so as to have
a widespread overview of both domains and problems affecting a patient’s QOL
to associate a frequency to the importance of each dimension and to the presence of

each problem.
From July 6 to 12 1996, over a period of 1 week, consecutive cancer patients attending
76 Italian medical oncology and radiotherapy centers (9 in tertiary care, 18 in teaching
hospitals, and 49 in common hospitals) were asked to fill out a self-administered question-
naire concerning the relevance of the above-mentioned domains as well as the presence of the
listed problems. Moreover, patients were asked to fill out three VASs: the first, regarding a
uniscale assessment of their QOL, the second and the third their perception of the severity and
curability of their own disease, respectively (IGEO, 1999a; IGEO, 1999b).
From this database we extracted information related to the uniscale assessment of QOL,
the presence/absence of 19 problems, and the patient’s and disease characteristics recorded in
the CRF (Case Record Form) so as to detect the problems that are particularly important
in defining the levels of QOL (Ballatori et al., 2007).
More precisely, patients were asked to mark a point in a 100-mm long horizontal line in
which the extremes were labeled with 0 (the worst QOL) and 100 (the best QOL). Answers
were classified as ‘‘bad QOL’’ if a point in the 0–30 mm interval was chosen on the VAS or as
‘‘good QOL’’ if a point in the 70–100 mm interval was selected (> Figure 10-1). The two cutoff
values, ‘‘30’’ and ‘‘70,’’ were chosen because they are specific approximations of the two tertiles
of the interval 0–100. Therefore, patients who gave a score between ‘‘30’’ and ‘‘70’’ were not
considered, allowing us to obtain two variables that could be separately analyzed.
Multifactorial analyzes were performed using additive logistic models, in which dependent
variables in turn considered each of the two responses, ‘‘bad QOL’’ or ‘‘good QOL,’’ assuming
as explanatory variables the following factors: sex, age (<50, 50–64, and 65 years), education
(primary school, middle school, high school, and university degree), family status (unmarried,
married, other), living alone versus not, occupation (employed/unemployed, retired/
civil disabled, housewife, other), Karnofsky performance status (KPS: 80, 90), setting
(inpatient, outpatient), reasons for being in a cancer center (follow-up control/palliative
. Figure 10-1
Rating the patient’s answer into the VAS used for the uniscale assessment of QOL. Below the
100-mm horizontal line, only 0 and 100 belong to the VAS as appeared to the patient. The other
elements of the Figure 10-1 (30, 70, the two dash lines, ‘‘Bad QOL,’’ and ‘‘Good QOL’’ are shown to
make more understandable how patient’s answer was evaluated. Patients were asked to mark a
point in the thermometer; its distance from 0 was assumed as measure of QOL. Patient’s answer
was classified as ‘‘Bad QOL’’/‘‘Good QOL’’ if the marked point belonged to 0–30/70–100 interval,
respectively. The other values (i.e., those belonged to 30–70 interval) were not considered as to
define the two dependent variables of the logistic models
care, chemotherapy/hormonotherapy, surgery/radiotherapy, other), time from diagnosis

(0–3 months, from 3 months to 1 year, from 1 to 5 years, >5 years), stage of disease (no
evidence of disease, localized disease, disseminated disease, at diagnosis). Moreover, among
the explanatory variables, binary information derived from the presence/absence of the 19
above-mentioned problems was considered.
Results of unifactorial analyzes were provided as adjusted odds ratios and their 95%
confidence intervals. The G-test (which is equal minus two times the logarithm of maximum
likelihood ratio and asymptotically distributed as a w2) was used to evaluate the overall
significance of each factor in the model. The z-test (signed square root of Wald’s test that is
asymptotically distributed as a w2 with 1 degree of freedom), obtained dividing the parameter
estimation by the estimation of the correspondent standard error, was used to assess the
significance of differences between levels of each factor, adjusting for the other factors in the
model.
Of 6,918 patients, 820 (11.9%) did not fill out the questionnaire, and, therefore, 6,098
patients were evaluated. Patients’ characteristics, and the percentages of patients perceiving as
‘‘good’’ or ‘‘bad’’ QOL with respect to them, are displayed in > Table 10-2.
The high number of valid responses assures that the VAS is easy to fill out and generally
accepted by Italian cancer patients.
Patients with a ‘‘good QOL’’ are mainly those who are in better physical condition (see
KPS), outpatients, and patients with no evidence of disease; a ‘‘bad QOL’’ is more common
among patients with a low KPS score, inpatients, and patients with disseminated disease.
Present problems, and the percentages of patients perceiving as ‘‘good’’ or ‘‘bad’’ their
QOL with respect to them are shown in > Table 10-3.
QOL was considered ‘‘good’’ by 2,099 (34.4%) as opposed to 962 (15.8%) patients who
found it ‘‘bad.’’ These percentages were influenced by the presence of problems. In fact, the
percentage of patients who felt ‘‘bad’’ is highest among patients who have difficulties in
‘‘washing and getting dressed,’’ in ‘‘daily life,’’ and in ‘‘physical activities.’’ Patients who have
these same problems less frequently than the others perceived their QOL as ‘‘good.’’
The results of the multifactorial analyzes (see > Tables 10-4–10-6) are shown for ‘‘good
QOL’’ (> Table 10-4) and ‘‘bad QOL’’ (> Table 10-5) separately, in terms of z-test and
corresponding significance level. Moreover, they were shown in > Table 10-6 in terms of
odds ratios adjusted for the other factors in the models, assuming equal to 1 the odds ratio
for each reference category. Only significant factors were reported. Gender, education,
Karnofsky performance status, and setting are important in explaining the variability of the
perception of a ‘‘good’’ QOL. The probability of perceiving their own QOL as ‘‘good’’ is
highest for males, for patients with the lowest levels of education, for outpatients and patients
with a KPS 90.
Finally, the presence of each of 12 of 19 listed problems (trouble in concentrating, living in
a particularly stressful, or anxious period, anxiety about follow up results, body changes due to
illness, lack of optimism, difficulties in physical, working, and sexual activity, economic
troubles, unsatisfactory communication with doctors, lack of desire of social relationship,
and change in working skill) less frequently led patients to perceive their QOL as ‘‘good.’’
Assuming ‘‘bad QOL’’ as a response variable, the pattern of significant explanatory variables is
similar but inversely correlated.
In conclusion, in this extensive evaluation, among the 19 problems referred by cancer
patients in the first phase of the study 12 were found to have a significant impact on defining as
‘‘good’’ or ‘‘bad’’ the patients’ QOL.
. Table 10-2
Percentages of patients perceiving as ‘‘Good’’ or ‘‘Bad’’ their QOL with respect to patient’s and
disease characteristics
No. Good QOL Bad QOL

Patient’s characteristics % (No.) % (No.)
Total 6098 34.4 (2099) 15.8 (962)
Gender
Male 2295 37.2 (855) 15.4 (353)
Female 3803 32.7 (1244) 16.1 (609)
Age
<50 1500 33.0 (495) 15.3 (229)
50–65 2473 34.4 (851) 16.4 (405)
65 2125 35.4 (753) 15.4 (328)
Education
Primary school 2960 36.4 (1077) 16.6 (492)
Middle school 1633 34.3 (560) 14.9 (244)
High school/degree 1424 30.6 (436) 14.9 (213)
NR* 81 32.1 (26) 16.1 (13)
Family status
Unmarried 589 32.6 (192) 17.2 (101)
Married 4642 35.6 (1653) 15.2 (704)
Other 803 28.7 (231) 18.3 (147)
NR* 64 35.9 (23) 15.6 (10)
Living
Alone 535 29.1 (156) 18.9 (101)
Not alone 5445 35.1 (1910) 15.3 (834)
NR* 118 27.9 (33) 22.9 (27)
Occupation
Employed/unemployed 1794 34.5 (619) 15.8 (283)
Retired/civil disabled 2532 35.5 (899) 15.9 (404)
Housewife 1660 32.7 (543) 15.7 (260)
Other (student + religious) 112 33.9 (38) 13.4 (15)
Karnofsky PS
80 2013 24.7 (498) 24.1 (484)
90 4085 39.2 (1601) 11.7 (478)
Setting
Inpatient 724 23.9 (173) 25.5 (185)
Outpatient 5374 35.8 (1926) 14.4 (777)
Reason for presence
Follow-up control/palliative care 2652 38.1 (1011) 14.0 (371)
Chemotherapy/hormonotherapy 2702 30.8 (834) 17.5 (472)

Patient’s characteristics % (No.) % (No.)
Surgery/radiotherapy 604 34.6 (209) 15.1 (91)
Other or NR* 140 32.1 (45) 20.0 (28)
Time from diagnosis
0–3 months 1636 34.5 (235) 14.4 (235)
3 months–1 year 1463 35.6 (257) 17.6 (257)
1–5 years 1928 35.2 (297) 15.4 (297)
>5 years 849 31.5 (132) 15.5 (132)
NR* 222 30.6 (41) 18.5 (41)
Disease extension
No evidence of disease 2580 41.1 (1061) 10.2 (263)
Localized disease 1197 33.2 (398) 17.6 (211)
Disseminated disease 2088 26.8 (560) 21.3 (445)
At the time of the diagnosis or NR* 233 34.3 (80) 18.5 (43)
*NR: Not reported
. Table 10-3
Percentages of patients perceiving as ‘‘Good’’ or ‘‘Bad’’ their QOL with respect to the presence of
problems in their present condition

Patients’ conditions % (No.) % (No.)
TOTAL 6098 34.4 (2099) 15.8 (962)
Trouble in concentrating 2446 26.4 (645) 22.0 (538)
Memory difficulties 2547 28.7 (730) 19.3 (493)
Living in a particularly stressful or anxious period 4244 28.6 (1213) 19.5 (828)
Anxiety about follow-up results 4303 30.6 (1317) 18.6 (802)
Body changes due to the illness 3624 27.9 (1011) 20.3 (736)
Lack of optimism 1722 22.3 (383) 27.6 (476)
Lack of support from relatives 443 27.7 (123) 19.2 (85)
Difficulties in washing and in dressing 392 19.6 (77) 38.1 (149)
Difficulties in daily life 995 17.0 (169) 37.5 (373)
Difficulties in physical activity 1953 18.3 (358) 29.6 (578)
Difficulties in working activity 2520 21.2 (535) 27.5 (693)
Difficulties in performing sexual activity 2859 25.2 (722) 23.8 (680)
Economic troubles 1033 23.5 (243) 27.7 (286)
Inadequate support from the health service personnel 268 27.3 (73) 24.6 (66)
Inadequate care and services 260 23.5 (61) 27.7 (72)
Unsatisfactory communication with doctors 311 19.6 (61) 27.1 (84)
The Uniscale Assessment of Quality of Life: Applications to Oncology

10 189

Patients’ conditions % (No.) % (No.)
Lack of desire of social relationship 2375 30.3 (720) 18.7 (444)
Change in working skill with respect to the past 3706 26.1 (965) 21.2 (786)
Change in one’s faith 934 31.3 (292) 20.8 (194)
Percentages of patients who have a ‘‘good’’ or a ‘‘bad’’ QOL could be read comparing them with those reported for
all the patients (i.e., ‘‘total,’’ independent of the presence of the problems; see the first line). Thus, the impact of
each problem on patient’s QOL becomes evident. For instance, 15.8% of all patients feel they have a ‘‘bad QOL’’;
the same proportion among those who have ‘‘difficulties in washing and in dressing’’ grows to 38.1%
4 Conclusions
In recent years QOL has been studied following a multidimensional approach. Many studies
have demonstrated that several domains are concurrent in defining the concept of QOL. Each
dimension must be explored using one or, more frequently, more items. Therefore, the QOL
questionnaires currently in use are comprehensive of a number of items often varying from
30 to 60. Worthy of note is that this high number of items appears extraordinarily small when
one thinks that each domain should be explored in three different dimensions: intensity,
frequency, relevance (i.e., the impact on patient’s daily life).
The most positively important aspect of the multidimensional evaluation consists in the
possibility of separately evaluating each domain, so as to detect which of them are most
affected by the growing severity of the disease or by the side effects of the therapies. However,
this approach suffers from some shortcomings; in particular, a nonnegligible percentage of
patients that refuse to fill out the first questionnaire in spite of having given their informed
consent to participate in the study (about 12% in Italy (IGEO, 1999a)). Moreover, in
longitudinal studies an increasing percentage of patients refuse to complete the questionnaire
in subsequent sessions, mainly because of disease progression. Thus, a severe selection bias
often affects the evaluation of QOL when, instead, it is most important that it be done
correctly. In addition, for reasons of comparability, the same items are used in subsequent
evaluations; in this way it is implicitly assumed that the same domains/items continue to be
the most important, even with the worsening of the disease. For instance, at early stage disease,
limitation in doing household jobs could be perceived as important by the patient, but
probably the concerns are different when the patient is bedridden due to disseminated disease.
Therefore, a psychometric questionnaire should be used only in parallel randomized
clinical trials, where the obtained results can be regarded as reliable only if the number of
dropouts is not large and the two arms are well balanced.
At the beginning of the 1980s, a unidimensional approach was suggested, using a VAS.
However, this procedure was soon abandoned because of much criticism, such as its low reliability,
the dependence of the answer on the patient’s contingent conditions, and the impossibility to
detect the domains that are most affected by changes in the patient. Some of these criticisms were
founded on empirical research; others, instead, were based only on a theoretical point of view.
Today, because of the serious difficulties arising from the use of questionnaires containing
too many items, the old uniscale might be reevaluated as a basic tool in measuring quality of
life. In fact, a VAS is very easy to fill out, and its reliability can be substantially improved in
. Table 10-4
Multifactorial analyzes of the ‘‘good QOL’’ perception performed using logistic additive models:
parameter estimations, z-test, and significance levels
Factors Parameter estimation z-test P<

General mean 0.930
Gender
Female – Male 0.217 3.42 0.001
Education
Middle school – Primary+ 0.226 3.20 0.002
+
High school/degree – Primary 0.471 6.15 0.0001
Karnofsky PS
90 – 80 0.193 2.58 0.01
Treatment setting
Outpatient – Inpatient 0.237 2.32 0.03
Disease extension
Localized disease – NED* 0.150 1.80 n.s.+
Disseminated disease – NED* 0.274 3.61 0.001
At the time of the diagnosis or NR – NED* 0.208 1.31 n.s.+
Present condition
Yes – No
Trouble in concentrating 0.251 3.96 0.0001
Living in a particularly stressful or anxious period 0.418 6.26 0.0001
Anxiety about follow-up results 0.210 3.14 0.002
Body changes due to the illness 0.268 4.39 0.0001
Lack of optimism 0.505 7.11 0.0001
Difficulties in physical activity 0.372 4.36 0.0001
Difficulties in working activity 0.355 4.43 0.0001
Difficulties in performing sexual activity 0.191 2.91 0.004
Economic troubles 0.350 4.04 0.0001
Unsatisfactory communication with doctors 0.351 2.25 0.03
Lack of desire of social relationship 0.273 4.75 0.0001
Change in working skill with respect to the past 0.354 5.22 0.0001
*NED = No evidence of disease; +n.s. = Not significant; NR: Not reported
Inalogisticmodel,theratiobetweenparameterestimationandthecorrespondingstandarderrorisasymptoticallynormally
distributed.Ineachcontrast,thepositive/negativesignmeansthattheprobabilitytohavea‘‘goodQOL’’isgreater/lesserfor
the first level than for thesecond, respectively. In this table are displayed the parameter estimations and the corresponding
significance levels referred only to significant factors in the multifactorial additive logistic model. Parameter estimations
allowustoobtaintheprobabilitytohavea‘‘goodQOL’’foreachpatient,givenhis/hercharacteristics.Example:letusevaluate
theprobabilityofa‘‘goodQOL’’(Y)forafemale,highschooldegree,outpatient,withNEDandaKarnofskyperformancestatus
equal to 100, who has ‘‘Trouble in concentrating,’’ ‘‘Anxiety about follow-up results,’’ ‘‘Unsatisfactory communication with
doctors,’’ and has no other listed condition. First of all, Linear Predictor (LP) should be calculated; then its value has to be
replacedin theequation ofthelogisticmodel: P(Y/.) = eLP/(1 + eLP). LP = 0.930 (general mean) – 0.217 (female) – 0.471
(High school) + 0.193 (Karnofsky PS = 100) + 0.237 (outpatient) + 0 (NED) – 0.251 (Trouble in concentrating) – 0.210
(Anxiety about follow-up results) – 0.351 (Unsatisfactory communication with doctors) = 0.14. Therefore, the
estimated probability that she has a ‘‘good QOL’’ is: P(Y/.) = e–0.14/(1+e–0.14) = 46.5%
. Table 10-5
Multifactorial analyzes of the ‘‘bad QOL’’ perception performed using logistic additive models:
parameter estimations, z-test, and significance levels
Factors Parameter estimation z-test P<

General mean 4.159
Treatment setting
Outpatient – Inpatient 0.238 2.22
Disease extension
Localized disease – NED* 0.300 2.70 0.01
Disseminated disease – NED* 0.347 3.64 0.001
At the time of the diagnosis or NR – NED* 0.516 2.56 0.02
Present condition: Yes – No
Trouble in concentrating 0.323 4.07 0.0001
Living in a particularly stressful or anxious period 0.545 5.02 0.0001
Anxiety about follow-up results 0.423 4.14 0.0001
Body changes due to the illness 0.365 4.08 0.0001
Lack of optimism 0.755 9.50 0.0001
Difficulties in daily life 0.487 4.97 0.0001
Difficulties in physical activity 0.273 2.75 0.01
Difficulties in working activity 0.734 7.21 0.0001
Difficulties in performing sexual activity 0.360 4.08 0.0001
Economic troubles 0.463 5.10 0.0001
Lack of desire of social relationship 0.285 3.62 0.001
*NED = No evidence of disease; NR: Not reported Using the same technique described in the Legend of
> Table 10-4, let us calculate the probability to have a ‘‘bad QOL’’ for an outpatient with disseminated disease
who is living in a particularly stressful period, with difficulties both in daily life and in working activity, and with
economic troubles, without any other condition among those listed in > Table 10-5. LP = –4.159 – 0.238
(outpatient) + 0.347 (disseminated disease) + 0.545 (particularly stressful period) + 0.487 (difficulties in daily life)
+ 0.734 (in working activity) + 0.463 (economic troubles) = –1.823. Therefore, the probability to have a ‘‘bad QOL’’
(PY/.) is equal to P(Y/.) = e-1.821/(1+e-1.821) = 13.9%
different ways (i.e., by analyzing the responses, not as numerical values, but grouping them in
classes). Unfortunately, there is no clear evidence that the use of a VAS allows us to obtain
better patient compliance than the use of a psychometric questionnaire, but this should be the
main aim of an ad hoc planned study.
The results of our study (Ballatori et al., 2007), performed on a very large population of
Italian cancer patients, can be considered as further proof of the uniscale external validity,
showing that it is strongly influenced by unfavorable patient characteristics and by the
problems related to their condition. These results are in accord with those reported in a recent
paper (de Boer et al., 2004) where it was shown that, in patients affected by esophageal
adenocarcinoma, the VAS used as the uniscale assessment of the QOL is an instrument with
good convergent and discriminant validity and good responsiveness.
Moreover, as shown in our paper, a VAS is able to summarize several adverse conditions,
and their importance can be evaluated only by the patient: this overcomes the difficulties
. Table 10-6
Multifactorial analyzes of the QOL perception performed using logistic additive models: odds
ratios} (95% confidence interval) for each significant factor adjusted for the other factors in the
models
Factors Good QOL Bad QOL

Gender n.s.+
Male* 1
Female 0.80 (0.71–0.91)
Education n.s.+
Primary school* 1
Middle school 0.80 (0.69–0.92)
High school/Degree 0.62 (0.54–0.72)
NR n.s.
Karnofsky PS n.s.+
80* 1
90 1.21 (1.05–1.40)
Treatment setting
Inpatient* 1 1
Outpatient 1.27 (1.04–1.55) 0.79 (0.64–0.97)
Disease extension
No evidence of disease* 1 1
+
Localized disease n.s. 1.35 (1.09–1.68)
Disseminated disease 0.76 (0.65–0.88) 1.41 (1.17–1.70)
At the time of the diagnosis or NR n.s.+ 1.67 (1.13–2.48)
Present condition 1 1
No*
Yes
Trouble in concentrating 0.78 (0.69–0.88) 1.38 (1.18–1.61)
Living in a particularly stressful or anxious period 0.66 (0.58–0.75) 1.72 (1.39–2.13)
Anxiety about follow-up results 0.81 (0.71–0.92) 1.53 (1.25–1.87)
Body changes due to the illness 0.76 (0.68–0.86) 1.44 (1.21–1.72)
Lack of optimism 0.60 (0.52–0.69) 2.13 (1.82–2.49)
+
Difficulties in daily life n.s. 1.63 (1.34–1.97)
Difficulties in physical activity 0.69 (0.58–0.81) 1.31 (1.08–1.60)
Difficulties in working activity 0.70 (0.60–0.82) 2.08 (1.71–2.54)
Difficulties in performing sexual activity 0.83 (0.73–0.93) 1.43 (1.21–1.70)
Economic troubles 0.70 (0.59–0.83) 1.60 (1.33–1.90)
Unsatisfactory communication with doctors 0.70 (0.52–0.95) n.s.+
The Uniscale Assessment of Quality of Life: Applications to Oncology

10 193
Factors Good QOL Bad QOL

Lack of desire of social relationship 0.76 (0.67–0.86) 1.33 (1.14–1.55)
Change in working skill with respect to the past 0.70 (0.61–0.80) n.s.+
*Reference category: For each reference category odds ratio is fixed equal to 1; +n.s. = Not significant; NR: Not
reported} Odds ratio (OR) is a nonnegative measure of association. OR = 1 indicates the independence (i.e., when
OR = 1, the probability of a ‘‘good QOL’’ is not affected by the variation of the other characteristic). When OR > 1, there
is a positive association, with the highest values indicating the strongest positive association (i.e., when considering
‘‘bad QOL’’ and ‘‘Trouble in concentration,’’ OR = 1.38 means that the probability of having a ‘‘bad QOL’’ is superior in
patients who have ‘‘Trouble in concentrating’’ than the others. OR < 1 indicates a negative association with the
smallest values indicating the strongest negative association (i.e., when considering ‘‘Trouble in concentration’’ and
‘‘good QOL,’’ OR = 0.78 means that the probability of a ‘‘good QOL’’ is inferior in patients having ‘‘Trouble in
concentration’’ than in those who do not have it
of requiring changes in both the domains and items when the disease becomes more severe.
In fact, remembering Cella’s definition of QOL (‘‘Quality of life refers to patients’ appraisal of
and satisfaction with their current level of functioning as compared to what they perceive to be
possible or ideal’’), the uniscale evaluation of QOL is able to summarize the patient’s
comparison between his/her actual condition with those he/she perceives ‘‘to be possible or
ideal,’’ where the perception of ‘‘possible or ideal’’ conditions varies with disease progression.
When there is the necessity to evaluate the changes in several QOL domains, a VAS could
be used to explore each of them, so as to reduce the many items of the psychometric
questionnaire (i.e., from 30 to 6). In this case, it would be sufficient to find a way to make
the content of each domain easily understandable to the patient.
In conclusion, a VAS can be considered as a reference point in multidimensional QOL
scales and should still be regarded as a useful and synthetic tool to investigate phenomena
related to the patient’s QOL. In this perspective, more research on the psychometric properties
of this instrument is still needed.
Summary Points
Measuring QOL is extremely important in clinical research not only because QOL is one of
the only two endpoints of effectiveness of treatments, but also for making clinical decisions
shared with the patient.
Today, assessment of QOL is made using psychometric questionnaires; nevertheless, these
latter have several shortcomings that often lead to unreliable results.
About 14 years ago, the Italian Group for the Evaluation of Outcomes in oncology (IGEO)
planned a research program articulated in two phases.
In the first phase, domains of QOL and problems connected with it were defined
performing a content analysis of the interviews of 248 Italian cancer patients.
The domains/problems reported by the patients were submitted to a large population of
more than 6,000 Italian cancer patients so as to assign a frequency to the relevance of each
domain and to the presence/absence of each problem. In this study, a uniscale evaluation
of QOL was also obtained using a Visual Analogue Scale (VAS).
From this databank were extracted the uniscale evaluation, information about the presence
of the problems, and patient’s and disease characteristics recorded in the CRF.
Each answer to the VAS was classified as ‘‘bad QOL’’/‘‘good QOL’’ if a point belonging to
0–30/70–100 interval was marked. Answers in the 30–70 interval were not considered
so as to assure independence to the chosen response variables.
The relationship between each of these responses (dependent variable) and the presence of
the 19 problems, and patient’s and disease characteristics (explanatory variables) were
analyzed using multifactorial logistic models.
12/19 problems were significant in explaining the variability of the two responses. This
confirms the external validity of the uniscale assessment of QOL.
A VAS aimed at measuring QOL should still be regarded as a useful and synthetic tool to
investigate phenomena related to a patient’s QOL. In the perspective of its further develop-
ment, more research on the psychometric properties of this instrument is still needed.
Acknowledgments
> Tables 10-2, 10-3, 10-6 were reproduced with kind permission of the Editor of Tumori.
We thank Mrs Katherine Brandt for her helpful assistance in reviewing the text.
References
Aaronson NK. (1990). Oncology. 4(5): 59–66. de Boer AG, van Lanschot JJ, Stalmier PF, van Sandick JW,
Ballatori E. (2001). Ann Oncol. 12(3): S11–S13. Hulscher JB, de Haes JC, Sprangers MA. (2004). Qual
Ballatori E, Porzio G, Roila F, Ruggeri B, Mattei A, Life Res. 13(2): 311–320.
Cortesi E. (2007). Tumori. 93: 78–81. Hiratsuka T, Kida D. (1993). Internal Med. 32: 832–836.
Cella DF, Tulsky DS. (1990). Oncology. 4(5): 29–38. IGEO (The Italian Group for the Evaluation of Out-
Coates A, Glasziou P, Mc Neil D. (1990). Ann Oncol. comes in Oncology). (1999a). Tumori. 85: 92–99.
1(3): 213–217. IGEO (The Italian Group for the Evaluation of
Costantini M, Mencaglia E, Di Giulio P, Cortesi E, Outcomes in Oncology). (1999b). Ann Oncol.
Roila F, Ballatori E, Tamburini M, Casali P, 10: 1095–1100.
Licitra L, Candiis DD, Massidda B, Luzzani M, Kemmler G, Holzner B, Kopp M, Dunser M, Margreiter R,
Campora E, De Placido S, Palmeri S, Angela PM, Greil R, Sperner-Unterweger B. (1999). Jco. 17(9):
Baracco G, Gareri R, Martignetti A, Ragosa R, Zoda 2932–2940.
L, Ionta MT, Bulletti S, Pastore L. (2000). Qual Life
Res. 9: 151–159.
11 The Bone Metastases Quality
of Life Questionnaire
X. Badia . A. Vieta . M. Gilabert
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
1.1 Why is it Important to Assess Quality of Life in Patients with
Bone Metastases? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
2 The BOMET-QOL Questionnaire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

2.1 What is the BOMET-QOL? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
2.2 Criteria Applied in Developing the Questionnaire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
3 Development of the BOMET-QOL-10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

3.1 Phase 1. Item Generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
3.2 Phase 2. Item Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
3.2.1 Identification of the Initial Group of Items . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
3.3 Phase 3. Item Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
3.3.1 First Reduction: Reduction of the BOMET-QOL from 35 to 25 Items . . . . . . . . . . . 201
3.3.2 Second Reduction: Reduction of the BOMET-QOL from 25 to 10 Items . . . . . . . . 202
4 Validation of the BOMET-QOL-10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

196 11 The Bone Metastases Quality of Life Questionnaire
Abstract: The > Bone Metastases Quality of Life Questionnaire (BOMET-QOL) is the first
> bone metastases-specific HRQOL measure. It is a simple, self-administered questionnaire
intended for use in clinical research and in the routine monitoring of patients with malignant
bone disease due to neoplasia. The BOMET-QOL questionnaire is unidimensional and
consists of 10 items that can be answered according to a Likert scale with five categories scoring
from 0 to 4. The timeframe refers to ‘‘last week.’’ The items refer to HRQOL topics such as
pain, mobility, vitality, sex life, worries about the future, perceptions and daily activities. The
global score is calculated by adding up the answers obtained in each item, and may range from
0 (worst HRQOL) to 40 (best HRQOL). These scores are standardized to make it easier to
interpret the scoring, with the final scores ranging from 0 (worst HRQOL) to 100 (best
HRQOL). The BOMET-QOL was developed in three phases. The item generation phase was
performed by means of a literature search, a panel of experts and 15 semi-structured inter-
views with patients. An initial set of 179 expressions was identified. The item selection phase
consisted of the identification of the initial group of items. The 15 experts carried out a
qualitative and quantitative reduction of the 179 expressions according to their clarity,
frequency and importance. This phase resulted in the 35-item version of the BOMET-QOL.
The item reduction phase was carried out in two steps. The initial reduction yielded a 25-item
questionnaire. This was administrated to a non-randomized sample of 92 patients with
malignant bone disease due to neoplasia (MBDN) and the reduction was carried out via
factorial analysis. Similarly, the BOMET-QOL-25 was reduced to an integrated version of 10
items by means of a sample of 263 oncology patients. It was then validated, showing high
homogeneity, good reproducibility and significant correlations with the ECOG and the
EORTC-QLQ-C30 questionnaire. The BOMET-QOL questionnaire is a feasible (easy and
user-friendly), reliable and specific 10-item instrument for assessing HRQOL in patients
with MBDN.
List of Abbreviations: BM, > bone metastases; BOMET-QOL, bone metastases quality of life
questionnaire; CARES, cancer rehabilitation evaluation system; FACT-G, functional assessment
of cancer therapy; HRQOL, health-related quality of life; MBDN, > malignant bone disease
due to neoplasia; PMI, > pain management index; QLQ- 30, quality of life questionnaire;
RSCL, Rotterdam symptom check list
1 Introduction
1.1 Why is it Important to Assess Quality of Life in Patients with

Bone Metastases?
Several developments in cancer treatment have promoted interest in health-related aspects of

quality of life. Firstly, while medical interventions have historically been evaluated in terms of
their effectiveness in reducing tumor progression and mortality, the major therapeutic goal for
many patients is to reduce the symptoms of the illness. Secondly, concerns about potential
treatment safety and tolerability make quality of life issues important components of patient
decision-making when choosing between alternative courses of treatment. Thirdly, the ability
of sophisticated medical technologies to extend lifespan raises significant questions about the
quality of the life that is being prolonged. Finally, with an increased emphasis on humanizing
healthcare, improving quality of life is considered an important outcome even if life is not
prolonged (Avis et al., 1996).
The Bone Metastases Quality of Life Questionnaire 11 197
For these reasons, assessment of Health-Related Quality of Life (HRQOL) in oncology has
increased in the last few years. HRQOL has become an important outcome measure of new
therapies in clinical trials (Cella et al., 2002). The importance of assessing HRQOL in clinical
practice is also widely acknowledged, since cancer treatment, in advanced cancer patients, is
aimed mainly at relieving symptoms, especially pain. Means of standardizing assessment of the
disease’s impact and treatments on HRQOL from the patient’s point of view are therefore
needed (Badia et al., 2003).
The skeleton, particularly the axial skeleton, is a frequent location for metastases, especially
in patients with breast, prostate, thyroid, kidney or lung cancer or multiple myeloma.
Specifically, bone metastases (BM) are the third most frequent metastatic site for primary
tumors and the first in terms of morbidity and impact on HRQOL. The incidence of bone
metastases in patients with advanced metastatic disease is approximately between 65 and 75%
in breast and prostate cancer, 30–40% in lung cancer, 14–45% in melanoma, 20–25% in renal
cell carcinoma, and 60% in thyroid and 40% in bladder neoplasia (Coleman, 2004). Bone
metastases are a major cause of morbidity and significantly reduce a patient’s quality of life.
Pain is the most frequent clinical sign and bone metastasis is likely to be the main cause of pain
in oncology patients (Lipton, 2003; Martinez et al., 2003; Reddi et al., 2003). Aside from pain,
BM frequently produces the following complications: pathological fractures, spinal cord
compression, tumor-induced hypercalcemia and bone marrow infiltration. It is well estab-
lished that these complications significantly reduce patients’ HRQOL, although this has not
been properly studied (Bunting and Shea, 2001).
Although patients can survive for long periods, treatment of bone metastasis tends to be
only of a palliative nature. External radiotherapy and palliative chemotherapy are two of the
most frequently used strategies to treat bone pain, along with the analgesic use and nerve
blocking of regional anesthesia as palliative therapeutic options. In the last few years, therapy
for malignant bone disease due to neoplasia (MBDN) has improved significantly due to its
multidisciplinary approach and to new therapeutic treatments, especially to the second and
third generation bisphosphonates (Djulbegovic et al., 2002). Initially used to treat tumor-
induced hypercalcemia, these were later associated with hormone therapy and chemotherapy,
showing benefits in the control of symptoms, reducing morbidity and bone progression. The
aims of the adjunct treatment are to alleviate pain and stabilize the bone, as well as to ensure
the patient’s well-being and independence (> Table 11-1).
The assessment of quality of life in oncology patients requires the use of standardized
instruments (usually self-administered questionnaires) specifically designed for this purpose.
It is essential that the instruments used to measure quality of life meet the basic characteristics
(> validity, > reliability and sensitivity to change) in order to guarantee the quality of the
outcomes deriving from their application. Using these questionnaires means that patients’
quality of life can be quantified, using this as an outcome measure for treatments and medical
interventions both in research and in clinical practice.
Nowadays, there are various instruments to assess HRQOL in oncology, such as the Cancer
Rehabilitation Evaluation System (CARES) (Ganz et al., 1992), > EORTC QLQ-30 Quality
of Life Questionnaire (Aaronson et al., 1993), Functional Assessment of Cancer Therapy
(FACT-G) (Cella et al., 1993), and the Rotterdam Symptom Checklist (RSCL) (Watson
et al., 1992). Taking into account the general nature of these questionnaires, which cover
common issues concerning impact on the quality of life in all types of neoplasia, they might
be insufficiently sensitive to some changes exclusively associated with MBDN. Consequently,
the 10-item BOMET-QOL questionnaire (BOMET-10) was designed in order to assess quality
of life in patients with MBDN.
. Table 11-1
Key features of bone metastases
1. Metastatic bone disease is a cancer starting in another location and spreading to the bones
2. The metastasis of tumor cells to bone requires a series of sequential steps, involving detachment
from the primary tumor site, invasion of the vasculature, migration and adherence to distant
capillaries of the bone, extravasation, and proliferation. Once tumor cells have invaded the bone
matrix, they produce growth factors that can directly or indirectly stimulate osteoclasts that
break down the bone
3. Bone metastases are generally classified as osteolytic, characterized by the destruction of normal
bone, or osteoblastic, with the deposition of new bone, based upon the predominant
radiological appearance
4. Bone is the third most common site of metastatic disease, most likely because of the favorable
microenvironment of the bone matrix and its ample blood supply
5. The incidence of bone metastases in patients with advanced metastatic disease is approximately
between 60 and 65% in breast and prostate cancer, 30–40% in lung cancer, 14–45% in
melanoma, 20–25% in renal cell carcinoma, and 60% in thyroid and 40% in bladder neoplasia
6. Bone metastases are a major cause of morbidity and significantly reduce the patient’s quality of
life, often accompanied by skeletal-related events including pathological fracture, spinal cord
compression, hypercalcemia or pain
7. Treatment of bone metastasis consists of active chemotherapy, hormonal therapy treatment of
the original cancer and the use of bisphosphonates
This table lists the key facts in bone metastases including physiology, epidemiology, medical impact and clinical
management
2 The BOMET-QOL Questionnaire
2.1 What is the BOMET-QOL?
The Bone Metastases Quality of Life Questionnaire (BOMET-QOL) is the first to measure
bone metastases-specific HRQOL. It is a simple, self-administered questionnaire, intended for
use in clinical research (trials) and in the routine monitoring of patients with bone metastases
or myeloma. The items refer to HRQOL topics such as pain, mobility, vitality, sex life, worries
about the future, perceptions and daily activities.
The BOMET-QOL questionnaire is unidimensional and consists of 10 items that
can be answered according to a Likert scale with five categories (always, almost always,
sometimes, rarely and never), scoring from 0 to 4, and the timeframe refers to ‘‘last week’’
(> Figure 11-1). The global score is calculated by adding up the answers obtained in each item,
and may range from 0 (worst HRQOL) to 40 (best HRQOL). These scores are standardized to
make it easier to interpret the scoring, with the final scores ranging from 0 (worst HRQOL) to
100 (best HRQOL) (> Figure 11-1).
2.2 Criteria Applied in Developing the Questionnaire
Any instrument for assessing outcome research should be patient-oriented (describe the
functional state, including daily activities), useful and simple (ideally should contain less
than 10 items, be acceptable for daily clinical practice and easy to interpret). Also, certain basic
. Figure 11-1
Scoring system and items on the BOMET-QOL-10 questionnaire. This figure presents the 10 items
of the BOMET-QOL questionnaire, answered according to a Likert scale of five categories
measuring standards (validity and reliability) should be carried out on the instrument in order
to ensure the quality of the results deriving from the questionnaire. The validity of a
questionnaire is defined as its ability to measure and describe what it is supposed to measure
and describe. Validity is evaluated in terms of cross-sectional (construct validity) and
> longitudinal validity. Cross-sectional or construct validity addresses the issue of whether
or not the instrument assesses the construct as defined in the measurement model. Longitu-
dinal construct validity or sensitivity to change implies that even small changes in the order of
appearance of questions, or question wording, may cause changes in the results. The validity
of a questionnaire relies first on reliability. Reliability means the statistical reproducibility of
measurements. This may be test-retest reliability, when repeating the questionnaire under the
same conditions produces the same results, or reliability within a scale, when all the items
designed to measure a particular attribute are definitely measuring the same attribute.
In view of the above, the development of the BOMET-QOL to assess the quality of life in
patients with MBDN focused on the following criteria:
1. The content of the questionnaire should be suitable and specific for patients with MBDN.
The scale should be suitable for all illness severity levels, no matter what the causes are.
2. The questionnaire should be based on assessing the perceived problems (subjective) so
they can be reported by the patient. The questionnaire should generate answers concerning
problems that may have been important or activities that may have been stopped because
of the illness.
3. The questionnaire should have a high applicability. Age, gender or any other socio-
demographic issue, such as the patient’s level of education, should not be a condition-
ing factor in its administration or a determining factor in the outcomes obtained. For
these reasons, the questionnaire should be easy to understand and fast to complete. It
should also be easy to administrate by the health carers and easy to process, analyze, and
interpret.
4. The measurement properties of the questionnaire should be validated so that it can be
applied rigorously both in a research context and in common clinical practice.
3 Development of the BOMET-QOL-10

The BOMET-QOL-10 questionnaire was developed in three phases:
3.1 Phase 1. Item Generation
This phase identified the areas of content or dimensions of the questionnaire.

The bibliography was reviewed in order to identify the clinical manifestations and clinical
characteristics of patients with bone metastases. A panel of experts (10 oncologists, 1 hema-
tologist and 4 urologists) then identified, in an interview, the most relevant signs and
symptoms for these patients. Lastly, exploratory interviews were carried out with 15 patients
with breast, lung or prostate cancer affected by bone metastases (> Table 11-2).
The aim of this phase was to analyze the impact of symptoms and their treatment on
quality of life: wellness, satisfaction with the state of health, and functional level according to
the patients’ age and preferences. Special interest was placed on how the illness might impact
areas such as personal, social and cognitive functioning or rest. The interviews were semi-
structured and were carried out by two monitors trained by researchers with expertise in this
area. The patients interviewed had different clinical and socio-demographic characteristics
and met all the criteria defined by the panel of experts. The interviews were recorded and
transcribed for subsequent qualitative and quantitative analysis.
This phase yielded the clinical criteria required to identify the patients to test the
questionnaire and its dimensions. nine domains were identified from this phase (physical,
psychological, social, daily activities, symptoms, cognitive dimension, health perception,
treatment perception, energy/vitality and pain) as well as an initial set of 179 expressions.
3.2 Phase 2. Item Selection
3.2.1 Identification of the Initial Group of Items
The 15 experts who were involved in phase 1 identified the initial group of items by means of a
qualitative and quantitative analysis.
For the qualitative analysis, the experts gathered the expressions obtained for the different
dimensions from phase 1 and identified the ones that were too similar, ambiguous or
inadequate, as these expressions could be converted into simple expressions suitable for a
. Table 11-2
Characteristics of MBDN patients interviewed for the item generation phase
Patient Gender Age Education level Primary tumor Pain score (0–10)
1 F 36 Secondary level Breast 6
2 F 53 Primary level Breast 5
3 F 43 University level Breast 7
4 F 62 Primary level Breast 6
5 F 58 Secondary level Breast 6
6 M 78 No education Prostate 7
7 M 69 Primary level Prostate 5
8 M 58 University level Prostate 4
9 M 65 Primary level Lung 3
10 F 72 No education Myeloma 5
11 F 67 No education Myeloma 6
12 M 56 Primary level Myeloma 3
13 M 61 No education Myeloma 7
14 M 49 University level Myeloma 8
15 M 75 No education Myeloma 2
This table summarizes the main patient characteristics, such as gender (F: female, M: male), level of education (no
education, primary, secondary and university level), primary tumor site (breast, prostate, lung or myeloma) and the
pain score from 1 to 10
self-administered questionnaire. The quantitative analysis consisted of recounting the fre-

quency of the terms used. The experts scored the initial group of items according to the clarity
of wording, frequency of occurrence, and importance using a 5-point Likert scale. As a result
of this analysis, a sample of items or representative questions was identified that represent the
perceptions of HRQOL in patients with bone metastases.
This qualitative and quantitative analysis carried out by the experts resulted in the 35-item
version of the BOMET-QOL.
3.3 Phase 3. Item Reduction
3.3.1 First Reduction: Reduction of the BOMET-QOL from 35 to 25 Items
This preliminary questionnaire (BOMET-QOL-35) was then administrated to a non-

randomized sample of 92 patients with MBDN from 21 centers throughout Spain. The
baseline neoplasia was: breast (37%), prostate (23%), myeloma (15%), lung (21%) and
other types (4%). Fifty percent of the patients were male. There were patients with different
levels of education, aged from 30 to 80 years, diagnosed with MBDN for up to a maximum of
9 years, who had or had not undergone chemotherapy. Nineteen percent had concomitant
osteoarticular disease and ninety percent a non-osteoarticular chronic disease.
From the answers of the patients in this initial administration, the items were analyzed
(> Rasch analysis) evaluating each one in terms of its discriminant validity, which is the
questionnaire’s capacity to distinguish between patient subgroups. The > Rash analysis con-
structs a line of measurement with the items placed hierarchically and provides fit statistics to
indicate just how well different items describe the group of subjects responding to a question-
naire (Rasch, 1993). Therefore, the items that showed the worst fit were eliminated from the
questionnaire. Using the Factorial analysis from the Rasch analysis, the most adequate item
grouping was established, as presented in the 25-item BOMET-QOL questionnaire.
Criteria such as the internal consistency of the items (using item-total correlation) and
reliability of the results were also taken into consideration. The questionnaire showed good
internal consistency with a Cronbach’s Alpha coefficient of 0.94.
This analysis resulted in the 25-item BOMET-QOL questionnaire (Adrover et al., 2005).
3.3.2 Second Reduction: Reduction of the BOMET-QOL

from 25 to 10 Items
The BOMET-QOL-25 was reduced to an integrated version of 10 items (Sureda et al., 2007).
The BOMET-QOL-25 was administered to 263 oncology patients from the oncology, urology
and hematology units of 46 hospital centers in Spain. The mean age (SD) of the patients was
62.20 (12) years old and 42.9% were males. Patients diagnosed as having breast (38.8%),
prostate (18.2%) or non-microcytic lung (16.7%) cancer, with MBDN or myelomas (26.3%),
were included.
The final reduction of the items in the BOMET-QOL questionnaire was carried out in two
phases. In the first phase, a factor analysis was carried out with varimax rotation of the
primary BOMET-QOL questionnaire’s items. The factor analysis showed the unidimensional
nature of the questionnaire, with only one factor explaining 61.2% of the variance. In the
second phase, each of the resulting factors was calculated using the Rasch Rating Scale model.
This analysis reduced the questionnaire to 10 items.
As a result of the reduction process, an easy and user-friendly questionnaire was obtained
with only 10 items and one dimension (> Figure 11-2).
4 Validation of the BOMET-QOL-10
The psychometric properties of the BOMET-QOL-10 were assessed under common clinical
practice conditions in an observational, prospective and multi-center study designed and
carried out with the above sample of 263 patients.
Patients were assigned to two groups: group A included stable patients with no expected
changes in disease control over a 15-day period; and group B consisted of patients with an
expected change in their health owing to their undergoing treatment of effective surgery. The
characteristics of each group in terms of age, gender, level of education, type of baseline
neoplasia, concomitant osteoarticular disease and non-osteoarticular chronic diseases were
similar.
Patients included in group A made two visits (baseline visit and 15 days after baseline visit)
and patients included in group B made three visits (baseline visit, 3 months after and 6 months
after baseline visit) (> Figure 11-3). The first visit gathered socio-demographic variables
and clinical variables such as site and date of diagnosis for the primary tumor, MBDN
sites, presence, number and duration of irruptive pain crises, concomitant chronic and
. Figure 11-2
Diagram of the development of the BOMET-QOL 10 questionnaire. This figure presents the
development of the BOMET-QOL-10 questionnaire. The BOMET-QOL was developed in three
phases: item generation (179 expressions), item selection (BOMET-QOL 35) and item reduction
(BOMET-QOL 10)
osteoarticular diseases and the treatment for the primary tumor and for the MBDN. The
investigator also included the ECOG Performance Scale (Oken et al., 1982) and the Pain
Management Index (PMI) (Cleeland, 1991), which relates the type of analgesic treatment
received to the pain level declared by the patient. After completing the first visit, the patient
fills out the Spanish version of the EORTC-QLQ-C30 questionnaire, the BOMET-QOL-25
questionnaire and the perception of general health status. Any changes in treatment, ECOG and
PMI were recorded in the second and third visits. Likewise, changes in health status perceived
by the patients were computed and the EORTC-QLQ-C30 and BOMET-QOL questionnaires
(BOMET-QOL-25 and BOMET-QOL-10) were administered again (> Figure 11-4).
The impact on HRQOL assessed by the BOMET-QOL-10 questionnaire and variables of
irruptive pain, patients’ self-reported general health status, PMI and ECOG index (> ECOG
. Figure 11-3
Graph of the observational study design. This figure presents the observational study design
used in reducing the BOMET-QOL from 25 to 10 items, and the validation of the psychometric
properties of the BOMET-QOL-10
. Figure 11-4
Socio-demographic, clinical and humanistic variables collected via the observational study. This
figure presents all the variables collected in the observational study at the baseline visit and/or
follow-up visits
index for performance status) were shown to be correlated. All the dimensions of the BOMET-
QOL-10 had a statistically significant correlation with the dimensions of the EORTC-QLQ-30
score (p < 0.01). No statistically significant differences were found regarding the HRQOL in
terms of the time of neoplasia evolution (p = 0.12).
The measurement properties analyzed of the BOMET-QOL-10 questionnaire were

> cross-sectional validity, sensitivity to change and reliability.
Cross-sectional validity was assessed evaluating the correlation number and duration of
the irruptive pain crisis. A correlation was found between the impact on HRQOL evaluated
with the BOMET-QOL questionnaire and the irruptive pain variable. A lower BOMET-QOL
score was observed when there were fewer irruptive pain episodes, when PIM = 0 (good pain
control) or when the ECOG score was between 0 and 1, and Group B patients scored lower in
the BOMET-QOL questionnaire (p < 0.001).
Longitudinal validity (sensitivity to change) was determined by the changes in the
question ‘‘general health status’’ between the baseline visit and the visit 3 months later.
Changes in the ECOG index were correlated with the scores observed in the BOMET-QOL-
10 questionnaire (p < 0.01). The BOMET-QOL-10 questionnaire detected changes better
than the ECOG index. Also the size of the effect was measured for patients in Group B at
3 and 6 months ( 0.84). This increased its score (better HRQOL) throughout the study
(p < 0.001).
In terms of reliability, good internal consistency was achieved (Cronbach’s a = 0. 92).
No significant differences in the questionnaire scores were observed at the two moments
of the study (baseline and 15 days visits). The Intraclass Coefficient Correlation (ICC)
was 0.93.
To conclude, the BOMET-QOL questionnaire of 10 items has shown good measurement
properties for changes (> Table 11-3), being of great use both in clinical research and common
clinical practice.
. Table 11-3
Psychometric properties of the BOMET-QOL-10 questionnaire
Psychometric
properties Measurement Statistics
Cross-sectional validity Relationship between BOMET-QOL-10 and the number of r = 0.293
irruptive pain crises (p < 0.01)
Relationship between BOMET-QOL-10 and the mean r = 0.226
duration of irruptive pain crises (p < 0.01)
Longitudinal validity/ Relationship between a change in the ‘‘general health p < 0.01
sensitivity to change status’’ question and a change in the scores between the
baseline visit and the visit 3 months later
Relationship between a change in the ECOG and a p < 0.01
change in scores between the baseline visit and the visit
3 months later
Size of the effect between the baseline visit and the visit 0.84
6 months later
Reliability Cronbach’s Alpha 0.93
Interclass correlation coefficient (ICC) 0.94
This table summarizes the measurement properties of the questionnaire: cross-sectional validity, sensitivity to
change and reliability. ‘‘r’’ corresponds to Pearson’s correlation coefficient
5 Conclusions
There are many reviews describing the importance of symptomatology in patients with
MBDN, either in general or in relation to the primary tumor. Nonetheless, these are mostly
descriptive and do not posses the proper methodology to evaluate HRQOL. Moreover, they do
not deal with MBDN as a unique and differential syndrome (irrespective of the primary
tumor), looking at the impact on HRQOL.
This article has presented the development and validation of a specific questionnaire to
measure HRQOL in patients with MBDN. The content of specific questionnaires is more
adequate for patients’ problems than generic questionnaires and is more sensitive to signifi-
cant clinical changes. HRQOL questionnaires enable standardized information to be obtained
about the impact of the disease or treatment on the patient’s HRQOL. However, at present
these questionnaires are not used in current clinical practice as many clinicians have difficulty
in interpreting the results of the multidimensional information outcomes, or with the
extension provided by the HRQOL questionnaires (Bezjak et al., 1998). For these reasons,
emphasis has been placed on developing and validating this 10-item questionnaire. The
BOMET-QOL-10 is user-friendly, easy to complete by the patient and to assess by the
professional and has good measurement properties.
The first step toward developing an HRQOL tool in patients with MBDN was the
identification by experts of the domains directly influenced by MBDN with an impact on
HRQOL. Afterwards, fifteen patients were asked to explain how the pathology influenced their
HRQOL and answers from them matched the domains the experts had previously selected. It
was obvious that MBDN has a well-known effect on HRQOL and patients welcomed the
opportunity to verbalize their health-related limitations. Patients place a high value on their
HRQOL and this fact is extensively reported in the literature.
After identifying an initial group of items, the number was progressively reduced by
carrying out an analysis based on sound methodology. The initial 179 expressions were
reduced to 35 items depending on their clarity, importance and frequency.
A sample of 92 individuals from different centers in Spain and at different stages of the
illness was selected to test the 35-item questionnaire. The items were reduced further, resulting
in a 25-item instrument with good consistency and feasibility. Lastly, questionnaire develop-
ment was completed in an observational prospective study with 263 patients, and the 10-item
instrument obtained showed good psychometric properties. The outcomes obtained with
regard to internal consistency and test-retest reliability indicate high homogeneity and good
reproducibility throughout the questionnaire. Regarding the validity, just like other specific
questionnaires for advanced cancer, the BOMET-QOL-10 has shown significant correlations
with the ECOG and the EORTC-QLQ-C30 questionnaire.
The procedure used to reduce the questionnaire, on both occasions, was the Rasch analysis
based on item response theory. This has some advantages over the classical test theory (CTT)
since it considers each answer as a probabilistic function, with the lineal probabilistic interac-
tion of a person’s ‘‘ability’’ and a question’s ‘‘difficulty,’’ and it constructs a line of measurement
with the items placed hierarchically, as well as being able to find people according to their
competence (e.g., health status) (Prieto et al., 2003).
The BOMET-QOL-10 is not an instrument that replaces the specific cancer questionnaires
we have today, but is complementary to them for assessing HRQOL in patients with MBDN in
clinical trials and daily clinical practice.
Summary Points
The Bone Metastases Quality of Life Questionnaire (BOMET-QOL) measures HRQOL

dimensions relevant to patients with Bone Metastases.
It is the first bone metastases-specific HRQOL measure.
It is a self-administered questionnaire intended for use in clinical research (trials) and in
the routine monitoring of patients with bone metastases.
It is unidimensional and consists of 10 items that can be answered according to a Likert
scale with 5 categories (always, almost always, sometimes, rarely and never), scoring from
0 to 4, and the timeframe refers to ‘‘last week.’’
The items refer to HRQOL topics such as pain, mobility, vitality, sex life, worries about the
future, perceptions and daily activities.
The global score is calculated by adding up the answers obtained in each item, and may range
from 0 (worst HRQOL) to 40 (best HRQOL). These scores are standardized to make it easier to
interpret the scoring, with the final scores ranging from 0 (worst HRQOL) to 100 (best HRQOL).
It is user-friendly, easy to complete by the patient and easy to assess by the professional.
It has shown good measurement properties (cross-sectional validity, discriminant validity,
sensitivity to change, reliability, etc.).
References
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Djulbegovic B, Wheatley K, Ross J, Clark O, Bos G,
Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman Goldschmidt H, Cremer F, Alsina M, Glasmacher
SB, M. de Haes JCJ, Kaasa S, Klee M, Osoba D, A. (2002). Cochrane Database Syst Rev. 4:
Razavi D, Rofe PB, Schraub S, Sneeuw K, Sullivan CD003188.
M, Takeda F. (1993). J Natl Cancer Inst. 85: 365–376. Ganz PA, Schag CA, Lee JJ, Sim MS. (1992). Qual Life
Adrover E, Allepuz J, Sureda A, Domine M, Barnadas A, Res. 1: 19–29.
Constela M, Lluch A, Ruiz M, Piera J, Mayordomo Lipton A. (2003). Curr Treat Options Oncol. 4: 151–158.
JI, Morales A, Muñoz M, Alcover J, Colomer R, Martinez MJ, Roque M, Alonso-Coello P, Català E.
Llombart A, Massutti B, Carballido J, Garrido P, (2003). Cochrane Database Syst Rev. 3:
Garcı́a R, Badia X, Lizan L, Gilabert M. (2005). J CD003223.
Outcomes Res. 9: 15–27. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE,
Avis NE, Smith KW, Hambleton RK, Feldman HA, McFadden ET, Carbone PP. (1982). Am J Clin
Selwyn A, Jacobs A. (1996). Med Care. 34: Oncol. 5: 649–655.
1102–1120. Prieto L, Alonso J, Lamarca R. (2003). Health Qual Life
Badia X, Muriel C, Gracia A, Núñez-Olarte JM, Outcomes. 28: 1–27.
Perulero N, Gálvez R, Carulla J, Cleeland CS, Rasch G. (1993). Probabilistic Models for Some Intelli-
Vesbpi G. (2003). Med Clin (Barc). 120: 52–59. gence and Attainment Tests. Paedagogiske Institut,
Bezjak A, Taylor KM, Macdonald K, DePetrillo AD. Copenhagen.
(1998). Cancer Pre Control. 2: 230–235. Reddi AH, Roodman D, Freeman C, Mohla S. (2003). J
Bunting RW, Shea B. (2001). Cancer. 92(Suppl. 4): Bone Miner Res. 18: 190–194.
1020–1028. Sureda A, Isla D, Cózar JM, Ruiz M, Domine M,
Cella D, Chang CH, Lai JS, Webster K. (2002). Semin Margelı́ M, Edrover E, Ramos M, Pastor M,
Oncol. 29(Suppl. 8): 60–68. Martı́n A, Llombart A, Massuti B, Muñoz M,
Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Barnadas A, Fernández J, Colomer R, Allepuz C,
Bonomi A, Silberman M, Yellen SB, Winicour P Gilabert M, Badia X. (2007). JME. 10: 27–39.
and Brannon J. (1993). J Clin Oncol. 11: 570–579. Watson M, Law M, Maguire GP, Robertson B, Greer S,
Cleeland CS. (1991). Cancer. 67: 823–827. Bliss JM, Ibbotson T. (1992). Psychooncology. 1:
Coleman R. (2004). Oncologist. 9: 14–27. 35–44.
12 The Impact of Weight on
Quality of Life Questionnaire
J. Manwaring . D.Wilfley
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
2 Why Develop Quality of Life Measures in Obesity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
3 IWQOL and IWQOL-Lite Development and Psychometric Properties . . . . . . . . . . . 212

3.1 IWQOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
3.2 IWQOL-Lite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
4 IWQOL in Comparison with Other Obesity-Specific Instruments . . . . . . . . . . . . . . . . 217
5 IWQOL and Weight Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
6 IWQOL Among Subgroups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
7 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
8 Information on Use of the IWQOL-Lite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

210 12 The Impact of Weight on Quality of Life Questionnaire
Abstract: Obesity is a complex disease with a multifactorial etiology that is reaching epidemic
proportions worldwide. Assessments are needed to adequately capture the decrements in
health and psychosocial well-being that are so often observed in > obese individuals. Accord-
ingly, researchers are realizing the importance of quality of life as a measure of health status
and weight loss treatment outcome in obese individuals. While weight loss is the primary
outcome of interest for most obesity treatments, measuring quality of life is a vital component
as individuals evaluate their treatment outcome. The Impact of Weight on Quality of Life
(IWQOL) questionnaire is the first questionnaire developed to specifically assess the effects of
obesity on health-related quality of life. The psychometric properties of the IWQOL are
excellent, but given its length, a briefer version was developed, the Impact of Weight
on Quality of Life-Lite Questionnaire (IWQOL-Lite). The five identified scales (Physical
Function, Self-Esteem, Sexual Life, Public Distress, and Work) and the Total score have
demonstrated excellent > reliability (0.90–0.94 for the scales, 0.96 for Total score), > validity,
and utility with various groups of obese individuals. In this chapter, the rationale for the
development of an obese-specific quality of life measure will be briefly reviewed, followed by
the background and development of the IWQOL and IWQOL-Lite (including their psycho-
metric properties), weight loss research using these instruments, and future research direc-
tions. It is concluded that the IWQOL-Lite is a reliable, valid instrument that can be utilized in
various obese populations, and may be particularly useful as a treatment outcome measure.
List of Abbreviations: BAROS, Bariatric analysis and reporting outcome system; BED, Binge
eating disorder; BMI, > Body mass index (kg/m2); DDFC, Duke University Diet and Fitness
Center; HRQOL, Health-related quality of life; IWQOL, > Impact of Weight on Quality of Life
questionnaire; IWQOL-Lite, > Impact of Weight on Quality of Life-Lite questionnaire; SF-36,
Medical Outcomes Study Short-Form Health Survey
1 Introduction
Obesity is a prevalent disease with significant negative effects on physical and psychosocial
functioning. As determined by > body mass index (BMI) (kg/m2), recent estimates indicate
that 32% of U.S. adults are obese (BMI 30); this prevalence has increased approximately
50% per decade over the last 30 years (Flegal et al., 2002). Among its myriad health problems,
obesity is associated with hypertension, diabetes, and cardiovascular disease, all of which are
among the leading causes of death in developed countries (e.g., Pi-Sunyer, 1995). Further, the
psychosocial consequences of obesity are devastating. Obese adolescents have been found to
have lower income, education, and marriage rates as adults than individuals with chronic
physical conditions such as asthma, diabetes, and musculoskeletal deformities (Gortmaker
et al., 1993).
Health related quality of life (HRQOL) has been defined as the “physical, psychological,
and social domains of health, seen as distinct areas that are influenced by a person’s
experiences, beliefs, expectations, and perceptions” (Testa and Simonson, 1996). Generic
measures of quality of life were utilized by clinicians before disease-specific instruments were
developed in response to the need for more sensitive measures. The medical field has come
to realize the importance of assessing psychosocial factors such as quality of life, as this
construct may more accurately convey treatment efficacy, more finely note treatment
outcome differences, aid physicians and patients in making treatment decisions, and allow
The Impact of Weight on Quality of Life Questionnaire 12 211
patients to comment subjectively on the outcome of treatment in addition to the objective

treatment outcome markers (e.g., disease status; Kolotkin et al., 2001a). As such, numerous
assessments have been developed to tap the dimensionality of health. This chapter will focus
on the Impact of Weight on Quality of Life (IWQOL) questionnaire, a measure developed in
response to the growing prevalence of obesity and need for sensitive and specific quality of
life measures.
2 Why Develop Quality of Life Measures in Obesity?
The idea that the majority of > overweight/obese individuals would suffer from a poor quality
of life may be a simple presumption, but some factors may be more associated with an
impaired quality of life than others, and these factors will vary between individuals (Kolotkin
et al., 2004). For example, one woman with severe obesity may struggle with activities of daily
living, be exposed to work discrimination, and have difficulty in her interpersonal relation-
ships because of her weight while another woman with the same level of obesity may
experience some physical limitations but have a supportive work environment and only a
few minor complaints regarding her interpersonal life. Thus, the typical medical evaluation
points of disease status, in obesity most often measured by BMI (kg/m2), would not provide
an adequate picture of the overall health of these two women. In addition to providing a
patient’s perspective of his/her health for a more multifaceted view of treatment outcome,
> Health-Related Quality of Life (HRQOL) measures are clinically useful in providing a
nuanced, comprehensive view of the individual to aid clinicians in treatment planning. Having
the patient’s perspective of his/her quality of life allows clinicians to more adequately discuss
treatment options, and then evaluate treatment outcome in comparison to the patient’s
baseline level of quality of life.
Both general and disease-specific measures have been used to study obesity. The most
commonly used HRQOL assessment instrument for a variety of medical problems is the
Medical Outcomes Study Short-Form Health Survey (SF-36; Ware et al., 1993), which
assesses eight discrete constructs including bodily pain and social functioning. The benefit
of general HRQOL measures such as the SF-36 is that they allow for comparisons of various
medical conditions across studies. However, their disadvantage is that they may not be
sufficiently sensitive to detect minor treatment effects (Fontaine and Barofsky, 2001). Thus,
researchers have recommended disease-specific measures for clinical use, and both disease-
specific and general quality of life measures for clinical trials (e.g., Kolotkin et al., 2001a;
Wadden and Phelan, 2002). Studies that have assessed quality of life in obesity using generic
measures have found greater impairment among obese adults (especially women) compared
to community norms (e.g., Fontaine et al., 2000); a dose-response relationship between
degree of overweight and HRQOL (e.g., Fine et al., 1999); and more impairment in physical
domains than mental health domains (e.g., Barajas et al., 1998). However, as previously
mentioned, generic instruments are most useful for general survey research, or comparisons
of disease states, and are unable to assess the specific aspects most relevant to a particular
disease. In response to these limitations of generic quality of life instruments, Kolotkin and
colleagues, the authors of the IWQOL, aimed to create a reliable and valid measure of the
impact of weight on quality of life, and in doing so, establish the aspects of quality of life
impacted by weight and the changes noted in quality of life following treatment (Kolotkin
et al., 1995).
3 IWQOL and IWQOL-Lite Development and Psychometric

Properties
3.1 IWQOL
Development. In the development of the IWQOL, Kolotkin et al. (1995) interviewed approxi-
mately 20 outpatients in treatment for obesity at the Duke University Diet and Fitness Center
(DDFC) to ascertain how their overweight status impacts their everyday lives. From this
information the authors compiled 74 items which were modified according to feedback from
other patients, and then divided into eight scales: Health (14 items), Social/Interpersonal
(11 items), Mobility (10 items), Self-Esteem (10 items), Comfort with Food (9 items), Work
(7 items), and Sexual Life (6 items). Items in the IWQOL begin with the phrase “because of my
weight” and the participant chooses between the responses “always true” (scored as 5),
“usually true,” “sometimes true,” “rarely true,” or “never true” (scored as 1), with higher
scores representing poorer quality of life. The IWQOL was then administered to 64 other
outpatients (37 women, 27 men) who completed the questionnaire on Day 1 of their visit, Day
2 of their visit (to assess > test-retest reliability), and Day 28 of their visit (to assess treatment
effects from Day 1).
Psychometric Properties. Item test-retest reliability ranged from 0.53 (“little attention to
how much I eat”; Comfort with Food) to 0.92 (“ankles and lower legs swollen”; Health), with
an average reliability coefficient of 0.75. Scale test-retest reliability fared even better, ranging
from 0.81 (Comfort with food) to 0.93 (Social/Interpersonal, Self-Esteem), with an average
reliability score of 0.89. Day 1 responses were used to measure the internal consistency of each
scale, which averaged 0.87 and ranged from 0.68 (Comfort with Food) to 0.93 (Social
Interpersonal, Self-Esteem). To measure treatment effects, 37 of the 64 outpatients (58%)
completed the IWQOL on Day 28; their scores showed significant improvement on seven of
the eight scales (greatest decrease/improvement on Mobility, p ¼ 0.0001); on the eighth scale –
Comfort with Food – outpatients demonstrated significantly less comfort with food post-
treatment, perhaps not surprisingly given the increased vigilance taught in behavioral weight
loss treatment programs such as those offered by the DDFC.
The authors of the IWQOL note that their studies support the clinical utility of the
questionnaire, its item and scale score stability, and internal consistency of the items. Further,
all but one of the scales (Comfort with Food) changed significantly in the expected direction
after treatment. However, the authors report that the Comfort with Food scale had the weakest
psychometric properties, exhibiting the poorest internal consistency (0.68), and thus posit
deletion unless further studies suggest otherwise. Limitations of the original evaluation of the
IWQOL include the lack of generalizability given the study sample used of treatment-seeking
patients who were mostly Caucasian, upper-middle class, and morbidly obese.
A later report in 1997 by Kolotkin and colleagues supported the > construct validity and
further supported the internal consistency and treatment sensitivity of the IWQOL (Kolotkin
et al., 1997). The IWQOL total and scale scores of 394 DDFC outpatients (243 women, 151
men) were compared to the scores on five questionnaires measuring aspects of health, and to
patients’ medical records. The total IWQOL score was significantly correlated with the author-
designed quality of life single-item scale (r ¼ 0.46, p < 0.0001), and with the DUKE General
Health scale (Parkerson et al., 1990, r ¼ 0.54, p < 0.0001). The IWQOL scale scores were
significantly correlated with other similar assessments, except for two comparisons between
the IWQOL scales and measures of similar constructs: IWQOL Social/Interpersonal with
DUKE Social Health, and IWQOL Health with cholesterol (although the latter may be
expected given the hidden symptoms of hypercholesterolemia). The construct validity of the
subscales Activities of Daily Living, Sexual Life, and Work could not be assessed since similar
measures of these constructs were not administered. Internal consistencies reliability scores
averaged 0.87 and ranged from 0.76 (Comfort with food) to 0.95 (Mobility). There were no
significant differences in internal consistency between the authors’ 1995 study and this 1997
report. In examining treatment effects, both 2-week and 4-week treatment groups demon-
strated significant improvements on all IWQOL scales. For men in the 2-week treatment
group, no treatment differences were demonstrated in the Work and Mobility subscales. As
with the original 1995 study, generalizability was limited given the demographic characteristics
of the DDFC outpatients.
3.2 IWQOL-Lite
Development. Despite its early demonstrated clinical and research utility, clinical researchers
commented on the burdensome length of the 74-item IWQOL for participants (requiring
approximately 15 min to complete, e.g., Mannucci et al., 1999). Thus, in 2001 Kolotkin and
colleagues developed a briefer version of the IWQOL with only 31 items, called the IWQOL-
Lite (Kolotkin et al., 2001b). The development of this version improved upon the original
version by using data from 1,987 individuals (randomly divided into a development sample
and cross-validation sample) from a variety of settings who were more ethnically and socio-
economically diverse than the previous normative sample (see > Table 12-1). Obese partici-
pants who completed the assessments were part of an open-label phentermine-fenfluramine
trial, a day treatment program for weight loss, an outpatient weight reduction studies or
. Table 12-1
Demographics for IWQOL-Lite development study
Age
Study Group N Gender (in years) BMI
Open-label phen-fen Obese 211 32 males 47.8 10.3 42.0 8.7
179 females 44.4 9.3 40.7 7.1
Day treatment Obese 834 322 males 52.1 14.3 41.7 11.1
512 females 50.2 17.6 37.0 9.1
Weight-reduction studies/ Obese 668 91 males 47.4 9.4 35.5 6.2
programs 577 females 43.9 11.3 35.0 6.1
Gastric bypass Obese 51 11 males 46.6 4.5 50.6 10.0
40 females 38.5 9.7 51.0 12.9
Employees/friends Community 223 159 males 37.2 11.4 27.7 3.6
64 females 39.0 14.1 26.5 10.1
Total 1987 615 males 47.3 14.1 37.2 10.8
1,372 45.9 14.3 36.6 9.4
females
Adapted from Kolotkin et al. (2001b, p. 104). BMI body mass index
programs, or were undergoing gastric bypass surgery or were volunteers from the community.
The majority of the participants (96%) provided BMI data, and all participants completed
the IWQOL.
To construct the IWQOL-Lite, the authors used data from the prior IWQOL studies to
select the items and scales for the IWQOL-Lite, deleting items that correlated poorly with the
scale score, total score, BMI, or changes in BMI (Kolotkin et al., 2001b). Factor analyses were
then performed, and further deletions were made for those items not loading adequately on
the derived factors. The resulting IWQOL-Lite was comprised of five scales: Physical Function
(11 items, e.g., feeling short of breath, getting up from chairs), Self-Esteem (7 items, e.g., afraid
of rejection, avoid looking in mirrors), Public Distress (5 items, e.g., fitting through aisles,
experience ridicule), Sexual Life (4 items, e.g., avoid sexual encounters, difficulty with sexual
performance), and Work (4 items, e.g., do not receive recognition, afraid to go on interviews),
and correlated highly with the original IWQOL (0.97). As in the IWQOL, items in the
IWQOL-Lite begin with the phrase “because of my weight” and the participant chooses
between the responses on a Likert scale (from “always true” ¼ 5 to “never true” ¼ 1), but
with the change that higher scores represent better quality of life.
Psychometric Properties. The IWQOL-Lite demonstrated excellent reliability, with an
overall reliability (Cronbach a coefficient) of 0.96 (Kolotkin et al., 2001b). The scales’
reliability coefficients were 0.94 for Physical Function, 0.93 for Self-Esteem, 0.91 for Sexual
Life, and 0.90 for Public Distress and Work. As can be seen in > Table 12-2, correlations
between the items and its designated scale are higher than any other scale, suggesting
discreteness between scales. When corrected for overlap, the correlations between individual
scales and the total score were in the tight range of 0.66 (Sexual Life) to 0.73 (Public Distress),
indicating comparable contributions of the scales to the total score.
All five scales and the total score of the IWQOL-Lite correlated significantly (p < 0.01)
with change in BMI after 1 year (average weight loss: ~18% body weight), with the highest
correlation seen in Physical Function and Total score (Kolotkin et al., 2001b). Further, even
small changes in BMI (< 10%) were correlated with decreased IWQOL-Lite scores (with the
exception of Work), ranging from effect sizes of 0.20 (Sexual Life) to 0.50 (Physical Function).
Thus, the IWQOL-Lite is sensitive to small decreases in weight, and these results suggest that
even modest weight loss is correlated with an increased quality of life. The IWQOL-Lite’s
sensitivity was also demonstrated by the large effect sizes seen when comparing groups at each
end of the weight spectrum (BMI < 25 versus > 40): 1.76 for Total score and Public Distress,
1.70 for Physical Function, 1.34 for Self-Esteem, 1.07 for Sexual Life, and 0.97 for Work. See
> Table 12-3 for further information on 1-year changes.
Since the original 2001 report, the IWQOL-Lite has undergone further psychometric
testing. Kolotkin and Crosby (2002) evaluated the test-retest, discriminant, and > convergent
validity of the questionnaire amongst 494 adult participants (341 females, 153 males) recruited
from the community (Kolotkin and Crosby, 2002a). The sample was racially diverse with an
average age of 38.1 (range 18–90). The participants’ average BMI of 27.4 (SD: 7.1; range:
18.6–73.0) fell in the overweight category (BMI 25). Overall, scores for this community
sample were consistently lower/less impaired than the previous normative treatment-seeking
samples (Kolotkin et al., 2001b). The authors examined psychometric properties of the
IWQOL-Lite using the overall sample, and the overweight/obese participants only, and
found internal consistency reliability, test-retest reliability, convergent validity, and discrimi-
native validity. In the full sample, internal consistency a coefficients ranged from 0.82 (Work)
to 0.94 (Self-Esteem), and 0.96 for the Total score. Test-retest intraclass correlation coefficients
. Table 12-2
Item-to-scale correlations for IWQOL-Lite
Physical Self- Sexual Public

function esteem life distress Work Total
Physical function (a = 0.94)
Picking up objects 0.84 0.43 0.50 0.61 0.54 0.75
Tying shoes 0.84 0.44 0.49 0.61 0.51 0.74
Getting up from chairs 0.84 0.44 0.47 0.64 0.55 0.75
Using stairs 0.84 0.46 0.48 0.63 0.53 0.76
Dressing 0.80 0.45 0.48 0.56 0.57 0.73
Mobility 0.84 0.48 0.49 0.62 0.61 0.77
Crossing legs 0.76 0.47 0.46 0.63 0.44 0.71
Feel short of breath 0.66 0.45 0.42 0.48 0.47 0.64
Painful stiff joints 0.61 0.32 0.39 0.38 0.43 0.55
Swollen ankles/legs 0.61 0.31 0.36 0.43 0.39 0.54
Worried about health 0.44 0.40 0.32 0.38 0.37 0.48
Self-esteem (a = 0.93)
Self-conscious 0.47 0.84 0.53 0.51 0.48 0.69
Self-esteem not what it 0.47 0.86 0.54 0.49 0.51 0.69
could be
Unsure of self 0.48 0.84 0.52 0.54 0.55 0.71
Do not like myself 0.41 0.78 0.54 0.44 0.47 0.63
Afraid of rejection 0.41 0.74 0.48 0.56 0.49 0.63
Avoid looking in mirrors 0.44 0.73 0.50 0.52 0.42 0.63
Embarrassed in public 0.50 0.73 0.54 0.56 0.51 0.69
Sexual life (a = 0.91)
Do not enjoy sexual activity 0.41 0.48 0.80 0.33 0.41 0.55
Little sexual desire 0.51 0.56 0.79 0.37 0.48 0.63
Difficulty with sexual 0.57 0.54 0.77 0.49 0.49 0.68
performance
Avoid sexual encounters 0.51 0.60 0.83 0.45 0.49 0.67
Public distress (a = 0.90)
Experience ridicule 0.42 0.55 0.35 0.62 0.41 0.57
Fitting in public seats 0.66 0.48 0.41 0.83 0.47 0.70
Fitting through aisles 0.67 0.52 0.43 0.87 0.48 0.73
Worry about finding chairs 0.65 0.47 0.38 0.83 0.47 0.69
Experience discrimination 0.48 0.61 0.37 0.64 0.44 0.62
Work (a = 0.90)
Trouble accomplishing 0.58 0.53 0.46 0.49 0.78 0.67
things
Less productive than 0.55 0.54 0.50 0.45 0.79 0.66
could be
Physical Self- Sexual Public

function esteem life distress Work Total
Do not receive recognition 0.57 0.47 0.49 0.49 0.85 0.66
Afraid to go on interviews 0.50 0.49 0.41 0.47 0.72 0.61
Correlations between each item and its designated scale are in bold type (larger correlation equals stronger
relationship). Also in bold type are correlations between each item and Total score. All correlations are corrected
for overlap. Adapted from Kolotkin et al. (2001b, p. 105)
. Table 12-3
One-year change effect sizes in IWQOL-Lite scores by percent BMI loss group
Percent BMI loss

Scale <10% (n = 25) 10–20% (n = 77) >21% (n = 58) Overall (n = 160)
Physical function 0.50 0.62 1.20 0.81
Self-esteem 0.43 0.65 0.95 0.73
Sexual life 0.20 0.36 0.73 0.46
Public distress 0.28 0.47 0.62 0.50
Work 0.09 0.19 0.44 0.26
Total score 0.46 0.65 1.12 0.79
Cohen (1988) recommends effect sizes as: 0.20 as small, 0.50 as medium, 0.80 as large (Cohen, 1988). Adapted from
Kolotkin et al. (2001b, p. 108). BMI body mass index
ranged from 0.81 (Public Distress) to 0.88 (Physical Function), and 0.94 for the Total score. To
test convergent validity, the IWQOL-Lite scores were compared to SF-36 scores (among other
measures) in overweight/obese subjects (BMI 25). The IWQOL-Lite Total score was most
highly correlated with the SF-36 general health (0.58) and physical summary score (0.54),
with the lowest correlation between the total score and the mental summary score (0.33).
Finally, to test discriminative validity, scores on the IWQOL-Lite were compared with scores
on the Marlowe-Crowne, the most widely used measure of social desirability, in overweight
subjects (Crowne and Marlowe, 1960). Only one scale correlated higher than the absolute
value of 0.19 with the Marlowe-Crowne (Self-Esteem, r ¼ 0.29, 8.4% shared variance),
indicating minimal overlap between these two scales. This study furthered the psychometric
qualities of the IWQOL-Lite by providing test-retest reliability, and psychometric data in a
community sample of both normal-weight and overweight/obese adults.
The psychometric properties of the IWQOL-Lite were also evaluated in individuals with
schizophrenia and bipolar disorder, due to the high rates of obesity in this population
(Kolotkin et al., 2006a). In this study, 111 individuals diagnosed with schizophrenia and 100
individuals diagnosed with bipolar disorder completed the IWQOL-Lite, among other mea-
sures. The questionnaire demonstrated excellent internal consistency (0.87–0.97) and test-rest
reliability (0.74–0.95), as well as construct validity. The correlation between BMI and the
IWQOL-Lite scores were lower for the schizophrenic group compared to previous psycho-
metric evaluations of this measure. A similar study with obese individuals with and without
type 2 diabetes found high, comparable internal consistency reliabilities between these two
groups (Kolotkin et al., 2003a).
Administration and Scoring. The IWQOL-Lite can be completed in 3 min, and is appro-
priate for adults ages 18 and over who can read at a 6.3 grade level. In administering the
IWQOL-Lite, raw scores for each scale can only be computed if at least 50% of the items for
that scale are answered, and for the total score only if 75% of the answers for all items
are completed. Thus, the authors recommend checking for unintentional missing data after
administration (Kolotkin and Crosby, 2002b). The IWQOL-Lite was originally criticized for
lacking interpretive value, since the level of decreased score that could be deemed clinically
meaningful was unknown. This was later addressed, when the authors of the IWQOL-Lite used
advanced statistical techniques to establish a 7.7–12 point total score increase (improvement)
as clinically meaningful (adjusting for an individual’s baseline score; Crosby et al., 2004).
Further information on administration and scoring can be found at the end of the chapter.
IWQOL-Lite Summary. In conclusion, the IWQOL-Lite demonstrates an adequate scale
structure with excellent internal consistency reliability, test-retest reliability, convergent valid-
ity, discriminative validity, and good construct validity using hypothesis-driven confirmatory
factor analysis. Further, the questionnaire appears to be sensitive to change, and is applicable
to a wide range of BMIs and populations. The authors recommend the IWQOL-Lite over the
original IWQOL because of its brevity, its development with a heterogeneous sample and
separate development and cross-validations samples, and its superior psychometric develop-
ment and results (Kolotkin et al., 2001b).
Limitations of the IWQOL-Lite include ambiguity regarding the subjective relevance and
clinical significance of the items to the individual as items were constructed based on group
feedback (Kolotkin et al., 2001b; Wadden and Phelan, 2002). In other words, the IWQOL-Lite
equally weighs the individual items in determining the total quality of life score, whereas
similar scores could have different personal impact depending on the person’s values and
expectations (Mannucci et al., 1999). However, this could be viewed as a weakness shared by
the majority of self-report measures. Another suggested weakness of the IWQOL-Lite is that
the introduction, “Because of my weight. . .” could be leading so that a comparison of the
questionnaire with and without these instructions would be useful (Wadden and Phelan,
2002). Finally, the measure’s utility may be confined to morbidly obese individuals given some
of the item content (e.g., difficulty getting up from a chair or picking up objects), and because
the scales and the total score of the IWQOL-Lite have not been able to significantly distinguish
between lower BMI groups (<30; Kolotkin and Crosby, 2002a; Kolotkin et al., 2001b; Mathias
et al., 1997).
4 IWQOL in Comparison with Other Obesity-Specific

Instruments
Although the IWQOL was the first measure designed specifically to assess quality of life in
obese individuals, other measures have also been developed in order to capture the specific
experiences commonly reported by obese individuals. While many of these measures have
distinct advantages, a major disadvantage to them is that most have only recently been
developed, and thus have limited psychometric studies (Wadden and Phelan, 2002).
When the North American Association for the Study of Obesity convened a task force to
aid in choosing obesity outcome measures, they reviewed the assessment of quality of life
in obesity, and concluded by recommending the IWQOL (with the limitations noted above) to
clinicians and researchers desiring an obesity-specific measure (Wadden and Phelan, 2002).
They also reported favorably on the Obesity-related Problems Scale (OP-Scale), but noted that
it needs further study among a broader sample outside the Swedish Obese Subjects study in
which it was developed (Karlsson et al., 2003). Kolotkin et al. (2001) provided a similar
overview of obesity-specific measures without comparing or recommending one assessment
over another; however, they did suggest the need for further research to clarify the advantages
and disadvantages of available instruments (Kolotkin et al., 2001a). The only report to do so
thus far identified 11 questionnaires on the quality of life in obesity (Duval et al., 2006). These
included eight developed in English (although the IWQOL has been translated into more than
50 languages), one in French, one in Italian, and one in Swedish. In Duval and colleagues’
psychometric comparison of the questionnaires (assessing reliability, validity, responsiveness,
and interpretability), the IWQOL-Lite fared better than the IWQOL and other obesity-specific
questionnaires (see > Table 12-4 for further details).
Thus, unless future studies determine that other measures perform better than the
IWQOL-Lite in assessing the impact of weight on quality of life in obese individuals,
the IWQOL-Lite has the psychometric data to warrant its recommendation.
5 IWQOL and Weight Loss
Non-Surgical. Weight loss among obese persons has consistently been found to improve the
impact of weight on quality of life, as measured by the IWQOL or IWQOL-Lite (e.g.,
Heshka et al., 2003). An improved quality of life as measured by the IWQOL or IWQOL-
Lite appears to depend on the amount of weight loss rather than treatment type (Heshka
et al., 2003), to occur even with modest weight loss (5–10% body weight; Foster et al., 2004;
Samsa et al., 2001), and to deteriorate again with weight regain (Engel et al., 2003). In one
study, a lower perceived quality of life (IWQOL-Lite) at baseline in women appeared to
predict poorer long-term outcomes, with the Self-Esteem and Work subscales being partic-
ularly tied to weight loss success and/or completion (Teixeira et al., 2004). In a report on
four studies investigating the effects of sibutramine versus placebo on weight loss, the
Health, Mobility, and Activity of Daily Living subscales of the IWQOL were more likely
to show changes than the Social, Work, Self-Esteem, and Sexuality subscales; weight losses of
5.01–10.0% were associated with 10-unit changes in the total score (Samsa et al., 2001).
Finally, other studies comparing psychotropic medication to placebo have reported similar
results of improved IWQOL scores in the treatment group compared to the placebo group
(though the improved subscales differ across studies), with even the drug dosage affecting
the amount of change in the IWQOL-Lite scores (Lustig et al., 2006). Both pharmaceutical
and non-pharmaceutical weight loss studies demonstrate improved scores on the IWQOL or
IWQOL-Lite following even modest weight loss.
Surgical. As might be expected given the serious nature of weight loss surgical techniques,
the literature suggests that patients presenting for gastric bypass surgery are significantly more
impaired on the IWQOL or IWQOL-Lite than obese individuals seeking residential treatment
(Stout et al., 2007) or obese individuals not seeking treatment (Kolotkin et al., 2003b). A
graded pattern is even seen, where obese individuals presenting for gastric bypass surgery
exhibit the greatest impairment on the IWQOL-Lite, followed by: individuals in day treatment
programs, individuals in outpatient weight-loss programs, and participants in clinical trials
(Kolotkin et al., 2002c). After surgery, patients have demonstrated significant improvement on
all subscales and Total score of the IWQOL or IWQOL-Lite, almost reaching scores of obese
. Table 12-4
Comparison of the obesity-specific quality of life questionnaires
Reliabilityb Validityb Responsivenessc

Number of Studies using Testing Testing Testing
Questionnaire Items methoda thoroughness Results thoroughness Results thoroughness Results Interpretabilityd
IWQOL 74 Few þþþ þþþ þþþ þþ þþþ þþ 0
IWQOL-Lite 31 Many þþþ þþþ þþþ þþþ þþ þþ þþ
Lewin-TAG, 55 Few þþþ þþþ þþ þþ þþþ þ 0
HSP
OSQOL 11 Few þ þþ þ þ 0 0 0
ORWELL 97 18 Few þþþ þþþ þþþ þþ þþþ 0 0
OAS-SF 20 Few þþþ þþþ þþþ þþ þþþ þ 0
OP-scale 8 Few þþ þþþ þþþ þþ þþþ þþ þ
BAROS 7 Many þ 0 þþ þþ þþþ þ þ
M-AQolQII 6 Few þþ þþ þþ þþ 0 0 þ
OWLQOL 17 Few þþþ þþþ þþþ þþ þ þ 0
WRSM 20 Few þþþ þþþ þþþ þþ þ þ 0
Modified from Duval et al. (2006, p. 358)
a
Few: 1–4 published studies have used the method; Many: 9þ or more different studies
b
Testing thoroughness: 0, no reported evidence of reliability or validity; þ, very basic information only; þþ, several types of test, or several studies have reported reliability/validity;
þþþ, all major forms of reliability/validity testing reported. Results: 0, no numerical results reported; þ, weak reliability/validity; þþ, adequate reliability/validity; þþþ, excellent
reliability validity
c
The Impact of Weight on Quality of Life Questionnaire
Testing thoroughness: 0, no reported evidence of responsiveness; þ, pre-posttreatment; þþ, controlled studies, but not randomized controlled trial; þþþ, randomized controlled
trial. Results: 0, no changes; þ, few changes; þþ, many changes
d
0, little information available on the interpretability of the scores; þ, moderate information available on the interpretability of scores; þþ, excellent information available on the
interpretability of the scores
Lewin-Tag, HSP the Health-related quality of life, health state preference (Mathias et al., 1997); OSQOL the Obese Specific Quality of Life (Le Pen et al., 1998); ORWELL 97 the Obesity
Related Well Being (Mannucci et al., 1999); OAS-SF the Obesity Adjustment Survey-Short Form (Butler et al., 1999); OP-scale the Obesity-related Psychosocial problems scale (Karlsson
et al., 2003); BAROS the Bariatric Analysis and Reporting Outcomes System (Oria and Moorehead, 1998); M-AQolQII the Moorehead-Ardelt Quality of Life Questionnaire II (Moorehead
et al., 2003); OWLQOL the Obesity and Weight Loss Quality of Life Questionnaire (Niero et al., 2002); WRSM The Weight-Related Symptom (Niero et al., 2002)
12
219
individuals from the community (Adami et al., 2005; Boan et al., 2004), with most improve-
ments continuing 3 years post-surgery (Adami et al., 2005). Additionally, comorbid health
conditions among patients seeking gastric bypass surgery were found to be significantly
associated with the IWQOL-Lite subscales Physical Function, Sexual Life, and Total score,
with patients having three or more conditions exhibiting poorer quality of life (Kolotkin
et al., 2003b). In this study, only group status (seeking surgery vs. non-treatment-seeking con-
trols), BMI, gender, and depression accounted for unique baseline variance in the IWQOL-Lite
scores.
Further demonstrating its sensitivity, a cross-sectional study that administered general and
specific measures of quality of life (SF-36, IWQOL-Lite, and Bariatric Analysis and Reporting
Outcome System (BAROS); Oria and Moorehead, 1998) to patients seeking gastric bypass
surgery found improvements already evident on the Physical Functioning subscale of the
IWQOL-Lite several weeks after surgery (Dymek et al., 2002). Between this point and 6 months
post-surgery, all subscales and Total score of the IWQOL-Lite demonstrated significant
improvement, and between 6 months and 1-year post-surgery, the Physical Functioning,
Self-Esteem, Public Distress, Sexual Life (on a trend level), and Total score of the IWQOL-
Lite exhibited significant improvements. The BAROS also showed significant differences on all
subscales during these time periods. Notably, no subscales of the SF-36 demonstrated signifi-
cant differences in this time period, suggesting the more sensitive nature of the IWQOL-Lite
and BAROS.
Although the American Society for Bariatric Surgery recommends a thorough assessment
(including a quality of life measure such as the IWQOL-Lite) for patients seeking life-altering
gastric bypass surgery (LeMont et al., 2004), surveys have shown that only 6–18.5% of clinical
programs actually administer a quality of life measure (Bauchowitz et al., 2005; Walfish et al.,
in press). Clearly, this would be indicated given the impaired scores demonstrated by pre-
surgery patients and the improvement on scores post-surgery; including this information in
pre- and post-surgery protocols would provide clinicians with valuable treatment recommen-
dations and outcome evaluation.
6 IWQOL Among Subgroups

Binge Eating Disorder. The IWQOL has been evaluated in subgroups of individuals who
struggle with their weight. For example, individuals with binge eating disorder (BED) engage
in frequent binge eating without compensatory behavior (e.g., vomiting); thus, BED patients
are typically obese. The prevalence of BED among obese individuals seeking weight loss
treatment ranges from 16 to 30% (de Zwaan, 2001). Because individuals with BED typically
exhibit greater psychopathology than comparable obese individuals without BED, investiga-
tors have examined whether a diagnosis of BED impacts an individual’s quality of life as well.
Two studies have administered the IWQOL-Lite to individuals with BED and treatment-
seeking obese individuals without BED (de Zwaan et al., 2003; Rieger et al., 2005). One study
found that individuals with BED seeking gastric bypass surgery were more impaired on the
Self-Esteem, Sexual Life, and Work subscales (de Zwaan et al., 2003), while the other study
found that individuals with BED were more impaired on all subscales except the Physical
Function subscale (Rieger et al., 2005). In contrast, a study that controlled for both BMI as
well as depression and overall psychopathology found that BED (as assessed by questionnaire
self-report) did not significantly contribute any independent variance to the IWQOL-Lite
scores, and that the impact of BED on quality of life appeared, at least in this study, to
be accounted for by the increased comorbid psychopathology in this group (Kolotkin
et al., 2004). However, a gender-by-BED interaction was significant for Total score, Physical
Function, and Public Distress, with women’s quality of life more adversely affected by the
presence of BED.
BMI, Gender, and Age. In the original 1995 IWQOL study, the relationship between the
IWQOL scores and BMI and gender was examined among 181 DDFC outpatients (117
women, 64 men) with a mean BMI of 38.3 (Kolotkin et al., 1995). Women demonstrated
significantly lower Self-Esteem than men (which was replicated in the 1997 study by the
authors (Kolotkin et al., 1997). After controlling for the effects of BMI on gender, women
evidenced significantly greater impairments than men on Self-Esteem and Sexual Life. Inter-
estingly, these effects differed according to the severity of weight. In the lowest weight group
(BMI < 32.7), significant differences emerged between the sexes on both Self-Esteem and
Sexual Life; when BMI was between 32.7 and 39.8 significant differences were found between
the sexes only on Self-Esteem; and when BMI > 39.8 no significant differences emerged
on IWQOL scale scores between men and women. These gender differences have also been
shown to vary according to treatment modalities (see > Table 12-5; Kolotkin et al., 2002c;
Kolotkin et al., 2006b).
In examining BMI and gender using the IWQOL-Lite, BMI at baseline was significantly
correlated with all scale and Total scores (p < 0.001; Kolotkin et al., 2001b), with specific
correlations as follows: Sexual Life, 0.30; Self-Esteem, 0.34; Work, 0.35; Physical Function,
0.61; Public Distress, 0.68; and Total score, 0.59. When divided into groups by BMI (<25,
25–29.9, 30–34.9, 35–39.9, and >40), all groups differed significantly from each other on the
scales and Total score (p < 0.01) except for the following: <25 versus 25–29.9 on all scales and
Total score; 25–29.9 versus 30–34.9 for Work; and 30–34.9 versus 35–39.9 for Self-Esteem,
Sexual Life, and Work. Females reported significantly more problems than males in Sexual
Life, and when taking BMI into account, reported significantly more problems with Self-
Esteem and Total score. Further, in a study of 512 individuals presenting for gastric bypass
surgery, white women showed the most impairment, despite having significantly lower BMI
than the other race/gender groups (see > Figure 12-1). However, it should be noted that BMI
contributes the largest amount of variance to the IWQOL-Lite scores of all potential mod-
erators examined thus far (Kolotkin et al., 2002c).
When examining the effect of age, the authors found that as age increased, both sexes
reported less effect of weight on quality of life (as measured by the IWQOL) in Self-Esteem and
Social/Interpersonal Life; greater effect of weight on quality of life in Mobility; and women
reported greater effect of weight on quality of life in Health. Researchers and clinicians thus
need to take these gender and age differences into account when interpreting IWQOL or
IWQOL-Lite scores from their patients.
7 Conclusion and Future Directions
The assessment of psychosocial correlates in obesity has increased almost as dramatically as the
prevalence of obesity itself. With the increased interest in assessment and development of
new measures comes a responsibility to “measure the measures” and ensure that frequently-
used assessments possess adequate reliability and validity. As such, the IWQOL and especially
the IWQOL-Lite have consistently demonstrated excellent reliability and validity through
. Table 12-5
IWQOL-Lite scores by gender and treatment modality
Outpatient All
IWQOL- weight-loss treatment
Lite Community Clinical programs/ Day Gastric modalities
scale volunteers trials studies treatment bypass by gender
Physical function
Women 80.4 21.4 69.7 19.8 68.5 20.1 58.9 26.2 46.7 29.0 67.0 23.11
Men 90.7 12.0 77.4 18.7 70.7 18.7 54.6 26.5 35.6 30.4 72.5 24.72
All 86.0 17.7 a
72.3 19.7 a
68.8 19.9 b
57.2 26.4 c
44.8 29.4 c
Subjects
Self-esteem
Women 76.5 24.2 62.2 26.1 60.1 25.7 52.7 26.3 46.8 27.4 60.3 26.81
Men 92.7 14.3 81.4 18.6 68.9 26.7 64.7 26.9 43.3 29.7 77.3 24.32
All 85.3 21.1 a
68.5 25.6 b
61.3 26.0 c
57.6 27.2 d
46.2 27.8 d
Subjects
Sexual life
Women 89.8 17.4 72.0 25.2 69.1 26.6 63.1 29.7 46.8 28.8 69.8 27.51
Men 97.4 8.4 85.6 16.7 75.1 26.4 69.4 25.6 35.2 32.9 81.7 23.32
All 94.0 13.8 a
76.5 23.6 b
70.0 26.6 c
65.7 28.3 c
44.7 29.8 d
Subjects
Public distress
Women 93.0 15.3 84.1 18.8 80.8 22.1 73.2 26.0 43.2 25.6 80.0 23.6
Men 97.3 9.7 89.7 15.1 82.2 21.3 69.3 27.6 32.5 24.6 83.8 23.2
All 95.3 12.7 a
86.0 17.9 a
81.0 22.0 b
71.6 26.8 c
41.4 25.7 d
Subjects
Work
Women 91.6 14.9 82.4 18.3 80.0 21.6 71.6 24.4 40.5 27.5 78.3 23.1
Men 95.1 11.8 84.0 18.0 78.6 20.8 72.6 22.3 40.1 32.7 81.8 21.4
All 93.5 13.4 a
82.9 18.2 b
79.6 21.5 c
72.0 23.5 d
40.4 28.4 e
Subjects
Total score
Women 84.1 16.3 72.3 17.0 70.1 18.0 61.9 20.7 45.3 22.0 69.3 19.91
Men 93.6 9.5 82.2 14.4 73.8 18.8 63.4 20.6 37.4 22.5 77.8 20.42
All 89.3 13.9 a
75.6 16.9 b
70.6 18.2 c
62.5 20.7 d
44.0 22.2 e
Subjects
Adapted from Kolotkin et al. (2002c, p. 752). Cell entries represent unadjusted mean SD (lower score is more
impaired). Treatment modality means with different letter superscripts (a–e) are significantly different at p < 0.05
with Bonferroni correction after controlling for age and body mass index. Gender means with different numerical
superscripts (1 and 2) are significantly different at p < 0.05 after controlling for age and body mass index
numerous studies using male and female patient populations from differing ethnicities (e.g.,
White et al., 2004), treatment groups (e.g., Fontaine, 2002), BMIs (e.g., Kolotkin and Crosby,
2002a), and psychiatric profiles (e.g., Kolotkin et al., 2006a; Rieger et al., 2005). Its brevity
benefits clinicians, researchers, and patients alike.
. Figure 12-1
BMI and IWQOL-Lite subscale scores for race and gender groups. From White et al. (2004, p. 952).
Group means with a common letter do not differ from one another; group means without a
common letter differ significantly (p < 0.05). Contrasts for IWQOL-Lite scores conducted after
controlling for BMI (where appropriate). BMI body mass index
While the medical field has advanced significantly in its recognition of the psychosocial
impact of obesity, the challenge remains for clinical researchers to increase awareness of
obesity-specific quality of life measures such as the IWQOL-Lite among community physi-
cians and psychologists who infrequently utilize these measures (Bauchowitz et al., 2005).
Obesity treatment would benefit from a more subjective understanding of a patient’s experi-
ence and a more comprehensive picture of weight loss treatment outcome. While it is
important to introduce obesity-specific measures such as the IWQOL-Lite to obese patients
to aid in treatment planning and outcome assessment, clinicians and researchers also need to
consider each patient’s unique constellation of presenting complaints in order to gauge the
areas of greatest concern to the patient.
Another future research direction is in the assessment of the impact of obesity on quality of
life across the developmental spectrum, warranted by the increasing prevalence of overweight
in children and adolescents, and the accompanying psychosocial sequelae. In these regards, it
would be beneficial to adapt the IWQOL for children. The authors of the IWQOL have
recognized the importance of a developmental perspective, as the IWQOL-Lite has recently
been used to develop a similar questionnaire targeting adolescents ages 11 to 19 called the
IWQOL-Kids (Kolotkin et al., 2006c). It appears promising, demonstrating good internal
consistency and sensitivity to BMI and treatment group, but this measure should be examined
further (Kolotkin et al., 2006c). For more information on the developmental perspective of
obesity, please see the accompanying chapters in this publication, “Obesity stigmatization and
quality of life in adolescents” and “Health-related quality of life in obese adolescents.”
Developing norms for the IWQOL-Lite appears indicated, given the differences seen across
ages, gender, and BMI status. In addition, it will be vital for future research to explicate
whether patients most value the amount of weight lost, the consequent improvement in
comorbidities or quality of life, or some combination of these factors (Ballantyne, 2003).
Knowing this answer, and how it may differ across gender, age, ethnicities, treatment groups,
and BMI, will further the development, utility, and validity of the IWQOL-Lite and other
obesity-specific assessments for clinicians and researchers alike.
8 Information on Use of the IWQOL-Lite
For scoring and other information on the IWQOL or the IWQOL-Lite, the reader should consult
the IWQOL/IWQOL-Lite Manual, which can be obtained from the authors. For permission to
use the IWQOL-Lite (licensing fee varies according to use), copyrighted by Duke University,
contact: Ronette L. Kolotkin, rkolotkin@qualityoflifeconsulting.com (telephone 919 493 9995) or
Dennis Thomas, Ph.D., Associate Director, Office of Licensing & Ventures, Duke University,
dennis.thomas@duke.edu, telephone (919) 681–7580. Copyright of the IWQOL-Kids is owned
by Ronette L. Kolotkin and Cincinnati Children’s Hospital Medical Center.
Summary Points
Given the increasing prevalence of obesity worldwide, and the associated psychosocial
consequences of this disease, obesity-specific measures of the quality of life provide a better
method of assessment for obese individuals than general measures of the quality of life.
The 74-item IWQOL was developed by Kolotkin and colleagues, and was the first obesity-
specific measure to assess one’s quality of life.
While the IWQOL demonstrated excellent reliability and validity, Kolotkin and colleagues
developed the 31-item IWQOL-Lite in response to concerns about the length of the
IWQOL.
The IWQOL-Lite has demonstrated excellent reliability, validity, and treatment sensitivity
for various groups of obese individuals in dozens of studies.
The IWQOL-Lite is a recommended measure for obesity researchers and clinicians who
wish to assess the impact of weight upon a patient’s quality of life, especially in regards to
treatment outcome. It is most sensitive and useful for obese patients (BMI 30).
References
Adami G, Ramberti G, Weiss A, Carlini F, Murelli F, Boan J, Kolotkin R, Westman E, McMahon R, Grant J.
Scopinaro N. (2005). Behav Med. 31: 53–60. (2004). Obes Surg. 14: 341–348.
Ballantyne G. (2003). Obes Surg. 13: 954–964. Butler G, Vallis T, Perey B, Veldhuyzen van Zanten S,
Barajas G, Robledo M, Garcia T, Cuesta S, Garcia M, MacDonald A, Konok G. (1999). Int J Obes Relat
Cerrada S. (1998). Rev Esp Sal Púb. 72: 221–231. Metab Disord. 23: 505–511.
Bauchowitz A, Gonder-Frederick L, Olbrisch M, Cohen J. (1988). Statistical Power Analysis for the
Azarbad L, Ryee M, Woodson M, Miller A, Behavioral Sciences. Lawrence Erlbaum,
Shirmer B. (2005). Psychosom Med. 67: 825–832. Hillsdale, NJ.
Crosby R, Kolotkin R, Williams G. (2004). J Clin Epide- Kolotkin R, Meter K, Williams G. (2001a). Obes Rev. 2:
miol. 57: 1153–1160. 219–229.
Crowne D, Marlowe D. (1960). J Consult Psychol. 24: Kolotkin R, Westman E, Ostbye T, Crosby R, Eisenson H,
349–354. Binks M. (2004). Obes Res. 12: 999–1005
de Zwaan M. (2001). Int J Obes Relat Metab Disord. 25: Kolotkin R, Zeller M, Modi A, Samsa G, Quinlan N,
S51–S55. Yanovski J, Bell S, Maahs DM, Gonzales de Serna
de Zwaan M, Mitchell J, Howell L, Monson N, Swan- D, Roehrig HR. (2006c). Obesity. 14: 448–457.
Kremeier L, Crosby R, et al. (2003). Compr Psychi- Le Pen C, Levy E, Loos F, Banzet M, Basdevant A. (1998).
atry. 44: 428–434. J Epidemiol Commun Health. 52: 445–450.
Duval K, Marceau P, Perusse L, Lacasse Y. (2006). Obes LeMont D, Moorehead M, Parish M, Reto C, Ritz S. (2004)
Rev. 7: 347–360. Suggestions for the Pre-surgical Psychological Assess-
Dymek M, Le Grange D, Neven K, Alverdy J. (2002). ment of Bariatric Surgery Candidates. Allied health
Obes Res. 10: 1135–1142. Sciences Sections Ad Hoc Behavioral Health Commit-
Engel S, Crosby R, Kolotkin R, Hartley G, Williams G, tee, American Society for Bariatric Surgery.
Wonderlich S, Mitchell J. (2003). Obes Res. 11: Lustig R, Greenway F, Velasquez-Mieyer P, Heimburger
1207–1213. D, Schumacher D, Smith D, Smith W, Soler N, Warsi
Fine J, Colditz G, Coakley E, Moseley G, Manson J, G, Berg W, Maloney J, Benedetto J, Zhu W,
Willett W, Kawachi I. (1999). JAMA 282: Hohneker (2006). Int J Obes. 30: 331–341.
2136–2142. Mannucci E, Ricca V, Barciulli E, Bernardoa M,
Flegal K, Carroll M, Ogden C, Johnson C. (2002). JAMA Travaglinia R, Cabras P, Rotella C. (1999). Addict
288: 1723–1727. Behav. 24: 345–357.
Fontaine K. (2002). Obes Res 10: 854–855. Mathias SW, CL, Colwell H, Cisternas M, Pasta D,
Fontaine K, Barofsky I. (2001). Obes Rev. 2: 173–182. Stolshek B, Patrick D. (1997). Qual Life Res. 6:
Fontaine K, Bartlett S, Barofsky I. (2000). Int J Eat Dis- 311–322.
ord. 27: 101–105. Moorehead M, Ardelt-Gattinger E, Lechner H, Oria H.
Foster G, Phelan S, Wadden T, Gill D, Ermold J, Didie E. (2003). Obes Surg. 13: 684–692.
(2004). Obes Res. 12: 1271–1277. Niero M, Martin M, Finger T, Lucas R, Mear I,
Gortmaker S, Must A, Perrin J, Sobol A, Dietz W. (1993). Wild D, Glauda L, Patrick D. (2002). Clin Ther. 24:
N Engl J Med. 329: 1008–1012. 690–700.
Heshka S, Anderson J, RL A, Greenway F, Hill J, Phinney S, Oria H, Moorehead M. (1998). Obes Surg. 8: 487–499.
Kolotkin R, Miller-Kovach K, Pi-Sunyer FX. (2003). Parkerson G, Broadhead W, Tse C. (1990). Med Care 28:
JAMA 289: 1792–1798. 1056–1072.
Karlsson J, Taft C, Sjostrom L, Torgerson J, Sullivan M. Pi-Sunyer X. (1995). Medical complications of obesity.
(2003). Int J Obes. 27: 617–630. In: Fairburn C, Brownell K (eds.) Eating Disorders
Kolotkin R, Binks M, Crosby R, Ostbye T, Gress R, and Obesity: A Comprehensive Handbook. The
Adams T. (2006b). Obesity. 14: 472–479. Guilford Press, New York, pp. 401–405.
Kolotkin R, Crosby R. (2002a). Qual Life Res. 11: Rieger E, Wilfley D, Stein R, Marino V, Crow S. (2005).
157–171. Int J Eat Disord. 37: 234–240.
Kolotkin R, Crosby R. (2002b). The Impact of Weight Samsa G, Kolotkin R, Williams G, Nguyen M, Mendel C.
on Quality of Life-Lite (IWQOL-Lite): User’s (2001). Am J Man Care. 7: 875–883.
manual. Obesity and Quality of Life Consulting, Stout A, Applegate K, Friedman K, Grant J, Musante G.
Durham, NC. (2007). Surg Obes Relat Dis. 3: 369–375.
Kolotkin R, Crosby R, Corey-Lisle P, Li H, Swanson J. Teixeira P, Going S, Houtkooper L, Cussler E, Metcalfe L,
(2006a). Qual Life Res. 15: 587–596. Blew R, Sardinha L, Lohman T. (2004). Int J Obes.
Kolotkin R, Crosby R, Kosloski K, Williams G. (2001b). 28: 1124–1133.
Obes Res. 9: 102–111. Testa M, Simonson D. (1996). N Engl J Med. 334:
Kolotkin R, Crosby R, Pendleton R, Strong M, Gress R, 835–840.
Adams T. (2003b). Obes Surg. 13: 371–377. Wadden T, Phelan S. (2002). Obes Res. 10(S1): 50S–57S.
Kolotkin R, Crosby R, Williams G. (2002c). Obes Res. 10: Walfish S, Vance D, Fabricatore A. (2007). Obes Res.
748–756. 17(12): 1578–1583.
Kolotkin R, Crosby R, Williams G. (2003a). Diabetes Res Ware J, Snow K, Kosinski M, Gandek B. (1993). SF-36
Clin Pract. 61: 125–132. Health Survey: Manual and Interpretation Guide.
Kolotkin R, Head S, Brookhart A. (1997). Obes Res. 5: The Health Institute, New England Medical Center,
434–441. Boston.
Kolotkin R, Head S, Hamilton M, Tse C. (1995). Obes White M, O’Neil P, Kolotkin R, Byrne T. (2004). Obes
Res. 3: 49–56. Res. 12: 949–955.
13 The Quality in Later Life
Questionnaire
S. Evans
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
2 QOL Measurement and Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
3 Why a New Measure? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
4 The QuiLL and Its Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
5 QuiLL Development and Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

5.1 Qualitative Interviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
5.2 Instrument Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
6 What Did We Learn? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
7 Applications of the QuiLL Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
8 The QuiLL’s Status as a QOL Measure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

228 13 The Quality in Later Life Questionnaire
Abstract: Having the ability to appropriately measure the life quality of > older people
has potential benefit for all of those engaged in the delivery of health and social care,
including policy makers, planners, clinicians and other practitioners, and patients/service
users and their carers. While there are a plethora of instruments available for the measurement
of quality of life (QOL) very few relate specifically to older people. To date studies have
focused almost exclusively on treated populations in hospital or residential settings and
upon aspects of life quality that can be attributed directly to illness or treatments, rather
than on the wider impact on family and social life, safety, housing and finances etc. The
Quality in Later Life (QuiLL) Assessment was designed to fill this gap. It is a short > opera-
tional measure that assesses objective life circumstances and subjective feelings relating to nine
> life domains (including health and mental health) that were identified as essential attributes
of life quality by older people, carers, professionals and academics in the field; it has good
psychometric properties and can be used routinely in operational practice, in evaluations of
services and clinical or treatment interventions, and in health services and epidemiological
research. The measure has been well received in the field and is already used widely in research
and practice. In this chapter the author summarizes the QuiLL’s development and validation
process, outlines the lessons learned about QOL and its measurement in older people
populations and describes the instrument’s potential applications in routine health and social
care practice. Examples of its service and research relevance, findings and presentational
attributes are also given.
List of Abbreviations: DALY, disability adjusted life year; HRQOL, health related quality of
life; QALY, quality adjusted life year; QOL, quality of life; QuiLL, quality in later life
1 Introduction
The development of interest in quality of life assessment in older adults can be seen as one part
of a more general movement to focus on positive aspects of ageing, with the aim of promoting
well-being for future generations (Bowling, 1995). Enabling older people to live longer either
independently in their own homes or with their carers is a common objective of health and
social policy. Nevertheless, achieving these objectives depends in part upon the ability of
services to assess, monitor, support and review the quality of life (QOL) of the person and
their carer, as well as on their responsiveness in accommodating changing health and > social
care needs.
Having the ability to appropriately measure the life quality of older people has potential
benefit for clinicians and other practitioners, service managers and planners, as well as
patients/service users and their carers (Chesterman et al., 2001). At an individual level,
focusing on the monitoring and maintenance of life quality, may prevent deterioration of
both physical and mental health, and could reduce the need for more intensive and expensive
forms of care and treatment. At an aggregate level, QOL data could be used to compare the life
quality of older people in different community, residential or treatment settings in order to
understand the relative cost and outcomes benefits of different interventions. Also, since
clinical and > service interventions can impact upon individual QOL the availability of
these types of data could be used to inform service developments that promote productive
and successful ageing.
The Quality in Later Life Questionnaire 13 229
2 QOL Measurement and Models
The development of QOL indicators is important to policy and service development

(Hagerty et al., 2001), evaluation and planning in facilitating effective measurement of the impact
of new initiatives, treatments and interventions. Nevertheless, the term QOL has multiple
conceptualizations and is associated with a wide range of theoretical models and measures. In
health, interest in QOL stemmed from a desire to evaluate the impact of clinical interventions
and to assess the relative merits of different health systems using patient-centered indicators
rather than more traditional service outcome measures such as morbidity, mortality or the
number of patients treated (O’Connor, 1993). This interest was stimulated by the recognition
that alleviation of symptoms and prolongation of patients’ lives were not the only criteria for
success (Cummins et al., 2004; Salek, 1998). As a result, many of the QOL models and measures
used in the evaluation of health treatments and interventions focus on those aspects of life quality
that can be attributed directly to illness or treatments, and as such are best described as health-
related quality of life (HRQOL) (Namjoshi and Buesching, 2001; Spiro and Bosse, 2000). Others
focus on specific aspects of functioning rather than on the general effects of a disease (e.g., asthma
or prostate cancer) and are referred to as disease-specific QOL measures; highly specific measures
known as quality-adjusted life years (QALYs) and disability-adjusted life years (DALYs) are also
used in outcomes evaluation, epidemiology and cost-effectiveness analyses. In contrast, those
interested in the social construction of illness and disease often regard QOL in more generic terms
as a broad concept that incorporates all aspects of life, referring to the sense of well-being
and satisfaction experienced by people (Andrews and Withey, 1976; Cameron et al., 2006;
Campbell et al., 1976) under their current life (or health) conditions (Lehman, 1983). There is
evidence that for some specific diseases (such as rheumatoid arthritis for instance) such generic
measures are able to demonstrate impacts on overall life-quality almost as well as disease-specific
measures (Anis et al., 2005). It is this generic conceptualization of life quality on which the QuiLL
(Quality of Life in Later Life) assessment is based.
The conceptual model on which the QuiLL is founded derives from the works of Campbell
et al. (1976) and Lehman (1983). The model developed by the author (presented in
> Figure 13-1) assumes that overall life quality is determined by a combination of personal
characteristics and attributes, material or objective circumstances and domain-specific > sub-
jective well-being. The ideas that underpin this conceptualization of life-quality mirror the
concerns of normal community, family, social and economic life (Cameron et al., 2006; Oliver
et al., 1996). The concept usually incorporates the basic essentials of life whilst also recognizing
the importance of less tangible values like sense of achievement, fulfillment of potential,
reward for efforts made and for stimulation and security in life (Campbell et al., 1976).
3 Why a New Measure?

While there are a plethora of instruments available for the measurement of QOL, at the time of
the QuiLL development (1999–2002) very few related to older people and in the interim very
few new measures have been introduced that focus specifically on older people (see Chapter 24
in this volume).
Much of the early work about QOL in older people was conducted on treated populations
in hospital settings or > nursing homes (Courtney et al., 2003), and tended to focus entirely
. Figure 13-1
An alternative model of life-quality (Evans, 2004). In this model of life quality single arrows are
used to illustrate direct and indirect associations between personal characteristics, personal and
clinical attributes (e.g., depression and disposition) and objective life circumstances, and
domain-specific and ‘‘general’’ or ‘‘overall’’ life quality. Double arrows illustrate reciprocal
relationships between domain-specific and ‘‘general’’ or ‘‘overall’’ life quality
on health-related quality of life taking no account of other aspects such as family, social life,
housing or finances. LEIPAD, an internationally applicable instrument to assess quality of life
in the elderly had been published at this time (De Leo et al., 1998) but as it included more
health and functioning domains than social or generic domains, it did not fulfill the require-
ments of our favoured QOL model. Many studies used disease-specific instruments designed
for use with general adult populations rather than older people. Studies often elicited staff
rather than the views of older people themselves and tended to exclude people with dementia
because staff believed that these individuals did not have the capacity to respond, despite
recent evidence to the contrary (Mozley et al., 1999; Trigg et al., 2007a, 2007b). Like others
(Farquhar 1995; Hyde et al., 2003) the development team (including the current author,
Professor Peter Huxley, Professor Sube Bannerjee, Claire Gately and Alyson Smith) felt that
the QOL concept should not be limited to health alone, and were convinced by evidence based
on comparisons between health-related and global QOL measures that assumptions about
QOL could not be based upon measures of health status (Covinsky et al., 1999). Therefore,
they sought to develop a generic QOL assessment that would complement rather than
substitute for measures of disease-specific or health-related QOL. This decision has been
supported by subsequent research, for instance a study of older people’s own views by Xavier
and colleagues (2003), which concluded that:
" Health seems to be a good indicator of negative quality of life, though an insufficient indicator of
successful elderliness (p 31)
Relatively recent research by Michalos and colleagues (2007), confirms that health-related
concepts are related to but are not synonymous with life satisfaction:
"
The Quality in Later Life Questionnaire 13
Among other things,.. (our).. results clearly show that respondents’ ideas about a generally healthy
231
life are different from, but not independent of, their ideas about a happy, satisfying or contented life,
or about the perceived quality of their lives or their subjective wellbeing (p 127)
Given that the meaning of QOL is thought to change over a life-span (Faden and
German, 1994), can vary by elderly age-group, place (Farquhar, 1995; Mollenkopf et al.,
2004; Knesebeck et al., 2007) and ethnicity (Bajekal et al., 2004), and is influenced by available
social support (Blane et al., 2004) and activities (Menec, 2003; Mozley et al., 1999; Wilhelmson
et al., 2005) it is important that any instrument claiming to the assess QOL of older people
reflects older peoples’ understanding of the term and the factors that contribute to or
detract from life quality in later life. Therefore, the views of older people and those concerned
with the quality of life of older people were central to the development of the QuiLL, ensuring
that the measure captured issues that were of direct relevance to older people and was capable
of assessing the impact of ageing and associated illnesses and diseases on older people’s
lives. The need to retain the views of the older person themselves in the understanding
and measurement of the quality of their life is now well documented (Bowling and
Gabriel, 2004a, b; Westerhof et al., 2001; Wilhelmson et al., 2005; Xavier et al., 2003).
Finally, it was clear from literature reviews that most of the available instruments had been
designed for research rather than operational use, and that there was no standardized and
systematic way of assessing older people’s QOL in routine practice. On the basis of their
previous experience of quality of life assessment in mental health services the research team felt
that the development of a new QOL measure for use routinely in older people’s services would
be valuable in individual treatment and care planning and reviews, for clinicians and practi-
tioners, older people and their carers, and managers and service planners. Therefore, the
QuiLL was developed as a reliable life quality assessment that can be used easily by care staff as
part of their assessment and monitoring procedures; while it was developed primarily for use
in community based care services it can also inform decisions about the future needs of people
being discharged from hospital to home or residential care settings. A number of studies of
care interventions have demonstrated improved quality of life, using generic measures (Brandi
et al., 2004; Chan et al., 2005a, b; Chesterman et al., 2001) and there is a growing interest in the
way in which the immediate physical care environment may be an important determinant of
quality of life (Barnes, 2002; Kearney and Winterbottom, 2005; Sugiyama and Thompson
2005; Tang and Brown 2005).
4 The QuiLL and Its Properties
The Quality in Later Life (QuiLL) Assessment is a short operational measure of life quality
aimed at people aged 65 and over. It includes demographic details and 27 questions covering
objective life circumstances and subjective feelings relating to the nine life domains shown in
> Table 13-1; these life domains were identified as essential attributes of life quality by older
people, carers, professionals and academics in the field. The QuiLL incorporates previously
validated items wherever possible and includes the Andrews and Withey (1976) seven-point
‘‘delighted-terrible’’ scale as a self-rated indicator of subjective well-being, on which a low
score indicates poor life quality and a high score indicates a good level of life-quality;
the inclusion of this validated scale facilitates comparison with numerous other studies of
life-quality in treated and general populations.
232 13
. Table 13-1
The Quality in Later Life Questionnaire
QuiLL structure and content
Subjective well-being (seven-point scale)

How do you feel about . . .?
Demographic details
your life as a whole, today? Disposition, Role of religious faith
Objective life circumstances
how you occupy your time Daily activities
your friendships Friends, Loneliness
your financial situation Difficulty paying bills
your accommodation State of repair of home
your living arrangements People you live with
your personal safety Safety and security at home
your family relationships Family contact
your marriage/relationship
your physical health Long standing illness or disability
your mental health Depression
Your neighborhood Access local amenities
The amount of independence you have
The amount of influence you have (over your own life)
The QuiLL contains items relating to personal characteristics, personal and clinical attributes, categorical indicators
of objective life circumstances in a life domains, and domain-specific and general indicators of subjective life
quality, assessed using a seven-point scale (1 = terrible; 7 = delighted)
For those who are interested, the QuiLL’s psychometric properties are good (as reported
in detail elsewhere by Evans et al. (2005); the alpha coefficient for subjective well-being was
0.88 (n = 1,044) and in tests of inter-rater reliability kappa values of one were common;
reliability between research and professional staff was not acceptable and requires further
work, but criterion validity with the Spitzer Quality of Life Index (Spitzer et al., 1981) was
reasonable at 0.64.
Unlike some measures, for which there are concerns about the ability to demonstrate
relationships between objective circumstances and subjective reporting of well-being (Atkinson
et al., 1997) the QuiLL and other similar measures are capable of demonstrating associations
between objective and subjective indicators at domain specific and global levels (Evans et al.,
2005, 2007). Examples based on the QuiLL (presented later in > Table 13-3) demonstrate the
QuiLL’s ability to show associations between overall QOL and living in a safe environment,
having access to local amenities, having friends to turn to, being able to pay bills, long-
standing illness/disability, family contact and the state of repair of one’s home; similarly at a
domain level the QuiLL was able to demonstrate associations between subjective feelings
about social life and having friends, being lonely, being able to access local amenities,
family contact and living in a safe environment. In the original QuiLL study it was difficult
to demonstrate changes over time in subjective QOL, possibly due to the lack of actual
objective change (60% of cases did not experience any change in objective conditions) that
occurred in the follow-up period, which might have been too short to allow measurable
changes to emerge. While some might argue that this finding suggests the QuiLL is not
responsive to change we do not believe that to be the case, for two main reasons: first analyses
of QuiLL data showed that where the domain-specific objective circumstances of service users
had improved subjective QOL ratings were statistically significantly higher and where circum-
stances had deteriorated subjective ratings were statistically significantly lower than for those
not experiencing these changes (Evans et al., 2002); secondly the Andrews and Withey (1976)
subjective well-being items that the QuiLL incorporates and other measures using the same
scales have a proven ability to demonstrate changes in treated and untreated groups (Huxley
et al., 2001; Evans et al., 2007).
At an individual level the objective items included in the QuiLL provide a clear insight into
an older person’s current situation in terms for example of social, accommodation or financial
credits or deficits, but it is only when examined alongside the individual’s subjective assess-
ment of that aspect of their life that the individual’s need can be determined. For example, a
person might have many friends but crave something more in relation to their social relation-
ships, which might be accessed via support groups for people with the same clinical needs as
them or engagement in some other form of social network. Alternatively, a person might not
be able to access local amenities independently but be very pleased to be living in their
neighborhood, where they might be surrounded by friends and family who can support
them in some way.
At an aggregate level, it is possible using QuiLL data to explore the nature of the
associations between for example loneliness and feelings about overall life quality, to demon-
strate the impact of treatments and service interventions on life quality, and to explain what
factors are most influential in maintaining high levels of QOL in later life.
The following examples illustrate some of the ways in which QuiLL data can be used,
providing comparisons between older people receiving care services in two areas of South-East
England (one a generic service for older people in London and the other a service dealing with
older people with mental health problems in a rural area) and older people in the general
population in South London.
The data presented in > Figure 13-2 relate to self-reported feelings of loneliness and
indicate high levels of loneliness among older people, particularly those in receipt of care
services living in London. More than half of this group reported feeling lonely compared to
38% of older people in the general population in a nearby area of South London, and 42% of
older people receiving care services in a rural area of South East England (w2 = 6.55 (df 2)
p < 0.001).
> Figure 13-3 illustrates subjective QOL profiles for the three older people samples and
illustrates that while the three older people samples did not differ in terms of general life
quality (top row) or quality of life in family, living arrangements and safety domains, the
groups did differ in other aspects of life quality. The similarity in shape of the profiles for older
people in receipt of care services in London and the other South East region indicates that
these samples were more alike each other (as one might expect) than they were like older
people in the general population.
The most significant between-sample differences were observed in finance, health and
occupation of time domains. Between sample differences in finance (F = 59.5, p < 0.001)
related to older people in receipt of care services being more satisfied with their financial
situation (London: mean 4.9 (sd 1.1) p = 0.016; other South East: mean 5.3 (sd 0.8) p < 0.001)
than older people living in the community in South London (mean 4.2, sd 1.4;), perhaps
. Figure 13-2
Reported loneliness in care-service and general population samples of older people. This
figure compares the proportion (%) of older people reporting feelings of loneliness in three
samples – people receiving care services in London, people receiving care services in Essex
and older people in the general population in London. While most older people did not
report feeling lonely, more than half of those receiving care in London were lonely
. Figure 13-3
Subjective QOL by sample. This figure illustrates the QOL profiles based on subjective ratings
of domain and general life quality for the three older people samples – a score of 1 indicates
poor QOL and 7 a good QOL. Scores of 5 and above indicate at least some degree of
satisfaction (i.e., mostly satisfied)
because the recipients of care were more likely to be receiving their full benefit entitlement.
Sample differences in the neighborhood domain (F = 9.65, p < 0.001) related to the general
population being less satisfied with their neighborhood (mean 5.2, sd 1.0, p = 0.010) than
older people in receipt of care in the rural location (mean 5.7, sd 1.0), understandably given
the deprived nature of the urban area, but the general population’s scores did not differ
significantly from those of care recipients in their own area (mean 5.2 (sd 1.2) cf 5.5 (sd 1.4)).
Understandably, the general population sample were more satisfied with their health (F = 56.3,
p < 0.001) and the way they were able to occupy their time (F = 37.36, p < 0.001) than people
in receipt of care (Health: general population mean 4.9 (sd 1.2) cf London cases mean 4.3 (sd
1.3; p = 0.001) and non-London cases mean 4.4 (sd 1.2; p = 0.013); Occupy time: general
population mean 5.0 (sd 1.2) cf London cases mean 4.4 (1.3; p = 0.001) cf non-London cases
4.5 (sd 1.2; p = 0.026)). The general population sample were also more satisfied in relation to
the self domain (independence and influence) than the recipients of care in London (mean 5.2
(sd 1.1) cf 4.6 (sd 1.3); p < 0.005) but not the non London cases (mean 4.8 (sd 1.1).
Given that self-reported loneliness and subjective QOL ratings differed significantly
between samples (as did depression – not presented here), that many subjective QOL ratings
were statistically significantly lower for people who reported feeling depressed or lonely (also
not presented here) and that the shape of QOL profiles was very similar for people who
reported feeling depressed and those reporting feeling lonely, it was important to examine the
nature of these associations with QOL, when other intervening variables were controlled for.
Linear regression models were used to determine what explained domain-specific, general and
‘‘overall’’ (calculated as the mean of domain ratings) life quality, using research interviews for
recipients of care in London and the rural area, and survey data. Age, sex, marital status,
ethnicity, living status, disability, depression, loneliness, disposition, having friends to turn to,
difficulty with household bills, state of repair of home, safety in the home, access to local
amenities, sum of activities undertaken and sample group (survey and research interviews)
were entered as independent variables. In many of the domains, substantial amounts of
variance were explained (compared to most other studies of this type), and the ‘‘overall’’
model explained 43% of the variance (> Table 13-2).
Loneliness and to a lesser extent depression variables appeared most frequently in the
regression models (see > Table 13-3), although the magnitude of associations with the various
aspects of life quality were sometimes similar. Loneliness made the major contribution to
the explanation of variance for ‘‘life in general,’’ ‘‘life overall’’ and in family, living situation,
occupation of time and ‘‘self ’’ domains; depression made the major contribution to the
explanation of variance in the health domain. The models also showed that contact with
family or with friends was important, as was having access to local amenities. Therefore,
improving people’s ability to access local amenities and reducing feelings of depression and
loneliness is likely to impact on people’s QOL. These data suggested that social interventions
such as providing people with welfare benefits advice, helping them to improve their home
security or improving the state of repair of their home may have an important role to play in
improving people’s QOL.
5 QuiLL Development and Testing
The development and validation process (which has been described elsewhere (Evans et al.,
2005) and is summarized here) involved several stages including literature review and
. Table 13-2
Regression Models of generic and domain life quality
QOL Domains Variables R2 (AR2) Beta 95% CI P

Life Loneliness 0.31 (0.30) 0.33 1.20 to 0.60 <0.001
Final model Depression 0.25 1.02 to 0.41 <0.001
Long-standing illness/disability 0.15 0.66 to 0.15 0.002
Friends to turn to 0.11 0.04 to 0.74 0.028
Married 0.1 0.54 to 0.02 0.036
Overall QOL Loneliness 0.46 (0.45) 0.22 0.55 to 0.22 <0.001
Final model Depression 0.24 0.61 to 0.25 <0.001
Safety in the Home 0.15 0.11 to 0.43 0.001
Long-standing illness/disability 0.16 0.42 to 0.13 <0.001
Disposition 0.11 0.04 to 0.33 0.014
State of repair of home 0.12 0.05 to 0.35 0.008
Family contact – daily contact 0.15 0.11 to 0.43 0.001
Difficulty meeting cost of bills 0.10 0.01 to 0.13 0.025
Family contact – yearly contact 0.09 0.01 to 1.35 0.047
Family Loneliness 0.28 (0.27) 0.29 0.96 to 0.46 <0.001
Final model Family contact – daily contact 0.25 0.42 to 0.95 <0.001
Safety in the home 0.18 0.22 to 0.73 <0.001
Family contact – 3 monthly contact 0.13 1.84 to 0.26 0.009
Sex 0.12 0.07 to 0.55 0.011
Family contact – Monthly contact 0.10 1.35 to 0.06 0.035
Finances Difficulty meeting cost of bills 0.55 (0.54) 0.68 0.64 to 0.81 <0.001
Final model Disposition 0.10 0.08 to 0.50 0.008
Sex 0.10 0.51 to 0.08 0.007
State of repair of home 0.08 0.01 to 0.44 0.040
Health Depression 0.42 (0.40) 0.26 0.95 to 0.42 <0.001
Final model Long-standing illness/disability 0.24 0.82 to 0.37 <0.001
Loneliness 0.22 0.78 to 0.29 <0.001
Disposition 0.16 0.17 to 0.60 0.001
State of repair of Home 0.10 0.04 to 0.46 0.021
Accessing Amenities – without help 0.10 0.03 to 0.46 0.029
Living Loneliness 0.31 (0.30) 0.20 0.80 to 0.23 0.001
situation
Final model State of repair of Home 0.26 0.39 to 0.88 <0.001
Depression 0.16 0.73 to 0.15 0.003
Living alone 0.17 0.67 to 0.16 0.001
QOL Domains Variables R2 (AR2) Beta 95% CI P

Disposition 0.11 0.05 to 0.52 0.020
Difficulty meeting cost of Bills 0.14 0.03 to 0.23 0.009
Essex sample 0.11 0.78 to 0.06 0.023
Neighborhood Safety in the home 0.19 (0.17) 0.18 0.20 to 0.77 0.001
Final model Friends to turn to 0.15 0.16 to 0.86 0.005
Family contact – No contact 0.14 5.72 to 0.84 0.009
Ethnic group 0.18 0.81 to 0.21 0.001
GP sample 0.23 0.95 to 0.31 <0.001
Loneliness 0.13 0.62 to 0.06 0.016
Family contact – daily contact 0.13 0.05 to 0.69 0.022
Occupy time Loneliness 0.32 (0.31) 0.27 0.99 to 0.44 <0.001
Final model Long standing Illness/disability 0.21 0.79 to 0.28 <0.001
Depression 0.17 0.77 to 0.19 0.001
Accessing amenities – without help 0.16 0.17 to 0.66 0.001
Disposition 0.13 0.08 to 0.57 0.008
Safety Safety in the home 0.28 (0.27) 0.33 0.55 to 1.02 <0.001
Final model Loneliness 0.20 0.70 to 0.22 <0.001
Depression 0.14 0.59 to 0.07 0.012
Long standing Illness/disability 0.11 0.47 to 0.03 0.025
Self Loneliness 0.29 (0.28) 0.15 0.63 to 0.10 0.007
Final model Accessing amenities – without help 0.19 0.21 to 0.68 <0.001
Safety in the Home 0.19 0.25 to 0.75 <0.001
Long standing Illness/disability 0.16 0.62 to 0.14 0.002
Depression 0.17 0.71 to 0.15 0.003
Family contact – Daily contact 0.14 0.11 to 0.62 0.006
Social Friends to turn to 0.26 (0.25) 0.34 0.75 to 1.36 <0.001
Final model Loneliness 0.25 0.82 to 0.35 <0.001
Essex sample 0.15 0.85 to 0.17 0.003
Safety in the home 0.14 0.10 to 0.60 0.006
> Table 13-2 illustrates the results of regression models which explain the nature of associations between
personal characteristics, personal and clinical attributes, objective life circumstances and subjective life quality
when all related variables are controlled for. The statistics in column three indicate the proportion of variance in
each aspect of life quality that is explained by the variables included in the model (see text), and the beta statistics
in column 4 highlight the magnitude of the association between individual independent variables and the
dependent QOL variable. Only statistically significant associations are included in this table
qualitative interviews to generate themes and relevant questions as well as instrument devel-
opment and modification via field-testing in the community and in health and social care
settings. The design required collaboration with various health and social care providers
including social services departments, > NHS Trusts, general practices and voluntary agencies.
. Table 13-3
Evidence about the impact of assessment
Adding quality of life assessment into a more general process can lead to Grimby and Svanborg,
improved outcome 1996
Screening in primary care resulted in more rapid recovery from common Johnstane and
mental disorder Goldberg, 1976
Screening schemes for elderly people have revealed unmet needs for Itzin, 1987
formal and informal care
An RCT of the effectiveness of screening showed that while it did not McEwan et al., 1990
improve physical health problems, or make activities of daily living easier
it did improve subjective morale
A therapeutic intervention based on quality of life assessment produced Grant et al., 1995
QoL improvements in a depressed community sample
In this table readers are directed to evidence relating to the impact of assessment on individual outcomes
These collaborations enabled us to assess the feasibility and utility of the new QOL measure in
routine practice and to establish the extent to which the information generated, helped to
monitor care in the community, and predicted decline or the increasing need for alternative
interventions. The instrument was tested in operational settings to ensure that it could be used
easily by care staff as part of their assessment and monitoring procedures. To maximize its
usefulness the instrument was applied across the range of settings in which older people live
and across the range of disabilities that older people may have (including mild and moderate
cognitive impairment).
5.1 Qualitative Interviews
In-depth qualitative interviews involving more than 100 individuals, mostly older people
(n = 70) but also carers of older people and professionals, policy makers and academics in the
field, generated themes associated with quality of life in later life. Participants from all groups
responded freely to the same open-ended questions relating to:
Life changes associated with increasing age.
Things that give life quality or take quality away from life in old age.
Things that would add quality to life or detract from it if they were or were not available.
Older people of all ages, ethnic backgrounds and levels of functional ability were involved
in individual discussions and group interviews as were older people who were not receiving
any social care provision. All interviews were audio-taped with the permission of participants,
and fully transcribed for analysis purposes.
Data were analyzed thematically to identify the range and frequency with which themes
were mentioned, in order to inform the content of a pilot instrument that would be tested
in the next phase of the study. The first draft interview schedule included 114 items relating
to personal characteristics, and subjective and objective indicators of life-quality across
11 life-domains, captured using open-ended and pre-coded items. Many of the domains
identified were similar to those for other client groups such as occupation of time, leisure,
family, friends and social life, health, finances, living situation, neighborhood, safety etc.
Others such as ‘‘self’’ (i.e., self-esteem, disposition and how others treat older people),
transport and mobility, loneliness and the role of services were identified by older participants
as being specific to their age-group, thereby supporting the case for a tailored QOL assessment
for older people.
5.2 Instrument Testing
The draft instrument was tested initially in interviews with older people and carers in order to
check the appropriateness of the content of the pilot questionnaire, in terms of the domains
and questions included. Participants were also asked to evaluate the > assessment tool and the
interview process using a semi-structured questionnaire. These data were analyzed systemati-
cally in SPSS using descriptive statistics to determine the amount of variance within categori-
cal items and correlation coefficients to assess the degree of association between items and to
identify any item overlap. Changes to the pilot questionnaire were remade on this basis as well
as on the author’s experience of conducting the pilot interviews and respondents’ comments
about the questionnaire. The result was a revised instrument that included 119 items, most of
which were fixed-response questions.
This revised version was tested in operational practice during interviews with a random
selection of older people identified by nurses, social workers and primary care teams according
to set inclusion and exclusion criteria. The purpose of these interviews was to check again the
appropriateness of domains and questions within domains, as well as checking the appropri-
ateness of response scales, clarifying wording and establishing response rates and completion
times for the assessment tool. The subsequent analytical tasks informed data reduction and
facilitated the development a brief instrument (27-item) for use in operational practice and in
the final field-testing stage of the study and a longer research version for use in the general
population surveys (64 item). A psychometric evaluation of the properties of the instruments
was performed to establish the reliability of individual items, to identify item overlap,
redundancy, frequency of use and missing item data.
Finally, > psychometric testing of the research (v64) and assessment versions (v27) of the
QuiLL were undertaken using data collected specifically for the purpose. The final research
instrument was used in two general population surveys of older people (aged 65+) who had
not been subject to previous testing. These local (n = 251) and national survey (n = 1,163) data
(collected using a postal survey method) provided preliminary population norms for the age
group.
The final assessment instrument was tested in operational practice, where mental health
staff in services for older people (including nurses, social workers and psychiatrists), were asked
to use the QuiLL in assessments undertaken at the point of referral of service users to a new
service. The same inclusion and exclusion criteria were applied as previously. The same
patients/service users were then re-interviewed by a researcher, within 2 weeks of the original
assessment and these data were used to establish test-retest and inter-rater reliability, and
construct validity according to the Spitzer QOL index (Spitzer et al., 1981). Finally, participants
were interviewed again by the same researcher after 3 months, to determine the responsiveness
of the tool as an outcome measure and to assess the impact of services upon client QOL.
6 What Did We Learn?
Having been developed specifically for use in operational health and social care services the
QuiLL assessment has the benefit of being brief. The development process indicated that
most older people have no difficulty completing the questionnaire, which on average takes
about 5–7 minutes when not part of an assessment and 10–15 minutes when completed as part
of an assessment. The QuiLL does not duplicate items that may be collected elsewhere in
health and social care assessments, but provides for systematic data collection utilizing
standard indicators to ensure that the same information is collected in the same way, for all
individuals. It is clear from the research to date that including the QuiLL in assessment
processes can reveal otherwise undetected issues and older people welcome the attention to
their personal views. Our favoured approach of using objective and subjective indicators of
well-being in a number of life domains enables practitioners working with individuals to easily
identify areas of potential need and to assess the impact that these life circumstances have on
how an individual feels about the quality of their life or that area of their life.
As previously reported (Evans et al., 2005) the QuiLL instruments were acceptable,
relevant and of interest to the target group, as indicated by the remarks made in the pre-testing
and preliminary field-testing phases of the study, and by the response rate to the local survey
(71%); the response rate was particularly pleasing given that studies employing the survey
method often achieve response rates in the region of 50–60% and can be much lower.
" QOL for older people is the same as for other groups, it’s about feeling comfortable with your life
both physically and emotionally. It’s got a more positive angle than just being ok (Social Care
Professional)
" Quality of Life is about having something to get up for (Older Person)
" Its good to think about these things and its nice to be asked. It didn’t seem like 40 minutes (Carer,
based on the early version)
" QOL is important and it’s what services should be striving for – it should be used in service planning
and commissioning to produce good outcomes (Social Care Professional)
Even so, the QuiLL was subject to the kinds of problems associated with the introduction
of routine outcome measurement that have been well documented elsewhere (Dunn, 2002;
Evans and Huxley, 2002), and its utility as an outcome measure in routine operational practice
(v27) was more difficult to establish. Efforts to demonstrate the QuiLL’s usefulness in routine
practice were hampered by poor responses from social workers (who in the UK have been slow
to pick up on the outcomes agenda) and doctors in London; nevertheless, the recruitment of
three additional teams from outside of London demonstrated that the QuiLL can be applied
usefully in routine practice, as these teams generated 46 interviews with older people in a
period of 1 month. The indications from these staff were that older people were happy to
complete the QuiLL and when used it was capable of enhancing the assessment process by
raising issues that would not have been captured in standard assessments. In addition, the
longitudinal component of the study had a very low > drop out rate over time, especially in
the nurses’ cases (Evans et al., 2005).
The benefits of using QOL assessment in practice were highlighted further by the qualita-
tive findings, which demonstrated that views about QOL differed between older people and
professionals, with perceptions about QOL apparently being influenced by one’s individual
perspective. Professionals tended to take a more negative stance than older people themselves,
often considering that older people’s QOL was dominated by what they hadn’t got rather
than what they did have, and what they weren’t able to do rather than what they were able to
do (Evans et al., 2005). Overall, professionals were more likely to define QOL in nebulous
terms relating to dignity or choice etc, whereas older people were more likely to define it
in relation to specific aspects of their life like leisure activities, sense of community, transport
and mobility etc. When professionals did focus on specifics there was a tendency for health
staff to view QOL as being dominated by health, whereas social care staff were often of
the opinion that QOL was determined by service availability and input. While both percep-
tions might be legitimate neither reflects accurately the views of the group of older respon-
dents in their care. Even where there was agreement about the importance of certain
factors in relation to QOL, for example in family, health, social life and safety domains
there was a tendency for professionals to emphasize negative aspects rather than positive
aspects of life. This was most evident in relation to the family domain, where older people
(and carers) were more likely to consider the positive impact of family relationships e.g., the
role of grandchildren or the pleasure of having family members visit, whereas professionals
often focused on the negative aspects of family life e.g., family members not doing enough
for older people or ‘‘stealing’’ their welfare benefits. This lack of congruence between
older people’s and professionals’ views of life quality suggests that professionals might not
be well placed to make proxy judgments about the quality of patients’/service users’ lives, and
provides support for the argument of needing to include self-report QOL assessments in
routine practice.
There are a number of studies that, taken together, lead us to believe that a standardized
quality of life assessment might even have beneficial impact in its own right, that is, irrespec-
tive of what intervention follows. Further research in this area is long overdue but some
examples of the effects of routine assessment are given in the following table.
7 Applications of the QuiLL Assessment
Quality of Life measures have long been used in operational practice in the mental health field
among others, in both clinical and social care settings. Our instruments are used routinely by
health and social care professionals in many areas in the UK and some have been adopted for
service evaluations in Europe, Australia and America. Our experience is that users of services
generally appreciate the opportunity to talk about their lives in this way. It was our intention
to create a similar opportunity for older peoples’ services by developing a reliable life quality
assessment that can be used easily by care staff as part of their assessment and monitoring
procedures.
Assessment tools are designed to support and not replace professional judgment, and this
is a feature of the measure we have developed. One of the key issues at contact assessment is a
consideration of the nature of the presenting problems and their relative significance for the
older person. The QuiLL lends itself to making older person’s views central to the assessment
process, because it asks for the person’s own well-being ratings within relevant life domains, as
determined by older people themselves, but also provides objective and verifiable information
about life circumstances in the same domains. This emphasis is a major benefit for clinicians
and social care practitioners, as low scores rated by the service user in important life domains
such as housing, finances, health, family, safety and leisure, will reveal the older person’s own
concerns and their relative significance for them. In this way the instrument contributes to
assessment, and to the planning of care to suit individual circumstances and preferences, and
provides a means to assess the ultimate outcome and effectiveness of that plan.
The QuiLL’s standardized structure for information gathering across the range of life
domains makes it useful at an individual level in screening, initial assessment and monitoring
change over time, and for highlighting the need for timely interventions that may ultimately
reduce the need for more costly services and might even help to prevent deterioration.
QOL assessment is certainly valuable as an outcome measure assessing the impact of service
interventions on individual quality of life and it can also be used to inform service planning
and delivery objectives such as maintaining older people in their own homes for as long
as possible. One particular benefit of the QuiLL is that its generic approach enables assess-
ments of both client and older carers’ QOL, which is often important in enabling people
to live at home independently for as long as possible. Using objective and subjective
indicators at a domain level and for life in general, the instrument facilitates the identification
of current circumstances, feelings about circumstances and changes over time for both
groups. Thus it has the potential to highlight problems or possible breakdown in carer
arrangements, isolating the domains in which service interventions may help alleviate a
problem. The generic approach to measurement is conducive to making comparisons between
older people receiving health and social care, and older people in the general population.
Normative data for UK community and hospital social work and nursing teams (n = 150)
and older people living in the community are now available (older general population n = 250;
older people living in a deprived area (n = 600) and retired health professionals n = 1,100),
providing useful benchmark levels of QOL attainment for older people living in different
circumstances.
The QuiLL is also useful in group level analyses in the evaluation of service interventions.
Purchasers and planners of health and social care need to be able to compare the life quality for
older people in different settings in the community, and in residential homes in order to assess
the relative benefits of certain intervention types and to understand costs and their relation to
QOL. Used longitudinally QOL instruments are regularly incorporated in assessments of the
impact on QOL of certain service interventions. For example one of our instruments was
recently used in a multi-centre study that assessed outcomes of intensive versus standard case
management in a severe mental illness population. In addition QOL measures can along with
indicators of problems and severity, form part of the framework for population needs
assessments. Similarly QOL assessments like the QuiLL are used in policy evaluations, a recent
example being the evaluation of an urban regeneration initiative on a community sample in
South Manchester.
8 The QuiLL’s Status as a QOL Measure

Since its development there has been considerable interest in the QuiLL both in terms of its use
in research, and for the purpose for which it was designed – routine use in operational
practice. For several years it has been one of seven indicators that the Department of Health
in England (DH, 2004) refers local services to with regard to assessing service user perspectives
and needs. The measure is also included in good practice guidance for services, issued by the
Centre for Policy on Ageing (CPA, 2005). The QuiLL is being used increasingly in practice
settings either routinely or in service evaluations in the UK and beyond. The research team has
received in excess of 100 requests for information from services and the QuiLL is used
routinely in some services in Queensland and Victoria (Australia), where routine outcomes
measurement is mandatory. The QuiLL is also the primary outcome measure against which
Westminster City Council evaluates the performance of preventative services, with the aim of
demonstrating a 2% improvement (over and above confidence intervals) over 3 years, in four
life domains and overall life quality (Westminster City Council, 2006). The QuiLL has been
translated into Swedish for use in a Swedish Medical Research Council funded, population
based study of older people being undertaken by academics at the Health University of
Linkoping. It is also included in a New Zealand study that compares the quality of life of
older people living alone in the community with those living in retirement communities where
structured group activities were available (Prasarao et al., 2006). In the UK it has been
included in an evaluation of ‘‘Telecare’’ being undertaken in association with an American
University, and in a study of ‘‘Extracare’’ housing being led by Professor Judith Phillips at
Swansea University; both projects involve evaluations of interventions involving information
technology supports aimed at enabling older people to life independently in their own homes.
The inclusion of the QuiLL in these studies and others of their type is highly appropriate given
the QuiLL was preferred to other measures of life quality that were developed specifically for
evaluating new technologies, in an independent review of measures included in the Telecare
Evaluation Framework (Doughty, 2006) developed at the Centre for Usable Home Technology
(CUHTEC) at the University of York in the UK.
The QuiLL also received a favorable report in ‘‘Quality of Life in older people: a structured
review of self-assessed health instruments’’ (Hayward et al., 2006). We would argue strongly
however that the QuiLL is a measure of generic life quality capable of determining the effects
of ill health and other forms of disadvantage of generic life quality, rather than being an
measure of self-assessed health. We would also question the authors’ view that some of the
evidence relating to the QuiLL was somewhat basic, especially as they appear to have based
their judgment on the 64-item research version, which was not subject to the same degree of
reliability testing as test-retest reliability was not undertaken for the self-report measure. We
would also challenge their belief that the measure was developed in Canada, given that we did
all of the work in England! Nevertheless, it was pleasing to find that the QuiLL was one of only
a few instruments considered by the reviewers to have been developed thoroughly and to have
provided evidence of reliability, validity and responsiveness. The QuiLL was one of only 5 of
the 25 older-people specific measures reviewed (along with 20 non-specific instruments) to
have done so. The QuiLL was one of only seven older-people specific instruments that could be
used flexibly either in interview or as a self-report assessment, and was one of four (not
including individualized assessments) that had involved older people in item generation; in
addition the QuiLL was one of only six age-specific instruments to be able to demonstrate
responsiveness to changes over time and one of 12 that had demonstrated internal consistency;
like four others it had also examined test-retest reliability, although the authors appeared to
have missed this element of the study.
Finally, in a review of assessment tools Addy (2006) favored tools that focused on patients’/
service users’ needs, the QuiLL was the only measure identified as focusing exclusively on the
needs of older people. The author concluded that:
" These assessments should become familiar to occupational therapists who wish to provide a person
centred service
Summary Points
Most measures of QOL that are used in evaluations of clinical services and treatment
interventions were not designed specifically for use with older people.
Most studies of QOL in older people focus upon treated populations in hospital or nursing
home settings, and as such do not facilitate comparisons with older people living in the
community.
The major benefit of the QuiLL is that it was developed with input from more than 70
older people, as well as their carers and professionals and academics in the field, and as
such covers all of the domains that were deemed essential components of life quality in
later life by those that matter.
The QuiLL is capable of examining the wider impacts of illness and treatments by focusing
on life domains such as daytime activity, leisure, family and social life, as well as on health,
mental health and life overall.
It was developed specifically for use with older people receiving health and social care
services and can be used at an individual level to inform care planning and review
planning, or at an aggregate level in service evaluations and planning.
The generic approach to measurement and its use in community and GP practice based
surveys facilitates benchmarking with older people living independently with or without
the support of community services.
The QuiLL has good psychometric properties, and the measure has been positively
received and is already used widely in research, service evaluations and routine practice.
The development phase demonstrated that older people have very different views
about what constitutes life quality than professionals involved in their care, emphasizing
the importance of asking individuals about their own life quality instead of relying
upon the views of clinicians and other professionals involved in health and social care
delivery.
Graphical outputs in the form of subjective QOL profiles provide clear illustrations
of QOL changes over time, and relationships between QOL and other intervening
variables.
References
Addy L. (2006). Occupational Therapy Evidence in Prac- Blane DB, Higgs PFD, Hyde M, Wiggins RD. (2004).
tice for Physical Rehabilitation. Blackwell, Oxford. Ageing Soc. 24: 693–708.
Andrews FM, Withey SB. (1976). Social Indicators of Bowling A. (1995). Soc Sci Med. 41: 1447–1462.
Well-Being: Americans Perceptions of Quality of Bowling A, Gabriel Z. (2004a). Soc Ind Res. 69: 1–36.
Life. Plenum, New York. Bowling A, Gabriel Z. (2004b). Ageing Soc. 24: 675–691.
Anis AH, Brazier JE, Esdaile, JM, Kopec JA, Marra CA, Brandi JM, Farley OW, Kelley-Gillespie N, Liese LH.
Offer R, Shojania K, Woolcott JC. (2005). Soc Sci (2004). J Hous Eld. 18: 73–88.
Med. 60: 1571–1582. Cameron E, Mathers J, Parry J. (2006). Crit Pub Hlth. 16:
Atkinson M, Zibin S, Chuang H. (1997). Am J Psychiat. 347–354.
154: 99–105. Campbell A, Converse P, Rogers WL. (1976). The Quality
Bajekal M, Blane D, Grewal I, Karlsen S, Nazroo J. (2004). of American Life: Perceptions, Evaluating and Satis-
Ageing Soc. 24: 709–728. factions. Russell Sage, New York.
Barnes S. Design in Caring Environments Study Group Centre for Policy on Ageing. (2005). Single Assessment
(2002). Ageing Soc. 22: 775–789. Process – training materials – assessment tools:
Social Work and Social Care Section, Health Ser- Farquhar M. (1995). J Adv Nurs. 22: 502–508.
vices Research Department, Institute of Psychiatry, Grant GM, Salcedo V, Hynon LS, Frisch MP, Poster K.
Kings College London The King’s College Quality in (1995). Psychol Rep 76: 1203–1208.
Later Life (QuiLL) Assessment. http://www.cpa.org. Grimby A, Svanborg A. (1996). Aging 8: 162–169.
uk/sap/sap_assessmenttools_list.html Hagerty MR, Cummins RA, Ferriss AL, Land K, Michalos
Chan L, Gagnon AJ, Grondines J, Morin I, Schein C. AC, Peterson M, Sharpe A, Sirgy J, Vogel J. (2001).
(2005a). J Am Geriat Soc. 53: 597–602. Soc Ind Res. 55: 1–96.
Chan SSC, Cheung JCK, Kwan AYH, Lau A, Leung EMF, Haywood KL, Garratt AM, Fitzpatrick R. (2006). Expert
Ng SH, Ngan RMH. (2005b). Soc Ind Res. 71: Rev Pharmacoeco Out Res. 6: 181–194.
291–334. Huxley P, Evans S, Burns T, Fahy T, Green J. (2001). Soc
Chesterman J, Bauld L, Judge K. (2001). Hlth Soc Care Psych Psych Epid. 36: 249–255.
Comm. 9: 31–42. Hyde M, Wiggins RD, Higgs P, Blane DB. (2003). Aging
Courtney M, Edwards H, Stephan J, O’Reilly M, Ment Hlth. 7: 186–194.
Duggan C. (2003). Aust J Ageing. 22: 58–64. Itzin C. (1987). Nursing Times 83: 47–50.
Covinsky KE, Wu AW, Landefeld CS, Connors AF Jr, Johnstone A, Goldberg D. (1976). Lancet 1: 605–608.
Phillips RS, Tsevat J, Dawson NV, Lynn J, Kearney AR, Winterbottom D. (2005). J Hous Eld. 19:
Fortinsky RH. (1999). Am J Med. 106 (4):435–440. 7–28.
Cummins RA, Lau ALD, Stokes M. (2004). Ex Rev Phar- Knesebeck O, Wahrendorf M, Hyde M, Siegrist J. (2007).
macoec Out Res. 4: 413–420. Ageing Soc. 27: 269–284.
De Leo D, Diekstra RFW, Lonnqvist J, Trabucchi M, Lehman A. (1983). Arch Gen Psychiat. 40: 369–373.
Cleiren MHPD, Frisoni GB, Della Buono M, McEwan RT, Davison N, Forster DP, Pearson P, Stirling E.
Haltunen A. (1998). Behav Med. 24: 17–27. (1990). Br J Gen Pract 40: 94–97.
Department of Health. (2004). Single Assessment Process Menec VH. (2003). J Geront Series B Psych Sci Soc Sci.
for Older People: Assessment scales. www.nimhe. 58B: S74–S82.
csip.org.uk/silo/files/single-assesment-scalesdoc.doc Michalos AC, Hatch PM, Hemingway D, Lavallee L,
Doughty K. (2006). Developing a Telecare Evaluation Hogan A, Christensen B. (2007). Soc Ind Res. 84:
Framework. Presentation to the London Telecare 127–158.
Service Group. Westminster City Hall, September Mollenkopf H, Kaspar R, Marcellini F, Ruopilla I,
26th. Szeman Z, Tacken M, Wahl H-W. (2004). Hallym
Dunn D. (2002). Paper presented in the Routine Out- Int J Aging. 6: 1–36.
comes Symposium at the Association of European Mozley CG, Huxley P, Sutcliffe C, Bagley H, Burns A,
Psychiatrists, Stockholm, May 5th. Challis D, Cordingley L. (1999). Int J Geriat Psy-
Evans S, Huxley P. (2002). Recent evidence in the use of chiat. 14: 776–783.
Quality of Life Assessment in Mental Health. In: Namjoshi MA, Buesching DP. (2001). QoL Res. 10:
Casas F, Saurina C (eds.) Proceedings of the Third 105–115.
Conference of the International Society for Quality Oliver JPJ, Huxley PJ, Bridges K, Mohammed H. (1996).
of Life Studies. Universitat de Girona: Servicio de Quality of Life and Mental Health Services.
Publicaciones. Girona. Routledge, London.
Evans S, Huxley P, Gately C. (2002). Quality in Later O’Connor R. (1993). Issues n the measurement of
Life (QuiLL): The Development of a New Generic health-related quality of life. National Centre for
Instrument for Use in Routine Practice. Final Health Program Evaluation [online]. Available at:
Report to the PPP Foundation. Institute of http:// www.rodoconnorassoc.com/issues_in_the_
Psychiatry (Health Services Research Department), measurement_of_qua.htm (accessed January, 2003).
London. Prasarao PSDV, Cheung G, Sun W. (2006). Quality
Evans S, Gately C, Huxley P, Smith A, Banerjee S. (2005). of Life in the Elderly. The New Zealand
QoL Res. 14: 1291–1300. Medical Journal: Proceedings of the Waikato
Evans S, Banerjee S, Leese M, Huxley P. (2007). QoL Res. Clinical Research Seminar Wednesday 22nd March,
16: 17–29. 2006.
Evans S, Huxley P. (2002). Recent evidence in the use of Salek S. (1998). A Ccmpendium of quality Quality of life
Quality of Life Assessment in Mental Health. In: Life Measures. Wiley, London.
Casas F, Saurina C (eds.) Proceedings of the Third Spiro A, Bosse R. (2000). Int J Aging Hum Devel. 50:
Conference of the International Society for Quality 297–318.
of Life Studies. Universitat de Girona: Servicio de Spitzer WO, et al. (1981). J Chron Dis. 34: 585–597.
Publicaciones, Girona. Sugiyama T, Thompson CW. (2005). J Hous Eld. 19:
Faden R, German PS. (1994). Clin Geriat Med. 10: 167–185.
541–551. Tang JW, Brown RD. (2005). J Hous Eld. 19: 187–202.
Trigg R, Jones RW, Skevington SM. (2007a). Age Ageing. csu/Cabinet/2006/27-02-06/Item%208%20Annex%

36: 663–669. 203%20-%20stretch%20target%20agreements.doc.
Trigg R, Skevington SM, Jones RW. (2007b). Accessed 16th April, 2008.
Gerontologist. 47(6): 789–797. Wilhelmson K, Andersson C, Waern M, Allebeck P.
Westerhof GJ, Dittmann-Kohli F, Thissen T. (2001). Soc (2005). Ageing Soc. 25: –585–600.
Ind Res. 56: 179–203. Xavier MF, Ferraz MPT, Marc N, Escosteguy N,
Westminster City Council. (2006). Local Area Agreement Moriguchi E, et al. (2003). Bras Psiquiat. 2521–2539.
Stretch Target 9. http://www3.westminster.gov.uk/
14 The MacDQOL Individualized
Measure of the Impact of
Macular Disease on Quality
of Life
Jan Mitchell . Alison Woodcock . Clare Bradley
1 Introduction: Macular Degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
2 Measuring Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
3 Design of the MacDQOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
4 Design and Development Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

4.1 Postal Pilot Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
4.2 Nottingham Validation Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
5 Psychometric Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

5.1 Factor Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
5.2 Internal Consistency Reliability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
5.3 Test-retest Reliability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
5.4 Face and Content Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
5.5 Concurrent Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
5.6 Construct Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
5.7 Responsiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
5.8 Missing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
6 Weighting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
7 Equivalence of Completion Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
8 Acceptability and Respondent Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
9 Studies Using the MacDQOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
10 Availability in Multiple Languages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
11 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
12 Use of the MacDQOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262

248 14 The MacDQOL Individualized Measure of the Impact of Macular Disease on Quality of Life
Abstract: The MacDQOL is an individualized measure of the impact of > macular disease
(MD) on quality of life. It was designed with reference to people who had MD, using focus
groups, and to the literature. An early draft was pilot tested with a postal study in which
participants (N = 65) were recruited from the membership of the UK Macular Disease Society.
This study showed significant differences in MacDQOL scores between people who were not
registered and those who were registered blind (p < 0.001) or partially sighted (p < 0.001) and
the findings offered early evidence of > construct validity.
There followed a > longitudinal study (N = 156) to enable further validation of the MacDQOL.
Participants were recruited from an ophthalmic specialist’s patient list. > Principal components
analysis revealed a single scale with excellent internal consistency reliability (Cronbach’s
alpha = 0.946). > Test-retest reliability was excellent with MacDQOL scores at time 1 and time
2 highly correlated (r = 0.946) and no differences in scores between time 1 and time 2 (p = 0.85).
Construct validity was demonstrated by the MacDQOL’s sensitivity to several measures of vision
(near and distance > visual acuity, contrast sensitivity, reading speed, color recognition). There
was some correlational evidence of responsiveness to change in vision over time.
Good response rates and completion rates indicated that the MacDQOL is acceptable to
participants and does not impose too great a burden.
The MacDQOL has been used in clinical trials and a number of other studies. Evidence to
date indicates that MD has a negative impact on the quality of life of people with the condition
and that the negative impact increases with increasing severity of MD. The MacDQOL
promises to be a valuable tool in the investigation of changes in patients’ quality of life in
clinical trials of medical treatments and rehabilitative interventions.
List of Abbreviations: ADDQOL, audit of diabetes dependent quality of life; AWI, average
weighted impact; FS, > functional status; HS, health status; LVQOL, low vision quality of life
measure; MacDQOL, macular disease dependent quality of life measure; MD, macular disease;
MDS, Macular Disease Society; NEI-VFQ25, National Eye Institute vision function question-
naire – 25 item; QOL, quality of life; RetDQOL, diabetic > retinopathy dependent quality of
life measure; SEIQOL, schedule for the evaluation of individual quality of life; VA, visual acuity
1 Introduction: Macular Degeneration
Age-related macular degeneration (MD) is a chronic, progressive eye disorder that mainly
affects people over the age of 50. Incidence increases with age. It is the leading cause of
blindness in the Western world in people over 60 yrs (WHO, 2004) and it is the third most
common cause of blindness globally after cataract and glaucoma (WHO, 2004). MD causes
8.7% of the global estimate of 161 million cases of visual impairment (Resnikoff et al., 2004).
Recently it was estimated that, in the UK, with a population of 59 million (National Statistics
Online, 2004), approximately 417,000 people have some degree of MD, of whom 214,000 have
sufficient visual impairment for registration as partially sighted or blind (Owen et al., 2003).
It has been estimated that there are 1.75 million people with some degree of MD in the USA
and this is likely to increase to almost three million by 2020 due to the aging population
(Friedman et al., 2004).
MD damages the central part of the retina, the macula, which is responsible for fine,
detailed vision needed for tasks such as reading, driving, watching TV and recognizing faces.
Peripheral vision is usually retained but impairment can be sufficient to warrant registration as
The MacDQOL Individualized Measure of the Impact of Macular Disease on Quality of Life 14 249
blind. MD impairs proficiency in carrying out many activities in daily living and can
compromise the ability to live independently (for illustrations of the effect of MD on vision
please see other chapter by Mitchell and Bradley in this book).
There are two types of MD. The less serious ‘‘dry’’ or ‘‘non exudative’’ MD accounts for
85–90% of cases of MD. It develops slowly, is usually bilateral and in most cases does not lead
to the most serious vision loss. It is characterized by the presence of fatty deposits behind the
retina which cause the retina to thin and dry out. Currently there is no medical or surgical
treatment for dry MD. Wet or neovascular MD (also known as exudative MD) usually
develops quickly and frequently leads to serious visual impairment. Wet MD is caused by
the growth of new blood vessels (a process known as choroidal neovascularization) behind the
retina. These new blood vessels are weak and have a propensity to leak, damaging the retinal
cells and leading to scar tissue. Although it represents only 10–15% of cases of MD, wet MD
accounts for over 90% of serious vision loss due to MD (Chisholm, 1998). Treatments
are available for some categories of wet MD. The treatments can halt the progress of the
condition for an indeterminate period rather than cure it although the most recent treatment
developments do offer the hope of an improvement in vision for a proportion of patients
(Kaiser and Do, 2007).
2 Measuring Quality of Life
The importance of measuring quality of life (QOL) in health care is increasingly recognized
but frequently the instruments used would more correctly be referred to as > measures of
health status (HS) and functional status (FS)(Gill and Feinstein, 1994). While such measures
are useful in investigating the impact of medical conditions and their treatment they are
not measures of QOL. HS measures investigate the quality of health rather than QOL
(Bradley, 2001) and a measure of vision function assesses the impact of vision impairment
on functioning, not its impact on QOL. Individuals regard some aspects of HS or FS as more
important than others and some as not important at all. The importance that is attributed to
these aspects differs from one individual to another and a measure of HS or FS that gives equal
importance to all aspects measured does not properly represent the impact of those different
aspects on an individual’s QOL. Joyce commented that ‘‘it is not the observed functioning of
the individual that is of primary concern but that individual’s perception of and reactions to
functioning’’ (Joyce, 1994, p. 46). The distinction between HS, FS and QOL is also often
overlooked in the ophthalmology literature. Since the impact of MD and other vision
impairment may have an effect on length of life only indirectly (possibly through accidents
or suicide), its impact is primarily on QOL and it is important that the distinction is made and
that an appropriate measure is used in the assessment of QOL.
Early measures of QOL tended to consist of items derived from researchers or health
professionals but not the patients themselves. The Schedule for the Evaluation of Individual
Quality of Life (SEIQOL) (McGee et al., 1991) differs fundamentally from such instruments
because it allows respondents to name the five > domains of life that they perceive as most
important to their own QOL and to rate the relative importance of each one to their overall
QOL. The importance ratings are used to weight the domain ratings and the weighted ratings
are summed to give a single QOL score. The Patient Generated Index (Ruta et al., 1999) uses
a similar approach but it is condition-specific in that it invites respondents to name five
areas of life that are most affected by their medical condition and to rate how badly affec-
ted they are in each area. Participants then indicate the areas in which they would most
value an improvement by giving points to each area. The individual area ratings are weighted
by the points given and the areas’ weighted scores are summed to produce a single
index designed to measure the impact of the medical condition in areas of their life most
important to them. Again the relevance of domains for the respondent is paramount.
> Weighting an assessment by an importance value allows respondents to indicate more
accurately the impact of any situation (e.g. a chronic health state) on their QOL by the use
of multiple criteria.
The philosophy underpinning the SEIQOL was adopted by Bradley and her colleagues
in the development of the Audit of Diabetes Dependent Quality of Life (ADDQOL) (Bradley
et al., 1999, Bradley and Speight, 2002; Wee et al., 2006), a diabetes-specific measure of
the impact of diabetes on QOL. Interviews with people who had diabetes, feedback from
clinicians including dieticians, and the research literature were used in determining domains
of life that were impacted by diabetes and important for QOL. For each item respondents rate
the impact of diabetes on that domain of life and the importance of the domain for QOL.
Impact and importance ratings are multiplied to give weighted impact scores for each domain.
Some items have a preliminary question that acts as a ‘‘not applicable’’ option. The ADDQOL
includes two overview items, the first measuring present QOL and the second investigating
diabetes-specific QOL. A substantial body of evidence attests to the value of the ADDQOL e.g.
(Bradley et al., 1999; Kinmonth et al., 1998; Woodcock et al., 2001; DAFNE Study Group,
2002; Speight et al., 2007;) and similar measures have been developed for use in diabetic
retinopathy, RetDQOL (Woodcock et al., 2004; Brose et al., 2007), renal failure, RDQOL
(Bradley, 1997), growth hormone deficiency, HDQOL (McMillan et al., 2006), hypothyroid-
ism, ThyDQOL (McMillan et al., 2007), age-related hormone decline in men, A-RHDQOL,
(McMillan et al., 2003), diabetes in teenagers, ADDQOL-Teen (McMillan et al., 2004)
and children, ADDQOL Junior and ADDQOL Junior+ (Wilson et al., 1998) and the
ADDQOL Senior for frail elderly people with diabetes in care homes (Speight et al., 2003).
The design of the MacDQOL individualized measure of the impact of macular disease on
quality of life was guided by the philosophy underpinning the SEIQOL and the ADDQOL
and related instruments.
3 Design of the MacDQOL
Items for the initial draft of the MacDQOL were derived in consultation with a person who
had MD and with reference to a survey of 1420 members of the UK Macular Disease Society
(MDS) (Mitchell et al., 2002) and to the research literature.
The MacDQOL was designed for completion by visually impaired people. Text is presen-
ted in Arial font 16 bold and is justified to the left. This helps respondents to navigate
down the page. The use of capital letters is avoided except where dictated by grammar as
lower case letters are easier to identify for people with MD. Response options are presented
vertically and dotted lines guide the reader to response boxes as shown in the example item
in > Figure 14-1.
The first draft of the MacDQOL was tested at meetings of two local groups of the MDS
(N = 6 and N = 11). There were four parts to each meeting:
. Figure 14-1
Format of the MacDQOL domain-specific items (with scoring indicated, not shown in actual
questionnaire). Part (a) investigates impact of MD on an aspect of life (e.g. friendships and social
life). Part (b) investigates the importance of the aspect of life to quality of life
1) Participants were told:

Imagine you wake up tomorrow and discover that, by some magic, you no longer have macular
disease and your central vision has been restored. In what important ways would that affect
your quality of life?
Participants wrote down ways in which their QOL would change. Help was given to people
who had difficulty writing.
2) Participants completed the draft MacDQOL, with assistance where necessary.
3) Participants discussed the MacDQOL and their ideas in small groups while the researchers
reviewed lists generated in (1) and questionnaires completed in (2).
4) A general discussion of the MacDQOL and QOL followed in which irrelevant and missing
items were identified and discussed and wording of some new items devised.
As a result of the two meetings, some changes were made to the measure.
The MacDQOL questionnaire begins with two overview items measuring: (a) Present QOL (In
general, my present quality of life is: scored from +3 [excellent], through 0 [neither good nor bad]
to 3 [extremely bad] on a 7-point scale); (b) MD-specific QOL (If I did not have MD, my
quality of life would be: scored from 3 [very much better] through 0 [the same] to +1 [worse]
on a 5-point scale). There follow 23 domain-specific items. Each item has two questions to
investigate a) the impact of MD on a particular aspect of life and b) the importance of that
aspect of life to the individual’s QOL (see > Figure 14-1).
Some domains have a preliminary question which acts as a ‘‘not applicable’’ option. For
example the family life item is preceded by the question ‘‘Do you have family/relatives?’’
For each domain-specific item, the impact score (from 3 to +1) is multiplied by the
importance score (from 0 to 3) to give a weighted impact score of between 9 (maximum
negative impact) and +3 (maximum positive impact). An > average weighted impact score
(AWI) is obtained by summing the weighted impact scores of all items except work and
dividing by the number of applicable items for each individual. Work is applicable to very few
people in this predominantly retired population but important for those to whom it is
applicable. Work item scores are, therefore, analyzed separately. In a final item respondents
are invited to state whether MD affected his/her life in any ways not already covered by the
questionnaire, with a space to elaborate for people who reply ‘‘yes.’’ Domains included in the
MacDQOL (UK-English version) are listed in > Table 14-1.
. Table 14-1
MacDQOL items and response options
MacDQOL overview items

1 In general, my present quality of life is Excellent – extremely bad
2 If I did not have MD, my quality of life would be Very much better - worse
Domain-specific items
If I did not have MD Response options
1 I could handle my household tasks Very much better – worse
2 I could handle my personal affairs (letters, bills, etc) Very much better – worse
3 My experience of shopping would be Very much better – worse
4* My working life and work-related opportunities would be Very much better – worse
5* My closest personal relationship would be Very much better – worse
6* My family life would be Very much better – worse
7 My friendships and social life would be Very much better – worse
8 My physical appearance (including clothes and grooming) Very much better – worse
would be
9 Physically, I could do Very much more – less
10 I could get out and about (e.g. on foot, or by car, bus or train) Very much better – worse
11* My holidays would be Very much better – worse
12 I could enjoy my leisure activities and interests (e.g. reading, Very much more-less
TV, radio, hobbies)
13 My self-confidence would be Very much better – worse
14 My motivation to achieve things would be Very much better – worse
15 The way people in general react to me would be Very much better – worse
16 My feelings about the future (e.g. worries, hopes) would be Very much better – worse
17 My financial situation would be Very much better – worse
18* I could do things independently Very much better - worse
19 I could do things for others as I wish Very much better – worse
20 I would have mishaps or would lose things Very much less – more
21 I could enjoy meals Very much more – less
22 The time it takes me to do things would be Very much less – more
23 I could enjoy nature Very much more – less
Each item starts with ‘‘If I did not have MD,’’ followed by the main part of the question (e.g. I could handle my
household tasks). The respondent chooses a response option from e.g. very much better; much better; a little
better; the same; worse (scored 3, 2, 1, 0, 1 respectively). In the second part of the item the respondent is
asked how important that aspect of life is to his/her quality of life. Response options are: very important,
important, somewhat important, not at all important (scored 3, 2, 1, 0 respectively)
*These items begin with a yes/no question e.g., item 6 ‘‘Do you have family/relatives?’’ If the respondent answers
‘‘no,’’ the item is not applicable and it is not completed
4 Design and Development Studies
Two studies were carried out to investigate the properties of the MacDQOL and to refine it as
necessary.
4.1 Postal Pilot Study
Following the initial design work, the second draft of the MacDQOL was tested in a > postal pilot
study (Mitchell and Bradley, 2004). The questionnaire was sent to 65 randomly selected members
of the MDS who had indicated in previous research (Mitchell et al., 2002) a willingness to
participate in future work. Forty-seven people responded. Further changes followed this study
and a small number of people (N = 5) completed a third draft during a trial of an electronic data
collection system. Data from the postal pilot and the electronic data collection trial were
combined with those obtained from the design phase focus groups to give a total of 69 respon-
dents (52 women, 17 men [sex unspecified for one person], mean age 76.6, SD 12.2). Fifty-two
people had MD in both eyes and 11 had only one eye affected (no data for 6 people). Twenty-eight
people were registered blind, 18 were partially-sighted and 16 were not registered (no data for 7
people). The data were used to investigate face, content and construct validity.
4.2 Nottingham Validation Study
A longitudinal study was carried out to investigate the > psychometric properties of the
MacDQOL (Mitchell et al., 2005). Participants with MD were recruited from a Nottingham
consultant’s patient list (99 women, 57 men, mean age 78.96 years, 150 people [96.2%] had
MD in both eyes, 6 people [3.8%] had it in one eye only). Participants took part in a telephone
interview during which they completed the MacDQOL. Within 14 days of the interview they
underwent a vision assessment. The vision assessment included measurement of monocular
and binocular distance visual acuity (VA), near VA, contrast sensitivity and comfortable
VA. Comfortable VA was computed from the time taken to read script of different sizes of
print. Time taken to read each line was recorded. When the time to read a line increased
substantially, this showed that it was no longer ‘‘comfortable’’ to read that size print and
smaller print. Presence of distortion or > scotoma in the central 10 degrees of vision was also
investigated for monocular and binocular vision. Color vision and recovery from glare were
assessed for binocular vision only. The MacDQOL interview and vision assessment were
repeated one year later (N = 135). Baseline data were used to investigate scale structure,
internal consistency reliability and construct validity. Baseline and follow-up data were used to
investigate test-retest reliability and responsiveness (Mitchell et al., 2008).
5 Psychometric Development
5.1 Factor Structure
Baseline data from the Nottingham study were used to investigate factor structure. Principal
components analysis yielded a 4-factor structure but six items double loaded and the factors
were not conceptually distinct. In a forced 1-factor solution all items except work and finances
loaded well (>0.4). Work was only applicable to three people but those for whom it was
applicable reported a high negative impact. The item was removed from the scale but retained
in the questionnaire to be scored separately. Finances had the lowest weighted impact score of
all the remaining 22 items. However negative impact was reported by 35 (23%) participants
and only nine (5.8%) thought it was not at all important. Finances was retained because it is
likely to be of particular relevance to people (whether in the UK or elsewhere) who have to pay
for treatment. In the forced 1-factor solution finances loaded at 0.356 and 49% of the variance
was explained (Mitchell et al., 2005).
In an international study to investigate the factor structure and properties of the
MacDQOL, Berdeaux et al. (Berdeaux et al., 2006) combined MacDQOL data from an
international clinical trial and a cross-sectional survey. In principal components analysis
four factors were elicited, all with Cronbach alpha > 0.8: (1) essential tasks, (2) family/social
life, (3) activities and capabilities, (4) embarrassment. The item finances did not load well on
to any of the factors and detracted slightly from the alpha in the subscale embarrassment.
Further research is needed to establish whether stable MacDQOL subscales can be elicited in
future samples. Subscales, including those demonstrated by Berdeaux et al. (2006) would be
valuable in evaluating rehabilitation needs, where they may indicate the need for practical low
vision rehabilitation and/or psychological intervention.
5.2 Internal Consistency Reliability
Several items in the MacDQOL have a ‘‘not applicable’’ (N/A) option and these result in
significant amounts of missing data in those items. For the purposes of internal consistency
reliability analysis, those missing data were recoded as zero to maximize the number of cases
included in the analysis. Under those conditions (with an overall N of 151 completed
questionnaires, 94 of which had missing data recoded as zero) Cronbach’s alpha coefficient
of internal consistency reliability was 0.944 which is highly satisfactory. When the analysis was
repeated with N/A items recorded as missing, Cronbach’s alpha was 0.946 (N = 62). In both
cases, only finances detracted marginally from the reliability, by 0.012 in each case. The pattern
of results was similar for both methods of dealing with N/A items (Mitchell et al., 2005).
5.3 Test-retest Reliability
MacDQOL data were collected on two occasions, one year apart (Mitchell et al., 2008). Among
participants whose visual acuity had changed by <0.2 logMAR during that period (N = 87),
AWI scores were highly correlated (r = 0.946). There were no differences in scores between
time 1 and time 2 (t = 0.19, df 86, p = 0.85). The findings indicate excellent test-retest
reliability for the MacDQOL.
5.4 Face and Content Validity
The design methodology, in particular the contributions of people with MD during the early
design stages ensured the > face validity of the measure (Mitchell and Bradley, 2004).
Following the Nottingham study in which the MacDQOL was completed on two occasions
(Mitchell et al., 2005), no new domains were identified that were not already included in the
MacDQOL (as evidenced by responses to the final, open question).
In the Nottingham study, at baseline the full range of scoring options for impact was used
in four domains and all options except +1 (indicating a positive impact of MD on QOL) were
used in all remaining items except work, which was an applicable domain for only three
people. The full range of importance scores were used in all domains except work and close
personal relationship where there were no scores of zero (which would indicate that the
domain was not at all important for QOL).
The findings suggest that the measure has good > content validity. The wide individual
variation in scores of impact and of importance for the items in the measure confirms that an
individualized measure is needed.
> Figure 14-2 shows the weighted impact scores of the 23 items in the MacDQOL
(Nottingham study follow-up data). Work shows the highest negative impact, followed by
independence, leisure and personal affairs.
. Figure 14-2
Weighted impact scores of MacDQOL items. Weighted impact score = impact of MD on aspect of
life X importance of aspect of life to quality of life
5.5 Concurrent Validity
There is no information on concurrent validity because there is no other appropriate measure

of the impact of MD on QOL that can be used to assess concurrent validity. A number of
measures are claimed to be measures of QOL for visually impaired people but they would
more appropriately be termed measures of vision function e.g. NEI-VFQ 25 (Mangione et al.,
2001), LVQOL (Wolffsohn and Cochrane, 2000).
In the postal pilot study (Mitchell and Bradley, 2004), construct validity was investigated by
comparing the scores of the MacDQOL overview items and the AWI scores of people who were
registered blind, registered partially-sighted and not registered. There were significant differ-
ences in the AWI scores between the not registered and both the blind and the partially-sighted
groups (> Table 14-2) but not between the blind and the partially-sighted groups. The two
overview items were found to be less sensitive than the AWI score (> Table 14-2). They did,
. Table 14-2
Results of Kruskal-Wallis tests comparing QOL scores of people registered blind, partially-sighted
and not registered and post hoc comparisons: mean differences in average weighted impact
scores, MD-specific QOL overview item scores and generic present QOL overview item scores
Kruskal-Wallis test Mann Whitney post hoc comparisons

Mann
Chi-square, N, df & Vision Comparison Mean Whitney
QOL measure p-value Category categories difference value
Present QOL chi2 = 7.81, N = 61, not registered blind 1.14 70.0**
overview item df = 2, p < 0.05 p/s 0.42 157
Blind p/s 0.72 176.0
MD-specific chi2 = 9.36, N = 61, not registered blind 0.81 70.0**
overview item df = 2, p < 0.01 p/s 0.66 123.5*
Blind p/s 0.15 221.5
Average chi2 = 14.03, N = 62, not registered blind 2.66 52.0***
weighted impact df = 2, p < 0.001 p/s 2.34 86.0***
score
Blind p/s 0.32 226.5
Average weighted impact score: lower score = greater negative impact of MD on QOL. The MacDQOL scores
distinguished between not registered and blind and between not registered and partially sighted but not
between blind and partially sighted participants
*p < 0.05, **p < 0.01, ***p < 0.001, N = number of cases; df = degrees of freedom; p/s = registered partially-
sighted. Table reproduced with kind permission of Springer Science and Business Media.
however, indicate the same differences that were shown using the AWI score, with the
exception of the comparison of not registered and partially-sighted groups using the generic
present QOL overview item. In this instance the difference was non-significant, whereas the
MD-specific overview item scores and the AWI scores showed significant differences between
the two groups. As expected, the AWI was correlated more highly with the MD-specific
overview item (r = 0.688, p < 0.01) than with the present QOL overview item (r = 0.541,
p < 0.01) though both associations were significant.
In the Nottingham study (Mitchell et al., 2005) construct validity was investigated by
correlation of MacDQOL scores with a number of measures of vision (> Table 14-3). Where
appropriate, measures of vision in the better eye, worse eye and with binocular vision were
compared with the MacDQOL. It is usual for stronger correlations to be found with the better
eye and binocular vision, as vision function depends more highly on the better eye than the
worse eye.
. Table 14-3
Correlations (Spearman’s r) between MacDQOL outcome variables and vision measures
Present MD-specific
QOL p-value QOL p-value AWI p-value
Distance VA better 0.301 <0.001* 0.310 <0.001* 0.431 <0.001*
eye
worse 0.229 0.004 0.258 0.001* 0.350 <0.001*
eye
binocular 0.292 <0.001* 0.311 <0.001* 0.419 <0.001*
Near VA better 0.327 <0.001* 0.192 0.017 0.326 <0.001*
eye
worse 0.140 >0.05 0.214 0.008 0.226 0.001*
eye
binocular 0.220 0.006 0.157 0.05 0.326 <0.001*
Contrast better 0.200 0.012 0.300 0.001* 0.392 <0.001*
eye
Sensitivity worse 0.064 >0.05 0.305 <0.001* 0.266 0.001*
eye
binocular 0.246 0.002 0.322 <0.001* 0.423 <0.001*
Color vision binocular 0.204 0.011 0.291 <0.001* 0.417 <0.001*
Comfortable VA binocular 0.207 0.012 0.121 >0.05 0.283 <0.001*
Recovery from binocular 0.069 >0.05 0.010 >0.05 0.022 >0.05
glare
Present QOL overview item: higher score = better QOL. MD-specific QOL overview item: lower score = greater
negative impact of MD on QOL. AWI (average weighted impact score): lower score = greater negative impact of
MD on QOL. Poorer MacDQOL scores were associated with poorer scores of most clinical measures of vision. VA¼
visual acuity
*Correlations were still significant after correcting for the possibility of chance associations due to multiple
correlational analyses (Bonferroni correction)
To control for the possibility of family wise error with 36 correlations, a Bonferroni
correction was applied (p < 0.00138 accepted as significant). Thirty of the 36 correlations
indicated associations of poorer QOL with worse vision, with p-values of <0.05. Twenty-one
of these associations were still significant after correcting for family wise error. In most cases,
the AWI score correlated with vision measures more strongly than the two overview items and
correlations between MacDQOL variables and vision measures were generally stronger with
better-eye and binocular scores than with worse-eye scores, as expected. For near and distance
VA, the strongest correlations were with better-eye scores. Associations between contrast
sensitivity and MacDQOL variables were all significant except between contrast sensitivity
in each eye separately and present QOL if the Bonferroni correction is applied. Comfortable
VA and color recognition were not associated with present QOL if Bonferroni is applied and
comfortable VA was not associated with the MD-specific QOL overview item with or without
Bonferroni. None of the three MacDQOL variables was associated with recovery from glare
even without applying Bonferroni’s correction (> Table 14-3), neither were individual items,
such as holidays or get out and about.
Findings from both the postal pilot study and the Nottingham study indicate that the
MacDQOL has good construct validity, differentiating between levels of visual ability using a
number of measures of vision as well as registration status.
Test-retest and construct validity have been clearly illustrated in the postal pilot study and
the Nottingham study.
5.7 Responsiveness
When investigating the impact of treatment or rehabilitative interventions on QOL an

important quality in an outcome measure is its potential to detect change over time (respon-
siveness). The responsiveness of the MacDQOL was investigated in the Nottingham study
(Mitchell et al., 2008). Of 135 people who completed baseline and follow-up investigations, 35
experienced a deterioration in their distance VA of 0.2 logMAR (minimum clinically impor-
tant change (Bailey et al., 1991)) or more during the year. Correlational analysis indicated that
poorer QOL at follow-up, measured by the MacDQOL present QOL overview item, was
associated with deterioration in both the better eye and binocular distance VA (r = 0.29,
p = 0.001; r = 0.21, p = 0.016 respectively, N = 135). There was a positive correlation between
deterioration in the MacDQOL AWI score and deterioration in both binocular near VA and
reading speed (r = 0.20, p = 0.019; r = 0.18, p = 0.041 respectively, N = 135). These early
indications of the responsiveness of the MacDQOL are encouraging and this is reinforced by
the test-retest reliability which de Boer and colleagues (2004) assert is a prerequisite in a
responsive measure.
In the Berdeaux et al. (2007) study, the range of scores across different visual acuities was
greater in the MacDQOL than in the NEI-VFQ25, a well validated measure of vision function
(Mangione et al., 2001). This suggests that the MacDQOL may be more responsive to change
than the NEI-VFQ25.
Further evidence of the MacDQOL’s sensitivity to change will be sought in forthcoming
studies. The measure is now being adopted in a number of studies and this increase in use can
be expected to increase health professionals’ confidence in the MacDQOL.
5.8 Missing Data
The MacDQOL AWI can be computed despite some missing data. Missing data for up to half
the items can be tolerated without Cronbach’s alpha falling below 0.8. The AWI can be
calculated from the items for which responses have been given providing at least 11 items
have complete responses (Mitchell et al., 2005).
6 Weighting
The impact of weighting was investigated using data from the postal pilot study. Investigation
of the impact scores for each domain indicated that the greatest negative impact was reported
for work, followed by personal affairs and getting out and about. When the impact scores were
multiplied by importance scores to give weighted impact scores the rank order of domains
changed for 12 out of the 22 domains. Scrutiny of the raw data revealed that impact and
importance scores were often the same other than when either score was zero. Correlations
between impact and importance scores ranged between 0.195 (personal affairs) to 0.865
(future). When all cases with zero scores for either impact or importance were removed the
correlation between the impact score and the importance score was very high in all domains
(r 0.744) except work (r = 0.320). It was considered that a simpler use of the data, which
might yield equivalent results, would be to score as zero all impact scores with a corresponding
importance rating of zero and then analyze the impact scores rather than the product of
importance and impact scores. This procedure was carried out for all domains. Using this
method the rank order of domains remained the same as unweighted impact scores except that
the positions were reversed in two pairs of domains (shopping and leisure; future and friends
and social life). The findings suggested that weighting does refine the measure, particularly
when the full range of importance ratings is used, as was the case in 14 of the 22 domains. The
fact that, in the postal pilot study, only three item means remained in the same rank order of
impact once importance ratings had been incorporated shows that incorporating importance
scores has a noticeable effect on QOL domain scores even at the level of group means and
individual scores are even more markedly affected by weighting with importance scores. Such
refinement is a characteristic of multi-criteria decision making (Nobre et al., 1999) and is
particularly valuable when the full range of importance ratings is used. The inclusion of ‘‘not
applicable’’ options for some domains further enhances the individualized nature and accept-
ability of the measure.
7 Equivalence of Completion Methods
Although the MacDQOL is designed for completion by visually impaired people, 20–25% of
people with MD are unable to read at all, even with low vision aids (data from UK Macular
Disease Society). They would, therefore, be unable to complete the MacDQOL without help
and, in a research study, assistance would need to be provided or the sample would be biased,
with only the less visually impaired people completing the questionnaire.
Self-completion, telephone interview and face-to-face interview are commonly used
methods of questionnaire implementation. Since self-completion of questionnaires received
by post is the cheapest administration method it would be advantageous if this method
produced equivalent results to more expensive interviewer-based methods. More than one
implementation method could then be used in the same study. Some vision-related ques-
tionnaires have been shown to yield different scores from self-completion and interview
(Wolffsohn et al., 2000; Frost et al., 2001) but others show no differences (Mangione et al.,
1992). A study was carried out to investigate the equivalence of MacDQOL scores obtained
by self-completion and telephone interview (Mitchell et al., 2004). Participants (N = 127,
100 women, 27 men, mean age = 78.22) were recruited at MDS local group meetings. They
were randomized to experimental subgroups (self-completion [paper] at time 1 then
telephone interview at time 2, one month later, or vice versa) or control group (self-comple-
tion twice). At time 1, there were no differences in MacDQOL AWI scores between the three
groups, (p > 0.05). At time 2 there were differences in AWI scores between groups (F (2,
124) = 3.39, p = 0.037). Mean AWI scores of the telephone/paper subgroup showed increased
negative impact of MD on QOL at follow-up than did those of the paper/telephone subgroup
(p = 0.016) and control group (p = 0.036). There was an interaction between time and
completion method (F (1,62) = 21.37, p < 0.001) showing that self-completion elicited scores
indicating greater negative impact of MD on QOL at time 2 compared with interview elicited
scores at time 1 (> Figure 14-3).
. Figure 14-3
Mixed model ANOVA: comparison of paper and telephone interview AWI scores at time 1 and
time 2 (experimental subgroups only). AWI average weighted impact score (sum of all applicable
weighted impact scores divided by number of applicable items). Paper/telephone: questionnaire
completed using pen and paper at time 1 and by telephone interview at time 2.
Telephone/paper: questionnaire completed by telephone interview at time 1 and using pen
and paper at time 2
It may be that the interview experience was pleasant, causing respondents to view their
situation more favorably, or that there was some social desirability bias in responding
(Oppenheim, 1968). Alternatively, telephone interviewees may have wanted to be seen to be
coping well with their condition (Wolffsohn et al., 2000). It is likely that self-completion is a
difficult and slow task for visually impaired people, particularly those with more severe
impairment. Responses may thus be negatively biased because of the effort of responding by
this method (Wolffsohn et al., 2000). The authors concluded that completion methods should
ideally not be mixed in one study. If participants self-completed at time 1 and had a telephone
interview at time 2 because their vision had deteriorated, completion method bias could lead
to under-reporting of negative impact of MD on QOL at time 2 and possibly mask a real
difference in QOL due to severity of MD.
8 Acceptability and Respondent Burden
The MacDQOL takes 10 to 20 minutes to self-complete, depending on reading speed, and

15–20 minutes to complete by interview. Studies using the MacDQOL have all had good
response rates and few missing data (99.8% completion rate for participants in the baseline
phase of the Nottingham study), suggesting that respondents do not experience significant
difficulty in completing the measure. In the longitudinal study only two participants declined
to take part at follow-up without giving a reason such as poor health or spouse’s poor health.
Participants’ willingness to complete the measure a second time and very low levels of missing
data in any studies attest to the measure’s acceptability.
9 Studies Using the MacDQOL
The MacDQOL has been used in a clinical trial of anecortave, a treatment for wet MD (Covert
et al., 2007) and it is to be used in a forthcoming UK National trial (the IVAN trial) comparing
two treatments and two treatment regimens for wet MD. The measure is being used to evaluate
programmes to train people with MD in eccentric viewing and steady eye skills. The increase
in use can be expected to increase health professionals’ confidence in the MacDQOL.
10 Availability in Multiple Languages
The MacDQOL is currently available in 17 languages. These language versions have been
translated and rigorously linguistically validated by Mapi Research Institute in collaboration
with the Royal Holloway team using gold standard procedures.
11 Conclusion
The MacDQOL is an individualized measure of the impact of MD on QOL that has good face
and content validity. It has excellent internal consistency and test-retest reliability. There is
good evidence of construct validity and encouraging indications of responsiveness. Findings
from studies using the MacDQOL show that macular degeneration has a considerable negative
impact on the QOL of people who have the condition and that the impact increases with
increasing severity of MD.
The MacDQOL, as with the ADDQOL and other related QOL instruments designed by
the Royal Holloway team, will remain under scrutiny and will be further refined if it is felt
to be necessary.
12 Use of the MacDQOL
For access to and license to use the MacDQOL contact the copyright holder, Professor Clare
Bradley. Email:c.bradley@rhul.ac.uk.
Summary Points
The MacDQOL is an individualized measure of the impact of macular disease (MD) on

quality of life (QOL). MD is a chronic, progressive eye condition that mainly affects people
over the age of 50. MD causes loss of central vision.
During the design of the measure the researchers talked to people with MD to elicit their
views on the ways in which MD impacted on QOL to ensure that all potentially important
and impacted aspects of life were investigated by the measure.
The MacDQOL has been psychometrically validated and studies have shown that it has
good psychometric properties and is a reliable and valid measure that can confidently be
used in clinical trials and other research where investigators wish to measure the impact of
MD on QOL.
The MacDQOL can detect differences in reported QOL due to differing severity of MD
and there is evidence that it is sensitive to changes in vision over time. These qualities are
important in evaluating medical or rehabilitative interventions.
When vision remains stable over time, MacDQOL scores remain unchanged, so it can
reliably be used in longitudinal studies.
There is some evidence that using different completion methods (pen and paper and
telephone interview) may yield different results, with less negative impact of MD on QOL
reported during telephone interviews. It would be best for only one administration
method to be used in any study.
The MacDQOL is currently linguistically validated in 17 languages.
References
Bailey IL, Bullimore MA, Raasch TW, Taylor HR. (1991). Covert D, Berdeaux G, Mitchell J, Bradley C, Barnes R.
Invest Ophthalmol Vis Sci. 32: 422–432. (2007). Surv Ophthalmol. 52: S20–S25.
Berdeaux G, Mesbah M, Bradley C. (2006). Value Health. DAFNE Study Group. (2002). BMJ. 325: 746–749.
9: A372–A373. de Boer MR, Moll AC, de Vet HC, Terwee CB, Volker-
Bradley C. (1997). Adv Perit Dial. 13: 116–120. Dieben HJ, van Rens GH. (2004). Ophthalmic
Bradley C. (2001). Lancet. 357(9249): 7–8. Physiol Opt. 24: 257–273.
Bradley C, Speight J. (2002). Diabetes Metab Res Rev. 18 Friedman DS, O’Colmain BJ, Munoz B, Tomany SC,
Suppl 3: S64–69. McCarty C, de Jong PT, et al. (2004). Arch Ophthal-
Bradley C, Todd C, Gorton T, Symonds E, Martin A, mol. 122: 564–572.
Plowright R. (1999). Qual Life Res. 8: 79–91. Frost NA, Sparrow JM, Hopper CD, Peters TJ. (2001).
Brose L, Watkins J, Bradley C. (2007). 2007 International Ophthalmic Epidemiol. 8: 1–11.
Society for Quality of Life Research meeting Gill TM, Feinstein AR. (1994). JAMA. 272: 619–626.
abstracts (www.isoqol.org/2007mtgabstracts). The Joyce CRB. (1994). In: McGee HM, Bradley C (eds.).
QLR Journal. A-60, Abstract 1198. Quality of Life Following Renal Failure: Psychoso-
Chisholm IH. (1998). Optom Today. August 1998: 39–42. cial Challenges Accompanying High Technology
Medicine. Harwood Academic, Chur, Switzerland, Nobre F, Trotta L, Gomes L. (1999). Stat Med. 18:
pp. 43–54. 3345–3354.
Kaiser PK, Do DV. (2007). Int J Clin Pract. 61: 501–509. Oppenheim A. (1968). Questionnaire Design and
Kinmonth AL, Woodcock A, Griffin S, Spiegal N, Attitude Measurement. Heinemann Educational,
Campbell MJ. (1998). BMJ. 317: 1202–1208. London.
Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Owen CG, Fletcher AE, Donoghue M, Rudnicka AR.
Berry S, Hays RD. (2001). Arch Ophthalmol. 119: (2003). Br J Ophthalmol. 87: 312–317.
1050–1058. Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajase-
Mangione CM, Phillips RS, Seddon JM, Lawrence MG, garam R, Pokharel GP, et al. (2004). Bull World
Cook EF, Dailey R, et al. (1992). Med Care. 30: Health Org. 82: 844–851.
1111–1126. Ruta DA, Garratt AM, Russell IT. (1999). Qual Health
McGee HM, O’Boyle CA, Hickey A, O’Malley K, Joyce Care. 8: 22–29.
CR. (1991). Psychol Med. 21: 749–759. Speight J, Amiel S, Bradley C, Heller S, James P, Oliver L,
McMillan C, Bradley C, Razvi S, Weaver J. (2008). Value et al. (2007). Diabetic Med. 24(Suppl 1): 95, 224.
Health. 11(2): 285–294. Speight J, Woodcock A, Plowright R, Bradley C. (2003).
McMillan CV, Bradley C, Gibney J, Russell-Jones DL, Qual Life Res. 12: 863.
Sonksen PH. (2006). J Eval Clin Pract. 12: 501–514. Wee HL, Tan CE, Goh SY, Li SC. (2006). Pharmacoeco-
McMillan CV, Bradley C, Giannoulis M, Martin F, nomics. 24: 673–682.
Sonksen PH. (2003). Health Qual Life Outcomes, WHO. (2004). Magnitude and causes of visual
1: 51. impairment. Available at: http://www.who.int/
McMillan CV, Honeyford RJ, Datta J, Madge NJ, Bradley mediacentre/factsheets.fs282/en, retrieved on 12
C. (2004). Health Qual Life Outcomes. 2: 61. March, 2006.
Mitchell J, Bradley C. (2004). Qual Life Res. 13: Wilson RJ, Christie MJ, Bradley C. (1998). Diabetic Med.
1163–1175. 15(Suppl 2): 122–123.
Mitchell J, Bradley P, Anderson SJ, ffytche T, Bradley C. Wolffsohn JS, Cochrane AL. (2000). Am J Ophthalmol.
(2002). Br J Ophthalmol. 86: 777–781. 130: 793–802.
Mitchell J, Wolffsohn JS, Woodcock A, Anderson SJ, Wolffsohn JS, Cochrane AL, Watt NA. (2000). Br J
ffytche T, Rubinstein M, et al. (2008). Am J Ophthalmol. 84: 1035–1040.
Ophthalmol, 146: 447–454. Woodcock A, Bradley C, Plowright R, ffytche T,
Mitchell J, Wolffsohn JS, Woodcock A, Anderson SJ, Kennedy-Martin T, Hirsch A. (2004). Patient Educ
McMillan CV, ffytche T, et al. (2005). Health Qual Couns. 53: 365–383.
Life Outcomes. 3: 25. Woodcock AJ, Julious SA, Kinmonth AL, Campbell MJ.
Mitchell J, Woodcock A, Bradley C. (2004). Qual Life (2001). Qual Life Res. 10: 661–670.
Res, 13: 1548 (abstract).
National Statistics Online. (2004). Population Estimates.
Available at: http://www.statistics.gov.uk/CCI/nug
get.asp?ID¼6.
15 Development and
Assessment of Chinese
General Quality of Life
Instrument
Y. Wu . G. Xie
1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
2 Development of the Chinese QOL-35 Instrument . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
3 Scoring for Chinese QOL-35 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
4 Reproducibility of Chinese QOL-35 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
5 Comparison of Chinese QOL-35 with WHO-QOL-100 and SF-36 . . . . . . . . . . . . . . 272

5.1 Internal Consistency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
5.2 Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
5.2.1 Construct Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
5.2.2 Criterion Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
6 Application and Re-Evaluation of QOL-35 in a Chinese

General Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
6.1 Internal Consistency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
6.2 Construct Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
6.3 Discriminatory Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
7 Considerations When Using the Chinese QOL-35 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
Appendix 1: Chinese Quality of Life 35-Items Questionnaire . . . . . . . . . . . . . . . . . . . 278
Appendix 2: Standard scores for each option of answers to

Chinese QOLtems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

266 15 Development and Assessment of Chinese General Quality of Life Instrument
Abstract: The measurements of quality of life have been increasingly studied and gradually
accepted as an important measure of health in many countries of the world since the 1960s. In
China, quality of life studies begun in the 1980s. A few general quality of life questionnaires
were translated into the Chinese language, such as 100-Item World Health Organization
Quality of Life Instrument (WHO-QOL-100) and the 36-Item Medical Outcomes Study
Short-Form Health Status Survey (SF-36). However, the sensitivity of the WHO-QOL-100
was not satisfactory for the Chinese population, while the SF-36 focused on measuring health
status and does not include all facets of quality of life. Considering the great differences in
culture and living habits between eastern and western populations, we carried out a series of
studies to develop a general quality of life instrument (Chinese QOL-35), which included 35
items and is well in accordance with the habits of Chinese language, culture, and daily life. This
article presents the development and evaluation of the Chinese QOL-35 with its reliability,
validity and sensitivity, in comparison with Chinese version of WHO-QOL-100 and SF-36.
List of Abbreviations: Chinese QOL-35, > Chinese Quality of Life Measurement Form – 35
Items; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer
Quality of Life Core Questionnaire 30; IIC, > Item-internal consistency; ICC, > intra-class
correlation coefficients; QOL, Quality of life; WHO-QOL-100, 100-Item World Health Orga-
nization Quality of Life Instrument; SF-36, 36-Item Medical Outcome Study Short Form
Health Status Survey
1 Background
Since the 1950s, chronic diseases, such as cardiovascular disease, cancer and chronic respira-
tory disease, etc., have been the leading causes of death in the world. In related medical studies,
the impact of these diseases and the effect of treatment on patients were often assessed by just
using rates of the disease such as mortality, incidence and prevalence. However a large
proportion of effected individuals would survive these diseases with great variability in their
disability and pain (either mental or physical) making reporting only rates of disease ineffec-
tive. Moreover, the concept of health had changed largely with the changes in disease pattern.
According to the definition of health by the World Health Organization (WHO), health is a
state of complete physical, mental and social well-being and not merely the absence of disease
or infirmity (WHO, 2006). The concept and assessment of quality of life was introduced in the
1930s, developed rapidly through the 1950 and 60s, and widely applied in the medical field
after 1970. A series of instruments were developed, including the Sickness Impact Profile,
Nottingham Health Profile and Medical Outcome Study 36-Item Short Form-36 (SF-36).
Although these instruments were often described as quality of life measures, their authors did
not design or call them as such. In 1991, WHO organized a study group on quality of life
(WHOQOL Group, 1993)and by 1993, they defined quality of life as an individual’s percep-
tion of their position in life in the context of the culture and value systems in which they live
and in relation to their goals, expectations, standards and concerns (WHO, 1993). In 1995, the
World Health Organization QOL Questionnaire (WHO-QOL-100) was developed (WHO,
1993). A Chinese translation of the WHO-QOL-100 was verified according to the protocol
recommended by WHO, between 1995 and 1996 (Fang, 2000). In 2003, the Chinese version of
the SF-36 was verified in China (Li et al., 2003). However, these questionnaires did not satisfy
sensitivity and validity in assessing quality of life in the Chinese population (Fang, 2000;
Development and Assessment of Chinese General Quality of Life Instrument 15 267
Li et al., 2003), which may be due to cultural differences and living habits of people in China
compared to western countries.
Recently, the Chinese health scientist community has become increasingly interested in
quality of life measures. Besides the wide use of QOL measures in patients in clinical trials,
there is also a strong need to include these measures in large population-based observational
and experimental studies, because they generate evidence directly linked to policy for popula-
tion health. Thus, an appropriate instrument for measuring quality of life among general
Chinese populations was urgently needed. This article describes the rationale and process of
developing the Chinese Quality of Life 35 Item (Chinese QOL-35) instrument and its evalua-
tion and verification.
2 Development of the Chinese QOL-35 Instrument
First, we established a quality of life study group of 5 researchers with backgrounds in

epidemiology, clinical medicine, biostatistics, and sociology. After reviewing a large number
of instruments that had been used to assess quality of life in western general population,
including WHO-QOL-100 (WHO, 2006; WHO, 1993; Fang, 2000; WHOQOL Group, 1998),
SF-36 (Li et al., 2003; Hopman et al., 2000; Ware and Shebourne, 1992) and the European
Organization for Research and Treatment of Cancer QLQ-C30(EORTC QLQ-C30) (Hunt
and McEwen, 1980), the study group came to the conclusion that a Chinese quality
of life instrument should be multi-facet and include six domains: general, independence,
physical, psychological, social, and environmental plus one single item on the changes of
quality of life in the last year, which is not included in the final scoring. We extracted the
common items from WHO-QOL-100 and SF-36 and added in 4 new items. The new items
included satisfaction of living ability, relationship with relatives and friends, relationship with
colleagues and bosses, and the changes of quality of life in the last year (Li et al., 2003;
WHOQOL Group, 1998; Hopman et al., 2000; Ware and Shebourne, 1992; Appendix, 2000).
The way of asking questions and the options of the answer to the questions were modified
and compiled to fit in with culture, linguistics and habits of Chinese people in their daily
life. After this process, a total of 32 items were determined and formed the first version of
the instrument.
The first pre-test was carried out among 30 participants in a Beijing community, where
participants were asked what they thought the most important contents of quality of life
are. According to the results, we added 8 items into the instrument to form the second version
(40-items). The second pre-test was carried out among 36 participants in the same Beijing
community with the same questions. We then combined 10 out of the 40 items into 5 items to
form the final version that included only 35 Items (See the appendix 1). The six domains in
Chinese QOL-35 are described below:
> General domain: Many quality of life instruments include assessment of general health
status and/or general quality of life (Hunt and McEwen, 1980). Thus, two items, one for each,
assessing general health status and general quality of life in the last month were included to
constitute general domain.
> Physical domain: This domain is used to assess physical health which usually includes
body pain, sleep quality, appetite and fatigue. Five items were included: physical pain or
discomfort to any part of the body during the last month; whether that pain or discomfort
interfered with normal life during the last month; appetite during the past month; difficulty in
sleeping during the last month; and fatigue/tiredness during the last month. Body pain is an
important indicator of physical function, which is included in many quality of life instruments
such as Nottingham Health Profile (Appendix, 2000; Hunt et al., 1985), SF-36 (Li et al., 2003;
Ware and Shebourne, 1992; Ware, 2000), WHO-QOL-100 (WHO, 2006; WHO, 1993;
WHOQOL Group, 1998), EURoQoL(EQ-5D) (Asher et al., 2003), EORTC QLQ-C30)
(Hunt and McEwen, 1980). Appetite is also an important facet of physical function even
though it has not been included in many quality of life instruments such as SF-36, English
version of WHO-QOL-100 and EQ-5D. Sleep and fatigue are also important indicators
of physical function and have been included in EORTC QLQ-C30 (Hunt and McEwan,
1980; Fayers et al., 2001).
> Independence domain: This domain is used to assess the ability to live independent-
ly, such as needing medical interventions and physical activity status which are considered
to be the most important indicators of quality of life. The independence domain contains
12 items. Ten items directly identify the individual’s ability to participate in physical
activities of their daily life during the last month. These include difficulties conducting
heavy physical activities, moderate physical activities, lifting daily necessities, climbing
several flights of stairs, climbing one flight of stairs, bending/kneeling/stooping, walking
three miles, walking one or two miles, walking around house and bathing or dressing. The
other two items included in this domain indirectly measure physical ability. One identifies
the need for medicines or treatment in an individual’s daily life during the last month, and
the other identifies his/her satisfaction in independent living ability during the last month.
The ten direct items on physical activities were derived from SF-36 (Li et al., 2003; Ware
and Shebourne, 1992; Ware, 2000) and revised so that they are more reflective to physical
activity habit for Chinese population. The other two indirect items were derived from
WHO-QOL-100.
> Psychological domain: This domain is used to assess the quality of life in psycholo-
gical health, such as affective states (feeling happy, optimistic, satisfied, and interested in life,
in contrast to feeling negative, anxious, or depressed), memory, and attention span. Six items
were included: self-confidence; living pleasure; nervousness; negative feeling (downhearted,
despaired, anxiety, melancholy); memory; and attention span. Among the 6 items, self-
confidence, living pleasure, memory and attention span are associated with positive psycho-
logical feeling, which are included in WHO-QOL-100 and other quality of life
measures (WHO, 2006; WHO, 1993; WHOQOL Group, 1998). Nervousness and nega-
tive feeling are associated with negative psychological feeling, which were also included
in many quality of life measures (WHO, 2006; WHO, 1993; WHOQOL Group, 1998;
Appendix, 2000).
> Social domain: This domain assesses quality of life by evaluating the individual’s ability
to accommodate to society, such as support from society, provision of support to society,

interpersonal relationships and loneliness. Five items were included: connections within
family, relative, friends and colleagues; help or support from your family members or friends
in your life during the past 1 month; help or support for your family members or
friends during the past 1 month; satisfaction with sex life during the past 1 month; loneliness
during the past 1 month.
> Environmental domain: This domain is used to assess quality of life by evaluating
environmental components, such as living conditions and financial status. Environmental

context was included in the QOL-35 because it has been shown to be important in the
evaluation of quality of life. Based on its relative importance in assessing quality of life, two
items were derived from WHO-QOL-100 (WHO, 2006; WHO, 1993; WHOQOL Group,
1998) but revised – financial status and condition of residence.
> Quality of life transition: In order to explore the change of quality of life recently, we
added a separate item by asking ‘‘Compared to 1 year ago, how would you rate your quality of
life now?’’ However, the score for quality of life transition was not added to any domain score
or total score.
3 Scoring for Chinese QOL-35

The difference among answer options of quality of life questions may not be equal to each
other. For example, the range between ‘‘very bad’’ and ‘‘bad’’ may not be equal to that between
‘‘bad’’ and ‘‘average’’ (Asher et al., 2003). In order to be able to add the score and make them
comparable, we conducted a survey on the response scale of each answer option among
43 men and 41 women aged 19–70 years in a community of Beijing. For example, participants
were asked to line out the position of ‘‘Bad’’ in the following line:
If the position of answer option ‘‘bad’’ is 2.5, the score for the option ‘‘bad’’ is 25 points for
that particular individual. We then took the median of the scores as the standard score for
option ‘‘bad’’. The inverse scores were transferred to positive scores by 10 minus the score.
Finally, the standard scores were multiplied by 10 and ranged from 0 to 100 points and are
positively associated with quality of life. A table summarizing all standard scores in accordance
with each answer options for each quality of life item in Chinese QOL-35 is provided (See
Appendix 2).
4 Reproducibility of Chinese QOL-35
In order to assess the > reproducibility of the Chinese QOL-35 questionnaire, 127 people were
randomly sampled from a residential district of Beijing. They were tested and retested on their
quality of life before and after an interval of at least 24 h. The characteristics of the 127
participants are outlined in > Table 15‐1. The reproducibility was evaluated by the consistency
of each item (proportion of participants whose answers were the same in test and retest among
all participants) and intra-group correlation coefficients of each domain and also the whole
instrument. Intra-group correlation coefficient was calculated by intra-group variance divided
by the sum of intra-group variance and variance due to retest.
The consistency of each item between test and retest was assessed by > Kappa (К) index,
which was calculated by the following formulas (Fayers PM and Machin D, 2000):
X X
pAgree ¼ xii =N and pChance ¼ ri ci =N 2
. Table 15‐1
Characteristics of participants in surveys for evaluation of Chinese QOL-35
Comparison with
WHO-QOL-100 and Re-assessment in a
Characteristics Test-retest survey SF-36 general population
N 127 135 1,356
Sample method Population-based convenience sample Population-based
two-stage cluster-randomized
random sample: first cluster sample
randomized and then
complete randomized
Men (%) 48 (37.80%) 62 (45.93%) 500 (36.87%)
Age SD (min– 55.87 7.80 (43–73) 50.50 11.04 56.58 8.23
max) (29–82) (43–73)
Educational level
Illiterate 15 (11.81%) 0 (0%) 228 (16.8%)
Primary school 41 (32.28%) 10 (7.41%) 443 (32.7%)
Middle school 67 (52.76%) 40 (29.63%) 614 (45.3%)
High school 4 (3.15%) 43 (31.85%) 58 (4.3%)
University (or 0 (0%) 42 (31.11%) 13 (1.0%)
college) and
above
Occupation
Administrator 2 (1.6) 24 (17.8) 21 (1.6)
Professional 6 (4.7) 42 (31.1) 70 (5.2)
Private business 3 (2.4) 10 (7.4) 51 (3.8)
owner
Manufacture 32 (25.2) 43 (32.6) 243 (18.0)
Laborer/clerk
Farmer 6 (4.7) 6 (4.4) 48 (3.5)
Retired/ 78 (61.4) 9 (6.7) 923 (68.1)
Housework/
unemployed
k ¼ ðpAgree pChance Þ=ð1 pChance Þ
Here, xii is the number of participants whose answers perfectly agree between test
and retest; N was the total number of participants; ri is the number of participants who
answer the ith option in first test; ci is the number of participants who answer the ith option in
retest. Pchance represents the proportion of chance agreement.
These equations give equal importance to any disagreement. Even though it is possible to
use this directly, it is generally more realistic to use a weighted form, such as Kweight. This takes
into account the level of disagreement, such that a difference between scores of 1 and 3 on the
two occasions would be considered of greater importance than the difference between 1 and 2.
Values that are off the diagonal in row i and column j are given scores or ‘‘weights’’ according
to their distance from the diagonal, which corresponds to their degree of discrepancy. Two
frequently used choices of weights are:

ji jj ij 2
wij ¼ 1 or wij ¼ 1 ;
g1 g1
In the above equation, g was the number of possible response categories; i was the response
category in the first test, and j was the response category in the retest.
The Kweight was calculated by the following formula:
!,
g X
X g
pwAgree ¼ wij xij N
i¼1 j¼1
!,
g X
X g
pwChance ¼ wij ri cj N2
i¼1 j¼1
k ¼ ðpwAgree pwChance Þ=ð1 pwChance Þ
The value of K is equal to 1 if there is perfect agreement, and equal to 0 if the agreement is no
better than chance. Negative values indicate an agreement that is even less than what would be
expected by chance. The criteria of very high agreement of test-retest surveys are indicated by a
Kappa index of more than 0.81(Fayers PM and Machin D, 2000). In our study, the Kappa index
for all items in Chinese QOL-35 was 0.86–1.00, compared with 0.39–1.00 for EuroQol EQ-5D in
66 patients during 2 weeks interval period (Fayers PM and Machin D, 2000); 0.60–0.80 for
OPTQoL in 200 women with a median interval of 17 days (Fayers PM and Machin D, 2000).
For continuous data, > intra-class correlation coefficients (ICC) were considered to be
more suitable for assessment of the reliability than correlation coefficients. The reason for this
is correlation is a measure of association, and repeated measurements may be highly correlated
yet systematically different (Konig et al., 2002). ICC was calculated by the following formula
(Fayers PM and Machin D, 2000):
ICC ¼ pðVsubject VError Þ

pVsubject þ rVRepeats þ ðp rÞVError
In the above equation, p is the number of subjects, r is the number of tests, V is mean squares
of standard deviation. If the ICC is close to 1, then the random error and variance due to
repeated tests are small and a high proportion of the variance in the observation is attributable to
variance between subjects. The measurements are then described as having high reliability.
For the Chinese QOL-35, ICC was 0.680–0.943 for six domains and 0.943 for the total
quality of life score. These results are similar to a study by (Bonomi, 2000) where ICC was
0.86–0.96 in the test-retest with a 2 week interval using WHO-QOL-100 among 443 adults.
Test-retest is used for assessment of the random variation of measuring quality of life. For a
good assessment, balancing the interval time between test and retest should be made. Interval
time should be short enough so that quality of life can not change significantly during this
period, and it should be long enough so that the participants memory of their answers to the
quality of life items are minimized as much as possible in the retest. Since there is not a
subjective way to measure the time balance, it is often decided arbitrarily. In fact, the interval
time has varied significantly in a range of studies that have considered health status and
feasibility of conducting test-retest in particular study populations (Li et al., 2003; QDS ). Our
test-retest interval time was 24–72 h which is shorter than most of the other studies but we
thought it fairly good for the reproducibility assessment.
5 Comparison of Chinese QOL-35 with WHO-QOL-100

and SF-36
Chinese QOL-35, WHO-QOL-100 and SF-36 were applied to 135 participants with a mini-
mum of primary school education selected from the residential community, hospital patients
and their family members. Self assessment method was employed and the three quality of life
instruments were given to the participants by a random sequential order decided before the
survey. > Internal consistency and validity were evaluated to compare Chinese QOL-35 with
WHO-QOL-100 and SF-36.
5.1 Internal Consistency
Internal consistency refers to the extent to which the items are interrelated (Fayers PM and
Machin D, 2000). Internal consistency was usually assessed by Cronbach’s Alpha, which is
calculated by the following formula (Fayers PM and Machin D, 2000):
P
m 1 Varðxi Þ
aCronbach ¼
m1 VarðSÞ
Here, Var(Xi) is the variance of the score for the ith item in the instrument, m is the
number of total items in the instrument (or in the domain), and S = S(xi).
Cronbach coefficient’s above 0.8 are defined as very good internal consistency. In our
study, Cronbach’s Alphas were 0.68–0.88 across domains for Chinese QOL-35, 0.83–0.93 for
WHO-QOL-100, and 0.35–0.89 for SF-36(P < .001) and for total for quality of life were 0.93,
0.97, and 0.89 respectively. Cronbach’s Alpha is a function of the average inter-item correlation
and the number of items in an instrument, and thus increases as either of these increases
(Fayers PM and Machin D, 2000). The Chinese QOL-35 has many items less than WHO-
QOL-100 and 1 item less than SF-36. We were satisfied with the Chinese QOL-35 internal
consistency because its Cronbach Alpha score was greater than that of SF-36 but lower than
the WHO-QOL-100.
5.2 Validity
Validity of an instrument is the degree to which the instrument measures what it is intended to
measure and how useful it is for its intended purpose (Chen et al., 2004). Validity of a quality of
life instrument should be evaluated by > construct validity, > criterion validity and discrimi-
natory validity.
5.2.1 Construct Validity
> Construct validity is one of the most important characteristics of a quality of life instru-
ment. It is an assessment of the degree to which an instrument measures the construct that it
was designed to measure.
> Item-internal consistency (IIC) coefficients, which are correlation coefficients between
scores for each item and its hypothesized domain, ranged from 0.11 to 0.93 for the Chinese
QOL-35 domains, 0.24–0.92 for WHO-QOL-100 domains, and 0.45–0.93 for SF-36 domains
among 135 participants (> Table 15‐2). 97.1, 98.0, and 100% of the items in Chinese QOL-35,
WHO-QOL-100, and SF-36 respectively, exceeded the minimum coefficients (0.4 require-
ment for this scaling criterion. Items are defined as good if the coefficient with its domain
scores are two standard error’s greater than the coefficients with other domain scores. Overall
91.2% for QOL-35, 67.2% for WHO-QOL-100, and 94.4% for SF-36 were defined as good
items. These results were similar to a study by Chen (2004) who found 90.5% of items were
good in a quality of life instrument conducted in young adults.
Seven factors selected by the Principal Components Factors Analysis as the principal factors
that composed the instruments could explain 66.5, 50.3 and 65.3% of the total variance of quality of
life measurement by Chinese QOL-35, WHO-QOL-100 and SF-36 respectively. Compared with
Chinese QOL-35, the variance of measurements for WHO-QOL-100 and SF-36 relied too much on
the first factor, and rapidly decreased from second to seventh factor. The contribution to variance
by the first factor was 10 and 9 times as that by the seventh factor in WHO-QOL-100 and SF-36.
However, the corresponding value was less than four times for QOL-35 (> Table 15‐3). Factorial
analyses showed that the cumulative % of variance from seven principal factors was higher for
Chinese QOL-35 than for WHO-QOL-100 and SF-36, while variances were distributed in the
seven components more equally for Chinese QOL-35 than for WHO-QOL-100 and SF-36.
Thus, we believe that Chinese QOL-35 has a higher satisfied construct validity.
5.2.2 Criterion Validity
> Criterion validity is assessing the degree to which an instrument is against the true value
of quality of life. Since quality of life measurement is a subjective feeling or experience by concept,
there is no true value or ‘‘gold standard’’ of quality of life. In practice, criterion validity is often
assessed against previous quality of life instruments that have been validated and widely accepted.
We assessed the criterion validity of Chinese QOL-35 against WHO-QOL-100 and SF-36.
In 135 participants, the Spearman correlation coefficients of total quality of life scores were
0.805 between Chinese QOL-35 and WHO-QOL-100 and 0.745 between Chinese QOL-35 and SF-
36. The Spearman correlation coefficients of domains of the Chinese QOL-35 with corresponding
domains of WHO-QOL-100 and SF-36 were 0.577–0.730 and 0.307–0.657 respectively. (See
> Table 60‐4) Hence we concluded that Chinese QOL-35 had satisfactory criterion validity.
6 Application and Re-Evaluation of QOL-35 in a Chinese

General Population
After the above validation was completed, the Chinese QOL-35 was applied in a
population-based sample of 1,356 Chinese men and women. > Table 15‐1 shows the features
of participants in the surveys. The purpose of this population-based survey was to re-assess the
internal consistency and discriminatory validity of Chinese QOL-35 instrument.
. Table 15‐2
Comparison of structure validity among Chinese QOL-35, WHO-QOL-100, and SF-36 in 135
participants
% for g with other % of good

Domains IICa IIC 0.4 domainsb itemsc
QOL-35 General 0.90–0.93 100 (2/2) 0.22–0.59 100 (10/10)
Physical 0.69–0.86 100 (5/5) 0.15–0.54 100 (25/25)
Independence 0.11–0.85 91.7 (11/12) 0.04–0.63 81.7 (49/60)
Psychological 0.69–0.79 100 (6/6) 0.14–0.56 100 (30/30)
Social 0.51–0.77 100 (7/7) 0.06–0.55 88.6 (31/35)
Environmental 0.85–0.89 100 (2/2) 0.13–0.49 100 (10/10)
Total 0.11–0.93 97.1 (33/34) 0.04–0.63 91.2 (155/170)
WHO-QOL- General 0.80–0.86 100 (4/4) 0.26–0.65 100 (24/24)
100
Physical 0.58–0.78 100 (12/12) 0.08–0.63 80.6 (58/72)
Independence 0.42–0.77 100 (16/16) 0.02–0.62 75.0 (72/96)
Psychological 0.48–0.69 100 (20/20) 0.07–0.57 46.7 (56/120)
Social 0.24–0.76 91.7 (11/12) 0.09–0.58 66.7 (48/72)
Environmental 0.39–0.71 96.9 (31/32) 0.02–0.62 66.1 (127/192)
Religious 0.59–0.92 100 (4/4) 0.11–0.61 75.0 (18/24)
Total 0.24–0.92 98 (98/100) 0.02–0.65 67.2 (403/600)
SF-36 Physical 0.58–0.80 100 (10/10) 0.03–0.51 95.7 (67/70)
function
Physical health 0.84–0.91 100 (4/4) 0.23–0.63 100 (28/28)
Bodily pain 0.91–0.93 100 (2/2) 0.35–0.66 100 (14/14)
General health 0.60–0.77 100 (5/5) 0.05–0.53 100 (35/35)
Vital 0.59–0.72 100 (4/4) 0.13–0.56 89.3 (25/28)
Social function 0.78–0.90 100 (2/2) 0.30–0.59 100 (14/14)
Mental role 0.87–0.89 100 (3/3) 0.29–0.60 100 (21/21)
Mental health 0.45–0.58 100 (5/5) 0.01–0.47 77.1 (27/35)
Total 0.45–0.93 100 (35/35) 0.01–0.66 94.4 (238/252)
a
Range of correlations between items and hypothesized domain corrected for overlap
"b
Range of correlations between items and other domains
c
Percentage of items whose correlation coefficients with their hypothesized domain were two standard errors
higher than those with other domains
6.1 Internal Consistency
Estimates of central tendency, disparity, and other characteristics of quality of life score
distribution are shown in > Tables 15-5 and > 15-6. Most domains had a negative skew,
with distributions showing a ‘‘pile-up’’ of respondents scoring at the positive pole of quality of
life. A mild ceiling effect was observed for the environmental domain (12.7%). Other ceiling
. Table 15‐3
The proportion of total variance attributed to principal component factors for WHO-QOL-100, SF-
36, and Chinese QOL-35 using factorial analyses (N = 135)
% of total variance distributed by principal component

factors
Instrument First Second Third Fourth Fifth Sixth Seventh Accumulated, %
QOL-35 18.1 12.5 9.3 8.5 6.9 6.3 4.9 66.5
WHO-QOL-100 27.1 5.5 5.3 3.4 3.2 2.9 2.7 50.3
SF-36 31.9 9.6 6.4 5.7 4.7 3.6 3.5 65.3
. Table 15-4
The Spearman correlation coefficients of each domain of Chinese QOL-35 with corresponding
domains of WHO-QOL-100 and SF-36
Domains WHO-QOL-100 SF-36

General 0.577 0.605
Physical 0.730 0.579
Independence 0.668 0.657
Psychological 0.633 0.535
Social 0.669 0.307
a
Environmental 0.587
a
quality of life transition 0.374b
Total 0.805 0.745
a
There was no item on quality of life transition in WHO-QOL-100 and no item on environmental domain in SF-36
b
Scores for quality of life transition in SF-36 were replaced by the scores for health status transition
. Table 15-5
The ceiling effect of Chinese QOL-35 among 1,356 participants
Statistics in score of quality of life

Domains Mean (SD) Range % Mina % Maxb 25th %tile 50th %tile 75th %tile
General 61.7 (19.4) 0.0–100.0 0.4 8.6 50.0 52.0 79.0
Physical 77.0 (18.2) 5.0–100.0 0.1 9.0 65.6 81.4 91.6
Independence 85.9 (15.4) 0.0–100.0 0.1 6.7 81.5 90.8 95.9
Psychological 69.3 (17.3) 0.0–100.0 0.1 2.8 58.4 71.3 81.2
Social 75.7 (16.1) 7.1–100.0 0.1 6.3 64.3 76.6 89.6
Environmental 65.6 (20.4) 0.0–100.0 0.2 12.7 50.0 64.5 79.0
Total 76.9 (12.1) 16.4–100.0 0.1 0.1 70.7 78.7 85.5
a
The proportion of those with min score
b
The proportion of those with max score
effects were less than 10%. Floor effects were negligible for all domains of QOL-35. Cronbach’s
a for the QOL-35 ranged from 0.88 for independence domain to 0.71 for environmental
domain; mean a was 0.72.
Construct validity was reassessed using principle components analyses. About 59.4% of the
total variance could be contributed by the seven selected principle factors, which was close to
66.5% in the small sample (135 participants). So the construct validity is considered stable for
the Chinese QOL-35 (see the > Tables 15‐3 and > 15‐7).
6.3 Discriminatory Validity
Discriminatory validity, also named known-groups validity or sensitivity, is based on the

principle that certain specified groups of patients may be anticipated to score differently from
others, and the instrument should be sensitive to these differences. The prevalence of several
. Table 15-6
The Cronbach Alpha of Chinese QOL-35 in small and large samples
Domains Small sample (n = 135) Large sample (n = 1,356)

General 0.79 0.72
Physical 0.83 0.75
Independence 0.88 0.88
Psychological 0.83 0.74
Social 0.79 0.77
Environmental 0.68 0.71
Total 0.93 0.91
. Table 15‐7
The Variance explained by the seven principal components extracted from the items in Chinese
QOL-35 in 1,356 participants
Extraction sums of squared loadings

Principal component factors Total % of variance Cumulative %
1 9.263 27.243 27.243
2 3.989 11.732 38.974
3 2.089 6.145 45.119
4 1.405 4.132 49.251
5 1.222 3.595 52.846
6 1.155 3.397 56.244
7 1.072 3.153 59.397
Extraction method principal component analysis
. Table 15‐8
Prevalence rate of severe chronic diseases by quartiles of total quality of life score using Chinese
QOL-35 (Wu et al., 2005)
Quartiles Prevalence Rate of Diseases, %

of total
score of
quality of Respiratory Liver Endocrine
life N Total Stroke CHD symptoms disease Kidney Tumors disease
Quartile 1 339 53.1 8.8 9.4 26.3 6.2 8.6 8.6 3.8
Quartile 2 341 33.1 2.9 6.7 13.2 5.6 2.9 5.0 4.4
Quartile 3 337 26.4 3.3 4.5 11.3 3.0 1.5 4.7 1.5
Quartile 4 339 25.1 3.2 2.7 9.1 5.6 2.1 4.7 1.8
Z values – 7.86 3.25 3.98 6.14 0.82 4.52 2.07 2.24
for trend
test
P values – <0.001 0.001 <0.001 <0.001 0.414 <0.001 0.038 0.025
The total number of participants was 1,356
major diseases exhibited a significant decreasing trend with the quartiles of total quality of life
scores for Chinese QOL-35, indicating good discrimination validity.
The rate of stroke, coronary heart disease (angina diagnosed by Rose’s code and myocar-
dial infarction), chronic respiratory symptoms (chronic cough, phlegm, and asthma attack),
kidney disease, tumor, and endocrine disease significantly decreased as the quartile of total
quality of life score of the QOL-35 increased. (See > Table 15‐8.) Prevalence of all major
chronic diseases were 53.1%, 33.1%, 26.4% and 25.1% for quintile 1–4 respectively (P < 0.05).
7 Considerations When Using the Chinese QOL-35
The Chinese QOL-35 was designed as a self-assessed questionnaire for adults with a minimum
education of 5 years in primary school. Firstly, participants with a satisfactory educational
level can complete the Chinese QOL-35 by themselves. For those who can not finish it due to
illiteracy, the interviewers can verbally ask the participants the questions and complete the
Chinese QOL-35 according to their answers. For those who can not speak well due to their
illness, such as stroke patients can enlist their family or nurse to help them complete the
survey. Secondly, the scores should be allocated according to the standard scoring system in
Appendix 2. Thirdly, the score for each domain should be calculated as the mean of scores for
all items in the corresponding domain. And finally, the total score of quality of life is calculated
as the mean of all items not including the item of quality of life transition.
8 Conclusion
This article provides strong evidences to suggest that the Chinese QOL-35 instrument has been
demonstrated to have satisfactory reliability, validity, and acceptability, and could be used to
assess quality of life in the Chinese general population.
Summary Points
An appropriate instrument for measuring quality of life among general Chinese popula-
tions (Chinese QOL-35) was developed, which includes six domains: general, indepen-
dence, physical, psychological, social, environmental domains plus one single item on the
changes of quality of life in the past year.
The Chinese QOL-35 was designed as a self-assessed questionnaire for adults with a
minimum education of 5 years in primary school.
The Chinese QOL-35 was evaluated and compared with WHO-QOL-100 and SF-36.
Cronbach’s Alpha for the Chinese QOL-35 was greater than SF-36 but lower than WHO-
QOL-100. Overall, 91.2% for QOL-35, 67.2% for WHO-QOL-100, and 94.4% for SF-36
were defined as good items using Item-internal consistency (IIC) coefficients to assess.
Factorial analyses showed that the cumulative percentage of variance from seven principal
factors were higher for Chinese QOL-35 than for WHO-QOL-100 and SF-36, while
variances were distributed on seven components more equally for Chinese QOL-35 than
for WHO-QOL-100 and SF-36.
The Spearman correlation coefficient of total quality of life score was 0.805 between
Chinese QOL-35 and WHO-QOL-100 and 0.745 between Chinese QOL-35 and SF-36.
Cronbach’s a for the QOL-35 ranged from 0.88 for independence domain to 0.71 for
environmental domain; for total score a was 0.91 when QOL-35 was reassessed in a
Chinese general population (n = 1,356).
The prevalence of several major diseases exhibited a significant decreasing trend with the
quartiles of total quality of life scores for Chinese QOL-35 in a Chinese general population,
indicating good discrimination validity.
Chinese QOL-35 instrument has been shown to have satisfactory reliability, validity, and
acceptability, and can be used to assess quality of life in the Chinese general population.
Acknowledgment
We are very grateful to Ms. Naomi Hammond at The George Institute, China for her kind help
and assistance in preparation of the manuscript.
Appendix 1: Chinese Quality of Life 35-Items Questionnaire
This questionnaire is used to understand your quality of life and health status in the last
month. Please read carefully each question then answer it according to your actual situation
and feelings by filling your chosen number in the subsequent blank square.
1. Generally speaking, how about your health status during the last month? HQ1□
1=very bad; 2=bad; 3=average; 4=good; 5=very good
2. Generally speaking, how about your quality of life during the last month? HQ2□
3. Compared to a year ago, how would you rate your quality of life now? QT□
1=Much worse 4=somewhat better

2=Somewhat worse 5=much better
3=About the same
4. Did you have any difficulties in conducting the following activities during the last month,if so,
how much?
Heavy physical activities (running/lifting 1=completely couldn’t; 2=mostly couldn’t; IL1□
heavy objects) 3=half and half; 4=mostly could; 5=no problem
Moderate physical activities(riding 1=completely couldn’t; 2=mostly couldn’t; IL2□
bicycle/ doing housework for at least 3=half and half; 4=mostly could; 5=no problem
one hour)
Lift daily necessities (buying vegetables) 1=completely couldn’t; 2=mostly couldn’t; IL3□
3=half and half; 4=mostly could; 5=no problem
Climbing several flights of stairs 1=completely couldn’t; 2=mostly couldn’t; IL4□
Climbing one flight of stair 1=completely couldn’t; 2=mostly couldn’t; IL5□
Bending/kneeling/ stooping 1=completely couldn’t; 2=mostly couldn’t; IL6□
Walking three miles 1=completely couldn’t; 2=mostly couldn’t; IL7□
Walking one or two miles 1=completely couldn’t; 2=mostly couldn’t; IL8□
Walking around house 1=completely couldn’t; 2=mostly couldn’t; IL9□
Bathing or dressing 1=completely couldn’t; 2=mostly couldn’t; IL10□
5. Did you have pain or discomfort during the last month?
1=very severe; 2=severe; 3=moderate; 4=mild; 5=very mild; 6=not at all PF1□
6. Did that pain or discomfort have effect on your normal life during the last month? PF2□
1=extremely; 2=quite a bit; 3=moderately; 4=a little bit; 5=not at all
7. How about your appetite during the last month? PF3□
8. How about your sleep during the last month? PF4□
1=Extremely difficult; 2=Quite difficult; 3=Moderately difficult; 4=rarely difficult 5= Not
difficult at all
9. Did you often feel fatigue/tired during the last month? PF5□
1=always; 2=often; 3=sometimes; 4=occasionally; 5=not at all
10. Did you need help from medicines or treatment in your daily life during the last month? IL11□
1=Not at all; 2=Occasionally; 3=Generally; 4=Mostly; 5=Completely
11. Were you satisfied with your own living ability during the last month? IL12□
1=Very unsatisfied; 2=Unsatisfied; 3=So so; 4=Satisfied; 5=Very satisfied
12. How was your psycholo gical status during the last month?
Having self-confidence 1=Not at all; 2=A little; 3=Generally; 4=Strongly; MF1□
5=Completely
Having living pleasure 1=Not at all; 2=Occasionally; 3=Generally; MF2□

4=Often; 5=Extremely
Having nervousness 1=Always; 2=Often; 3=Sometimes; MF3□
4=Occasionally; 5=Not at all
Having negative feeling (Downhearted/ 1=always; 2=Often; 3=Sometimes; MF4□
despaired/anxiety/ melancholy) 4=Occasionally; 5=Not at all
Memory 1=very bad; 2=bad; 3= average; 4=good; 5=very MF5□
good
Attention Span (doing something for at 1=Could not at all; 2=Occasionally could; MF6□
least ten minutes) 3=Generally could; 4=Mostly could;
5=Completely could
13. How did you rate your social connections during the last month? MF6□
Family 1=very bad; 2=bad; 3= average; 4=good; 5=very SF1□
good
Relative 1=very bad; 2=bad; 3= average; 4=good; 5=very SF2□
good
Colleague/superior/subordinate 1=very bad; 2=bad; 3= average; 4=good; 5=very SF3□
good
14. Could you get help or support from your family members or friends in your life during SF4□
the last month?
1=Could not at all; 2=Occasionally could; 3=Generally could; 4=Mostly could;
5=Completely could
15. Could you provide help or support to you family members or friends in their life during SF5□
the last month?
1=Could not at all; 2=Occasionally could; 3=Generally could; 4=Mostly could;
5=Completely could
16. Were you satisfied with your sex life during the last month? SF6□
1=Very unsatisfied; 2=Unsatisfied; 3=So so; 4=Satisfied; 5=Very satisfied
17. Did you feel lonely during the last month? SF7□
1=Always; 2=Often; 3=Sometimes; 4=Occasionally; 5=Not at all
18. How is your financial status at present? LC1□
1=very bad; 2=bad; 3= average; 4=good; 5=very good
19. How is the condition of your current residence? LC2□
1=very bad; 2=bad; 3= average; 4=good; 5=very good
Date: □□□□year □□month □□day

Thanks for your support!
Appendix 2: Standard scores for each option of answers to

Chinese QOL-35 items
Standard
Chinese QOL-35 items Answer options scores
General health status; general quality of life; appetite; Very bad 0
memory; connections with family, relative, and colleague/ Bad 25
superior/ subordinate; Financial status; condition of
Average 50
residence
Good 79
Very good 100
Difficulties in conducting the following activities: (1) Heavy Completely couldn’t 0
physical activities; (2) Moderate physical activities; (3) Mostly couldn’t 25
Lifting daily necessities; (4) Climbing several flights of stairs;
Half and half 50
(5) Climbing one flight of stairs; (6) Bending, kneeling, or
stooping; (7) Walking three miles; (8) Walking one or two Mostly could 75
miles; (9) Walking around house; (10) Bathing or dressing No problem 100
Pain and discomfort Not at all 100
Very mild 82
Mild 70
Moderate 58
Severe 16
Very severe 0
Effects of pain and discomfort on normal life Not at all 100
A little bit 80
Moderately 50
Quite a bit 20
Extremely 0
Sleep Not difficult at all 100
Rarely difficult 80
Moderately difficult 50
Quite difficult 25
Extreme difficult 0
Fatigue/tired, nervousness, negative feeling, feel lonely No at all 100
Occasionally 78
Sometimes 50
Often 25
Always 0
Need help from medicines or treatment Not at all 100
Occasionally 76
Generally 50
Mostly 25
Completely 0
Standard
Chinese QOL-35 items Answer options scores
Living ability; sex life Very unsatisfied 0
Unsatisfied 25
So so 50
Satisfied 77
Very satisfied 100
Self-confidence Not at all 0
A little 23
Generally 50
Strongly 80
Completely 100
Living pleasure Not at all 0
Occasionally 24
Generally 50
Often 74
Extremely 100
Attention Span; Support from family members or friends; Could not at all 0
Support to family members or friends Occasionally could 25
Generally could 50
Mostly could 79
Completely could 100
Change in quality of life Much worse 0
Somewhat worse 25
About the same 49
Somewhat better 70
Much better 100
References
WHO. (2006). Constitution of the World Health Orga- Hopman WM, Towheed T, Anastassiades T, Tenenhouse
nization. World Health Organization. A, Poliquin S, Berger C, Joseph L, Brown JP, Murray
WHOQOL Group. (1993). Qual Life Res. 2(2): 153–159. TM, Adachi JD, Hanley DA, Papadimitropoulos E.
WHO. (1993). The development of the WHO quality of (2000). CMAJ. 163(3): 265–271.
life assessment instrument. Geneva. Ware JE, Shebourne CD. (1992). Med Care. 30(6):
Fang J. (2000). The Assessment and Application of Qual- 473–483.
ity of Life. Publishing House of Beijing Medical Hunt SM, McEwen J. (1980). Soc Health illness. 2(3):
University, Beijing. 231–246.
Li L, Wang HM, Shen Y. (2003). J Epidemiol Commun Appendix E4: EURoQoL(EQ-5D). (2000). In: Fayers PM
Health. 57(4): 259–263. and Machin D (eds.) Quality of Life Assessment,
WHOQOL Group. (1998). Soc Sci Med. 46(12): Analysis and Interpretation. Wiley, New York,
1569–1585. pp. 355–356.
Hunt SM, McEwen J, McKenna SP. (1985). J Roy Coll Bonomi AE, Patrick DL, Bushnell DM, Martin M.
Pract. 35: 185–188. (2000). J Clin Epidemiol. 53(1): 1–12.
Ware J. (2000). Appendix E3: Medical Outcomes Study Konig HH, Ulshofer A, Gregor M, von Tirpitz C,
(SF-36). In: Fayers PM and Machin D (eds.) Quality Reinshagen M, Adler G, Leidl R. (2002). Eur J
of Life Assessment, Analysis and Interpretation. Gastroenterol Hepatol. 14(11): 1205–1215.
Wiley, New York, pp. 352–354. Questionnaire Development and Scoring. In: Fayers PM,
Asher M, Min Lai S, Burton D, Manna B. (2003). Spine. Machin D (eds.) Quality of Life Assessment, Analisis
28(1): 63–69. and Interpretation. Wiley, New York, pp. 135–153.
Fayers PM, Aaronson NK, Bjordal K, et al. (2001). On Fayers PM and Machin D. (2000). Multi-Item Scales.
behalf of the European Organisation for Research In: Fayers PM, Machin D (eds.) Quality of Life
and Treatment of Cancer and Q.o.L.S. Group (eds.) Assessment, Analisis and Interpretation. Wiley,
The EORTC QLQ-C30 Scoring Manual, 3rd edn. New York.
EORTC, Brussels. Chen H, Cohen P, Kasen S, et al. (2004). Qual Life Res.
Fayers PM and Machin D. (2000). Scores and 13: 747–759.
Measurements: Validity, Reliability, Sensitivity. Wu Y, Xie G, Li Y, Zhou B, Zhang P, Shi P, Ren F, Ma L.
In: Fayers PM and Machin D (eds.) Quality of Life (2005). Chinese J Epidemiol. 26(10): 751–756.
Assessment, Analisis and Interpretation. Wiley,
pp. 45–71.
16 The Japanese Version of the
EORTC Quality of Life
Questionnaire
G. Tóth . M. Tsukuda
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
2 QoL and its Measurement in Healthcare: Important Principles and Tools . . . . . 288
3 QoL Questionnaires of the European Organization for Research and

Treatment of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
3.1 The Translation and Cultural Adaptation Procedure of EORTC QoL
Questionnaires and Supplementary Modules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
3.2 The EORTC QLQ-C30: Development and Cross-Cultural Validations . . . . . . . . . . . 296
3.2.1 The Japanese Version of the EORTC QLQ-C30 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
3.3 Supplementary Modules of the QLQ-C30 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.4 Asian Culture Specific Dimensions of QoL Measurement and the
Japanese Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
3.4.1 Problems and Difficulties in the Translation Procedure of the Japanese
Versions of EORTC QLQ Modules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

286 16 The Japanese Version of the EORTC Quality of Life Questionnaire
Abstract: This Chapter summarizes > quality of life (QoL) questionnaires for various types
of cancer. Most of the patient-centered QoL measurement tools have been developed in
English-speaking cultures. Thus, it has been a vitally important question whether or not
these questionnaires could be used in other cultures – like African and Eastern countries –
and cross a broad cultural divide.
The > European Organization for Research and Treatment of Cancer (EORTC) quality of
life questionnaires (QLQ) were continuously developed and used since 1993 first in European
countries and later on worldwide in international trials. Therefore, a standardized translation
and cultural adaptation procedure was also developed by the EORTC Quality of Life Group
(QLG) to respond to the international interest in non-English speaking countries and cultures.
To date, the EORTC QLQ 30-item core questionnaire (QLQ-C30) has been translated and
validated into more than 60 languages and its cancer site/type specific modules (e.g., Palliative
care, Breast-, Cervix-, Head and Neck cancer etc.) are under further translation and validation
process. Translations and cultural validations include all major Western, and many African
and Asian languages.
The aim of this Chapter is to give a brief account of the existing EORTC QLQ modules and
their cultural validation (linguistic and psychometric validation) into Japanese language for
use in cancer patients. We give an overview of the translation problems and different priorities
of social issues between Western and Eastern – in our case Japanese – culture.
List of Abbreviations: APPI, Action concerning Protection of Personal Information; BR23,
breast cancer module; BRM, Brahma gene; C15-PAL, palliative care core questionnaire;
C30, 30-item cancer core; CR, Complete Response; CX24, cervical cancer module; ECOG
PSR, Eastern Cooperative Oncology Group Performance Status Rating scale; EGFR, Epidermal
Growth Factor Receptor; EORTC, European Organization for Research and Treatment of
Cancer; FACT-G, Functional Assessment of Cancer Therapy-General; FACT-H&N, Functional
Assessment of Cancer Therapy-Head and Neck cancer subscale; FLIC, Functional Living
Index-Cancer; GHQ, General Health Questionnaire; H&N35, 35-item module for Head and
Neck cancer; HRQoL, Health-related Quality of Life; IMRT, Intensity-Modulated Radiation
Therapy; IN-PATSAT32, cancer in-patient satisfaction with care questionnaire; KPS, Karnofsky
Performance Scale; LC13, lung cancer module; MY20, multiple myeloma module; OES18,
esophageal cancer module; OV28, ovarian cancer module; POMS, Profile of Mood States; PSS-
HN, Performance Status Scale for Head and Neck Cancer; QLG, Quality of Life Study Group;
QLQ, Quality of Life Questionnaire; QLU, Quality of Life Unit; QoL, Quality of Life; QOL-ACD,
Quality of Life Questionnaire for Cancer Patients Treated with Anti-Cancer Drugs; QOL-RTI/
H&N, Quality of Life-Radiation Therapy Instrument with Head and Neck Module; SF36,
Medical Outcomes Study 36-Item Short-Form Survey; SOV, subject-object-verb; STO22,
gastric cancer module; SVO, subject-verb-object; UWQOL, University of Washington Quality
of Life Questionnaire for Head and Neck Cancer; WHO/QOL-26, World Health Organization
Quality of Life 26
1 Introduction
" ‘‘Ultimately, man should not ask what the meaning of his life is, but rather must recognize that it is
he who is asked. In a word, each man is questioned by life; and he can only answer to life by
answering for his own life; to life he can only respond by being responsible.’’ (Viktor Frankl (1905–
1997): Man’s Search for Meaning, Touchstone, New York, p. 172, 1984)
The Japanese Version of the EORTC Quality of Life Questionnaire 16 287
Before the Second World War, most of the health-related deaths were caused by infectious
diseases (e.g., pneumonia, tuberculosis and gastroenteritis) in Japan. As infectious diseases are
brought under control and increased longevity results, the incidence of so-called life style related
diseases (e.g., malignant neoplasms, heart diseases and cerebrovascular diseases) started to rise.
Nowadays, malignant neoplasm (cancer) is the leading cause of death in Japan and in many
other industrialized countries. Thus, cancer has been synonymously associated with death;
however, in the end of the twentieth century it has yielded to the advances in modern treatments
that include surgery, radiotherapy, chemotherapy and a combination of these. These days, nearly
1 out of 3 Japanese has been diagnosed with cancer, and approximately 40–50% of those
diagnosed as cancer patients will probably die from their disease. The number of cancer deaths
in 2004 was approximately 320 thousand (Tsukuma et al., 2004), and the death rate was 253.9
per 100,000 population, which is a 31.1% of the total number of deaths in Japan (Nomura,
2005). The cancer incidence in the year 2020 in Japan was estimated by the Research Group for
Population-based Cancer Registration and the estimated number of cancer incidence found to
be 838 thousand (538 thousand in the year 2000) (Ohno et al., 2004). > Figure 16-1 shows the
total number of cancer cases in Japan during the last 10 years.
. Figure 16-1
Total number of cancer cases in Japan (1997–2005). The 3-year sequential report on patient
survey by the Ministry of Health and Welfare shows the continuously increasing pattern of total
number of cancer patients receiving healthcare in Japan (Statistics and Information Department
Ministers Secretariat, 2007)
Unfortunately, the Action concerning Protection of Personal Information (APPI), which

was issued on May 30, 2003, with total enforcement on April 1, 2005 by the Japanese
Government, has made cancer registration quite difficult. Thus, to collect personal informa-
tion even by an official cancer registry system can be regarded as ‘‘illegal activity’’ in Japan. The
APPI could cause significant data collection problems, questioning the scientific validity and
social value of health and welfare data as a source of reliable national statistics (Matsui and Lie,
2007). Because the Governmental support on this issue has not been available, medical
societies – such as the Japan Society for Head and Neck Cancer – suspended the registration of
newly diagnosed cancer patients. Presently, the duration of this situation is not clear, but there
is a possibility to solve this problem in the future with an extensive revise and modification of
the APPI.
The Japanese research and treatment of cancer is highly advanced with strong connections
to leading US and European research and treatment centers (e.g., MD Anderson Cancer
Center, European Organization for Research and Treatment of Cancer). On the other hand,
Japanese treatment (optionally) includes East Asian (Oriental) Medicine (Onishi et al., 1998),
which was introduced to Japan with other elements of Chinese culture during the fifth to ninth
century. Traditional Japanese medicine has been used for 1,500 years and includes Kampo-
yaku (herbal medicine), acupuncture and acupressure. Kampo-yaku is now widely practiced
in Japan and is fully integrated into the modern healthcare system. Kampo-yaku is based on
East Asian Medicine, but has been adapted to Japanese culture. Thus, it has to be mentioned,
that even today a person who becomes ill in Japan has a number of alternative additional
options along with modern Western Biomedicine (Yu et al., 2006).
Advances in cancer treatment over the past 40 years have led to an increase in the survival
of cancer patients. The traditional cancer treatment outcomes focus upon biomedical end-
points (e.g., tumor response, disease-free survival, treatment related toxicity and overall
survival). The recognition and increased interest on the impact of cancer and its treatment
on the functional and psychosocial health of the patients resulted in the development of
patient based outcomes. If a healthcare system aims to make the best possible treatment for a
patient with cancer, it has to think of a patient as a whole person together with his/her medical,
psychological, social, cognitive and spiritual dimensions, which could be defined and
measured by a multi-dimensional construct called ‘‘Quality of Life’’ (QoL). Since the second
half of the twentieth century QoL measurement has become an essential consideration in
cancer treatment, and it is recognized as an important factor in assessing treatment outcome
(Fayers and Machin, 2000). This Chapter is attempting to explore and interpret QoL instru-
ments for persons with cancer in Japan. In the case of health-related issues, clinical medicine
uses the term ‘‘Health-related Quality of Life’’ (HRQoL). Although, this chapter is predomi-
nantly concerned with HRQoL, we use the more common abbreviation QoL, as a title of this
Handbook contains this synonym. We reviewed the literature related to QoL instruments that
have been translated into Japanese and used for the QoL evaluation of Japanese cancer
patients. This Chapter summarizes QoL questionnaires for various types of cancer in the
Japanese cultural context, especially those developed by the European Organization for
Research and Treatment of Cancer (EORTC).
2 QoL and its Measurement in Healthcare: Important

Principles and Tools
Relevant aspects of QoL could vary from study to study, but usually include the following: general
health, physical functioning, physical symptoms, toxicity, emotional functioning, cognitive
functioning, role functioning, social well-being/functioning, sexual functioning, and existential
issues. Accordingly, definitions of QoL range from those with a holistic emphasis on the social,
emotional, and physical wellbeing of patients after treatment to those that describe the impact
of a person’s health on his/her ability to lead a fulfilling life. Thus, it is a very difficult task to
quantify someone’s QoL and making it objectively measurable, when it has an essential
subjective genesis. People assess their QoL by comparing their expectations with their experi-
ence (Bullinger et al., 1993), but people are different and the response of a person differs from
others with the same disease – even for the same question – because their cultural values,
priorities in life and personal needs differ and continuously evolve in time. From a measure-
ment perspective the use of the QoL construct in healthcare is continuously changing.
Increasingly, it is being used as conceptual framework for assessing health-related quality
outcomes, a social construct that guides quality enhancement strategies, and a criterion for
assessing the effectiveness of those strategies. This new role places additional emphasis on the
valid assessment of a patient’s QoL and its dimensions worldwide. Over the past two decades,
numerous instruments have been developed to measure QoL. Both European and American
cancer clinical organizations have developed QoL instruments to assess the outcomes of cancer
interventions. The nature of measurements and questionnaires that are employed usually
depend on the objectives of the actual clinical trial or the specific treatment and type of cancer.
The philosophy behind the development of a QoL questionnaire is to provide a practical QoL
measure that gives information about changing in patients’ health state and their life situation
(> Figure 16-2).
. Figure 16-2
A Simple Conceptual Model of QoL. Traditionally medicine concentrates on symptom relief as an
outcome measure. QoL studies and instruments reveal other issues that are equally or more
important to patients. It captures in detail those dimensions most likely to be influenced by
therapeutic interventions and evaluates other dimensions globally
The ultimate goal of cancer therapy is to cure the disease or to prolong life (Einhorn,
2003). Until the 1980s research and treatment groups of cancer have mainly focused on local
recurrence and survival rates. But as cancer treatment became more advanced and continu-
ously develops with various combination options, the survival of patients with cancer is
improving, and more interest is coming in the QoL of cancer survivors. Another reason for
assessing QoL is to collect information in a form that can be communicated to future patients,
enabling them to anticipate and understand the consequences of the illness and its treatment.
Nowadays, the assessment of QoL is becoming a standard component in the overall care of
patients with cancer (> Figure 16-3).
Any tool designed to measure QoL should be multidimensional, subjective, useful in the
setting, valid, and reliable. Both validity and reliability are critical in instruments that measure
. Figure 16-3
An example of a cancer treatment model when QoL is the main outcome. This figure shows an
example when the best possible QoL of a patient is the major secondary outcome in treatment
together with the primary curative intent, the possible cure of cancer. QoL, Quality of Life;
CR, Complete Response; BRM, Brahma gene; IMRT, Intensity-Modulated Radiation Therapy;
EGFR, Epidermal Growth Factor Receptor
QoL (Stromborg, 1998). From this view point we can make a criteria list of an instrument
which tends to measure QoL of patients with cancer:
The instruments must be multidimensional.
Instruments should provide subjective data obtained via self-report of patients.
Instruments must be useful in the settings in which they will be used (readability and
length).
Instruments must be valid and reliable (Schipper and Levitt, 1985).
As the second point states in the list above, patient completed QoL assessments (self-administered
questionnaires) are perceived as essential tools to the evaluation of successful treatment and
rehabilitation (Kaasa, 1992). The reason for this is that the patient’s self-assessment often
differs not only from the judgment of their doctor and other healthcare professionals, but also
from that of other patients’. People assess their QoL by comparing their expectations with their
experience (Bullinger et al., 1993). The increasing use of QoL measures in cancer care reflects a
growing appreciation of the importance of how patients feel and how satisfied they are with
treatment in addition to the traditional focus on disease outcomes. There are four main
categories of instruments which could be used for the measurement of QoL in Japanese
patients with cancer:
1. Global Health QoL instruments: these are intended to measure general QoL, irrespective of
the illness or condition of the patient.
2. General cancer QoL instruments: these are disease-specific questionnaires that are used to
measure QoL related to cancer and its treatment.
3. Cancer site/type specific QoL instruments: these standalone questionnaires or additional
modules to general cancer questionnaires are developed to measure different types of
cancer or a specific cancer-treatment and its effects on the patients.
4. Performance and function oriented instruments: these are strongly related to QoL, but act as
additional scales to measure specific functions (emotional, mental etc.) and performance
dimensions of cancer patients (> Table 16-1).
. Table 16-1
Examples of health-related performance and quality of life measures for cancer patients in Japan
Performance and Function Quality of Life

General Clinical Assessment Global Health
Karnofsky Performance Scale: KPSa (Karnofsky Medical Outcomes Study 36-Item Short-Form
and Burchemajh, 1949) Note: Based on the Survey: SF36b (Fukuhara et al., 1998)
physician’s observation. No permission World Health Organization Quality of Life 26:
required to use this tool. WHO/QOL-26b (Tazaki et al., 1998)
Eastern Cooperative Oncology Group General Cancer
Performance Status Rating scale: ECOG PSRa Functional Living Index-Cancer: FLICa (Eguchi,
(Oken et al., 1982) Note: Based on the 1995)
physician’s observation. No permission Functional Assessment of Cancer Therapy-
required to use this tool. General: FACT-Gb (Fumimoto et al., 2001)
General Health Questionnaire: GHQb \EORTC QLQ 30-item Core Scale: QLQ-C30b
(Nakagawa and Daibo, 1985) (Kobayashi et al., 1998)
Profile of Mood States: POMSb (Yokoyama Quality of Life Questionnaire for Cancer
et al., 1990) Patients Treated with Anti-Cancer Drugs:
QOL-ACDb (Kurihara et al., 1999) Note: This is
a questionnaire originally developed in Japan
Cancer Specific Performance Scale Cancer site/type specific
Performance Status Scale for Head and Neck FACT Head and Neck cancer subscale:
Cancer: PSS-HNa (List et al., 1996) Note: FACT-H&Nb (Bonomi et al., 1996)
Japanese version is in progress by a team at the EORTC QOL Head and Neck cancer module:
Japanese National Cancer Center Hospital East, QLQ-H&N35b (Toth et al., 2005)
Division of Radiation Oncology
University of Washington Quality of Life
Questionnaire for Head and Neck Cancer:
UWQOLa (Weymuller et al., 2001)
Function and treatment modality specific
Quality of Life-Radiation Therapy
Instrument þ Head and Neck Module:
QOL-RTI/H&Nb (Karasawa et al., 2003)
This table shows some examples of QoL instruments used for Japanese patients of the previously mentioned
categories
a
Japanese translation
b
Validated Japanese version EORTC QLQ: European Organization for Research and Treatment of Cancer Quality of
Life Questionnaire; FACT: Functional Assessment of Cancer Therapy
In this Chapter we do not intend to explore all the possible instruments of these categories,
but overview those developed by the EORTC and have been used in Japan.
3 QoL Questionnaires of the European Organization for

Research and Treatment of Cancer
The aim of this Chapter is to give a brief account of the existing EORTC QLQ modules and
their cultural adaptation (linguistic and psychometric validation) into the East Asian context
for use with Japanese cancer patients. We give an overview of the translation problems and
different priorities of social issues between Western and Eastern – in our case Japanese –
culture.
The EORTC is one of the oldest and largest cancer clinical trial organizations in Europe.
The original organization was founded as an international organization under Belgian law in
1962 and became the ‘‘EORTC’’ in 1968. The aims of the EORTC are to develop, conduct,
coordinate, and stimulate translational and clinical research in Europe to improve the man-
agement of cancer and QoL of patients. Thus, 28 years ago a special unit was established called
‘‘Quality of Life Study Group’’ (QLG) within the EORTC to deal with the design, implemen-
tation and analysis of QoL related studies and clinical trials (first QoL Meeting, Institute
Bordet in Brussels, Belgium, 1979). Presently, the QLG is composed of members from 25
countries (Koller et al., 2007) and within the group there are a broad range of professionals
(e.g., oncologists, surgeons, radiotherapists, palliative-care specialists, psychiatrists, psychol-
ogists, statisticians, social workers and research methodologists) working together as an
international body with a strong multicultural and multilingual (representing 21 languages)
background on QoL issues. Therefore, the main profile of the QLG is to provide high-quality
information and measurement (outcome) tools for QoL assessment in clinical trials.
In 1986, the QLG initiated a research program to develop an integrated, so-called ‘modular
approach’ for evaluating QoL of patients participating in international cancer clinical trials
(Aaronson et al., 1988). They named the 30-item core instrument QLQ-C30, which covers a
range of QoL issues relevant to a broad spectrum of patients with cancer (Aaronson et al.,
1993). The QLQ-C30 is designed to be supplemented by more specific subscales, so-called
‘modules’, to assess aspects of QoL in specific subgroups of patients. The QLG established
guidelines and manuals for supplementary module development (Sprangers et al., 1993). The
primary aim of these guidelines was to standardize the supplementary module development
process. The supplementary modules included those for body image, high-dose chemothera-
py, leukemia, myeloma, palliative-care and many different type of cancers like: the bladder,
brain, breast, colorectum, head and neck, lung, esophagus, ophthalmus, ovary, pancreas
and prostate (Sprangers et al., 1998). Other disease specific modules are under continuous
development.
3.1 The Translation and Cultural Adaptation Procedure of EORTC QoL

Questionnaires and Supplementary Modules
The QLG gives its recommendation and support on QoL issues to the EORTC Data Center
(Brussels) and various cooperative groups related to patient outcomes research (design, imple-
mentation and analysis). Within the EORTC Data Center a special group, called ‘‘Quality of Life
Unit’’ (QLU) was organized to coordinate and supervise the evaluation of QoL in selected cancer
clinical trials and the data management of QoL evaluations in EORTC studies. Thus, the QLU
has the role to control data quality, maintain and improve standard data management strategies
and where possible encourages investigators to adopt a standard approach. These coordination
activities require collaboration with the QLG and involvement with all EORTC cooperative
groups and other international groups who undertake QoL assessment. The QLU reviews all new
protocols at the EORTC Data Center and participates in the development of protocols where
QoL is an endpoint. The QLU is also responsible for the quality and standards of questionnaires
translated into other languages. All translation procedures are managed and supervised by a
Translations Coordinator. The increased use of EORTC QLQ modules in international cancer
research and treatment, especially those in non-English speaking cultures, led to the develop-
ment of a standardized translation procedure of these instruments (Toth and Tsukuda, 2003).
The aim of this standardized translation procedure is to produce good quality translations,
make each of the questionnaires clear (i.e., able to be read and understood), expressed in
languages in common use and conceptually equivalent to the original. To achieve such quality-
control the QLU developed a Translation Manual which has been updated to correspond to
the continuous international interest (Cull et al., 2002). This standard manual is intended
to help guide the process of translation from one (official) language into other national and
local languages. The process of translation itself often deepens understanding of the question-
naire modules and can reveal some special aspects of QoL from a different cultural perspective;
therefore the translation process itself has a great importance in future module development.
Translation of EORTC instruments should not be initiated without first checking with the QLU
and/or the principal author of the questionnaire (Cull et al., 2002). The decision to translate a
questionnaire module into a national language or a local language must be taken at QLU level
(presently, the contact person for translation matters is Linda Dewolf: linda.dewolf@eortc.be).
Firstly, the forward-backward translation procedure involves two independent forward
translations from English into language X (in our case Japanese language), carried out by
two native Japanese speakers (who have high level of fluency in English). The local coordinator
of the linguistic validation and cultural adaptation (possibly a native speaker of Japanese
language, with high level fluency in English) is appointed to ensure that the procedure is
adhered to, and to also make a final judgment, when necessary, if translations should differ in
some points (Cull et al., 2002). Where there is agreement, the translation can be accepted for
the provisional forward translation (e.g., First Intermediate version of the Japanese transla-
tion). If there are differences in translations, the local coordinator of the translation process
should aim to resolve these by discussion with the translators (reconciliation) to yield a
provisional forward translation. In some case, when it is difficult to resolve the problem,
alternative wording may be offered in the provisional forward translation for resolution
through the back translation process (Koller et al., 2007). In the case of multiple or principal
disagreements, a third independent translator is invited to make the best possible settlement
between the two versions. An important note, that this third translator should independently
translate the problematic parts before being included in the actual discussion process, then
they all agree or the third one proposing alternative wording for the back translation.
However, it is not the purpose of the translation procedure to modify the original questionnaire
(Cull et al., 2002). The whole translation process should be documented (copies of all interim
forward and back translations) in sufficient detail by the local coordinator. The coordinator
has to explain any difficulties and their solutions. This documentation will compose an
important part of the Interim Report of the translation later on. The provisional forward
translation (e.g., First Intermediate version of the Japanese translation) is then ready for back
translation (Toth et al., 2005).
Secondly, it involves two independent backward translations from Japanese language into
English, carried out by two native English speakers strongly familiar with Japanese (without
reference to the English original) (Koller et al., 2007). Again, the local coordinator has the role
to compare the English (backward) translations with the original (English) questionnaire. If
there is agreement between the two backward and the original version, the translation may be
considered semi final, called the Second Intermediate version of Japanese questionnaire. If
there are differences in backward translations, the local coordinator should resolve these by
discussion (Reconciliation) or with the involvement of a third backward-translator and reach
consensus during the similar process discussed above in the previous paragraph. After the
establishment of a best possible semi final forward translation, the local coordinator of
the linguistic validation and adaptation should write an Interim Report and send it to the
Translations Coordinator of the QLU for acceptance to start the Pilot Testing phase. There is a
possibility of a minor revision before starting the Pilot Testing phase. This minor revision is
reached by a bidirectional agreement (i.e., ready for Pilot Testing) between the local coordina-
tor and the Translations Coordinator of the QLU (Cull et al., 2002).
The third step of translation procedure is Pilot Testing of the Japanese questionnaire with
10–15 patients belonging to the target population (adequately representative of those
for whom the questionnaire was designed). They all should be native Japanese speakers (or
in another case, native speaker of the language of translation). During the Pilot Testing
process all patients should fill the questionnaire. After administering the translated question-
naire, all patients should participate in a structured interview (individual or focus group),
where designed questions are asked to identify the wording, which best meets the aims of the
translation process (i.e., clear, difficult to answer or understand, confusing, language of
common use, conceptual equivalence to original, upsetting and/or offensive). Patients are
also asked to freely express their thought related to any necessary change in the wording of
questions. When a patient finds an item problematic and/or suggests alternative wording/
character (in the case of an Asian language), this item should be recorded on the patient
response sheet together with his/her comments. The interview of the Pilot Testing should be
well documented and the local coordinator uses these documentations to write a Pilot Test
Report to the QLU for further consideration (Cognitive Debriefing) and establishment of the
final Japanese version of the actual questionnaire (Toth et al., 2005). The Pilot Test Report
should include:
An account of the Pilot Testing procedure, including the characteristics of the sample
population and details of any deviation from the standard interview;
Qualitative and quantitative data from the Pilot Testing to justify the final translation (Cull
et al., 2002).
The full report (include the Translation Report and the Pilot Test Report together or as separate
documents) should be submitted to the Translations Coordinator of the QLU (in the case of the
core C30 and Phase III-IV modules) or to the principal author of the module (in the case of
Phase I-II modules). That person will then contact a nominated EORTC QLG member who was
not involved in the translation process to review the full report (whenever it is possible, the
reviewer should be fluent in the language of translation) (Cull et al., 2002). This review will
confirm if the result of the Linguistic Validation (translation and language adaptation) is
accepted by being adequately tested and found to be appropriate for use in the target
population (> Figure 16-4).
Following the agreement and acceptance of the final version, it could be used to start the
Field Testing phase and the Psychometric Validation (see > Figure 16-5 and > Table 16-2)
process of the questionnaire for the target population of the actual cultural context.
. Figure 16-4
Outline of the Translation Procedure of EORTC QLQ modules EORTC QLQ: European Organization
for Research and Treatment of Cancer Quality of Life Questionnaire, QLG: Quality of Life Study
Group. Legend: This is an example of the full translation procedure when the target language
was Japanese
. Figure 16-5
Outline of the full cultural validation process of a QoL instrument Legend: Cultural validation
includes both the linguistic- and psychometric validation
. Table 16-2
Brief outline of the psychometric validation process of QoL instruments
Psychometric Procedure Explanation (Fayers and Machin, 2000)

Construct Validity An assessment of the degree to which an instrument measures
the construct that it was designed to measure.
Known-groups validation The instrument should be sensitive and successfully distinguish
between groups with known differences.
Internal consistency It refers to the extent to which items of a scale are interrelated and
assess the same construct (usually used Cronbach’s alpha a
coefficient of consistency).
Convergent and These two represent the extremes in a continuum of associations
discriminant validity between the dimensions of QoL: whether a dimension correlates
(appreciably) or not (relatively unrelated) with other relating or
non-relating dimensions.
Exploratory and These are to explore new constructs and confirm hypothesized
confirmatory factor analysis constructs of a measurement.
Reliability The scale has the potential to yield reproducible and consistent
results: whether it is stable over time when there is no change of
the construct over time.
Responsiveness The ability of a measure to detect and respond to relevant
changes over time.
Sensitivity The ability of a scale to detect and distinguish small but important
(clinically relevant) differences between groups.
This table shows the generic process of the Psychometric Validation of QoL instruments with short explanation
(Fayers and Machin, 2000) of the major statistical methods
3.2 The EORTC QLQ-C30: Development and Cross-Cultural

Validations
The QLQ-C30 cancer core instrument is a 30-item multidimensional self-report measure of

QoL designed for use in clinical trials (Aaronson et al., 1993). The QLQ-C30 measures QoL in
the past week using a global QoL scale, which intends to measure the global health status of a
patient. It also incorporates five functional scales (physical, role, social, cognitive, and emo-
tional), three symptom scales (fatigue, pain, and nausea/vomiting), five single symptom items
and financial difficulty (all together six single items). All items of the core questionnaire have
four response options (i.e., ‘‘Not at all,’’ ‘‘A little,’’ ‘‘Quite a bit’’ and ‘‘Very much’’), except
those two items assessing global QoL (using a seven-point scale). All scales/items are trans-
formed to scores ranging between 0 and 100. In the case of functional scales a higher
score represents high/healthy level of functioning and a high score for the global health
status represents higher QoL. In the case of symptom scales/items the higher score represents
a higher level (‘‘worse’’) of symptoms and lower QoL (high level of symptomatology/
problems) (Fayers et al., 2001).
Previous studies using the QLQ-C30 revealed high internal consistency in most scales (except
for cognitive functioning), moderate interscale correlations (which supported the distinct com-
ponents of the QoL construct), good discriminant validity (Aaronson et al., 1993), test-retest
reliability (Hjermstad et al., 1995) and patient-observer agreement (Groenvold et al., 1997). The
functional and symptom measures discriminated among patients according to clinical status. In
addition, significant differences were found in QLQ-C30 scores over time for patients whose
clinical status changed with treatment (Aaronson et al., 1993).
After the development of the QLQ-C30, its linguistic and psychometric validity was
originally evaluated with 305 patients in 13 countries, thus it was found to be a feasible,
reliable and valid questionnaire and one of the most widely used measurement instrument in
cancer clinical trials worldwide (Gotay and Wilson, 1998). During the original study of
Aaronson et al. (1993) an average of 11 min was needed to complete the questionnaire, and
most patients required no assistance. The reliability and validity of the QLQ-C30 were highly
consistent across the different cultural and language groups of the study (English-speaking
countries, Northern Europe, and Southern Europe). Hence, the QLQ-C30 was developed as a
parallel approach toward cross-cultural application from the beginning, working with health
professionals and patients from different countries and cultures during the development
process of the questionnaire. The reason for this might be the fact, that the EORTC itself
has a multinational/multilingual composition as we mentioned it before. The linguistic and
psychometric validation of the QLQ-C30 into Japanese (Kobayashi et al., 1998) was a very
important step in the course of international use of the core questionnaire (Aaronson, 1998). It
was a significant study where ‘‘East Meets West’’ as Aaronson (1998) calls it in his editorial
comment on the work done by Kobayashi et al. (1998) for using the QLQ-C30 in the Asian
cultural context for the first time since its development.
The QLQ-C30 is a copyrighted instrument, which to date, has been translated and
validated into more than 60 languages (all major European, Asian and African languages),
applicable in 70 countries and is used internationally (together with its supplementary
modules) in more than 9,000 clinical studies worldwide (Koller et al., 2007). The QLQ-C30
and some disease specific modules are still being translated into several different languages.
Presently, the QLQ-C30 version 3.0 is the most recent version and should be used for all new
studies (Bjordal et al., 2000). The QLQ-C30 and its modules are downloadable from the
official webpage of the EORTC after a user agreement (see web-address below). Conditions for
its use are dependent on whether it will be employed in a university-based investigation, in
which case its distribution is free, or if it is to be used in a study that is carried out or sponsored
by the pharmaceutical industry, when its use is subject to a royalty fee. A royalty fee is required
for each clinical study. The funds that are generated through the copyright arrangement are
used exclusively to support the ongoing research of the QLG on the development and
refinement of QoL instruments. Therefore, for industry sponsored studies it is kindly
requested to contact the Secretary for Pharmaceutical QoL Contracts (presently Ms. Sarah
Williams: sarah.williams@eortc.be). Academic users can download the questionnaires and the
user’s agreement form directly from the official website of the EORTC QLG (www.eortc.be/
home/qol/downloads/default.htm.)
3.2.1 The Japanese Version of the EORTC QLQ-C30
Since the original QLQ-C30 was developed in European countries, in order to determine if this
instrument could cross a broad cultural divide and be used in Japan, the cross-cultural adapta-
tion (linguistic and psychometric validation) of its Japanese version was accomplished and
used in studies (Kobayashi et al., 1998; Matsumoto et al., 2002). In evaluating psychometric
testing of the original study of Kobayashi et al. (1998), internal consistency by Cronbach’s
alpha, item-discrimination by multitrait scaling analysis and validity analysis with ECOG PSR
and KPS (for reference see > Table 16-1) were performed. The QLQ-C30 (version 1.0) was
given to 105 patients with lung cancer. Approximately 90% of eligible patients completed the
QLQ-C30 at the time of hospital admission, and 83% completed all questionnaires during
their hospitalization. Although the response rate was low in patients with ECOG PSR 4 (most
of the patients were in advanced stage), the questionnaire was well accepted by patients with
ECOG PSR 0–3. Kobayashi et al. gave sufficient support to their patients to receive the best
possible compliance rate even from patients with advanced disease. Thus, the overall compli-
ance rate of QLQ-C30 was satisfactory.
The psychometric validation study of Kobayashi et al. (1998) revealed good cross-cultural
validity except a low discriminant validity of role functioning scale in Japan. Internal consis-
tency by Cronbach’s alpha coefficient was above 0.70 (the recommended value by the EORTC
is a 0.70) for seven of the eight multi-item scales. It had a weak scale of cognitive functioning
in items of discriminative validity and internal consistency. > Table 16-3 (mean scores of
QLQ-C30) and > Table 16-4 (internal consistency of QLQ-C30) show an overview of results
from various studies in Europe and in Japan.
Known-group comparison showed the expected clinical validity with ECOG PSR for all
the scales except for financial impact, and longitudinally clinical validity with KPS was shown
in scales of cognitive functioning, fatigue, and nausea and vomiting. Multitrait scaling analysis
showed that the predicted scales constituting QoL in the European culture were extracted from
the Japanese QLQ-C30 (observed scaling errors in only 2.1% of the test, while it was 4% in the
international study). Generally speaking, the correlations between scales were higher than
those found in the original international study (Aaronson et al., 1993), especially in the case of
physical versus psychosocial health domains. Aaronson points out in his Editorial that a
reason for this might be explained by the difference between Japanese and European culture
(Aaronson, 1998). Aaronson describes that maybe Japanese patients have a more holistic
nature of illness experience than Europeans, who have a stronger Cartesian view of health (the
mind and body are separate entities).
The Japanese version of QLQ-C30 was found to be valid in Japan, indicating its usefulness
as an instrument that is universally applicable across cultures (Kobayashi et al., 1998). Taking
these results into consideration, the study of Kobayashi et al. (1998) was one of the most
important steps in the international use of the QLQ-C30 in the East Asian cultural context.
3.3 Supplementary Modules of the QLQ-C30
The EORTC QLQ system is a modular approach, where the QLQ-C30 is the core module and it
is used in conjunction with additional specific modules (see in > Figure 16-6).
These additional QLQ modules are also translated into many different languages and
culturally validated to be used in many different cultural contexts worldwide. Presently, the list
of validated modules include the BR23 breast cancer module (translated and validated into over
40 languages), the LC13 for lung cancer, the H&N35 for head and neck cancer (translated and
validated into over 30 languages), the CX24 for cervical cancer, the STO22 for gastric cancer,
the MY20 for multiple myeloma, the OES18 for esophageal cancer, the OV28 for ovarian
cancer, and the IN-PATSAT32 for the measurement of cancer inpatient satisfaction with care
(which are translated and validated into 20 languages) (Koller et al., 2007). Further specific
. Table 16-3
Summary of mean scores (SD)a of subscales/items of the QLQ-C30 in various studies in Europe and Japan
Aaronson et al., 1993 Kobayashi et al., 1998 Bjordal et al., 2000 Toth et al., 2005 (Japanese
Subscales/Items (European N = 305 LC) (Japanese N = 93 LC) (European N = 204 HNC) N = 108 HNC)
(Code) Items Mean Score (SD) Mean Score (SD) Mean Score (SD) Mean Score (SD)
Global QoL (QL) Q29, Q30 57 (23.5) 54 (24.8) 63 (23.9) 55 (24.1)
Physical Q1–Q5 66 (27.1) 49 (36.5) 84 (21.4) 64 (22.7)
Functioning (PF)
Role Functioning Q6, Q7 57 (38.6) 51 (43.6) 81 (30.2) 64 (26.1)
(RF)
Emotional Q21-Q24 70 (22.3) 72 (27.8) 72 (25.2) 70 (22.3)
Functioning (EF)
Cognitive Q20, Q25 84 (20.5) 65 (28.0) 83 (21.5) 75 (22.2)
Functioning (CF)
Social Q26, Q27 77 (27.6) 65 (27.8) 85 (21.5) 64 (26.8)
Functioning (SF)
Fatigue (FA) Q10, 39 (25.4) 47 (29.8) 26 (24.7) 47 (22.4)
Q12, Q18
The Japanese Version of the EORTC Quality of Life Questionnaire
Nausea and Q14, Q15 7 (15.5) 17 (24.9) 5 (12.0) 32 (26.0)

Vomiting (NV)
16
299
300
16
Aaronson et al., 1993 Kobayashi et al., 1998 Bjordal et al., 2000 Toth et al., 2005 (Japanese
Subscales/Items (European N = 305 LC) (Japanese N = 93 LC) (European N = 204 HNC) N = 108 HNC)
(Code) Items Mean Score (SD) Mean Score (SD) Mean Score (SD) Mean Score (SD)
Pain (PA) Q9, Q19 29 (30.8) 35 (32.7) 20 (24.9) 30 (24.1)
Dyspnea (DY) Q8 41 (28.7) 31 (31.0) 20 (27.8) 27 (25.3)
Insomnia (SL) Q11 32 (33.1) 32 (32.2) 28 (31.6) 36 (29.6)
Appetite Loss Q13 27 (35.1) 34 (34.6) 15 (28.1) 42 (31.1)
(AP)
Constipation (CO) Q16 20 (31.0) 26 (34.4) 13 (25.1) 25 (27.4)
Diarrhea (DI) Q17 4 (14.0) 9 (20.0) 5 (15.6) 17 (22.9)7
Financial Impact Q28 12 (24.8) 24 (27.9) 12 (22.6) 43 (32.8)
(FI)
SD, standard deviation; QLQ-C30, 30-item cancer core questionnaire; N, number of patients; LC, lung cancer; HNC, head and neck cancer; QoL, quality of life
a
Scores range from 0 to 100. A high score for a functional scale or global QoL represents high level of functioning or global QoL. A high score for a symptom scale or single item
represents a greater degree of symptoms. The data of Bjordal et al. (2000) were from a newly diagnosed group of patients (QLQ-C30 v.3.0). The data from Toth et al. (2005) were
from patients with total laryngectomy studying esophageal speech (QLQ-C30 v.3.0)
. Table 16-4
Internal consistency (cronbach’s alphaa) of the QLQ-C30 scales in various studies between 1992
(version 1.0) and 2005 (version 3.0)
Data reported by (version) PF RF EF CF SF QL FA NV PA

Bjordal et al., 1992 (International study, v.1.0 0.74 0.74 0.83 0.28 0.77 0.90 0.84 0.82 0.70
with N = 126 HNC)
Aaronson et al., 1993 (International study, 0.68 0.54 0.73 0.56 0.68 0.86 0.80 0.65 0.82
v.1.0 with N = 305 LC)
Kobayashi et al., 1998 (Japanese study, v.1.0 0.83 0.74 0.90 0.63 0.72 0.88 0.90 0.86 0.87
with N = 93 LC)
Toth et al., 2005 (Japanese study, v.3.0 with 0.77 0.79 0.86 0.61 0.75 0.88 0.82 0.78 0.77
N = 108 HNC)
PF, physical functioning; RF, role functioning; EF, emotional functioning; CF, cognitive functioning; SF, social
functioning; QL, global quality of life; FA, fatigue, NV, nausea and vomiting; PA, pain; N, number of patients;
HNC, head and neck cancer; LC, lung cancer
a
Cronbach’s alpha value 0.70 indicate adequate scale reliability
. Figure 16-6
An example of a Modular Measure by the EORTC Legend: This figure is a for example of
conjunction of QLQ-C30 together with the QLQ-H&N35 cancer specific supplementary module
for head and neck cancer
modules are under development and/or in the phase of translation/linguistic validation

process (> Table 16-5).
The distribution of the QLQ-C30 and its supplementary modules continues to spread
globally. The QoL instruments of the EORTC are recognized by physicians as a very efficient
tool for QoL measurement in patient-centered outcomes studies and also in clinical practice
during cancer treatment.
3.4 Asian Culture Specific Dimensions of QoL Measurement and the

Japanese Experience
Conducting QoL research and apply questionnaires for patients in Asian countries and
cultures is a challenging task and needs to have a deep insight into the actual cultural context
. Table 16-5
The european organization for research and treatment of cancer quality of life questionnaires
and modules (as per 2007 November)
Validated Questionnaires Japanese version

QLQ-C30 Cancer core final
C15-PAL Palliative care core final
IN-PATSAT32 Cancer in-patient satisfaction with care
Validated Modules Japanese version
CX24 Cervical cancer
H&N35 Head and Neck cancer final
BR23 Breast cancer final
LC13 Lung cancer final
MY20 Multiple Myeloma
OES18 Oesophageal cancer translation phase
STO22 Gastric cancer final
OV28 Ovarian cancer
Developmental Phase IV modules Japanese version
PR25 Prostate cancer
BN20 Brain cancer final
LMC21 Colorectal Liver Metastases
PAN26Pancreatic cancer translation phase
INFO26 Information Module
CIPN20 Chemo-Induced Peripheral Neuropathy final
G.I. NET20 Carcinoid/Neuroendocrine tumors
Developmental Phase III modules (completed) Japanese version
BLS24 Superficial Bladder cancer
BLM30 Muscle Invasive Bladder cancer
HCC18 Hepatocellular carcinoma
HDC29 High Dose Chemotherapy
OPT30 Ophthalmic cancer
CLL16 Chronic Lymphocytic Leukaemia
OG25 Oesophago-gastric cancer
CR38 Colorectal cancer final
CR29 modified abridged version of CR38 pilot testing phase
Developmental Phase III modules (ongoing) Japanese version
FAR15 Fatigue (cancer related)
SWB38 Spiritual Wellbeing translation phase

16 303
CHC47 Cholangiocarcinoma
PRT21 Radiation Proctitis
NPC42 Nasopharyngeal cancer
BM22 Bone metastases
This table shows the validated questionnaires and the list of modules (validated final, phase IV and III modules) with
the actual developmental phase of their linguistic and cultural adaptation for use in Japanese patients. Information
retrieved from the official public website of the European Organization for Research and Treatment of Cancer
Quality of Life Study Group (http://groups.eortc.be/qol/;) for more comprehensive information on questionnaires
(i.e., specimen) and most recent information on modules under development, please visit the official website
where the instrument will be used. Mostly all major QoL measurement tools were originally
developed for North American and Western European cultures; therefore it was an essential
question whether those could be used in Asian countries (Aaronson, 1998). Since the end of the
90’s, many QoL questionnaires were translated and culturally validated in different Asian cultures
and local languages (Chie et al., 2003). The EORTC QLG is highly committed to the international
use of its QoL questionnaires and provides strong infrastructure and quality control to support
linguistic and psychometric validation in Asian countries. Why it is so important to support the
development of QoL questionnaires in the Asian cultures? It is important, because about half of
the world’s population live in Asia. Chinese, Hindi and Japanese are among the ten languages
spoken by the largest number of primary speakers, while the numbers of Tamil and Malay
speakers are expected to grow rapidly in the next few decades (Cheung and Thumboo, 2006).
In this section we discuss several major issues in the development (linguistic validation) and use
of EORTC QLQ supplementary modules in Asia, especially in Japan.
The availability of QoL instruments in various Asian countries seems to reflect the status of
economic development of the countries rather than their disease burden. For instance,
presently many important QoL instruments are already available in Japanese and Chinese
(Standard Mandarin, Cantonese Chinese, and Taiwanese versions), but not in Hindi or Tamil.
The opinion of professional healthcare providers is diverse as to whether there are differences
in the concepts of QoL between Asian and Western cultures (North American and Western
European) that are important enough to justify the development of original local QoL
instruments, as opposed to the translation and cultural adaptation of existing instruments
like the EORTC QoL questionnaires (Cheung and Thumboo, 2006). There are also substantial
cultural differences concerning what questions (and how) are appropriate to ask and answer in
the Asian cultural context (especially related to death, family and sexual life). Most of the QoL
instruments are designed as self-reported outcomes tools using self-completion by the patient.
This mode of administration is often not feasible in specific parts of Asia because of low
literacy rates and the presence of many different regional languages. Thus, alternative admin-
istration methods and different analytic strategies are needed to find solution to these
difficulties in Asian countries.
3.4.1 Problems and Difficulties in the Translation Procedure of the

Japanese Versions of EORTC QLQ Modules
Both the Japanese language and culture are greatly different from those of Western cultures, where
the EORTC QLQ modules were developed. To understand the difficulty of the translation
procedure from English into Japanese, first we have to explain the Japanese writing system
and the differences in basic grammar. The Japanese language and its writing system were
described by early Christian missionaries as inventions of the devil. Understanding of them has
improved in the last 400 years (after many language reforms), but it remains true that written
Japanese is still unique in its complications (> Figure 16-7).
Kanji (logographic characters of Chinese origin) is used for nouns, the stems of adjectives
and verbs, and Japanese names. A kanji may have none, one, or several Chinese-derived
reading (on-yomi) and Japanese-derived reading (kun-yomi). On the other hand, a simple
English word could be expressed in many variations of Japanese characters, where the user’s
choice depends on the situation and context of the text (> Figure 16-8).
Accompanying letters (okurigana) are suffixes following kanji stems in Japanese written
words. Okurigana are written after the initial kanji for verbs and adjectives to give inflection
and to help disambiguate a particular kanji’s reading (Nishi, 2001). Therefore, the same kanji
character may be read by several different pronunciations depending on the full word. In
modern usage, okurigana are almost invariably written with hiragana. Hiragana (syllabic char-
acters) are used to write inflectional endings for adjectives and verbs, grammatical particles,
Japanese words that have no kanji, and indications of how to read kanji (furigana) (Nishi,
2001). Loanwords (foreign words borrowed from the European languages, especially English)
and names, commonly used animals, plants or objects (whose kanji are uncommonly used),
onomatopoeia, technical and scientific words (such as mineral names) are usually spelled in
katakana. On the other hand, modern written Japanese also uses the Latin alphabet (called
‘‘rōmaji’’) in the case of acronyms and abbreviations (e.g., UNESCO, QOL), company names,
brand or product names, and those scientific terms which are commonly used in studies,
but difficult to explain or no Japanese word for it, etc. (Nishi, 2001). Most simple Japanese
. Figure 16-7
Simple Demonstration of the Japanese writing system (with examples) Legend: Modern
Japanese writing system uses three main scripts called ‘‘kanji,’’, ‘‘hiragana’’ and ‘‘katakana’’ (see
the examples of these in this figure)
. Figure 16-8
Examples of kanji, hiragana and katakana characters for the word ‘‘CARE’’ in Japanese Legend:
This figure shows an example of the English word ‘‘care’’ with possible Japanese characters of
the same or very similar reading
sentences will have both kanji and hiragana in them and if it is a longer sentence, possibly
includes katakana and some words or abbreviation in Latin alphabet as well. Thus, translation
of any questionnaire into Japanese is rather a difficult task.
There are generation differences in the use of kanji, katakana and words with Latin
alphabet in the Japanese written language (Seeley, 1984). Usually older people use more
kanji, but less katakana and foreign words written with Latin alphabet. The capacity of
Japanese language to absorb innovations from abroad easily matches or exceeds that of English
or German. Recently, the largest Japanese language dictionary ‘‘Nihon Kokugo Daijiten’’ had
to be updated with hundreds of new katakana words and phrases, because of the intensive use
of new loanwords during the past 10–15 years. As a result of this update, now it includes the
phrase ‘‘quality of life’’ in its written katakana version as well (see in > Figure 16-7).
In linguistic typology, subject-verb-object (SVO) is a sentence structure where the subject
comes first, the verb second and the object third. Languages may be classified according to the
dominant sequence of these elements. Examples of languages that can follow an SVO pattern
are English, Chinese, Russian, Bulgarian, Malay, and Indonesian, etc. Japanese belongs to the
so-called SOV type of languages in which the subject, object, and verb of a sentence appear or
usually appear in that order (others are Korean, Mongolian, Hindi and most other Indian
languages, etc.). Therefore, there is a deep linguistic difference between the English (SVO) and
the Japanese (SOV) sentence structures, which makes it difficult to translate from one to
another.
Another difficulty appears when we try to find the best wording for the name of the subject
‘‘quality of life’’ in Japanese. In Japanese many variations exist for the translation of QoL, but
none of them found to be the most appropriate during the last 10 years. Thus, the Japanese
healthcare literature uses the original English phrase, sometimes written in English
(the full phrase or its abbreviation: QOL) or using the Japanese katakana characters (see in
> Figure 16-7).
Cultural differences arise when we look at the different scales and questions in the Asian
cultural context. Possibly the most problematic part in many Asian versions (i.e., Chinese,
Hindi, Korean, Japanese etc.) were questions related to sexual life and social activities. These
questions are considered too direct and have to be asked much more delicately in Asian
countries. It is a difficult task, because the EORTC translation protocol is strict and basically
do not allowed changing the original sentences. In general most translations go smoothly, but
these culture related problems occasionally occur. Most of these problems in translation
usually appear during the Pilot Testing of the questionnaire (West, 2002). The Japanese
versions have to be translated in a way to be acceptable by the patients (not offending or
disturbing), but without losing the meaning of the original English questions. However, some
questions are not possible to change in a way we would like. During the Japanese linguistic
validation of the head and neck module (QLQ-H&N35), where a question asked about
‘‘physical contact’’ with family members and friends, the translated sentence was very close
to the original English version, but it was somewhat misunderstandable for Japanese by
cultural reasons. It is culturally not customary to Japanese people to embrace, hug or kiss
with relatives or friends, hence during the Pilot Testing phase with Japanese patients, it was
often misinterpreted as sexual behavior (Toth and Tsukuda, 2004). To get around this problem
words explaining the nature of this type of physical contact (embrace, hug, holding hands etc.)
were added in brackets after the problematic question. Other questions related to social
activities and social contact with family members and friends were also difficult to understand
without examples. The final version used the same solution as the previous one, to give
examples within brackets. Re-administering the revised version of the QLQ-H&N35 module
with other patients resulted in good understanding of these questions, thus the QLG accepted
the revised Japanese version with examples after the problematic sentences (Toth et al., 2005).
On the other hand, we have to stress the fact that the translation should not modify the
original questionnaire (Cull et al., 2002).
During translation of the original English questions, allowance should be made for
grammatical differences. Some of the original English questions are asked ‘‘Have you
had. . .’’ (to continuous episodes) others ‘‘Did you have. . .’’ or ‘‘Do you have. . .’’ (to a single
instance). In the Japanese version these sentences are usually translated into simple past tense
in Japanese. Some common English words or questions are often a problem when translating
and during backward-translation from the local language the result doesn’t mach the original
one. The most commonly mistranslated word in the QLQ modules is ‘‘bothered’’ (West, 2002),
which is commonly used in English, but in many Asian languages it has no direct equivalent.
In general, the typical translation problems in Japanese versions of the QLQ modules include
missing characters and specific linguistic markers, incorrectly used or meaningless expressions
and culturally irrelevant or not acceptable wordings in the East Asian cultural context
(> Table 16-6).
. Table 16-6
Main translation problem types of EORTC QLQ modules in Japan
Problem Type
Semantic equivalence (meaning Consistency (time Cultural diversity/appropriateness
of words, expressions) related, expressions) (social domain, sexual life etc.)
This table shows the summary of main translation problems found during cultural validation of QLQ modules with
Japanese patients
In this Chapter reviewed the linguistic and psychometric validation of EORTC QoL
instruments in the Asian, especially in the Japanese cultural context. Presently, nine ques-
tionnaires and supplementary modules of the EORTC QLG are final validated Japanese
versions, one is under Pilot Testing, and three are in the translation phase. The limit of a
Chapter length does not allow us to review all these questionnaires one by one; therefore we
explained the most common problems and their solutions.
4 Conclusion
QoL is an integral part of assessing the outcome of a treatment of patients with cancer. The
clinician has a wide selection of validated questionnaires from which they can choose. This
makes it possible to include QoL as a standard outcome parameter in clinical trials. Defini-
tions of QoL are controversial because different instruments use different definitions, thus no
specific model for QoL is stated formally yet (Rogers et al., 2007). There is a wide range of QoL
instruments available, although this range is likely to be reduced once the purpose of evaluat-
ing QoL is considered. In a clinical trial setting, the disease area and therapies being evaluated
will usually limit the choice (Fayers and Machin, 2000). In the last 10–15 years researchers and
clinicians requested approval for using some of the EORTC QoL instruments in Asia, among
them are groups from China, Taiwan, Japan, Singapore, Iran and Turkey. These groups
translated and culturally validated the questionnaires and supplementary modules of the
EORTC for use in cancer patients in their own culture. The copyright of the translated
questionnaires belongs to the EORTC and all new studies need to sign an agreement form if
someone wants to use them again in clinical studies. The full translation report of a question-
naire should be forwarded to and confirmed by the Translations Coordinator at the QLU in
Brussels. After the linguistic validation of the questionnaire it should undergo a Field Testing
phase, where the questionnaire is administered to higher number of patients and its psycho-
metric properties are analyzed and compared with the observations made in the original
EORTC studies (Koller et al., 2007). Specific culturally and linguistically diverse problems were
reported from these Asian countries, but in most cases the local group and the QLU found the
solution by changing or modifying certain items. Further translations and cultural adaptations
are needed for the QoL measurement of cancer patients in the future.
In this Chapter, the important issues in QoL measurement in Japanese patients with cancer
have been explained and some of the literatures have been reviewed. We think that a clinician
is able to choose from several validated questionnaires; the basic choice is between a single
broad questionnaire designed specifically for a specific type of cancer patients, or a more
comprehensive set of questionnaires that have been developed for use in modules (e.g.,
EORTC, FACT). It is an important issue that every different country and culture has to have
QoL instruments translated and cross-culturally validated for the use of measure QoL.
Summary Points
Quality of Life means different things to different people, and takes on different meanings
according to the area of application.
Health-related Quality of Life refers to the degree to which a disease and its treatment affect
the patient’s perception of his/her ability to live a satisfying life.
The evaluation of health-related quality of life in patients with cancer is fundamental,
recognized as an important factor in assessing treatment outcome and became an impor-
tant end-point in clinical trials.
The availability of cross-culturally validated health-related quality of life questionnaires in
many languages is an important factor for international clinical research on cancer and its
treatment effects.
The original English versions of the EORTC QLQ modules were culturally adapted into
Japanese language with the use of a standardized, iterative, forward-backward translation
protocol and have undergone centralized quality control by the Translation Coordinator
within the EORTC Quality of Life Unit in Brussels.
During translation and cultural adaptation of the Japanese versions the following pro-
blems were perceived: lack of expressions for specific symptoms, difficulty to choose the
most understandable Japanese characters between medical terms and common language,
different priorities of social issues between Western and Japanese cultural context.
The Japanese versions of the EORTC QLQ modules have good psychometric validity, thus
they are recommended for further study to assess health-related quality of life in Japanese
cancer patients.
References
Aaronson NK. (1998). Eur J Cancer. 34: 767–769. Kurihara M, Shimizu H, Tsuboi K, Kobayashi K,
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Murakami M, et al. (1999). Psychooncology. 8:
Cull A, et al. (1993). J Natl Cancer Inst. 85: 365–376. 355–363.
Aaronson NK, Bullinger M, Ahmedzai S. (1988). Cancer List MA, D’Antonio LL, Cella DF, Siston A, Mumby P,
Res. 111: 231–249. et al. (1996). Cancer. 77: 2294–2301.
Bjordal K, de Graeff A, Fayers PM, Hammerlid E, van Matsui K, Lie RK. (2007). Eubios J Asian Int Bioeth. 17:
Pottelsberghe C, et al. (2000). Eur J Cancer. 36: 41–49.
1796–1807. Matsumoto T, Ohashi Y, Morita S, Kobayashi K,
Bjordal K, Kaasa S. (1992). Acta Oncol. 31: 311–321. Shibuya M, et al. (2002). Qual Life Res. 11: 483–493.
Bonomi AE, Cella DF, Hahn EA, Bjordal K, Sperner- Nakagawa Y, Daibo I. (1985). An Introduction to Mental
Unterweger B, et al. (1996). Qual Life Res. 5: Health Measurement: Japanese Version of the Gen-
309–320. eral Health Questionnaire (GHQ). Nihon Bunka
Bullinger M, Anderson R, Cella D, Aaronson N. (1993). Kagakusha Co., Tokyo.
Qual Life Res. 2: 451–459. Nishi G. (2001). Japanese Step by Step: An Innovative
Cheung YB, Thumboo J. (2006). Pharmacoeconomics. Approach to Speaking and Reading Japanese.
24: 643–650. McGraw-Hill, New York, NY.
Chie WC, Hong RL, Lai CC, Ting LL, Hsu MM. (2003). Nomura K. (ed.) (2005). Cancer Statistics in Japan 2005.
Qual Life Res. 12: 93–98. Vital and Health Statistics Division, Statistics and
Cull A, Sprangers MAG, Aaronson NK, Bjordal K, Information Department, Minister’s Secretariat,
West K, et al. (2002). European Organization for Ministry of Health, Labour and Welfare, Tokyo.
Research and Treatment of Cancer quality of life Ohno Y, Nakamura T, Murata K, Tsukuma H, Ajiki W,
study group translation procedure, 2nd ed. EORTC et al. (2004). In: Oshima A, Kuroishi T, Tajima K
Quality of Life Group, Brussels. (ed.) Cancer Statistics - Incidence, Mortality, and
Eguchi K. (1995). In: Urushizaki I (ed.) Guidebook of Survival - 2004. Shinohara Shuppan, Tokyo, pp.
Quality of Life Assessment and Questionnaires. Cancer 201–217.
and Chemotherapy Publishers INC, Tokyo, pp. 23–29. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE,
Einhorn LH. (2003). Support Care Cancer. 11: 620–622. et al. (1982). Am J Clin Oncol. 5: 649–655.
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran Onishi Y, Yamaura T, Tauchi K, Sakamoto T, Tsukada K,
D, et al. (2001). EORTC QLQ-C30 Scoring Manual, et al. (1998). Biol Pharm Bull. 21: 761–765.
3rd ed. EORTC Quality of Life Group, Brussels. Rogers SN, Ahad SA, Murphy AP. (2007). Oral Oncol. 43:
Fayers PM, Machin D. (2000). Quality of Life: Assess- 843–868.
ment, Analysis and Interpretation. Wiley, New York/ Schipper H, Levitt M. (1985). Cancer Treat Rep. 69:
Singapore. 1115–1125.
Fukuhara S, Bito S, Green J, Hsiao A, Kurokawa K. Seeley C. (1984). Visible Lang. 18: 267–302.
(1998). J Clin Epidemiol. 51: 1037–1044. Sprangers MA, Cull A, Bjordal K, Groenvold M,
Fumimoto H, Kobayashi K, Chang CH, Eremenco S, Aaronson NK. (1993). Qual Life Res. 2: 287–295.
Fujiki Y, et al. (2001). Qual Life Res. 10: 701–709. Sprangers MA, Cull A, Groenvold M, Bjordal K,
Gotay CC, Wilson M. (1998). Eval Health Prof. 21: Blazeby J, et al. (1998). Qual Life Res. 7: 291–300.
157–178. Statistics and Information Department Ministers Secretariat.
Groenvold M, Klee MC, Sprangers MA, Aaronson NK. (2007). Patient Survey (2005): Vol. 1 (All Japan). Health
(1997). J Clin Epidemiol. 50: 441–450. and Welfare Statistics Association, Tokyo.
Hjermstad MJ, Fossa SD, Bjordal K, Kaasa S. (1995). Stromborg MF (ed). (1998). Instruments for Clinical
J Clin Oncol. 13: 1249–1254. Nursing Research. Appleton & Lange, Norwalk, CT.
Kaasa S. (1992). Oncology. 49: 289–294. Tazaki M, Nakane Y, Endo T, Kakikawa F, Kano K, et al.
Karasawa K, Sasaki T, Okawa T, Takahashi T, Hayakawa (1998). Jpn J Clin Oncol. 28: 134–141.
K, et al. (2003). J Oncol Manag. 12: 18–24. Toth G, Sakaguchi T, Mikami Y, Hirose H, Tsukuda M.
Karnofsky DA, Burchemajh JH. (1949). In: McLeod CM (2005). Auris Nasus Larynx. 32: 175–183.
(ed.) Evaluation of Chemotherapeutic Agents. Toth G, Tsukuda M. (2003). Jibiinkoka Tenbo. 46:
Columbia University Press, New York, pp. 191–205. 368–383.
Kobayashi K, Takeda F, Teramukai S, Gotoh I, Sakai H. Toth G, Tsukuda M. (2004). Gan To Kagaku Ryoho. 31:
et al. (1998). Eur J Cancer. 34: 810–815. 461–467.
Koller M, Aaronson NK, Blazeby J, Bottomley A, Tsukuma H, Ajiki W, Oshima A. (2004). In: Tajima K,
Dewolf L, et al. (2007). Eur J Cancer. 43: 1810–1820. Kuroishi T, Oshima A (ed) Gann Monograph on
Cancer Research (2004) Japan Science Society Press, Yokoyama K, Araki S, Kawakami N, Takeshita T. (1990).
Tokyo, pp. 95–130. Nippon Koshu Eisei Zasshi. 37: 913–918.
West K. (2002). Quality of Life Group, Newsletter, Issue Yu F, Takahashi T, Moriya J, Kawaura K, Yamakawa J,
2, pp. 2–4. et al. (2006). J Int Med Res. 34: 231–239.
Weymuller EA Jr., Alsarraf R, Yueh B, Deleyiannis FW,
Coltrera MD. (2001). Arch Otolaryngol Head Neck
Surg. 127: 489–493.
1 Instruments and Methodological
Aspects
1.2 Contemporary Issues in
Assessment
17 Calculating QALYs and
DALYs: Methods and
Applications to Fatal and
Non-Fatal Conditions
F. Sassi
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
1.1 The Development of QALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
1.2 The Development of DALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
1.3 Additional Sources on QALYs and DALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
2 Calculating DALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

2.1 Disability Followed by Premature Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
2.2 Switching Off Age-Weighting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
3 Calculating QALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

3.1 QALYs with Quality of Life Varying over Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
4 Comparing QALYs and DALYs: Practical Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

4.1 A Non-Fatal Condition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
4.2 A Potentially Fatal Condition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
5 Convergence and Divergence Between QALYs and DALYs . . . . . . . . . . . . . . . . . . . . . . . . 325
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

314 17 Calculating QALYs and DALYs: Methods and Applications to Fatal and Non-Fatal Conditions
Abstract: Quality-adjusted life years (QALYs) have been used in the assessment of health
interventions for three decades. The popularity of the QALY approach has been constantly
increasing, although the debate on its theoretical underpinnings and practical implications
is still ongoing. Disability-adjusted life years (DALYs), also widely debated, were shaped some
20 years later, broadly within the same conceptual framework but with a number of important
differences.
This chapter provides an illustration of DALY and QALY calculation methods, offering
practical instruments for assessing the impact of health interventions. Systematic differences
between QALYs and DALYs are explained by reference to two examples: the prevention of
tuberculosis, and the treatment of bipolar depression. When a health intervention is aimed at
preventing or treating a non-fatal disease the relationship between QALYs gained and DALYs
saved depends on age of onset and duration of the disease, as well as by quality of life and
disability weights. In the case of a potentially fatal disease, a larger number of factors may
determine differences between outcomes assessed with the two metrics. The relative impor-
tance of some of these factors is discussed and graphically illustrated in the chapter. Under-
standing similarities and differences between QALYs and DALYs is important to researchers
and policy makers, for a sound interpretation of the evidence on the outcomes of health
interventions.
List of Abbreviations: DALY, disability-adjusted life year; GBD, global burden of disease
(study); QALE, quality-adjusted life expectancy; QALY, quality-adjusted life year; YLD, year of
life lived with disability; YLL, year of life lost
1 Introduction
Quality-Adjusted Life Years (QALYs) and Disability-Adjusted Life Years (DALYs) are today
the most commonly used health outcome measures among those that combine length of
life and health status. The ways in which these two measures developed, and the timing of
their development, are very different. QALYs developed gradually as a multi-disciplinary effort
of the academic community to overcome the limitations of the uni-dimensional health
outcome measures that dominated clinical medicine and epidemiology and the social sciences
up to the 1970s. The development of DALYs came substantially later, in the early 1990s, and
was rather more sudden. DALYs were also the result of a multi-disciplinary academic effort,
but unlike QALYs, they were developed specifically to fulfil a mandate by the World Bank to
devise a measure that could be used in world-wide comparisons of health outcomes, or burden
of disease, and in the assessment of the value of interventions to reduce that burden. Partial
overlap between the two measures has occurred, in particular, in the latter area. Both QALYs
and DALYs can be used, and have been used, in the assessment of the cost-effectiveness of
health interventions, although only QALYs were primarily devised for this purpose.
QALYs and DALYs are based on similar conceptual frameworks and share many features.
However, in their most typical forms, they are not interchangeable. Among the main differ-
ences, it is worth mentioning, in particular, the approaches used to measure health-related
quality of life and disability, respectively, in QALY and DALY calculations, and the presence
of an age-weighting function in DALYs. Approaches to health status measurement could in
principle be swapped, and age-weighting could be switched off in DALYs or added to QALYs,
without transforming either measure into something totally different. But when QALYs and
Calculating QALYs and DALYs: Methods and Applications to Fatal and Non-Fatal Conditions 17 315
DALYs preserve their most typical features, estimates of health outcomes based on the two
measures are likely to diverge, at least to some extent.
1.1 The Development of QALYs
The QALY was developed in the early 1970s, initially as a ‘‘health status index’’ combining
duration and quality of life (Fanshel and Bush, 1970; Torrance, 1970; Torrance et al., 1972),
although an earlier study of the treatment of chronic renal disease (Klarman et al., 1968) had
used a subjective adjustment for quality of life. Early applications of the health status index
include one on tuberculin screening (Bush et al., 1972) and one on screening for phenylke-
tonuria (Bush et al., 1973). The term quality-adjusted life year appeared only a few years later
(Zeckhauser and Shepard, 1976), while the underlying assumptions of the QALY model were
spelled out by Pliskin et al. (1980), who demonstrated that the QALY maximization criterion is
justified in a multiattribute utility theory framework under the following conditions: utility
independence between life years and health status; constant proportional tradeoff; and risk
neutrality over life years. These conditions and the utility theory foundations of QALYs were
further discussed in a number of contributions, including those of Myamoto and Eraker
(1985), Loomes and McKenzie (1989), Mehrez and Gafni (1989). A study by Williams (1985)
on coronary artery bypass grafting, published in the British Medical Journal and later identified
in a poll of health economists as the single most influential health economics paper, made the
QALY concept accessible to a wide audience of researchers, health care professionals and policy
makers. An extensive review published in 1992 counted 51 economic evaluations using
QALYs as the outcome measure (Gerard, 1992). Only a few years later the QALY framework
was widely accepted as the reference standard in cost-effectiveness analysis (Drummond et al.,
2005; Gold et al., 1996; McPake et al., 2002), amid a continuing debate on its theoretical
underpinnings and practical implications (e.g., Bleichrodt and Johannesson, 1996). Today,
QALYs are used in most economic evaluations, and by many regulatory agencies which have
made cost-effectiveness analysis an integral part of their decision making processes.
1.2 The Development of DALYs
The QALY framework provided a basis for the development of a number of health outcome
measures, including the DALY in the early 1990s. The DALY is primarily a measure of disease
burden (disability weights measure loss of functioning) but its use in cost-effectiveness
analysis is also relatively common. As a measure of outcome in economic evaluation, the
DALY differs from the QALY in a number of respects. Most importantly, the DALY incorpo-
rates an age-weighting function assigning different weights to life years lived at different ages.
In addition, health-related quality of life weights used in QALY calculations differ from
disability weights (D) used in DALY calculations. Although measured on similar scales, the
former represent levels of quality of life enjoyed by individuals in particular health states, while
the latter represent levels of loss of functioning caused by diseases. The former are normally
measured on a scale in which 1 represents full health and 0 represents death, therefore higher
values correspond to more desirable states and states deemed worse than death can take
negative values. The latter are measured on a scale in which 0 represents no disability, therefore
lower scores correspond to more desirable states. The two types of weights are also derived in
different ways, using different elicitation techniques and different groups of subjects. In
practice, DALY calculations tend to be based on a universal set of standard weights based on
expert valuations, while QALY calculations often rely on preference-based health-related
quality of life measures directly elicited from general population samples or from groups of
patients. The most common preference elicitation techniques are the standard gamble and the
time trade-off, both choice-based (Torrance, 1986). These may be applied directly, or indirectly
in the assessment of the value of individual dimensions of multi-attribute systems like the
Health Utilities Index (Torrance et al., 1996) or the EuroQOL (Dolan, 1997).
Although the disability profiles upon which DALY calculations are based tend to be simple
(e.g., a constant disability is often assumed), the actual calculations may be relatively compli-
cated (e.g., see: Murray, 1994; Fox-Rushby and Hanson, 2001). On the other hand, quality of
life profiles (or health profiles) for QALY calculations tend to be more elaborate, allowing for
sequential upward or downward health status changes over time, but the corresponding
calculation methods can be made less cumbersome by using a discrete approximation of a
continuous health function (Drummond et al., 2005). An early mathematical formulation of a
QALY-type measure, the ‘‘health status unit years,’’ was produced by Torrance (1976) with
reference to a population perspective. Sassi (2006) provided a comprehensive mathematical
formulation of QALYs, upon which this chapter relies in part.
1.3 Additional Sources on QALYs and DALYs
This chapter illustrates the methods for calculating QALYs and DALYs. The chapter also
provides two practical examples, in which the results of QALY and DALY calculations are
compared and systematic differences are shown.
Readers may refer to other sources for a more detailed discussion of the conceptual and
methodological differences between the two measures. In particular, Broome (1993) provides
a detailed discussion of the conceptual framework of QALYs, while methods for eliciting
health state utility values are presented in Torrance (1986). Readers may refer to Loomes and
McKenzie (1989) and Mehrez and Gafni (1989) for a critique of the utility framework on
which QALYs are based, and to Sassi et al. (2001) for a review of the ethical and distributional
issues involved. Most of the challenges to the QALY framework have been based on the
difficulties involved in making interpersonal comparisons and aggregating individual utilities;
on the assumptions on which health utility elicitation methods are based; and on the implicit
discrimination against the elderly and the chronically ill or disabled. The debate on the
conceptual framework, key assumptions and ethical implications of DALYs is illustrated in
Anand and Hanson, 1997; Murray and Acharya, 1997; Williams, 1999; Arnesen and Nord,
1999. Key challenges to the DALY framework have focused on the equity implications of age-
weighting and of the standard life expectancy assumption used in cross-country comparisons,
but also on the methods used to assess disability weights. A direct comparison of the two
measures is presented in Gold et al. (2002).
2 Calculating DALYs
Whether used as part of burden of disease calculations, or in the context of a cost-effectiveness

analysis, the number of DALYs lost by one person in 1 year is a function of the level of
disability (D) experienced by the person in that particular year. The disability weight D will
take a value between 0 (no disability) and 1 (complete disability). Due to the presence of an
age-weighting function in the typical formulation of DALYs, the number of DALYs lost in one
particular year depends also on the age of the individual in that particular year. Therefore:
DALYs lost in one year ¼ DCxebx with 0 < D < 1
where e is Napier’s mathematical constant, x is the age of the person in question, while C and b
are parameters of the age weighting function, which give the latter function its characteristic
shape, as shown in > Figure 17-1.
DALYs lost over a certain period of time, e.g., someone’s residual life expectancy, can
simply be calculated as the sum of all DALYs lost in each year of life lived within the period, as
follows:
X
aþL
DALYs lost ¼ DCxebx
x¼a
. Figure 17-1
Alternative DALY age-weighting functions. Alternative shapes of age-weighting functions
for DALY calculations, based on the following three alternative sets of parameters, respectively:
(a) GBD parameters, C = 0.1658; b = 0.04; (b) C=0.25; b= 0.04; (c) C = 0.1658; b = 0.05
However, DALYs are traditionally formulated as a continuous, rather than discrete, function of
time. They are also discounted at a constant rate to account for time preferences. Therefore,
the number of DALYs lost over a period of time is usually calculated using the following
integral formulation:
ð
x¼aþL
DALYs lost ¼ DCxebx erðxaÞ dx ð1Þ

x¼a
2.1 Disability Followed by Premature Death
Of course, the integral formulation above involves that the level of disability D remains
constant throughout the period (L) over which DALYs lost are calculated. Therefore, the
formula is appropriate when calculating the loss of DALYs due to a constant level of disability
over a period of time, or when calculating the loss of DALYs due to premature mortality
(D = 1), but it is not sufficient when calculating the loss of DALYs in relation to a period of
disability followed by premature death. In the latter case, D is no longer a constant for the
entire duration of the period in question. More specifically, D will take a value between 0 and 1
during the period lived with disability, and it will take a value of 1 for the period representing
the life expectancy lost as a consequence of premature mortality. Essentially:
ð i
x¼aþL ð i þLii
x¼aþL
bx rðxaÞ
DALYs lost ¼ DCxe e dx þ Cxebx erðxaÞ dx ð2Þ
x¼a x¼aþLi
with 0 < D < 1

Where the first component of the formula reflects years lived with disability (YLDs),
during the period Li, while the second reflects years of life lost (YLLs) due to premature
mortality causing a loss of potential residual life expectancy Lii. Integrating by parts, the two
integrals, respectively, for YLDs and YLLs, can be resolved as follows:
DCera n ðrþbÞðaþLi Þ o
YLDs ¼ 2
e ½ðr þ bÞða þ Li Þ 1 eðrþbÞa ½ðr þ bÞa 1 ð2aÞ
ðr þ bÞ
Cera n
YLLs ¼ eðrþbÞðaþLi þLii Þ ½ðr þ bÞða þ Li þ Lii Þ 1
ðr þ bÞ2 ð2bÞ
o
ðrþbÞðaþli Þ
e ½ðr þ bÞða þ Li Þ 1
Unlike DALY calculation formulas provided elsewhere, those illustrated above for YLDs and
YLLs directly generate present (discounted) values of DALYs lost at age a, without requiring
further calculations. In fact, when an individual is expected to live with a disability for a
certain period of time and then die prematurely, the loss of disability adjusted life expectancy,
including both YLDs and YLLs, should generally be calculated as a present value at the start of
the period of disability, i.e., at age a (although this is not necessarily the case for YLLs, as
discussed below).
Standard DALY calculation methods involve setting Lii as the residual life expectancy at the
time of premature death (age = a + Li), based on the relevant life-tables. This may generate
inconsistencies, in particular when DALYs are used in the context of a cost-effectiveness

analysis. For instance, the number of DALYs saved by an intervention which increases life
expectancy by a given length of time will decrease as the age at which the intervention is
delivered increases. To avoid such inconsistencies, it is advisable to calculate the residual life
expectancy at age a, based on relevant life-tables, and determine the number of years of life
lost, before age-weighting and discounting (Li + Lii), as the difference between such residual
life expectancy value and the number of years lived with disability, again before age-weighting
and discounting (Li). However, if the latter method is followed, this must be declared explicitly
when reporting the results of DALY calculations, in order to avoid potentially misleading
comparisons with figures based on different approaches.
A further issue regarding life expectancy in DALY calculations is that the appropriate life-
tables from which this should be derived vary depending on the purpose of the DALY
calculations that are being undertaken. In the Global Burden of Disease study (Murray,
1994) a standard life table was used as a common reference for all countries, to prevent the
adverse distributional implications involved in making comparisons across countries with
widely different levels of life expectancy. However, when DALY calculations are set in a specific
national context, country-specific life-tables would be the appropriate reference in DALY
calculations (e.g., see Fox-Rushby and Hanson, 2001).
2.2 Switching Off Age-Weighting
As mentioned in the previous section, DALYs typically incorporate an age-weighting function,

but the latter is not an indispensable feature of DALYs. In some instances (e.g., Murray and
Acharya, 1997), the age-weighting function is multiplied by a binary constant K, which can
take the value of 0 or 1, used as a switch to include (K = 1) or exclude (K = 0) age-weighting
when calculating DALYs lost. When age-weighting is switched off, DALY calculations are
simplified as follows:
ð
x¼aþL
1 erL
DALYs lost ¼ DerðxaÞ dx ¼ D ð3Þ
r
x¼a
when D is constant throughout the period over which the loss of DALYs is calculated.
Alternatively, when a period of disability (with D between 0 and 1) is followed by premature
death (equivalent to D = 1), YLDs have to be added to YLLs, and the DALY calculation
formula, in the absence of age-weighting, becomes as follows:
ð i
x¼aþL ð i þLii
x¼aþL
rðxaÞ D þ ð1 D erLii ÞerLi
DALYs lost ¼ De dx þ erðxaÞ dx ¼
r
x¼a x¼aþLi
ð4Þ
with 0 < D < 1

Where, as before, Li and Lii represent, respectively, the number of years lived with
disability, before discounting, and the number of years of life expectancy lost as a consequence
of premature death, again before discounting.
3 Calculating QALYs
Quality adjusted life years (QALYs) are primarily used to correct someone’s life expectancy
based on the levels of health-related quality of life they are predicted to experience throughout
the course of their life, or part of it. The number of QALYs lived by an individual in 1 year is
simply:
QALYs lived in one year ¼ 1 Q with Q 1;
where Q is the health-related quality of life weight attached to the relevant year of life.
From this descends that someone’s quality adjusted life expectancy (QALE) at age a can be
calculated as:
X
aþL
QALE ¼ Qt ;
t¼a
where L is the average residual life expectancy of the individual at age a, and t represents
individual years within that life expectancy range. If someone’s quality of life is predicted to
change over shorter than yearly periods, t can be taken to represent correspondingly shorter
units of time, such as a month, a week or even a day. In these cases L will have to be defined
consistently. When time preference, and thus discounting, are incorporated into the equation,
QALE becomes:
X
aþL
Qt
Discounted QALE ¼ ;
t¼a ð1 þ rÞta
where r is the discount rate.

However, QALYs are rarely used to simply assess someone’s quality adjusted life expectancy.
The main use of QALYs is within the framework of cost-effectiveness analysis, to assess the
improvement in quality adjusted life expectancy obtained through a specific health interven-
tion (i) relative to a situation in which either no intervention or a standard alternative
intervention is provided. In such analysis, the number of QALYs gained can be determined
as follows:
aX
þLi X
aþL
Qit Qt
QALYs gained ¼ ta ta ;
t¼a ð1 þ rÞ t¼a ð1 þ rÞ
where Qi is a vector of health-related quality of life weights predicted (or observed) for each
time period t following the intervention. When QALY calculations are undertaken for the
purpose of assessing the QALY gain following an intervention, the focus is on the time period
during which an individual is affected by a disease, or by the effects of its treatment. Therefore
L should be defined as the duration of the disease, while Li is the period over which the
individuals enjoys the benefits of treatment (or possibly suffers the adverse consequences
of it). Normally, the period Li will be at least as long as L, but it will be longer than L when
treatment extends the individual’s life expectancy (in this case Li will correspond to the
individual’s entire life expectancy with treatment), or when treatment may negatively affect
the individual’s quality of life for a period longer than L (in this case, Li will correspond to the
entire period over which treatment affects the individual’s quality of life).
QALYs do not incorporate an age-weighting function. Therefore, one QALY has always the
same value, regardless of the age at which it is lived, although this does not imply neutrality
over age distributions (Sassi et al., 2001). Discounting procedures are also different in QALYs
and DALYs (discrete the first, continuous the second). If the DALYdiscounting procedure were
applied, the QALE formula could be revised as:
ð
aþL
1 erL
QALE ¼ QerðxaÞ dx ¼ Q ð5Þ
r
x¼a
where x is the individual’s age. The corresponding QALYs gained formula follows from this:
i
1 erL 1 erL
QALYs gained ¼ Qi Q ð6Þ
r r
Where Li and Qi are, respectively, the period over which treatment affects the individual’s
quality of life, and the quality of life weight with treatment; while L and Q are the
corresponding parameters without treatment.
When treatment does not affect the duration of the disease, but only the individual’s
quality of life, i.e., when Li = L, (> equation 2) becomes:
1 erL
QALYs gained ¼ ðQi QÞ ð7Þ
r
3.1 QALYs with Quality of Life Varying over Time
> Equations (1–3) are based on the assumption that health-related quality of life remains
constant throughout the individual’s residual life expectancy, or disease duration. While this
assumption is common in DALY calculations, it is much less so in QALY calculations, in which
health-related quality of life is normally allowed to vary with disease progression. A more
general formula for calculating QALE, which allows quality of life to vary over time, can be
developed by assuming that the individual’s residual life expectancy (L) is divided into N
consecutive time periods nm (with 1 mN), each upper-delimited by time point tm, whereby
tN = a + L, and each characterized by a level of health-related quality of life Qm. The time
periods nm may be of different duration. Based on this information, the QALE formula can be
rewritten as:
X
N
erðtm aÞ erðtm1 aÞ
QALE ¼ Qm with t0 ¼ a ð8Þ
m¼1
r
The formula for calculating the number of QALYs gained through an intervention i follows
directly from the above:
X
P
erðtp aÞ erðtp1 aÞ X
i i
N
erðtm aÞ erðtm1 aÞ
QALYs gained ¼ Qip Qm ð9Þ
p¼1
r m¼1
r
where the life expectancy with the intervention (Li) is divided into P time periods np, defined
in the same way as the nm above, and Qpi is a vector of health-related quality of life weights
predicted (or observed) for each time period np following the intervention, as illustrated in
> Figure 17-2.
. Figure 17-2
Health profiles with variable quality of life. Quality-adjusted life expectancy profiles with
intervention i (solid line), and without intervention (broken line)
4 Comparing QALYs and DALYs: Practical Examples
The calculation methods illustrated in the previous sections will be applied in two examples,
one on tuberculosis, a temporary non-fatal disease, and one on bipolar disorder, a chronic
disease potentially affecting life expectancy. In both examples, it is initially assumed that the
loss of quality of life determined by the respective diseases in QALY calculations is equivalent
to the level of disability estimated in DALY calculations (i.e., 1-Q = D). This assumption will
be subsequently dropped to illustrate the impact of potential differences between the two
measures. A 3% discount rate is used, in line with the Global Burden of Disease (GBD) study.
Finally, quality of life is assumed stable throughout the duration of the disease.
4.1 A Non-Fatal Condition
An individual affected by tuberculosis will experience a temporary, non-fatal disability, if the

disease is appropriately diagnosed and treated. The level of disability attributed to tuberculosis
in the GBD study varies in a relatively narrow range (0.264–0.294), depending on the age of
the individual affected. In this example we shall use the disability weight (D) for the age group
45, i.e., 0.274. Therefore, under the assumption that Q = 1-D, the corresponding quality of
life weight Q (life with tuberculosis) will be 0.726.
The number of QALYs an individual will live while affected by the disease can be
determined using (> equation 5). We shall assume that the average duration of the disease
(L) is 6 months (or 0.5 of 1 year). Therefore:
1 e0:030:5
QALYs lived while affected by TB ¼ 0:726 ¼ 0:36;
0:03
If such a case of tuberculosis could be prevented, for instance by administering a vaccine, 0.14
QALYs would be gained by the individual. This can be determined using (> equation 6) as
follows:
1 e0:030:5
QALYs gained ¼ ð1 0:726Þ ¼ 0:14;
0:03
The corresponding loss of DALYs due to the same episode of tuberculosis may be measured
using (> equation 1), which can be solved as illustrated in (2a) to calculate YLDs (there are no
years of life lost in this example). In practice, based on the following values, which include the
standard GBD age-weighting parameters:
D (disability weight) = 0.274
r (discount rate) = 0.03
C (age-weighting constant) = 0.1658
b (age-weighting parameter) = 0.04
a (age at disease onset) = 45
L (duration of disability) = 0.5 (years)
The number of DALYs lost would be as follows:
DALYs (YLDs) lost due to tuberculosis = 0.17: > Figure 17-3 shows the number of QALYs-
gained by preventing one case of tuberculosis, as a function of the expected duration of the
disease, had it not been prevented. The same figure also shows what the corresponding
numbers of DALYs saved would be, depending on the age of onset of the disease, had this
not been prevented. For convenience and ease of comparison it has been assumed that
D = 0.274 for all ages. The figure shows that, for most age groups, numbers of QALYs gained
and DALYs saved tend to diverge progressively as disease duration becomes longer.
The impact of dropping the assumption Q = 1-D can be assessed by using appropriate
quality of life weights for tuberculosis. Dion et al. (2002) report a mean standard gamble value
of 0.68 for moderate disease. If this was used in QALY calculations, the QALY gain would
change to 0.16, and this would vary with disease duration as illustrated by the relevant curve in
> Figure 17-3.
4.2 A Potentially Fatal Condition
Our second example refers to a chronic disease affecting both quality and duration of life, and
is based on a case described by Fox-Rushby and Hanson (2001) to illustrate DALY calculations.
A Chilean woman becomes affected by bipolar depression at age 35. In the absence of
treatment, this woman would live a further 10 years with a disability (D) of 0.6 and then
die. The woman’s quality-adjusted life expectancy (QALE) at the age of disease onset can be
calculated using (> equation 5). It is initially assumed that Q = 1-D = 0.4. The life expectancy
. Figure 17-3
Benefits of preventing a non-fatal disease, by disease duration. Comparison of QALYs gained
and DALYs saved under alternative assumptions regarding age at disease onset (DALYs)
and quality of life weights (QALYs)
lost is simply ignored, as QALYs focus on the duration and quality of life of the years actually
lived by individuals.
1 e0:0310
QALE ¼ 0:4 ¼ 3:46;
0:03
If treatment were available, the woman would be able to live her entire residual life expectancy,
with a disability reduced to 0.302 for the rest of her life. Female life expectancy in Chile at the
age of 35 is 44.13 years, therefore:
1 e0:0344:13
QALE with treatment ¼ 0:698 ¼ 17:08;
0:03
The QALY gain is the difference between the woman’s QALE with and without treatment – as
in (6):
QALYs gained ¼ 17:08 3:46 ¼ 13:62
On the other hand, the number of DALYs lost in the case of bipolar depression illustrated here
can be calculated on the basis of (2), by adding years of life lived with disability (as in 2a) and
years of life lost (as in 2b), using the following values for the relevant parameters:
D (disability weight) = 0.6
r (discount rate) = 0.03
C (age-weighting constant) = 0.1658
b (age-weighting parameter) = 0.04

a (age at disease onset) = 35
Li (duration of disability) = 10 years
Lii (potential life expectancy lost) = 34.13 years (equivalent to residual life expectancy at age
35, i.e., 44.13 years, minus 10 years of life lived with disability)
which generate the following result:
DALYs lost due to bipolar depression = 21.67: In order to assess the number of DALYs saved
through treatment, the difference between the above figure and the number of DALYs that
would be lost in the presence of treatment should be calculated. To determine the latter,
(> equation 1) may be used, as in this case no loss of life expectancy is involved, with the
parameter L taking the value of the woman’s residual life expectancy at age 35, i.e., 44.13 years.
DALYs saved through treatment for bipolar depression = 13.721: Given the assumptions
made here, and given the use of the same discounting procedure in QALY and DALY
calculations, the difference between the two measures in this example is entirely attributable
to the age weighting factor (included in DALY calculations but not in QALY calculations).
When Li≠L, the relationship between QALYs gained and DALYs saved is determined by a
large number of parameters, including: the quality of life, or disability, weights with and
without treatment; the age of onset of the disease; the duration of the disease with and without
treatment.
If the assumption that Q = 1-D is relaxed, appropriate quality of life weights can be used to
assess the value of Q. Tsevat et al. (2000) report a mean (standard gamble) utility of 0.77 in a
sample of patients undergoing various types of treatment. Applying this in QALY calculations
leads to a QALY gain figure of 15.38 (instead of 13.62) in the baseline case. > Figure 17-4
illustrates how QALYs gained and DALYs saved vary in relation to changes in age of disease
onset (a), which is the factor potentially generating the largest divergence between the two
measures, when Q = 1-D, while other factors have more limited impact. However, even
relatively small departures of the value of Q from 1-D may determine substantial differences
between QALYs gained and DALYs saved.
5 Convergence and Divergence Between QALYs and DALYs
This chapter provides an illustration of calculation methods for DALYs and QALYs, both for
assessing disability- and quality-adjusted life expectancy and for measuring the outcomes of
health interventions. Two examples in different disease areas have shown that age of disease
onset is an important factor determining variations between numbers of QALYs gained and
DALYs saved, when interventions are compared using the two metrics. The pattern of varia-
tion is mostly dictated by the shape of the age-weighting function. QALYs gained exceed
DALYs saved when disease starts in the very early years of life and is of short duration; when
the disease starts in later years, up to young adulthood, DALYs saved exceed QALYs gained
sometimes by a relative large margin; finally, when the disease starts in late adulthood and in
1
Fox-Rushby and Hanson indicate the slightly different figure of 13.81 DALYs saved. This is because, in their
calculation of Years of Life Lost (YLL), Fox-Rushby and Hanson determine the loss of life expectancy (L) as the
‘‘standard expectation of life at age (of death),’’ rather than the expectation of life at the time of disease onset minus the
number of years lived with disability
. Figure 17-4
Benefits of preventing a potentially fatal disease. Comparison of QALYs gained and DALYs
saved under alternative assumptions regarding age at disease onset (DALYs) and quality of life
weights (QALYs)
older ages, QALYs gained again exceed DALYs saved. These conclusions are based on the use of
the age-weighting function originally proposed in the GBD study (Murray and Lopez, 1996),
still most widely applied in DALY calculations. Results would have been different if based on a
different function, or if QALYs had been age-weighted too, as advocated by some (see Sassi
et al., 2001 for a discussion).
The examples have also shown that differences between quality of life and disability
estimates may cause further divergence between QALYs gained and DALYs saved. In some
cases, estimates of the loss of quality of life used in QALY calculations may be very close, or
equal, to disability estimates used in DALY calculations. However, variations can often be
expected in either direction. In our examples, we have used quality of life weights derived from
the literature to illustrate the possible extent of such variations.
The examples in this chapter are based on the assumption that the assessment of the
relevant interventions is country-specific. Instead, the original formulation of DALYs for the
GBD study was aimed at supporting cost-effectiveness comparisons on a global scale, therefore
a standard life expectancy was assumed in order not to disadvantage populations with a
shorter actual life expectancy. The two approaches may lead to different results, an example
being an intervention that avoids premature mortality caused by a given disease (as in the
second example above). The standard life expectancy assumption leads to a consistently larger
estimate of DALYs saved, and the difference is greater where actual life expectancy is shorter.
Although QALYs and DALYs stem from the same broad conceptual framework, they are
not completely interchangeable, as they are partly based on different assumptions and
different methodologies (for instance, methods for eliciting quality of life and disability
scores). Understanding systematic differences between the two measures is important to
enabling policy makers to form a sound judgment on the existing evidence about the out-
comes of health interventions.
Summary Points
Quality-adjusted life years (QALYs) and disability-adjusted life years (DALYs) are health
outcome measures that may be used in the assessment of the burden associated with a
disease, in terms of reduced longevity and impaired health, or in the context of a cost-
effectiveness analysis aimed at evaluating the impact of health interventions.
QALYs and DALYs share many features, but they are not completely interchangeable. Two
important differences in the most typical formulations of the two measures concern the
approaches used in determining quality of life and disability weights, and the fact that
DALYs, unlike QALYs, incorporate an age-weighting function that assigns different values
to years of life lived at different ages.
The framing of QALYs differs from that of DALYs, as the former are designed to estimate
health gains while the latter to estimate the burden associated with given diseases. When
used in the context of a cost-effectiveness analysis, the benefits of an intervention may be
measured either in terms of QALYs gained or DALYs saved.
In the case of non-fatal diseases, DALYs are used to measure years of life lived with
disability. In the case of potentially fatal diseases leading to premature mortality, DALYs
are used to measure years of life lost, as well as years of life lived with disability.
In their most typical formulations, QALYs display a greater flexibility than DALYs in
accounting for varying levels of quality of life over time, and offer greater opportunities to
tailor approaches for measuring quality of life to the characteristics of specific settings.
When DALYs incorporate age weights, as they most commonly do, the single most
important factor determining a divergence of measures of health outcomes based on
QALYs and DALYs is the age of the individual at the onset of the disease. The extent of
such divergence depends on the shape of the age-weighting function used but, generally,
the values of DALY-based measures exceed those of QALY-based measures when diseases
arise in late childhood or early adulthood, otherwise the opposite is true.
References
Anand S, Hanson K. (1997). J Health Econ. 16(6): Bush JW, Fanshel S, Chen MM. (1972). J. Socio-Econ
685–702. Plan Sci. 6: 49–69.
Arnesen T, Nord E. (1999). BMJ. 319(7222): 1423–1425. Dion M, Tousignant P, Bourbeau J, Menzies D, Schwartz-
Bleichrodt H, Johannesson M. (1996). Med Decis man K. (2002). Med Decis Making. 22: s102–s114.
Making. 17: 21–32. Dolan P. (1997). Med Care. 35(11): 1095–1108.
Broome J. (1993). J Public Econ. 50: 149–163. Drummond MF, Sculpher MJ, Torrance GW, O’Brien BJ,
Bush JW, Chen MM, Patrick DL. (1973). Health status Stoddart GL. (2005). Methods for the Economic
index in cost-effectiveness analysis of PKU Evaluation of Health Care Programmes. Oxford
programme. In: Berg RL (ed.) Health Status Indexes. University Press, Oxford.
Hospital Research and Educational Trust, Chicago. Fanshel S, Bush JW. (1970). Oper Res. 18(6): 1021–1066.
Fox-Rushby J, Hanson K. (2001). Health Policy Plan. Myamoto JM, Eraker SA. (1985). Med Decis Making.
16(3): 326–331. 5: 191–213.
Gerard K. (1992). Health Policy. 21(3): 249–279. Pliskin JS, Shepard DS, Weinstein MC. (1980). Oper Res.
Gold MR, Siegel JE, Russell LB, Weinstein MC. (ed.) 28(1): 206–224.
(1996). Cost-Effectiveness in Health and Medicine. Sassi F. (2006). Health Policy Plan. 21(5): 402–408.
Oxford University Press, New York. Sassi F, Archard L, Le Grand J. (2001). Health Technol
Klarman HE, Francis JOS, Rosenthal GD. (1968). Med Assess. 5(3): 1–138.
Care. 6(1): 48–54. Torrance GW. (1970). A Generalized Cost-Effectiveness
Loomes G, McKenzie L. (1989). Soc Sci Med. 28: Model for the Evaluation of Health Programs.
229–308. Research Report 101. McMaster University, Faculty
McPake B, Kumaranayake L, Normand C. (2002). Health of Business, Hamilton.
Economics. An International Perspective. Routle- Torrance GW. (1976). Manage Sci. 22(9): 990–1001.
dge, London. Torrance GW. (1986). J Health Econ. 5(1): 1–30.
Mehrez A, Gafni A. (1989). Med Decis Making. 9: Torrance GW, Feeny DH, Furlong WJ, Barr RD, Zhang Y,
142–149. Wang Q. (1996). Med Care. 34(7): 702–722.
Murray C. (1994). Bull World Health Organ. 72(3): Torrance GW, Thomas WH, Sackett DL. (1972). Health
429–445. Serv Res. 7(2): 118–133.
Murray CJ, Acharya AK. (1997). J Health Econ. 16(6): Tsevat J, Keck PE, Hornung RW, et al. (2000). Qual Life
703–730. Res. 9(5): 579–586.
Murray CJL, Lopez AD. (ed.) (1996). The Global Burden Williams A. (1985). Br Med J. 291: 326–329.
of Disease: A Comprehensive Assessment of Mortal- Williams A. (1999). Health Econ 8: 1–8.
ity and Disability from Diseases, Injuries and Risk Zeckhauser R, Shepard DS. (1976). Law Contemp Probl.
Factors in 1990 and Projected to 2020. Harvard 40: 5–45.
University Press, Cambridge, MA.
18 Accuracy of Death
Certifications and the
Implications for Studying
Disease Burdens
J. R. Pierce . A. V. Denison
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
2 History of Death Certification and Vital Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
3 Vital Statistics in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
4 Certification of Fetal Death and Abortion Certifications . . . . . . . . . . . . . . . . . . . . . . . . . . 334
5 Legal Issues Pertaining to Death Certificates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
6 Use of Death Certificates to Estimate Disease Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
7 Accuracy of Death Certificates and How Inaccuracies Affect Estimations of

Disease Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
8 Inaccuracies in Cause of Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
9 Inaccuracies in Demographic Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
10 So Where Does This Leave Us? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
11 Strategies to Improve Death Certificate Accuracy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
12 Future Trends in Death Certificates and Vital Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . 342
13 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

330 18 Accuracy of Death Certifications and the Implications for Studying Disease Burdens
Abstract: For at least five centuries, > death certificates had been used by governments and
scientists to judge the health of populations, study epidemiologic associations, and formu-
late public policy. In most modern countries, the maintenance, dissemination, and study of
> vital statistics is an important governmental function. Death certificates are also impor-
tant legal documents. Many previous studies have established significant inaccuracies in the
cause of death as reported on death certificates. Other studies have reported inaccuracies in
demographic information, such as race, occupation, and alcohol use, as reported on death
certificates. Despite these limitations, death certificates remain an important tool for
researchers, > population health scientists, and policymakers. Strategies to improve the
accuracy of death certificates include education of certifiers, performance of more autop-
sies, and comparison of information on death certificates to similar information contained
in other databases.
List of Abbreviations: ICD, > International Classification of Disease; > UK, United Kingdom;
> US, United States of America; > WHO, World Health Organization
1 Introduction
Death certificates are permanent legal records that provide important personal and medical
information about the decedent. These records are used by family members, insurance
companies, employers, governmental agencies, and courts to settle estates and to document
the cause of death. In addition, death certificates are one of the primary sources of mortality
statistics that allow health workers, governments, researchers, and public policy makers to
study the health of populations, develop hypotheses about factors which influence the health
of populations, and develop > population health goals. The collection and study of birth and
death records constitutes the work of ‘‘vital statistics’’ and has been used by Western societies
for at least five centuries for legal and scientific purposes.
This chapter will examine the history, utility, and limitations of using death certificates to
study > disease burdens in populations. In addition, we will briefly discuss recent efforts to
improve the accuracy of death certificates and to improve access and timeliness of collective
data on death certificates.
2 History of Death Certification and Vital Statistics
The history of > death registration and death certificates has been summarized by several
recent authors (Hanzlick, 1997; Hetzel, 1997; Potrzebowski, 2001).
In 1194, the Articles of Ayre established ‘‘custos placitorum coronae’’: three knights and a
clerk in each English county to protect the Crown’s financial interest when deaths occurred.
These ‘‘keepers of the pleas of the Crown’’ were known as ‘‘crowners.’’ This word is thought to
be the origin of the modern term ‘‘coroner.’’
Beginning in 1538, the King required all English clergy to keep a weekly record of
christenings, marriages and burials in their parishes. The Grand Assembly of Virginia passed
a law in 1632 requiring similar records of all clergy in this American colony. These records,
which served as a proxy for births and deaths, were initially kept as official records to protect
individual rights, especially as it pertained to the ownership of property. In 1639,
Accuracy of Death Certifications and the Implications for Studying Disease Burdens 18 331
the Massachusetts Bay colony legislated that the courts, rather than the clergy, record all
marriages, births, and deaths, consistent with the American idea that church and state should
be separate.
It was not until 1662 that John Graunt, a haberdasher by profession, used statistical
methods to combine death records with population numbers to study disease burdens in
populations. His book, Natural and Political Observations Made upon the Bills of Mortality
(Graunt, 1662), along with the work of William Petty, an English economist and political
philosopher of the same era, established the field of modern demography. The English
astronomer Edmund Halley used early statistical techniques to publish the first actuarial
tables in 1693. In 1721, Cotton Mather in the United States used death certificate records to
demonstrate the efficacy of smallpox vaccination.
As death registration became more prevalent during the nineteenth century, increas-
ing numbers of social scientists turned to these records in order to describe the natural
history of epidemic diseases and social conditions that characterized the cities of Europe
and the British Isles during the Industrial Revolution. Studies of death certificates by
Pierre Louis in 1825 and 1828, demonstrated higher mortality in Paris neighborhoods
with poor housing.
With increasing use of death statistics, came the need for increased standardization and
regulation of death registration. The inadequacy of accurate vital statistics and a European
cholera epidemic led to the enactment by Parliament in 1836 of legislation that created a
national office responsible for recording and preserving a record of births and deaths (by
cause) for all persons in England and Wales. This law also required a certificate for burial, a
doctor’s attendance at an inquest, and allowed coroners to order an autopsy. This legislation
was later proclaimed ‘‘the most important public health measure ever adopted in England’’
(Winslow, 1948). Soon thereafter, many European nations and the US followed this example
by creating governmental offices to collect and study vital statistics.
In most nations, collection and maintenance of vital statistics are functions of the national
government. In the US, the need for vital statistics was not recognized at the time of the
writing of the American Constitution, which held that all powers not specifically granted to
the central government were retained by the individual states. Thus the development of the
American vital statistics system lagged behind that of most European nations, and is unique.
By 1880, the American Medical Association, the American Public Health Association, the
National Board of Health, and Superintendent of the Census recommended legislation for a
centralized national vital statistics system. The US Bureau of the Census developed the first
standard certificates for the registration of births and deaths in 1900. In 1902, the US Congress
passed legislation establishing the Bureau of the Census as the agency assigned to develop a
registration system for births and deaths. By 1910, a standard death certificate was promul-
gated to the various states and the Census Bureau established a central registration database.
Vital statistics functions were moved from the US Bureau of the Census in 1946 to the
National Office of Vital Statistics.
3 Vital Statistics in the United States
In the US today, the responsibility for death registration resides with the registration areas,
which consist of each state and every territory, New York City, and Washington D.C. The
National Center of Heath Statistics (within the Department of Health and Human Services),
promotes uniformity of collecting and reporting data by proposing model standards, forms,
and state laws, which are then adopted by the legislative bodies of the respective registration
areas. This allows the data collected by the various registration areas to be consistent and result
in meaningful vitals statistics for comparative and national analysis. Vital statistics maintained
by the registration areas are reported to the National Office of Vital Statistics (within the
National Center of Heath Statistics) which produces and reports national vital statistics
through the Vital Statistics Cooperative Program.
In the US, there is still some variation from state to state in the death certificate form.
However, the cause of death section is quite similar in each of the registration areas. The cause
of death section of the standard death certificate in the US, follows that of the World Health
Organization (WHO). The coding system uses the International Classification of Diseases
(ICD), and is based on WHO guidelines and recommendations. In most states, the responsi-
bility for completion of the death certificate is assigned to the funeral director. In general, this
system has worked well because funeral directors have financial incentives to finalize the death
certificate.
The standard US death certificate (> Figure 18-1) records certain demographic informa-
tion (name, gender, social security number, age, date of birth, birthplace, residence of
decedent, previous service in the military, marital status at time of death, surviving
spouse’s name, father’s and mother’s name, decedent’s address and place of death, county
of death, method and place of disposition, identifying information about the certifiers,
and decedent’s education, race, and occupation). This demographic information is usually
completed by the funeral director. Information about the circumstances of death (date
and time of death, if an autopsy was performed, if the deceased was pregnant at the time
of death, whether or not tobacco and alcohol contributed to the death, if the death was
natural or due to an accident, homicide, or suicide, and cause of death) is completed by
the attending physician or coroner. This information is provided ‘‘to the best of the
certifier’s knowledge.’’
The National Center for Health Statistics has prepared handbooks to assist funeral
directors and physicians complete these forms (National Center of Heath Statistics 2003,
2004) but surveys suggest that physicians and funeral directors often feel inadequately trained
to accurately complete death certificates (Ashworth, 1991; Hahn et al., 2002). That this affects
the accuracy of vital statistics has been the subject of much study and discussion, and will be
addressed subsequently in this chapter.
Once completed, the death certificate is filed by the funeral director with the local
governmental jurisdiction, who forwards it to the appropriate registration area (usually a
state government). At the state level, a trained nosologist classifies and codes the cause of death
using the latest version of the ICD. State data is then forwarded to the National Center for
Health Statistics using a standardized ICD code format (> Figure 18-2).
In Europe as well as in the US, the standard death certificate follows the recommendations
of the WHO. In this system, an underlying cause of death is used for statistical analysis of
mortality. The certifying physician records the one immediate cause of death, as well as any
proximate causes and other significant conditions which contributed to death. This system is
often cited as a source of confusion for certifying physicians (see below). The underlying cause
of death listed on the certificate is encoded to one of the 17 ICD categories and then to a
disease specific cause of death. There is considerable variation between countries in the type
and comprehensiveness of information on death certificates. This has lead to difficulties in
studies involving multiple countries (> Figure 18-3).
. Figure 18-1
Standard United States death certificate (sample of an official public document obtained from
the public domain and not subject to copyright). An official death certificate in the United States
that is to be completed
. Figure 18-2
Flow of vital records and statistics in the United States. Steps in the United States for completion
of death certificate to the publication of vital statistics
4 Certification of Fetal Death and Abortion Certifications
In 1925, the Health Committee of the League of Nations drafted a definition of ‘‘stillbirth.’’ In
the US, a Certificate of Fetal Death was required for stillbirths, beginning in 1955 (Hetzel,
1997). The certificate contained a number of items, including the education of the father and
mother, prenatal care, complications related to pregnancy, complications of labor, congenital
malformations of the child, and birth injuries of the child. A number of other medical items were
later added to this form. In 1973, the US Supreme Court ruled that state abortion laws were
unconstitutional, and thus induced abortion became legal in the US. In 1978, the National Center
for Health Statistics recommended that the registration areas adopt a Standard Report of Fetal
Death. Spontaneous fetal deaths at 20 weeks of gestation or over are reported on this form. A new
form, the Standard Report of Induced Termination of Pregnancy, was used to collect information
about induced abortions, regardless of the length of gestation. This new form did not include the
name of the woman having the abortion but did include a number of items such as facility name
and location, the age of the mother, whether the mother was married or not, previous pregnan-
cies and type of termination procedures, estimated gestational age of the fetus, and name of the
attending physician. This form is been revised on a number of occasions since, and now includes
information about the medical method used for terminating the pregnancy. Abortion statistics
are summarized and reported each year by the National Center for Health Statistics (Centers for
Disease Control and Prevention, 2007).
5 Legal Issues Pertaining to Death Certificates
In the US, the death certificate is a legal document that proves that a person is dead. In general,
courts have held that the clause of death as recorded on the death certificate is not admissible
. Figure 18-3
Standard death certificate in the United Kingdom (official public document obtained from the public domain and not subject to copyright). An official
death certificate in the United Kingdom that is to be completed
Accuracy of Death Certifications and the Implications for Studying Disease Burdens
18
335
as evidence in courts of law (Hanzlick, 1997). Though the certifier is legally accountable for
certification that death occurred, the certifier is not legally accountable for the accuracy of the
stated cause of death, as long as the opinion is based on reasonable medical probability. In
the US, availability of death certificates to the general public varies according to state law
(Hetzel, 1997).
6 Use of Death Certificates to Estimate Disease Burden
Vital statistics from death certificates are used to calculate mortality rates for specific diseases,
and for geographic regions, governmental jurisdictions, and subsets of the population for a
specific time period. Each year, the National Center for Health Statistics publishes these figures
for the US (Kung et al., 2007). See > Table 18-1 for a summary of the types of reports
. Table 18-1
Sample of mortality reports published yearly by the Center for Health Statistics, United States
1 Number of deaths, death rates, and age-adjusted death rates, by race and sex
2 Life expectancy at selected ages by race and sex
3 Death rates by age and age-adjusted death rates for the 15 leading causes of death
4 Number of deaths from 113 selected causes by age, race, and sex
5 Number of deaths, death rates, and age-adjusted death rates for injury deaths
6 Number of deaths, death rates, and age-adjusted death rates for injury by firearms
7 Number of deaths, death rates, and age-adjusted death rates for alcohol-induced causes
8 Number of deaths, death rates, and age-adjusted death rates for drug-induced causes
9 Number of deaths, death rates, and age-adjusted death rates by educational attainment
10 Number of deaths, death rates, and age-adjusted death rates for injury at work
11 Infant, neonatal, and postneonatal mortality rates by race and sex
12 Number of infant deaths and infant mortality rates for 130 selected causes
13 Number of maternal deaths and maternal mortality rates for selected causes
Specific types of reports obtained from death certificates that are published every year by the Center for Health
Statistics in the United States
published each year. In addition, the National Center for Health Statistics maintains an
interactive website (http://209.217.72.34/hdaa/ReportFolders/ReportFolders.aspx?IF_Active-
PathName ¼ P/Mortality) where inquirers can design specific reports generated from the
national database of vital statistics. Many other countries, the European Union, and the WHO
publish similar data (World Health Organization, 2007a), and also have interactive websites.
Each year, the WHO publishes worldwide health statistics, which included national mortality
data (> Table 18-2).
The WHO has difficulty in collecting reliable mortality data in poor countries. Many of
these countries lack central registration systems, have a shortage of physicians or health care
providers who can serve as certifiers, and many deaths occur at home or in local facilities
where they are unattended by healthcare professionals. The WHO estimates that ideal death
registration systems operate in only 29 member countries, covering only 13% of the world’s
population. In an attempt to improved vital statistics in those countries without effective
. Table 18-2
Sample of mortality reports published yearly by the World Health Organization
1 Life expectancy at birth

2 Healthy life expectancy at birth
3 Adult mortality rate
4 Under five mortality rate
5 Infant mortality rate
6 Neonatal mortality rate
7 Maternal mortality rate
8 Deaths due to HIV/AIDS
9 Deaths do to tuberculosis among HIV-positive persons
10 Age-standardized mortality rate by cause
11 Distribution of years of life lost by broader causes
12 Distribution of causes of death among children under 5
Types of reports obtained from death certificate data that are published each year by the World Health
Organization
death registration systems, the WHO has recommended the development of ‘‘verbal autop-
sies’’ to serve as > death certification in these areas. The verbal autopsy is a structured
interview of family members and/or caregivers to elicit information which can then be used
to assign a probable cause of death. After two decades of considerable research, development,
and testing, the verbal autopsy is now being used to assist the WHO in assessing mortality
statistics in many poor areas of the world. In an attempt to standardize verbal autopsies, the
WHO has recently published recommendations and standardized interview instruments for
verbal autopsies (World Health Organization, 2007b).
Mortality statistics, and disease specific mortality rates, as well as other information
derived from death certificates is used by population health researchers, academicians, public
policy planners, and governmental officials and agencies to assess the health of populations
and to make projections and plans for future interventions or study.
Vital statistics derived from death certificates have been used to study the association of
certain diseases with exposure to alcohol, tobacco, and certain occupations, and the effects of
education and race on mortality (Bell and Cremona, 1989; Bidulescu et al., 2007; Daula and
Hanzlick, 2006; Frost et al., 1994; Russell and Conroy, 1991). Studies using death certificates
have been used to estimate the natural history and survival of persons with a number of
common and uncommon diseases, including trisomy 21, coronary artery disease, diabetes, and
hypertension (Baird and Sadovnick, 1990; Lu et al., 2006). Studies involving death certificates
have also been used to study the effectiveness of therapy, especially in coronary artery disease
(Lloyd-Jones et al., 1998). Thus death certificates have been used for over a hundred years in
important epidemiologic, etiologic, ecological, and hypothesis generating studies.
Mortality rates are calculated using numerator data, as represented by the ‘‘cause of death’’
as recorded on death certificates, and denominator data based on population estimates for the
time of interest. The use of population data interjects another potential source of bias and
inaccuracy, especially in studies that compare mortality between countries. Taking an accurate
and comprehensive census is a labor intensive and expensive activity. Most countries take the
census intermittently and with varying degrees of rigor. Inter-census estimates may not
reflect changes in population resulting from recent political and social unrest or natural
disasters. As a general rule, mortality rates relating to broad segments of the population and
common causes of death tend to be relatively accurate. Increased stratification of either or
both ‘‘cause of death’’ numerator data and population based denominator data may result
in significant over or under estimation of disease burdens. This is especially true if the
population under study is a transient minority or children under the age of 5 years, groups
which tend to be systematically under-represented in population estimates in many countries
(Preston et al., 1972).
7 Accuracy of Death Certificates and How Inaccuracies Affect

Estimations of Disease Burden
Since information obtained from death certificate data is used to calculate vital statistics,
inaccuracies in death certification lead to inaccuracies in population based studies that rely on
vital statistics. This limitation of the accuracy of vital statistics has been recognized by the
WHO and in the US, Great Britain, Canada, and many other countries (Kelson and Heller,
1983; Lahti and Penttila, 2003; Lu et al., 2006; Maudsley and Williams, 1996; McKelvie, 1993;
Sibai et al., 2002; Zumwalt and Ritter, 1987).
There are two basic types of error inherent in the death registration process. These include
errors of commission and errors of omission. Errors of commission result when false infor-
mation is intentionally or unintentionally inserted into the death certificate. Aside from
outright fraud, this may happen if the decedent lies about their date of birth. In societies
that revere the elderly or where great age is equated with great wisdom there may be an
inflationary effect. In youth oriented societies the opposite may occur. Relatives of the
decedent may pressure physicians to suppress a major or contributing cause of death that
they feel results in shame or embarrassment for the family.
Errors of omission may also be intentional or unintentional. Sometimes there are no
relatives to supply the data needed to complete all the blanks on the registration form. In time
of war or natural disaster the sheer volume of deaths may contribute to missing data. Again,
families in many parts of the world may bring pressure on the person responsible for
completing the death registration to omit facts perceived to be embarrassing or shameful.
The WHO cautions ‘‘in some countries improper completion of death certificates or system-
atic biases in diagnoses are quite common’’ (World Health Organization, 2007a).
Many items on the death certificate have been studied for completeness and accuracy.
Several reviews of the literature on this subject have been previously published, and note the
inaccuracies of many death certificates (> Table 18-3). Some of the more major studies are
cited below.
8 Inaccuracies in Cause of Death
The major death certificate error that has been cited in the literature is inaccurate cause of
death as assigned by certifying physicians. At least in Greece, this is more likely to occur for
elderly decedents and when the certifier was a primary care physician as opposed to a specialist
(Katsakiori et al., 2007). This is due in part to misunderstandings by physicians as to the
proper way to certify the cause of death (Pritt et al., 2005). Sensitivity of traumatic brain injury
. Table 18-3
Types of death certificate inaccuracies reported in the literature
Item Inaccuracies reported

Cause-of-death Cause-of-death not confirmed at autopsy
Diagnoses identified at autopsy not included on death certificate
Poor inter-rater reliability on chart review
Poor reliability with tumor registries and other databases
Demographic Race
Occupation
Education
Place of residence
Whether or not autopsy performed
Areas where errors on death certificates have been studied by researchers
from death certificates compared to an independent injury surveillance system in Oklahoma,

US, was only 78%, due primarily to listing by physician of ‘‘multiple trauma’’ rather than
traumatic brain injury as the cause of death. This was more likely to occur among decedents
from traffic accidents and in the elderly (Rodriguez et al., 2006). Some researchers have cited
the contributions of physician misunderstanding of instructions and fundamental difficulties
with the sequential diagnostic logic and one-single-cause that is required to complete certifi-
cation (Maudsley and Williams, 1996).
Physicians have limited accuracy in assigning the proper cause of death without an
autopsy. Compared to autopsy at the Cleveland Clinic in the US, death certificates incorrectly
assigned the diagnosis of acute myocardial infarction 25% of the time, and failed to assign a
diagnosis of acute myocardial infarction to 48% of patients diagnosed with one at autopsy
(Ravakhah, 2006). When compared to autopsies done at Buckinghamshire, UK, death certi-
ficates were only 42% sensitive in predicting cause of death (Sington and Cottrell, 2002).
When comparing death certificate cause-of-death to autopsy results at the Johns Hopkins
Hospital in Baltimore, US, death certificates had an incorrect cause of death 34% of the time
(Smith Sehdev and Hutchins, 2001). Similarly, compared to autopsy diagnoses, incorrect
cause of death was assigned 37% of the time by US military physicians (Cina et al., 1999).
Physicians often disagree on the cause of death for an individual decedent. Inter-rater
reliability was low (kappa ¼ 0.34) among United Kingdom physicians studying patients
records and autopsies from decedents in West Midlands, UK (Mant et al., 2006). When
hospital records of decedents were re-reviewed by faculty physicians in Bahrain, the cause of
death was changed 24% of the time (al-Mahroos, 2000). Similar results were found in a study
from Taiwan (Lu et al., 2000a). When compared to an expert panel of reviewers at the National
Heart, Lung, and Blood Institute in the US, local physicians attributed 24% more deaths to
coronary artery disease in elderly decedents (Lloyd-Jones et al., 1998). Compared to expert
panels at medical schools death from asthma was underreported by UK (Guite and Burney,
1996) and Irish (Smyth et al., 1996) physicians and interstitial lung disease was under
diagnosed by physicians in New Mexico, US (Coultas and Hughes, 1996).
A number of studies have cited that physicians sometimes report death in a nonspecific or
incomplete manner. In a survey of New Zealand physicians, general practitioners cited clinical
uncertainty and the role of the deceased’s family as major contributors to difficulties in
accurately completing death certificates. These general practitioners also reported that some-
times pressure from the family would compel them to inaccurately report a cause of death
(McAllum et al., 2005).
9 Inaccuracies in Demographic Information

Inaccuracy of demographic information on death certificates has also been studied, and
creates special problems for population health researchers and policy makers. Some studies
have suggested underreporting of alcohol-related and cocaine related deaths (Blake et al.,
1988; Daula and Hanzlick, 2006). Epidemiologic studies have used death certificate data to
study the association of cancer with occupational exposure to electric and magnetic field
exposures. When comparing information about occupation from death certificates and
company work records, Andrews found only a 75% agreement about utility industry employ-
ment (Andrews and Savitz, 1999). They estimated that this error attenuated the calculated
odds ratio for the association from 1.7 to 1.2. Investigators at the Southern California (US)
Injury Prevention Center estimated that ‘‘injury at work’’ designation on death certificates was
only 78% sensitive (Kraus et al., 1995). Other authors have cited many studies in which
misclassification of the decedent’s occupations on death certificates occurred 30–50% of the
time (Dubrow et al., 1987). After reviewing the literature and reporting their own experience,
Andrews and Savitz (1999) concluded that ‘‘occupational information on death certificates is
of limited value in addressing occupational exposure and disease.’’
Geographical location where the death occurred may also influence the accuracy of the
death certificate data. Pierce and Denison (Pierce and Denison, 2006) demonstrated a large
error rate (14%) in recording the county of residence for deaths in one county. A similar rate
was not seen in an adjacent county. This led to significant miscalculation of mortality rates
for these two counties. They postulated that this non-random error on assigning county of
death may have arisen because funeral directors use internet programs which incorrectly
assigned county by ZIP code. Researchers in Taiwan noted incorrect location of death that
affected the accuracy of studies examining mortality from motor vehicle accidents (Lu et al.,
2000b). Studies that examine end-of-life issues may require an accurate record of place of
death to set policies regarding out-of-hospital death; previous authors have noted that this
data is difficult to obtain and especially in a form that permits comparisons cross-nationally
(Cohen et al., 2007).
A number of difficulties and limitations in assigning race have been reported by research-
ers. Several studies have shown discrepancies between race as it appears on death certificates
and other sources, including birth certificates (Eschbach et al., 2006; Kelly et al., 1996).
In the US, American Indians are frequently misidentified as white or black on death certifica-
tes (Harwell et al., 2002). When surveyed, funeral directors often determined race from
reports of next of kin, or by assigning the race based on their inspection of the corpse, or
the race of the next of kin. (Hahn et al., 2002). In Hahn’s survey, nearly 80% of funeral
directors reported difficulty in completing certain demographic items. The items most
commonly cited were race and education. Among funeral directors surveyed in this study,
over 50% reported receiving no formal training in death certification. These funeral directors
also reported that next of kin were often embarrassed or unhappy about answering demo-
graphic questions that included the race and/or education of the deceased.
One author noted inaccuracies in recording the performance of autopsies (Hanzlick and
Parrish, 1993). Other studies have documented inaccuracies on death certificates in reporting
suicide (Hlady and Middaugh, 1988; Lu et al., 2006) and the decedent’s age and educational
attainment (Hahn et al., 2002).
Some difficulties and inaccuracies have been noted with fetal death certificates (Cole,
1989), although with regard to maternal information they appear to be quite accurate (Lydon-
Rochelle et al., 2005). This may be the case because with fetal death certificates, the mother
often provides the information about her own health.
10 So Where Does This Leave Us?
Historically, death certificates have been very important in understanding epidemiologic

associations, the health of populations, and the effect of governmental policy. Despite the
difficulties with death certificate accuracy, they remain an enormously important source of
information for epidemiologists, policymakers, and > population health scientists. Reflecting
on the limitation of death certificate accuracy, several authors have noted the following: those
who used death certificate data must be aware of the limitations of this data; the accuracy of
death certificate data varies by geographic location, cause of death, type of information
obtained, and nature of the certifier; and those who complete death certificates should try
to do so as accurately and completely as possible.
11 Strategies to Improve Death Certificate Accuracy

Several strategies have been proposed to improve the accuracy of physicians in certifying the
cause of death. These include education, quality assurance programs with feedback, and
encouraging more autopsies (Sington and Cottrell, 2002; Smith Sehdev and Hutchins, 2001).
There are several reasons why physicians may not be accurate in completing the cause of
death portion of the death certificate. First, many physicians complete few death certificates
over the life of their clinical practice, and therefore gain little experience in completing them.
Secondly, the completion of the death certificate often occupies a low priority in the minds of
many physicians who are pressed with the urgencies of modern clinical practice. Thirdly, the
fact that the death certification process varies from state to state, may make it difficult for
physicians when they change practice locations to another state. Also, few medical schools and
postgraduate training programs provide formal instruction on how to complete death certi-
ficates. Because of this, several state medical societies and professional organizations (such as
the College of American Pathologists) have developed training materials for physicians in
practice. More recently, some postgraduate medical education programs have developed
training materials for resident physicians and medical students and have reported on the
success of these materials in improving the accuracy of death certification.
In Spain, academicians developed a 90 min seminar with case scenarios for medical
trainees from various medical specialties and at various Spanish teaching hospitals. This single
seminar improved accuracy of trainees by over 60% (Villar and Perez-Mendez, 2007). In each
seminar a number of items were reviewed: current legislation, distinction between causes and
mechanisms of death, review of the most common errors in death certification, and recom-
mendations to improve the quality and completion of death certificates. This was designed as
an interactive session. A similar single seminar session involving ten case scenarios, improved
the accuracy of internal medicine residents in Ontario by 50% (Myers and Farquhar, 1998).
Academic physicians in the US, found that an interactive session was more effective than
written material in improving the accuracy of the internal medicine residents completing
death certificates (Lakkireddy et al., 2007).
Hahn (Hahn et al., 2002) proposed several measures to assist funeral directors in obtaining
more accurate demographic information for death certificates. These measures included
providing more clear criteria for certain demographic categories, developing a standard
worksheet for the initial recording of demographic information, developing computer soft-
ware to assist with completing death certificates, and developing a mechanism for funeral
directors to provide feedback on uses of the data that they collect.
Comparing cause of death as reported on death certificates to other databases, might also
improve the accuracy of death certificates. In many countries, other national databases collect
and record cause of death as part of their system. These databases include cancer registries,
injury and drowning registries, transportation databases, and certain industry databases. Some
researchers have advocated developing these databases in electronic forms in order to facilitate
the work of vital statistics researchers who validate and compare cause of death among the
databases (Ossiander and Milham, 2006).
Authors have commented on strategies to improve demographic data contained on death
certificates. Such strategies include comparing geographic location and ZIP code to other
public databases that are geocoded (Pierce and Denison, 2006). Comparing race as reported
on birth certificates and death certificates, and using geocoding and surname analysis to
estimate race have been suggested as ways to improve the accuracy of race as reported on death
certificates (Fiscella and Fremont, 2006). Hoyert and Lima reported that asking the certifier for
more information when the death certificate was incomplete or vague (querying) resulted in
change in the underlying cause of death over two-thirds of the time (Hoyert and Lima, 2005).
12 Future Trends in Death Certificates and Vital Statistics
National and international authorities have recognized some of the difficulties in the death
registration process, and have considered several strategies to improve vital statistics. Interna-
tionally, vital statistics are moving from a paper-based system to an electronic one. This allows
greater access to the data, more timely reporting of the data, and more sophisticated manipu-
lation of vital statistics. Comparison of the vital statistics database to other databases will
hopefully result in more accurate reporting of demographic information on death certificates.
Education of certifiers will hopefully improve the accuracy of cause of death as reported on
death certificates.
13 Conclusions
For over 500 years, death certificates had been used to study and improve the health of
populations, and to set public health policy. Despite the fact that there are major difficulties
with the accuracy of information as reported on death certificates, vital statistics remains an
important part of population health science. Improving the accuracy of information
contained on death certificates is an important strategy to improve the health of populations.
Summary Points
A death certificate is an official legal record of the death of a person. It usually also contains
information about the cause of death and certain demographic information about the
deceased such as age, gender, race, occupation, and place of death.
For hundreds of years, information from death certificates has been used to study health
and disease in populations.
Analysis of death certificates is frequently used by population health scientists to under-
stand trends of illness and health of populations, to study cause of disease, and to
understand the effectiveness of interventions to modify and treat diseases.
The analysis of death certificate information is often used by policymakers, governments,
and agencies to study health and disease and to plan social interventions that might
improve health and/or ameliorate disease.
Death certificates are legal records to prove that a person is dead and to settle estate
matters.
In many countries, the collection and archiving of death certificates is a governmental
function.
Many studies have documented inaccuracies in the cause-of-death and demographic
information as recorded on death certificates, and thus studies using death certificate
information must be interpreted cautiously.
The causes for the inaccuracies on death certificates are many and complicated.
Because the study of information on death certificates can be so useful to understanding
health and disease in populations, many advocate for improving the accuracy of death
certificate information, and a number of specific interventions have been shown to be
useful in this regard.
References
al-Mahroos R. (2000). East Mediterr Health J. 6(4): Cole SK. (1989). Community Med. 11(1): 1–8.
661–669. Coultas DB, Hughes MP. (1996). Thorax. 51(7): 717–720.
Andrews KW, Savitz DA. (1999). Bioelectromagnetics. 20 Daula M, Hanzlick R. (2006). Am J Forensic Med Pathol.
(8): 512–518. 27(4): 355–358.
Ashworth TG. (1991). J Clin Pathol. 44: 265–268. Dubrow R, Sestito JP, Lalich NR, Burnett CA, Salg JA.
Baird PA, Sadovnick AD. (1990). Can J Public Health. (1987). Am J Ind Med. 11(3): 329–342.
81(6): 456–461. Eschbach K, Kuo YF, Goodwin JS. (2006). Am J Public
Bell G, Cremona A. (1989). Br J Addict. 84(12): Health. 96(12): 2209–2215.
1523–1525. Fiscella K, Fremont AM. (2006). Health Serv Res 41(4 Pt 1):
Bidulescu A, Rose KM, Wolf SH, Rosamond WD. (2007). 1482–1500.
BMC Public Health. 7: 229. Frost F, Tollestrup K, Starzyk P. (1994). Am J Prev Med.
Blake JE, Compton KV, Schmidt W, Orrego H. (1988). 10(6): 335–339.
Alcohol Clin Exp Res. 12(1): 168–172. Graunt J. (1662). Natural and Political Observations
Centers for Disease Control and Prevention. (2007). Mentioned in a Following Index, and Made Upon
MMWR 56(No. SS-9). the Bills of Mortality. London, Jho: Roycraft.
Cina SJ, Selby DM, Clark B. (1999). Mil Med. 164(12): Guite HF, Burney PG. (1996). Thorax. 51(9): 924–928.
897–899. Hahn RA, Wetterhall SF, Gay GA, et al. (2002). Public
Cohen J, Bilsen J, Miccinesi G, et al. (2007). BMC Public Health Rep. 117(1): 37–43.
Health. 7: 283. Hanzlick R. (1997). J Forensic Sci. 42(2): 265–269.
Hanzlick R, Parrish RG. (1993). JAMA. 269: 47. Myers KA, Farquhar DR. (1998). CMAJ. 158(10):
Harwell TS, Hansen D, Moore KR, Jeanotte D, Gohdes D, 1317–1323.
Helgerson SD. (2002). Public Health Rep. 117(1): National Center of Heath Statistics. (2003). Physicians’
44–49. Handbook on Medical Certification of Death.
Hetzel AM. (1997). History and Organization of the Vital Department of Health and Human Services, Centers
Statistics System. National Center for Health Statis- for Disease Control, Washington, DC.
tics, Washington, DC. National Center of Heath Statistics. (2004). Funeral
Hlady WG, Middaugh JP. (1988). Suicide Life Threat Directors’ Handbook on Death Registration and
Behav. 18(3): 237–244. Fetal Death Reporting. Department of Health and
Hoyert DL, Lima AR. (2005). Public Health Rep. 120(3): Human Services, Centers for Disease Control,
288–293. Washington, DC.
Katsakiori PF, Panagiotopoulou EC, Sakellaropoulos GC, Ossiander EM, Milham S. (2006). Am J Ind Med. 49:
Papazafiropoulou A, Kardara M. (2007). Rural 854–857.
Remote Health. 7(4): 822. Pierce JR Jr, Denison AV. (2006). Popul Health Metr. 4: 6.
Kelly JJ, Chu SY, Diaz T, Leary LS, Buehler JW. (1996). Potrzebowski PW (2001). Report of the Panel to Evaluate
Ethn Health. 1(1): 87–94. the U.S. Standard Certificates. National Center for
Kelson MC, Heller RF. (1983). Rev Epidemiol Sante Health Statistics, Washington, DC.
Publique 31: 423–432. Preston SH, Keyfitz N, Shoen R. (1972). Causes of Death.
Kraus JF, Peek C, Silberman T, Anderson C. (1995). Am J Life Tables for National Populations. Seminar Press,
Epidemiol. 141(10): 973–979. New York.
Kung H-C, Hoyert DL, Xu J, Murphy SL. (2007). Deaths: Pritt BS, Hardin NJ, Richmond JA, Shapiro SL. (2005).
Final Data for 2005. National Vital Statistics Reports Arch Pathol Lab Med. 129(11): 1476–1479.
56: 1–66. Prepublication copy posted at http://www. Ravakhah K. (2006). South Med J. 99(7): 728–733.
cdc.gov/nchs/data/nvsr/nvsr56/nvsr56_10.pdf. Rodriguez SR, Mallonee S, Archer P, Gofton J. (2006).
Lahti RA, Penttila A. (2003). Forensic Sci Int. 131: Public Health Rep. 121(3): 282–289.
113–124. Russell J, Conroy C. (1991). Am J Public Health. 81(12):
Lakkireddy DR, Basarakodu KR, Vacek JL, et al. (2007). 1613–1618.
J Gen Intern Med. 22(4): 544–548. Sibai AM, Nuwayhid I, Beydoun M, Chaaya M. (2002).
Lloyd-Jones DM, Martin DO, Larson MG, Levy D. Bull World Health Organ. 80: 555–561.
(1998). Ann Intern Med. 129(12): 1020–1026. Sington JD, Cottrell BJ. (2002). J Clin Pathol. 55(7):
Lu T-H, Lee MC, Chou MC. (2000a). Int J Epidemiol. 29 499–502.
(2): 336–343. Smith Sehdev AE, Hutchins GM. (2001). Arch Intern
Lu T-H, Chou MC, Lee MC. (2000b). Accid Anal Prev. 32 Med. 161: 277–284.
(1): 65–69. Smyth ET, Wright SC, Evans AE, Sinnamon DG,
Lu T-H, Sun SM, Huang SM, Lin J. (2006) Am J Forensic MacMahon J. (1996). Thorax. 51(3): 293–297.
Med Pathol. 27(4): 352–354. Villar J, Perez-Mendez L. (2007). BMC Health Serv Res.
Lydon-Rochelle MT, Cardenas V, Nelson JL, Tomashek 7(1): 183.
KM, Mueller BA, Easterling TR. (2005). Am J Public Winslow C-E A. (1948). Shattuck L, et al. Report of the
Health. 95(11): 1948–1951. Sanitary Commission of Massachusetts. Harvard
Mant J, Wilson S, Parry J, et al. (2006). J Clin Epidemiol. University Press, Cambridge, p vii.
59(8): 862–867. World Health Organization. (2007a). World Health
Maudsley G, Williams EM. (1996). J Public Health Med. Statistics. WHO Press. Geneva.
18(1): 59–66. World Health Organization. (2007b). Verbal Autopsy
McAllum C, St George I, White G. (2005). Br J Gen Pract. Standards. WHO Press, Geneva.
55(518): 677–683. Zumwalt RE, Ritter MR. (1987). Postgrad Med. 81(8):
McKelvie PA. (1993). Med J Aust. 158(12): 816–818, 245, 247, 250, 253–254.
820–821.
19 Completeness and Accuracy
of Death Dates and the
Implications for Studying
Disease Burdens: Focus on
Alternative Data Sources
Min-Woong Sohn . Elissa Oh
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
2 Accuracy, Completeness, and Coverage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
3 Sources of Death Dates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348

3.1 Civil Registration System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
3.2 U.S. Mortality Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
3.3 The National Death Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
3.4 Social Security Administration Death Master File . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
3.5 Medicare Vital Status File . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
3.6 Mortality Data Available in the Department of Veterans Affairs (VA) . . . . . . . . . . . . . . 353
4 Evaluating Accuracy of Death Dates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
5 Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

346 19 Completeness and Accuracy of Death Dates and the Implications for Studying Disease Burdens
Abstract: Death dates comprise a critical piece of mortality data for studying disease burden.
This paper reviews various sources of death dates available for disease burden studies and
evaluates them in terms of their > completeness and > accuracy. Civil registration systems are
the most frequently used sources of dates and causes of death for Global Burden of Disease
studies and other studies of population health. A review of the mortality data submitted to the
World Health Organization suggests that tremendous variations in the completeness and
> coverage exist from country to country and large improvements in the quality of civil
registration systems are still to be achieved. For studies of disease burden that require person-
level data, not only the civil registration systems but some alternative sources can be utilized.
These alternative sources may not have the completeness and accuracy of the data from the
civil registration systems, but when they are combined judiciously they can be a valuable
source of death dates that can match the civil registration system in completeness and
accuracy.
List of Abbreviations: BIRLS, the VA beneficiary identification and record locator subsystem;
CMS, Centers for Medicare and Medicaid Services; DALY, disability-adjusted life year; GBD,
global burden of disease; NCHS, National Center for Health Statistics; NDI, national death
index; PPV, > positive predictive value; ResDAC, Research Data Assistance Center; SSA, Social
Security Administration; VA, The U.S. Department of Veterans Affairs; WHO, World Health
Organization; YLD, years of life lost due to disability; YLL, years of life lost due to premature
mortality
1 Introduction
Mortality is perhaps the most frequently used indicator of population health and disease
burden, outcome measures of health care services, and end points in epidemiologic studies. It
makes an intuitive sense to quantify the burden of a disease in terms of its death toll in a given
population. The Global Burden of Disease (GBD) studies use disability-adjusted life year
(DALY) as an indicator of population health. DALY, which is the sum of the years of life lost
due to premature mortality (YLL) and the years lost due to disability (YLD), critically depends
on dates and causes of death in a population (Lopez et al., 2006; Mathers et al., 2005; Murray
and Lopez, 1996; Murray et al., 1994).
GBD estimates so far have typically relied on summary statistics such as national cause-
specific death rates that are compiled from death certificates. However, as previous studies
have shown, estimates of disease burden relying only on the summary statistics can be
unreliable or even misleading (Coultas and Hughes, 1996; Johansson and Westerling, 2002;
Roglic et al., 2005). For example, Roglic et al. (2005) showed that the actual burden of diabetes
might be three times higher than its mortality burden estimated based on summary statistics.
Underestimation of disease burden is problematic especially for chronic diseases such as
hypertension, diabetes, or obesity. As people throughout the world live longer and die less
of acute and/or communicable diseases than before (Lopez et al., 2006), they are now more
likely to experience chronic conditions that directly or indirectly contribute to mortality risks.
These conditions are known to elevate risks of death but are not generally recognized as
proximal causes in death certificates and are more likely to be ignored than listed on them
(Cheng et al., 2007). Burden of mortality attributable to these conditions, therefore, tend to be
underestimated if death certificates are used as the sole source of causes of death.
Another aspect of the increasing importance of chronic conditions as mortality risks is
that certain segments of a population often suffer from two or more chronic conditions at
Completeness and Accuracy of Death Dates and the Implications for Studying Disease Burdens 19 347
the same time. A recent study reported that, in 2004, about 24% of all Americans and 67%
of all Americans 65 years old or older had two or more chronic conditions (Partnership for
Solutions, 2004). For populations with high prevalence rates of multiple chronic conditions,
making causal attributions of their deaths to any single disease would be more difficult and
problematic. Furthermore, several studies suggested that some combinations of multiple
conditions may synergistically increase mortality. These synergistic effects cannot easily be
captured in a study of disease burden without multivariable analysis that adjusts for multiple
co-existing conditions (Lee et al., 2007; Vogeli et al., 2007).
One way of improving disease burden estimates is to use person-level data such as hospital
records, health surveys, disease-specific registries, or data collected directly from patients
through cohort studies or randomized controlled trials. The use of person-level data to
model mortality events can help produce more reliable and accurate estimates of burden of
mortality attributable to a disease, adjusted for age, sex, other individual characteristics, and
co-existing conditions. Estimates such as incidence, prevalence, and relative risks obtained
from the person-level data can in turn be used in obtaining GBD estimates that would
more accurately reflect the unique contribution of each disease (Barendregt et al., 2003; Roglic
et al., 2005).
Person-level data, however, do not generally come with death dates. In order to use
person-level data for obtaining disease burden of mortality, death dates linkable to person-
level data are needed. Many researchers have paid much attention to the quality of cause of
death data in the death certificates but little or no attention to the availability and quality of
data on death dates. Causes of death are typically available from death certificates; but accurate
dates of death can be obtained from sources other than death certificates. These dates can be
linked to person-level data with medical diagnoses and used to derive estimates of burden of
mortality attributable to each disease one might have had.
The objective of this chapter is to discuss various sources of death dates and to examine
their completeness and accuracy. Accurate and complete death dates are critical in obtaining
useful person-level statistics that can in turn improve the quality of mortality data used in
diseases burden estimation. Some strategies to improve the completeness of data on death
dates are also discussed.
2 Accuracy, Completeness, and Coverage
When evaluating a source of data for death dates, two questions come up. The first is whether
all the deaths that occurred in a population were recorded in the source. The second is
whether a recorded date is accurate. The first question relates to completeness, which can be
formally defined as the percent of total number of deaths that are recorded in a source
(Mathers et al., 2005). The second question refers to accuracy and is defined as the probability
that a person actually died on the day that a data source says he/she died (Coultas and Hughes,
1996; Sohn et al., 2006; Williams et al., 1992). The two are both relevant and important in
accurately compiling and reporting mortality statistics of a population. Even when the data
in a source is highly accurate, its usefulness can be limited if it lacks in completeness.
When evaluating accuracy of death dates in a data source, one may need to ask the level of
precision required for a death date to be considered accurate (Sohn et al., 2006). For annual
mortality statistics, a death date accurate to the year may be sufficient, even though the actual
month or date of death were not known. However, there are many uses of mortality data that
require more precision. For example, data on the year and month of death are needed when
monthly vital statistics are compiled for a population. When compiling infant mortality
(deaths within a year of birth), a death date whose month is missing may create too many
misclassified deaths and hence too large a margin of error for the statistic to be reliable.
Further, an accurate tallying of such statistics as neonatal mortality (deaths within 28 days of
birth) requires death date accurate to the date.
Like accuracy, completeness partly depends on the precision required for a particular
usage. Some data source might contain death dates with missing months or dates; if one
requires precision at the year level, the completeness of such a data source will be higher than
when one requires precision at the month or date level.
The statistics often used in evaluating accuracy of death dates in a source include > sensi-
tivity and positive predictive value. A data source can contain death records for persons
who are actually alive (false positives) and miss some records of actual deaths (false negatives).
Sensitivity measures the percent of death dates correctly recorded in a source and is computed
as the ratio of the number of correctly recorded death dates (true positives) to the sum
of all deaths that occurred to the covered population (the sum of true positives and
false positives). In this sense, sensitivity is more appropriately a measure of completeness
than accuracy.
On the other hand, the positive predictive value (PPV) indicates the probability that a
death date recorded in a source indicates an actual death. It is computed as the ratio of true
positives to the sum of true and false positives. The PPV is thus a measure of how accurately a
death ‘‘as an event’’ is recorded in a source rather than a measure of how accurately death dates
are recorded. To evaluate the extent to which a data source contain death dates that are not
accurate, some agreement statistics measured at different levels of precision can be used (Sohn
et al., 2006).
Finally, coverage refers to geographic areas or segments of the population ‘‘covered’’ in a
data source, and is expressed the percentage of the total population covered in a data source.
A civil registration system typically purports only to cover citizens and other legal residents,
leaving illegal immigrants, guest workers, or refugees unaccounted for in mortality statistics.
In some cases, some regions of the country may not be reachable due to geographical
remoteness or internal conflict or other reasons. Most of the mortality data sources, unless
it is national in scope, have limited coverage and a good understanding of the coverage is
important in using the data.
3 Sources of Death Dates
3.1 Civil Registration System
The single most important source of mortality data is the civil registration system through
which deaths are officially recorded with the date of occurrence and causes of death, along
with age, sex, and other demographic indicators (Pol and Thomas, 2001; Yaukey and
Anderton, 2001). They are used as the ‘‘gold standards’’ for death ascertainment for the
populations they cover since they are with rare exceptions the most complete and accurate
source of death dates a country can have (Cowper et al., 2002). Almost all countries have
legislation for mandatory reporting of deaths to the government authorities as they occur
(Mathers et al., 2005).
Death dates in civil registration data are however lack in completeness and accuracy due to
delayed reporting or non-reporting of deaths (especially still-births or early infant deaths).
In many countries, registering death as occurring on the day of report rather than on the
day of death are not still such uncommon practices (Pol and Thomas, 2001; Yaukey and
Anderton, 2001).
The level of completeness and coverage vary widely from country to country with many
developing countries struggling with less than satisfactory completeness in death registration.
According to the World Health Organization (WHO) Mortality Database (accessible through
the WHO website http://www.who.int/healthinfo/morttables/en/index.html), 115 of 192
member countries of the WHO reported mortality data to the WHO and estimated coverage
and completeness are available for 108 countries (> Table 19-1). Of 108 countries, only 58
countries had 100% coverage and 62 countries had 100% completeness. Countries with 100%
completeness mainly included developed countries in Europe, the Americas, and the Western
Pacific regions. Other regions, including Africa, Eastern Mediterranean, and South-East
Asia, had only a few countries with 90% or higher completeness, reflecting the large
disparities in the completeness of death registration in these regions and across the world
Some countries without an effective civil registration system collect death records through
sample registration systems such as those used by China and India. China’s civil registration
system currently is known to cover only about 8% of the total population, with varying
degrees of completeness in different regions of the country. Yang et al. (2005) reported that
rural and western regions have lower completeness than urban and eastern regions, resulting
in potentially serious biases in national mortality statistics. As a result, the Chinese govern-
ment initiated a disease and mortality surveillance system based on a nationally representative
sample that covers about 1% of the total population. The estimated completeness of death
. Table 19-1
Estimated coverage and completeness of mortality data by WHO region for WHO member
countries
Coverage Completeness
Total Data <50% or <50% or
WHO region no. available unknown 50–90% >90% unknown 50–90% >90%
Africa 46 6 4 1 1 3 2 1
The Americas 35 35 4 16 15 8 11 16
Eastern 21 4 1 2 1 1 0 3
Mediterranean
Europe 52 49 2 9 38 2 8 39
South-East 11 2 0 2 0 0 1 1
Asia
Western 27 12 4 5 3 4 2 6
Pacific
Total 192 108 15 35 58 18 24 66
Source: WHO Mortality Database > Tables 19-3 and > 19-4. Available from http://www.who.int/healthinfo/
morttables/en/index.html (Accessed December 2007)
reporting in the 1998 surveillance data showed that the sample-based system can produce
highly complete and unbiased estimates of the population with about 86% completeness for
all deaths and 79% for infant deaths (Yang et al., 2005).
India also has only about 54% completeness in its death registration (UNICEF India,
2006) with several states not reporting any deaths at all. To obtain usable data on mortality,
India systematically collects mortality data through the Sample Registration System since early
1970s (Agrawal, 1969; Mari Bhat, 2002). The estimates based on a sample population of about
six million are still lacking in coverage (<50%) but are high in completeness (95% for men
and 88% for women) (Mari Bhat, 2002).
3.2 U.S. Mortality Data
The death records in the U.S. have been collected for its citizens and legal residents even before
the founding of the nation, and by 1933 all states and the District of Columbia established a
formal death registration system with completeness of death reporting reaching 90% or higher
(Pol and Thomas, 2001).
In the U.S., the collection of death certificates remains to be the responsibility of state
officials. Research studies requiring mortality information from several states needed to
contact each state Vital Statistics office to obtain person-level mortality data. Due to confi-
dentiality and data security issues, person-level mortality data (with identifiers that can be
used to link them to hospital records or other demographic data) are generally not available to
researchers.
3.3 The National Death Index
Recognizing the need for national mortality data for research use, a computerized repository
of mortality data that contain death certificates collected by all state vital statistics offices,
called the National Death Index (NDI), was established in 1982 to assist in mortality
ascertainment. The NDI includes data on all deaths that occurred since 1979 in 50 states,
the District of Columbia, New York City, Puerto Rico and the Virgin Islands with an essentially
100% coverage of its entire population (Patterson and Bilgrad, 1985).
Several studies examined the completeness of the NDI by compiling subjects with known
deaths and searching them in the NDI (Boyle and Decoufle, 1990; Lash and Silliman, 2001;
Schall et al., 2001; Wentworth et al., 1983). These studies typically had a well-defined sample
that was followed closely by the researchers over time for mortality and other follow-up data,
and the known deaths were searched in the NDI to ascertain whether they were also found in
the NDI. They reported excellent completeness of the NDI that was well in excess of 95%
(Cowper et al., 2002).
Despite the excellent overall completeness, there can potentially be variations in the
completeness of the NDI data by states and demographic characteristics. For instance, a
study showed that New York City has only 71.4% completeness, and males, whites, and
persons 30 years or older display considerably better completeness than females, non-whites,
and persons less than 30 years old, respectively (Acquavella et al., 1986). This study was
published more than 20 years ago and it is not known whether the lacking completeness in
some segments of the population has improved in the NDI since then.
There are several limitations and caveats to keep in mind when using the NDI data. First,
the NDI data are available to researchers for a fee that can sometimes be prohibitively expensive
when a large sample is searched. Second, one needs to keep the delay in death reporting in mind
when obtaining data from the NDI. Computerized death records submitted by state vital
statistics offices are added to the NDI file annually and, depending on when death occurred in
a given year, a death record may take between 12 and 24 months to appear in the NDI. As
of December 2007, the NDI provides data on deaths that occurred until the end of 2005.
Because of this delay, researchers requiring more timely data may have to look elsewhere.
Another potential limitation in utilizing the NDI data is that about 9% of all deaths in the
NDI do not have the social security numbers (Patterson and Bilgrad, 1985). Given that
the social security numbers is one of the key variables to link mortality to person-level data
and that the rate of correct match considerably increases when social security numbers are
used in an NDI search (Williams et al., 1992), this may potentially be a limiting factor in the
usefulness of the NDI for studying disease burden of mortality for those without social
security numbers such as infants, illegal immigrants, and guest workers.
Other government agencies also collect data on deaths for their own administrative
purposes. Government programs that administer entitlement programs for the poor, the
elderly, the disabled, or the veterans are typically required to collect and maintain data on
the enrollees to verify eligibility or to determine timing for benefit payments. Unless these
agencies work with the civil registration systems through an interagency agreement, they may
need to collect and maintain mortality data for their enrollees on their own. Such government
agencies in the US include the Social Security Administration, the Center for Medicare and
Medicaid Services, and the Department of Veterans Affairs.
3.4 Social Security Administration Death Master File
An important source of mortality data for the U.S. population other than the NDI is the Death
Master File compiled by the Social Security Administration (SSA). The SSA administers
federal income support programs for the elderly, disabled, and their dependents. Even though
its beneficiaries cover part of the U.S. population, it currently issues social security numbers to
and tracks earnings records of approximately 95% of the population (SSA, 2008). When a
person dies, regardless of whether he/she is a beneficiary or not, the SSA requires that the
funeral director or a member of the family notify the SSA of the death so that the payments are
stopped or dependents’ benefits are newly established. Even though the vast majority of deaths
reported to the SSA are by funeral directors, the SSA also uses other sources to collect the data
including financial institutions, postal authorities, and other government agencies (Hill and
Rosenwaike, 2001).
The Death Master File covers deaths occurring to the U.S. population who were issued
social security numbers (Hill and Rosenwaike, 2001). Since social security numbers are
issued only to citizens and legal residents, its coverage is smaller than the NDI. According to
a study that compared the number of deaths that are recorded in the SSA Death Master File
with the number of deaths published by the National Center for Health Statistics (NCHS) for
years between 1960 and 1997 by age groups (Hill and Rosenwaike, 2001), the completeness
varied over time and by age groups. Its completeness (with the entire U.S. population as its
coverage) was 87.8% for 1974–1980 (Wentworth et al., 1983) and improved slightly over time,
reaching 90% of all deaths in the US in 1997 (Hill and Rosenwaike, 2001).
Its completeness exceeded 95% for individuals who were 65 years or older in 1997 while
the overall completeness for individuals of all ages was 89.7%. However, those aged 0–24 had
the poorest completeness at 42.4% in the same year. The reason for the excellent completeness
for the elderly may be that the SSA has financial incentives to monitor closely the deaths
occurring to their beneficiaries who receive regular payments (Hill and Rosenwaike, 2001).
Another study estimates that the completeness of the SSA Death Master File within its covered
population (i.e., those with social security numbers) may be as high as 92% for individuals of
all ages (Sohn et al., 2006). Additional information on the coverage and availability of the SSA
Death Master File is shown in > Table 19-2.
. Table 19-2
Data sources of death dates in the U.S.a
Source Covered population Availability

National All persons residing in the U.S., Data are available for a fee for research use only.
death index Virgin Islands, and Puerto Rico See http://www.nchs.cdc.gov/ndi.htm for the NDI
User’s Manual, data request forms and procedure,
and fees
SSA death U.S. legal residents with social It is a public use file that can be purchased through
master file security numbers the National Information Technology Service. See
http://www.ntis.gov/products/pages/ssa-death-
master.asp for the data request procedure and
fees. The full file and periodic updates (weekly,
monthly, and quarterly) can be purchased
separately. The data are available for both research
and non-research use
Medicare Medicare beneficiaries This is a cumulative file that contains all deaths that
vital status have occurred to Medicare beneficiaries and can
file be purchased from the Center for Medicare and
Medicaid Services. For availability for research use,
initial contact and consultation on data request
process, contact Research Data Assistance Center.
See http://www.resdac.umn.edu for contact
information
VA birls VA beneficiaries The file is for VA internal use only and VA-affiliated
death file researchers can access the data through the
mainframe at the Corporate Franchise Data Center.
See http://www.virec.research.va.gov/
DataSourcesName/BIRLS/BIRLS.htm for more
information
VA vital VA beneficiaries The access is limited to the VA-affiliated
status file researchers. See http://www.virec.research.va.gov/
DataSourcesName/VitalStatus/VitalStatus.htm for
more information
a
SSA refers to the social security administration; VA the department of veterans affairs; BIRLS the beneficiary
identification and record locator subsystem
3.5 Medicare Vital Status File
The Centers for Medicare and Medicaid Services (CMS) is a U.S. government agency that is in
charge of two largest federal health care programs, Medicare for the elderly and the disabled
and Medicaid for the poor. While Medicaid is jointly funded by states and the federal
government and is managed by states, Medicare is managed directly by the CMS.
Like the SSA, the CMS has compiled a file that can be used to ascertain mortality of
Medicare beneficiaries. It is a cumulative file containing demographic information about
each Medicare beneficiary ever entitled to Medicare benefits. The death dates in this file
mainly come from the SSA Master Beneficiary Record (Bert Kestenbaum, Office of the Chief
Actuary, SSA, personal communication), but it also obtains death dates from other sources,
including Medicare claims files (Sohn et al., 2006). Given that over 97% of all the elderly in
the U.S. are enrolled in Medicare (U.S. Census Bureau, 2007), Medicare Vital Status file is
another significant source of death dates for the U.S. elderly population. A study suggested
that its completeness was essentially 100% of Medicare beneficiaries (Sohn et al., 2006).
This file can be obtained for a data processing fee through special data request to the CMS.
Potential users of this data source are strongly advised to consult with the Research Data
Assistance Center (ResDAC) for more information on the availability of this file and contact
information (> Table 19-2).
3.6 Mortality Data Available in the Department of Veterans

Affairs (VA)
The Department of Veterans Affairs (VA) keeps a master record of its beneficiaries in a file
known as the Beneficiary Identification and Record Locator Subsystem (BIRLS). Death dates
for the deceased beneficiaries are recorded in the file, from which a subset known as the Death
File is derived for death ascertainment of the VA beneficiaries (Cowper et al., 2002; Sohn et al.,
2006). The death dates in this file are collected from family members applying for death
benefits, VA hospitals, or the VA National Cemetery Administration. Through a monthly
automated process, the VA also obtains death dates from the SSA Death Master File to identify
additional deaths that are not already recorded in the BIRLS.
Until recently, this file has been the main source of death dates for veterans receiving health
care services from the VA. Several studies reported its completeness ranging between 73.5% for
the VA outpatient users and 96.5% for the World War II era veteran twins (Boyle and Decoufle,
1990; Dominitz et al., 2001; Fisher et al., 1995; Lorenz et al., 2005). These studies used samples
of veterans who were different in their frequency in using VA health care services. Therefore,
the differences in the completeness of the BIRLS Death File in recording deaths of those
veterans may be attributable to their frequency of contact with the VA. A recent study
evaluated its completeness using a random sample of veterans that includes VA health care
users and non-users and reported 77% completeness of its covered population, namely the VA
beneficiaries (Sohn et al., 2006).
Concerns with the limited completeness of the BIRLS Death File have prompted some
researchers to suggest that the combined SSA and VA mortality data can considerably improve
completeness of mortality data for the VA beneficiaries (Fisher et al., 1995; Page et al., 1996).
The VA recently funded a special project through which a file was constructed that pulled
together death dates from various sources such as the BIRLS Death File, the SSA Death Master
File, Medicare Vital Status File, the VA inpatient records, and veteran deaths known to the U.S.
Department of Defense. This file is currently available to VA-affiliated researchers and is
known as the VA Vital Status File. In a previous study, this file is shown to have a completeness
and accuracy that compare favorably with those of the NDI for its covered population (Arnold
et al., 2005; Sohn et al., 2006).
4 Evaluating Accuracy of Death Dates
Researchers have so far been much more concerned with completeness than with accuracy of
mortality data. A review (Cowper et al., 2002) of seven studies that evaluated death dates in the
NDI showed that two studies reported sensitivity and specificity, three studies reported
sensitivity alone and two other reported statistics other than these two. Interestingly, none
reported positive predictive values or different measures of agreement or accuracy.
One study compared the various sources of death dates discussed above with those found
in the NDI and examined various completeness and accuracy measures for a random sample
of veterans (Sohn et al., 2006). For the VA beneficiaries, sensitivities varied between 12% for
the inpatient records and 92% for the SSA Death Master File, with the combined data
exceeding 98% completeness (> Table 19-3). Positive predictive values on the other hand
were consistently 98% or higher, suggesting that all of the deaths recorded in any of these
sources were essentially actual deaths according to the NDI.
> Table 19-4 shows accuracy of death dates in these data sources evaluated at different levels
of precision. The accuracy of all these sources was excellent. Over 95% of all dates in any of the
source matched exactly with those in the NDI with the hospital records being the most accurate
source with 100% accuracy and the SSA Death Master File and the Medicare Vital Status File
with about 96% accuracy. At a lower precision, all sources exhibited essentially 100% accuracy;
over 97% of all dates from any source matched within 2 days of the NDI death date.
The reason that SSA and Medicare files do not have as high accuracy as the others is that,
when the actual day of death is not known, the SSA generally imputes 1 or 15 (the first day or
middle of month) and the CMS imputes the last day of month to the missing day field.
However, given the accuracy for these sources, such imputations were done to less than 5% of
all death records in their respective files.
Exceptional accuracy of death dates in these sources however should not be taken as a
suggestion that evaluating accuracy of death dates is a superfluous exercise. A study of death
certification in Beirut, Lebanon, shows that delay in death reporting was common as recently
as 1998 (Sibai et al., 2002). Over a quarter of all deaths in Beirut were reported 3 months or
longer after the fact and almost 40% of all deaths in areas farthest from Beirut was reported
over 7 months after. As mentioned above, delayed reporting is a source of inaccuracies in death
dates, especially when it is done by family members rather than by funeral directors or
physicians who are more likely to have written records of the death. Given that it is not a
practice isolated to Beirut, it is strongly advisable to evaluate accuracy of death dates where
death reporting is not strongly enforced due to economic, cultural or other reasons.
5 Implications
Needless to say, the burden of disease studies can benefit from improved data on dates and
causes of death. As mentioned above, due to limitations in coding causes of death in death
. Table 19-3
Comparison of VA mortality data with NDI data by source (N = 2,998)a
Deceased in NDI Sensitivity Specificity PPV NPV

Data source Deceased in source Yes No (95% Confidence interval)
BIRLS-DF Yes 226 3 77.4 99.9 98.7 97.6
No 66 2,703 (72.2–82.1) (99.7–100.0) (96.2–99.7) (97.0–98.2)
MSID Yes 35 0 12.0 100.0 100.0 91.3
No 257 2,706 (8.49–16.3) (99.9–100.0) (90.0–100.0) (90.3–92.3)
MVS Yes 243 3 83.2 99.9 98.8 98.2
No 49 2,703 (78.4–87.3) (99.7–100.0) (96.5–99.7) (97.7–98.7)
SSA-DMF Yes 269 3 92.1 99.9 98.9 99.2
No 23 2,703 (88.4–94.9) (99.7–100.0) (96.8–99.8) (98.7–99.5)
Combined datab Yes 287 5 98.3 99.8 98.3 99.8
No 5 2,701 (96.0–99.4) (99.6–99.9) (96.0–99.4) (99.6–99.9)
Source: Sohn et al. (2006)
a
NDI indicates the National Death Index; BIRLS-DF the Beneficiary Identification and Resource Locator Subsystem Death File; MSID the VHA Medical SAS Inpatient Datasets; MVS
Medicare Vital Status; SSA-DMF the Social Security Administration Death Master File; PPV, positive predictive value; NPV negative predictive value
b
Completeness and Accuracy of Death Dates and the Implications for Studying Disease Burdens
The combined data refers to a file that combined death dates from all other sources according to a computer algorithm that took into account accuracy of dates in these sources
(Arnold et al., 2005)
19
355
. Table 19-4
Agreement of VA mortality data with NDI dates by source and level of precisiona
Death dates in a source that agree with NDI dates

(%)
Source Number of deaths Exactly Within 2 days In year and month
BIRLS-DF 229 222 (96.9) 224 (98.2) 225 (98.7)
MSID 35 35 (100.0) 35 (100.0) 35 (100.0)
MVS 246 235 (95.5) 239 (97.2) 244 (99.2)
SSA-DMF 272 260 (95.6) 265 (97.4) 270 (99.3)
Combined data 292 285 (97.6) 288 (98.6) 291 (99.7)
Source: Sohn et al. (2006)
a
NDI indicates the national death index; BIRLS-DF the beneficiary identification and resource locator subsystem
death file; MSID the VHA medical SAS inpatient datasets; MVS medicare vital status; SSA-DMF the social security
administration death master file; Combined data, the file that derives death dates from the other four sources
certificates, the estimates of burden of some diseases are found to be unreliable and need to
be improved with more rigorous examination of person-level data. This typically requires
linkage of death dates to the person-level data from hospital records or other sources. Such a
linkage will allow one to verify whether the cause of death on the death certificates match
one of the main conditions the person had at the last few hospitalizations or to identify
co-morbidities one might have had along with the main diagnosis and/or the underlying cause
of death.
A person-level mortality database analogous to the U.S. National Death Index would
improve the quality of the burden of disease studies. This type of service will encourage and
facilitate studies with a rigorously identified disease cohorts to link death dates for more
reliable estimates of disease burden. Several countries with centralized death registration data
already make them available to researchers. Australia, for example, established its own
National Death Index which provides death dates and other information collected from
state death certificates strictly for research use (Powers et al., 2000). In other countries,
however, death registration data are sometimes scattered in local governments and agencies
around the country. Efforts to compile a centralized repository of mortality data at the
national level and to make them available to researchers are desperately needed as a first
step to improve estimates of disease burden of mortality.
An alternative to the centralized index such as the NDI is to identify various sources of
mortality data that may exist in public agencies and civil organizations and to pull them
together into a combined database. In the U.S., the SSA Death Master File which covers about
95% of the entire population is a good source of death dates. It is a public use file that can be
purchased for a reasonable price and be linked to other sources. When it is combined with
other sources, the data can be comparable to the NDI in completeness and accuracy. The
Medicare Vital Status and the VAVital Status files are good examples, both of which rely on the
SSA Death Master File as an important source.
Public health officials at various government agencies in the U.S. and elsewhere can learn
from the model exemplified by these two Vital Status files. Such a source can provide a cost-
effective, yet highly complete and accurate death dates for the respective population, thus
facilitating more rigorous studies of disease burden.
Summary Points
While many researchers have paid much attention to the quality of data on the cause of
death, many paid little or no attention to the availability and quality of data on death dates.
The most complete and important source of death dates is the civil registration systems.
There are large variations in the quality of the civil registration systems from country to
country.
For studies of disease burden that require person-level data, not only the civil registration
systems but some alternative sources can be utilized. In the U.S., these alternative sources
include Social Security Administration Death Master File, Medicare Vital Status File and
the Department of Veterans Affairs Vital Status File.
For death dates, both completeness and accuracy need to be evaluated. Completeness
refers to whether all deaths that occurred in the covered population were recorded, and
accuracy refers to whether a recorded date of death is accurate at the desired level of
precision.
Each alternative data source may not have the completeness and accuracy of the data of the
civil registration systems, but when they are combined judiciously they can be a valuable
source of death dates that can match the civil registration system in completeness and
accuracy.
For more accurate estimation for the disease burden, researchers can use the death dates
available in the Civil Registration systems as well as the combined database that can be
constructed by pulling together the death information available from various public
agencies and civil organizations.
References
Acquavella JF, Donaleski D, Hanis NM. (1986). Am J Ind Johansson LA, Westerling R. (2002). J Epidemiol
Med. 9: 181–187. Commn Health. 56: 301–308.
Agrawal BL. (1969). Popul Stud. 23(3): 379–394. Lash TL, Silliman RA. (2001). Epidemiology. 12: 259–261.
Arnold N, Sohn MW, Maynard C, Hynes DM. (2005). Lee TA, Shields AE, Bogeli C, Gibson TB, Sohn M,
VA-NDI Mortality Data Merge Project: Technical Marder WD, Blumenthal D, Weiss KB. (2007).
Report. In Report Submitted to the Health Services J Gen Intern Med. 22(Suppl 3): 403–407.
Research and Development Services, Department of Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray
Veterans Affairs. CJL. (2006). Lancet. 367: 1747–1757.
Barendregt JJ, van Oortmarssen GJ, Vos T, Murray CJ. Lorenz KA, Asch SM, Yano EM, Wang M, Rubenstein LV.
(2003). Popul Health Metr. 1: 1–8. (2005). Popul Health Metr. 3: 2.
Boyle CA, Decoufle P. (1990). Am J Epidemiol. 131: Mari Bhat PN. (2002). Popul Stud. 56: 119–134.
160–168. Mathers CD, Fat DM, Inoue M, Rao C, Lopez AD.
Cheng WS, Wingard DL, Kritz-Silverstein D, Barrett- (2005). Bull World Health Organ. 83: 171–177.
Connor E. (2007). Diabetes Care. 31(2): 279–284. Murray CJL, Lopez AD. (1996). The Global Burden of
Coultas DB, Hughes MP. (1996). Thorax. 51: 717–720. Diseases: A Comprehensive Assessment of Mortality
Cowper DC, Kubal JD, Maynard C, Hynes DM. (2002). and Disability from Diseases, Injuries and Risk Fac-
Ann Epidemiol. 12: 462–468. tors in 1990 and Projected to 2020. Harvard Univer-
Dominitz JA, Maynard C, Boyko EJ. (2001). Ann Epide- sity Press, Cambridge.
miol. 11: 286–291. Murray CJL, Lopez AD, Jamison DT. (1994). Bull World
Fisher SG, Weber L, Goldberg J, Davis F. (1995). Am J Health Organ. 72: 495–509.
Epidemiol. 141: 242–250. Page WF, Mahan CM, Kang HK. (1996). Ann Epidemiol.
Hill ME, Rosenwaike I. (2001). Soc Secur Bull. 64: 45–51. 6: 102–109.
Partnership for Solutions. (2004). Chronic conditions: Social Security Administration. (2008). Strategic Plan for
Making the case for ongoing care, September 2004 FY 2006-FY 2011.
Update. Robert Wood Johnson Foundation. Avail- Sohn MW, Arnold N, Maynard C, Hynes DM. (2006).
able at: http://www.rwjf.org/pr/product.jsp? Popul Health Metr. 4: 2.
id=14685. US Census Bureau. (2007). Statistical Abstracts of the
Patterson J, Bilgrad R. (1985). In: Kliss B, Albeyj W (eds.) United States. Washington, DC.
Proceedings of the Workshop on Exact matching UNICEF India. (2006). Birth Registration – the picture in
Methodologies US Department of the Treasure. In- India. India Child Protection. New Delhi, UNICEF,
ternal Revenue Service (Publication No. 129), India. 2006 (http://www.unicef.org/india/child_
Arlington, VA, pp. 245–254. protection_1629.htm, accessed on January, 2008).
Pol LG, Thomas RK. (2001). The Demography of Health Vogeli C, Shields AE, Lee TA, Gibson TB, Marder WD,
and Health Care. Kluwer Academic/Plenum Pub- Weiss KB, et al. (2007). J Gen Intern Med. 22
lishers, New York. (Suppl 3): 391–395.
Powers J, Ball J, Adamson L, Dobson A. (2000). Aust NZ J Wentworth DN, Neaton JD, Rasmussen WL. (1983). Am
Public Health. 24: 526–528. J Public Health. 73: 1270–1274.
Roglic G, Unwin N, Bennett PH, Mathers C, Williams BC, Demitrack LB, Fries BE. (1992). Am
Tuomilehto J, Nag S, et al. (2005). Diabetes Care. J Public Health. 82: 1145–1147.
28: 2130–2135. Yang G, Hu J, Rao KQ, Ma J, Rao C, Lopez AD. (2005).
Schall LC, Buchanich JM, Marsh GM, Bittner GM. Popul Health Metr. 3: 3.
(2001). Am J Epidemiol. 11: 292–296. Yaukey D, Anderton DL. (2001). Demography: The
Sibai AM, Nuwayhid I, Beydoun M, Chaaya M. (2002). Study of Human Population. Waveland Press,
Bull World Health Organ. 80(7): 555–561. Prospect Heights, IL.
20 Utility Scores for Comorbid
Conditions: Methodological
Issues and Advances
C. N. McIntosh
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
2 Comorbidity: an Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

2.1 Definition of Comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
2.2 Co-Morbidity is a Ubiquitous and High-Impact Phenomenon . . . . . . . . . . . . . . . . . . . . . 362
2.3 Comorbidity is a Challenge for Health Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
3 Approaches to Deriving Utility Scores for Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . 364

3.1 Direct Utility Elicitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
3.2 Indirect Utility Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
3.3 Combining Single–Condition Utilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
3.4 Testing Mathematical Models for Combining Single-Condition Utility Scores . . . . . 373
3.5 A Hybrid Mathematical Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

360 20 Utility Scores for Comorbid Conditions: Methodological Issues and Advances
Abstract: > Utility scores quantify > health-related quality of life (HRQOL) along a continu-
um that typically ranges from 0.0 (dead) to 1.0 (full health), and are essential in developing
> summary measures of population health (SMPH), as well as performing > cost-effectiveness
analysis (CEA) of different treatments and intervention strategies. A key methodological issue is
that traditionally, utility scores have been developed primarily for single health conditions, even
though comorbidities are common in both general and patient populations.
Inaccuracies in health measurement are likely to occur when > comorbidity is ignored in
the estimation of utility scores. In this chapter, methodological issues and advances with
regard to deriving utility scores for comorbid health conditions are reviewed.
Direct utility elicitation protocols such as the standard gamble (SG) or time trade-off (TTO)
are the most theoretically desirable approaches, but are cognitively burdensome for raters. With
population survey data, scores from utility-based HRQOL instruments (e.g., the Health Utilities
Index) can often be computed for self-reported comorbidities, but this strategy is often
constrained by the limited number of conditions queried, as well as potentially compromised
by self-report bias. Another suggested, yet little-used strategy is to map the expected impact of a
given comorbidity into the descriptive system of a generic, multiattribute utility instrument,
and then compute the corresponding utility score with the scoring algorithm.
Convenient mathematical models (e.g., additive, multiplicative, minimum) for combining
single-condition utility scores have also been proposed, but the empirical evidence for their
performance is mixed, as well as difficult to assess due to a lack of standardization in utility
instrumentation and analytical procedures used. An “encompassing” mathematical model that
subsumes traditional models as special cases appears to be more accurate, but has only been
examined with respect to directly elicited utilities in the prostate cancer context. A crucial next step
is evaluating its performance with respect to a wider variety of health conditions and data sources.
In future work on evaluating and refining methods for obtaining comorbidity-
related utilities, cross-study comparability can be enhanced by striving for more consistency
in utility instrumentation and analytical techniques.
List of Abbreviations: 15D, 15-Dimensions Index; BoD, > burden of disease; CCHS, Canadian
Community Health Survey; CCC, Clinical Classification Category; CEA, cost-effectiveness
analysis; CHF, congestive heart failure; CLAMES, Classification and Measurement System of
Functional Health; COPD, chronic obstructive pulmonary disease; D, disutility score; EQ-5D,
EeuroQol Five Dimensions Index; GBoD, global burden of disease; HRQOL, health-related
quality of life; HUI3, Health Utilities Index Mark III; ICD-9, International Classification of
Diseases-Ninth Revision; IHD, Ischemic Heart Disease; MEPS, Medical Expenditures Panel
Survey; NPHS, Canadian National Population Health Survey; ODD, Ontario Diabetes Data-
base; OHS, Ontario Health Survey; PAR, population attributable risk; PCEHM, Panel on Cost-
Effectiveness in Health and Medicine; PTO, person trade-off; QALY, quality-adjusted life year;
QBW, Quality of Well-Being Index; QWB-SA, Quality of Well-Being Index – Self-Adminis-
tered; RR, relative risk; SF-6D, Short-Form Six Dimensions Index; SES, socio-economic status;
SG, standard gamble; SMPH, summary measure of population health; TTO, time trade-off; U,
utility score; WHO, World Health Organization
1 Introduction
It is now well-recognized that health measurement is incomplete unless it incorporates both

health-related quality of life (HRQOL) and survival (Drummond et al., 2005; Gold et al., 1996;
Utility Scores for Comorbid Conditions: Methodological Issues and Advances 20 361
Murray et al., 2002). For developing summary measures of population health (SMPH) that
integrate both mortality and morbidity, as well as for conducting cost-effectiveness analysis
(CEA) of different treatments and intervention strategies, a major methodological cornerstone
is a set of utility-based scores or weights for representing the HRQOL associated with
particular health conditions. Typically anchored at 0.0 (dead) and 1.0 (full health), utility
scores are used to prorate the time spent in suboptimal > health states, in order to place both
premature death and HRQOL losses from disease on the same metric within a single
numerical index. More extensive discussions of the derivation and application of utility scores
are provided in other works (Drummond et al., 2005; Murray et al., 2002; Salomon and
Murray, 2004). Recently, there has been a surge of interest in ensuring that utility scores
accurately reflect comorbidity, that is, the clustering of different health conditions within the
same individual (Basu et al., 2008; Dale et al., 2008; Fu and Kattan, 2008). While a number of
methods have been developed to deal with comorbidity when computing SMPH and
performing CEA of treatments and intervention strategies, few comprehensive reviews of
this area have been conducted. The purpose of the current work is to carry out a focused
survey of key methodological issues and advances in obtaining utility scores for comorbid
conditions.
In particular, this chapter contains the following major sections:
An overview of the phenomenon of comorbidity and the difficulties it poses for health
measurement;
A presentation of methods used to incorporate comorbidity into utility measurement,
along with a synopsis of recent applications;
A review of studies examining the empirical performance of mathematical models for
combining single into multicondition utility scores; and
Recommendations for future work aimed at developing and refining current methods for
obtaining utility scores for comorbid conditions.
2 Comorbidity: an Overview
2.1 Definition of Comorbidity
Comorbidity is the presence of one or more health conditions in addition to a target or

“index” condition (i.e., the condition of primary interest in a given research study or
treatment program; Gijsen et al., 2001). Comorbidities can occur for a variety of reasons.
Independent comorbidities are those in which health conditions occur simultaneously by
chance alone (e.g., arthritis and mania); whereas dependent comorbidities, the more common
type, consist of health conditions that are systematically associated (Andrews et al., 1998).
A key example of dependent comorbidity is where multiple health conditions share a
common underlying risk factor, as is the case with obesity (> Table 20-1). Sometimes condi-
tions arise as complications of others, as in the situation where a person with diabetes mellitus
develops diabetic retinopathy (Gijsen et al., 2001). Dependent comorbidities can also be
concurrent side effects of treatment; for example, the combination of impotence and urinary
incontinence that often follows radical prostatectomy (Kao et al., 2000). In the present paper,
the generic term comorbidity is used to refer to all situations in which health conditions are
experienced concomitantly.
. Table 20-1
Obesity-related relative risks (RR) and population attributable risks (PAR%) in Canada, 8 chronic
conditions
Condition RR PAR%
Hypertension 4.50 15.4
Coronary artery disease 2.24 6.8
Stroke 1.50 34.0
Colon cancer 1.45 6.2
Breast cancer 1.47 6.5
Type 2 diabetes 3.73 28.6
Gall bladder disease 3.33 25.5
Osteoarthritis 1.99 12.7
Potential for dependent comorbidity as a consequence of obesity. RRs are summaries based on meta-analysis, and
represent the increase in the risk of developing the condition for obese versus non-obese persons. Adapted with
permission from Katzmarzyk PT, Janseen I (2004) APPl. Physiol Nutr. Metab. 29: 90–115. NRC Research Press. The
PAR% values indicate the proportion of prevalent or extant cases that would be averted if obesity were eliminated.
RR relative risk; PAR population attributable risk
2.2 Co-Morbidity is a Ubiquitous and High-Impact Phenomenon
Comorbidity is common in both clinical and general populations (Broemeling et al., 2005;
Feeny, 2005; Fortin et al., 2004; Gijsen et al., 2001; Hall et al., 2005; Laux et al., 2008). In fact, in
those with chronic conditions, comorbidity appears to be the norm rather than the exception.
For example, a recent study of the British Columbia Linked Health Database (Broemeling
et al., 2005) showed that among people 18 years of age or older diagnosed with diabetes, many
also had one or more other “High Impact/High Prevalence” (HI/HP) chronic conditions
(> Table 20-2).
The prevalence of comorbidity is expected to increase substantially in the future. A study
in the US by RAND Health projected that the number of Americans afflicted with co-morbid
chronic conditions would climb from an estimated 57 million in 2000 to 81 million by 2020
(Wu and Green, 2000). This expected increase corresponds to the continued growth of elderly
populations, in which comorbidities are particularly common (Boyd et al., 2005).
Comorbidity is positively related to mortality, disability, and health care utilization, as well
as negatively related to HRQOL (Gijsen et al., 2001; Fortin et al., 2004; Broemeling et al., 2005;
Hall et al., 2005). This substantial social and economic toll of comorbidity makes it a high
priority for clinicians, researchers, and health policy makers (Gijsen et al., 2001).
2.3 Comorbidity is a Challenge for Health Measurement
Accurately accounting for comorbidity is of critical importance when calculating SMPH, as

well as executing CEAs of treatments and intervention strategies, since the results are intended
to inform resource allocation in the health care sector. However, comorbidity introduces a
number of perplexing methodological challenges into health measurement.
. Table 20-2
Commonly co-occurring HI/HP conditions among persons aged 18 and older with diabetes,
BC linked health database 2005
Proportion with Proportion with Proportion with Proportion with

diabetes diabetes and diabetes, hypertension, diabetes, hypertension,
(n = 117,274) AND: hypertension depression (n = 3,746) depression, IHD
(%) (n = 35,987) AND: (%) AND: (%) (n = 637) AND: (%)
Hypertension 31
Depression 11 10
IHD 10 13 17
Degenerative 6 8 11 12
joint
Cardiac 4 6 7 16
arrhythmia
Cancer 4 4 6 7
CHF 4 5 6 21
Cerebrovascular 3 4 6 11
Asthma 3 3 5 5
COPD 2 2 3 5
Chronic conditions rarely exist alone. As shown here, the index condition of diabetes is often accompanied by a
variety of other conditions. Reproduced with permission from Broemeling A-M, Watson D, Black C (2005) Chronic
conditions and comorbidity among residents of British Columbia. Centre for Health Services and Policy Research,
University of British Columbia, British Columbia, Canada. UBC Centre for Health Services and Policy Research. HI/HP
high impact/high prevalence; IHD ischemic heart disease; CHF congestive heart failure; COPD chronic obstructive
pulmonary disease; n number of persons
One problem is that many established repositories or “off-the-shelf ” lists of condition-

specific utility scores have focused on single conditions only (Bell et al., 2001; Murray and
Lopez, 1996; Tengs and Wallace, 2000), as has the collection of epidemiological information
(i.e., incidence and prevalence) required for SMPH (Murray and Lopez, 1996). There is no
standardized and proven approach for partitioning the overall burden among conditions
that occur simultaneously; and consequently, there is potential for over- or underestimation
of the actual HRQOL impact of particular conditions (Feeny, 2005).
And in many CEAs of treatment and intervention strategies, it has been assumed that the
baseline HRQOL score for people with a certain health condition is exactly the reduction from
full health (i.e., 1.0 on the utility scale) resulting from that condition only, and that corre-
spondingly, alleviation of that condition will restore affected persons to full health. Due to
possible comorbidities and other factors such as aging, however, many people with a given
condition would not be in full health otherwise (Fryback and Lawrence, 1997; Harris and
Nease, 1997). Ignoring comorbidities in CEA can therefore exaggerate treatment benefits,
threatening the generalizability of the results to real-life clinical settings where patients often
have multiple conditions (Tunis et al., 2003). A more realistic assumption is that a given
treatment can, at best, raise average HRQOL for persons with the targeted condition to
the same level as that of persons without that particular condition (Manuel et al., 2002)
(> Figure 20-1).
. Figure 20-1
Idealized and actual HRQOL benefits of a hypothetical new treatment for congestive heart failure
(CHF), in persons 45 years of age and older. An illustration of how ignoring comorbidity can
artificially enhance the estimated benefits of a treatment. As shown here, persons aged 45 and
older without CHF are not in full health. But if one assumes that remediation of CHF will restore
full health (1.0), the treatment-specific HRQOL gain could be overestimated by 0.16 points on the
utility scale: 0.43 (idealized HRQOL increase) 0.27 (true HRQOL increase). The CHF prevalence
and mean utilities (Health Utilities Mark III; Feeny et al., 2002) shown here were estimated from
the 2000–2001 Canadian Community Health Survey (cycle 1.1). HRQOL health-related quality of
life; CHF congestive heart failure; n: number of persons
As noted by Hall et al. (2005), “comorbid illness must be integrated into treatment
decisions and outcomes research in rationale and quantifiable ways (p. 28)”. To meet these
objectives, it is essential that reliable and valid utility scores be developed for comorbid
conditions. > Figure 20-2 contains some key facts to remember about each of utility scores
and comorbidity.
3 Approaches to Deriving Utility Scores for Comorbidities

3.1 Direct Utility Elicitation
One approach to measuring utility scores for comorbid conditions is to directly elicit them
from individual raters or focus groups. As with the single condition case, this is accomplished
by describing the impact of the comorbidity on health status (e.g., physical, mental, and
social functioning), and then conducting a utility elicitation interview to obtain the scores
(Drummond et al., 2005; Gold et al., 1996; Salomon and Murray, 2004) (> Table 20-3).
. Figure 20-2
Key facts about utility scores and comorbidity.
While direct utility elicitation for comorbidities is the most theoretically desirable
approach, it is probably the least attractive option from a practical standpoint. As the number
of comorbid conditions increases, construction of the health state descriptions becomes
increasingly laborious for investigators, as does the mental processing of this information
for raters. Thus, this method should be reserved only for situations where there is no other
trustworthy source of utility scores for the comorbidities of interest (Naglie et al., 1997).
Indeed, only a handful of studies have directly elicited utilities for comorbid conditions,
and the majority of these have been conducted in the context of prostate cancer. For example,
with a sample of 162 male volunteers, Stewart et al. (2005) used computer-assisted VAS, SG,
and TTO protocols to elicit utilities for 19 prostate cancer-related health states, which included
typical, co-occuring side effects of radical prostatectomy (e.g., impotence and urinary incon-
tinence, impotence and bowel problems). About 40% of raters showed one or more incon-
sistencies in their ratings; that is, they assigned higher utility to a more severe than to a less
severe health state. The majority of these errors were resolved by automated warnings and
prompts built into the preference elicitation software, with ultimately only 5% of respondents
giving any inconsistent ratings, which were excluded from computation of average utilities.
In the final score list, all comorbidities had significantly worse mean utilities than each of the
constituent conditions in isolation. Unfortunately, it was not reported how many of the initial
errors were cases in which a comorbidity was rated higher than a single condition. Therefore, it
was not possible to assess the extent to which having to process these more complex
comborbid states was the source of the inconsistencies.
In a study by Dale et al. (2008), 147 men provided TTO utilities for common post-
prostatectomy side effects, both alone and in combination. However, no self-correction prompts
were used in the TTO software, and all data from all participants were used to compute mean
. Table 20-3
Summary of direct utility elicitation methods
Name of Method Description of Protocol

Visual Analogue Respondents are asked to rank a given health state on an equal-interval
Scale (VAS) scale ranging from 0 (worst imaginable) to 100 (best imaginable). The utility
score or the health state is simply the proportion corresponding to the
ranking
Time Trade-off (TTO) Respondents are asked to imagine themselves in a suboptimal health state
for the rest of their lives, and then indicate how much of their remaining life
expectancy (i.e., x years) they would sacrifice in order to spend the rest of
their lives in full health. If, for example, the remaining life expectancy is set
at 10 years then health state utilities are derived as: 1.0 - (x/10)
Standard Gamble Respondents are presented with a hypothetical scenario where they can
(SG) either remain in a given suboptimal health state for the rest of their lives, or
accept a treatment with a probability (p) of restoration to full health and a
corresponding probability (1-p) of instant death. The probability of p is
systematically varied until the respondent is indifferent between enduring
life in that health state or gambling on the treatment. The value of p at the
indifference point is the health state utility
Person Trade-off A two-part exercise used in the first Global Burden of Disease (GBoD) study
(PTO) to obtain disability weights (i.e., the complement of utility scores) ranging
from 0 (full health) to 1 (dead) for health conditions (Murray, 1996). The first
exercise aims at finding out how many disabled persons (n1) respondents
believe are equivalent in societal value to 1000 healthy persons. The
disability weight is then computed as: 1 - (1000/n1). In the second exercise,
the objective is to find out how many people cured of a given condition (n2)
are believed to be equivalent to extending the lives of 1000 healthy
persons, and another disability weight is computed as: 1000/(n2). If the
disability weights under both exercises are inconsistent, the respondent
must select new values of n1 and n2 that harmonize them. The PTO is not a
popular method, because of its being perceived as ethically objectionable
and generating artifactual weights (Arnesen & Nord, 1999)
Application of these direct utility elicitation techniques usually requires trained interviewers with custom instru-
mentation (e.g., props). Pencil-and-paper methods, as well as utility elicitation software, have also been developed
to help reduce research costs and respondent burden. VAS visual analogue scale; TTO time trade-off, SG standard
gamble; PTO person trade-off
utilities for the conditions involved, whether or not inconsistencies existed. While the mean
utility scores were logically consistent, there was a high degree of error at the individual level. In
particular, 28–40% of the utilities for the comorbidities were higher than those for the single
conditions involved, depending on the specific comorbidity considered. In another similar
investigation, all raters assigned higher utilities to the co-occurrence of impotence and
incontinence than to each condition experienced in isolation (Knight et al., 2002).
In a different context, Bravata et al. (2005) used the SG to derive utility ratings for depen-
dencies in activities of daily living (ADLs) such as bathing, dressing, and continence, both alone
and in combination. Out of 400 respondents, 175 (44%) rated at least one combination of
dependencies as having higher utility than a single dependency. While not specifically examining
comorbid diseases, this study also highlights the methodological difficulties encountered in
direct utility elicitation when health state descriptions become more complex.
In sum, researchers should be aware of the high potential for errors when directly eliciting
utilities for comorbidities. In the classic volume on CEA by the Panel on Cost-Effectiveness in
Health and Medicine (PCEHM; Gold et al., 1996), it was recommended to always use utilities
from a cognitively robust sample, and studies which have strictly followed these guidelines
completely discard data for raters showing any inconsistencies (Feeny et al., 2002). However, in
a given application, it is difficult to determine to what extent inconsistent utility ratings reflect
acceptable levels of measurement error, versus more serious misunderstandings or misinter-
pretations of the elicitation exercise (Dale et al., 2008). Some studies have used the frequency
distribution of inconsistent responses to identify cutoffs above which utility data are discarded
(McIntosh et al., 2007). Clearly, how to handle inconsistent utility ratings requires further
research, particularly in the case of comorbidities. The self-correction prompts implemented
in modern utility elicitation software would appear to be a promising avenue for quality
assurance (Stewart et al., 2005).
3.2 Indirect Utility Measurement
Another, more practically appealing way to obtain utility scores for comorbid conditions is
through generic, utility-based HRQOL assessment instruments. These tools describe a given
individual’s health state in terms of levels of function across a series of domains or attributes
(e.g., mental, physical, and social functioning), and then use a utility-based scoring function to
synthesize all of this categorical information into a single global score representing HRQOL.
In this case, the utility measurement is “indirect”, because the health state utilities used in the
scoring function are not elicited from the current sample but rather from a previous calibra-
tion sample of raters. These measures are well suited to assessing HRQOL in the presence of
comorbidity, since their non-disease-specific nature allows them to capture the impact of a
broad variety of health conditions (> Table 20-4).
Population-based health surveys often include self-report modules on chronic condition
prevalence and generic, utility-based measures of HRQOL. Maddigan et al. (2005) used the
1996–1997 Canadian National Population Health Survey (NPHS) to estimate mean HUI3
scores for people aged 18 and over who reported having diabetes, heart disease, stroke or
arthritis, as well as all of their possible combinations. An analysis of covariance (ANCOVA)
was used to adjust the mean utilities for the impact of other factors (i.e., age, sex, education,
and number of chronic conditions aside from the four conditions of interest). Generally, an
HRQOL gradient emerged with respect to the number of conditions present, with mean utility
scores ranging from 0.89 (heart disease) to 0.46 (diabetes, heart disease, stroke, and arthritis).
In a similar investigation, Bowker et al. (2006) used the 2000–2001 Canadian Community
Health Survey (Cycle 1.1) to compute mean HUI3 scores for people aged 12 and older who
reported having diabetes, cancer or both. The mean score for the comorbid group (0.67) was
significantly lower (p < 0.0001) than that for the cancer only (0.78) and diabetes only (0.78)
groups. Even after applying ANCOVA to adjust for several covariates (age, sex, marital status,
education level, smoking status, body mass index, physical activity level, depression status, and
number of other chronic conditions), the comorbid group still had a significantly lower mean
utility score than the other two groups.
368
. Table 20-4
Descriptions of five generic, utility-based HRQOL instruments
20
Instrument QWB(-SA) HUI3 EQ-5D SF-6D CLAMES
Health status Mobility, Physical Vision, Hearing, Mobility, Self-care, Physical functioning, Role Pain or discomfort, Physical
attributes/domains activity, Social Speech, Ambulation, Usual activities, Pain/ limitations, Social functioning, Emotional state,
included activity, Symptoms/ Dexterity, Emotion, discomfort, Anxiety/ functioning, Pain, Mental Fatigue, Memory and thinking,
Problems Cognition, Pain depression health, Vitality Social relationships, Anxiety,
Speech, Vision, Use of hands
and fingers
Number of functional 3–27 5–6 3 4–6 4–5
levels per attribute
Number of unique 1,215 972,000 243 18,000 10,240,000
health states
possible within
descriptive system
Type of utility VAS VAS and SG TTO SG SG
elicitation method combination
with initial
calibration sample
Nature of utility- Linear additive Multiplicative Modified linear Modified linear additive Multiplicative
based scoring additive
function
Range of global 0.0–1.0 0.36–1.0 0.59–1.0 0.0–1.0 0.0–1.0
HRQOL score
All of these instruments differ conceptually and empirically, and thus, the utility scores produced by each are not directly comparable. Researchers should thoroughly investigate the
properties of each instrument in order to determine which is the most suitable for their purposes. Adapted from Furlong et al., (2005) Health Qual. of Life Outcomes 3: 3. BioMed
Utility Scores for Comorbid Conditions: Methodological Issues and Advances
Central Open Access Journals (no permission required).QWB Quality of Well-Being Index; QWB-SA QWB Self-administered; HUI3 Health Utilities Index Mark III; EQ-5D EuroQol Five
Dimensions Index; SF-6D Short Form Six Dimensions Index; CLAMES Classification and Measurement System of Functional Health; VAS visual analogue scale; TTO time trade-off;
SG standard gamble
(CLAMES was developed in McIntosh CN et al., 2007)
These studies show that comorbidity has a substantial impact on HRQOL and that
archival datasets can obviate the need for expensive and time-consuming direct elicitation
of utility scores. The main disadvantage of this approach is potential bias in self-reports of
condition prevalence. For instance, Manuel and Schultz (2004) linked the 1996–1997 Ontario
Health Survey (OHS) to the Ontario Diabetes Database (ODD), and found that 53.2% of
people in the ODD with a physician diagnosis of diabetes mellitus reported on the OHS that
they did not have this condition. Such linkages can certainly help reduce classification errors,
but are not infallible, as some studies show that administrative databases tend to under-report
comorbidities relative to corresponding patient charts (Quan et al., 2002). Further, because of
constraints on interview time and concerns about respondent burden, the number of health
conditions queried in national surveys is limited, and detail on the many condition subtypes
and severity levels is not typically requested. Alternatively, investigators could administer
utility instruments to various patient groups for whom this detailed diagnostic information
is known (Rutten-van-Mölken et al., 2006), although this would be more resource-intensive. It
is also difficult to get “pure” utilities for a given comorbidity of interest. In the two studies
reviewed above (Maddigan et al., 2005; Bowker et al., 2006), people were allowed to have
conditions other than the focal ones, and as a result, the utility scores were contaminated
to some degree by additional HRQOL impacts. Lastly, the institutional population is usually
not surveyed or included in such analyses, thereby excluding the unhealthiest portion of
the population. Surveys of residents of health institutions have been conducted (StatCan,
2002–2003), but are not common. In sum, researchers must always be aware of potential
trade-offs between the convenience and abundance of secondary data and their lack of control
over survey content and data collection methods.
With utility instruments, however, researchers can circumvent the limitations of both
direct utility elicitation and archival data sources. Specifically, the expected impact of selected
comorbidities can be mapped into the health state description system, and the scoring
algorithm can then be applied to produce the utilities. The investments in this case would
be in reviews of the medical literature and clinician consultations to ensure accuracy of the
comorbidity-related health state descriptions. This approach has been used to obtain utilities
for single conditions in burden of disease studies in the Netherlands (Stouthard et al., 1997),
Australia (Mathers et al., 1999), and most recently in Canada (McIntosh et al., 2007). With
regard to comorbidities, Ritvo et al. (2005) used a prostate cancer-specific instrument to
describe health states and compute utilities for joint side effects of treatment. However, the
generic approach offers greater flexibility for incorporating a wider variety of comorbidities,
and warrants future exploration.
3.3 Combining Single–Condition Utilities
Another method for deriving utility scores for comorbidities is to use a mathematical
function to combine the scores for each of the individual conditions involved. Given the
availability of utility score lists for single conditions (e.g., Bell et al., 2001; Murray and
Lopez, 1996; Tengs and Wallace, 2000), this approach could be used to generate utilities for
the majority, if not all, of the comorbidities that would be of interest when calculating
SMPH and performing CEAs of treatment and intervention strategies. Three main mathe-
matical models for combining utility scores have been suggested: the additive, multiplicative,
and minimum models.
The additive model. Also referred to as the constant decrement model (Basu et al., 2008;
Dale et al., 2008), the additive model for combining single-condition utility scores can be
expressed as follows: !
X N
UCM ¼ 1:0 ð1:0 Ui Þ ; ð1Þ
i¼1
where UCM represents the overall utility score for the comorbidity of i single health conditions
(i = 1 through N), and Ui is the utility score for the ith condition implicated in the
comorbidity. (The experience of a single condition can be viewed as just a special case of
the additive and other models). The major assumption is that the separate HRQOL losses
resulting from each of the individual conditions involved in the comorbidity are additive. For
example, for two single conditions having utility scores of 0.90 and 0.80, the overall utility
score for the corresponding comorbid state under the additive model is: 1.0 – [(1.0 - 0.90)
(1.0 - 0.80)] = 0.70. Each additional health condition acquired lowers overall HRQOL by a
fixed amount (i.e., a constant decrement), irrespective of initial HRQOL.
A “peculiarity” of (1) is that it can yield UCM scores <0.0, particularly with combinations
of severe conditions. This feature is not theoretically unreasonable, given the possibility of
health states regarded as worse than death (Feeny et al., 2002). However, out-of-range utility
scores are problematic for CEA, because of the requirement that > quality-adjusted life years
(QALYs), the standard CEA outcome measure, must rely on the utility scale anchored at 0.0
(dead) and 1.0 (full health) (Fryback and Lawrence, 1997). Negative UCM scores could be
truncated at 0.0 to make CEA feasible, but some degree of bias would probably have to be
accepted (Franci and Pathak, 2003).
The additive model for combining utilities was used in the first Global Burden of Disease
(GBoD) study conducted by the World Health Organization (WHO) and its collaborators
(Murray and Lopez, 1996), as well as in a subsequent BoD study in the Netherlands (Stouthard
et al., 1997). In this context, the additive model was tantamount to making no adjustments for
comorbidity, since the total HRQOL impact of disease was calculated by simply adding the
disease-specific HRQOL decrements. Murray and Lopez (2000) have since acknowledged that
this approach was naı̈ve and implausible, and certainly overestimated total burden. For
instance, when very severe conditions such as Alzheimer’s disease or cancer are present, simply
adding on the HRQOL decrements for concurrent milder conditions (e.g., mild vision loss) is
probably not reflective of the true HRQOL impact of the comorbidity (Mathers et al., 1999).
However, a variant of the additive model known as the marginal decrement or marginal
disutility model helps to resolve some of the above issues (Franks et al., 2006; Sullivan et al.,
2005; Sullivan and Ghushchyan, 2006). In this approach, multiple regression is used to model
people’s utility-based level of HRQOL as a function of various health conditions and often of
other covariates such as age, sex, and socio-economic status (SES). With the overlap among
the predictors removed, the unique effect of each on HRQOL is obtained. After these statistical
corrections, a utility score for a given comorbidity can then be computed by subtracting the
appropriate regression coefficients for single conditions from the overall utility score for the
“average” case (i.e., the intercept). This technique helps prevent the double-counting of
HRQOL impacts inherent in the traditional additive model, and also does not assume that
people who report no conditions are in full health.
The marginal decrement model has been used extensively to develop utility score catalo-
gues for diabetic comorbidities. Within a sample of 2,048 diabetic patients, Coffey et al. (2002)
used linear regression modeling to obtain the unique reductions in QWB-SA utility scores
linked to several co-occurring conditions (e.g, retinopathy, obesity, stroke, hypertension).

In 3192 patients with type 2 diabetes, Clarke et al. (2002) modeled VAS- and EQ-5D-based
utility scores using six other conditions (myocardial infarction, blindness in 1 eye, ischemic
heart disease, heart failure, stroke, and amputation), all of which caused significant HRQOL
decrements.
Another study by Maddigan et al. (2006) examined type 2 diabetes and associated
comorbidities within a general rather than a patient population. Using the 2000–2001
CCHS (cycle 1.1), the HUI3 scores of 4678 respondents aged 18 and over and reporting a
diagnosis of type 2 diabetes were modeled using a variety of individual determinants of health
(e.g., socio-demographic characteristics, SES, lifestyle, geographic location, access to health
care), four diabetic comorbidities (osteoarthritis, stroke, heart disease, and depression), and
the number of chronic conditions reported aside from type 2 diabetes. Each of the comorbid-
ities significantly reduced HRQOL, with the largest deficits being associated with stroke and
depression.
Other studies have used the marginal decrement model to examine the joint HRQOL
impact of a broader variety of health conditions. Within the general Finnish population,
Saarni et al. (2006) modeled the simultaneous effects of 29 chronic conditions on utilities
from both the EQ-5D and 15D instruments. Schultz and Kopec (2003) predicted HUI3-
based utility scores using 21 self-reported chronic conditions on the 1996–1997 National
Population Health Survey (NPHS). A more extensive investigation by Sullivan et al. (2005)
pooled three cycles of the US-based Medical Expenditures Panel Survey (MEPS 2000–2002),
and estimated marginal decrements in EQ-5D scores for 68 self-reported chronic conditions.
Ten of these were specific “Quality Priority Conditions” (e.g., diabetes, asthma, hyper-
tension, etc.) known to have high prevalence and well-established care standards. All
other self-reported chronic conditions on the MEPS were grouped on the basis of Inter-
national Classification of Diseases-Ninth Revision (ICD-9) codes into 58 homogeneous
Clinical Classification Categories (CCCs). In an extension of this study, Sullivan and
Ghushchyan (2006) decomposed the CCCs into specific ICD-9 codes and repeated
the analysis, providing a more refined list of condition-specific marginal decrements in
EQ-5D utilities.
Research on the marginal decrement model has provided more methodologically robust,
“comorbidity-adjusted” catalogues of scores for potential use in BoD and CEA applications.
However, some limitations must be noted, in particular, the comparability problems among
studies due to variation in analytical and measurement approaches. Different utility instru-
ments are used across investigations, and these are based on differing underlying conceptual
frameworks for health as well as scoring methodologies (Brazier et al., 1999). However,
recent work demonstrates that standardization can enhance inter-measure comparability
(Franks et al., 2006). Further, some studies have used non-parametric regression methods to
deal with non-normally distributed utility scores (e.g., Sullivan et al., 2005; Sullivan and
Ghushchyan, 2005; Saarni et al., 2006), while others have used conventional regression
methods (e.g., Schultz and Kopec, 2003). Given the tendency for utility scores to cluster
around 1.0 (full health) in general populations (Austin, 2002), studies should try to use
appropriate corrective methods. In addition, when researchers borrow utilities for CEA or
BoD purposes, they should ensure that their definitions of the conditions of interest are the
same as those used in the studies where the estimates were originally computed. Further, the
limitations associated with self-reported chronic condition prevalence must be kept in mind
when using the results.
The multiplicative model. The multiplicative model combines utility scores in the following
manner:
Y
N
UCM ¼ Ui ; ð2Þ
i¼1
and has a couple of intuitively appealing properties. First, for utility scores anchored at
0.0 (dead) and 1.0 (full health), their product is also guaranteed to be bounded by 0.0 and
1.0. Second, developing an additional health condition reduces HRQOL proportional to its
previous level. For example, those in full health who developed a condition having a utility
score of 0.90 would maintain 90% of their original level of HRQOL. If they developed a second
condition for which the utility score was 0.80, the new utility score for the comorbid
combination would be 0.72 (0.80 * 0.90), representing 72% of full health. Therefore, the
HRQOL impact of a comorbidity is always sub-additive, but still worse than experiencing any
of the constituent individual conditions in isolation. As with the additive model, the multi-
plicative model is convenient to apply, provided that the utility scores for the individual
conditions involved are available.
Recognizing that the additive approach overestimated total HRQOL burden in the original
GBoD 1990 study (Murray and Lopez, 1996), the WHO adopted the multiplicative model for
performing comorbidity adjustments in its subsequent GBoD calculations (Mathers et al.,
2006). A number of country-specific BoD studies have also used this approach (Begg et al.,
2007; Boswell-purdy et al., 2007; Mathers et al., 1999; Vos and Begg, 2000).
In the CEA context, the multiplicative model for single-condition utilities has been
popular for even longer, appearing in published work around the mid-1980s (Hazen, 2004).
Several CEAs by Eckman and his colleagues on treatments for Lyme disease (Eckman
et al., 1997), atrial fibrillation (Eckman et al., 1998), and venous thromboembolism
(Eckman et al., 2002; Johnston et al., 2005) have used the multiplicative model to account
for the joint HRQOL impact of different events that co-occur during the time horizon of the
simulation. In a teaching piece on CEA, Naglie et al. (1997) also promoted the use of
the multiplicative model in CEA, and suggested that it be modified slightly by (1) multi-
plying the utility scores associated with any enduring or long-term concurrent health condi-
tions (i.e., those that persist together for the entire CEA time horizon), and then (2)
subtracting the HRQOL decrement or disutility associated with the experience of any
short-term conditions (i.e., those that last only a few days or weeks). More formally, the
calculations would be: !
Y
N XM
UCM ¼ ULT i ð1:0 UST j Þ ; ð3Þ
i¼1 j¼1
where ULTi and USTj represent, respectively, the utility scores for the ith long-term and jth
short-term states. To my knowledge, however, there have been no applications of this particu-
lar variant of the multiplicative model in the published literature.
Fairly recently, Hazen (2004) mathematically outlined the assumptions necessary for use
of the multiplicative model (2), specifically with respect to SG- and TTO-based utility scores.
The details of Hazen’s proofs are not presented here, but his essential findings were as follows.
If the SG or TTO-based utilities for each member of a set of particular health conditions are
mutually and unconditionally independent of each other, then one can apply a purely
multiplicative model and obtain valid a utility score for the comorbid combination. If the
independence assumption does not fully hold, that is, if there are any interactions
among preferences for the conditions involved, then the purely multiplicative model must
be augmented with appropriate weights and interaction terms to reflect the dependencies, as is
done in the scoring system for the HUI3 instrument (Feeny et al., 2002). While such assump-
tions are extremely difficult to verify in practice (Naglie et al., 1997), the multiplicative model
nevertheless remains a popular and intuitively appealing approach.
The minimum model. The simplest method for converting single-into comorbid-
condition utilities is the minimum model (Basu et al., 2008; Dale et al., 2008; Mas-Colell
et al., 1995):
UCM ¼ minfU1 . . . UN g: ð4Þ
The primary assumption here is that the HRQOL impact of a comorbidity is entirely
attributable to the most severe single condition in the set. For example, if person develops a
health condition having a utility score of 0.90, and subsequently develops a second, more
serious condition with a utility score of 0.80, the utility score for the comorbid combination is
0.80. The minimum model is similar to the practice of classifying patients in accordance with
their nominated main health problem, that is, the one they view as the most disabling
(Andrews et al., 1998).
It is worth noting at this point that the relationship or hierarchy among combined utility
scores derived from the additive, multiplicative, and minimum models is as follows (see also
van Baal et al., 2006):
!
XN YN
UCM ¼ 1:0 ð1:0 Ui Þ < UCM ¼ Ui < UCM ¼ minfU1 . . . UN g: ð5Þ
i¼1 i¼1
One assumes the highest HRQOL impact of comorbidity in the additive model, the lowest in
the minimum model, and an intermediate amount in the multiplicative model. Model
selection obviously has important implications for computing SMPH in BoD studies and
performing CEA of treatments and intervention strategies, as well as for programs and policies
based on the findings. Therefore, it is important to choose the most reliable and valid method
so as to ensure that BoD and CEA results are accurate, and that corresponding decisions about
the allocation of scarce Societal resources to different intervention and treatment programs are
properly informed.
3.4 Testing Mathematical Models for Combining Single-Condition

Utility Scores
Thus far, applications of the various mathematical models for combining single-condition
utility scores have proceeded largely in the absence of supporting evidence. Only recently have
researchers begun to study the empirical performance of these models. The basic steps
involved can be summarized as follows:
Obtain empirical utility scores for individual conditions and their comorbidities, using
either direct or indirect measurement approaches;
Apply a selected mathematical functional form or “comorbidity rule” (e.g., additive,
multiplicative, minimum) for combining the individual condition scores into an overall
preference score for their comorbidity;
Determine the closeness of fit between the scores reproduced by each of the mathematical
functions and the corresponding observed preference scores for the comorbidities, with
the latter being regarded as the “gold standard” measure of the HRQOL linked to the
comorbidities (Basu et al., 2008); and
Compare the fit of all models tested, and determine which one best reconstructs the
observed utility scores for the comorbidities from the single-condition utility scores.
The multiplicative model was evaluated in a study by Flanagan et al. (2006). On the 2000–
2001 CCHS (cycle 1.1), 278 distinct pairs of comorbid conditions were identified. Age- and sex-
standardized mean HUI3 scores were computed for persons reporting each comorbid pair, as well
as for those reporting only one of the conditions involved. To help ensure that the HUI3 means
reflected only the utility of the condition(s) reported, they were divided by the mean HUI3 score
for all CCHS respondents who reported being condition-free (0.94); this resulted in “purified”
mean utilities. The purified mean utilities for the comorbid pairs were then modeled as the
product of the purified mean utilities for each single condition involved, using linear regression.
The multiplicative model performed well, closely reproducing the purified mean observed
utilities for the comorbid pairs (> Table 20-5).
Further, the b coefficient from the linear regression was estimated to be 0.99. These results
were replicated with triple comorbidities on CCHS cycle 1.1 (2000–2001), and with both
double and triple comorbidities on CCHS cycle 2.1 (2003–2004).
Fu and Kattan (2008) used a similar approach with data from the 2001 and 2003 MEPS to
compare the multiplicative model to both the minimum and additive models, as well as to
three unconventional approaches: (1) the largest of the mean single-condition utilities, (2) the
mean single-condition utility associated with the smallest sample size, and (3) the grand mean
of the mean single-condition utilities. All self-reported chronic conditions were collapsed into
238 homogeneous CCCs, from which 760 comorbid pairs were identified. Based on linear
regression modeling using purified mean EQ-5D utilities, none of the models yielded
completely unbiased estimates. The differences between the observed and model-reproduced
utilities were statistically significant in each case. However, the minimum model showed the
best performance (b = 1.029), while the additive model was the worst (b = 0.842). The
multiplicative model (b = 0.878) outperformed only the additive model.
In the context of prostate cancer, Dale et al. (2008) used directly elicited TTO utilities for both
single conditions and their comorbid combinations to evaluate the multiplicative, minimum,
and additive models. Theoretical utility scores for the comorbid pairs (e.g., impotence and
urinary incontinence) were computed by applying the models to the individual condition scores,
and then tested for consistency with the directly elicited scores for the comorbidities.
The main results are summarized in > Figure 20-3, and are similar to those of Fu and
Kattan (2008).
Although all the models were biased and inefficient in an absolute sense, the minimum
model demonstrated the best relative performance in reconstructing the observed utilities for
the comorbidities, and the multiplicative model was superior to the additive model.
On the basis of their findings, both Fu and Kattan (2008) and Dale et al. (2008) suggest that in
the absence of a better alternative for obtaining utility scores for comorbidities, investigators
could apply the minimum model, but with the recognition that it is the “best of a bad lot”. It is
difficult to determine why Flanagan et al.’s (2006) results were not in line with these other two
studies. The discrepancies could stem from method effects (i.e., differences in utility measure-
ment and the health conditions considered) or true discrepancies between the actual and
. Table 20-5
Observed, purified and theoretical estimates of mean health utility for the 20 most prevalent
comorbid condition pairs (descending) in cycle 1.1 of CCHS
Mean Observed Mean Purified Mean Theoretical

Comorbid Pair UtilityF Utility{ Utility{
Non-food allergies + Asthma 0.93 1.00 0.98
Non-food allergies + Back problems 0.86 0.92 0.94
Food allergies + Non-food allergies 0.92 0.99 0.99
Arthritis/Rheumatism + Back problems 0.78 0.83 0.88
Non-Food allergies + Migraine 0.91 0.98 0.97
headaches
Arthritis/Rheumatism + High blood 0.85 0.91 0.93
pressure
Non-Food allergies + Arthritis/ 0.83 0.89 0.94
Rheumatism
Back problems + Migraine headaches 0.82 0.88 0.91
Non-Food allergies + High blood 0.92 0.98 0.98
pressure
Back problems + High blood pressure 0.86 0.92 0.92
High blood pressure + Diabetes 0.89 0.96 0.96
Non-Food allergies + Thyroid 0.92 0.99 1.00
condition
High blood pressure + Heart disease 0.91 0.97 0.95
Arthritis/Rheumatism + Migraine 0.84 0.90 0.91
headaches
Food allergies + Back problems 0.88 0.94 0.93
Asthma + Back problems 0.87 0.93 0.92
High blood pressure + Migraine 0.84 0.90 0.95
headaches
Food allergies + Asthma 0.92 0.98 0.97
Arthritis/Rheumatism + Thyroid 0.90 0.96 0.94
condition
Food allergies + Migraine 0.91 0.98 0.96
headaches
Conditions are shown in descending order of prevalence of the observed co-morbidity. The mean theoretical
utilities for the comorbid pairs are all quite similar to the purified versions of the observed utilities for the comorbid
pairs. All mean utilities are based on the Health Utilities Index Mark III (HUI3; Feeny et al., 2002) instrument. CCHS
Canadian Community Health Survey
* Back problems excluding fibromyalgia and arthritis
F
Observed refers to the average, age-sex standardized HUI3 score for the pair of conditions reported together on
CCHS before being purified
{
Purified refers to the average observed utility after division by the average utility of those reporting no conditions
(0.94)
{
Theoretical refers to the average utility estimated from the multiplicative rule (no synergy), using the mean
purified HUI3 scores of the two conditions reported alone
(Adapted from Flanagan et al., 2006)
376
. Figure 20-3
Observed versus theoretical utilities for comorbid side-effects of prostatectomy. “Cameron McIntosh_fig3.jpg” Directly elicited utilities for comorbid pairs
of prostatectomy side effects are plotted against theoretical utilities, which are calculated by applying mathematical models to the appropriate utilities
20
for single side effects. The straight lines superimposed on each plot are the “ideal” lines representing perfect model fit, while the dashed lines reflect
the actual model fit. First row: additive model. Second row: multiplicative model. Third row: minimum model. Columns represent the side effect
combinations of, respectively, impotence and watchful waiting, impotence and incontinence, and impotence and post-prostatectomy without
complications. (Reproduced with permission from Dale W, Basu A, Elstein A, Meltzer D. (2008). Med Decis Making. 28: 102–112. Sage Publications.)
Utility Scores for Comorbid Conditions: Methodological Issues and Advances
hypothesized underlying processes that generate multi- from single-condition utilities. Further
empirical work is needed to more reliably determine the strength of the evidence for each model.
3.5 A Hybrid Mathematical Model
Very recently, an “encompassing” model has been proposed that merges features of
the additive, minimum, and multiplicative approaches (Basu et al., 2008). Denoting a
condition-specific HRQOL decrement or disutility as Di (i.e., 1 - Ui), the encompassing
model for two comorbid conditions can be written as:
E fUCM g ¼ a0 þ a1 maxfD1 ; D2 g þ a2 minfD1 ; D2 g þ a3 D1 D2
ð6Þ
and E fUCM g ¼ 1:0 E fDCM g;
where E denotes expected value, a0 is the intercept term, and a1, a2, and a3 are weights that
determine, respectively, the relative contributions of the maximum, minimum, and multipli-
cation of the disutilities associated with conditions 1 and 2. By systematically assigning values
to these weights, it is fairly easy to prove that all three traditional models are special cases or
submodels of the encompassing model (Basu et al., 2008):
If a0 = 0.0, a1 = 1.0, a2 = 1.0, and a3 = 0.0, then (6) reduces to the additive model.
If a0 = 0.0, a1 = 1.0, a2 = 1.0, and a3 = 1.0, then (6) reduces to the multiplicative model.
If a0 = 0.0, a1 = 1.0, a2 = 0.0, and a3 = 0.0, then (6) reduces to the minimum model.
As an extension of an earlier study (Dale et al., 2008), Basu et al. (2008) compared the
empirical performance of their encompassing model to all three traditional models, in
the prostate cancer context. The three separate models still performed suboptimally, but the
encompassing model showed a good fit to the directly elicited utilities for the comorbidities.
The final, fully parameterized model is given as:
E fUCM g ¼ 0:05 þ 0:72 maxfD1 ; D2 g þ 0:33 minfD1 ; D2 g 0:18 D1 D2
ð7Þ
and E fUCM g ¼ 1:0 E fDCM g:
All of the estimated weights range between 0 and 1, showing that the process through which
single-condition utilities combine into a multi-condition utility is much more complex than
any one of the traditional models can capture alone. However, both the utility elicitation
exercise in this study and estimation of (6) assumed that HRQOL was affected only by the
particular treatment side effects studied. Men with prostate cancer often have other conditions
(Hall et al., 2005), and so E{UCM} = 1.0 - E{DCM} might not have represented HRQOL in a
real-life treatment setting. A less-than-perfect upper bound on the utility scale may have been
more appropriate. The encompassing model appears promising, but needs to be verified
beyond the prostate cancer context.
4 Conclusion
This chapter has provided a summary of the major methodological issues and advancements
in obtaining utility scores for comorbid conditions. While this rapidly expanding field offers
a number of methodological innovations, there is as yet no unequivocal evidence for a
convenient and universally applicable approach. Therefore, researchers applying these meth-
ods in BoD and CEA should be aware of the particular advantages and disadvantages as
discussed here.
More empirical research is needed to evaluate and refine the methods proposed thus
far, with a focus on enhancing cross-study comparability via standardization of
utility measurement and analytical techniques. One particularly fruitful avenue for future
investigation is the encompassing mathematical model for single-condition utility scores
(Basu et al., 2008).
Some proponents of > value-based medicine fear that CEAs which explicitly adjust for
comorbidity and reduce apparent treatment benefits will lead to discrimination, as it may be
seen as more cost-effective to treat the targeted condition in patients with no comorbidities
(Brown et al., 2005). Others have suggested that if any HRQOL gains are shown to be
possible with treatment, then comorbidity corrections should not lead to favouring the
treatment of those without comorbidities (Andrews et al., 1998). Whatever the case, it is
important to accurately and objectively assess the HRQOL impact of comorbidity, as well as
the HRQOL benefits of treatments and interventions. It is hoped that the present work will
help move the field toward establishing optimal strategies for dealing with comorbidity in
utility measurement, which would improve the quality of the evidence base necessary for
health care decision-making at both the individual and population levels. This will be
particularly important given that elderly populations, who are particularly at risk for
experiencing multiple chronic conditions (Boyd et al., 2005), are expected to continue to
grow in most economically developed countries over the next couple of decades (US Bureau
of the Census, 1992).
Acknowledgments
The author thanks William Dale, Patrick Sullivan, George Hazen, Mark Eckman, Alex Fu,
David Feeny, Sherri Maddigan, Janel Hanmer, and Jeff Johnson for supplying copies of
key papers. Thanks are also due to Michelle Rotermann and Kathy White for valuable
feedback on earlier versions of this manuscript, as well as to Rasha Bradic for assistance with
preparation of figures. Any remaining errors and/or omissions are the sole responsibility of
the author.
Summary Points
Utility scores anchored at 0.0 (i.e., dead) and 1.0 (i.e., full health) serve to quantify the
health-related quality of life (HRQOL) associated with health conditions, and are the
foundation of summary measures of population health (SMPH) and cost-effectivesness
analysis (CEA) of treatments and interventions.
Comorbidity is common, and must be accounted for in utility measurement so as to avoid
biased estimates of both disease burden and treatment benefits.
Utilities for comorbid conditions can be directly elicited using conventional protocols
(e.g. visual analogue scale, standard gamble, or time trade-off), yet the approach is too
cognitively burdensome for raters to have wide practical appeal.
Data from population surveys on chronic condition prevalence and utility-based HRQOL
instruments can be used to compute scores for comorbidities, but self-report bias, limited
selection of health conditions, and exclusion of institutionalized persons often limit the
approach.
Mathematical models for combining single-condition utility scores have been developed
(e.g., additive, multiplicative, minimum), and are easily applied.
Empirical support for the validity of these models is mixed, and confounded to some
extent by a lack of standardized testing methodology across the relevant studies.
A hybrid mathematical model that encompasses previous approaches is a promising
alternative, but has been examined only in the context of prostate cancer and needs
broader evaluation.
Continuing to refine utility scores for comorbid conditions is important for enhancing the
evidence base necessary for sound health care decision-making, especially given the aging
of the population.
References
Andrews G, Sanderson K, Beard J. (1998). Br J Psychiatry. Clarke P, Gray A, Holman R. (2002). Med Decis Making.
173: 123–131. 22: 340–349.
Arnesen T, Nord E. (1999). BMJ. 319: 1423–1425. Coffey JT, Brandle M, Zhou H, Marriott D, Burke R,
Austin PC. (2002). Med Decis Making. 22: 152–162. Tabaei BP, Engelgau MM, Kaplan RM, Herman
Basu A, Dale W, Elstein A, Meltzer D. (2008). J. WH. (2002). Diabetes Care 25: 2238–2243.
Health Econ. Sep4 [Epub ahead of print] PMID: Dale W, Basu A, Elstein A, Meltzer D. (2008). Med Decis
18773392. Making. 28: 102–112.
Begg S, Vos T, Barker B, Stevenson C, Stanley L, Lopez A. Drummond MF, Sculpher MJ, Torrance GW, O’Brien BJ,
(2007). Burden of disease and injury in Australia, Stoddardt GL. (2005). Methods for the economic
2003. AIHW cat. no. PHE 82. Australian Bureau of evaluation of health care programmes, 3rd ed.
Health and Welfare, Canberra. Oxford University Press, Oxford.
Bell CM, Chapman RH, Stone PW, Sandberg EA, Neu- Eckman MH, Steere AC, Kalish RA, Pauker SG. (1997).
mann PJ. (2001). Med. Decis. Making. 21: 288–294. N Engl J Med. 337: 357–363.
Boswell-Purdy J, Flanagan WM, Roberge H, Le Petit C, Eckman MH, Falk RH, Pauker SG. (1998). Arch Intern
White KJ, Berthelot JM. (2007). Chron Dis Can. 28: Med. 158: 1669–1677.
42–55. Eckman MH, Singh SK, Erban JK, Kao G. (2002). Med
Bowker SL, Pohar SL, Johnson JA. (2006). Health Qual Decis Making. 22: 106–124.
Life Outcomes. 4: 17. Feeny DA. (2005). ISOQoL Res. Newsletter 10: 1 and 8.
Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Feeny D, Furlong W, Torrance GW, Goldsmith CH,
(2005). JAMA. 294: 716–724. Zhu Z, DePauw S, Denton M, Boyle M. (2002).
Bravata DM, Nelson LM, Garber AM, Goldstein MK. Med Care 40: 113–128.
(2005). Med Decis Making. 25: 158–167. Flanagan W, McIntosh CN, Le Petit C, Berthelot JM.
Brazier J, Deverill M, Green C, Harper R, Booth A. (2006). PHM. 4: 13.
(1999). Health Technol. Assess. 3: 1–164. Fortin M, Lapointe L, Hudon C, Vanasse A, Ntetu AL,
Broemeling A-M, Watson D, Black C. (2005). Chronic Maltais D. (2004). Health Qual. Life Outcomes.
conditions and comorbidity among residents of 20: 51.
British Columbia. Centre for Health Services and Franci DM, Pathak DV. (2003). Int J Technol. Assess.
Policy Research, University of British Columbia, Health Care 19: 347–361.
British Columbia. Franks P, Hanmer J, Fryback DG. (2006). Med Care.
Brown MM, Brown GC, Sharma S. (2005). Evidence- 44: 478–485.
based to value-based medicine. AMA, Chicago, Fryback D, Lawrence W. (1997). Med Decis Making.
Illinois. 17: 276–284.
Fu A, Kattan M. (2008). Med Care. 46: 984–990. Murray CJL, Lopez AD. (2000). Health Econ. 9: 69–82.
Furlong W, Barr RD, Feeny D, Yandow S. (2005). Health Murray CJL, Salomon JA, Mathers CD, Lopez AD (eds).
Qual. Life Outcomes. 3: 3. (2002). Summary measures of population health:
Gijsen R, Hoeymans N, Schellevis FG, Ruwaard D, Satar- Concepts, ethics, measurement and applications.
iano WA, Bos van den GA. (2001). J Clin Epidemiol. World Health Organization, Geneva.
54: 661–674. Naglie G, Krahn MD, Naimark D, Redelmeier DA,
Gold MR, Siegel JE, Russell LB, Weinstein MC. (1996). Detsky AS. (1997). Med Decis Making. 17: 136–141.
Cost-Effectiveness in Health and Medicine. Oxford Quan H, Parsons GA, Ghali WA. (2002). Med Care.
University Press, Oxford. 40: 675–685.
Hall WH, Jani AB, Ryu JK, Narayan S, Vijayakumar S. Ritvo P, Irvine J, Naglie G, Tomlinson G, Bezjak A,
(2005). Prostate Cancer Prostatic Dis. 8: 22–30. Matthew A, Trachtenberg J, Krahn M. (2005).
Harris R, Nease R. (1997). J Health Econ. 16: 113–120. J Clin Epidemiol. 58: 466–474.
Hazen G. (2004). Decis Analysis. 1: 205–216. Rutten-van-Mölken MPMH, Oostenbrink JB, Tashkin,
Johnston JA, Brill-Edwards P, Ginsberg JS, Pauker SG, DP, Burkhart D, Monz BU. (2006). Chest. 130:
Eckman MH. (2005). Am J Med. 118: 503–514. 1117–1128.
Kao TC, Cruess DF, Garner D, Foley J, Seay T, Salomon JA, Murray CJL. (2004). Health Econ.
Friedrichs P, Thrasher JB, Mooneyhan RD, 13: 281–290.
McLeod DG, Moul JW. (2000). J Urol. 163: 858–864. Saarni S, Härkänen T, Sintonen H, Suvisaari J,
Katzmarzyk PT, Janssen I. (2004). Appl. Physiol. Nutr. Koskinen S, Aromaa A, Lönnqvist J. (2006). Qual.
Metab. 29: 90–115. Life Res. 15: 1403–1414.
Knight SJ, Nathan DP, Siston AK, Kattan MW, Elstein AS, Schultz SE, Kopec JA. (2003). Health Rep. 14: 41–53.
Collela. (2002). Clin Prostate Cancer 1:105–14. Statistics Canada. (2002–2003). National Population
Laux G, Kuehlein T, Rosemann T, Szecsenyi J. (2008). Health Survey: Health Institutions Component
BMC Health Serv Res. 8: 14. Cycle 5. http://www.statcan.ca/english/sdds/instru-
Maddigan SL, Feeny DH, Johnson JA. (2005). Qual Life ment/5003_Q1_V5_E.pdf.
Res. 14: 1311–1320. Stewart ST, Lenert L, Bhatnagar V, Kaplan RM. (2005).
Maddigan SL, Feeny DH, Majumdar SR, Farris KB, Med Care. 43: 347–355.
Johnson JA. (2006). Am J Public Health. 96: Stouthard MEA, Essink-Bot ML, Bonsel GJ, Barendregt
1649–1655. JJM, Kramers PGN, van de Water HPA, Gunning-
Manuel DG, Schultz SE. (2004). PHM 2: 4. Schepers LJ, van der Maas PJ. (1997). Disability
Manuel DG, Schultz SE, Kopec JA. (2002). J Epidemiol weights for diseases in the Netherlands. Department
Community Health 56: 843–850. of Public Health, Erasmus University, Rotterdam.
Mas-Colell A, Whinston MD, Green JR. (1995). Micro- Sullivan PW, Ghushchyan V. (2006). Med Decis Making.
economic theory. Oxford University Press, New 26: 410–420.
York. Sullivan PW, Lawrence WF, Ghushchyan V. (2005). Med
Mathers CD, Iburg KM, Begg SB. (2006). PHM 4:4. Care. 43: 736–749.
Mathers CD, Sadana R, Salomon JA, Murray CJL, Lopez Tengs T, Wallace A. (2000). Med Care. 38: 583–637.
AD. (2001). Lancet. 357: 1685–1691. Tunis S, Stryer DB, Clancy CM. (2003). JAMA. 290:
Mathers C, Vos T, Stevenson C. (1999). The burden of 1624–1632.
disease and injury in Australia. Australian Institute US Bureau of the Census. (1992). International Popula-
of Health and Welfare, AIHW cat. no. PHE 17. tion Reports, an Aging World II. P25, 92–3.
Australian Bureau of Health and Welfare, Canberra. US Government Printing Office, Washington DC
McIntosh CN, Gorber SC, Bernier J, Berthelot JM. van Baal PHM, Hoeymans N, Hoogenveen RT,
(2007). Chron Dis Can. 28: 29–41. de Wit GA, Westert GP. (2006). PHM 4: 1
Murray CJL. (1996). In: Murray CJL, Lopez AD (ed). The Vos T, Begg S. (2000). The Victorian Burden of Disease
global burden of disease: A comprehensive assess- Study: Morbidity. Public Health Division, Depart-
ment of mortality and disability from diseases, ment of Human Services, Melbourne.
injuries, and risk factors in 1990 and projected to Wu SY, Green A. (2000). Projection of Chronic Illness
2020, Volume 1. Harvard University Press, Boston, Prevalence and Cost Inflation. RAND Health,
pp. 1–98. Washington DC.
21 Subjective Quality of Life
Measures – General Principles
and Concepts
C. L. K. Lam
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
2 Quality of Life as an Health Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
3 Applications of Quality of Life Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
4 Concepts of Subjective Quality of Life Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

4.1 Dimensions and Domains of Quality of Life Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
4.2 Indicators of Quality of Life Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
5 Subjective Quality of Life Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

5.1 Generic and Disease Specific Health-related Quality of Life Measures . . . . . . . . . . . . . 388
5.2 Preference-Based Measures of Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
6 Scoring QOL Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
7 Choosing the Right QOL Measure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

7.1 Validity of an HRQOL Measure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
7.2 Reliability of an HRQOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
7.3 Feasibility and Acceptability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
7.4 Sensitivity and Responsiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
7.5 Interpretation of QOL Measure Scores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
7.6 Minimal Clinically Important Difference (MCID) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

382 21 Subjective Quality of Life Measures – General Principles and Concepts
Abstract: Subjective > quality of life (QOL) is becoming a standard health outcome measure
especially for people with multiple, chronic, functional, psychological, or incurable illnesses. A
good instrument is the pre-requisite of any measurement, which is in the form a questionnaire
for QOL. This chapter reviews the concepts, principles, applications, scoring methods and
selection criteria of subjective QOL measures to enable users to choose the most appropriate
instruments for their purposes.
Quality of life (QOL) is a logical outcome measure of the effectiveness of modern health
care much of which aims at relieving suffering and restoring normal living. The essential
concepts of QOL measures are subjectivity, multi-dimensionality and well-being. Health-
related quality of life (HRQOL) focuses on > dimensions that are modifiable by health.
General health perception, psychological well-being and functioning are essential dimensions
of HRQOL while symptoms and vitality are important causative variables.
Quality of life is a latent variable that cannot be directly measured. It needs to be converted
to indicators of its component dimensions and domains to be quantified. To serve the
purpose, the indicators must be valid, important, representative and adequate. A QOL
measure presents the > indicators as items that can be rated on response > scales, which are
then presented as a profile domain scores or a composite index of quality of life.
Hundreds of QOL measures have been developed mostly for the assessment of HRQOL.
Generic measures that are applicable to people with different health status are more suitable for
population and comparative studies. Disease specific measures tend to have high > sensitivity
and are best used for evaluative purposes. Preference-based measures of health (PBMH)
convert a multidimensional QOL state to a fractional index for the calculation of quality
adjusted life years (QALYs) and cost-effectiveness. A critical appraisal of the nature and
psychometric properties of a QOL measure can assure that it will meet the needs of the user.
List of Abbreviations: COOP/WONCA Charts, The Dartmouth Corporation Functional
Health Assessment Charts/World Organization of Family Doctors; EQ-5D, European Quality
of Life-5 Dimension; HRQOL, > Health-related quality of life; HUI-3, Health Utilities Index-
Mark 3; ICC, intra-class correlation; MCID, > minimal clinically important difference; MID,
minimally important difference; PBMH, preference-based measures of health; PRO, patient
reported outcome; QALYs, quality adjusted life years; QOL, quality of life; RS, rating scale; SD,
standard deviation; SEM, standard error of measurement; SF-12, The Medical Outcomes
Study 12-item Short-form Health Survey; SF-36, The Medical Outcomes Study 36-item
Short-form Health Survey; SG, standard gamble; SIP, sickness impact profile; SRM, standar-
dized response mean; TTO, time trade-off; VAS, visual analogue scale; WHOQOL, World
Health Organization Quality of Life Assessment Instrument
1 Introduction
The ultimate goal of health care is to improve, restore and maintain the health of people so
that they can enjoy a quality life. Quality of life (QOL) is defined by the World Health
Organization (WHO) as ‘‘an individual’s perception of their position in life in the context
of the culture and value systems in which they live in relation to their goals, expectations,
standards and concerns’’ (WHOQOL Group, 1993). Health is one of the most important
determinants of quality of life that is potentially modifiable. This has led to the conceptualiza-
tion of health-related quality of life (HRQOL), which is best understood by Bullinger’s
Subjective Quality of Life Measures – General Principles and Concepts 21 383
definition as ‘‘the impact of perceived health on an individual’s ability to live a fulfilling life’’
(Bullinger et al., 1993).
A good measuring instrument is the pre-requisite to any measurement. The instrument
that is used to measure QOL is usually in the form of a questionnaire. The > validity and
accuracy of the results depend on the quality of the questionnaire. Research over the last thirty
years has gradually established the science, method and standard of subjective QOL measure-
ment. Many QOL measures have been developed to suit different purposes, populations and
settings. When used properly, QOL measures can improve quality of care and inform clinical
decision but inappropriate use can be misleading, costly and harmful. A clear understanding
of the concepts and scoring principles of subjective QOL measures is essential for choosing an
instrument that is fit for purpose.
2 Quality of Life as an Health Outcome
Rapid advances in life-saving technologies since the late 1960s has perpetuated sick lives more
than healthy lives. More and more people are living with multiple chronic diseases that can
impair quality of life. The modern medical ethics movement in the 1960s has called for the
incorporation of subjective perception in the evaluation of care, in response to the dilemma of
whether life-sustaining treatment is adding life to years or merely years to life. Mortality and
morbidity indicators including disability adjusted life years (DALY) are no longer sensitive
enough to capture the outcomes of illnesses or treatments. The modern outcomes movement
in the 1980s has established QOL as a standard outcome measure of health and medical
treatment (Geigle and Jones, 1990). The term health-related quality of life (HRQOL) has
emerged to highlight those aspects of QOL that are modifiable by health and to differentiate
them from other aspects of QOL that have little direct relationship with health. The relation-
ship of different health outcomes is shown in > Figure 21-1.
. Figure 21-1
Health outcome measures. Quality of life is a type of patient reported outcomes, and
health-related quality of life is a subset of quality of life outcomes
Health-related quality of life (HRQOL) is probably the only non-fatal health outcome that
can be applied to all people, illnesses and settings. It is a unifying measure of the ultimate effect
of health and medical interventions. It is congruent to the aims of the majority of modern
health care for the relief of symptoms, maintenance of function or promotion of well-being.
Evidence supporting the validity, sensitivity and > responsiveness of HRQOL as an outcome
measure is abundant (Efficace et al., 2003; Fayers and Sprangers, 2002). Subjective QOL is a
strong determinant of health service utilization (Lam et al., 2002), it is a sensitive predictor of
mortalities and morbidities (Reid et al., 2006), institutional care (Fan et al., 2002), or return to
work (Petrie et al., 1996). They can detect treatment effects that clinical parameters cannot
(Efficace et al., 2003).
3 Applications of Quality of Life Measures
The applications of QOL measures can be broadly classified into four main purposes:
1. Evaluative measures for the assessment of population health, impact of an illness, effec-
tiveness or side effects of treatment, or quality of care. QOL is now routinely included in
population health surveys, and is becoming a standard outcome measure in clinical trials.
2. Discriminative measures for the differentiation between groups of people with different
needs to guide service planning and policy (Clarke et al., 2002). HRQOL is commonly
included as a medical-risk adjustment factor in health care plans.
3. Predictive measures for the identification of people at risk or for the prediction of service
needs or outcomes (Lam et al., 2002; Reid et al., 2006).
4. Preference (also known as utility) measures for health economic analyses (National
Institute for Clinical Excellence (NICE), 2004; Weinstein et al., 1996). HRQOL is a generic
outcome that allows direct comparison of the cost-effectiveness between treatment pro-
grams, or determination of any adverse health effect of cost containment programs.
Although QOL measurement has wide applications, indiscriminate use can be misleading,
costly and burdensome to the subjects. QOL is a most relevant outcome measure for patients
with multiple, disabling, psychological, functional or incurable diseases. It may not be
appropriate or necessary in some situations e.g., a clinical trial on the treatment of an acute
life-threatening infection. > Table 21-1 shows a checklist to guide the decision on whether
QOL assessment can add useful information to a study or program.
QOL is often used as a measure of the benefit of palliative treatments including cancer drugs but
vague and general QOL claims are not acceptable. To be credible, QOL claims should fulfill the
criteria summarized in > Table 21-2 (European Medicines Agency Evaluation of Medicines for
Human Use (EMEA), 2005; FDA, 2006; National Institute for Clinical Excellence (NICE), 2004).
The incorporation of HRQOL assessment into daily clinical practice to guide diagnosis
and management is a future direction. QOL assessment can facilitate doctor-patient commu-
nication and better identification of patients’ health problems (Velikova et al., 2004). The main
obstacle to routine clinical application is time. Brief measures such as the Dartmouth COOP
Functional Health Assessment Charts/WONCA (Scholten and van Weel, 1992), and the use
of computerized individualized measures can make QOL measurement more practical.
There is also a need to improve the precision of QOL measures up to a > reliability coefficient
of 0.9 for them to be useful for individual patient assessment (McDowell and Newell, 1996).
. Table 21-1
Checklist on whether quality of life (QOL) should be used as an outcome measure
1. Is QOL an appropriate outcome of the health condition?

2. Is QOL an important outcome of the intervention or service?
3. Is the purpose of measuring QOL clearly defined?
4. Is QOL a primary, secondary or confounding outcome?
5. Is QOL assessment feasible for the study population and setting?
6. What type of QOL data is required for the purpose?
7. Can the QOL data be incorporated in the data analysis?
8. Can meaningful interpretation of the QOL data be made?
All the questions should be confirmed before quality of life is used as an outcome measure in a study or program
. Table 21-2
Quality of life (QOL) claims by interventions
1. It should be supported by evidence from controlled clinical trials.

2. There should be a clear conceptual framework on the QOL outcome measured.
3. Assessment should include all relevant domains.
4. QOL should be measured by instruments that have been shown to be valid for the target
population
5. QOL assessment should be based on patient’s perspective.
6. The method of data collection should be described in details.
7. The results should reflect the totality of findings.
This is s summary of the requirements for an intervention to make a quality of life claim, based on a review of the
guidelines from the Food and Drug Administration (FDA), U.S.A., National Institute for Clinical Excellence (NICE),
U.K. and the European Medicines Agency (EMEA)
References on > population norms and the > minimal clinically important difference
(MCID) can help clinicians interpret QOL data more meaningfully.
4 Concepts of Subjective Quality of Life Measures
A good understanding of the conceptual base of QOL measures will enable the user to choose
the right instrument for the purpose. The essential concepts of QOL measures are subjectivity,
multi-dimensionality and well-being. This implies that proxy response to QOL measures is
not conceptually valid, and uni-dimensional measures or symptom checklists are inadequate.
The use of subjective patient information has always been recognized to be important in
that the process of making a diagnosis always starts with the patient’s history (McDowell and
Newell, 1996). The term patient-reported outcome (PRO) is used to represent patients’
subjective perceptions and QOL is one of them, others include symptoms and patient
satisfaction. The correlation between subjective and objective assessments of psychological
state is generally weak, indicating that they are complimentary constructs.
The second essential concept of QOL is multi-dimensionality in that QOL consists of

different components that may or may not be correlated. The number of dimensions of QOL
is large ranging from activities of daily living to living environment and finance, as those
measured by the WHO QOL Assessment Instrument (WHOQOL Group, 1998). The term
HRQOL is used to distinguish dimensions that are related to health from those that are not
(Sousa and Kwok, 2006; Wilson and Cleary, 1995).
The concept of well-being implies QOL is a positive > construct, which is consistent with
the World Health Organization (WHO) definition of ‘‘health is a complete state of physical,
mental and social well-being and not merely the absence of disease or infirmity.’’ Positive and
negative perceptions are separate constructs in that the absence of sufferings does not
automatically imply well-being (Ware et al., 1993).
4.1 Dimensions and Domains of Quality of Life Measures
The term ‘‘dimension’’ refers to the broad component and the term ‘‘domain’’ refers to the
sub-components. Some people use these two terms interchangeably and some measures, e.g.,
the WHO QOL Assessment Instrument, uses the term ‘‘domain’’ for the main components
and the term ‘‘facet’’ for sub-components (WHOQOL Group, 1993, 1998). There is still no
general consensus on what are the essential dimensions of QOL measures although health has
been identified to be a very important determinant. On the other hand, a review by Wilson
et al has identified general health perception, psychological well-being and functioning to be
the essential dimensions of HRQOL (Wilson and Cleary, 1995). The dimension of functioning
includes physical, psychological, daily role and social domains. The dimensions of vitality and
symptoms especially bodily pain are also included in many HRQOL measures because they
have been found to be sensitive and responsive indicators (Revicki et al., 2000; Ware et al.,
1993; Wilson and Cleary, 1995). A HRQOL measure usually has four or more scales covering
different domains. HRQOL measures that are targeted to specific conditions tend to have
more emphasis on the symptom dimension.
Some people use the term ‘‘health status’’ interchangeably with HRQOL (Wilson and
Cleary, 1995), but they are two different constructs (Bullinger et al., 1993; Revicki et al., 2000).
Health status refers to the state of health while HRQOL is the perceived impact of health on
life. Health status can be objective or subjective while HRQOL is always subjective.
4.2 Indicators of Quality of Life Measures
QOL is a latent variable that cannot be directly measured. It has to be converted to indicators
of its component dimensions to be quantifiable. An indicator is an observable variable that can
be quantified. Since QOL is multi-dimensional, one needs to measure an adequate sample of
indicators of all the relevant domains in order to reflect the whole picture. The indicators
should have an empirical conceptual base, and be valid, relevant, appropriate, adequate,
specific, reliable, and sensitive. Both positive indicators of well-being and negative indicators
should be included.
A typical QOL measure is a questionnaire that presents each of the indicators as an
item of question or statement with corresponding response options in terms of intensity
(mild to severe), frequency (never to always), or agreement (totally disagree to totally agree).
. Figure 21-2
Construction framework of quality of life measures. The latent construct of quality of life is
converted to its component domains, and each domain is then represented by indicators that
can be directly observed
The collection of item(s) that measure the same domain is called a scale (McDowell and
Newell, 1996). Each scale can have one or more items. Single-item scales are easy to use but
they tend to be less reliable, sensitive or responsive than multiple-item scales (McDowell and
Newell, 1996). According to the item-measurement theory, summation of scores of items of
the same scale is possible because they measure the same construct and it gives an indication of
the achievement in the respective domain. The profile of domain scores in turn gives a
representation of the latent variable of QOL. The general construction framework of a QOL
measure is shown in > Figure 21-2.
The items of QOL measures can be broadly classified into true effect indicators and causal
variables. Effect indicators such as general health perception and emotions depend on and are
strongly correlated with the latent construct of QOL whose change will be reflected in
measurable changes in the variable (Fayers and Hand, 1997). Strictly speaking causal variables
such as symptoms are not true indicators in that their correlation with QOL is variable. Most
causal variables of QOL are negative, e.g., pain, in that their presence may cause poor quality
of life but their absence does not always imply good quality of life (Fayers and Hand, 1997).
5 Subjective Quality of Life Measures
There is a wide range of QOL measures with different conceptual bases, dimensions, content,
scale constructions and scoring algorithms to meet the needs of different purposes, settings
and target populations (MAPI Research Trust, 2007). Some commonly used QOL measures
are listed in > Table 21-3. Many of them have been adapted and tested in different languages
and cultures. The SF-36 and its abbreviated version (the SF-12) are probably the most
widely used. The COOP/WONCA Charts is the shortest, which makes it most practical for
daily clinical application. The WHOQOL-100 Assessment Instrument and its short form
(WHOQOL-BREF) are QOL measures that assess not only HRQOL domains but also the
domains of environment, social support and spirituality (WHOQOL Group, 1998).
. Table 21-3
Commonly used quality of life (QOL) measures
Generic measures
MOS SF-36 Health Survey
MOS SF-12 Health Survey
WHOQOL-100
WHOQOL-BREF
Sickness Impact Profile (SIP)
The Nottingham Health Profile (NHP)
Duke Health Profile
The COOP/WONCA Charts
Child Health Questionnaire (CHQ)
Disease-specific measures
European Organization for Research and Treatment of Cancer Quality of Life- Core 30-item
Questionnaire –(EORTC-QLQ-30)
Functional Assessment of Cancer Treatment (FACT) – General and specific cancer modules
Chronic Respiratory Disease Questionnaire
Chronic Heart Failure Questionnaire
Adult Asthma QOL Questionnaire
Pediatrics Asthma QOL Questionnaire
Arthritis Impact Measurement Scale (AIMS)
Calgary Sleep Apnoea QOL Questionnaire
Chronic Liver Disease Questionnaire (CLDQ)
MOS-HIV Health Survey
Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO)
Preference-based Measures of Health (PBMH)
– Health Utilities Index-3 (HUI-3)
– EQ-5D (previously known as EuroQol)
– SF-6D
– Quality of Well Being Scale (QWB)
MOS Medical Outcomes Study; WHOQOL World Health Organization Quality of Life Assessment Instrument; COOP/
WONCA Dartmouth Corporative Functional Assessment Charts/World Organization of Family Doctors; SF-6D Short
Form-6 Dimension; HIV Human immunodeficiency virus. Generic measures are applicable to people of all health
status. Disease specific measures are applicable only to people with the relevant condition or group of diseases. A
preference –based measure of health (PBMH) converts a health state to a preference index that can be used for the
calculation of quality adjusted life years (QALYs) and cost-effectiveness
5.1 Generic and Disease Specific Health-related Quality of Life

Measures
HRQOL measures are broadly classified into generic and disease specific measures according
to their target populations. Generic QOL measures refer to those that are applicable to people
with different health status or disease types, while disease specific measures are intended for
people suffering from a particular illness. The debate on whether generic or diseases specific
measures are better is irrelevant because the choice should depend on the purpose and context.
Each type of measures has its advantages and limitations, inappropriate applications of either
will defeat the purpose.
Generic Measures are most appropriate for the assessment of people with multiple diseases
or heterogeneous populations. The use of a common generic measure allows direct compar-
isons of results between different groups and with population norms. However, no one generic
measure really fits all. Measures designed for adults are not meant for children, and those that
are targeted to ambulatory subjects may not be applicable to people living in institutions. The
main limitation of generic measures is that they may not include indicators that are uniquely
important to some special disease groups (Guyatt et al., 1999). The other disadvantage of
generic measures is inadequate sensitivity and responsiveness, which may limit their useful-
ness in clinical trials (Oh and Ku, 2006).
The majority of the QOL measures developed in recent years are disease specific measures
to meet the demand for more sensitive measures in clinical trials. Disease specific measures are
designed specifically to capture the concerns of patients suffering from a particular condition,
e.g., the Asthma Quality of Life Questionnaire (AQOL) for asthma (Marks et al., 1993), or a
group of diseases e.g., the European Organization for Research and Treatment of Cancer
30-itme Quality of Life Questionnaire (EORTC QLQ-30) for cancers (Aaronson and ERORTC
Study Group on Quality of Life, 1993). They often contain many items on specific symptoms
that are causal rather than effect indicators. A disease specific measure should be used if one
wants to detect specific and small changes. They tend to be more sensitive and responsive than
a generic measure (Guyatt et al., 1999; Oh and Ku, 2006), although this is not always true
(van der Molen et al., 1997). It should be pointed out that excessively sensitive instruments
may not be the best for clinical trials because they may detect changes that are not clinically
important or random in the placebo group. Highly selective disease specific domains may miss
unexpected important QOL effects. Comparison between results from different patient groups
is almost impossible if different measures are used for different conditions.
A combination of generic and disease-specific measures may overcome the limitations of
using only one type of measures, but this has to be balanced against the decrease in accept-
ability of a lengthy and repetitive survey.
5.2 Preference-Based Measures of Health
An important application of QOL is as a measure of effectiveness in health economic analysis.

Quality adjusted life years (QALYs) is recommended to be the unit of effectiveness in cost-
effectiveness analysis of medical interventions by both the National Institute for Clinical
Excellence (NICE) in the United Kingdom (National Institute for Clinical Excellence
(NICE), 2004) and the US Public Health Service (Weinstein et al., 1996). To calculate
QALYs, QOL needs to be expressed as a single fraction on the full health to dead scale based
on preferences obtained from the general population, where full health is one and states
deemed as bad as being dead are given a value of zero (Brazier et al., 2002). Negative preference
is possible for states that are deemed worse than being dead.
The conceptual base of preference-based measures of health (PBMH) originates from the
von Neumann-Morgenstern modern utility theory that is intended to help decision making
under uncertainty (Von Neumann and Morgenstern, 1953). It recommends a normative
approach of how rational decisions ought to be made. It assumes that preference exists and is
transitive and continuous. A more preferred choice has a higher value. The term ‘‘utility
measures’’ is often used interchangeably with PBMH but the latter is preferred because it
reflects the underlying concept better.
A PBMH has two components: a multi-dimensional health state classification that describes a
patient’s health in terms of a level at each dimension, called attribute, and a set of preference
weights for the attributes. The most crucial of a PBMH is how the preference weights are gener-
ated (McDowell and Newell 1996; Torrance and Feeny, 1989). The judgment method in which a
group of judges value different health states is most commonly used. The judges should be
sampled from the general population to reflect the normative approach in preference measures.
Standard gamble (SG) is the standard method of preference valuation base on the original von
Neumann-Morgenstern modern utility theory (Von Neumann and Morgenstern 1953), but it is
quite demanding on the subjects (Brazier et al., 2002; Torrance and Feeny, 1989). The time trade-
off (TTO) method was developed as a simpler alternative to SG that gives similar results
(Morimoto and Fukui, 2002; Torrance and Feeny, 1989). The rating scale (RS) method, although
easy to administer, is not recommended because it is not a true measure of preference and it gives
significantly different results (Brooks and EuroQol Group, 1996; Morimoto and Fukui, 2002).
Most QOL measures give a profile of domain scores that cannot be used for the calculation of
QALYs. In theory if the relative preference of each attribute is known, it would be possible to
convert the multi-dimensional QOL ratings to a single preference index (McDowell and Newell,
1996; Torrance and Feeny, 1989). The number of possible health states is very large for each given
PBMH, e.g., the SF-6D has 18,000 health state combinations, so it is not feasible to value each one
by an adequate number of judges. Base on the multiattribute utility theory (MAUT), the
preference weight of each attribute can be estimated from the preference values of a representative
sample of the health states by mathematical modelling (Brazier et al., 2002; Torrance and Feeny,
1989), and this is the method of how the scoring algorithms of most PBMH are developed.
Generic measures are recommended for the estimation of preference to be consistent with
the normative approach (National Institute for Clinical Excellence (NICE), 2004; Von
Neumann and Morgenstern, 1953). Commonly used PBMH include the Health Utility
Index Mark 3 (HUI-3) (Feeny et al., 2002), EQ-5D (Brooks and EuroQol Group, 1996),
SF-6D (Brazier et al., 2002) and the Quality of Well Being (QWB) Scale (Kaplan and Andersen,
1996). Different PBMH may give different results because they have different component
dimensions and methods of preference valuation (Pichard et al., 2005). HUI-3 has eight
dimensions including hearing, vision, speech and dexterity that may be of special relevance
for some conditions or populations. EQ-5D, measuring five dimensions, was developed by a
multi-cultural group in Europe making it a popular cross-cultural measure in the West. The
SF-6D has six dimensions extracted from the SF-36 so that it can generate preference values
from any data set of the latter. The QWB has four dimensions including one on symptom/
problem complexes that covers an extensive list of morbidities. The preference values were
generated by SG in HUI-3 and SF-6D, TTO in EQ-5D, and RS in QBW.
6 Scoring QOL Measures
The results of QOL measures are usually presented as scores to facilitate statistical analysis,
interpretation and communication. Different instruments have different scoring algorithms
and types of scores. Some measures such as the SF-36 use higher scores to indicate better
quality of life but the reverse is true for other measures, e.g., the COOP/WONCA Charts. The
items and scoring algorithm of the General Health (GH) scale of the SF-36 is shown in
> Table 21-4 to illustrate the principles of scoring of a QOL measure.
Each item is rated on a response scale. A QOL measure can use different types of response
scales to suit the nature of the indicators The Likert scale with 3–7 ordinal response options of
fixed intervals is used in most measures (McDowell and Newell, 1996). A 5-point Likert scale is
used for each of the GH items of the SF-36, as shown in > Table 21-4. Response scales can also
be dichotomous (yes/no) or continuous (e.g., visual analogue scale). The visual analogue
scale (VAS) is a 100 mm line anchored at one end of the worst and the other of the best
possible response and the respondent is asked to mark the position of his/her self-perception
on the line. The sensitivity of a scale increases with the number of response options but the
differentiation between choices may be difficult if there are too many. Theoretically the VAS
gives the best precision and sensitivity but some people find it too abstract to place their
answers on a line.
The response to each item is converted to a score so that scores of items of the same
domain scale can be summated to give a scale score. Since most QOL measures consist of
both positive and negative items, reverse coding is necessary for some items so that the
linear relationship between the score and level of QOL is consistent. Recoding is needed
for three of the five general health (GH) items of the SF-36 (> Table 21-4). Care should be
taken to group the appropriate items of the same scale together because they may be presen-
ted under different questions in the QOL questionnaire. In the case of the GH scale of
the SF-36, one item is presented under question 1 and four items are presented under
question 11.
Multi-dimensional QOL measures usually give a profile of scores with one score for each
domain, e.g., the SF-36 has eight scale scores. Summation of scores that measure different
domains is conceptually invalid and meaningless unless they have a common underlying
factor component. Scores of domains that share a correlated underlying factor component can
be combined if appropriate weightings are made, e.g., the SF-36 scale scores can be summar-
ized into two (physical and mental) component summary scores (Ware and Kosinski, 2001).
Different measures and different scales of the same measure may have different scoring
ranges, therefore their raw scores are not directly comparable. Transformation of a raw scale
score to a standardized scoring range of 100, as in the case of the SF-36, facilitates statistical
analysis, interpretation and comparison of the QOL data. This is done by the following
formula:
½ðraw scale score lowest possible raw sacle scoreÞ possible raw score range 100
The transformation of the raw GH scale score of the SF-36 is illustrated in > Table 21-4.
> Norm-based scoring is very useful if population norms are available by the following.
Formula of z-score transformation:

½ðobserved score population meanÞ population SD 10 þ 50
The population mean and SD are calibrated to 50 and 10, respectively. A QOL score can then
be interpreted more meaningfully with reference to the population normative values. Norm-
based scoring also facilitates cross-cultural or group comparisons by adjusting for the baseline
‘‘normal’’ variations. It can be seen from > Figure 21-3 that there are marked differences in
. Table 21-4
Scoring algorithm of the General Health Scale of the SF-36
Response Response Recoding to item

Scale Item (question number) options value score needed
gh 1 (1) In general, would you say Excellent 1 5.0
your health is Very good 2 4.4
Good 3 3.4
Fair 4 2.0
Poor 5 1.0
gh 2 (11a) I seem to get sick a little Definitely 1 No
easier than other people true
Mostly true 2 No
Don’t know 3 No
Mostly false 4 No
Definitely 5 No
false
gh 3 (11b) I am as healthy as anybody Definitely 1 5.0
I know true
Mostly true 2 4.0
Don’t know 3 3.0
Mostly false 4 2.0
Definitely 5 1
false
gh 4 (11c) I expect my health to Definitely 1 No
get worse true
Mostly true 2 No
Don’t know 3 No
Mostly false 4 No
Definitely 5 No
false
gh 5 (11d) My health is excellent Definitely 1 5.0
true
Mostly true 2 4.0
Don’t know 3 3.0
Mostly false 4 2.0
Definitely 5 1.0
false
Raw Scale Score (rGH) = gh1 + gh2 + gh3 + gh4 + gh5
Transformed Scale Score (GH) = (rGH 5) 20 100
The response values of three items (gh1, gh3 and gh5) need to be recoded to obtain the relevant item scores. The
response values of items that do not require recoding equate to the item scores. The scores of the items are
summated to give the raw scale score. The raw GH scale has a minimum score of 5 and a range of 20, which are
applied to the formula for transformation to a scoring range of 100
. Figure 21-3
Unadjusted SF-36 scores of patients with heart diseases in the United States and Hong Kong. The
graph compares the eight SF-36 scale scores of patients with heart diseases in the United States
and Hong Kong, without any adjustment to the general population norm. PF physical
functioning; RP role-physical; BP bodily pain; GH general health; VT vitality; SF social functioning;
RE role-emotional; MH mental health
. Figure 21-4
Norm-based SF-36 scores of patients with heart diseases in the United States and Hong Kong.
The graph compares the eight SF-36 scale scores of patients with heart diseases in the United
States and Hong Kong, adjusted to the respective general population norms. The population
mean and standard deviation are 50 and 10, respectively. PF physical functioning; RP
role-physical; BP bodily pain; GH general health; VT vitality; SF social functioning; RE
role-emotional; MH mental health
the unadjusted SF-36 scale scores of patients with heart diseases between the populations
in the United States and Hong Kong (Lam et al., 2003; Ware et al., 1993), giving the impression
that heart diseases have different impact on the QOL of the two populations. However, the
difference becomes insignificant when norm-based scoring is used (> Figure 21-4).
7 Choosing the Right QOL Measure
The quality of QOL data depends on the quality of the measuring instrument. A review of the
literature has identified 14 criteria for the assessment of a QOL measure, as shown in
> Table 21-5 (McDowell and Newell, 1996; Scientific Advisory Committee of the Medical
Outcomes Trust, 2002).

The first nine criteria are self-explanatory and can be assessed by a review of the QOL
measure and its manual. The last five criteria need evidence from empirical testing on the
target population. The evidence from one population may not be generalizable to another
especially when cross-cultural adaptation is required. Linguistic adaptation, content validation
and pilot psychometric testing should be done before a QOL measure developed in one culture
is applied to another.
7.1 Validity of an HRQOL Measure
Validity is the most essential requirement of a measure. It is defined as the ability to measure
what it purports to measure (McDowell and Newell, 1996). There is no one best method of
testing validity and some think validation of a QOL measure is never complete. Three types of
validity are commonly described for QOL measures (McDowell and Newell, 1996):-
1. Content validity refers to whether the items are appropriate, relevant, important, repre-
sentative and adequate for the concept measured (McDowell and Newell, 1996). Evalua-
tion by lay or expert panels on face validity is the first but insufficient step. Qualitative
cognitive debriefing interviews with a representative sample of the population is very
. Table 21-5
Assessment criteria of a quality of life (QOL) measure
The purpose should be stated as whether it is an evaluative, predictive, discriminative or
preference measure
The intended target population, e.g., generic or disease group, ambulatory or institutionalized,
should be specified
The concepts, dimensions and domains measured are clearly defined
There is a sound conceptual base for the items, domains and dimensions
The domains and items are relevant and adequate
The recall time frame is defined and appropriate for the purpose and population
The method(s) of data collection (self, interviewer, telephone or computer administration) and the
time required for completion are described
The scoring method and algorithm are explained
The data are presented in a mode, e.g., a summary index or a profile, that is easy to interpret
There is evidence on its validity for the target population and culture
There is evidence on adequate reliability
There is evidence on feasibility and acceptability for the population and setting
There is evidence on sensitivity and responsiveness
The scores can be interpreted meaningfully
useful to make sure that the content is understood, correctly interpreted, relevant
and adequate (Wild et al., 2005). Quantitative psychometric tests such as multi-trait
analysis of item-scale correlations and factor analysis are also useful (McDowell and
Newell, 1996).
2. Criterion validity is the degree of agreement between the results of the measure and a ‘‘gold
standard.’’ A ‘‘gold standard’’ QOL measure does not exist, therefore, true criterion validity
cannot be achieved. An alternative is convergent validity that is supported by a correlation
with similar domains of another QOL measure and no correlation with unrelated domains
(divergent validity).
3. Construct validity can be considered as a substitute for criterion validity in the absence of a
gold standard measure. A construct is an abstract variable (e.g., QOL) that is constructed
to reflect a hypothesis on how measurable variables will correlate with one another. There
are three steps in testing construct validity. The first starts with the conceptual construc-
tion of the domains and item variables. The second is the establishment of the structure
and correlation of observed variables, Item-scale correlations and factor analysis are
commonly used for this purpose. The third is the verification of the hypothesized
correlations between the theoretical construct (QOL) and external criteria (e.g., age) by
known group comparison (McDowell and Newell 1996).
7.2 Reliability of an HRQOL
Reliability is defined as the degree to which an instrument is free from errors. It is an essential
but insufficient requirement of a QOL measure (McDowell and Newell, 1996). The level of
reliability determines the highest degree of validity possible but it does not automatically
imply validity. There are two aspects of reliability: Internal reliability, commonly measured by
Cronbach’s alpha, is based on the theory that the result is likely to be true if the responses to
different items measuring the same domain are consistent. Test-retest reliability assesses
reproducibility. There should not be any significant difference between the test-retest scores
(Bland and Altman, 1986; McDowell and Newell, 1996), and intraclass correlation (ICC)
can give an indication on the average similarity of subjects’ actual scores on repeat measure-
ments (McDowell and Newell, 1996). Pearson or Spearman correlation is not an appropriate
measure of test-retest reliability because it measures association instead of agreement
(Bland and Altman, 1986). A reliability of 0.7 or more is generally regarded as adequate for
group comparison but 0.9 or more is required for individual assessment (McDowell and
Newell, 1996).
7.3 Feasibility and Acceptability
Some items of a QOL measure may be irrelevant, or even a taboo in some cultures or groups
of people. The items may not be fully understood, especially if the subjects have low educa-
tional level or limited cognitive function. QOL measures that can only be administered by
self-completion have limited use in populations with low literacy rates such as many found in
Asia. The use of a proxy for children or people with cognitive impairment violates the
subjective concept of QOL perception. Excessive respondent burden from lengthy instruments
will decrease acceptability. It is recommended that the number of items should be below 50
and the time required for completion should not be longer than 20 min. Completion rate and
the proportion of missing data are good indicators of feasibility and acceptability.
7.4 Sensitivity and Responsiveness
Sensitivity refers to the discriminatory power of an instrument and is measured by its ability to
detect differences between groups, which is most important when a QOL measure is used as a
discriminative or predictive tool (Scientific Advisory Committee of the Medical Outcomes
Trust, 2002). Responsiveness is the ability to detect relevant changes over time, and is
particularly important when QOL is used as an evaluative outcome measure in clinical trials.
The Scientific Advisory Committee of the Medical Outcome Trust advocates that sensitivity
and responsiveness should be assessed by effect size (Scientific Advisory Committee of the
Medical Outcomes Trust, 2002), which is the quotient of mean difference or change divided by
the baseline standard deviation (Kazis et al., 1989).
Insufficient responsiveness is often a concern for generic QOL measures (Oh and Ku,
2006), but this may not be true for all conditions (van der Molen et al., 1997). The use of
excessively sensitive or responsive disease-specific measures may detect very small differences
or changes that are not clinically important.
7.5 Interpretation of QOL Measure Scores
There is no absolute threshold of good or bad QOL, which has to be interpreted in the context
of the population norm, the content, or external criteria. Population-based normative values
are very useful references to estimate how much a particular QOL score deviates from
‘‘normal’’ (Ware and Kosinski, 2001). The interpretation of QOL scores can also be made
with an inference to the probability of responses to its content. For example, 90% of the people
scoring 90 or above in the physical functioning (PF) scale of the SF-36 can walk one block
without any limitation, while only 32% of those with a PF score of 45 can do so (Ware et al.,
1993). Correlations of QOL scores with important external indicators such as morbidity,
service utilization or employment provide additional information for interpretation. For
example, more than 70% of people who scored below 30 in the PF scale of the SF-36 reported
that their health kept them from working at a paying job, while less than 10% of those scoring
more than 80 reported the same (Ware et al., 1993). The significance and implications of QOL
scores will become better understood with more experience and applications of the measure.
Results of a widely used instrument are easier to interpret than results of those that have
limited empirical data.
7.6 Minimal Clinically Important Difference (MCID)
An important but difficult question is what the minimally important difference (MID) in
QOL score is. The term minimal clinically important difference (MCID) is often used in the
context of health care, which can be defined as the smallest difference that is beneficial to the
patient (Jaeschke et al., 1989). No one method or one standard of MCID is the best for all.
Triangulation of results from different methods is recommended, and the MCID of each
measure should be determined by empirical studies (Crosby et al., 2003; Wrywich et al., 2005).
The anchor-based approach is commonly used to determine the MCID of QOL scores
(Jaeschke et al., 1989; Lydick and Epstein, 1993). Using patients’ global rating of change as
an anchor the MCID is determined by the smallest change in QOL score that is associated
with a perceivable global change. Studies have shown that the MCID ranged from 0.42 to 0.64
(6–9%) on the 7-point scales of several HRQOL measures (Jaeschke et al., 1989; Juniper et al.,
1994), and ranged from 5 to 10 on a 100-point scale (Osoba et al., 1998). A review of 11 studies
found that the mean MCID of PBMH were 0.04 for the SF-6D scored on a scale from 0.29 to 1,
0.07 for the EQ-5D scored on a scale from 0.59 to 1 (Walters and Brazier, 2005), and 0.03 for
HUI-3 (Pichard et al., 2005). The MCID of most HRQOL measures seem to cluster around 5–
8% of the scale range.
The MCID can also be estimated statistically by distribution-based methods in terms of
effect size, standardized response mean (SRM = change SD of change) or standard error of
measurement {SEM = change [SD square root of (1-reliability)]}. Data from clinical trials
showed that effect size changes in QOL scores were mostly between 0.3 and 0.5 in the
treatment group and less than 0.2 in the placebo group (Kazis et al., 1989; Osoba et al.,
1998). The MCID derived from the anchor-based method correspond to effect sizes of
0.34–0.37 and benchmark around 1 SEM (Wrywich et al., 2005). The MCID in preference
scores of the SF-6D and EQ-5D correspond to an SRM of 0.39 and 0.24, respectively (Walters
and Brazier, 2005).
8 Conclusions
Subjective health-related quality of life is a valid and important outcome measure of modern
health care. QOL is measured indirectly through the observation of its indicators. The
conceptualization, selection and construct of the indicators as items of a QOL measure have
great influence on the validity and reliability of the results. The psychometric properties,
interpretation and MCID of a QOL measure have to be determined by empirical studies. Many
QOL measures are available and new measures are being developed. A careful selection of the
right measure to suit the needs of the target population and purpose of application is
important for QOL assessment to inform rather than mislead decisions and policy.
Summary Points
Health-related quality of life (HRQOL) is the most appropriate outcome measure of

modern health care.
The essential concepts of quality of life (QOL) measures are subjectivity, multi-
dimensionality and well-being.
HRQOL measures assess those aspects of QOL that are modifiable by health.
QOL is a latent variable that needs to be converted to observable indicators to be
measured.
A careful evaluation of the conceptual base, purpose, operation methods, scoring algo-
rithm and psychometric properties of a QOL measure should be carried out before its
application.
Generic QOL measures should be used for the assessement of heterogenous populations
and people with multiple illnessess.
Disease specific QOL measures may be more suitable for clinical trials because they are
usually more sensitive and responsive.
Preference-based measures of health converts QOL into a fractional index for the calcula-
tion of quality adjusted life years.
References
Aaronson NK, ERORTC Study Group on Quality of Life. Kazis LE, Anderson JJ, Meenan RF. (1989). Med Care.
(1993). J Natl Cancer Inst. 85: 385–376. 27 (Suppl): S178–S189.
Bland JM, Altman DG. (1986). Lancet. I: 307–310. Lam CLK, Fong DYT, Lauder IJ, Lam TP. (2002). Soc Sci
Brazier J, Roberts J, Deverill M. (2002). J Health Econ. 21: Med. 55: 1635–1646.
271–292. Lam CLK, Lauder IJ, Lam TPD. (2003). Asia Pac Fam
Brooks R, EuroQol Group. (1996). Health Policy. 37: Med. 2: 98–106.
53–72. Lydick E, Epstein RS. (1993). Qual Life Res. 2: 221–226.
Bullinger M, Anderson R, Cella D, Aaronson N. (1993). MAPI Research Trust. (2007). PROQOLOD. http://www.
Qual Life Res. 2: 451–459. proqolid.org/proqolid.
Clarke PM, Gerdtham UG, Johannesson M, Bingefors K, Marks GB, Dunn DM, Woolcock AJ. (1993). J Clin Epi-
Smith L. (2002). Soc Sci Med. 55: 1923–1928. demiol. 46: 1103–1111.
Crosby RD, Kolotkin RL, Williams GR. (2003). J Clin McDowell I, Newell C. (1996). Oxford University Press,
Epidemiol. 56: 395–407. New York.
Efficace F, Bottomley A, Osaba D, Gotay C, Flechtner H, Morimoto T, Fukui T. (2002). J Epidemiol. 12: 160–178.
D’haese S, Zurb A. (2003). J Clin Oncol. 21: National Institute for Clinical Excellence (NICE).
3502–3511. (2004). http://www.nice.org.uk/niceMedia/pdf/TAP_
European Medicines Agency Evaluation of Medicines Methods.pdf.
for Human Use (EMEA). (2005). http://www.emea. Oh S, Ku JH. (2006). Qual Life Res. 493–501.
europe.eu/pdfs/human/ewp/020595en.pdf. Osoba D, Radrigues G, Myles J, Zee B, Pater J. (1998).
Fan VS, Cartis JR, Tu S, McDonell M, Film SD. (2002). J Clin Oncol. 16: 139–144.
Chest. 122: 429–436. Petrie KJ, Weinman J, Sharpe N, Buckley J. (1996).
Fayers PM, Hand DJ. (1997). Qual Life Res. 6: 139–150. Br Med J. 312: 1191–1194.
Fayers PM, Sprangers MAG. (2002). The Lancet. 359: Pichard AS, Johnson JA, Feeny D. (2005). Qual Life Res.
187–188. 14: 207–219.
FDA. (2006). Guidance for Industry-Patient-Reported Reid LD, Tueth MJ, Handberg E, Nyanteh H. (2006).
Outcome Measures: Use in Medical Product Devel- Qual Life Res. 15: 675–686.
opment to Support Labeling Claims. http://www. Revicki DA, Osoba D, Fairclough D, Barofsky I,
fda.gov/cder/guidance/ Berzon R, Leidy NK, Rothman M. (2000). Qual
Feeny D, Furlong W, Torrance GW, Goldsmith CH, Life Res. 9: 887–900.
Zhu Z, DePauw S, Denton M, Boyle M. (2002). Scholten JHG, van Weel C. (1992). Functional Status
Med Care. 40: 113–128. Assessment in Family Practice: The Dartmouth
Geigle R, Jones SB. (1990). Inquiry. 27: 7–13. COOP Functional Health Assessment Charts/
Guyatt GH, King DR, Feeny DH, Stubbing D, Goldstein WONCA. Lelystad, Meditekst.
RS. (1999). J Clin Epidemiol. 52(3): 187–192. Scientific Advisory Committee of the Medical Outcomes
Jaeschke R, Singer J, Guyatt GH. (1989). Control Clin Trust. (2002). Qual life Res. 11: 193–205.
Trials. 10: 407–415. Sousa KH, Kwok O. (2006). Qual Life Res. 15: 725–737.
Juniper EF, Guyatt GH, Willan A, Griffith LE. (1994). Torrance GW, Feeny DH. (1989). Intl J Tech Ass in
J Clin Epidemiol. 47: 81–87. Health Care. 5: 559–575.
Kaplan R, Andersen R. (1996). In Spilker B (ed.) Quality van der Molen T, Postma DS, Schreurs AJM, Bosveld
of Life and Pharmacoeconomics in Clinical Trials. HEP, Sears MR, Meyboom de Jong B. (1997). Qual
Lippincott-Raven, Philadelphia, PA, pp. 309–322. Life Res. 6: 353–361.
Velikova G, Booth L, Smith AB, Brown PM, Lynch P, Weinstein MC, Siegel JE, Gold MR, Kamlet MS,
Brown JM. (2004). J Clin Oncol. 22: 714–724. Russel LB. (1996). JAMA. 276: 1253–1258.
Von Neumann J, Morgenstern O. (1953). Theory of WHOQOL Group. (1993). Qual Life Res. 2: 153–159.
Games and Economic Behavior. Princeton Univer- WHOQOL Group. (1998). Soc Sci Med. 46: 1569–1585.
sity Press, Princeton, NJ. Wild D, Grove A, Martin M, Eremenco S, McElroy S,
Walters SJ, Brazier JE. (2005). Qual Life Res. 14: Verjee-Lorenz A, Erikson P. (2005). Value Health.
1523–1532. 8: 94–104.
Ware JE, Kosinski M. (2001). SF-36 Physical & Mental Wilson IB, Cleary PD. (1995). JAMA. 273(1): 59–65.
Health Summary Scales: A Manual for Users of Wrywich KW, Bullinger M, Aaronson N, Hays RD,
Version 1. Quality Metric, Lincoln, Rhode Island. Patrick DL, Symonds T. (2005). Qual Life Res. 14:
Ware JE, Snow KK, Kosinski M, Gandek B. (1993). 285–295.
SF-36 Health Survey Manual and Interpretation
Guide. The Health Institute, NEMC, Boston.
22 Standard Expected Years of
Life Lost as a Measure of
Disease Burden: An
Investigation of Its
Presentation, Meaning and
Interpretation
R. J. Marshall
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
2 Meanings of SEYLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

2.1 Definition of Total SEYLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
2.2 SEYLL per Death (SEYLLd) and per Person-Time (SEYLLp) . . . . . . . . . . . . . . . . . . . . . . . . 404
2.3 Age-Standardized SEYLL Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
3 Norms for SEYLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406

3.1 Life Table Norm of SEYLLd . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
3.2 Norm of Age-Standardized Values of SEYLLd . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
3.3 Norm-Adjusted Total SEYLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
4 Discounting and Age-Weighting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

4.1 Norm Adjusted Total SEYLL with Age-Weighting and Discounting . . . . . . . . . . . . . . . . 410
5 Final Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
Continuous Age Analysis of Norm of SEYLLd . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

402 22 Standard Expected Years of Life Lost as a Measure of Disease Burden
Abstract: > Standard expected years of life lost (SEYLL) is a measure of the years that might
have been lived from the time of death. Although the global burden of disease project attempted
to standardize this measure with respect to standard model life tables, authors use alternative
standards. Manipulations of SEYLL – > discounting, > age-weighting, age-standardizing – are
also variously applied, and SEYLL may be presented as a total, or per living person, or per death.
Further, whenever a death occurs there is potential living time lost, and SEYLL is never zero, or
even close to zero, so that reference values for ‘‘acceptable’’ SEYLL are needed in order to assess
whether an observed SEYLL really is an adverse contributor to the burden of disease.
In this chapter, the way that SEYLL is presented in the literature is discussed and the effects
of different manipulations of SEYLL are investigated, in particular, their effect on rank order of
causes of death. Reference values, or norms, for SEYLL measures are discussed and these
provide a new way to present, and rank by cause of death, total SEYLL by adjusting for
normative values.
List of Abbreviations: COPD, chronic obstructive pulmonary disease; DALY, disability
adjusted life year; GBD, global burden of disease; IHD, ischemic heart disease; MLTW,
> model life tables west; SEYLLadj, > norm-adjusted total standard expected years of life
lost; SEYLLd, > standard expected years of life lost per death; SEYLLnorm, > norm for standard
expected years of life lost per death; SEYLLp, > standard expected years of life lost per person
per year; SEYLLt, > total standard expected years of life lost
1 Introduction
Many measures of premature death in populations have been proposed based on years of life
lost (Gardner and Sanborn, 1990). With its adoption as the mortality component of a DALY
(disability adjusted life years), the standard expected person years of life lost, or SEYLL
(Murray and Lopez, 1996), is now commonly calculated. SEYLL is the total, over all deaths,
of the additional years that a person might have been lived had he or she not died. In the global
burden of disease (GBD) analyses (Murray and Lopez, 1996) the additional years that a person
might have lived are specified in formal model life tables for Western developed nations (Coale
and Guo, 1989, 1990): Model Life Table West (MLTW) levels 25 and 26 with 80 and 82.5 years
expected lifespan respectively. The former is suggested in Murray and Lopez (1996) as the
model for males and the latter for females.
Despite these MLTW ‘‘standards’’ to define SEYLL, other standards are often adopted. For
example, using local national life expectancy instead, as in Holland (Melse et al., 2000),
Australia (Mathers et al., 2001), Korea (Ha et al., 2003) and, Canada (James et al., 2007)
where the life expectation of the richest quintile was used. Different standards, of course, make
comparison of SEYLL between populations more difficult. Indeed, the use of a different
standard for men and women has been criticized (Bonneux, 2002).
Other ways in which reporting of SEYLL is not uniform include ‘‘age-discounting’’ and
‘‘age-weighting.’’ Much has been written about these two manipulations (see Mathers et al.,
2006 for a summary). While they may not appreciably alter the ranking of SEYLL or DALYs by
cause, they may substantially alter absolute magnitude. On top of these adjustments the
practice of age-standardizing is also sometimes done, in the same way that mortality rates
are usually standardized to account for different age profiles. Given these possibilities, what is
reported in the literature is seldom uniform and comparisons of SEYLL between studies
Standard Expected Years of Life Lost as a Measure of Disease Burden 22 403
is often difficult. Further, with essentially four different manipulations that somehow adjust
for age (the standard life expectancy, age-weighting, discounting and age-standardizing) what
the eventual quantity actually represents is not obvious.
Another hindrance to making comparison between studies is that total SEYLL in
a population is often presented. Total SEYLL has no immediate import, at least, as a single
figure. For example, in a Serbian study (Jankovic et al., 2006) there were reported 136,151
years of life lost due to ischemic heart disease. In itself this figure tells little, though of course
when considered against other causes in the same population (e.g., 17,233 years for road traffic
accidents) it takes on meaning. It can also be scaled by a denominator to relate it to population
size, and various denominator choices are presented. For example, either a ‘‘living’’ or ‘‘dead’’
population can be considered to provide SEYLL per unit of person time or SEYLL per death
respectively. These two ways of presenting SEYLL are sometimes reported, more often the
former. Other denominators have been proposed (Marlow, 1995) based on total person years
remaining in the entire population.
A further feature of SEYLL, and other measures based on expected years of life lost, is that it
is never zero, a value might reasonably be thought a point of reference for a perfectly healthy
population, since at whatever age a person dies there are always additional years that the person
might have lived. Bonneux (2002) noted, for example, that even in a life table with just 50 years
life expectancy, a death at 90 years old will lose more than 2 years of life. Years of life lost is only
near zero if everyone lives to be the age at which the number of years of life left is effectively
zero, which is clearly Utopian. Therefore in assessing what a particular SEYLL means, it is
instructive to know what an ‘‘ideal’’ SEYLL is, that is, a norm SEYLL against which to judge an
SEYLL calculated from another population. This question was addressed by Marshall (2004)
by determining SEYLL in populations that actually achieve the model life expectancy set out in
the life table that is used to calculate SEYLL, that is, the MLTW levels 25 and 26.
In this article the way SEYLL is presented in the literature is appraised. The use of different
standards specifying years of life remaining is discussed and the effects of age-standardizing
presented. Further, the idea and the method used in Marshall (2004) to set realistic norms on
SEYLL is discussed. Calculation of these norms using an alternative continuous time model of
SEYLL is advanced and a new way to adjust total SEYLL to take account of the norms is
presented. How this affects the rank order of years of life lost by cause of death is examined.
A sensitivity analysis of the effects age-weighting and discounting is also presented.
2 Meanings of SEYLL
2.1 Definition of Total SEYLL
Consider a population of size P and suppose there are Dac deaths in a period of time T years,
due to a particular cause c, in an age group a. Suppose ea is a measure of the expected years of
life that remain to be lived for a death from any cause at age a. Then the total expected years
of life lost due to c, denoted SEYLL t, is
X
SEYLLt ¼ e D
a a ac
ð1Þ
The summation here is assumed to be over the age groups. In the GBD project ea is as
specified by MLTW tables; one for females (level 26) and one for males (level 25). These form
the ‘‘standard’’ in the concept of SEYLL.
As mentioned in > Section 1, some authors use other standards. However, this may not
matter when making within population comparisons. Further, the size of the population P and
period of follow-up T are immaterial when making within population comparisons of SEYLLt for
different causes of death. Otherwise, knowing T and P are crucial to make sense of total SEYLL.
There are two natural ways to relate SEYLLt to the population: by considering years lost per death
and years lost per living person.
2.2 SEYLL per Death (SEYLLd) and per Person-Time (SEYLLp)
Dividing equation (1) by Dc = Σa Dac, the total deaths from a specified cause, gives the SEYLL
per death:
X
SEYLLd ¼ e D =Dc
a a ac
ð2Þ
If instead the denominator Dc is replaced by the accumulated person time over which the
death occurred SEYLL per person per year is obtained. The estimated cumulative person-time,
assuming a stable living population, is PT so SEYLL per person per year is:
X
SEYLLd ¼ e D =PT
a a ac
Note that, since the denominator, PT, is the same, whatever cause of death is considered, rank
order of SEYLLp by cause of death is the same as rank order of SEYLLt.
Also, since the crude annual mortality rate in the population is Dc/PT, SEYLLp is the
product of crude mortality rate and SEYLLd, that is,
SEYLLp ¼ SEYLLd Dc =PT ð3Þ
which shows what is otherwise fairly obvious, that SEYLLp, and total SEYLL, is an expression
of the life lost per death and the mortality rate in the population.
Therefore, low mortality rates at an early age, and high mortality at a late age may result in
similar SEYLLp. As an example consider a Dutch study (Melse, 2000). Suicide and chronic
non-specific lung disease (bronchitis, emphysema, asthma) in 1994 had more or less the same
total SEYLL (50,300 and 50,100 years respectively) and so have the same SEYLLp, yet SEYLLd
for suicide is 3.6 times greater for suicide than chronic lung disease (50,300/1,584 = 31.8 years
vs. 50,100/5,697 = 8.8 years). The point is that, though the total years of life lost for suicide and
lung disease are the same, they are qualitatively different. Years of life lost per death captures
the distinction.
Another example is a 1998 Italian study (Mariotti et al., 2003). The authors use the MLTW
standards and rank the total SEYLL by different causes of death. Top of the list is ischemic
heart disease (IHD) with 1,143,400 years of life lost (> Table 22‐1), next is stroke with 612,100
years. In fourth place is road traffic accidents with 324,700 years. However, in terms of years
lost per death, road traffic accidents is far ahead of stroke and heart disease with 36.9 years
compared to 9.3 and 8.5 years for IHD and stroke respectively. Accordingly, the rank order
SEYLLp by cause of death to be quite different to the rank order of SEYLLd (> Table 22‐1). For
the 23 leading causes of death in (> Table 22‐1), Spearman’s rank correlation (which is a useful
way to assess agreement of rank order and which is used again below) between SEYLLp and
SEYLLd is 0.12, that is, there is effectively very little agreement.
. Table 22-1
Rank order of total SEYLL (SEYLLt) and SEYLL per death (SEYLLd) in Italy in 1998
Cause of death SEYLLt(1000s of years) Rank of SEYLLt SEYLLd (years) Rank of SEYLLd
IHD 1143.4 1 9.31 16
Stroke 612.1 2 8.47 19
Lung cancer 485.0 3 14.74 8
Road traffic accidents 324.7 4 36.90 2
Colorectal cancer 233.3 5 13.33 11
Breast cancer 215.4 6 18.41 4
Cirrhosis of liver 204.2 7 16.60 6
Diabetes mellitus 196.6 8 10.92 15
Hypertensive disease 188.1 9 8.28 22
Stomach cancer 162.9 10 13.24 13
COPD 156.9 11 8.39 20
Liver cancer 146.5 12 13.82 10
Self inflicted injury 134.8 13 28.68 3
Lymphomas 123.2 14 15.79 7
Pancreatic cancer 113.4 15 14.00 9
Alzheimer/dementias 96.7 16 7.68 23
Falls 95.9 17 9.05 17
Birth trauma 94.5 18 78.75 1
Leukemia 94.4 19 17.16 5
Lower respiratory tract 90.2 20 8.35 21
Other neoplasms 86.3 21 13.28 12
Inflammatory disease 73.0 22 12.37 14
Prostatic cancer 65.8 23 8.89 18
Adapted and calculated from data in Mariotti et al. (2003). SEYLL stands for standard expected years of life lost;
SEYLLt is total years lost. SEYLLd is the expected number of years lost per death. Ranked in order of SEYLLt but ranks
of SEYLLd also given. Spearman’s rank correlation is 0.12
The Italian population in 1998 was about 57 million so that the 1,143,400 years of life lost
due to ischemic heart disease reported in > Table 22‐1 gives an SEYLLp of 0.02006 years per
person per year (which is 7.32 days). This figure can be seen as the product of SEYLL per death,
9.31 years, and crude mortality rate 2.154 per 1,000 per year (122,800 IHD deaths in 57 million
people in 1998).
Many studies, as in those just mentioned, base their analyses on 1 year’s data, T ¼ 1. If data
are accumulated over a different, longer period of say T ¼ 5 years, the SEYLL values should be
viewed in the context of a dynamic population model, in which the population is continually
replenished as deaths occur, while remaining stable. An alternative model, in which the initial
population of size P is continually depleted by deaths over time would require more detailed
mathematical consideration.
2.3 Age-Standardized SEYLL Measures
It is also common practice to age-standardize both SEYLLd and SEYLLp (e.g., in New Zealand
by Connor et al. (2005) and in Canada by James et al. (2007)). This is done by transferring
the observed cause-age-specific probability of death Dac/Pa into a reference population (such
as Segi’s world population) which has P 0 a in age group a. The numbers of deaths that would
be expected in age group a is D 0 ac = (Dac/Pa)P 0 a with total deaths D 0 c = ΣaD 0 ac among the
reference population of P 0 = ΣaP 0a people. So the > age-standardized SEYLL values per death
and per person-time become:
X X
SEYLL0d ¼ a
e a D 0
a =D0
c and SEYLL 0
p ¼ e D0 =P0T
a a a
It follows that, age-standardized SEYLLp is the product of the age standardized mortality rate
and the age-standardized SEYLLd, analogous to equation (3).
Age-standardizing of SEYLL measures is usually justified, as it is for age-standardizing
mortality rates, as a means to account for different age distributions in groups that are being
compared. However, the logic that justifies age-standardizing mortality rates is questionable
for SEYLL. In standardizing mortality rates, for example, to the Segi population as above, the
age-specific mortality rates are transferred to a virtual ‘‘Segi-world’’ which has a specified age
structure. The argument for doing this is that, since mortality rates are generally age depen-
dent, fixing comparisons to a reference age structure, removes the confounding effect of age.
By analogy, standardizing SEYLLd imagines calculating years of life lost in a Segiworld
with the transferred age-specific mortality rates. This maneuver is questionable for SEYLL
since, rather than seeking to remove the effect of age, age is intrinsic to an SEYLL analysis.
Consider for example, comparing two populations, with different age structures, one predom-
inately ‘‘young’’, the other predominately ‘‘old’’, but with identical age-specific mortality rates.
Because age-specific rates are the same, age-standardized SEYLL measures are the same for
both populations. However, it debatable whether it is sensible to conclude that there really is
no SEYLL difference. Certainly more years of life are lost in the younger population which the
process of age-standardizing removes entirely.
The effects of standardization can also be considerable in terms of magnitude of measures
of SEYLL. For example, in European New Zealand males standardized all-cause SEYLLd (with
respect to the Segi world population) is 21.9 years (Marshall, 2004). With no standardizing it is
16.8 years. The corresponding SEYLLp values are 0.124 years per person per year (standar-
dized) and 0.145 years (not standardized). Notice, how in this example standardizing increases
SEYLLd and decreases SEYLLp.
3 Norms for SEYLL
As mentioned in the Introduction, one feature of SEYLL is that it is never zero since there
are always additional years that the person might have lived. Since zero is not a sensible
reference point against which to judge SEYLL, Marshall (2004) proposed setting norms
by determining SEYLL in populations that achieve the model life expectancy set out in
the MLTW levels 25 and 26 to set reference points. To further examine this issue the
norms are here re-calculated by a method that treats age as a continuous time variable (as it
essentially is).
3.1 Life Table Norm of SEYLLd
The MLTW tables are tabulated for ages x = 0,1,5,10,. .,100 with notation ex0 for expected years
of life remaining and lx for cohort size at age x. Three ways to evaluate the norm for SEYLLd,
which is denoted SEYLLnorm, are used here: two based on different discretisations of age and a
continuous age model. In the first approach the age groups are as specified in the tables, in the
second finer gradations of age, using linear interpolation, into annual increments are used,
and in the third a continuous time model is adopted. The first method is described in detail
and reported in Marshall (2004). The second is essentially the same but with interpolation to
yearly age intervals.
The third, continuous time approach, is developed in the Appendix. It shows how the
norm for SEYLLd in a continuous time formulation can be expressed in terms of e(a), a
continuous representation of expected years of life remaining at age a and it enables a third
way of calculating a norm for prescribed function e(a). This method is independent of the lx
cohort size at age x values that accompany the MLTW tables which is effectively determined in
the continuous time formulation by e(a).
The first row of (> Table 22‐2) gives computed norms of SEYLLd, for the male and female
standards, with 80 and 82.5 life expectancy respectively, by these three analyses. It shows that
there are between about 9 to 10 years of life lost per death in a population that achieves the life
expectancy of the MLTW tables 25 and 26. There are only small differences between men and
women, or rather between the level 25 and 26 standards, and largely good agreement between
the three different methods of computation. In particular, it is reassuring that the continuous
time approach, which is based on rather complex mathematical relationships (appendix)
confirms the discrete time analysis reported in Marshall (2004).
Therefore, if years of life lost per death is calculated to be about 9–10 years, it is not out of the
ordinary and means that the age at death is congruent to the MLTW age structure. IHD and
stroke for example in (> Table 22‐1), which together contribute one third of the years of life lost,
. Table 22-2
Estimated norms SEYLLnorm of years of life lost per death, crude and age-standardized, using
Segi, WHO and Japanese reference populations with no discounting and no age-weighting
Method 1. 5 year Method 2.: annual Method 3.: continuous

intervals intervals time analysis
Reference Male: 80 Female: 82.5 Male: 80 Female: 82.5 Male: 80 Female: 82.5
population years years years years years years
Model life table 9.87 9.18 10.11 9.43 9.58 9.94
level West
Age-standardized
WHO 18.50 19.02 17.80 18.45 16.17 21.81
Segi 21.41 21.91 20.65 21.26 19.78 22.44
Japanese 16.14 13.42 15.79 13.03 15.43 13.62
Method 1 is by using age-grouped life table data on ex0 and lx for x = 0,1,5,10, . . .,100 where
ex0 is expected years of
life remaining and lx is cohort size at age x from MLTW life tables; Method 2 is by using MLTW data interpolated to
annual increments of ea and la for a = 0,1,2,3, . . ., 100. Method 3 is using theoretical analysis based on regarding
MLTW data as points on a continuous function e(a) for expected life remaining at age a (see Appendix)
have SEYLLd 9.31 and 8.47 respectively but the deaths are occurring late in life and, given the
inevitability of death, are not such a concern as the rank order of total SEYLL would suggest.
3.2 Norm of Age-Standardized Values of SEYLLd
Although it has been argued above (Section 2.3) that age-standardizing SEYLL measures is
best avoided, it is helpful, since age-standardizing is sometimes done, to also consider norms
on > age-standardized SEYLL. These can be computed by transferring the model life-table
age-specific death rates into a population with specified age-structure distribution, as de-
scribed in Marshall (2004), with analogous extension for the continuous time model.
A common standard population that is widely used in epidemiology is the Segi world
population. Another is the newer WHO standard (Ahmad et al., 2000). Both Segi and WHO
standard populations are the same for men and women, though the norms for men and women
will differ because a different model life table is used for each. Two other reference populations
are also used for comparison: the Japanese men and Japanese female populations in 1995.
The lower panel of (> Table 22‐2) presents these norms. The process of age-standardizing
increases them relative to the non-standardized values; for the WHO standard they are
roughly doubled and for a Segi standard more than doubled. The Japanese reference does
not increase the norms as much because the Japanese population is younger than both the
WHO standard and the Segi standard, but it is not as young as the model life table.
3.3 Norm-Adjusted Total SEYLL
Since the norm value for non-standardized SEYLLd is 9–10 years (> Table 22‐2), it follows
that, if there are Dc deaths from cause c, there would be conservatively expected to be at least
9 Dc years of life lost, even if these deaths represent a population with an ideal MLTW
structure. Accordingly, it seems reasonable to subtract the expected years lost from total
SEYLL, SEYLLt in equation (1), to give an adjusted total SEYLL that reflects the excess:
SEYLLadj ¼ SEYLLt 9 Dc ð4Þ
> Table 22‐3 compares the magnitude and rank order of total SEYLL and the adjusted figures.
Clearly the rank order is quite different, Spearman’s rank correlation is 0.34 with stroke
moving from second place to bottom and IHD from first to thirteenth. Road traffic accidents
move from fourth place to head the new rank order. The total years lost is reduced from 5137.2
to 1161.9 thousand-years, a reflection of there being 441,700 deaths, from which
9 441.7 = 3975.8 thousand-years lost are expected. At the bottom of the rank order some
causes have negative SEYLLadj. This simply reflects the fact that everyone must die and the age
at death of these causes is comparable or ‘‘older’’ than the MLTW age structure. The rank order
of SEYLLadj is similar to that of SEYLL per death (> Table 22‐1) (Spearman correlation 0.9),
however, there key differences, for example, birth trauma heads the SEYLLd list, but is sixth
with respect to SEYLLadj.
The new rank order seems to be a more realistic assessment of the relative contribution of
different causes of death to years of life lost. Since death is inevitable, the main issue is its pre-
maturity. It is not particularly helpful to know that IHD and stroke (> Table 22‐1) are top of
the league of total years of life lost; it is well known that in most Western countries more than a
third of deaths are from either of these causes. The adjusted raking seems to capture where
. Table 22-3
Rank order of norm-adjusted total SEYLL in Italy
Rank of
Cause of death Rank SEYLLadj (1,000s of years) SEYLLt (1,000s of years) SEYLLt
Road traffic accidents 1 245.5 324.7 4
Lung cancer 2 188.9 485.0 3
Breast cancer 3 110.1 215.4 6
Cirrhosis of liver 4 93.5 204.2 7
Self inflicted injuries 5 92.5 134.8 13
Birth trauma 6 83.7 94.5 18
Colorectal cancer 7 75.8 233.3 5
Lymphomas 8 53 123.2 14
Stomach cancer 9 52.2 162.9 10
Liver cancer 10 51.1 146.5 12
Leukemia 11 44.9 94.4 19
Pancreas cancer 12 40.5 113.4 15
IHD 13 38.1 1143.4 1
Diabetes mellitus 14 34.6 196.6 8
Other neoplasms 15 27.8 86.3 21
Inflammatory disease 16 19.9 73 22
Falls 17 0.5 95.9 17
Prostate cancer 18 0.8 65.8 23
Lower respiratory tract 19 7.0 90.2 20
COPD 20 11.4 156.9 11
Hypertensive disease 21 16.2 188.1 9
Alzheimer/dementias 22 16.7 96.7 16
Stroke 23 38.6 612.1 2
Total 1161.9 5137.2
Adapted and calculated from data in Mariotti et al. (2003). SEYLL stands for standard expected years of life lost.
SEYLLt is total years lost. SEYLLadj is the norm-adjusted total years lost. Ranked in order of SEYLLadj but ranks of
SEYLLt are also given (from > Table 22‐1). Spearman’s rank correlation is 0.34
important years of life are lost and has a logically sound basis, that is, as a measure of excess
above expected norms.
4 Discounting and Age-Weighting
Some burden of disease projects introduce ‘‘discounting’’ to reflect present rather than
potential future benefits and ‘‘age-weighting’’ to attach less weight to deaths of the elderly.
Discounting and age-weighting are applied according to formulae in Murray and Lopez (1996,
p. 65). There has been much debate of the value and effect of these manipulations (Anand and
Hanson, 1997; Bonneux, 2002; Barendreght et al., 1996; Mathers et al., 2006).
The rank order of DALYs has been shown to be largely insensitive to the effects of age-
weighting and discounting (Mathers et al., 2006), so that one might expect the same insensi-
tivity for the SEYLL component of a DALY. That this is so is evident from data in Mariotti et al.
(2003). They present the rank order of the four combinations: no discounting and no age-
weighting, discounting alone (at the recommended 3%), age-weighting alone, and both
discounting and age-weighting. Spearman’s rank correlation among these combinations is
always greater 0.96 and, the ranking order of the top four contributors – IHD, stroke, lung
cancer, road traffic deaths – is not changed, except that, with discounting alone, road traffic
accidents drops to fifth place, the fourth being replaced by colorectal cancer. The same
conclusion applies to the rank order of SEYLL per death. It is insensitive to the application
of age-weighting and discounting as well, with Spearman correlations always above 0.95
among the four age-weighting/discounting combinations in the Mariotti data.
4.1 Norm Adjusted Total SEYLL with Age-Weighting and Discounting
The impact of discounting and age-weighting on the norms of SEYLLd was investigated
in Marshall (2004). It was found that 3% discounting reduces the 9–10 year norm to about
7–7.5 years; age-weighting reduced it to about 5.5–6 years, and combining 3% discounting
with age-weighting reduced it still further to 4–4.5 years. If discounting and/or age-weighting
are to be used in the calculation of total SEYLL, and if the logic of a norm-adjusted total SEYLL
is accepted (Section 3.2), norm-adjusted total SEYLL should be computed with discounted/
age-weighted norms. This is simply achieved, given the results just mentioned, by respectively
replacing 9 in equation (4) with the conservative norms 7, 5 and 4 years for discounting, age-
weighting, and both combined.
The resulting norm-adjusted SEYLL are also relatively insensitive to age-weighting and
discounting, although not as insensitive as non-adjusted total SEYLL or SEYLLd. Taking the
Mariotti data again and the rank order of norm-adjusted SEYLL in > Table 22‐3, it is found
that Spearman’s rank correlation among the four age weighting/discounting combination of
norm-adjusted SEYLL is always greater than 0.85. The most notable rank order change being
that with discounting and age-weighting, IHD climbs up the rank order from thirteenth place
(> Table 22‐3) to seventh.
5 Final Remarks
Despite attempts by the Global Burden of Disease project to implement a common DALY
currency for measurement of disease burden, there appears to be no standardized way of
reporting one component of the burden, namely the standard expected years of life lost.
Studies use different standards for the standard expected years of life lost and they may or may
not age-standardize, age-weight and discount. Age-standardizing, it has been argued, has no
place in the analysis of SEYLL and age-weighting and discounting are controversial practices
that have little effect on rank order of SEYLL by cause of death. Accordingly age-standardizing,
age-weighting and discounting may be best avoided altogether.
But if SEYLL is to become a common currency for international comparisons, it is
important that a common standard for the expected years of life remaining is adopted.
Whatever standard is used is ultimately an arbitrary judgment about what life expectancy is
attainable, but the MLTW standard, as suggested by Murray and Lopez (1996), seems to be a
reasonable choice, though it may be argued that having a separate standard for men and
women violates the notion of a ‘‘standard’’ (Bonneux, 2002).
Most studies present either the total SEYLL or the SEYLL per person SEYLLp; seldom is the
years lost per death, SEYLLd, reported. As SEYLLp is the product of mortality rate and years
lost per death, it is a summary measure that compounds two aspects: the age of death and
underlying mortality rate. In computing the overall mortality burden, SEYLLp has some value,
but may mask the distinction between the contribution to years of life lost from a condition
which has low mortality in the young against one that has high mortality in the elderly.
SEYLLd focuses on years lost among those who have actually died rather than, in SEYLLp,
dispersing those years among the entire population. Naturally, years of life lost per death seems
to be favored more in clinical studies (e.g., of cancer Horm and Sondik, 1989), where the
public health burden is of lesser consideration.
But whether total SEYLL, or years lost per person or per death is reported, there remains
the issue that years of life will always and inevitably be lost relative to the standard life-table
used in the computation of SEYLL. The issue addressed here, by consideration of norms, is
whether the years that are lost are beyond what might be expected. The norms provide
benchmarks against which to judge actual years lost in a population. By quite different
approaches to computing them, one based on discrete age the other on a continuous age
model, the years of life lost, per death, in a population that meets the MLTW standards (with
no discounting or age-weighting) is about 9–10 years.
It follows from the argument that years of life lost should be considered with respect to norms,
that total years of life lost can be more realistically assessed by considering the excess years of life
lost above the expected. A ‘‘norm-adjusted’’ total SEYLL statistic has been presented which seems
of offer an alternative, and preferable, way to rank contributions to total years of life lost.
Summary Points
SEYLL is presented in different ways in the literature. In particular, the use of the
‘‘standard’’ MLTW is not always adopted.
SEYLL can be presented as a total, or as per death, or as per person-time.
There is little to justify age-standardizing of SEYLL measures.
Reference values, or norms, for SEYLL measures have been presented. The reference for
SEYLL per death is 9–10 years (no age-standardizing, no age-weighting and no discounting)
A norm-adjusted total SEYLL measure is suggested to rank years of life lost by cause.
The effects of age-weighting and discounting have little effect on rank order of SEYLL
measures by cause of death.
Appendix
Continuous Age Analysis of Norm of SEYLLd
Although age is most often recorded in age bands or to the nearest year, it is an underlying
continuous measure. If a person dies at age a and e(a) is a continuous measure of the
expected remaining years of life a person reaching the age might be expected to live then
the expected SEYLL when a person dies is, by analogy to equation (2):
Z
SEYLLd ¼ eðaÞf ðaÞda ðA1Þ
where f(a) is the distribution of age at death and the integral is from zero to an indefinite
upper value (formally infinity 1).
The probability density of life left, t, for someone alive at age a is the function f(t)/S(a),
where S(a) is the survivor function, and so e(a) can be expressed
Z Z
eðaÞ ¼ S ðaÞ1 ðt aÞf ðtÞdt ¼ S ðaÞ1 t f ðtÞdt a ðA2Þ
a a
with integration over t from a to 1

Differentiating (A2) with respect to a leads to the differential of e(a), say e(a)0 , satisfying
e(a)0 = h(a)e(a)-1, where h(a) = f(a)/S(a) is the hazard function, from which

hðaÞ ¼ eðaÞ1 eðaÞ0 þ1 ðA3Þ
Consequently, replacing f(a) in equation (A1) by f(a) = h(a)S(a) with h(a) substituted by h
(a) = e(a)-1(e(a)0 + 1) from (A3) gives the norm for SEYLLd
Z

SEYLLnorm ¼ eðaÞ0 þ1 S ðaÞda ðA4Þ
with integration from 0 to 1. Further, the hazard h(a) and survivor function S(a) are
mathematically linked by the well known
Z
S ðaÞ ¼ exp hðtÞdt ðA5Þ
with integration over t from 0 to a, so that if h(a) is replaced by formula (A3), S(a) can be
expressed in just terms of e(a).
Together equations (A3), (A4) and (A5) specify SEYLLnorm in terms only of e(a). Unfor-
tunately replacing even simple expressions for e(a) leads to intractable solutions and
the Model Life Tables (Coale and Guo, 1989, 1990) are based on smoothed Gompetz functions
that defy direct analysis. However, SEYLLnorm can be approximated assuming ea, for annual
age increments, are points on the e(a) function and putting e(a)0 ea + 1 -ea and using
quadrature for numerical integration.
References
Ahmad OB, Boschi-Pinto C, Lopez AD. (2000). Age Connor J, Broad J, Rehm J, Vander Hoorn S, Jackson, R.
Standardization of Rates: A New WHO Standard. (2005). N Z Med J. 188: 1–12.
GPE Discussion Paper Series: No 31. World Health Gardner JW, Sanborn JS. (1990). Epidemiology. 1:
Organization. 322–329.
Anand S, Hanson K. (1997). J Health Econ. 16: 685–702. Ha BM, Yoon SJ, Lee HK, Ahn HS, Kim CY, Shin YS.
Barendreght JJ, Bonneux L, Van der Mass PJ (1996). Bull (2003). Public Health. 117: 358–365.
World Health Organ. 74: 439–443. Horm JW, Sondik EJ. (1989). Am J Public Health. 79:
Bonneux L. (2002). J Epidemiol Community Health. 56: 1490–1493.
128–131. James PD, Wilkins R, Deysky AS, Tugwell P, Manual DG.
Coale A, Guo G. (1989). Popul Index. 54: 613–43. (2007). J Epidemiol Community Health. 61:
Coale A, Guo G. (1990). Popul Index. 56: 26–41. 287–296.
Jankovic S, Vlajinac H, Bjegovic V, Marinkovic J, Sipetic- factor estimates. In: Global Burden of Disease
Grujicic S, Markovic-Denic L, Kocev N, and Risk Factors. Oxford University Press, New
Santric-Milicevic, Terzic-Supic Z, Maksimovic N, York, pp. 399–426.
Laaser U. (2006). Eur J Public Health. 17: 80–85. Mathers CD, Vos ET, Stevenson CE, Begg SJ. (2001). Bull
Mariotti S, Errigo S, Mastroeni S, Freeman K. (2003). Eur World Health Organ. 79: 1076–1084.
J Epidemiol. 18: 513–521. Melse JM, Essink-Bot ML, Kramers PGN, Hoeymans N.
Marlow AK. (1995). Int J Epidemiol Community Health. (2000). Am J Public Health. 90: 1241–1247.
49: 320–322. Murray CJ, Lopez AD. (1996). The global burden of
Marshall RJ. (2004). Aust N Z J Public Health. 28: disease. In: Harvard University and World Health
452–457. Organization. Harvard University Press, Boston.
Mathers CD, Salomon JA, Ezzati M, Begg SJ, Vander
Hoorn S, Lopez AD. (2006). Sensitivity and
uncertainty analyses for burden of disease and risk
Part 2
2 Disease Burdens and Economic

Impacts
2.1 General Aspects, Geographical
Aspects, Pathologies and
Metabolic Disorders
23 Health-Adjusted Life
Expectancy: Concepts and
Estimates
J. A. Labbe
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
2 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
2.1 Health Expectancies (HE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
2.2 Health-Adjusted Life Expectancy (HALE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
2.3 Calculating Hale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
3 Hale Estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

418 23 Health-Adjusted Life Expectancy: Concepts and Estimates
Abstract: This paper review the concepts and results of > Health-Adjusted Life Expectancy.
Health-adjusted life expectancy (HALE) is a comprehensive indicator because it introduces
the concept of quality of life. It is interpreted as the number of years in > full health that an
individual can expect to live given the current morbidity and mortality conditions. The
Sullivan’s method has been widely used to estimate the measure the simplicity of its inputs.
The most comprehensive estimates correspond to WHO and several studies have been
published since. Results show differences in healthy life expectancy by sex and country level
of development.
List of Abbreviations: ADL, activities of daily living; DALE, disability-adjusted life expec-
tancy Synonym for HALE (q.v.) or healthy life expectancy; DALY, disability-adjusted life year;
DFLE, > disability-free life expectancy; GBD, > global burden of disease project; HALE,
health-adjusted life expectancy; HE, > health expectancy; WHO, World Health Organization
1 Introduction
Several summary measures are used to describe the population health but only few capture the
disability caused by diseases. The indicator Healthy Life Expectancy (HALE) combine both
fatal an non-fatal outcomes in a summary measure that represents the average level of the
population health (Mathers et al., 2001, 2006). The characteristics, methodology and current
results of the measure are presented in the following pages.
2 Background
Health is a ‘‘state of complete physical, mental and social well-being and not merely the
absence of disease or infirmity’’ (WHO, 1946). Health assessment include a range of indicators
including mortality rates, morbidity rates and life expectancy.
In most countries, life expectancy increased over the last decades due to the decrease in
the major causes of death; however there are some concerns that some of extra years lived
are being spent in ill-health. This has led to the development of health-related quality of
life measures (Jitapunku et al., 2003; Mont, 2007; WHO, 2000). Quality of life measures
capture several domains of an individual’s life; including to education, employment, ability to
perform among and others to assess quality of life.
2.1 Health Expectancies (HE)
Health measures has been categorized in health gaps and health expectancies. Health gaps
measure the difference between the actual health of a population and some goal for population
health such as disability-adjusted life years (DALYs) (Murray and Lopez, 1996). In contrast,
HE estimate the average expectation of life years lived in various health states in a single
summary measure. They include life expectancy in good health, life expectancy free from
disability, life expectancy free from dementia or free from any other disease and health-
adjusted life expectancy (HALE) (Murray and Lopez, 1996). > Table 23-1 presents major
characteristics of health measures.
Health-Adjusted Life Expectancy: Concepts and Estimates 23 419
. Table 23-1
Summary of health measures
Health measures Health states measured Units are expressed in

Mortality Death Rate (death per population)
Morbidity Illness Rate (death per population)
Life expectancy (LE) Death Years to live
DALY Death and disability Years lost
HALE (DALE) Death and health utility Years to live in a state of full health
This table presents the health measures, health states measured and the indicators units
2.2 Health-Adjusted Life Expectancy (HALE)
Health-adjusted life expectancy (HALE), formerly denominated DALE, is a health expectancy

measure which value several health states capturing the full health experience of the popula-
tion. The indicator is especially useful in countries where health improvement is based on the
increase of the well being such as European countries (OECD Health Data, 2001).
2.3 Calculating Hale
HALE is based on life expectancy (LE) but includes an adjustment for time spent in poor
health. The calculation can be separated in two stages:
1. Life expectancy calculation at age X, and
2. Adjustment of years lived by the frequency of the health states
1. Life expectancy calculation: Life expectancy at birth is the number of years a person would
be expected to live, starting at birth, if the age and sex specific mortality rates for a given
observation period were held constant over the estimated life span. Standard methods for
measuring LE are based on abridged life tables. They are constructed from population
census data and registrations of deaths. > Table 23-2 presents and example of the calcula-
tion of Life Expectancy.
To calculate life expectancy data from Chile is used. The calculation includes (1) a
computation of age-specific death rates, (2) computing the survivorship function from the
observed age-specific death rates and populations, (3) estimation of the main life table
functions (Armitage, 2002). Detailed information of life table calculation can be obtained
elsewhere.
2. Adjustment of years lived by the health states: Information on health status include the
measure of health status and definitions of health states. Measures of health status can refer
to one aspect of health or be more generic such as self-assessed health and disability
measures. Self-assessed health is a measure of perceived health status that it is collected in
surveys and capture the prevalence of a variety of health conditions (Clark et al., 2004;
Mont, 2007). Examples of disability measures include activities of daily living (ADL) that
reflects individuals ability to perform basic physical tasks. Also, WHO has developed
protocols that include 11 states and 7 domains (mobility, self-care, usual activities, pain
. Table 23-2
Calculation of life table for Chilean males
x nx nPx Mx ax qx px lx dx Lx Tx ex
0 1 125,477 0.00925 0.1 0.00918 0.9908 100,000 918 99,174 7,450,613 74.5
1 4 513,942 0.00041 0.4 0.00163 0.9984 99,082 161 395,943 7,351,439 74.2
5 5 692,214 0.00021 0.5 0.00106 0.9989 98,921 105 494,344 6,955,496 70.3
10 5 760,740 0.00029 0.5 0.00144 0.9986 98,816 142 493,727 6,461,152 65.4
15 5 1,592,746 0.00031 0.5 0.00154 0.9985 98,675 152 492,993 5,967,424 60.5
20 5 643,680 0.00121 0.5 0.00604 0.9940 98,523 595 491,127 5,474,431 55.6
25 5 608,378 0.00134 0.5 0.00668 0.9933 97,928 654 488,005 4,983,304 50.9
30 5 626,369 0.00154 0.5 0.00769 0.9923 97,274 749 484,497 4,495,299 46.2
35 5 628,833 0.00192 0.5 0.00955 0.9905 96,525 921 480,322 4,010,802 41.6
40 5 599,517 0.00245 0.5 0.01218 0.9878 95,604 1,164 475,109 3,530,479 36.9
45 5 515,270 0.00355 0.5 0.01757 0.9824 94,440 1,659 468,050 3,055,371 32.4
50 5 408,516 0.00558 0.5 0.02751 0.9725 92,780 2,553 457,520 2,587,321 27.9
55 5 331,445 0.00913 0.5 0.04465 0.9553 90,228 4,029 441,066 2,129,801 23.6
60 5 260,539 0.01447 0.5 0.06983 0.9302 86,199 6,019 415,945 1,688,735 19.6
65 5 195,069 0.02314 0.5 0.10936 0.8906 80,179 8,769 378,976 1,272,790 15.9
70 5 147,893 0.04025 0.5 0.18284 0.8172 71,411 13,057 324,412 893,814 12.5
75 5 99,016 0.06082 0.5 0.26396 0.7360 58,354 15,403 253,261 569,402 9.8
80 5 49,901 0.13586 0.5 0.50707 0.4929 42,951 21,779 160,306 316,141 7.4
85 5 24,516 0.13586 0.5 0.50707 0.4929 21,172 10,736 79,019 155,835 7.4
90+ 11,650 0.13586 0.5 1.00000 0.0000 10,436 10,436 76,816 76,816 7.4
x age group
nx width of the age interval in years
nPx population
Mx mortality rate
ax average fraction of the age interval survived by the individuals who die
qx probability that an individual will die during the age interval
px probability that an individual will survive
Ix number of individuals who would survive to the start of each age interval
dx number of deaths that would have occurred in the age interval
Lx number of years lived
Txtotal number of years lived beyond the age interval
ex life expectancy
Calculation by Concha M and Labbé J
and discomfort, cognition, anxiety and depression, social participation). The states are
weighted from 100 to full health and 0 to death (WHO, 2000, 2002).
To calculate years lived by the health states two methods are used; Sullivan’s
method and Multi-State Life Table Method. This last method is based on period
transition rates whereas the Sullivan’s method gives the average health expectancy (Math-
ers, 2001, 2006). > Table 23-3 shows an example of the calculation of HALE using
Sullivan’s method.
. Table 23-3
Calculation of HALE using Sullivan’s method for Chilean females, 2004
x Lx ex Ux Ulx HTx Hex

0 99,354 80.42 1.75% 1,738 97,617 64.4
1 396,785 80.00 1.90% 7,537 389,248 63.9
5 495,531 76.11 2.30% 11,404 484,127 60.1
10 495,197 71.16 2.98% 14,742 480,456 55.2
15 494,849 66.21 3.93% 19,456 475,393 50.4
20 494,085 61.26 5.20% 25,700 468,385 45.7
25 492,852 56.39 6.82% 33,625 459,227 41.0
30 491,461 51.54 8.83% 43,398 448,063 36.5
35 489,798 46.68 11.26% 55,158 434,640 32.0
40 487,708 41.85 14.15% 69,015 418,692 27.7
45 484,161 37.04 17.54% 84,899 399,262 23.5
50 478,091 32.38 21.45% 102,552 375,539 19.6
55 468,472 27.85 25.93% 121,483 346,989 15.9
60 453,460 23.50 31.02% 140,644 312,817 12.6
65 429,649 19.35 36.74% 157,844 271,805 9.6
70 391,578 15.55 43.13% 168,905 222,673 7.0
75 337,800 12.21 50.24% 169,715 168,085 4.9
80 241,282 9.13 58.09% 140,170 101,112 3.1
85 137,528 9.13 66.73% 91,771 45,757 2.5
90+ 182,298 9.13 76.18% 138,877 43,421 2.2
x age group
Lx number of years lived
ex life expectancy at the beginning of the age interval
p prevalence in per cent
UxDisability prevalence
UlxPerson years lived with disability
HTxTotal years lived healthy from age x
HexHealthy Life Expectancy (HALE)
Calculation by Concha M and Labbé J
In the table, the first column correspond to age groups, the second and third column
correspond to the Chilean life table for the same sex and calendar year. Disability
prevalence (fourth column) is based on YLD prevalence per 100 population gathered
from the Chilean GBD study (Concha et al., 1997). Years lived with disability (fifth
column) are obtained multiplying disability prevalence between age x and x+5 and the
number of years of life lived by the life table cohort between age x and x+5. Years Lived
without disability (sixth column) correspond to the difference between the number of
years of life lived by the life table cohort between age x and x+5 and the Years lived with
disability. Finally, HALE are obtained adding years lived without disability for ages x and
above, divided by number of survivors at age x in the life table cohort. In the table, Life
Expectancy at birth is estimated to be 80.42 years while Health-Adjusted Life Expectancy
at birth is estimated to be 64.4 years. This indicates that 80.1% of total Life Expectancy is
expected to be free from disability.
3 Hale Estimation
The most comprehensive estimates correspond to WHO that has published HALE for its 192
member states since 2000. For calculating the measure, WHO combines estimates from Global
Burden of Disease and comparable population surveys (Mathers, 2001).
In males, HALE ranges from 72 to 27 years. Sixteen countries; all developed; presented
indicator values of 70 years or more; whereas males from 51 countries expect to live in a
healthy state 50 or less years. These males live in African countries and only a few in Asia.
Because male mortality declines less than female mortality, there is a gap between female
and male life expectancy. Healthy life expectancy resembles this difference between sexes. The
expected life span at birth lived without disability in females varies from 78 to 30 years and in
males ranges from 72 to 27 years (> Figure 23-1).
The gap between life expectancy and healthy life expectancy in males ranges from 11 to
3 years and in females from 13 to 5 years. No clear pattern is observed between poorer and
richer countries (> Figure 23-2). Differences of the measure between sexes have been attrib-
uted to lifestyle. In wealthier countries women live longer than men and in poorer countries
live shorter and in ill health (WHO, 2001).
. Figure 23-1
Health adjusted life expectancy by sex and selected countries (WHO, 2002). Based on The world
Health Report, 2003. WHO
. Figure 23-2
Difference (in years) between life expectancy and health adjusted life expectancy for females in
selected countries (WHO, 2002). Based on The world Health Report, 2003. WHO
Trend analysis shows increase in both LE and HALE but life expectancy increased more
than health adjusted life expectancy. Thus, the population is living longer but not healthier
specially females that are getting older and more disabled (Clark et al., 2004).
Since the publication of WHO, several studies has been published; most using Sullivan’s
method. Survey data on disability has been used to calculate the indicator in several settings
such as Scotland, USA among others (Clark et al., 2004; Crimmins et al., 2001; The Parlia-
mentary Office of Science and Technology, 2006). Less richer countries included Cuba,
Brazil and Chile have also estimated HALE (Concha et al., 2006; Dominguez, 2005; Romero
et al., 2005).
4 Conclusion
Healthy Life expectancy is an advance in the measurement of the health status of population
because it includes both mortality and quality of life.
Summary Points
Instead of using death rates to identify the population health a new measure has been
developed: Healthy Life Expectancy. The indicator is an estimate of how many years are
lived in good health over the lifespan.
The indicator is based on life expectancy and disability data giving a broader picture of the
impact of the diseases in the quality of life of the population. Moreover its results easy to
understand for the layman population.
The steadily increase in lifespan in several countries has not been accompanied by a similar
increase in quality of life according to HALE analysis.
HALE has several uses such as evaluation of health services and programme, identification
of inequalities, prediction of needs, trend identification and policy impact among others.
Getting older, probably, may not jeopardize the well being of the population if it were not
accompanied by restriction of daily life activities. In this context. one of the most valuable
uses of HALE is in the measurement of the impact of social policies on the health of the
elderly.
References
Alonso ED, Seuc A. (2005). Esperanza de vida ajustada Mont D. (2007). Lancet. 369: 1658–1663.
por algunas enfermedades crónicas no transmisibles Murray CJL, Lopez AD. (eds.) (1996). The global
Rev Cubana Hig Epidemiol 43. burden of disease: a comprehensive assessment
Armitage P, Berry G, Matthews JNS. (2002). Statistical of mortality and disability from diseases. Injuries
Methods in Medical Research, 4th ed. Blackwell and risk factors in 1990 and projected to 2020.
Science, Oxford. Global Burden of Disease and Injury. vol. 1. Harvard
Clark D, McKeon A, Sutton M, Wood R. (2004). Healthy School of Public Health on behalf of WHO,
Life Expectancy in Scotland. Available at: http:// Cambridge, MA.
www.isdscotland.org/HLE. OECD Health Data. (2001). A Comparative Analysis
Concha M, Labbé J. (2006). Impacto de la Discapacidad of 30 Countries. Data sources: Definitions and
Sobre la Esperanza de Vida. Ciencia y Trabajo. 22: Methods. OECD, Paris.
177–179. Romero DE, Costa Leite I, Landmann C. (2005). Expec-
Concha M, Aguilera X, Gonzalez C, Jadue L, Bedregal P. tativa de vida saudavel no Brasil: uma aplicao do
(1997). La carga de enfermedad en Chile. Epi- Método de Sullivan Cadernos de Saúde Pública 21.
Visión, Boletı́n Epidemiológico de Chile. 18: 1–3. The Parliamentary Office of Science and Technology.
Crimmins EM, Saito Y. (2001). Soc Sci Med. 52: (2006). Healthy Life Expectancy. Available at: www.
1629–1641. parliament.uk/parliamentary_offices/post/pubs2006.
Jitapunku S, Kunanusont L, Phoolcharoen Wt, Suriya- cfm.
wongpaisa Pl, Ebrahim S. (2003). Age Ageing. 32: World Health Organization. (1946). In Preamble to the
401–405. Constitution of the World Health Organization as
Mathers C, Iburg k, Begg S. (2006). Popul Health Metr. adopted by the International Health Conference.
4: 4 (doi: 10.1186/1478). New York.
Mathers C, Murray C, Lopez A, Salomon J, Sadana R, World Health Organization. (2000). The World Health
Tandon A, Üstün TB, Chatterji S. (2001). Estimates Report 2000. Health systems: Improving Perfor-
of Healthy Life Expectancy for 191 Countries in the mance. World Health Organization, Geneva.
Year 2000: Methods and Results. World Health World Health Organization. (2002). The World Health
Organization (GPE discussion paper No. 38), Report Reducing Risks. Promoting Health Life.
Geneva. Available at: http://www.who.int/whr/2002/en/.
24 Individual Disability-Adjusted
Life Year: A Summary Health
Outcome Indicator Used for
Prospective Studies
P. Zhang . M. Woodward . J. Shen . Y. Wu
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
2 Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
2.1 Choosing Disability as the Measurement of Disease Burden . . . . . . . . . . . . . . . . . . . . . . . . 427
2.2 Disability Weighting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
2.3 Measurement of Disability Weights for Individual DALY . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
2.4 Individual DALY Caused by Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
2.5 Time Preference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
2.6 Age Weighting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
3 The Formula of Individual DALY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
4 Case Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
5 Further Explanations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433

5.1 Comparison Between Individual DALY and Other GBD Measures . . . . . . . . . . . . . . . . . 433
5.2 Advantages of Using Disability Weights in Individual DALY . . . . . . . . . . . . . . . . . . . . . . . 434
5.3 Utilities of Individual DALY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
5.4 Precautions in Use of Individual DALY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435

426 24 Individual Disability-Adjusted Life Year
Abstract: In order to assess global health at individual level in prospective studies, a standard
summary indicator of health – Individual DALY was established. It integrated all kind of
disease into one measure, reflecting the healthy years lost during a period of time for an
individual, with consideration of societal “ideal.”
Similar to Disability-Adjusted Life Year (DALY), Individual DALY used disability and
disability weight to measure health problem and its severity after adjusting age and > time
preference. Following assumptions were made: (1) individual DALY be defined as the cumu-
lated > healthy life years lost for an individual during follow-up; (2) health status during a
certain period of time kept stable, and the corresponding disabilities and disability weights
could be assessed either by standard assessment tools during follow-up, or using the disease
specific disability weights reported by > Global Burden of Disease study, with the precondi-
tion that the synthetic disability weight of > comorbidity had been resolved; (3) death be
regarded as a special disability and assumed to be followed up until the end-point of follow-
up. As a supplement to traditional population health assessment indicators, Individual DALY
provides individual data and hence leads approaches in finding determinant factors of overall
health more directly, evaluating effect of intervention more reasonably, and allocating health
resource more effectively.
The calculation procedure, results, possible application and attentions were also illustrated
using individual cases as an example.
List of Abbreviations: BMI, > body mass index; CHD, coronary heart disease; DALE, > dis-
ability-adjusted life expectancy; DALY, disability-adjusted life year; DW, disability weight;
GBD, global burden of disease; HeaLY, healthy life year; ICIDH, international classification
of impairments, disabilities and handicaps; Individual DALY, > individual disability-adjusted
life years; QALY, quality-adjusted life year; RR, > relative risk; SEYLL, standard expected years
of life lost; WHODAS, WHO’s disability assessment schedule; YLD, years lost due to disability;
YLL, years of life lost
1 Introduction
Summary measures of health evaluate health by combining data on mortality and non-fatal
health outcomes into a single measurement, which help to understand health as a whole rather
than a certain disease alone. Since the initiation of the Global Burden of Disease (GBD) studies by
WHO (Murray, 1994), disability-adjusted life year (DALY) has been most widely used to reflect
the burden of > premature mortality and disability for major diseases or disease groups.
However, based on population health indicators such as > incidence and mortality, the DALY
can only be used as a summary measure of population health, and can not be applied to the
assessment of disease burden for individuals. However, studies of risk factors and health out-
comes at individual level bear strong significance in establishing the causal relationship (Rose,
2001).
Obviously, GBD studies have made great contribution on quantifying the burden of
disease and setting priorities of risk-factor-intervention. In Global Burden of Disease studies
(Ezzati et al., 2002; Murray and Lopez, 1997; Mathers et al., 2002), risk factors of health lost
(DALY), relative risks (RR) were all determined from past studies on the relationship
between diseases and risk factors (factor-incidence relationship) instead of between disabilities
and risk factors (factor-disability relationship). Thus the DALY-based priority setting on risk
Individual Disability-Adjusted Life Year 24 427
factor control is indirectly determined and may not be of most efficiency. To solve this
problem, longitudinal analysis on individual level shall be used to determine directly the
factor-disability relationship. But as a precondition, there needs a summary health indicator
suitable for measurement of each individual.
Besides the DALY, several other such measures have been developed, including the
Quality-Adjusted Life Year (QALY), the Disability-Adjusted Life Expectancy (DALE) and the
Healthy Life Year (HeaLY) (Hyder et al., 1998; Murray and Lopez, 1996a; Murray et al., 2000;
Weinstein and Stason, 1977). But none of these measures are suitable for individual mea-
surement with taking social values into account.
In this section, we developed a new indicator, Individual Disability-Adjusted Life Years
(Individual DALY), based on main social values and theories of DALY to satisfy the calculation
of summary health outcome for individuals in > longitudinal studies.
2 Rationale
Individual DALY is based on the following social values and theoretical basis.
2.1 Choosing Disability as the Measurement of Disease Burden
The International Classification of Impairments, Disabilities and Handicaps (ICIDH, Geneva,

World Health Organization, 1980) proposed a linear progression from disease to pathology to
manifestation to impairment to disability to handicap. Impairment is defined at the level of
organ system, disability is the impact on the performance or function of the individual, and
handicap is the overall consequences, which depend on the social environment. Handicap is
affected by many social factors, such as occupation, education and economic level. For
example, for a concert violinist and a bank-teller, the disability of a loss of a finger may be
the loss of fine driving function, but the handicap or disadvantage is markedly different. In
order to ensure comparability of burden across individuals, and decrease the inequalities
between different social circumstances, we adopted the “Treating like health outcomes as like”
principle, which requires using disability instead of handicap (Murray, 1994).
2.2 Disability Weighting
In order to use time as a common currency for non-fatal health states and for years of life lost
due to mortality, we used the method of disability weighting developed in the GBD study to
define, measure and numerically value the time lived with disabilities. Such weights are mostly
measured as a number on a scale of 0–1. In the Individual DALY calculation, we allocated 0 to
a state of optimal health (no loss of disability), 1 to the worst state equivalent to death, and a
value between 0 and 1 to a non-fatal state between optimal health and death.
2.3 Measurement of Disability Weights for Individual DALY
In order to use Individual DALY for the burden of disease, the disability weights need to be
individualized according to the specific health state, namely the severity of disability, without
the consideration of other social status such as economic status, educational level and
occupation. The WHO has embarked on large-scale efforts to improve the methodological
and empirical basis for the valuation of health states (Salomon and Murray, 2002; Ustun et al.,
2000). A set of disability weights for most disability situations has been published in GBD1990
and GBD2000 reports (Murray and Lopez, 1996b; Mathers et al., 2003).
Comorbidity, which is common for the elderly, must be considered in the calculation of
disease-specific disability weights. If two or more impairments occurred for a person at the
same time, the following equation can be used to calculate the > synthesized disability weight:
Y
k
DWs ¼ 1 ð1 DWi Þ ð1Þ
i¼1
where DWs is the disability weight for a person who experiences k events at that moment
(the events can also be recurrent for the same disease at different times); DWi is the disability
weight of one of the diseases.
We assume that disability is independent from one to another. Disability weight can be
regarded approximately as a certain proportion loss of left health, although the GBD2000
stresses that a disability weight of 0.5 does not mean a person in this health state is “half dead”
or is experiencing life as halfway between life and death (Mathers et al., 2001).
For example, according to the GBD 2000 (Mathers et al., 2003), the disability weight of
diabetics with diabetic foot is 0.136, which can be assumed as 13.6% loss of health, or 86.4%
(i.e., 1–0.136) health left. If a person with diabetic foot got stroke simultaneously (the
disability weight of first-ever stroke is 0.920), the remaining health will be (1–0.136)*(1–
0.920) = 0.069. The synthesized disability weight (DWs) for this health state with comorbidity
would be 1–0.069 = 0.931, meaning 93.1% loss of health.
As shown in the example above, Formula (1) can restrict the overall disability weight into
the interval of 0–1. In GBD study, however, the DALY theory treats the disability weight as
0.136 + 0.920 = 1.056, a simple aggregated value. That implies a disability is more severe than
death, which is practically wrong.
An alternative method as established in the GBD study is to directly measure disability
weights for individuals as a whole during follow-up. This method should be encouraged
because it can avoid the complicated valuation procedure for hundreds of sequela. However, it
is of great need to design a measurement approach which uses a standardized descriptive
system based on multiple domains of health to measure the health levels for the participants
periodically. WHO has provided a set of disability or health measuring instruments. Available
instruments can be found in the > World Health Organization Disability Assessment Schedule
II (WHODAS II) (http://www.who.int/icidh/whodas) and World Health Survey system
(http://www.who.int/healthinfo/survey/instruments/en/index.html).
2.4 Individual DALY Caused by Mortality
DALY measures health gap from the disease onset to the ideal life expectancy, while the
Individual DALY only assesses the loss of healthy years due to disability during a certain
time of follow-up, and there is no need to calculate the age specific life expectancy by sex. To
estimate the part of health loss caused by premature death, Individual DALY regards death as a
special disease with the highest and fixed disability weight (disability weight = 1), and will be
observed until the end of follow-up. If neither age weighting nor time preference is taken into
account, the disability of an individual caused by death would equal to the death years from
the death to the end of follow-up (i.e., the product of 1 and the death years).
2.5 Time Preference
Time preference is the economic concept. Individuals prefer benefits now rather than in the
future. The Individual DALYapplies a 3% per year discount rate to lost years during the period
of observation to estimate the net value of lost years at the beginning of follow-up. The discrete
discount function is (1–r)(x–a), where r is the discount rate (3%), x and a are the ages at specific
time and at the beginning of the follow-up respectively. With this discount rate, a year of
healthy life gained in the 10th year is 26.3% less than one gained at the beginning. For ease
of calculation, the Individual DALY formula uses a continuous discount function of the form
e–r(x–a), although the result is not precisely the same as the discrete form above. For example,
the value 26.3% mentioned above will change into 25.9% while using the continuous function.
2.6 Age Weighting
In all societies, social roles vary with age. The young, and often the elderly, depend on the rest
of society for physical, emotional and financial support. Given different roles and changing
levels of dependency with age, it may be appropriate to consider valuating the time lived at a
particular age unequally. Higher weight for a year of time at a particular age does not mean
that the time lived at that age is per se more important to the individual, but that because of
social roles the social value of that time is greater. Just like the Global Burden of Disease Study,
Individual DALY weights a year of healthy life lived at young ages and older ages lower than for
other ages. Murray and Acharya (Murry and Acharya, 1997; Murray et al., 2000) have argued
that age weights are not in themselves inequitable, because everyone potentially lives through
every age, and that they do reflect legitimate societal priorities.
An exponential function deriving from the DALY can express this age-weighting:
C xebx
Where b determines the importance of age-weights and is chosen arbitrarily; C is an
adjustment constant, retains the meaning and value of the DALY. It is recommended that the
GBD 1990 values of C = 0.1658 and b = 0.04 be used for standard age weighting in Individual
DALY, for comparability with other studies.
3 The Formula of Individual DALY

As illustrated in > Figure 24-1, the life time of an individual during a follow-up study can be
divided into several portions. In each of them, the health status, expressed by disability weight
here, keeps relative stable. Death is regarded as a special kind of disability and should be
observed until the end of follow-up. The Individual Disability-Adjusted Life Year is an
indicator of the healthy time lost for an individual due to disability on account of some social
values and time preference during the follow-up. If age and time preference are not taken into
account, the area of the shadow as shown in > Figure 24-1 between the starting and the end of
. Figure 24-1
A sample model of the disability weight transition for an individual during follow-up. DW1~DW8:
Mean values of disability weights during a period of time in which the health status of the
individual is relative stable. The health situation of an individual during follow-up can be
separated into several stages. In each stage, the health status is relative stable, and the disability
weight can be measured or calculated. If social ideals were not taken into account, the area of
shadowed part would be the healthy years lost during the follow-up by the individual
follow-up would be the lost healthy years during that time. Referring to the DALY formula
(Murray, 1994), and considering the influence of the age weight and time preference, a general
formula for the number of Individual DALY lost by an individual can be developed:
k Z
Tiþ1
X
Individual DALY ¼ DWi C x ebx erðxaÞ dx
i¼1
Ti
The solution of the definite integral from Ti to Ti+1 gives:

X
k
Individual DALY ¼ DWi C eðraÞ =ðb þ rÞ2 feðbþrÞTiþ1 ½ðb þ rÞTiþ1 1
i¼1
eðbþrÞTi ½ðb þ rÞTi 1g ð2Þ
where i represents a period in which the health status is relatively stable and k is the number
of this type of period that an individual experiences during follow-up (in the case of
th
> Figure 24-1, k is 8); DWi is the disability weight during the i period; C is the age weighting
correction constant; b is the parameter from the age-weighting function; r is the discount rate
(r = 0.03); Ti and Ti+1 are the onset ages of disabilities at the ith and the next period; a and b
are the ages at the starting and the end of follow-up, respectively.
4 Case Study
To illustrate the calculation process of Individual DALY, we chose a case from one of
our prospective studies – the China Muti-center Collaborative Study of Cardiovascular
Epidemiology Cohort I (MUCA Cohort I), in which 30,560 participants were recruited from
1982 to 1985 and followed up every 2 years, to find the relationship between cardiovascular
disease and baseline risk factors in China. In order to calculate the Individual DALY lost in this
case, the date 1 January 2003 were assumed as the end time of follow-up, though the follow-up
is still ongoing. In the GBD study, disability weights vary with age and treatment. It is necessary
to decompose the whole time into several stages in which the disability weights are relatively
stable. > Figure 24-2 illustrates the transition of his health status, showing the major health
events, starting and end ages, and the situation of comorbidity, and > Table 24-1 gives the
disability weights for each health status according to the GBD2000 study without considering
other concurrent diseases (comorbidities) (Mathers et al., 2003). > Table 24-2 shows the
results of synthesized disability weight, duration and Individual DALYs for each health stage
according to formula 1 and 2.
. Figure 24-2
Health status transition of a particular case from the China MUCA Cohort I: the events and their
starting and end ages. Unhealthy or ill situations could occur in any stage separately or
simultaneously. All these health situations and their duration could be illustrated one by one in
this kind of figure. This will be helpful to understand and calculate the synthesized disability
weights
Sometimes, one event (such as diabetes and long-term stroke) was divided into two or
more parts because the health status (or disability weight) may vary with age and treatment.
As shown in > Table 24-2, during the 16.25 years of follow-up, the case experienced
diabetes mellitus, angina pectoris, stroke and death. The total Individual DALY is 2.488,
implying that 2.488 healthy years was lost due to these sequelae, including 2.037 years lost
due to disability (YLD) and 0.451 years of life lost (YLL) due to premature death. The averaged
Individual DALY is 0.153, reflecting 0.153 health years lost per year.
> Table 24-3 shows the result of a univariate variance analysis with MUCA Cohort I data to
illustrate the role of cardiovascular risk factors to Individual DALY and its components, YLD
and YLL, showing that male, age, smoke history, inactivity and SBP were contributing to Indi-
vidual DALY, but the degree of the effect of these factors were not the same on YLD and YLL.
. Table 24-1
Health events and the disability weights according to GBD2000 (for example)
Health events DWa

Untreated diabetic case 0.012
Treated diabetic case 0.033
Untreated angina pectoris 0.227
Treated angina pectoris 0.095
First-ever stroke (28days) 0.920
Long-term stroke (age <60 yr) 0.224
Long-term stroke (age >60 yr) 0.258
Death due to second stroke 1.000
Specific disability weights have been given for most health status in Global Burden of Disease studies (Mathers
et al., 2003). Here is just used as an example
a
DW is the disability weight for each health status according to GBD2000 without considering other concurrent
diseases (comorbidities)
. Table 24-2
The results of synthesized disability weight, duration and Individual DALYs for each health stage
of the particular example case
Starting Duration Individual

Event or comorbiditya DWsb age End age (years)c DALYsd
Untreated diabetes 0.012 46.08 49.78 3.70 0.049
Treated diabetes 0.033 49.78 50.23 0.45 0.015
Treated diabetes & untreated angina pectoris 0.253 50.23 52.68 2.45 0.575
Treated diabetes & treated angina pectoris 0.125 52.68 56.83 4.15 0.407
Treated diabetes & treated angina pectoris & 0.930 56.83 56.91 0.08 0.052
First-ever stroke (28 days)
long-term stroke (age <60 yr)
long-term stroke (age >60 yr)
Death due to second stroke 1.000 61.49 62.33 0.84 0.451
Overall – 46.08 62.33 16.25 2.488
One may experience different kind of unhealthy situations, for which, the synthesized disability weights, durations
and concurrent ages could be listed in a table. This will be helpful to calculate individual DALYs
a
Comorbidity is the situation in which a person experienced at least two different kinds of health events
simultaneously
b
DWs is the synthesized disability weight calculated according to formula 1. For example, the DWs of treated
diabetes & treated angina pectoris & long-term stroke (age >60 yr) is 0.351, the result of 1–(1–0.033)*(1–0.095)*
(1–0.258)
c
Duration is the difference of end age and starting age
d
Calculated according to formula 2 The total Individual DALYs is 0.049 + 0.015 + 0.575 + 0.407 + 0.052 +
0.641 + 0.299 + 0.451 = 2.488. The mean Individual DALYs is 2.488/16.25 = 0.153
. Table 24-3
The role of cardiovascular risk factors to individual DALY and its components – results of a
multivariate analysis
Dependent variables Parameter B Std. error t Sig.

Individual DALY Male 0.127 0.017 7.591 0.000
Age at baseline (year) 0.016 0.001 16.102 0.000
Smoke history 0.020 0.017 1.193 0.233
Inactivitya 0.080 0.017 4.592 0.000
BMIb 0.026 0.002 10.968 0.000
c
SBP 0.005 0.000 13.717 0.000
Individual YLD Male 0.009 0.003 2.980 0.003
Age at baseline (yr) 0.000 0.000 0.844 0.399
Smoke history 0.014 0.003 4.910 0.000
Inactivitya 0.001 0.003 0.347 0.729
BMIb 0.003 0.000 8.470 0.000
c
SBP 0.001 0.000 19.291 0.000
Individual YLL Male 0.118 0.016 7.151 0.000
Age at baseline (yr) 0.016 0.001 16.467 0.000
Smoke history 0.006 0.017 0.357 0.721
Inactivitya 0.078 0.017 4.558 0.000
BMIb (kg/m2) 0.029 0.002 12.613 0.000
SBP (mmHg) 0.004 0.000 10.544 0.000
Like incidence or prevalence indicators, Individual DALY could be used directly in etiological analysis as indepen-
dent variable. This may tell the researchers which factors contribute most to the overall health, or which
intervention do the greatest help to the health of human being. Individual DALY: Disability Adjusted Life Year
for an individual, calculated as the sum of the years of life lost due to premature mortality (YLL) and the equivalent
“healthy” years lost due to disability (YLD)
a
Inactivity, less than 2 h of exercise per week
b
BMI, body mass index, calculated as body weight in kilogram divided by square of height in meters
c
SBP, systolic blood pressure (mmHg)
BMI was negatively correlated with Individual DALY mainly because 90% of participants in
MUCA Cohort I had BMI less than 25.3 km/m2 at baseline.
5 Further Explanations
5.1 Comparison Between Individual DALY and Other GBD Measures
Traditionally, incidence data are used to identify risk factors in prospective studies. But for
the purpose of finding risk factors that influence the overall health, it is much more suitable to
use composite measures (Murray et al., 2000) such as DALY, QALY and Individual DALY.
These indicators contain incidence, duration, and societal preference information. Compared
with incidence or > prevalence index, these overall health measures reflex people’s wants
better, and be more helpful in directing the allocation of health resource. However, as
mentioned in the introduction part, DALY and QALY all have limitation in practice.
Although developed on the principals of DALY, Individual DALY is completely different
from DALY. DALY is a health gap between a health state and an ideal health (Murray, 1994),
which is often set as the highest life expectancy (82.5 and 80.0 years at birth, for women and
men, respectively) observed for any nation, by the Standard Expected Years of Life Lost
(SEYLL) method. This will inevitably exaggerate the disease burden in developing countries
(Murry and Lopez, 1999). Individual DALY, however, integrates the lost healthy life years for
individuals from the beginning to the end of the follow-up. It may vary from study to study
but will remain the same between individuals and between sexes in one study. Therefore,
Individual DALY does not suffer from such weaknesses.
> Table 24-4 illustrated the features of Individual DALY in hypothesis, calculation, utili-
zation, and advantages of Individual DALY when compared with DALY.
. Table 24-4
Features of individual disability-adjusted life years
1. Using disability and disability weight to measure health problem and its severity, taking age and
time preference into account
2. Assuming that health status during a certain period of time keep stable, and the corresponding
disabilities and disability weights could be assessed
3. Regarding death as a special disability and followed up until the end-point of follow-up
4. Avoiding the problem of comorbidity by calculation of synthetic disability weights, this problem
may exaggerate the burden of disease in DALY studies
5. Being a composite health indicator for individuals, rather than population information based
index
6. Being healthy life years lost during follow-up, not a health gap between a health state and an
ideal health
7. Including life years lost due to premature mortality and the equivalent “healthy” years lost due to
disability
8. Helpful in: finding determinant factors of overall health directly, evaluating effect of intervention
reasonably, and allocating health resource effectively
9. Paying attention that the magnitude of Individual DALY is significantly related to the duration of
follow-up and the age of participants at baseline
This table lists the main features in hypothesis, calculation, utilization, and advantages of Individual DALY when
compared with DALY
5.2 Advantages of Using Disability Weights in Individual DALY
In GBD study, the disability from each disease is dealt with separately, assuming an additive
effect of two or more comorbidities in one person, which inevitably overestimate the burden
of disease. In individual DALY study, however, use of the technique of synthesized disability
weight (formula 1) and the direct use of standardized measuring instruments can avoid this
kind of overestimation.
5.3 Utilities of Individual DALY
Just like other measures such as blood pressure, or occurrence of CHD events, Individual DALY
is an individual measure of his/her health status. To identify overall health related risk factors,
Individual DALY and assumed factors can be measured and recorded simultaneously at individ-
ual level without dozens of assumptions of linkages and relative risks between diseases and risk
factors (Ezzati et al., 2002). Efforts should be made in the use of Individual DALY in order to find
related risk factors of overall health lost more directly and reliably, especially the factors with
great variation among individuals such as hereditary, biological, biochemistry, psychological and
behavioral factors. As an individualized indicator, individual DALY is not suitable to be used to
identify the role of population specific risks such as air pollution and nationality.
Individual DALY will allow us to: (1) describe the distribution of the loss of health during
the follow-up; (2) analyze the relationship between loss of health and its risk factors, and
identify factors that have most influence on the global burden of disease; (3) assess the
effectiveness of an intervention or treatment on the overall loss of health. Together with the
traditional outcomes study, Individual DALY will ultimately help the decision-makers to
allocate competing resources more efficiently.
Utilizations of Individual DALY will certainly not be limited in cardiovascular disease
and its risk factors which are shown in the example; it can be used for nearly all diseases and
conditions, especially suitable for long-lasting variables. What you need is to recode the
variation of health situations and related factors, or evaluate overall disability weights period-
ically with standard instruments for individuals.
5.4 Precautions in Use of Individual DALY
However, the magnitude of Individual DALY is significantly related to the duration of follow-
up and the age of participants at baseline. The researchers should pay much attention to the
following aspects:
First, if a study aims at finding the relationship between loss of health caused by specific
diseases and risk factors, the participants should be free from these kinds of diseases and be old
enough to obtain a larger number of Individual DALYs in a relatively short term. If the
purpose is to study the relationship between the possible risks and overall burden, it is
impossible to ensure all of the participants at baseline are optimally healthy. In this situation,
the target population can be a natural one without such limitation.
Second, it is not necessary to follow up the cohort for a life time to get the estimate of
Individual DALY. Just like incidence or mortality used in follow up studies, the starting age
and period of follow-up affect the observed part-life disability markedly. The length of follow-
up for an Individual DALY study may be several years or longer, which is largely depended on
the purpose and characteristics of the study. We should make sure to follow up longer enough
to obtain enough Individual DALYs.
Summary Points
Summary measures of health evaluate health by combining data on mortality and non-
fatal health outcomes into a single measurement, help people to understand health as a
whole rather than a certain disease alone.
Based on population health indicators, Disability-Adjusted Life Year (DALY) can not be
applied to evaluate disease burden for individuals.
Individual DALY is defined as the cumulated healthy life years lost for an individual during
follow-up.
Individual DALY uses disability and disability weight to measure health problem and its
severity, after adjusting age and time preference.
Individual DALY assumes that health status during a certain period of time keeps stable,
and the corresponding disabilities and disability weights can be assessed.
According to the theories of Individual DALY, death is regarded as a special disability and
assumed to be followed up until the end-point of follow-up.
When calculating synthetic disability weights, Individual DALY resolves the problem of
comorbidity, which is inevitable in past Global Burden of Disease studies.
Unlike DALY, Individual DALY is not a health gap between a health state and an ideal
health, this help people avoid the exaggeration of disease burden in developing countries.
Individual DALY is of help in finding determinant factors of overall health more directly,
evaluating effect of intervention more reasonably, and allocating health resource more
effectively.
Attention should be paid that the magnitude of Individual DALY is significantly related to
the duration of follow-up and the age of participants at baseline.
References
Ezzati M, Lopez AD, Rodgers A, Vander HS, Murray CJ. Murray CJL, Lopez AD. (1996a). Science. 274(5288):
(2002). Lancet. 360: 1347–1360. 740–743.
Hyder AA, Rotllant G, Morrow RH. (1998). Am J Public Murray CJL, Lopez AD. (eds.) (1996b). The Global Bur-
Health. 88(2): 196–202. den of Disease: A Comprehensive Assessment of
Mathers CD, Bernard C, Iburg KM, Inoue M, Fat DM, Mortality and Disability from Diseases, Injuries
Shibuya K, Stein C, Tomijima N, Xu H. (2003). and Risk Factors in 1990 and Projected to 2020.
Global Burden of Disease in 2002: Data Sources, Harvard University Press, Cambridge (Global Bur-
Methods and Results. Global Programme on Evi- den of disease and Injury Series, Vol. 1).
dence for Health Policy Discussion, WHO, Geneva, Murry CJL, Lopez AD. (1999). Epidemiology. 10: 594–605.
Paper No. 54 (revised February 2004). Murray CJL, Salomon JA, Mathers C. (2000). Bull World
Mathers CD, Ezzati M, Lopez AD, Murray CJL, Health Organ. 78(8): 981–994.
Rodgers AD. (2002). In: Murray CJL, Salomon J, Rose G. (2001). Int J Epidemiol. 30(3): 427–432.
Mathers CD, Lopez AD (ed.) Summary Measures Salomon JA, Murray CJL. (2002). In: Murray CJL,
of Population Health: Concepts, Ethics, Mea- Salomon JA, Mathers CD, Lopez AD (ed.) Summary
surement and Applications. WHO, Geneva, Measures of Population Health: Concepts, Ethics,
pp. 273–290. Measurement and Applications. WHO, Geneva,
Mathers C, Vos T, Lopez A, Salomon J, Ezzati M. (2001). pp. 487–500.
National Burden of Disease Studies: A Practical Ustun TB, Chatterji S, Villanueva M, Bendib L, Celik C,
Guide, 2nd ed. Global Program on Evidence for Sadana R, Valentine N, Ortiz J, Tandon A, Salomon J,
Health Policy, WHO, Geneva. Cao Y, Xie WJ, Özaltin E, Mathers C, Murray CJL.
Murray CJL. (1994). Bull World Health Organ. 72: (2000). WHO Multicountry survey study on health
429–445. and responsiveness 2000-2001. GPE discussion,
Murray CJL, Acharya AK. (1997). J Health Econ. 16: WHO, Geneva, Paper No. 37.
703–730. Weinstein MC, Stason WB. (1977). N Engl J Med. 296
Murray CJL, Lopez A. (1997). Lancet. 349: 1436–1442. (13): 716–721.
25 Integration of Quality of Life
and Survival for Comparative
Risk/Outcome Assessment in
Healthcare Industry
J.-D. Wang . J.-S. Hwang
1 Quantification of Burdens of Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
2 Method of Extrapolation to Life Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
3 Estimation of Loss of Quality-Adjusted Life Expectancy Because of

Premature Death Resulted from a Specific Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
4 Examples for Applications in Health Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
5 Extension to the Estimation of Financial Burden to the National

Health Insurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
6 Extension to Outcome Research in Clinical Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445

438 25 Integration of Quality of Life and Survival
Abstract: Survival and quality of life (QOL) are two key measurements for outcome
evaluation in health care services. While the former can be objectively determined, the latter
can only be obtained from subjective reports of the patients with specific health conditions.
Considering these two outcome functions together can derive a universal equation in
healthcare evaluation with quality-adjusted life year (QALY) as the common unit, when
the QOL is measured in utility or preference. Because many patient cohorts are only followed
for a limited period of time with a high censored rate or above 50%, we have developed a
Monte Carlo method that borrows information from age- and sex- matched general popula-
tion for extrapolation of survival function to life time. By doing so, we are able to simulta-
neously quantify the years of life expectancy loss for a specific health condition. When the
QOL function is measured by psychometric instruments, the resulted score-time can be used
on outcome evaluation on clinical medicine; when the QOL function is replaced by medical
cost reimbursed by the National Health Insurance, we can obtain the lifetime financial
burden for a specific health condition; both developments can be used for comparative
outcome assessment in health care services. Empirical examples are provided as a demon-
stration of feasibility.
The objective of this chapter is to introduce a novel method of integration between
survival and quality of life functions and illustrate how it can be directly applied for compara-
tive health risk and clinical outcome assessments. We shall begin with the original concept of
quantifying the burden of diseases, followed by deriving the equation for health, application
of such methods for health risk assessment in three different settings, extension of the QOL
measurement to psychometry and estimation of lifetime medical costs.
List of Abbreviations: AIDS, acquired immunodeficiency syndrome; DALY, disability-
adjusted life year; EQ-5D, euroQOL 5D; HCC, hepatocellular carcinoma; HIV, human immu-
nodeficiency virus; NHI, National Health Insurance; NIS, National Insurance System; QALE,
quality-adjusted life expectancy; QALM, quality-adjusted life month; QALY, quality-adjusted
life year; QAS, quality-adjusted survival; QAST, quality-adjusted survival time; QOL, quality of
life; RME, reasonable maximum exposure; SG, standard gamble; WHOQOL, World Health
Organization quality of life
1 Quantification of Burdens of Diseases
Beginning in the late 1960s, the integration of QOL and survival for quantification of healthy
life expectancy was first proposed for the evaluation of healthcare of chronic renal disease
(Klarman et al., 1968). It has been developed into a summary measure for population health
(Murray et al., 2002) in the later several decades with quality-adjusted life year (QALY) and/or
disability-adjusted life year (DALY) as the common unit (Ezzati et al., 2004) for international
comparison.
However, since the DALYapproach assumes a universal life expectancy and utility values for
physical disability only, which does not reflect the actual condition for each country or state, the
direct application of such calculations for health policy decision at country and/or company
level may not be feasible. Alternatively, we may re-consider the original question of health risk
assessment and quantify the changes or loss of life expectancy and QOL simultaneously for
different health conditions or diseases for comparison. While the life expectancy of the disease
may be obtained through the long term follow-up of a cohort of patients, the QOL function
Integration of Quality of Life and Survival 25 439
usually must be surveyed in a sample of patients with the disease of interest. Then, the life
expectancy for the patients can be multiplied with the overall mean of QOL to obtain a crude
estimate of quality-adjusted life expectancy (QALE).
However, because the QOL of patients actually fluctuates along with time after develop-
ment of the disease of interest, simply taking the overall average may not represent the
dynamic changes of such a time course, which will also affect the accuracy of the summary
QALE. To more accurately estimate the QALE for the disease x, one can collect the QOL data
from a cross sectional sample of patients to calculate the mean of QOL at each time point
t through smoothing method (Hwang et al., 1996). Then, the mean QOL function is multi-
plied with the survival function for each time point t, and the lifetime summation of these
values, or the total sum of area under the quality adjusted survival curve, is the QALE
of patients with disease x under the unit of QALY, if the measurements are taken yearly,
as shown on > Figure 25-1.
. Figure 25-1
Estimation of quality of life integrated with survival. The survival probability, mean QOL,
quality-adjusted survival of patients with the disease x, and the QALE (namely, the total sum of
shadowed area under the quality adjusted survival curve) (modified from Hwang et al. (1996))
ð
Or; QALE ¼ E ½Qol ðtjxÞS ðtjxÞdt ð1Þ
The same equation has also been proposed or verified by Glasziou et al. (1998) and Shen et al.
(1999) with a similar concept, though with somewhat distinctive approaches. In fact, the
equation can be regarded as a special condition of lifetime utility for the health condition x, or,
replaced the QOL function by a general utility function, as proposed by Freeman (1991):
ð
E½UðtjxÞ SðtjxÞdt ð2Þ
The calculation of this equation can be demonstrated with the survival function taken from
the typical life table of a specific disease with actual measurements of QOL taken from a cross
sectional survey, of which the means of QOL during each time period titiþ1 after diagnosis
are obtained, as shown on > Table 25-1 (modified from Wang (2002)).
. Table 25-1
Calculation of quality-adjusted survival based on life table and quality of life at time t
Interval Survival probability QOL(ti) QAST

t1–t2 S(t1) = 1.00 QOL(t1) QAST1
t2–t3 S(t2) QOL(t2) QAST2
ti–tiþ1 S(ti) QOL(ti) QASTi
ts1–ts S(ts1) QOL(ts1) QASTs1
ts–1 S(ts) QOL(ts) QASTs
Notation of a QAST that takes both survival function obtained from a typical life table and measurements of QOL
from a cross sectional sample with subjects of different durations-to-dates (modified from Wang (2002))
The QALE is the summation of all areas under the quality-adjusted survival time (QAST),
which can be expressed as the total summation of average survival probability adjusted by
average QOL, as follows:
X X
QALE ¼ ½Sðti Þ þ Sðtiþ1 Þ=2 ½Qolðti Þ þ Qolðtiþ1 Þ=2 ¼ QASTi
As an illustrative example, we took the survival function that was estimated by a cohort of
36,668 cases of breast cancer recruited from the National Cancer Registry of Taiwan during
1990–2000 and followed through 2004 (Chu et al., 2008). Suppose a surgeon took a consecu-
tive sample of 138 patients who were regularly followed at her clinic and measured their QOL
by standard gamble (SG) method, which were calculated to obtain the mean for each time
period, or years after diagnosis of breast cancer, as shown on > Table 25-2. Through simple
calculation of the area under each time periods and summed up, we shall obtain the quality-
adjusted survival time with a uniform unit of QALY. If we are able to extrapolate to lifetime,
then we shall obtain the QALE.
2 Method of Extrapolation to Life Time
Because many patient cohorts with specific diseases may not have been followed for a sufficient
long time, especially those with chronic diseases such as diabetes mellitus or breast cancer, we
often end up with data with a high censored rate and may be unable to obtain the lifetime
survival function; and the calculation or estimation under the above equation becomes
infeasible. Thus, we have developed a method to extrapolate the survival function of disease
x, when the follow-up period may not be long enough or with a high censored rate, i.e., over
50% (Hwang and Wang, 1999). The general concept is to assume that the disease x can produce
premature mortality (or excess mortality) which can be quantified from follow-up of the
patient cohort for a shorter period of time, say, the first 5–7 years for cancer. If the excess
. Table 25-2
Estimation of QAST (quality adjusted survival time) for breast cancer
Years after diagnosis Survival rates QOL (SG) QAST

0 1.0000 0.84 0.7781
1 0.9452 0.76 0.7028
2 0.8802 0.78 0.6857
3 0.8235 0.83 0.6631
4 0.7744 0.83 0.6257
5 0.7334 0.83 0.5876
6 0.6998 0.81 0.5443
7 0.6696 0.78 0.4995
8 0.6450 0.74 0.4725
9 0.6234 0.75 0.4551
10 0.6065 0.73 0.4384
11 0.5863 0.74 0.4367
12 0.5704 0.77 0.4326
13 0.5532 0.77 0.4220
14 0.5430 0.77 0.4139
15 0.5320 0.77 0.4042
16 0.5179 0.77 0.3941
17 0.5057 0.77 0.3846
18 0.4933 0.77 0.3748
19 0.4803 0.77 0.3646
20 0.4668 0.77 0.3541
21 0.4529 0.77 0.3432
22 0.4386 0.77 0.3326
23 0.4253 0.77 0.3220
24 0.4110 0.77 0.3109
25 0.3965 0.77 0.2996
26 0.3817 0.77 0.2883
27 0.3671 0.77 0.2765
28 0.3512 0.77 0.2646
29 0.3361 0.77 0.2532
30 0.3215 0.77 0.2476
Calculation of quality-adjusted survival for a cohort of breast cancer, of which the survival function was established
by following up 36,668 cases of breast cancer recruited from the National Cancer Registry during 1990–2004 and
the QOL estimated from a small sample (N = 138) through SG method
mortality appears to be a constant hazard compared with the general population without such a
disease during the first several years of follow-up, then we may borrow information from the
general population to extrapolate, which can be easily obtained from the life table of national
vital statistics. With the constant excess hazard assumption, we have mathematically prove
that it is a valid method (Fang et al., 2007b), which is also corroborated by several real examples
(Chu et al., 2008; Fang et al., 2007b; Ho et al., 2006a; Ho et al., 2006b; Ho et al., 2006).
Let us take another real example of quantifying the long term survival and loss due to
hepatocellular carcinoma (HCC), a prevalent cancer in Taiwan. We took the cohort data of
about 2,600 patients with HCC diagnosed in the National Taiwan University Hospital and
followed them for 5 years to estimate the survival function of HCC. A cross sectional survey
of 161 HCC patients with utility value of their QOL (Lee et al., 2007) provides expected value
or mean at each duration-to-date which can serve to adjust the survival curve. And the
area under the quality-adjusted survival curve is the QALE for HCC.
3 Estimation of Loss of Quality-Adjusted Life Expectancy

Because of Premature Death Resulted from a Specific
Disease
In many occasions, we are interested in estimating the lifetime loss of quantity of utility of
health related to the development of a specific disease that can cause premature death. Under
such circumstances, we may estimate the expected QALE assuming the same cohort without
the disease. In other words, we can simulate an age-, gender- matched reference population
with mortality rate taken from the national statistics to obtain the survival function and
assume their QOL utility as one. Then, to each patient with HCC, we may apply a Monte Carlo
method to simulate an age-, gender- matched person with the survival function (or hazard
function) of the general population from the national vital statistics and produce an average
survival curve of the reference population without HCC, of which the QOL value can be
assigned to be one. Then, the difference between these two QALE is the area between the
two quality-adjusted survival curves, or, 233.6 quality-adjusted life month (QALM), which
is the consequence of developing HCC, as shown in > Figure 25-2.
. Figure 25-2
Loss of utility due to a specific disease such as liver cancer. The difference (shadowed area) of
QALE between the cohort of liver cancer and age-, gender- matched reference population, which
represents the average utility loss of developing a case of liver cancer, or 233.6 QALM
4 Examples for Applications in Health Risk Assessment
The above estimation can be used in comparative health risk assessment. As there are different
definitions for risk, we adopt the quantifiable definition from BS8800, which stipulates that risk
can be quantified through multiplying the likelihood (or probability) of event with the conse-
quence of the event. In other words, we can compare different health risks for policy decision if each
one of them is quantified under the same metrics of loss of QASTwith QALYas the common unit.
One of our studies evaluated the potential health impact from pollution of underground water
by dumping of chlorinated solvents to the ground occurred in an electronics manufacturing
company. After measuring the concentrations of seven major pollutants from water samples of
43 local wells at downstream, we estimated that the likelihood of developing liver cancer from
underground water pollution of vinyl chloride, trichloroethylene, and tetrachloroethylene were
8.4 106, 1.4 104, and 1.9 104, respectively, based on cancer slopes and the estimated
RME (reasonable maximum exposure) obtained from measurements of water samples (Lee
et al., 2002). As the population at risk in the exposed community at the downstream
community were about 1,000 people, we estimated the potential health impact would be a
loss of 2, 32, and 44 QALM, accordingly. Similarly, we have estimated that the health impact
resulting from enforcement of helmet law for motorcycle riders in Taipei city is about 6,240
QALY per year (Tsauo et al., 1999). A third example is the estimation of utility gained from
different occupational health policies to protect the offspring of female lead workers (Chuang
et al., 2005).
5 Extension to the Estimation of Financial Burden to the

National Health Insurance
The method can be extended into calculating the direct medical cost of illness paid by the
National Health Insurance (NHI). Based on the data retrieved from the reimbursement data
file, one can calculate the average financial burden for disease x for each time point t. It can
be multiplied with the survival probability at each time point t and summed up to estimate
the lifetime cost for different diseases after considering the annual discount rate. And the total
lifetime cost of a disease x can be expressed as follows:
ð
E½CostðtjxÞ SðtjxÞ dt ð3Þ
with the QOL function at time t replaced by the cost function, denoted as Cost(t|x). We have
demonstrated the feasibility on the top 17 cancers in Taiwan (Chu et al., 2007), HIV/AIDS
(human immunodeficiency virus/acquired immunodeficiency syndrome) (Fang et al., 2007a),
thalasemia (Ho et al., 2006), etc. In fact, we have also demonstrated that the loss of utility due
to smoking includes at least the financial burden of smoking related diseases, impaired QOL,
and premature mortality or shorten of life expectancy (Chung et al., 2007).
6 Extension to Outcome Research in Clinical Medicine
The method can also be extended to the measurement of QOL under psychometry, with the
unit changed to score-time or score-year (Hwang and Wang, 2004). Unlike the measurement of
QOL under expected utility theory, there might be conditions that a patient would rather die
than live uncomfortably with the disease x. In other words, there might be health conditions
that are worse than death from patient’s subjective point of view. Thus, we must add another
term for the score-time saved of the deceased, and the equation becomes as follows:
ð ð
E½QolðtjxÞ SðtjxÞ dt þ d ½1 SðtjxÞ dt ð4Þ
In which a score is assigned to the QOL of the deceased for sensitivity analysis. The method
was demonstrated in a study comparing the quality-adjusted survival of patients with and
without bone marrow transplantation after chemotherapy for leukemia (Hsu et al., 2003). But
a score-time may not be directly linked to any particular meaning in life. Thus, we have tried to
quantify the monetary value that a worker might be willing to pay for a unit of score-time in a
. Figure 25-3
Use of quality of life measurement for two types of health policy decisions. The integration of
QOL and survival can be used in outcome research in healthcare industry: When the QOL is
measured in utility or preference values or units, such as QALY, they are useful for assessment of
cost-effectiveness analysis and efficient allocation of resources; When the QOL is measured in
psychometry, the score-time units can be applied in quantifying the clinical outcomes for
comparison across different health conditions and healthcare settings (modified from Wang
(2002))
study for the removal of physical pain resulting from permanently-disabling occupational
injuries with contingent valuation method (Ho et al., 2005). Namely, we have showed that
workers in Taiwan would be willing to pay about 65–70 US dollars for a painkilling pill with an
effect of lasting for 24 h.
In conclusion, the integration of survival with QOL measurement can be summed up for
estimation of the consequences of different health conditions or diseases with the unit of QALY,
which can be multiplied with the likelihood of the event in usual risk assessment to obtain the
expected health impact. When the medical cost can be estimated for the specific disease for each
time point (say, monthly or yearly) based on the reimbursement database of the NHI, we are able
to calculate the lifetime financial burden for a specific disease after summing up the lifetime
medical cost. The concept and method are useful for comparative risk/impact assessment in
public health for policy making in the allocation for national health services. Moreover, when
the QOL measurement is replaced by psychometry, it can also be applied on clinical medicine
for taking patients reported outcome into consideration, as summarized in > Figure 25-3
(modified from Wang (2002)). By doing so, preventive, therapeutic, rehabilitative, and
alternative healthcares can be evaluated under the same metric and with the same unit.
Summary Points
Utility measurements of quality of life across different durations-to-date can be integrated
with survival function to obtain the quality-adjusted life expectancy (QALE) with QALY
(quality-adjusted life year) as the common unit, and comparative health impact/risk
assessment can be conducted based on QALY.
Lifetime survival functions of most chronic diseases are usually unavailable because of
inadequate duration of follow-up. Assuming a constant excess mortality rate for the
specific disease, we can extrapolate the survival function by borrowing information from
an age-, gender- matched reference population from national vital statistics.
By comparing the QALE’s between the general population and subjects with specific health
condition x, we can obtain the lifetime utility loss due to condition x, then the utility
gained from prevention can be compared with diagnosis, treatment, and rehabilitation
under the same metrics.
When the quality of life is measured in psychometry, the above equation becomes score-
time for different domains and/or facets, which can be useful for outcome evaluation in
clinical medicine.
When the function of quality of life is replaced by medical cost spent for the health
condition x at different durations-to-date, then the lifetime financial burden of x can be
estimated.
Acknowledgements
I am most grateful to my respected colleagues, including Grace Kaiping Yao (Department of

Psychology, NTU), Jin-Tan Liu (Department of Economics, NTU), and all the faculty and
students of both College of Public Health and College of Medicine of the National Taiwan
University for their kind assistance and support in the development of the above research and
the National Health Research Institutes for funding the research (No. NHRI-EX95–9204PP).
References
Chu PC, Hwang JS, Wang JD, Chang YY. (2008). Ho JJ, Liu JT, Wang JD. (2005). Accident Anal Prev. 37:
J Formos Med Assoc. 107: 54–63. 537–548.
Chu PC, Wang JD, Hwang JS, Chang YY. (2008). Value Ho WL, Lin KH, Wang JD, Hwang JS, Chung CW, Lin
Health. 7: 1102–1109. DT, Jou ST, Lu MY, Chern JPS. (2006). Bone Mar-
Chuang HY, Chao KY, Wang JD. (2005). J Toxicol Envi- row Transplant. 37: 569–574.
ron Health. 68: 1485–1496. Hsu C, Wang JD, Hwang JS, Tien HF, Chang SM, Cheng
Chung CW, Wang JD, Yu CF, Yang MC. (2007). Tob AL, Chen YC, Tang JL. (2003). Qual Life Res. 12:
Control. 16: 394–399. 503–517.
Ezzati M, Lopez AD, Rodgers A, Murray CJL (ed.) Hwang JS, Tsauo JY, Wang JD. (1996). Stat Med. 15:
(2004). Comparative Quantification of Health 93–102.
Risks: Global and Regional Burden of Disease At- Hwang JS, Wang JD. (1999). Stat Med. 18: 1627–1640.
tributable to Selected Major Risk Factors. World Hwang JS, Wang JD. (2004). Qual Life Res. 13: 1–10.
Health Organization, Geneva. Klarman H, Francis J, Rosenthal G. (1968). Med Care. 6:
Fang CT, Chang YY, Hsu HM, Twu SJ, Chen KT, Chen 48–54.
MY, Huang LYL, Hwang JS, Wang JD. (2007a). Lee LJH, Chan CC, Chung CW, Ma YC, Wang GS, Wang
J Formos Med Assoc. 106: 631–640. JD. (2002). J Toxicol Environ Health. 65: 219–235.
Fang CT, Chang YY, Hsu HM, Twu SJ, Chen KT, Lin CC, Lee LJH, Chen CH, Yao G, Chung CW, Sheu JC, Lee PH,
Huang LYL, Chen MY, Hwang JS, Wang JD, Chuang Tsai YJ, Wang JD. (2007). J Surg Oncol. 95: 34–39.
CY. (2007b). QJM-An Int J Med. 100: 97–105. Murray CJL, Salmon JA, Mathers CD, Lopez AD (ed.)
Freeman AM III. (1991). The Measurements of Environ- (2002). Summary Measures of Population Health:
mental and Resource Values: Theory and Methods. Concepts, Ethics, Measurement and Applications.
Resources for the Future, Washington DC, World Health Organization, Geneva.
pp. 314–366. Shen LZ, Pulkstenis E, Hoseyni M. (1999). Stat Med. 18:
Glasziou PP, Cole BF, Gelber RD, Hilden J, Simes RJ. 1541–1554.
(1998). Stat Med. 17: 1215–1219. Tsauo JY, Hwang JS, Chiu WT, Wang JD. (1999). Acci-
Ho JJ, Hwang JS, Wang JD. (2006a). Accident Anal Prev. dent Anal Prev. 31: 253–263.
38: 961–998. Wang JD. (2002). Basic Principles and Practical Applica-
Ho JJ, Hwang JS, Wang JD. (2006b). Scand J Work tions in Epidemiological Research. World Scientific,
Environ Health. 32: 91–98. Singapore, pp. 147–153, 326.
26 Disability-Adjusted Life Years
in Occupational Injuries and
Accidents
M. Concha-Barrientos . J. Labbé Cid
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
2 Relevant Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
3 Methodological Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
4 Premature Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
5 Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
6 An Analysis of the Role of DALYs in Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456

448 26 Disability-Adjusted Life Years in Occupational Injuries and Accidents
Abstract: This paper provides estimates of Disability-Adjusted Life Years (DALYs) in

> occupational injuries and > occupational accidents. After a careful search, only four studies
were found. The numbers presented should not be compared due to substantially different
methods. However, some insight about the limitations of the calculation and characteristics of
the burden should be drawn. First, the magnitude is usually underestimated due to the lack of
mortality data. Second, males are the largest contributors accounting for at least four-fifths of
the burden. Third, falls and road traffic > injuries are the leading causes in both sexes. Fourth,
despite data restrictions, developing countries have the biggest share of the burden of
occupational injuries.
Disability-adjusted life years, give a unique perspective on workers health. This frequently
used and promoted metric should be a tool to obtain not only the attention of policy makers
about the importance of injuries in the workplace, but also as a resource to decrease this
preventable burden.
List of Abbreviations: ACHS, Asociación Chilena de Seguridad; AF, attributable fraction,
BIREME, Centro Latinoamericano y del Caribe de Información en Ciencias de la Salud; BoD,
burden of disease; DALY, disability-adjusted life years; EAP, economically active population;
GBD, > global burden of disease; ICD, international classification of diseases; ILO,
International Labor Organization; MEDLINE, biomedical database; RTI, road traffic injuries;
WHO, World Health Organization; YLD, years lived with disability; YLL, years of life lost
1 Introduction
Occupational injuries annually produce approximately 360.000 fatalities and 270 million
accidents around the world (Takala, 2002). However, occupational injuries capture limited
public attention and resources devoted to their prevention are lacking (ILO, 2003).
This report summarizes available information on the burden of workplace injuries using
Disability Adjusted-Life Years (DALYs). These provide a measure of injuries, which range from
minor to fatal and from temporary to permanent.
2 Relevant Literature
A systematic literature search was undertaken from 1993 onwards. Ovid Medline, OSH-ROM,
NIOSHTIC, BIREME and other occupational and safety databases were used. Key words
included: burden, DALY, injury, occupational, work-related AND mortality, morbidity, unin-
tentional, falls, road traffic, poisonings, burns, fires, and drowning.
The selection process consisted on: (1) reading the title and abstract, (2) reading the entire
text of selected articles; (3) disregarding articles without a focus on the theme of central
interest (4) making a manual search of the relevant citations; and (5) reading and analyzing
the definitive set. No quality criteria were used in the article selection. The initial search
produced 22 studies and was ultimately reduced to four.
3 Methodological Considerations
Three out of four studies are country specific; the fourth is The Global and Regional Burden
of Disease Attributable to Selected Major Risk Factors carries out by WHO in the year 2000
Disability-Adjusted Life Years in Occupational Injuries and Accidents 26 449
(Begg et al., 2007; Concha et al., 2003; Concha-Barrientos et al., 2005; Mathers et al., 2001).
Detailed data sources and methods used in DALYs calculation are documented elsewhere
(Ezzati et al., 2002; Mathers et al., 2003; Murray and Lopez, 1997). Particular characteristics of
these studies are presented.
All studies analyze subsets of unintentional injuries (Murray 1997; WHO 1992). These
include road traffic injuries (RTI), poisonings, falls, burns or fires, drowning and ‘‘others’’ such
as exposure to animate and inanimate mechanical forces (including firearms). Also included is
exposure to electric current, radiation, extreme ambient temperature, pressure, and to forces
of nature. Lastly, contact with heat and hot substances, and venomous plants and animals
(> Table 26‐1). Intentional injuries are included in both versions of the Australian burden
(Begg et al., 2007; Mathers et al., 2001).
In the absence of sufficiently reliable data, the global burden relies on mortality data found
in the literature. The selected data appeared the most sound in terms of register coverage and
quality, and the choices were validated by experts (Concha-Barrientos et al., 2005). Fatality
data was almost non-existent in developing countries. Mortality data was extrapolated from
country data to the region when available, and from a similar region when there were no data
in any of the countries of the region. Data limitations prevent the inclusion of deaths under
15 years and those resulting from commuting injuries. In the other studies, data is gathered
from country registries and surveillance systems (Begg et al., 2007; Concha et al., 2003;
Concha-Barrientos et al., 2005; Mathers et al., 2001).
As expected, population at risk varies in the selected studies. In the global and regional
burden population at risk is estimated based on the economically active population (EAP) of
. Table 26‐1
Features of Occupational Injuries and Accidents
1. An injury at work is the physical damage that results when a human body is subjected to
intolerable levels of energy. The energy causing an injury may be mechanical, radiant, thermal,
electrical, and chemical.
2. The injury definition correspond to acute events, it does not include conditions resulting from
continuous stress, such as carpal tunnel syndrome.
3. The most useful injury classification is the division according to whether or not they were
deliberately inflicted and by whom: Unintentional, Intentional, and Undetermined intent.
4. Unintentional and intentional injuries are considered preventable public health problems.
5. Injuries are listed in Chapter XIX (Injury, poisoning and certain other consequences of external
causes) and Chapter XX (External causes of morbidity and mortality) in the International
Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10).
6. Statistical sources of injuries reflect the requirements of national labor legislation and are of
limited coverage such as employees, insured persons, full-time workers.
7. The injury spectrum is a mapping of injury over time, starting with the host’s exposure to hazard,
followed by the event, through to the occurrence of the injury and finally the possible resultant
disability and or death.
8. Identification of high-risk occupations and economic sector are relevant for focusing prevention
and control and for setting priorities.
Key facts of occupational injuries including definition, classification, international coding, mapping of the injury
natural history, statistical sources and key prevention issues are presented are presented in the table
ICD-10 international classification of diseases, 10th version
15 years and older. EAP was divided into nine economic sectors and seven occupational
categories using data from country statistics. (Nelson et al., 2005). Different risk for injuries
explained the categorization of the EAP. In the Asociación Chilena de Seguridad (ACHS)
study, the population at risk consisted of workers affiliated to one of the three non-profit
insures companies that compensate the workforce from the events resulting from occupational
injuries and other hazards (Concha et al., 2003).
4 Premature Mortality
Years lost due to > premature mortality in each age-sex category are calculated from the
observed mean age at death in the age interval and the life expectancy figures at the exact ages
defining the age. A life expectancy at birth of 82.5 years in women and 80 years in men from
the standard life table (West level 26) is used in the Global and Regional Burden and in the
ACHS study. Estimated life expectancies based on Australian data is used in the burden of this
country; differences in life expectancy at birth by sex increase from 2.5 to 4.5 years for
Australians (Mathers et al., 2001).
5 Disability
Estimating years lived with a > disability (YLD) require data from incident cases, the average
duration of disability (measured in years) and its severity level (Mathers et al., 2003). All
studies define cases as those injuries severe enough to warrant medical attention but that do
not lead to death; thus, injuries treated outside of the medical system are not taking into
account. Definitions of injury categories in terms of ICD codes are presented in > Table 26‐2.
Definitions of injury > sequelae and corresponding ICD codes are presented in > Table 26‐3.
Years lived with disability are calculated using YLD to YLL ratios by age, sex and type of
injury in all studies except the ACHS study. The ratio of hospital episodes where ‘‘workplace’’
was the place where the injury took place to the total hospital episodes is used in the Australian
burden (Begg et al., 2007; Mathers et al., 2001). Incidence and duration from occupational
injuries is extracted from the databases of the insurer company in the Chilean study (Concha
et al., 2003). The databases included workers injuries who receive not only hospital care but
also primary care beyond first aid (Concha et al., 2003). > Table 26‐4 presents a comparison of
the weights for duration and severity for disabling injuries.
Finally, DALYs are estimated undiscounted and discounted at 3% in the four studies. Also,
they are estimated using age-weighting with the exception of the Australia burden.
6 An Analysis of the Role of DALYs in Injuries
Worldwide, more than 10 million years of healthy life or 0.45 DALYs per 1,000 exposed
workers were lost due to unintentional injuries in the workplace. This figure accounts for 8%
of the world burden. In Australia, injuries at work accounted for a much smaller proportion
of DALYs, even though the calculation included suicide and self-inflicted injuries (0.5% in
1996 and 2.3% in 2003). > Table 26‐5 summarizes the most important results of the selected
studies.
. Table 26‐2
Definition of injury categories at work in terms of ICD codes
Cause ICD revision Code

Road traffic accidents 9 E810-819, E826-829, E929.0
10
Poisonings 9 E850-869
10 X40-X49
Falls 9 E880-888
10 W00-W19
Fires 9 E890-899
10 X00-X09
Drowning 9 E910
10 W65-W74
Other unintentional 9 E800-E807, E820-E848,E870-E879, E900-E909, E911-E949
injuries 10 Rest of V, W20-W64, W75-W99, X10-X39, X50-X59, Y40-Y86,
Y88,Y89
Unintentional injuries 9 E800-949
10 V01-X59, Y40-Y86, Y88, Y89
Definition of injury categories are relevant to establish comparability across studies. The table presents injury
categories used in GBD studies. Codes from ICD-09 and ICD-10 are presented in order to estimate DALYs trends.
Adapted from WHO, 2000
DALY disability-adjusted life years; GBD global burden of disease; ICD-09 international classification of diseases,
ninth version; ICD-10 international classification of diseases, 10th version
. Table 26‐3
Definitions of injury sequela in terms of ICD codes
Injury sequela ICD-09 code ICD-10 code

Fractures
Skull 800–801 S02.0/1/7/9, T90.2
Face bones 802 S02.2/6/8
Vertebral 805 S12, S22.0/1, S32.0/7, T91.1
column
Rib or sternum 807 S22.2–9
Pelvis 808 S32.1–5/8, T91.2
Clavicle, 810–812 S42, S49.7
scapula or
humerus
Radius or ulna 813 S52, S59.7, T10, T92.1
Hand bones 814–817 S62, S69.7, T92.2
Femur 820–821 S72, S79.7
Patella, tibia or 822–823 S82.0–4, S82.7/9, S89.7, T12
fibula
. Table 26‐3 (continued)
Injury sequela ICD-09 code ICD-10 code

Ankle 824 S82.5–6/8
Foot bones 825–826 S92, S99.7
Injured spinal 806 and 952 S14, S24, S34, T06.0/1, T08, T91.3
cord
Dislocations
Shoulder, 831, 832, 835 S43, S73
elbow or hip
Other 830, 833–834, S03.0–3, S13, S23, S33, S53, S63.0/1, S83.1–3, S93.1–3, T03,
dislocation 836–839 T11.2, T13.2, T14.3, T92.3, T93.3
Sprains 840–848 S03.4/5, S16, S29.0, S39.0, S46, S56, S63.5–7, S66, S76,
S83.4/7, S86, S93.4/6, S96, T06.4, T11.5, T13.5, T14.6, T92.5,
T93.5
Intracranial 850–854 S06, T90.5
injury
Internal injuries 860–869 S25–S27, S35–S37, S39.6, T06.4, T91.4/5
Open wound 870,872–884, S01, S08, S11, S15, S21, S31, S41, S45, S51, S55, S61, S65,
890–894 S71, S75, S81, S85, S91, S95, T01, T11.1/4, T13.5, T14.6,
T90.1, T92.5, T93.5
Injury to eyes 871,95 S05, T90.4
Amputation
Thumb 885 S68.0
Finger 886 S68.1/2
Arm 887 S48, S58, S68.3–9, T05.0/2, T11.6
Toe 895 S98.1/2
Foot 896, 897.0–1 S98.0/3/4, T05.3
Leg 897.2–3 S78, S88, T05.4/6, T13.6
Crushing 925–929 S07, S17, S28, S38, S47, S57, S67, S77, S87, S97, T04, T14.7,
T92.6, T93.6
Burns
<20% 940–94,948.0–1 T31.0/1
20–60% 948.2–5 T331.2/5
>60% 948.6–9 T31.6/9
Injured nerves 951,953–957 S04, S44, S54, S64, S74, S84, S94, T06.2, T11.3, T13.3, T14.4
Poisoning 960–979, 980–989 T36–T65, T96–T97
ICD-09 and ICD-10 are currently used in the countries. Also, a change of classification from ICD-09 to ICD-10
occurred between GBD studies. In order to make comparisons between countries using either version of the
classification or across time, codes in both versions of the classification are listed in the table
GBD global burden of disease; ICD-09 international classification of diseases, ninth version; ICD-10 international
classification of diseases, 10th version
. Table 26-4
Duration and disability (severity) weights for injuries used in the Australian burden of disease
study and the global burden of disease study
Nature of injury Victoria BoD WHO, GBD

Spinal cord lesion
severity weight 0.725 ( ) Treated: 0.725
Untreated:
0.725
duration Lifelong ( ) Long-term
Burns to > 60% of body
surface
severity weight 0.255 Treated:0.441 Treated: 0.255
Untreated: Untreated:
0.469 0.255
duration Lifelong Short-term Long-term
Burns to 20–60% of body
surface
severity weight 0.255 Treated:0.441 Treated: 0.255
0.469 0.255
Fractured skull
severity weight 0.350 Treated: 0.431 Treated: 0.350
0.431 0.410
duration Lifelong (15% of incident Short-term Long-term
cases)
Fractured femur
0.372 0.272
duration Lifelong (5% of incident cases) Short-term Long-term
Nerve injuries
0.078 0.078
To estimate YLD, data of duration and severity of injury sequelae is required. Studies estimating both factors are
not usually conducted, and data from GBD is used instead. The table presents, using as reference the GBD study
and the Australian Burden of Disease, weight values for different durations and severities
BoD burden of disease; GBD global burden of disease; YLD years lived with disability; WHO World Health
Organization
. Table 26‐5
Summary of results of burden of occupational studies in DALYs
GBD – WHO Australia BoD Australia BoD Chile: ACHS study

Indicator 2002 2001 2007 2003
Deaths 132,000 77 NA 110
YLL 7,107,000 1,726 NA 3,965
YLD 6,018,000 1,302 NA 485
DALYs 13,125,000 3,029 51,966 44,50
DALYs/Exposed workers 0.5 NA NA 3.2
(per 1,000)
As percentage of total 8% 0.5% 2.0% NA
DALYs
Percent in Males 92% 82% 68.3% 94%
Ratio YLL/YLD 1.2 1.3 NA 8.2
Four studies of DALY calculation for injuries in the workplace were found. The GBD, the Australia BoD (both
versions) and the Chilean study correspond to a worldwide estimation, to a country estimation and to a subset of
country workers respectively. In spite of the methodological differences some issues emerged. First, males present
the greatest amount of years lost in every study. Second, as it is expected, developing countries (such as Chile)
present greater mortality than disability
NA not available; ACHS Asociación Chilena de Seguridad; BoD burden of disease; DALY disability-adjusted life years;
GBD global burden of disease; YLL years of life lost; YLD years lived with disability; WHO World Health Organization
The contribution of mortality to the total burden is slightly higher than disability.
Similarly in the GBD and Australia studies, YLL to YLD ratios were 1.2 and 1.3, respectively.
In contrast, the contribution of premature mortality in Chile is approximately 6–7 times
higher than in the other studies. This finding may be due to different injury severities, lack of
prevention in the enterprises and factors related to health services. The quality of ACHS
provided medical care, widespread networking and access to health service have considerably
reduced the factors pertaining to health services. In addition, research indicates that financial
status does not limit access to health services (Concha et al., 2003).
The number of deaths and the age at death cause a differential in injury burden by sex and
age. The burden for males is over 90% in the GBD and the ACHS study; it is less than 70% in
the year 2003 in Australia. The sex differences are mostly due to the larger number of
premature deaths in males that is related to the risky jobs that they perform. Different age
patterns are presented in the studies. For example, in the GBD study, the burden is concen-
trated in the 15–59 years age group while in Chile, it is clustered in the youngest and the oldest
age groups (15–29 years and 70–79 years) See > Figure 26‐1. The differences are partly
explained for different age grouping between studies.
Worldwide, falls were the leading cause of healthy life lost in both sexes, followed by road
traffic injuries (RTI). In Chile, the highest percentage of DALYs lost were due to injuries
produced by exposure to inanimate mechanical force, followed by RTI and falls. Overall, falls
and RTI are the leading causes of injuries and the burden in males was greater than females for
every cause (> Figure 26‐2).
In the GBD study, years of healthy life lost are clustered according to the level of
development. The less developed regions such as South East Asia, the Western Pacific Region
. Figure 26‐1
DALY rates (per 100,000) due to workplace injuries by sex and age-group. The ACHS study, 2000.
The graph compares DALYs of workplace injuries by sex and age group. DALY rates due to
occupational injuries are bigger in males than females in any age-group. The biggest rates are in
the elderly (70 years and older) in both sexes. Reprint with permission of the Asociación Chilena
de Seguridad; DALY disability-adjusted life years
. Figure 26‐2
Attributable Fractions of workplace injuries by external cause of injuries and sex (% DALYs from
each cause). This graph compares the percentage of DALYs attributable to different types of
unintentional injuries in the workplace across sexes. Falls are the main cause of years of life lost
in both sexes, followed by RTI. Adapted from WHO, 2002. DALY disability-adjusted life years; RTI
road traffic injuries; WHO World Health Organization
. Figure 26‐3
Attributable Fractions of workplace injuries risk factors by level of development of countries and
sex (% DALYs from each cause). The graph compares the AF of workplace injuries between sex
and external causes of unintentional injuries in the workplace using DALYs. Males lost more
DALYs due to injuries than females at any level of development of the country, corresponding
to the biggest lost to developing countries with low level of mortality. Adapted from WHO, 2002.
AF attributable fraction; Developed countries developed countries; DALY disability-adjusted life
years; HM Developing high mortality in developing countries; LM Developing low mortality in
developing countries; WHO World Health Organization
and Africa have the biggest rates of DALYs. On the other hand, DALYs are similar in females in
all levels of regional development but important gaps existed between sexes in a same region,
being the gap greater in the less developed region (> Figure 26‐3).
7 Conclusions
Variations in methods, assumptions, and data sources limited the comparability of the selected
studies. However, estimating DALYs for occupational injuries provides a comprehensive
assessment of the event in the working population compared to what is available using
mortality alone. Insight can be drawn for the studies in relation to information and injury
characteristics.
Summary Points
Few studies of the consequences of workplace injuries using DALYs are available in the
literature, denoting the low interest of researches in a new metric that has the advantage to
link health problems with resources.
The lack and inadequacy of data sources about occupational injuries make it difficult if not
impossible to estimate accurate burden specifically in developing countries. At least,
adequate mortality data is required to identify the magnitude of fatal injuries.
The contribution of workplace injuries to the burden of injuries in particular and to the
global burden of disease in general will not be recognized unless adequate registries and
epidemiological data are put in place.
Leading causes of injuries at work are preventable. Special attention should be given to
planning and implementing intervention programs. The ultimate aim should be the
development of policies and programs that decrease the overall impact of disability and
premature death.
References
Concha M, Salas J, Labbé MC, Giaconi J. (2003). C&T. Burden of Disease in 2002: data sources, methods
10: 13–23. and results. GPE Discussion Paper No. 54. World
Concha-Barrientos M, Nelson DI, Fingerhut M, Driscoll T, Health Organization, Geneva. Available at: http://
Leigh J. (2005). Am J Ind Med. 48: 470–481. www.who.int/evidence/bod.
Begg S, Vos T, Barker B, Stevenson C, Stanley L, Lopez A. Murray CJL, Lopez A. (1997). Lancet. 349: 1436–1442.
(2007). The burden of disease and injury in Nelson DI, Concha-Barrientos M, Driscoll T, Steenland K,
Australia 2003. Available at: http://www.aihw.gov. Fingerhut M, Prunett L, Pruss-Ustun A, Leigh J,
au/publications/index.cfm/title/10317. Corvalan C. (2005). Am J Ind Med. 48: 400–418.
Ezzati M, Lopez A, Rodgers A, Hoorn S, Murray C, The Takala J. (2002). Introductory Report: Decent Work –
Comparative Risk Assessment Collaborating Group. Safe Work. Paper presented at the 16th World Con-
(2002). Lancet. 360: 1342–1343. gress on Safety and Health, Vienna, May 27.
ILO. (2003). Safe Work: Thirteenth Session of the Joint World Health Organization. (1992). International Clas-
Committee on Occupational Health. ILO, Geneva. sification of Diseases and related health problems –
Available at: www.ilo.org/public/english/protection/ Tenth Revision (ICD 10).WHO, Geneva. Available
safework/health/session13/. at: http://www.who.int/classifications/icd/en/.
Mathers CD, Vos ET, Stevenson CE, Begg S. (2001). Bull World Health Organization. (2002). The world
World Health Organ. 79: 1–14. Health report 2002. Reducing risks, promoting
Mathers CD, Bernard C, Iburg KM, Inoue M, Ma Fat D, healthy life. Statistical Annex. Available at:
Shibuya K, Stein C, Tomijima N, Xu. (2003). Global http://www.who.int/
27 The Income-Associated
Burden of Disease in the
United States
P. Muennig . M. Gold . E. Lubetkin . H. Jia
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
1.1 The Importance of Income . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
1.2 Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
1.3 Datasets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
1.4 Regression Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
1.5 Life Expectancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
1.6 Qale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
1.7 YLL and QALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
2 Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
2.1 Impact on Individual LE and QALE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
2.2 Interpretations of Our Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
2.3 Policy Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
2.4 Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
2.5 Lessons for Burden of Disease Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
3 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471

460 27 The Income-Associated Burden of Disease in the United States
Abstract: In this chapter, we estimate and discuss the total burden of disease associated with
income in the United States. We calculate the relationships between income and life expectancy,
health-adjusted life expectancy, annual years of life lost (YLLs), and quality adjusted life years
(QALYs). We used the 2000 United States Medical Expenditure Panel Survey to derive quality
of life estimates by income and age, the 1990–1992 United States National Health Interview
Survey linked to National Death Index data through the end of 1995 to derive mortality risks
by income and by age, and 2000 United States mortality data from the National Center for
Health Statistics to derive current mortality estimates for the United States population by age-
group. The bottom 80% of adult income earners’ life expectancy is calculated as 4.3 years and
5.8 QALYs shorter relative to those in the top 20% of earnings. This translates into the loss of
11 million YLLs and 17.4 million QALYs each year. Compared with persons living above the
poverty threshold, those living below the poverty threshold live an average of 3.2 million fewer
QALYs per year – a difference of 8.5 QALYs per individual between age 18 and death. The
income-associated burden of disease appears to be a leading cause of morbidity and mortality
in the United States. Studies are needed to ascertain which policies might best mitigate
income-associated health effects.
List of Abbreviations: HR, hazard ratio; HRQL, health-related quality of life; MEPS, medical
expenditure panel survey; NDI, National Death Index; NHIS, National Health Interview
Survey; QALE, quality-adjusted life expectancy; QALY, quality-adjusted life year; YLL, years
of life lost
1 Introduction
This chapter expands upon a burden of disease analysis we conducted on the income gradient
seen in the United States general population (Muennig et al., 2005b). Here, we aim to present a
more comprehensive and accessible version of that work, while showing the utility of burden
of disease analysis for estimating the impact of the social determinants of health (Muennig and
Woolf, 2007). Burden of disease studies enable comparisons using a common metric of health
of the relative effects of different health-related problems on society. Burden of disease studies
have been used both in the United States and elsewhere as a policy tool to prioritize health
risks and interventions with which to treat them (Gold et al., 1996; Michaud et al., 2001).
Burden of disease studies that seek to capture both morbidity and mortality outcomes
typically rely on a measure such as the quality-adjusted life year (QALY). QALYs blend
information about survival with information about health-related quality of life (HRQL)
such that one QALY represents a year lived in perfect health. The inclusion of the EQ-5D in the
Medical Expenditure Panel Survey since the year 2000 has permitted the generation of HRQL
scores associated with any health state, thus opening the door to broad-based explorations of
social risk factors for disease, such as income, education, and race, as well as issues surround-
ing gender (Franks et al., 2006; Levin et al., 2007b; Muennig et al., 2005b, 2006; Muennig
and Woolf, 2007). This was previously only possible using indirect methods, such as corre-
spondence analysis and mapping techniques (Erickson et al., 1995; Franks et al., 2005;
Gold et al., 1998).
The Income-Associated Burden of Disease in the United States 27 461
1.1 The Importance of Income
The risk factors underlying the leading causes of death have been referred to as the ‘‘actual
causes’’ of death (McGinnis and Foege, 1993). However, these causes, which include tobacco
use, poor diet, physical inactivity, infectious disease exposure, and motor vehicle accidents are
in turn influenced by another risk factor – income (Adler and Ostrove, 1999). Income has been
proposed as one of the root (‘‘actual, actual’’ or ‘‘fundamental’’) causes of disease alongside
education (Krieger, 1994).
The cumulative effect of income-related exposures appears to be large; Roget et al. found
that the top 5% of income earners live about 25% longer than the bottom 5% (Rogot, 1992).
Some of this excess mortality is seen as a direct effect of income on health (Lynch et al., 1997;
Muennig, 2008a, b). For instance, having higher income means escaping high crime neighbor-
hoods, a higher quality job that offers health insurance, and the ability to afford safer housing
(Adler and Ostrove, 1999; Muennig et al., 2005a). But the pathway may operate in both
directions with poor health also influencing income (Smith, 1999). For instance, some people
who become ill lose their job as a result of their illness, and illness among the uninsured can
have a large impact on wealth. While income gradients can work in either direction, we define
the net effect of income on health as the ‘‘income gradient.’’
Income-related health effects span the range of earnings in a curvilinear dose-response
relationship that levels off for the top 20% of income earners (Sorlie et al., 1995; Wolfson et al.,
1993). To capture the full burden of disease, we thus compare persons relatively unaffected by
the income gradient (the top 20% or so) with the remainder of the population. We have
chosen to examine the income gradient broadly, controlling only for age. In doing so, our
intent is to provide a fuller picture of the extent to which level of income itself influences
health in the U.S.
> Figure 27-1 plots the change in life expectancy by income using data from the National
Longitudinal Mortality Survey (Sorlie et al., 1995). For ease of presentation, these data
were converted from 1980 dollars to 2007 dollars using the Consumer Price Index, risk
ratios were converted to life expectancy values using a risk calculator (developed by author
PM and available on his website: http://www.pceo.org/learn.html), and data points were
smoothed by interpolation. Here, we see that the curve tapers off as income increases.
The income gradient in life expectancy is roughly equal to the area under the curve in
> Figure 27-1.
Regardless, at present, most policy in the United States seems to be pointed more
toward assisting the very poor than toward social insurance or other redistributive programs
(Haveman, 1995; Smeeding et al., 2000). We thus include a sub-analysis of this population in
order to estimate the potential impact of poverty reduction programs. We explore the burden
of disease using a traditional outcome measure (mortality), scores on a comprehensive
summary measure of population health (EQ-5D), and the combination of the two, the
QALY (Cohen, 2003).
1.2 Approach
Outcomes associated with a family income below the poverty threshold are referred to here
as ‘‘poverty associated.’’ For instance, poverty associated deaths are the total deaths for those
at risk beyond what would be expected had their risk been equal to the reference group
. Figure 27-1
Change in life expectancy in years plotted against household income (Data from Sorlie et al.,
1995 adjusted to 2007 United States Dollars. The data used to generate values between $63,000
and $126,000 have been interpolated based on three data points.)
(i.e., those in the top 20% of income). Outcomes associated with family income less than
approximately 80% of all households (<80%) are referred to here as ‘‘income associated’’ (i.e.,
the increased deaths seen in these households when compared to the reference group). We
examine the annual numbers of poverty-associated deaths and income related deaths, the
annual number of years of life lost (YLL) to death, the annual QALYs lost, and changes in
quality adjusted life expectancy (QALE) for all groups under study.
The calculation of QALYs and QALE is achieved using HRQL scores, which provide an
assessment of the value people place on the morbidity associated with illness. These scores
assume a value between 0 (death) and 1 (perfect health). Thus a year of life lived at an HRQL
of 0.8 is equal to 0.8 QALYs, and a simplified estimation of QALE is the product of life
expectancy and the mean HRQL for a particular group.
1.3 Datasets
We obtained HRQL values from the 2000 MEPS, and mortality ratios from 1990 to 1992
National Health Interview Surveys linked to the National Death Index through the end of 1995
(‘‘National Center for Health Statistics. National Death Index. Available online at: http://www.
cdc.gov/nchs/r&d/ndi/ndi.htm. Accessed 10/1/07.; NCHS). This is the most recent source of
nationally representative data that links household income to death certificate data that is
publicly available.
The MEPS is representative of the non-institutionalized population in the United
States. This annual survey includes detailed socio-demographic, utilization, and health status
information. The household income data are recoded into discrete categories relating
household income to the poverty threshold (<100%, 100–124%, 125–199%, 200–399%,
and 400%). For instance, those with household earnings 400% of the poverty threshold or
greater have over four times the earnings of those living at the federal poverty threshold.
In 2000 the MEPS included the EQ-5D, a QALY-compatible and preference-based instru-
ment, for persons over age 18 (Coons et al., 2000; Rabin et al., 2001). The EQ-5D assesses
5 dimensions of health: (1) mobility, (2) self-care, (3) ability to perform usual activities,
(4) pain or discomfort, and (5) anxiety or depression. Each dimension is scaled as ‘‘no
problem,’’ ‘‘some problem,’’ or ‘‘extreme problem.’’ EQ-5D index scores were obtained from
a representative sub-sample of 13,646 persons excluding proxy respondents. Responses to
these five items in the MEPS were linked to United States general population weights
for each of these health states (Cohen, 2003; Coons et al., 2000). The EQ-5D also contains
a visual analog scale, however, this was not included in our HRQL calculations. All
scores were generated using recently published United States preference weights (Shaw
et al., 2005).
The NHIS contains socio-demographic variables similar to MEPS. The 1990–1992 NHIS
data have been linked to National Death Index (NDI) data through the end of 1995, which
allows mortality analyses to be conducted on subjects in the original sample. The NHIS linked
data sample 256,900 persons, 11,214 of whom died by the end of 1995.
1.4 Regression Analyses
Analyses were conducted using SAS version 8.2 (SAS Institute Inc., Gary, NC) and SUDAAN
version 8.0.1 (Research Triangle Institute, Research Triangle Park, NC) a statistical package
that allows adjustment for the complex sampling design used in the MEPS and NHIS. All
calculations were weighted and adjusted for the multi-stage cluster design of the data to
achieve population parameter estimates.
Spline regressions were used to derive smoothed age-specific EQ-5D scores for persons
18 and older. Spline regression uses a piecewise polynomial function that fits data locally. This
method corrects for bias, particularly at boundary regions when independent variables are
skewed or have outliers (Simonoff, 1996). We generated HRQL values for persons 18–24,
25–44, 45–64, 65–74, and 75+. Intervals were chosen to maximize sample sizes for the hazards
analysis, and are age-adjusted within each age interval. Regression was also used to extrapolate
EQ-5D index scores for persons under 18. These age 0–17 scores only were used in secondary
analyses to provide an estimate of QALE at birth.
Cox proportional hazard survival models were used to generate the hazard ratios (HR) for
the poverty associated (vs. not) and income related (vs. not) analyses using the same intervals
generated for HRQL. Each analysis was adjusted for age and age squared. For life expectancy
calculations, we calculated the risk of mortality for each income group under study relative to
the mean age-specific mortality rates in the United States. These relative comparisons allow for
estimation of life expectancy for the general population rather than the non-institutionalized
population and allow for estimation of year 2000 (rather than 1990–1995) life expectancy.
We calculated relative risk by dividing age-specific rates for the lower income group (< line
or <80%) of household income by the higher income group in each analysis ( line or 80%
of household income).
1.5 Life Expectancy
Abridged life tables were generated for the general United States population for the year
2000 using age intervals of 5 years (or less) to age 90 and over. They were populated with
year 2000 mortality data obtained from the National Center for Health Statistics (Minino
et al., 2002). Life tables were constructed using a hypothetical cohort of 100,000 individuals
exposed to a risk of death over each age interval. For instance, if the risk of death between age
0 and 1 is 0.00693, then 693 persons will die over this interval, leaving 100,000–693 = 99,307
persons to be exposed to the risk of death in the next age interval. To calculate life expectancy
at birth, the number of person years in each age interval are then summed across intervals and
divided by the number of persons at the start of the first interval (100,000).
In the base-case analysis, life expectancy and QALE were calculated at age 18 because EQ-
5D index scores were not available for younger persons. To provide familiar reference points
for life expectancy and to provide estimates for the entire population, we also conducted a
secondary analysis examining life expectancy at birth using mean population infant mortality
rates (via the NCHS separation factor) to estimate deaths in the first interval (Anderson,
1999). Infant mortality was corrected for births occurring the year before the recorded deaths.
1.6 Qale
To calculate QALE, the number of person years in each interval is multiplied by the mean
HRQL score for that interval. As with life expectancy calculations, these health-adjusted
person years are summed over all age intervals and divided by the 100,000 persons at the
start of the first interval. Further details pertaining to the general construction of our life tables
have been published elsewhere (Anderson, 1999; Muennig, 2002).
Income and poverty related deaths were calculated as follows:
ððRx Rx Px þ Px 1ÞPx Þ=ðRx Px þ 1 Px ÞD

1 Px
where R = the hazard ratio for at risk persons relative to the reference group at age x, P = the
proportion of persons in the at risk group at age x, and D is the national number of deaths in
2000. Total deaths were obtained from death certificate data (Minino et al., 2002). In 2000,
there were 2,352,074 deaths, of which 0.01% were excluded because no information on
subjects’ age was available.
1.7 YLL and QALYs
Total YLLs were calculated as:

X
5
Dx Lx
x¼1
where x = the age interval, DX is the number of poverty associated or income related deaths
within age interval x and LX is the life expectancy for persons above the two lines at the mid-
point of age interval x. LX was obtained from life table values for the reference group (e.g., for
the < line group, life expectancy at age x was used from the line group) to reflect the full
potential life lost.
The total QALYs are equal to the difference in HRQL between the groups under study plus
the HRQL-adjusted years of future life lost when a premature death occurs. Total QALYs were
calculated as:
X
x
ððHAx HBx Þ Px þ Yx HBx Þ
1
where, HAx is the HRQL score for persons above either of the two cut-off points ( line
or 80% household income) in age interval x, HBx is the HRQL score for persons below
either of the two income thresholds in age interval x, PBx is the number of persons below either
of the two cut-off points in age interval x, and Yx is the YLL in age interval x.
2 Findings
> Table 27-1 shows the demographic profile of persons by income group in the MEPS sample.
As expected, adults living in poverty, and with <80% in household earnings are more likely to
be Hispanic, African American or Native American.
The income disadvantages faced by these groups translate into poorer health outcomes as
well. > Table 27-2 shows annual age-specific income related and poverty-associated deaths
alongside YLL and QALYs. In the year 2000, there were 361,253 additional deaths and almost
11 million years of life lost to adults in the bottom 80% of earnings relative to those in the top
income category. There were also 17.4 million excess income related QALYs lost among adults.
In our analysis of QALYs based on an extrapolation of HRQL to birth, this number increases
to roughly 20 million QALYs (data not shown). Poverty-associated values totaled 1.9 million
additional YLL and 3.2 million additional QALYs among adults relative to those living above
the poverty threshold.
Many earlier burden of disease analyses are based on a global HR (rather than age-specific
HRs). While this method is known to overstate burden of disease findings, it is useful to present
the results this way for ease of comparison with older studies. The technique produces 861,000
income related deaths and 93,000 poverty-related deaths. Since virtually all of these older studies
present results in terms of deaths, we do not present the results for excess QALYs lost here.
> Table 27-3 shows the lifelong effects of living above or below the relevant cut-off
points for the average individual. Life expectancy was 59.7 for the average 18-year-old, 54.9
for poor 18-year-olds, 60.5 for 18-year-olds living above the poverty threshold, 58.8 for persons
in the bottom 80% of household income, and 63.2 for those in the top 20% of household
income. This amounts to a 5.6-year difference in adult life expectancy between those above and
below the poverty threshold, and a 4.3-year difference for those above and below the 80%
income line. (Differences between numbers in the table and text are due to rounding.)
2.1 Impact on Individual LE and QALE
We first present results based on our rough analysis of findings extrapolated to children
not included in the present sample. Life expectancy at birth for persons living below the
poverty threshold was roughly 71.7 years compared with 77.8 years for those living above
. Table 27-1
Basic demographic characteristics of the MEPS sample
Variable Total <T T <80% 80%

Age distribution
0–17 26.3 38.3 24.7 30.4 19.8
18–44 39.3 35.5 39.8 38.9 40.0
45–64 22.4 15.1 23.3 16.7 31.4
65+ 12.0 11.0 12.2 14.0 8.89
Race and ethnicity
White, non-Hispanic 71.2 49.3 74.0 63.2 84.0
Black, non-Hispanic 12.6 23.7 11.1 16.1 6.89
Asian, non-Hispanic 3.39 2.64 3.49 3.30 3.55
Native American, non-Hispanic 0.64 1.85 0.49 0.88 0.27
Hispanics 12.2 22.5 10.9 16.5 5.25
Sex
Male 48.8 43.2 49.5 47.3 51.3
Female 51.2 56.8 50.5 52.7 48.7
Marital status
Married 53.6 32.0 56.0 46.5 63.7
Widowed 6.94 11.9 6.39 9.53 3.27
Divorced 10.6 14.0 10.2 11.9 8.72
Separated 1.59 3.98 1.33 2.24 0.67
Never married 27.3 38.1 26.1 29.9 23.6
Metropolitan Statistical Area (MSA)
Non-MSA 18.5 20.4 18.3 21.2 14.2
MSA 81.5 79.6 81.7 78.8 85.8
Insurance
Any private 72.6 26.9 78.6 60.8 91.6
Public only 15.7 51.6 11.0 23.4 3.35
Uninsured 11.7 21.5 10.4 15.8 5.02
Self-reported health (18+ only)
Fair or poor 15.0 32.4 13.1 20.0 7.85
Numbers are in percentages within the column (e.g., 48.8% male + 52.2% female = 100%). T poverty threshold,
<80% reflects the bottom 80% of households with respect to income, and 80% reflects the top 20% of
households with respect to income ($80,040 in 2000)
the poverty threshold in 2000. Life expectancy for the <80% group was 76 years, and was
80.3 years for the 80% group. The mean life expectancy for all United States households
was 76.8 years. It should be noted that even if the wealthiest 20% of U.S. residents were a nation,
that nation would not rank among G7 nations in terms of life expectancy (WHO, 2002).
Persons living below the poverty threshold live 6.1 years and 9.6 QALYs less than those
above the poverty threshold. Those in the top 20% of household income live an average of
. Table 27-2
Income related (top 20% relative to bottom 80%) and poverty associated (below the poverty
threshold relative to those above it) hazard ratio (HR), deaths, years of life lost, and health
adjusted life years (QALYs)
HR Deaths YLLs QALYs

<Poverty threshold
18–24 1.56 (1.05, 2.31) 1,527 104,348 311,447
25–44 2.51 (2.11, 3.00) 17,013 792,741 1,326,379
45–64 2.08 (1.82, 2.39) 32,785 921,410 1,231,009
65–74 1.33 (1.15, 1.53) 12,589 202,280 304,959
>75 0.94 (0.85, 1.04) 9,605 107,629 23,228
Total 1.34 (1.25, 1.43) 54,308 1,913,148 3,150,566
<80% income
18–24 1.41 (0.88, 2.27) 5,094 361,583 1,149,863
25–44 2.38 (1.96, 2.94) 70,283 3,460,112 6,376,129
45–64 1.96 (1.72, 2.22) 171,824 5,188,837 7,077,095
65–74 1.45 (1.22, 1.69) 114,052 1,942,506 2,328,160
>75 1.00 (0.88, 1.22) 0 0 493,200
Total 1.59 (1.47, 1.69) 361,253 10,953,038 17,424,446
. Table 27-3
Income-related changes in life expectancy and quality-adjusted life expectancy in the United
States, 2000
Mean <T >T <80% 80%

Life expectancy (years)
Age 18 59.7 54.9 60.5 58.8 63.2
Alla 76.8 71.7 77.8 76.0 80.3
Quality-adjusted life expectancy (QALYs)
Age 18 51.1 43.7 52.2 49.8 55.6
Alla 67.2 59.1 68.6 66.0 72.3
a
Estimates based on HRQL scores and hazard ratios derived by regression
T poverty threshold, <80% reflects the bottom 80% of households with respect to income, and 80% reflects the
top 20% of households with respect to income ($80,040 in 2000)
approximately 4.3 years and 6.4 QALYs longer from birth than those with family incomes in
the bottom 80% of households.
Our analysis of 18-year-olds through death is much more certain, since all of the subjects
were within range of our available data. The average 18-year-old in poverty lived 8.5 QALYs
less than the average 18-year-old above the poverty threshold in 2000, and the average adult in
a household below the 80% earnings threshold lived 5.8 fewer QALYs relative to adults in the
top 20% of households.
2.2 Interpretations of Our Findings
There is a good deal of debate surrounding the source of morbidity and mortality differences
between the richest Americans and all others (Marmot and Wilkinson, 2001). This debate
mostly surrounds the extent to which psychobiological factors are more important than
resource-related factors like access to health care or healthy foods. Psychosocial factors include
social support networks, job control, and perceived social status (Adler et al., 2000; Cohen
et al., 1999; Markowe et al., 1985; McEwen, 1998; Muennig, 2007; Muennig et al., 2007).
Another important consideration surrounds whether the income gradient in health in
mostly explained by forward (income producing health) or reverse (health producing income)
causality. Prospective, incidence-based data show that reverse causality (illness causing lower
income) plays a smaller role in the threefold to fourfold higher risk of morbidity and mortality
(Lynch et al., 1997; Muennig, 2008b; Mulatu and Schooler, 2002). Nonetheless, reverse
causality is significant, and should be considered in policymaking decisions (Smith, 1999).
The policy implications of viewing causality of income gradients as ‘‘forward’’ or ‘‘reverse’’ are
substantial as we discuss below.
2.3 Policy Considerations
The policy implications for forward causality within the income gradient are very different
from the policy implications of reverse causality (Deaton, 2002; Muennig, 2008b; Smith,
1999). If most of the excess loss of healthy life in the income gradient is due to the effects of
low income on health, the policy priority might include redistributive programs, such as early
education interventions, earned income tax credits, or social insurance. Such programs help to
reduce income inequalities, improve earnings, and reduce financial blows associated with job
loss, thereby addressing downstream health risks such as exposure to crime or lack of health
insurance.
On the other hand, if the negative effect of poor health on income explains most of the
gradient, then society’s resources should be diverted to preventive health interventions
and disability insurance. Job loss due to health affects total household income in part because
disability insurance is often either lacking or inadequate to sustain a family’s income (Smith,
1999). This is especially true in single income households because there is no second adult
available to compensate for the hours of work lost. While disability insurance programs would
do less to improve the general health of the population, they would reduce the income
gradient in health.
Another dichotomy within the income gradient surrounds the extent to which material
deprivations (e.g., poor health arising from the inability to pay for medical care) or psy-
chological factors (e.g., the stress arising from the inability to pay for medical care) are
more important determinants of health in the forward causality pathway (Deaton, 2002;
Macleod et al., 2005; Marmot and Wilkinson, 2001; McEwen and Mirsky, 2002). However,
regardless of which is the dominant determinant of health, the policy implications may not
differ much.
There are many reasons to believe that policies intended to address material deprivations
will also reduce psychosocial stressors. First, low income populations report that the inability
to purchase needed goods and services, such as healthcare, are one the strongest sources of
psychosocial stress in their lives (Taylor, 2002). Second, a comprehensive review of education
interventions, including a randomized controlled trial, found that effective education inter-
ventions produce reductions in social pathologies (a good proxy measure for psychological
stressors), such as child abuse and crime (H. Levin et al., 2007a). Third, a natural experiment
of income redistribution found that social pathologies in poor communities fall greatly
with large cash transfers (Costello et al., 2003). This conclusion is also supported by the
Gary Income Maintenance Experiment, which found that high-risk women that were rando-
mized to an experimental alternative negative income tax group had higher birth weight
neonates than control mothers (Kehrer and Wolin, 1979). Finally, Korean children that were
essentially randomly assigned to adoptive families with higher income have better health
outcomes and are more likely to go to college than if they were assigned to lower income
parents (Sacerdote, 2004). In fact, housing vouchers, public transportation improvements,
health insurance, daycare, and earned income tax credits on face value seem to be good
options whether one is focused on reducing psychological stress or addressing material
deprivations.
While those studies examine more proximal or less complete health outcomes than is
practical in burden of disease analysis, such interventions may also be expected to produce
improvements in HRQL and reductions in mortality. One recent study, for instance, found
that small class sizes, an early education intervention, may produce greater health benefits than
any medical intervention evaluated to date (Muennig and Woolf, 2007).
2.4 Limitations
We used age as the only covariate in this analysis, reasoning that other variables such as
education, occupation, and risk factors are all in the poverty-health pathway. For instance,
low-income persons are also more likely to have dangerous jobs. Controlling for occupation
would thus erase a large proportion of this effect. However, some covariates exert both positive
and negative effects outside of the poverty pathway. For instance, immigrants and native-born
Hispanics are both more likely to be poor and more likely to be healthy than native-born non-
Hispanic whites (Muennig and Fahs, 2002; Sorlie et al., 1995). Presumably, the health of these
groups has nothing to do with their low income. African-Americans, on the other hand, are
both more likely to have lower incomes and to be sick. Most of this effect is due to lower socio-
economic status (Williams, 1999) but there is evidence that discrimination may play a role
that is independent of socio-economic status (Williams, 1999).
Second, our data measure income at a single point in time and follow subjects over a short
interval for mortality. It is therefore difficult to gauge the extent to which the cumulative
versus transient effects of deprivation affect our results. There is some work that health is
adversely affected by sustained exposure to economic hardship. Lynch et al. (1997) examined
prospective data on healthy persons over a 25-year period. Relative to those without economic
hardship measured over three time intervals, those with sustained economic hardship have a
5.9-fold increased risk of difficulties performing basic physical tasks while those with one or
two episodes of hardship have a risk of 1.6 and 3.5 respectively. While our findings are
consistent with a dose response of health to income, we do not know for how long different
members of the study population were exposed to their income levels. . .
Third, while our outcomes were projected into 2005, we calculated age-specific risk ratios
for mortality using mortality data from 1990 to 1992 through the end of 1995. Mortality rates
change over time and the relative risk of mortality by income appears to have increased
recently in the U.S. (thus producing an underestimate of the burden of disease) (Blane et al.,
1990; Kunst et al., 2004).
Fourth, because of differences in the conceptualization of health and the method by which
health states are valued, HRQL measures vary in their ability to capture morbidity. The EQ-5D
displays reasonable reliability and validity when compared to other health-related quality of
life measures, however, the measure has known ceiling effects stemming from the limited
number of severity levels (Johnson and Coons, 1998). Thus, this tool may produce an
underestimate of all cause morbidity. Finally, the data sources we used to calculate annual
data (total deaths, the YLL, and the QALY) only include the non-institutionalized United
States population. Those in institutions (primarily nursing homes and prisons) are poorer and
sicker on average than those not in institutions. (In addition, persons who responded by proxy
would be expected to be sicker and have lower scores.)
2.5 Lessons for Burden of Disease Analyses
This study used nationally representative datasets to calculate age-specific U.S. HRs
associated with income gradients. The incorporation of a preference-based QALY-compatible
measure (the EQ-5D included in the 2000 MEPS) allowed us to represent the disease burden
associated with income more fully than has been previously possible. (Coons et al., 2000;
Gold et al., 1996).
Because we used age-specific estimates to calculate the burden of disease we were able to
increase the accuracy of the estimates of numbers of Americans affected by the income
gradient. Total deaths are typically calculated using adjusted hazard ratios. An adjusted hazard
ratio will correctly estimate deaths provided the total number of deaths is relatively consistent
in each age interval or the ratio does not change with age. Since most deaths occur late in life,
and the risk of death due to most factors diminishes with age (possibly due to the survivor
effect), traditional methods tend to overestimate deaths. Using this traditional approach, over
a third (861,000) of all deaths are attributable to income differences. However, when age-
specific ratios are used, this number drops to 361,000. Of the 2.4 million registered deaths in
the year 2000, 361,000 (15%) were income related and 54,000 (2.3%) were poverty associated
as we have defined them in this study. We await improved age-group adjusted estimates of
other causes of death; with those downwardly revised estimates, however, we find that
the income-associated deaths greatly exceed those due to obesity. Moreover, the income-
associated burden of disease measured in QALYs using the same techniques approaches
threefold that of obesity (Muennig et al., 2006).
3 Summary
In the United States, poor adults suffered 1.9 million YLL, lost 3.2 million QALYs, and lived 5.6
fewer years relative to adults living above the poverty threshold. These numbers grow
substantially when estimates for poor children are included. However, even if the morbidity
and mortality experience of the poorest persons were erased, it would account for a relatively
small proportion of the income-associated burden of disease in the United States. Thus, most
of the loss of health and longevity in the U.S. arises among the middle classes.
Persons in the top 20% of households by earnings enjoy substantially longer lives and
experience considerably less morbidity than the bottom 80%. They live 4.3 years and 6.4
QALYs longer than the remainder of the population. This amounts to an annual difference of
nearly 11 million years of prematurely lost life or 17.4 million QALYs. Nonetheless, even if the
wealthiest 20% of U.S. residents were a nation, that nation would not rank among G7 nations
in terms of life expectancy (WHO, 2002).
Further studies are needed to examine the extent to which this large-scale loss of life might
be ameliorated through interventions (educational and fiscal), such as those currently under-
way in Europe and Australia (Acheson, 2002).
Summary Points
For accurate stratification of social health risks, burden of disease analysis can and should
address larger social risk factors such as income, health insurance, and education.
Differences in income appear to be the largest risk factor for poor health and lower life
expectancy among those studied via burden of disease analysis.
Few other social risk factors have been studied, and may pose greater health threats than
income differences.
A review of the literature suggests that:
Low-income appears to cause poor health outcomes and reduces life expectancy.
Poor health also leads to lower income.
The association between income and health works through multiple pathways.
Differences in income predict a greater loss of health and longevity for the poorest
Americans than other income groups.
A larger net loss of health and life expectancy occurs across the middle class than across
those living below the poverty line because there are far more middle class Americans than
poor Americans.
Even if only the richest 20% of Americans were counted, life expectancy in the United
States would still be below that of Japan, Singapore, and most European countries.
This burden of disease analysis suggests that there is a need for improved social programs,
such as earned income tax credit, disability insurance, and education reform.
References
Acheson D. (2002). Independent Inquiry into Inequalities Cohen S, Doyle WJ, Skoner DP. (1999). Psychosom Med.
in Health Report. The Stationary Office, London, p. 61(2): 175–180.
164. Coons SJ, Rao S, Keininger DL, Hays RD. (2000). Phar-
Adler NE, Epel ES, Castellazzo G, Ickovics JR. (2000). macoeconomics. 17(1): 13–35.
Health Psychol. 19(6): 586–592. Costello EJ, Compton SN, Keeler G, Angold A. (2003).
Adler NE, Ostrove JM. (1999). Ann N Y Acad Sci. 896: JAMA. 290(15): 2023–2029.
3–15. Deaton A. (2002). Health Aff (Millwood). 21(2):
Anderson R. (1999). Vital Health Stat. 2(129): 1–35. 13–30.
Blane D, Smith GD, Bartley M. (1990). Br Med J. 301 Erickson P, Wilson R, Shannon I. (1995). Years of
(6749): 429–432. Healthy Life. Statistical Notes. Centers for Disease
Cohen SB. (2003). Med Care. 41: 1115–1121. Control and Prevention, Washington, DC.
Franks P, Muennig P, Gold M. (2005). BMC Health Serv Muennig P, Fahs MC. (2002). Prev Med. 35(3): 225–231.
Res. 5(1): 23. Muennig P, Franks P, Gold M. (2005a). Am J Prev Med.
Franks P, Muennig P, Lubetkin E, Jia H. (2006). Soc Sci 28(1): 59–64.
Med. 62(10): 2469–2478. Muennig P, Franks P, Jia H, Lubetkin E, Gold MR.
Gold M, Siegel J, Russell L, Weinstein M. (1996). Cost- (2005b). Soc Sci Med. 61(9): 2018–2026.
Effectiveness in Health and Medicine. Oxford Uni- Muennig P, Lubetkin E, Jia H, Franks P. (2006). Am J
versity Press, New York. Public Health. 96(9): 1662–1668.
Gold MR, Franks P, McCoy KI, Fryback DG. (1998). Med Muennig P, Sohler N, Mahato B. (2007). Prev Med. 45
Care. 36(6): 778–792. (1): 35–40.
Haveman R. (1995). Reducing Poverty While Increasing Muennig P, Woolf SH. (2007). Am J Public Health. 97
Employment: A Primer on Alternative Stategies, and (11): 2020–2027.
a Blueprint. Organization for Economic Coopera- Mulatu MS, Schooler C. (2002). J Health Soc Behav. 43
tion and Development, Paris. (1): 22–41.
Johnson JA, Coons SJ. (1998). Qual Life Res. 7: 155–166. National Center for Health Statistics. National Death
Kehrer BH, Wolin CM. (1979). J Hum Resour. 14(4): Index. Available online at: http://www.cdc.gov/
434–462. nchs/r&d/ndi/ndi.htm. Accessed 10/1/07.
Krieger N. (1994). Soc Sci Med. 39(7): 887–903. NCHS. National Center for Health Statistics. National
Kunst AE, Bos V, Lahelma E, Bartley M, Lissau I, Health Interview Survey. Available online at: http://
Regidor E, et al. (2005) Int J. Epidemiol. 34(2): www.cdc.gov/nchs. Accessed 10/1/05.
295–305. Rabin R, de Charro F. (2001). Ann Med. 33: 337–343.
Levin H, Belfield C, Muennig P, Rouse C. (2007a). The Rogot E. (1992). A Mortality Study of 1.3 Million Per-
Price We Pay: Economic and Social Consequences of sons by Demographic, Social, and Economic Fac-
Inadequate Education. Brookings Institution Press, tors: 1979–85 Follow-Up. National Institutes of
Washington, DC. Health, Bethesda, MD.
Levin HM, Belfield C, Muennig P, Rouse C. (2007b). Sacerdote B. (2004). What Happens When We Randomly
Econ Educ Rev. 26: 700–709. Assign Children to Families?. NBER Working Paper
Lynch JW, Kaplan GA, Shema SJ. (1997). N Engl J Med. No. 10894.
337(26): 1889–1895. Shaw JW, Johnson JA, Coons SJ. (2005). Med Care. 43(3):
Macleod J, Davey Smith G, Metcalfe C, Hart C. Soc Sci 203–220.
Med. 2005. Simonoff J. (1996). Smoothing Methods in Statistics.
Markowe HL, Marmot MG, Shipley MJ, Bulpitt CJ, Springer-Verlag, New York.
Meade TW, Stirling Y, et al. (1985). Br Med J (Clin Smeeding, Timothy M, Phillips, Katherin Ross and
Res Ed). 291(6505): 1312–1314. O’Connor, Michael A, The EITC: Expectation,
Marmot M, Wilkinson RG. (2001). Br Med J. 322: Knowledge, Use, and Economic and Social Mobility.
1233–1236. (April 2000). Center for Policy Research Working
McEwen BS. (1998). N Engl J Med. 338(3): 171–179. Paper No. 13. Available at SSRN: http://ssrn.com/
McEwen BS, Mirsky AE. (2002). Eur Heart J. 23(22): abstract=186690 or DOI: 10.2139/ssrn.186690.
1727–1728. Smith JP. (1999). J Econ Perspect. 13: 145–166.
McGinnis JM, Foege WH. (1993). JAMA. 270(18): Sorlie PD, Backlund E, Keller JB. (1995). Am J Public
2207–2212. Health. 85(7): 949–956.
Michaud CM, Murray CJ, Bloom BR. (2001). JAMA. Taylor H. (2002). Poor People and African-Americans
285(5): 535–539. Suffer the Most Stress from the Hassles of Daily
Minino A, Arias E, KD K, Murphy S, Smith B. (2002). Living. (Accessed February 17, 2005). The Harris
Natl Vital Stat Rep. 50(15): 1–120. Poll (p. 5): Harris Interactive.
Muennig P. (2002). Designing and Conducting Cost- WHO. (2002). World Health Report 2002. World Health
Effectiveness Analyses in Medicine and Health Organization, Geneva.
Care. Jossey-Bass, San Francisco. Williams DR. (1999). Ann N Y Acad Sci. 896: 173–188.
Muennig P. (2007). Teach Coll Rec. 14606: 1–17. Wolfson M, Rowe G, Gentleman JF, Tomiak M. (1993).
Muennig P. (2008a). JAMA. 299(6), 633; author reply J Gerontol. 48(4): S167–S179.
633–634.
Muennig P. (2008b). J Health Care Poor Underserved. 19
(2): 574–579.
28 Financial Burdens and
Disability-Adjusted Life Years
in Los Angeles County
G. F. Kominski . P. A. Simon . A. Y. Ho . J. E. Fielding
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
2 Calculation of Years of Life Lost (YLLs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
3 Calculation of Years Lived with Disability (YLDs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
4 Calculation of DALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476

4.1 Rate Calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
5 Distribution of DALYs in Los Angeles County . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
6 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482

474 28 Financial Burdens and Disability-Adjusted Life Years in Los Angeles County
Abstract: This chapter assesses the burden of disease and injury in the Los Angeles County
population using disability-adjusted life years (DALYs), a composite measure of premature
mortality and disability that equates to years of healthy life lost. DALYs were calculated for 105
health conditions, and aggregated groups of conditions, in the Los Angeles County population
in 2005. Years of life lost (YLLs) were calculated using 2005 county mortality statistics and
published life tables. Years lived with disability (YLDs) were derived from age- and gender-
specific disease incidence and disability data published in the Global Burden of Disease Study.
DALYs produce a substantially different ranking of disease and injury burden than did
mortality rates alone. The leading five causes of DALYs among males in the county are
ischemic heart disease, alcohol dependence, homicide/other violence, diabetes, and depres-
sion. Among females, the leading five causes are Alzheimer’s disease/other dementias, ischemic
heart disease, alcohol dependence, diabetes, and depression. Differences in disease burden are
also observed by race/ethnicity. The > age-adjusted rates of DALYs for all health conditions
combined was highest in African-Americans, followed by whites, Latinos, and Asians/Pacific
Islanders. DALYs are a useful tool for assessing population health and burden of disease at the
local level, and produce results that are notably difference from those based on mortality rates.
The combined economic impact of the top 15 causes of DALYs produced an estimated $28.92
billion loss to the Los Angeles economy in 2005.
List of Abbreviations: > COPD, chronic obstructive pulmonary disease; DALYs, disability
adjusted life years; EME, emerging market economies; > GBD, global burden of disease;
> ICD-9, International Classification of Diseases, 9th Edition; > ICD-10, International
Classification of Diseases, 10th Edition; > NIH, National Institutes of Health; YLDs, years
lived with disability; YLLs, years of life lost
1 Introduction
Efforts to assess disease and injury burden have been hampered by the lack of a single measure
of burden that accounts for both morbidity and mortality. To address this limitation at the
international level, the disability-adjusted life years (DALYs) measure was developed more
than a decade ago to assess global patterns of disease and injury burden and to project future
trends (Murray and Lopez, 1996; World Bank, 1993). DALYs combine the impacts of prema-
ture mortality and disability associated with various health conditions; one > DALYequates to
1 year of healthy life lost. They have been used to measure disease burden in both developed
and developing countries (Abdalla et al., 2007; Gan et al., 2007; Gwatkin et al., 1999; Sinha
et al., 2007; Lopez et al., 2006). In the United States, DALYs have been used to assess whether
funding decisions by the National Institutes of Health (NIH) correspond to the burden of
disease within the U.S. population (Gross et al., 1999).
This chapter uses DALYs to assess the burden of disease and injury in a large urban
population and compares the results to those of more traditional measures of disease burden
(i.e., crude mortality and premature mortality), and updates a previously published study
we conducted (Kominski et al., 2002). We discuss the methods for assigning DALYs, as well as
the potential benefits and limitations of using the DALYs methodology at the local health
department level for assessing and prioritizing population health needs. In addition, we
provide an estimate of the financial impact of the leading causes of burden of disease based
on the estimated economic value of DALYs.
Financial Burdens and Disability-Adjusted Life Years in Los Angeles County 28 475
DALYs measure population-level disease burden based on mortality and disability rates.
They are the sum of the number of years of life lost (YLLs) to premature mortality plus the
number of years lived with disability (YLDs), adjusted for the level of disability. We calculated
DALYs for 105 disease and injury categories defined in Murray and Lopez (1996) for the
Los Angeles County population in 2005. Using the crosswalk provided in Lopez and Murray
(2006), we converted the ICD-10 codes of the 2005 Los Angeles County death records into
ICD-9 codes. This conversion enabled us to replicate the methods described in Murray and
Lopez (1996) and make our findings comparable to those published elsewhere.
2 Calculation of Years of Life Lost (YLLs)
All deaths reported in 2005 among persons residing in Los Angeles County were eligible for
inclusion in the analysis. A total of 59,803 death certificate-based records were grouped by
underlying cause of death into 105 disease and injury categories.
Standard life tables for males and females from Murray and Lopez (1996) (indicating
remaining life expectancy at each year of age) were then used to calculate YLLs. These tables
are based partially on the maximum life expectancy observed for women and partially on ideal
life expectancies for males based on models of the true biological male/female difference in life
expectancy, controlling for other risk factors (Murray and Acharya, 1997). For women, the
standard life tables use the maximum life expectancy observed internationally, i.e., 82.5 years
for Japanese women. For men, the standard life expectancy is 80.0 years. Use of Los Angeles
County population specific life expectancies would not have changed the relative rankings of
conditions in our study but would have increased slightly the overall burden of disease and
injury measured for the county population, because of lower life expectancy among younger
age groups in the county.
YLLs were calculated for each disease and injury category as the difference between life
expectancy and age at death in months, summed across the total county population and by
gender and race/ethnicity (i.e., white, African American, Latino, and Asian/Pacific Islander).
We stratified our analyses according to race/ethnicity to examine potential disparities in
disease burden.
3 Calculation of Years Lived with Disability (YLDs)
Direct calculation of YLDs requires data on disease and injury incidence, the frequency of
associated disabilities, and the average duration and severity of the disabilities. In Murray
and Lopez (1996), data on disease and disability incidence and duration were obtained or
estimated through an exhaustive review of the published and unpublished literature and input
from experts in epidemiology. The severity of disabilities was quantified using disability
weights, ranging from zero (perfect health) to one (death). A panel of health care providers
from around the world participated in formal exercises using two different person trade-off
protocols to determine disability weights associated with various conditions. For example,
treated angina pectoris has a disability weight of 0.095 for all ages, whereas untreated unipolar
major depression has a weight of 0.600 for all ages.
Given the relative lack of disease incidence and disability data for the Los Angeles County
population, we used YLD-to-YLL ratios and > YLD rates reported in the GBD Study for
Established Market Economy (EME) countries to estimate YLDs in the county population.
Updated age- and gender-specific YLD-to-YLL ratios and YLD rates for each disease and
injury category were obtained from the Harvard University School of Public Health Burden of
Disease Unit and incorporated into the analysis.
YLDs for each age/gender stratum in the county population were estimated in one of two
ways: (1) if the EME YLD-to-YLL ratio was stable (defined as <10 in Murray and Lopez
(1996)), this ratio was multiplied by the county’s YLLs to determine the county’s YLDs; or
(2) if the EME YLD-to-YLL ratio was unstable because of low mortality (defined as 10 in
Murray and Lopez (1996), the EME YLD rate was used to determine the county’s YLDs by
applying the rate to the county population number. Then the products were summed across
strata to obtain totals for each disease and injury category.
4 Calculation of DALYs
Before summing the YLLs and YLDs within each disease category, we applied the same age-
weighting and > discounting factors used in Murray and Lopez (1996). > Age-weighting is
applied to adjust for the widely held perception (at least in many developing nations) that a year
of healthy-life has greater social value during early adulthood than during earlier or later life.
Discounting accounts for the perception that a current year is worth more than a future year of
healthy life, and is widely used in studies of the cost-effectiveness of health services and inter-
ventions (Gold et al., 1996). We applied the same age-weighting function and discounting factor
(3% per year) used in Murray and Lopez (1996). We then examined the sensitivity of our results
to remove of both age-weighting and discounting, and found no substantial differences in the
findings.
4.1 Rate Calculations
Rates per 1,000 population were calculated for YLLs, YLDs, and DALYs by gender and race/
ethnicity using 2005 county population projections from the 2000 census. Rates were age-
adjusted to the 1990 United States population.
5 Distribution of DALYs in Los Angeles County

> Table 28‐1 shows the 15 leading causes of disease and injury burden in the county popula-
tion based on measures of crude mortality, premature mortality measured by YLLs, and
DALYs. Although ischemic heart disease leads the list for all three measures, there was
considerable variation in the rank order of the other conditions. For example, alcohol
dependence is second on the DALYs list but is the 33rd and 48th leading cause of YLLs and
mortality, respectively. Similarly, depression is among the leading causes of DALYs but does
not appear among the top 15 causes of either crude mortality or YLLs. Conversely, pneumonia
is the seventh leading cause of mortality, but is the 15th leading cause of YLLs and the 27th
leading cause of DALYs.
. Table 28‐1
Leading causes of crude mortality, YLLs, and DALYs, Los Angeles county, 2005
Crude mortality YLLs DALYs

Rank Cause Deaths Rank Cause Years Rank Cause Years
1 Ischemic heart 14,846 1 Ischemic 72,155 1 Ischemic heart 79,281
disease heart disease disease
2 Stroke 3,905 2 Homicide/ 31,250 2 Alcohol 65,198
other violence dependence
3 Lung cancer 3,663 3 Lung cancer 24,630 3 Diabetes 53,364
4 COPD 2,890 4 Motor vehicle 21,086 4 Alzheimer’s/ 52,463
crashes other dementias
5 Alzheimer’s/ 2,530 5 Stroke 19,771 5 Depression 47,698
other dementias
6 Diabetes 2,361 6 Diabetes 16,883 6 Homicide/other 40,069
violence
7 Pneumonia 2,340 7 Breast cancer 13,668 7 Osteoarthritis 39,931
8 Hypertension 1,882 8 COPD 13,350 8 Motor vehicle 30,691
crashes
9 Colon cancer 1,716 9 Cirrhosis 13,284 9 Stroke 30,642
10 Breast cancer 1,396 10 Suicide 13,104 10 COPD 28,766
11 Pancreas cancer 1,107 11 Colon cancer 12,550 11 Poisoning 26,773
12 Homicide/other 1,094 12 Poisoning 10,907 12 Lung cancer 26,747
violence
13 Lymphomas 1,080 13 Hypertension 10,297 13 Endocrine/ 20,564
metabolic
diseases
14 Cirrhosis 1,067 14 Inflammatory 9,599 14 Drug overdose/ 18,666
heart disease other
intoxications
15 Inflammatory 973 15 Pneumonia 9,025 15 Cirrhosis 17,587
heart disease
This table compares the 15 leading causes of crude morality, years of life lost, and disability-adjusted life years
(DALYs) in Los Angeles County in 2005, and illustrates the importance of using DALYs to identify conditions that
result in substantial combined years of life lost and years lived with morbidity. COPD chronic obstructive
pulmonary disease; DALYs disability-adjusted life years; YLLs years of life lost
According to > Table 28‐1, the total DALYs lost in Los Angeles County in 2005 as a result
of the 15 leading causes of mortality and morbidity is 578,441. If we assume that the economic
value of a DALY is worth $50,000, a commonly used willingness-to-pay threshold in economic
evaluations of health interventions, then the economic loss resulting from these top 15 causes
of DALYs is an estimated $28.92 billion dollars, or about 6.3% of Los Angeles County’s total
economic output (Kyser et al., 2008).
The ten leading causes of DALYs by gender are shown in > Table 28‐2. Ischemic heart
disease leads the list among males, while Alzheimer’s disease/other dementias lead the list
among females. Homicide/other violence, poisoning, and motor vehicle crashes accounted for
. Table 28‐2
Comparison of leading causes of DALYs by gender, Los Angeles county, 2005
Male Female
Cause Percent Cause Percent
1 Ischemic heart disease 9.6 Alzheimer’s disease/other 8.7
dementias
2 Alcohol dependence 7.2 Ischemic heart disease 7.1
3 Homicide/other violence 7.0 Alcohol dependence 6.6
4 Diabetes 5.0 Diabetes 6.5
5 Depression 4.7 Depression 5.6
6 Poisoning 4.6 Osteoarthritis 4.9
7 Motor vehicle crashes 4.1 Stroke 3.8
8 Osteoarthritis 3.8 Breast cancer 3.7
9 Alzheimer’s disease/other 3.0 COPD 3.2
dementias
10 COPD 3.0 Lung cancer 2.9
Total 52.0 53.0
This table compares the ten leading causes of DALYs by gender in Los Angeles County in 2005, and shows
important differences. COPD chronic obstructive pulmonary disease; DALYs disability-adjusted life years
a much higher percentage of DALYs in males than females. Stroke and breast cancer accounted
for a higher percentage of DALYs in females than males. Alcohol dependence, diabetes,
depression, chronic obstructive pulmonary disease, and osteoarthritis are leading causes of
DALYs in both gender groups.
Substantial variation in the DALYs rankings are observed by race/ethnicity, as shown in
> Table 28‐3. For example, while ischemic heart disease is the leading cause of DALYs in whites
and African Americans, homicide/other violence is the second leading cause of DALYs among
African Americans, while alcohol dependence and depression are leading causes of DALYs
among both Latinos and Asians/Pacific Islanders. Endocrine/metabolic diseases are among the
top ten leading causes of DALYs among African Americans, but not among the leading causes
in other racial/ethnic groups.
For all conditions combined, the age-adjusted rate of DALYs is higher in males (110.2 per
1,000) than females (88.3 per 1,000), as shown in > Table 28‐4. This difference is attributable
almost totally to a 64% higher rate of YLLs in males (58.1 per 1,000) than females (35.4 per
1,000), because there is essentially no difference in age-adjusted YLDs by gender. The rate of
DALYs also varies substantially by race/ethnicity and is highest in African Americans (171.2
per 1,000), followed by whites (102.9 per 1,000), Latinos (94.1 per 1,000), and Asians/Pacific
Islanders (78.2 per 1,000).
6 Discussion
This study uses DALYs to assess the burden of disease and injury in the United States at a local
level. The findings suggest that DALYs produce a substantially different ranking of disease and
. Table 28‐3
Comparison of leading causes of DALYs by race/ethnicity, Los Angeles County, 2005
Asian/Pacific Islander African American Latino White

Cause Percent Cause Percent Cause Percent Casuse Percent
1 Alcohol dependence 8.4 Ischemic heart disease 9.2 Alcohol dependence 9.5 Ischemic heart disease 11.1
2 Ischemic heart disease 6.9 Homicide/other violence 8.8 Depression 6.1 Alzheimer’s/other 9.4
dementias
3 Depression 6.2 Diabetes 7.9 Homicide/other violence 6.1 COPD 5.0
4 Osteoarthritis 5.9 Alzheimer’s/other 4.2 Diabetes 5.5 Alcohol dependence 4.9
dementias
5 Diabetes 5.2 Alcohol dependence 4.2 Ischemic heart disease 4.9 Diabetes 4.7
6 Alzheimer’s/other 4.4 Stroke 3.9 Osteoarthritis 4.8 Lung cancer 4.2
dementias
7 Stroke 4.3 Endocrine/metabolic 3.9 Motor vehicle crashes 4.4 Osteoarthritis 3.9
diseases
8 Lung cancer 2.9 COPD 3.7 Alzheimer’s/other dementias 3.2 Depression 3.9
9 COPD 2.8 Poisoning 3.2 Stroke 2.6 Poisoning 3.7
10 Motor vehicle crashes 2.4 Lung cancer 3.0 Drug overdose/other 2.6 Stroke 3.3
intoxications
Financial Burdens and Disability-Adjusted Life Years in Los Angeles County
Total 49.4 52.0 49.7 54.1

American Indians/Alaska Natives were not included in this analysis because of insufficient numbers. This table compares the ten leading causes of DALYs by race/ethnicity in Los
Angeles County in 2005, and show important variation across categories in the rank order and composition of DALYs. COPD chronic obstructive pulmonary disease; DALYs disability-
adjusted life years
28
479
. Table 28‐4
Age-adjusted rates per 1,000 population of YLLs, YLDs, and DALYs, by gender and race/ethnicity,
Los Angeles County, 2005
Variable YLLs YLDs DALYs

Gender
Male 58.1 52.1 110.2
Female 35.4 52.8 88.3
Race/ethnicity
African American 89.1 82.1 171.2
Asian/Pacific Islander 28.1 50.1 78.2
Latino 42.3 51.7 94.1
White 45.7 57.2 102.9
American Indians/Alaska Natives were not included in this analysis because of insufficient numbers. This table
shows the age-adjusted rates per 1,000 population of YLLs, YLDs, and DALYs, by gender and by race/ethnicity.
Rates are age-adjusted to the 1990 United States population distribution. DALYs disability-adjusted life years; YLDs
years lived with disability; YLLs years of life lost
injury burden than do mortality rates alone. For example, alcohol dependence, depression,
and osteoarthritis impose a substantial burden in the Los Angeles County population not
reflected in county mortality statistics. Our findings highlight the impact of homicide/other
violence as a leading cause of both YLLs and DALYs among males in the county, and also
highlight the importance of ischemic heart disease and diabetes in all population groups. The
results further document the considerable disparities in disease burden across population
groups in the county. Age-adjusted DALYs per 1,000 population are more than twice as high
in the African-American population compared to the Asian/Pacific Islander population,
indicating a substantial disparity in burden of disease within Los Angeles.
Although DALYs represents a potential advance in population health assessment because
they addresses the impacts of disease and injury on both the quantity and quality of life, it is
important to note that the measure has been the subject of some debate (Murray and Lopez,
1997; Sayers and Fliedner, 1997). For example, the use of age weighting and discounting has
been criticized by some researchers (Anand and Hanson, 1997). To address this concern, we
conducted our analyses with and without the age-weighting and discounting adjustments and
found only minimal differences. Others have questioned the validity and universality of the
disability weights because of the value judgments inherent in the process and the fact that
the determination of weights in Murray and Lopez (1996) was done exclusively by health care
providers (Arnesen and Nord, 1999; James and Foster, 1999). A study by Usten et al. (1999)
examined variation in disability rankings across 14 countries and several different informant
groups, including persons with disabilities and found significant variation in disability rank-
ings by country and informant group, although the rankings for all groups combined was
nearly identical to Murray and Lopez (1996).
Our analysis is limited because the county YLD estimates are based on gender- and age-
specific YLD/YLL ratios and YLD rates for a broad geographic area (including the United States,
Canada, Japan, Western Europe, and Australia) rather than data for the county population. If the
actual ratios and rates in the county population are significantly different then those used in our
analysis, the YLDs and DALYs reported here may be overstated or understated for specific health
conditions. For example, we believe that > YLL rates may vary substantially across ethnic groups
within the United States and Los Angeles County, but our results do not reflect these potential
differences. Efforts by state and local health departments to use DALYs to assess disease burden
should incorporate these data as well as state and local data where available.
Because our analysis is based on mutually exclusive categories of disease and injury, we
could not assess the impact of interactions between disease states. Furthermore, because DALYs
focus on health outcomes coded using the International Classification of Diseases, they do not
measure attributable risk (Evans and Stoddart, 1990). For example, an estimated 40% of all
deaths in the United States in 2000 were attributable to smoking, poor diet or physical
inactivity, and alcohol consumption (Mokdad et al., 2004). Although DALYs are not exposure
specific, these health risks are important to consider in identifying and prioritizing opportu-
nities for prevention. For example, chronic obstructive pulmonary disease and lung cancer are
the ninth and tenth leading causes of DALYs among women in Los Angeles County, but when
combined they represent the sixth leading cause of DALYs, further highlighting the importance
of developing effective interventions to reduce smoking among women in the county.
We conclude that DALYs are important for informing decisions on public health priorities,
recognizing that information on disease burden must be combined with other inputs in the
priority-setting process. For example, information on the preventable fraction and cost-
effectiveness of available interventions are also important to consider. Furthermore, the
burden of disease identified in our analysis does not fall solely on the health care delivery
system. There are also significant impacts on families, employers, schools, social service
programs, and the criminal justice system as well. Our previous findings have played a key
role in the Los Angeles County Department of Public Health’s efforts to inform and, in some
cases, persuade policymakers and community constituencies of the disproportionate health
impacts of violence and chronic non-infectious diseases in the county population (Kominski
et al., 2002). Those results were helpful in bridging the divide between those in public health
and those who provide mental health and drug and alcohol treatment and prevention services.
In disseminating the findings in local community meetings, the use of ‘‘years of healthy life
lost’’ is the most understandable conceptualization of the DALYs measure and an extremely
compelling construct among both professional and lay audiences.
Our previous study was also used to support several successful requests for external
funding, including a physical activity promotion campaign funded by the Centers for Disease
Control and Prevention and a community-based nutrition intervention supported by the
California Department of Health Services (2005). In addition, the results were used to lobby
successfully for a portion of the Master Tobacco Settlement funds to be reserved for chronic
disease prevention programs.
In summary, DALYs represent a new tool for improving the capacity of local health depart-
ments and other health agencies to assess and prioritize population health needs. To increase
the validity of the measure at the local and regional levels, efforts will be needed to refine the
YLD calculations by incorporating local estimates of disease incidence and applying disability
weights that are specific to the United States population and important subpopulations.
Summary Points
DALYs produce a substantially different ranking of disease and injury burden than do
mortality rates alone. Alcohol dependence, depression, and osteoarthritis represent a
substantial disease burden in the Los Angeles County population not reflected in county
mortality statistics.
For all conditions combined, the age-adjusted rate of DALYs is higher in males (110.2 per
1,000) than females (88.3 per 1,000). This difference is attributable almost totally to a 64%
higher rate of YLLs in males (58.1 per 1,000) than females (35.4 per 1,000), because there is
essentially no difference in age-adjusted YLDs by gender.
The rate of DALYs also varies substantially by race/ethnicity and is highest in African
Americans (171.2 per 1,000), followed by whites (102.9 per 1,000), Latinos (94.1 per
1,000), and Asians/Pacific Islanders (78.2 per 1,000).
DALYs are important for informing decisions on public health priorities, recognizing that
information on disease burden must be combined with other inputs in the priority-setting
process. Information on the preventable fraction and cost-effectiveness of available inter-
ventions are also important to consider.
DALYs have played a key role in the Los Angeles County Department of Public Health’s
efforts to inform and, in some cases, persuade policymakers and community constitu-
encies of the disproportionate health impacts of violence and chronic non-infectious
diseases in the county population.
DALYs represent a new tool for improving the capacity of local health departments and
other health agencies to assess and prioritize population health needs.
References
Abdalla SI, Malik EM, Ali KM. (2007). Malar J. 6: 97. Gwatkin DR, Guillot M, Heuveline P. (1999). Lancet.
Anand S, Hanson K. (1997). J Health Econ. 16: 354: 586–589.
685–702. James KC, Foster SD. (1999). Lancet. 354: 87–88.
Arnesen T, Nord E. (1999). British Med J. 319: Kominski GF, Simon PA, Ho A, Luck J, Lim YW, Fielding
1423–1425. JE. (2002). Pubic Health Rep. 117: 185–191.
California Department of Health Services. (2005). Data Kyser J, Sidhu ND, Martinez EJ, Hynek CF. (2008). 2008–
Statistical Master File 2005. Modified by Los Angeles 2009 Economic Forecast and Industry Outlook for
County Department of Health Services, Office of California and Southern California. Los Angeles
Health Assessment and Epidemiology, Data Collec- County Economic Development Corporation, Los
tion and Analysis Unit. Angeles, CA.
Evans RG, Stoddart GL. (1990). Soc Sci Med. 31: Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray
1347–1363. CJL (eds.). (2006). Global Burden of Disease and
Gan Q, Smith KR, Hammond SK, Hu TW. (2007). Tob Risk Factors. Oxford University Press, New York.
Control. 16: 417–422. Mokdad AH, Marks JS, Stroup DF, Gerberding JL.
Gold MR, Siegel JE, Russell LB, Weinstein MC (eds.). (2004). J Am Med Assoc. 291: 1238–1245.
(1996). Cost-Effectiveness in Medicine and Health. Murray CJL, Lopez AD (eds.). (1996). The Global Bur-
Oxford University Press, New York, NY. den of Disease: A Comprehensive Assessment of
Gross CP, Anderson GF, Powe NR. (1999). N Engl J Med. Mortality and Disability from Diseases, Injuries,
340: 1881–1887.
29 Burden of Disease Between
Two Time Frames: Mexico
Perspectives
G. Rodriguez-Abrego . J. Escobedo-de la Peña . R. B. Zurita Garza .
T. Ramı́rez-Sánchez
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
2 Socioeconomic Context of Mexico Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486

2.1 Transformation of the Health/Disease Conditions in Mexico . . . . . . . . . . . . . . . . . . . . . . . 486
3 The Health System in Mexico and Social Security . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
4 Measuring the National Burden of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490

4.1 Identification of Health Priorities at the IMSS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
4.2 Conducting the Burden of Disease Studies at the IMSS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
4.3 Life Expectancy at Birth, LE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
4.4 Years of Life Lost Due to Mortality, YLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
4.5 Years Lived with Disability, YLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
4.6 Disability Adjusted Life Years, DALY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
4.7 Disability Adjusted Life Expectancy, DALE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
5 Demographic and Epidemiological Transition. Future Perspective

in Population with Social Security in Mexico . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
5.1 Mortality Trend . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
5.2 Population Dynamics and Demographic Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
6 Disability Adjusted by Years of Life, DALY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495

6.1 The Diminution of the Burden of Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
7 An Analysis of the Burden of Disease at the IMSS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501

484 29 Burden of Disease Between Two Time Frames: Mexico Perspectives
Abstract: This is an overview of the Mexican > burden of disease and injury studies carried
out in the > Mexican Institute of Social Security (IMSS). Methods developed for the > World
Bank (WB) and > World Health Organization (WHO) Global Burden of Disease Study (NBD)
were adapted and applied to Mexican IMSS beneficiary population. Estimations of the burden
of disease for 129 causes were carried out in order to identify health priorities in Mexico’s
different geographic regions and to present comparative data between 1995 and 2005.
Indicators such as disability-adjusted life years (DALY) and > disability adjusted life
expectancy (DALE) were analyzed for the population covered by IMSS in 1995 and 2005;
for both years, the methodology proposed by the Global Burden of Disease Study was applied.
Data corresponding to 1995 were analyzed in 1997, while data corresponding to 2005 were
analyzed in 2006. The comparative study was carried out in 2007 by IMSS, Mexico.
Higher proportion of DALY was due to chronic diseases and the 2005 rate is 1.3 times
higher than that of 1995. Among health priorities identified, diabetes mellitus was found to be
the top-ranking cause of non-fatal disease burden in México, causing 7.5% of the total years
lost due to disability in 2005, followed by ischemic heart disease and stroke. The loss due to
these causes was mainly accounted for by premature death, as well as by diseases related to
disability with an important burden of disease, such as AIDS or depression. Epidemiological
backwardness can still be observed.
The population covered by IMSS is still in a phase of epidemiologic transition, favoring
polarization in health conditions. Health policies need to be directed toward bringing an
improved response and reversing the trend in diseases that represent an institutional risk for
the financing of health care.
List of Abbreviations: AIDS, acquired immune deficiency syndrome; BANXICO, national
bank of Mexico; CEBS, > children ever born and children surviving; CONAPO, National
Council of population; DALE, disability adjusted life expectancy; DALY, disability adjusted life
years; DFLE, > disability free life expectancy; DISMOD, disease modeling; ECLAC, economic
commission for Latin America and the Caribbean; ENDD, > national survey of demographic
dynamic; ENEC, > national survey of chronic diseases; GBD, global burden of disease study;
GDP, > gross domestic product; HALE, > health adjusted life expectancy; HIV, human
immunodeficiency virus; ICD, International Classification of Disease; IMSS, Mexican Institute
of Social Security; IMSS- OPORTUNIDADES, health services to highly marginalized popula-
tion; ISSSTE, state workers social service and security institute; INEGI, National Institute of
Statistics, Geography and Informatics; LE, > life expectancy; LED, > life expectancy with
disability; MORTPACK, > package for mortality measurement; NBD, > national burden of
disease; OECD, > Organization for Economic Co-operation and Development; SISMOR,
mortality information system; SMPH, > summary measures of population health; SSA,
Ministry of Health of Mexico; UN, United Nations; UNDP, > United Nations Population
Division; WB, World Bank; WHO, World Health Organization; YLD, > years lived with
disability; YLL, > years of life lost due to mortality
1 Introduction
The increase of life expectancy (LE) in developing countries in the last decades has had
important social and sanitary consequences, such as the relative increase in the elderly
population and the predominance of chronic diseases and disability in the morbidity pattern.
Burden of Disease Between Two Time Frames: Mexico Perspectives 29 485
In this context, simple health indicators based exclusively on mortality are insufficient to
describe the evolution of the population health status. Therefore, health indicators which
consider not only the mortality experience of a population but also its morbidity and disability
experiences need to be considered.
In the past two decades there has been a heightened interest in the use of compound
indicators at a world-wide level. A diversity of works related to the estimation of burden of
disease has been published, where use of indicators is proposed, such as Disability adjusted life
expectancy (DALE) and Disability adjusted life years (DALY) that together measure both the
non-fatal health damage and the time lost as a result of premature mortality (Murray and
Lopez, 1996a). This last one has been used by the WHO in its studies to estimate the burden of
disease and risk factors in the world (Murray, 1996) and has also been used in several nation-
wide studies. Important to point out is the fact that burden of diseases estimations derive from
the WHO current efforts to assess the performance of national health systems in the entire
world, where the burden of diseases constitutes one of the most important indicators to
integrally evaluate such performance –together with an indicator to quantify the degree of
health inequity (WHO, 2000).
Periodical assessment of national health in Mexico represents a public-policy-process key
component aimed at improving health levels and reducing health inequalities. Current
estimates of death and disability in the country disaggregated by age, sex and cause are useful
for several public health purposes, including the monitoring of new health problems for which
disease control programs are in place. To adequately describe health patterns according to age,
sex and cause a vast array of estimates need to be generated (Matters et al., 2000).
The National Burden of Disease NBD project developed two summary measures: Disability-
Adjusted Life Year (DALY) and Disability-Adjusted Life Expectancy (DALE), to provide a com-
prehensive assessment of the burden of disease and injury as well as information for national health
research priority setting, and to report on trends in population health. Both of these summary
measures of population’s health (SMPH) combine information on the impact of premature death
or years of life lost due to mortality (YLL) and of disability or years lived with disability (YLD) and
other non-fatal health outcomes. The burden-of-disease methodology provides a way to link
information on disease causes and occurrence at the population level on both short-term and
long-term health outcomes, including impairments, functional limitations (disability), restric-
tions in participation in usual roles (handicap), and death (Murray and Lopez, 1996b).
DALYs are a gap measurement; they measure the gap between a population’s actual health
and some defined goal, while DALE belongs to the family of health expectancies, summarizing
the expected number of years to be lived in what might be termed the equivalent of ‘‘full health.’’
The DALE is a population-based measurement that measures the vital period, which is
expected to be healthy (free of disease) and indicates the average number of years that a new
born can live free of disease, if there are no changes in mortality and disability levels at a
specific society.
DALE is based on the estimates of severity-weighted disability prevalence developed for
the non-fatal component of disease and injury burden. As a summary measure of the burden
of disability from all causes in a population, DALE has two advantages over other summary
measures. The first is that the concept of an equivalent ‘‘healthy’’ life expectancy is relatively
easy to explain to a non-technical audience. The second is that DALE is measured in units of
expected years of life (Matters et al., 2000).
This compound indicator is more frequently used. It allows the combination of the
prevalence of health condition in a population to the mortality data on a life table; at the
same time, it generates estimations of expected years of life in different health status condi-
tions (Bone, 1992; Matters et al., 1994; Robine and Jagger, 1999; Sullivan, 1971).
Both DALE and DALYs require a number of social value choices related, among other
things, to the valuation of the time spent in health states worse than the ideal health, to the
definition of an implied norm for population health, and the weighting of years of life lived at
different ages (Murray and Lopez, 1997a,b; Matters et al., 2000a; Mathers, 2002).
The interest raised upon these indicators is based on the potential uses they have, among
which the following stand out (Matters et al., 2000; WHO, 2000):
They facilitate the monitoring of epidemiological behaviors through the comparison of
health conditions in one population with respect to another one.
They allow the comparison of the health status of one population at different moments in
time.
They enable the identification and quantification of health inequalities in the population.
They contribute to the health care of the effects and results of non-fatal health conditions
in the population.
They foster debate over the identification of priority planning and health care.
They favor the debate on the identification of research, training and health sector devel-
opment priorities.
Analysis of the benefits of health interventions and cost-effectiveness analysis.
They generate knowledge and debate on public health.
Evaluation of the health systems performance.
2 Socioeconomic Context of Mexico Health
Social security systems in Latin America and the Caribbean always have been under the almost
exclusive responsibility of the public sector. In spite of the all advances, these systems show
important deficiencies generally translated into low population coverage rates, significant
and persistent financial imbalances and inadequate resources allocation and management
(Titelman et al., 2000).
The available statistical information confirms that Latin America populations have a
noticeable tendency to aging, which Mexico also shares. In an intermediate development
society with a young population structure, there is the underlying presence of a highly
heterogeneous demographic and epidemiological process, in addition to a longer life expec-
tancy of the population, which poses enormous challenges. Rather than a demographic
progress, it constitutes a challenge for current population policies, social planning and the
development of governmental programs, since the population demands exceed the capacity of
the productive system (Ham, 1995; CEPAL, 1998).
2.1 Transformation of the Health/Disease Conditions in Mexico
As a result of the changes in the development model, productive processes were transformed as
well as consumption patterns, territorial population distribution and women’s increasingly
incorporating to labor markets.
Mexico is a country of contrasts and contradictions. In the past decade the country has been
immersed in processes of change that have expressed through diverse transitions of economic,
political and social nature. Additionally, the urban transition is interesting since a previous
rural exporting country became a middle income capitalist nation, increasingly urbanized and
integrated to the world-wide economy through the process of globalization, where the search
for remunerated employment and satisfaction of basic needs continue to be demanded by the
population in large cities. This process of ‘‘modernization’’ has influenced changes in life style
and dietary patterns, caused increased inactivity, stress levels and addictions, which together
with others, are behaviors that have favored the increase of chronic diseases and high cost
treatments. On the other hand, the higher levels of social problems, insecurity and unemploy-
ment are related to increases of intentional injuries, which have changed disease patterns in the
country (Lozano Ascencio, 1994; López and Blanco, 2006).
In Mexico, modernization rate has been unequal in different segments of society and the
improvement of life standards has not been uniform among the population. The poorest
sector is more vulnerable as a result of economic programs that have not impacted this sector
positively. This has led to a regional panorama in the country characterized by a group of
northern and central states where the most industrialized, intermediate or advanced transition
process regions are found, in contrast to other group of states located in the south, with greater
indigenous and rural population, which shows extreme lag or incipient transition.
Additionally, the economic modernization is incapable of absorbing a growing informal
sector and progresses in democratization face old practices and political structures. The health
field has experienced transformation under this complex clash of trends and is showing the
effect of epidemiological polarization -higher health gaps among different sectors of society,
which becomes one of the most important challenges to face (Lozano Ascencio, 1994).
Backwardness is the characteristic of this process; despite the national sanitary progress,
some population sectors move forward more slowly than others, making urgent effective
actions.
Thus the combination of a fast and unequal growth confronts us to a series of new health
needs, in addition to previous demands that have not been fully solved. Hence, the current
health system must face more complex environments with less resources and it is for this
reason that the challenges we face require the measuring of the burden of diseases and the
identification of priorities to enable the suitable allocation of resources in and efficient and
equitable way.
In spite of these great progresses, we are still lagging in our efforts to reach social
satisfactions. While health level of Mexicans has improved significantly, we still observe
deficiencies in health services, quality of medical care and medical care financing. In
> Table 29-1 we show several selected indicators with comparative data in the period of
study that allow us to locate Mexico in the world-wide context.
3 The Health System in Mexico and Social Security
In order to respond to health problems of the population, Mexico has a public health care
system comprised by two subsystems: social security institutions (the Mexican Institute of
Social Security -IMSS- and the State Workers Social Service and Security Institute -ISSSTE-
mainly) and health services that provide care to population without access to social security
(Ministry of Health -SSA-, State Health Services and IMSS-Opportunities, among others).
. Table 29-1
Main demographic, economic, health and social indicators, Mexico 1995–2005
Indicator 1995 2005

Demographics (CONAPO)
Population in Mexico (millions) 91.9 103.9
Percentage of population under age 14 36.3 31.3
Percentage of 15–64 years old population 59.4 63.5
Percentage of population over age 65 4.3 5.2
Net migration 2000–2005 (in thousands) No data available –583.4
Economics (BANXICO)
Size of economy 18 12
GDP per capita (US million dollar) 3,320 7,310
Percentage of GDP annual increase –6.2 2.8
Percentage of people living with less than one dollar per day –8.2 3.0
Unemployment rate 7.6 3.6
GDP % underground economy 25.7 55.6
Health (OECD, 2006)
Health budget % GDP 4.06 6.5
Infant mortality (per 1,000 persons) 20.2 16.4
Prevalence of hypertension 26.6 30.8
Prevalence of diabetes (%) (Olaiz-Fernández, et al., 2006) 7.2 7.5
Prevalence of smoking (%) 26 18.9
Prevalence of obesity, BMI >30 (%) 21.4 29.3
Prevalence of depression (%) (Medina-Mora et al., 2003) No data available 9.1
Prevalence of anxiety (%) No data available 14.3
Coverage for basic vaccination program, age 2 (%) 99.3
Mammogram screening rate (%) 22.1
Cervical cancer mortality per 100, 000 women 17.7 8.9
Uncontrolled diabetes admission rate per 100, 000 No data available 7.6
Hypertension admission rate per 100, 000 discharges No data available 87.9
In-hospitalmortalityratewithin30daysofhospitaladmissionforAMI 14.3 24.5
Social security
Percentage of population insured by IMSS (millions) 34.3 44.9
While demographic indicators show an older population in 2005, economics show a better profile. Health
parameters show an increase in chronic disease and health costs, with a reduction in infant mortality. OECD
(2006) Health care quality indicators project 2006 data collection update report. http://www.oecd.org/dataoecd/
57/22/39447928.pdf. CONAPO. Consejo Nacional de Población. Indicadores demográficos básicos 1990–2030 at
www.conapo.gob.mx/00cifras/00indicadores.htm. BANXICO. Banco de México (2006). Información económica y
financiera, at http://www.banxico.org.mx/. SSA. Secretarı́a de Salud (2005). Dirección de Información en Salud.
Indicadores Financieros. México. Acceded on January 9, 2008 at http://sinais.salud.gob.mx/sicuentas/indicadores.
html. SSA. Secretarı́a de Salud. (1993) Dirección General de Epidemiologı́a. Encuesta Nacional de Enfermedades
Crónicas. México
This system has its own resources and a broad national medical-sanitary infrastructure
network. Nevertheless, the historical conformation of this network reveals serious inequalities
amongst subsystems, regions and provinces in terms of distribution of medical centers,
equipment, health personnel and resources to operate, which have experienced a state of crisis
in the last two decades (SSA, 2001).
From its creation in the 1940s, the IMSS has emphasized the benefits of social development
policies. In turn, the efforts carried out are reflected in better population health indicators,
which show the effects of the plans and programs that have positively impacted the health of
affiliated workers and their families.
The IMSS is the largest social security institution in Mexico and in 2005 it affiliated
41 million social security holders, 35 million of whom are using the services.
During the 1960s, the IMSS underwent an expansion of infrastructure and human
resources due to the growing demand for services resulting from high population growth
rates. At the same time actions towards health care programs were fostered with emphasis
on maternal-child health and family planning that produced a transition from a phase
of demographic explosion to a gradual reduction of fertility and birth rates, which in
turn changed dramatically age groups structures. The reduction of the general, maternal
and infant mortality rates and the improvements in health conditions have increased the
life expectancy that has translated into an increase in the proportion of the population over
the age of 65.
At the end of the economic expansion phase, Mexico experienced a new economic crisis
characterized by an increase of the foreign debt and inflation. Although rural population sectors
were incorporated to the Social Security Extension Program Regimen in this period, no
great advances in health were observed due to the gradual reduction in the public health budget
as a percentage of the Gross Domestic Product, (GDP). The 1990s became the hallmark of
the Mexican economy integration to the globalization process. A series of structural reforms
were implemented, including the reform of the social security system that concluded with the
privatization of IMSS pension administration, the reduction in employers’ contributions and a
substantial reduction of hired administrative personnel in the institution (IMSS, 2003; Orsatti and
Riquelme, 1985).
The integrating process was affected by other economic crisis, with increased unemploy-
ment rates that brought about a steep fall of worker-employer contributions and a period
of economic adjustment that has not reached stability even to date. During this phase the
entire health sector, but particularly the IMSS, underwent a lack of public investment, which
led to a saturation of hospitals as a result of excessive demand of health care services and
a negative effect in the medical services quality indicators.
At present, Mexico is aiming at continuing the pending structural reforms. The main
prevailing problem is the lack of economic growth that has not created enough jobs to satisfy
the growing demand from a predominantly productive age population that directly impacts
social security, which depends on the contribution of IMSS-affiliated workers.
Within this particular context, and in the face of a lack-of-financial-resources scenario
within the social security sector that results from longer life expectancy, ever growing costs
of health care, and a setting of less economic growth that negatively impacts the funding of
the services provided by this sector, a ‘‘new package of social security reforms’’ aimed at
reducing the costs for the State has been recently introduced.
4 Measuring the National Burden of Disease
Mexico was one of the first developing countries in calculating the national burden of disease
using DALY and DALE indicators. The results of these estimations have been used in planning
health services (Bobadilla, 1997; SSA, 2001). It is worth highlighting the contributions of the
Economy and Health Study carried out in Mexico in 1994 that gave way to the drafting of
health policies for specific groups (Frenk et al., 1994). Between 1990 and 2006 several
programs were instrumented with the purpose of extending the coverage of socially under-
served groups by means of the provision of a basic package of health interventions selected for
their cost-effectiveness (Gómez-Dantés et al., 1999). More recently the Seguro Popular Pro-
gram was put in place, which comprises an insurance model through public funding addressed
at the low-income population. The Seguro Popular incorporates 91 health interventions
selected for their cost-effectiveness (Seguro Popular).
4.1 Identification of Health Priorities at the IMSS
Since 1995 the Mexican Institute of Social Security, IMSS, has conducted exercises to estimate
the burden of disease in order to learn about the evolution and health dynamics of the
beneficiary population (Rodrı́guez-Abrego et al., 2007). In 2005 a new study was implemented
as part of a national exercise for the assessment of health needs and the identification of public
health, health services and medical health research priorities.
The IMSS has conducted three studies to measure the burden of disease using DALY, LE
and DALE indicators. These measurements were performed within a 5-year span difference,
but using the same methodology to maximize the use of available information (correction of
the under-registration and of deaths), favor the systematization of generally scattered infor-
mation on multiple conditions (prevalence, fatality, duration, among others), and improve the
internal and external consistency of these estimations, thus making it a reliable decision-
making instrument.
The main purpose of this project was to compare the demographic and epidemiological
panorama of social security beneficiary population in the country for years 1995 and 2005
and, additionally, evaluate future perspectives to foresee health actions within the beneficiary
population.
4.2 Conducting the Burden of Disease Studies at the IMSS
For conducting a study of the burden of disease, the proper methodology is the one used by
the World Health Organization (WHO) and the World Bank (WB) (Murray 1995; Murray
1996; Murray and Lopez 1996; World Bank 1993).
One of the key features of a burden of disease study is to have reliable health statistics. The
IMSS information system records health information since its inception. However, other
sources of information are also essential. For both studies we have used the National
Health Surveys implemented by the Ministry of Health in Mexico (SSA, 1993; Olaiz et al.,
2003, 2006).
An important input to DALY estimates is mortality. Some adjustments to death registries
are needed, to correct for miscoded signs, symptoms and misclassification of diseases or
unknown categories. These adjustments have to be proportionally redistributed by age groups

(Lozano et al., 1995; Michaud et al., 1995).
In the analyzed period, two different International Classification of Diseases (ICD) were
employed, the ninth and tenth versions (OPS, 1975, 1995) taking into consideration the
diseases included in the global burden of disease study (Murray et al., 1995). For the burden
of disease study at IMSS, health conditions were classified in three groups of diseases: Group I
included communicable and reproduction diseases, perinatal conditions and nutritional
deficiencies; Group II, non-communicable diseases; and Group III, injuries.
4.3 Life Expectancy at Birth, LE
The first step on measuring the burden of disease is to estimate life expectancy at birth.
National and state delegations life tables were developed and mortality rates were estimated for
specific quinquennial groups and gender. IMSS is administratively divided into delegations
which in most cases coincide with the federal provinces the country is officially divided into.
Fertility indicators, births and deaths data were used for the calculation of infant mortality.
The mean maternity age was calculated first, using the information from the 1992 and 1997
National Demographic Dynamics Survey, (ENDD, acronym in Spanish), with data extrapo-
lated to 1995, and the data of the 2005 National Population Count from the National Institute
of Statistic, Geography and Informatics (INEGI, 2005). Afterwards, specific fertility rates were
obtained for each federal province, as well as the average number of live births, dead births and
survivors according to the age of the mother, using the indirect method. The proportion of
mothers by quinquennial age groups as a measure of mortality from birth to a specific age
served to estimate the average of children who have died. According to the original procedure
(Brass, 1975), this method involves mortality and fertility models used to estimate the factors
that transform the proportion of dead children into the likelihood of dying. Deaths of 1–4
years old children were finally calculated.
In this phase the Coale and Demeny model developed by United Nations (Palloni-
Heligman equation) is preferred, since it has the advantage of using fertility patterns which
are characterized for their capacity of adapting to a wide variety of fertility observed experi-
ences, with mortality patterns based on data from developing countries (Coale et al., 1983).
The estimation of mortality by federal states was made once the mortality pattern had been
selected. Children ever born and children surviving, CEBS, components from the MORTPAK
lite program (1990) were used.
Once the specific quinquennial group’s nMx mortality rates and the likelihood of dying
before an nqx year had been calculated, the remaining lifetable functions were estimated until
arriving to the life expectancy for different ages (Chiang, 1978).
Information from a 15 year period mortality series was analyzed to establish the mortality
trend by groups of diseases and then a 25 year period projection of these data was done, with
linear and polynomial regression models to evaluate mortality behaviors.
4.4 Years of Life Lost Due to Mortality, YLL
The years of life lost due to mortality were estimated using standard expected years of life lost.
Coale and Demeny model ‘‘West 26 life table’’ was chosen as the standard with a 82.5 years life
expectancy at birth for females and 80 years for males. Time lost due to premature mortality was
discounted at three per cent. To calculate the number of YLLs lost to a condition, the number of
YLLs lost per death at each age must be multiplied by the number of deaths at each age and then
summed across all ages. Details in general formula and parameters used for YLL and YLD
calculations should be useful to understand this procedure (Murray and Lopez 1996).
4.5 Years Lived with Disability, YLD
The DISMOD II software gives internal consistency to the available information on incidence,
prevalence and mortality. An epidemiological model was built for each disease and incident
cases, average onset age and duration of each disease and disabling disabilities were estimated.
Subsequently, the YLD were calculated with the help of spreadsheets where the disability
quantification methodology was applied. Incident cases are multiplied by the duration of the
diseases and the average age of onset. These corrected case are multiplied by the disability
weigh to estimate YLD. These disability weights are selected from a disability map with values
from 0 to 1 according to the severity of the disability or disease, where 0 is perfect health and 1
is a state equal to death (Murray, 1994).
4.6 Disability Adjusted Life Years, DALY
As defined, YLL and YLD are two types of DALY. Thus DALY from any given condition is
simply the sum of YLL and YLD from the condition such that:
DALY ¼ YLL þ YLD
4.7 Disability Adjusted Life Expectancy, DALE
The DALE index for the country and state delegations were estimated for 1995 and 2005 based
on the IMSS beneficiary population lifetables (Matters et al., 2000). For this purpose, the
lifetable was adjusted by the prevalence of disability (Matters et al., 2000).
This method is favored primarily because it only requires a population lifetable (using
observed mortality rates at each age in a given time period) and prevalence data for the health
state of interest. Sullivan’s method (Sullivan, 1971) can be described as an observed prevalence
lifetable method. The starting point is a period lifetable constructed using prevailing age- and
sex-specific mortality rates. For the purpose of both burden of disease point estimates, period
lifetables for each Mexican state were employed.
In DALE estimation, the measurement of co-morbidity entailed the analysis of each one of
the diseases and the disabling disabilities independently. The prevalence of disability for each
disease was estimated, where prevalent cases were adjusted by the severity of the disability.
The concept of combining population health state prevalence data with mortality data in a
lifetable to generate estimates of expected years of life in various health states (health
expectancies) and Disability-free Life Expectancy DFLE introduces the concept of quality of
life. It is used to distinguish between years of life free of any activity limitation and years
experienced with at least one activity limitation. The emphasis is not exclusively on the length
of life, as is the case for life expectancy, but also on the quality of life. (Mathers et al., 1994).
5 Demographic and Epidemiological Transition. Future

Perspective in Population with Social Security in Mexico
5.1 Mortality Trend
> Figure 29-1 shows comparative data of proportional mortality by selected causes: Tubercu-
losis, pneumonia, diarrheic diseases and perinatal causes, among others, have decreased in the
study period, with the exception of HIV infections which has increased. On the other hand,
group II diseases, such as diabetes mellitus, ischemic heart disease and stroke, have shown
significant increase. The same applies to injuries.
There is a strong correlation between mortality rate and the time elapsed. Diseases of
Group I are showing a gradual reduction. In 1990, the mortality rate for this group of diseases
was 49.3 deaths per 100,000. It could be expected that for 2025 the rate drops to 8.3 deaths per
100,000, with a R squared = 0.75. In contrast, there is a rising trend for Group II non-
communicable diseases, that moved from a mortality rate of 143.6 deaths per 100,000 in 1990
to 524.0 per 100,000 in 2025. Group III of injuries have a similar effect growing from 12.0 deaths
per 100,000 to 43.4 per 100,000 in the same period (> Figure 29-2 and > Figure 29-3).
5.2 Population Dynamics and Demographic Change
In the IMSS the age population structure has changed significantly and the percentage change is
evident, mainly in the age group over 65 years, since it has gone from 4.4% in 1980 to 10% in
2005. On the other hand, the reduction of mortality rate has modified life expectancy at birth
which has been steadily increasing in the last 10 years. In men it has raised from 71.3 years in 1995
to 76.3 years in 2005, whereas in women it has switched from 77.1 years in 1995 to 78.9 years in
2005. In 2005, the national LE average among IMSS beneficiaries was estimated in 77.7 years.
In the same period, DALE estimates for 1995 was 64.5 years, increasing significantly to 68.6
in 2005; this indicates that healthy life expectancy increased 4.1 years in average in this period.
Gender analysis reveals that women have a DALE of 69.9 years and men 67.8 years. The
difference between LE at birth and DALE in fact is the health gap translated in life expectancy
with disability (LED), which for women in 2005 was estimated in 9.1 years, with a differential
for females of little more than half a year (0.6 years) with respect to men.
> Figure 29-4 shows epidemiological maps from the country where LE and the Proportion
of LED reveal inner variations in each delegation that depend on the degree of economic and
social development reached by each one of them. The data collected correspond to 2005. The
delegations with elevated LE and low proportion of LED exhibit better health conditions. This
group includes those delegations with higher socioeconomic development and health infra-
structure levels, located in the northern states of the country like Baja California, Chihuahua,
Coahuila, Nuevo Leon, Tamaulipas. In contrast, those states with low LE and high LED
proportion are located in central and southern states. These are Puebla and Zacatecas,
Chiapas, Oaxaca, Guerrero, where significant backwardness is observed in health indicators,
such as infant mortality, that have an impact on health conditions.
494
. Figure 29-1
Proportional mortality of selected causes. IMSS, Mexico 1976–2005. The proportion of deaths related to these fifteen causes is compared between 1995
and 2005. While the proportion of deaths due to non-communicable diseases increased substantially, the proportion of deaths due to infectious diseases
29
and perinatal conditions decreased in an important fashion during this period
Burden of Disease Between Two Time Frames: Mexico Perspectives
. Figure 29-2
Epidemiological transition, mortality trends, IMSS, Mexico 1990–2025. Mortality shows an
increasing trend since the last decade of last century. Non-communicable diseases are the major
contributor of mortality, but its contribution will increase substantially in the first quarter of this
century. While the proportion of deaths due to injuries will also increase, the contribution of
deaths due to infectious diseases and maternal, perinatal and nutritional conditions will be
negligible
6 Disability Adjusted by Years of Life, DALY
In 2005, the total number of lost DALY in the Mexican Institute of Social Security increased to
4.9 million years and a rate of 14.031 years of healthy life lost per 100,000 beneficiaries. In
comparison to 1995, the burden of disease in 2005 increased 1.3-fold 1995 loses, when
approximately 3.7 million DALY had been estimated (> Table 29-2).
Group II of non-communicable diseases shows higher loss of DALY with a total of
3,457,576 healthy years of life lost, figure that represents 70.2% of the total. This means that
some non-communicable disease causes seven out of every ten DALYs that are lost at the
IMSS. When this figure is compared to that obtained in the 1995 exercise, lost DALYs are 2.4
million altogether, which represents a 31% increase with respect to estimation in 1995.
In 2005, non-communicable diseases increased significantly from 56 to 65% of the total
DALYs. In this group, diabetes mellitus, hypertensive disease of the heart, ischemic diseases of
the heart, hepatic cirrhosis, chronic obstructive pulmonary disease, stroke disease, depressive
disorders, renal failure, alcohol dependency and breast cancer, are the ten first causes that
contribute with major number of lost years of healthy life. The lost of years by premature death
(YLL) is slightly smaller (47.6%) than the lost observed per years lived with disability (YLD)
(52.4%).
In group III of injuries, 816,658 years of life were lost, which means 16% with respect to the
total in 2005. This finding is important if it is compared to 1995 data, where 571,000 DALYs
were lost; in other words, injuries increased 1.5 times more in this 10 years period.
It is worth mentioning that motor vehicle accidents are the most frequent injuries,
followed by intentional aggressions. Likewise, in the case of injuries, the major loss of years
. Figure 29-3
Mortality trends of no communicable diseases and Injuries. IMSS, México 1990–2020. Non-
communicable diseases mortality trend is well explained by a linear regression model, which
means a constant increase as time goes by- The shape of the curve may be modified in a
polynomial regression model if proper health interventions are implemented. The observed and
projected trend is well explained by this alternative model. Mortality due to injuries shows an
increasing trend with either model, although its magnitude is quite less (only a tenth of) than the
magnitude of non-communicable diseases
is observed in the years lived with disability component that represents almost two thirds of
the total DALYs; in contrast, loss by premature death in this group does not exceed one third
(29.6%).
6.1 The Diminution of the Burden of Infectious Diseases
From the estimated 2005 DALYs, 652,255 years of healthy life were lost due to Group I
diseases, 44% of which correspond to perinatal causes, 36% to infectious diseases, being
HIV/AIDS the main contributing cause.
In this sense, the scenario has radically changed nation-wide, but particularly at the IMSS
since the reduction of Group I diseases represented 20.4% of the total number of years lost in
. Figure 29-4
Life expectancy at birth (LE) and life expectancy with disability (LED) proportion indicators for
each states of country IMSS, Mexico 2005. LE and LED depend on the degree of economic and
social development reached by each delegation (state). Those with elevated LE and low LED have
better health conditions, related to a higher socioeconomic development and health
infrastructure. In contrast, those states with low LE and high LED have significant backwardness
health conditions. This polarization is an essential component of epidemiologic transition
1995 compared to a 16% burden of disease in 2005. In absolute terms, they moved from
761,000 in 1995 to 652,255 in 2005. The main causes in order of priority are perinatal and
HIV/AIDS infections, but with regard to other pathologies in this group, pneumonias and
hypertensive diseases of pregnancy remain as the most important.
7 An Analysis of the Burden of Disease at the IMSS

The measurement of health in such a way that it is comparable over time and across
populations is an essential requirement for the evaluation of health policies, the assessment
of intervention effectiveness, and the measurement of health systems efficiency. Without
meaningful measurements of health it would be impossible to evaluate whether health systems
are achieving their primary goals, namely improving population health levels and reducing
health inequalities. One major shift over the past decade has been the awareness that infor-
mation on both mortality and health as a living state are required in order to describe health at
the individual or population levels (World Health Organization, 2000).
The use of a summary indicator such as DALY allowed us to identify changes in IMSS
population health profile and the way in which their health conditions have been modified
throughout time. It also revealed that the use of morbidity and mortality rate alone does not
properly allow the identification of health care priorities.
IMSS morbidity, documented by demand for medical care and hospital discharges, express
the perceived demand for health care, as well as the clinical expression of severity of some
nosological entities that requires hospitalization.
. Table 29-2
Burden of disease in Mexican population covered by IMSS: Comparative analysis with DALY
selected causes, México 1995–2005
1995 2005
Disease/disorder/by order of DALY DALY Rate* DALY Rate*
a
TOTAL 3,734,140 10,892 4,926,489 14,031
Group I. Communicable, maternal, perinatal and nutritional 761,008 2,220 652,255 1,858
conditions
HIV- AIDS 58,245 170 76,369 217
Lower respiratory infections 102,972 300 84,326 240
Diarrheal diseases 41,312 121 15,096 43
Conditions arising during the perinatal period 276,747 807 286,476 816
Maternal conditions 52,609 153 53,798 153
Nutritional deficiencies (Protein-energy malnutrition) 124,490 363 19,875 57
Group II. Non communicable disease 2,401,680 7,006 3,457,576 9,847
Malignant neoplasia 354,255 1,033 414,350 1,180
Stomach cancer 21,888 64 35,024 100
Colon and rectum cancers 15,887 46 29,951 85
Trachea, bronchus and lung cancers 26,916 79 45,077 128
Breast cancer 34,484 201 60,404 172
Cervix uteri cancer 42,581 249 34,807 99
Prostate cancer 13,128 38 22,195 63
Leukemia 35,505 104 38,918 111
Diabetes mellitus 272,782 796 569,062 1,621
Neuro-psychiatric conditions 416,230 1214 506,739 1,443
Unipolar depressive disorders 100,080 292 185,110 527
Sense organ diseases 33,683 98 187,864 535
Glaucoma 60,338 176 175,524 500
Cardiovascular diseases 390,137 1,138 794,858 2,264
Ischemic heart disease 147,934 432 248,770 708
Cerebrovasculars disease 90,294 263 216,495 617
Respiratory diseases 134,375 392 239,509 682
Chronic obstructive pulmonary disease 56,601 165 210,812 600
Asthma 40,723 119 28,697 82
Digestive diseases 187,055 546 236,571 674
Cirrhosis of the liver 97,721 285 214,835 612
Peptic ulcer disease 7,844 23 18,768 53
Genital-urinary diseases 130,960 382 114,210 325
Nephritis and nephrosis 106,888 304
Musculoskeletal diseases 139,308 406 232,831 663
Rheumatoid arthritis 171,931 490
Burden of Disease Between Two Time Frames: Mexico Perspectives

29 499
1995 2005
Disease/disorder/by order of DALY DALY Rate* DALY Rate*
Congenital anomalies 260,292 759 157,084 447
Group III. Injuries 571,452 1,667 816,658 2,326
Unintentional injuries 463,459 1,352 656,722 1,870
Intentional injuries 107,993 315 159,936 455
Number of DALYs are shown for each of the selected disease and each of the three groups of diseases. The rate per
100,000 persons year is also expressed. Comparisons can be made between both studied years (1995–2005), and
the importance of each disease can also be assessed either in absolute (number of DALYs) or relative (rate) terms.
IMSS 2005. One Hundred thousand. Population IMSS 1995 (34.282.000), Population IMSS 2005 (35.112.262) (Source:
MexicanBurdendiseaseStudyIMSS;1995andHealthNeedsAssessmentProject).Comparativedata,discountingrate3%
a
The total by group does not match given that only selected causes are presented in the table
The need to homogenize the available information sources is a challenge. The measure-
ment of disease burden, irrespective of the observed technical difficulties due to heterogeneity
and quality of the registries, as well as the need to consult diverse sources of information, and
the search of support for the consensus of experts, allows us -through the experience acquired
throughout three National Burden of Disease studies of- to unify criteria in diverse aspects,
but all directed towards the optimization of available information sources.
The amount of available information allows us to extrapolate the data and even it they
do not correspond to a national registry, because of the population size that is benefited by
the IMSS, the results could be applied to all the Mexican population. The IMSS covers nearly
50% of the population in the country and has a reliable source of data. Additionally, the
validity of the information has been documented by means of a follow up of diverse indicators
(Coria et al., 2000), which has helped to find a high agreement between the registries, an
acceptable internal consistency and an average of discrepant cases similar to report from other
countries. This makes us consider that the collected data show as much internal as external
validity.
The use of information sources from 1993 to 2000 National Health Surveys, identifies
that there is more morbidity and exposure to risk factors component within the population
with social security, that shows a health profile with significant higher prevalence of chronic
disease as compared to the general population (for example, diabetes mellitus, heart hyper-
tensive disease, obesity and renal failure). This situation indicates that the burden of disease is
growing at the expense of the disability component and that it has a significant impact on the
demands for services and on the costs of health care from these diseases (Arredondo and
Zúñiga, 2004).
On the other hand, life expectancy adjusted by health indicator data (SSA, 2005) for the
general population in Mexico were recently published, which in contrast to the conventional
life expectancy that considers every year in the same way, in the health adjusted life expectancy
(HALE) indicator the years of life are weighted with the health state. It is therefore necessary
that information be obtained from surveys that measure different health states (SSA, 2005).
An essential input for the calculation of HALE is therefore a set of weights that represent
scalar index values for the overall levels of health associated with different states, measured on a
meaningful cardinal scale anchored by perfect health and death. These ‘‘health state valuations’’
constitute the critical link between information on mortality and information on the spectrum of
health states experienced by individuals.
In the case of IMSS these estimations are not yet available; however, the DALE indicator
allows combination of the prevalence of health conditions in the population with mortality
data in a life table, while at the same time generating estimations of expected years of life in
several health conditions. Then it is possible to measure the years with complete heath.
The results of this study show the change in the health profile of a social security
beneficiary population in whom mortality, morbidity and disability patterns are related to
characteristic risks of developed countries, which cause a greater portion of the burden of total
disease in Mexico than that caused by diseases typical of developing countries. Specifically,
risks associated with over nutrition and addictive substances (high body mass index, blood
glucose, blood pressure, cholesterol, and the abuse of alcohol and tobacco) were more
important than those associated with malnutrition (‘‘childhood underweight, and iron,
zinc, and vitamin A deficiency’’). Alcohol, body mass index and other behavior risk factor
contributing to most accidents, injuries, diseases, and death mainly in youth, stand out for
being the causes of the burden of disease in Mexico, situation which is similar to the one
mentioned in the Health Metrics 2004 Report (SSA, 2005).
8 Conclusion
This exercise is very helpful in establishing Mexico’s Health Sector priorities and particula-
rly of the IMSS, so it is from this technical standpoint that it is possible to make progress in the
next years despite predominant methodological, conceptual and operative challenges in
the Institute.
It is essential that health information is available and that the systematization processes help
process data in less time as possible. The periodic identification of emergent problems must be
aimed at exercises of planning that may frequently enough allow the channeling of investments
into plans and high-priority health programs focused on risk approaches. In this context, DALY
constitutes an indicator that allows the planning to future in terms of risks prevention.
In summary, because of health changes that go along with Mexico’s transformations, the
country is experiencing a transition characterized by quick changes and great contrasts in
population needs. IMSS is taking care of the emerging health problems such as chronic
diseases, injuries and disabilities that demand higher use of health services, more complex
technology to diagnose them, treatment and rehabilitation at an increasing cost.
Therefore, we would expect that in the future, strategies be consolidated towards an equal
development based on the change of the health care paradigm and in the health system
structural change. Some proposals available at present are: the conformation of integral health
services for all the population; reinforcement of preventive programs focused on improving
certain health indicators (for instance, perinatal, infant or maternal mortality), as well as
fostering more inter-sectorial cooperation to optimize resources for the entire sector, avoiding
duplication of efforts. It should be stressed that developed countries are developed, among
other things, because they have devoted increasing resources to maintain their human capital
in optimal conditions. Hence, investment in health must be a strategic element to speed up our
Mexico’s future development.
Finally, a fundamental aspect for social security is the generation of conditions to establish
new financing schemes that guaranty the permanence of the system.
Summary Points
Disability adjusted life years are a tool for health services planning and so their periodic
measurement keeps decision makers updated on the population health situation.
The use of complex indicators such as disability adjusted life years does not only identify
priorities through explicit criteria, but also enables to support the design of policies and
programs as a fundamental basis for resource allocation and distribution and cost-effec-
tiveness analysis aimed at the design of service packages.
Periodical measurement of the population’s health state is an instrument that, in con-
junction with other indicators, facilitates the evaluation of health systems and services
performance as it takes into consideration health actions that have direct effects on
welfare.
Therefore, the quality of services and program efficiency are implicitly assessed; i.e., we can
monitor whether they maintain, move forward, decelerate or change the course of
epidemiological trends as a result of health problems in the population in the previous
period.
The implementation of evidence-based health policies and exercises with robust method-
ology enable a more objective evaluation of program impacts at the operational level, thus
determining progresses in the improvement of clinical-administrative management and
allocation of resources.
DALYs identify research priorities in order to build knowledge and identify ways to reduce
existing gap in health among different population groups.
When results of burden of disease studies in the population are used as part of the baseline
information to establish national health policies, modifications in the content of basic
health packages can be determined.
Compound indicators describe the health state of a population and can be used to assess
the impact of alternative health programs in cost-utility terms.
References
Arredondo A, Zúñiga A. (2004). Diabetes Care. 27: Coale AJ, Demeny P, Vaughan B. (1983). Coale AJ (ed.)
104–109. Regional Model Life tables and Stable Population.
BANXICO. Información económica y financiera, Banco Academic press, New York, pp. 3–7.
de México at http://www.banxico.org.mx/. CONAPO. Consejo Nacional de Población. Indicadores
Bobadilla JL. (1997). Frenk J (ed.) Observatorio de la demográficos básicos 1990–2030. Available at www.
salud. Necesidades, servicios, polı́ticas. Fundación conapo.gob.mx/00cifras/00indicadores.htm.
Mexicana para la Salud, México, pp. 255–274. Coria I, Mata J, Acevedo F, Recio M, Zurita B, Esquivel G.
Bone MR. (1992). J Epidemiol Comm Health Care. 46: (2000). Martı́nez-Salgado H, Villası́s MA, Torres J,
555–558. Gómez-Delgado A (eds.) Las múltiples facetas de la
Brass W. (1975). Chapel Hill, International Programme investigación en Salud 4. Instituto Mexicano del
of Laboratories for Population Statistics, North Car- Seguro Social, México.
olina Population Center. Editorial IMSS. (2003). Acceded on 9 January 2008 at
CEPAL. (1998). Panorama Social de América Latina. http//www.imss.gob.mx/NR/rdonlyres/794387B7–
Comisión Económica para América Latina y el Ca- 62BE-401F-AA07-04A7515FA63C/0/Boletı́n9.pdf.
ribe. Santiago de Chile. Frenk J, Lozano R, González-Block MA, Ruelas E,
Chiang CH. (1978). Life tables and Mortality Analysis. Bobadilla JL. (1994). Economı́a y Salud. Fundación
World Health Organization, Geneva. Mexicana para la Salud, México. 123p.
Gómez-Dantés O, Garrido-Latorre F, López-Moreno S, and Disability from Diseases, Injuries and Risk
López-Cervantes M. (1999) Rev Saúde Publica. Factors in 1990 and Projected to 2020. Harvard
33(4): 401–412. University Press, Boston.
Ham Chandi R. (1995). The Elderly in Mexico: Another Murray CJL, Lopez A. (1996b). Science. 274: 740–743.
challenge for a Middle-income country. Valleta, Murray CJL, Lopez A. (1997a). Lancet. 49: 1436–1442.
Malta, International Institute on Ageing. Murray CJL, Lopez A. (1997b). Lancet. 349: 1347–1352.
Instituto Nacional de Estatı́stica, Geografı́a e Informática. OECD, Organization for Economic Co-operation and
(1992). Encuesta Nacional de la Dinámica Demo- Development. (2006). Health Care Quality Indica-
gráfica, México. 1994: 418. tors Project 2006 Data Collection Update Report.
López O. y Blanco J. (2006). Peña F, Alonso LA (eds.) http://www.oecd.org/dataoecd/57/22/39447928.pdf.
Cambio Social, Antropologı́a y Salud. CONA- Olaiz-Fernández G, Rivera-Dommarco J, Shamah-Levy
CULTA/INAH, México, pp. 15–26. T, Rojas R, Villalpando-Hernández S, Hernández-
Lozano Ascencio R. (1994). Frenk J (ed.) Observatorio Ávila M, Sepúlveda-Amor J. (2006a). Encuesta
de la Salud. Necesidades, Servicios y Polı́ticas. Funda- Nacional de Salud y Nutrición. Instituto Nacional
ción Mexicana para la Salud, México, pp. 23–61. de Salud Pública, México.
Lozano R, et al. (1995). J Int Dev. 7:555–563. Oláiz -Fernández G, Rivera-Dommarco J, Shamah-Levy T,
Lozano R, Murray CJL, López AD, Satoh T. (2001). GPE Rojas R, Villalpando-Hernández S, Hernández-Ávila
Discussion Paper No. 12. World Health Organiza- M, Sepúlveda-Amor J. (2006b). INSP.
tion, Geneva. OPS. (1995). Organization Panamericana de la Salud.
Mathers C. (2002). Murray CJL, Salomon JA, Mathers Classification estadistica international de enferme-
CD, Lopez AD (eds.) Summary Measures of Popu- dades y problemas relacionados la salud. 10a revi-
lation Health: Concepts, Ethics, Measurement and sion. Washington.
Applications. World Health Organization, Geneva, OPS. (1975). Organization Panamericana de la Salud,
pp. 177–204. Classification estadistica international de enferme-
Mathers CD, Robine JM, Wilkins R. (1994). Mathers CD, dades y problemas relacionados con la salud. 9na
McCallum J, Robine JM (eds.) Advances in Health revision. Washington.
Expectancies, Proceedings of the Seventh Meeting of Orsatti A, Riquelme G. (1985). Nueva Sociedad. 75:
the International Network on Health Expectancy 85–96.
(REVES), Australian Institute of Health and Wel- Robbine JM, Matters C, Brouard N. (1996). Caselli G,
fare, Canberra. Lopez A (eds.) Health and Mortality Among
Matters CD, Sadana R, Salomon JA, Murray CJL, Lopez Elderly Population. Clarendon Press, Oxford,
AD. (2000). Working Paper No. 16. World Health pp. 182–201.
Organization, Geneva, Switzerland. Robine JM, Jagger C. (1999). Developing Consistent
Medina-Mora ME, Borges G, Lara C, Benjet C, Blanco J, Disability Measure to Address Public Policy Needs
Fleiz C, et al. (2003). Salud Mental. 26: 1–16. for Older Population. Background Paper Prepared for
Michaud C, Mahapatra P, Acharya A, Shibuya K, Lozano R, OECD Meetings on Implications of Disability for
Galddou E. (1995). In: Murray CJ (ed.) Designing and Ageing Population: Monitoring Social Policy Chal-
Implementing a National Burden of Disease Study. lenges. Paris.
Burden of Disease. Harvard Center for Population Rodrı́guez-Abrego G, Escobedo de la Peña J, Zurita B,
and Development Studies, pp. 91–118. Ramı́rez TJ. (2007). Salud Publica Méx. 49: 132–143.
Murray CJL. (1994). Bull World Health Organ. 72: Secretaria de Salud (2001). Información para la rendi-
429–445. ción de cuentas. 2. ed. México.
Murray CJL. (1995). In: Murray CL, Michaud C, Maha- Secretaria de Salud. (2005). Dirección de Información
patra P, Acharya A, Shibuya K et al .(eds.) Designing en Salud. Indicadores Financieros. México. Acceded
and Implementing a National Burden of Disease on 9 January 2008 at http://sinais.salud.gob.mx/
Study. Burden of Disease. Boston, pp. 37–75, sicuentas/indicadores.html.
91–118. Secretarı́a de Salud. (1993). Dirección General de Epide-
Murray CJL. (1996). In: Murray CL, Lopez Alan D (eds.) miologı́a. Encuesta Nacional de Enfermedades
The Global Burden of Disease and Injuries Series. Crónicas. México D.F.
World Health Organization, Geneva, Switzerland, Seguro Popular. (2004). Acceded on 9 January 2008
pp. 201–246. at www.seguro-popular.salud.gob.mx/contenidos/
Murray CJL, Lopez AD. (1994). Bull World Health seguro_popular/seguro_popular.html.
Organ. 72: 481–494. Sullivan D. (1971). Health Rep. 86: 347–354.
Murray CJL, Lopez AD. (1996a). The Global Burden of Titelman D, Uthoff A, Jiménez LF. (2000). Pan Am Public
Disease: A Comprehensive Assessment of Mortality Health. 8: 112–116.
United Nations. (1988). MortPak-Lite: The United World Health Organization. (2000). World Health Report.
Nations Software Package for Mortality Measure- Health systems improving performance. Geneva
ment. New York: Population Studies 104. Health Metrics 2004 Report: Health Assessment.
World Bank. (1993). World Development Report: Invest- Acceded on 9 January 2008 at http://sinais.salud.gob.
ing in Health. Washington, DC. mx/metrica/areas/resumenejecutivoreporte2005.pdf.
30 East/West Differences in
Health in Europe: Rates,
Expectancies and DALYs
J. Powles . H. Gouda
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
2 Rates and Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507

2.1 All Cause Mortality – Rates and Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
2.2 Cause – Specific Mortality Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
2.3 Uses of Cause Specific Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
3 Life Expectancies and Health Gap Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510

3.1 Decomposition of Life Expectancy Differences by Cause . . . . . . . . . . . . . . . . . . . . . . . . . 512
3.1.1 DALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512
4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516

506 30 East/West Differences in Health in Europe: Rates, Expectancies and DALYs
Abstract: There is a very large health gap between Eastern and Western Europe. We show how
different health metrics can be used to characterize this gap. We compare the 15 countries that
joined the European Union prior to May 2004 (EU15), the ten who joined since May 2004 –
excluding Malta and Cyprus – (EU10) and the three Slavic states of Russia, Ukraine and
Belarus (Slavic 3). > Rates and > risks show that mortality differences are most pronounced
amongst adult males, with those in the Slavic 3 being worst off. They also identify the diseases
of the circulatory system and injuries as leading contributors to this gap. > Life table methods
can show how different life stages and different causes of death each contribute to the overall
mortality gap. Summary measures – > health expectancies and health gaps – combine
information on health losses from premature death with information on losses from disease
and injury among the living. A particular advantage of health gap metrics (such as the
Disability adjusted life years (DALY)) is their capacity to ‘‘decompose’’ health differences
into the conditions that produce them. These can, in turn, be attributed to the risk factors that
cause them. We illustrate this process with an assessment of the contribution of alcohol to the
health gap. Health losses attributable to alcohol are several times higher in males than in
females and much higher for males in EU10 and especially Slavic 3 than in EU15.
Metrics for public health assessments should be chosen carefully with the purpose for
conducting the assessment clearly in mind.
List of Abbreviations: DALY, disability adjusted life year; EU, European Union; EU15,
European Union Members before May 2004 (see > Table 30‐1); EU10, European Members
since May 2004 (Excluding Malta and Cyprus, see > Table 30‐1); HALE, > Health Adjusted
Life Expectancy; Slavic 3, Three Slavic States, Russia, Belarus and Ukraine (see > Table 30‐1);
WHO, World Health Organisation
1 Introduction
There is now a very large gap in health indicators between the populations of Eastern and
Western Europe. This gap was tending to reduce during the 1950s and 1960s before a sustained
increase set in around 1970.
Here we explore how different health metrics can serve to illuminate the nature and causes
of this health gap. We will show that different metrics have different strengths and weaknesses
and that the metric of choice depends on the question being addressed – adding further to the
need to always be clear about one’s intentions.
We shall deal successively with the use of (1) rates and risks, (2) life-table based measures
(expectancies) and (3) ‘‘health gap’’ metrics such as the Disability Adjusted Life Year (DALY).
We have chosen to limit our geographic scope to three groups of countries: those that were
members of the EU before May 2004 (EU15), those that have become members of the
European Union (EU) since May 2004 (excluding Malta and Cyprus) – referred to here as
the EU10 – and the three Slavic states of Russia, Ukraine and Belarus (> Table 30‐1).
We consider data for ages 0 to exact age 15 and from exact age 15 to exact age 65, mostly
over the period from 1970 to 2002. Cross-sectional analyses are for 2000 and 2002 where
available. National mortality data are those supplied to, and collated by the World Health
Organization. DALY estimates are also from the World Health Organisation (WHO) and
the Global Burden of Disease project (personal communication, C Mathers, World Health
Organization, Geneva).
East/West Differences in Health in Europe: Rates, Expectancies and DALYs 30 507
. Table 30‐1
The sub-regions in Europe used in this analysis
Total population
Countries in 2000
EU15 Austria, Belgium (1997), Denmark (1999), Finland, France, Germany, 377,635,881
Greece, Ireland, Italy, Luxemburg, Netherlands, Portugal, Spain,
Sweden, UK
EU10 Bulgaria, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, 104,354,593
Romania, Slovakia, Slovenia
Slavic 3 Belarus, Russia, and Ukraine 203,751,823
Most recent data for Belgium and Denmark was available from 1997 and 1999 respectively
2 Rates and Risks

2.1 All Cause Mortality – Rates and Risks
Age-standardized rates are the most commonly used metric in comparisons of mortality levels
across populations. Such metrics remove biases arising from differences in age composition.
We will illustrate their use with cause-specific mortality rates further below. For public health
purposes, age standardized rates do, however, have a problem of interpretability. Non-expert
readers will not immediately be able to judge whether an age-standard death rate of (say)
512 per 100,000 person years is ‘‘high’’ or ‘‘low.’’
Partly for this reason, a series of mortality metrics have been devised, which are usually
referred to (incorrectly) as rates but which are actually risks (i.e., probabilities of specified events
within specified periods). These include the Infant Mortality ‘‘Rate’’ (risk of death before the first
birthday), the Under 5 Mortality ‘‘Rate’’ (risk of death before the 5th birthday) and the Adult
Mortality ‘‘Rate’’ (risk of death between the 15th and 60th birthdays). Although typically
rescaled to a base of 1,000, these risk metrics have the advantage, particularly for non-expert
users, that their scale (0–1 or 100 or 1,000) is intuitively interpretable. Their quantitative import
is therefore easier to judge. Special familiarity with mortality statistics is not needed in order to
sense, for example, that for a 15 year old Russian male to have (at current mortality rates)
around a 47% chance of dying before 60 (i.e., an ‘‘Adult mortality rate’’ of 470 per 1,000) is a very
grim state of affairs indeed (http://www.who.int/countries/rus/en/ accessed 21/4/08).
Age specific rates can readily be converted to risks using the formula:
P
rt
Risk ¼ 1 e
where e is the base of natural logarithms, r is a component rate and t is the duration of
exposure to each rate. The Srt in the formula sums rates across the age range of interest: if,
for example, these are rates for 5 year age bands then each such constituent rate is multiplied
by 5 and then they are all summed.
Summarizing mortality levels across different ages – whether in an age-standardized rate
or in a risk covering part of the lifespan – inevitably sacrifices detail. It would therefore be very
convenient if mortality risks in one part of the lifespan could serve as a proxy for mortality
risks at all ages. The idea that the Infant Mortality Rate could play this role did, in fact, gain
ground early in the twentieth century and even persists to this day:
‘‘IMR is also a useful indicator of a country’s level of health’’ (Wikipedia, http://en.
wikipedia.org/wiki/Infant_mortality_rate, accessed April 3, 2008).
Whether using rates or risks to compare populations it is therefore important to check
whether relative differences in mortality levels are, or are not, consistent across the life span. In
> Figure 30‐1 we examine the association between child (i.e., under 5) and adult male
mortality risks across the three groups of countries of interest.
. Figure 30‐1
All cause mortality risks (1,000) ages 0–5 versus in adult males (ages 15–65), 2000. We have
departed from the conventional range of 15–60 and used 15–65 because we wish to make other
comparisons for this range. While there is considerable overlap in under-5 mortality risk, these
countries are grouped into three distinct groups where adult male mortality is concerned. Data
source: Authors analyses using WHO Statistical Information System – mortality database
Looking up from the under 5 mortality risk axis (i.e., the x axis) in > Figure 30‐1 we see
that child mortality risks in the EU15, EU10 and the Slavic 3 overlap. On the other hand,
looking in from the adult male mortality risk axis (the y axis) we see no overlap: there are three
separate clusters with the Slavic 3 as high outliers.
The idea that differences in infant or child mortality can serve as a marker for mortality
differences across the life span doesn’t really work and should be abandoned. East/west
mortality differences are largest in adults and the characterization of these differences there-
fore needs to concentrate on the adult ages.
2.2 Cause – Specific Mortality Risks
Given that the largest relative mortality differences are in working age males, it is of interest to
examine reasons for this by comparing absolute risks of death from specific causes in this group.
Because we are no longer dealing with the risk of death from all causes, the interpretation of risks
becomes a little more complicated. For the concept of risk to continue to work in a simple way,
we need to assume, for each group of causes being considered, that no other risks of death are
operating. With this qualifier, cause specific risks can still serve to convey a sense of the absolute
magnitude of mortality levels. For example, knowing that 15 year old males in the Slavic 3 would
have a risk of death from injury by the age of 65 (in the absence of competing risks) of around
19% (compared to 2% for the corresponding group in the EU15) is informative both absolutely
and comparatively (> Table 30‐2). So too is the comparison in the Slavic 3 males between the
risks of death from injury (19%) and the risk of death from vascular causes (25%).
. Table 30‐2
Risks of dying (%) from major causal groups (in the absence of competing risks), adult
males, 2000
Infectious Diseases of the circulatory Malignant

diseasesa systemb neoplasmc Injuriesd
EU15 0 5 6 2
EU10 1 13 10 4
Slavic 3 3 25 11 19
a
ICD9 BTL [01–07]; ICD10 [A00–B99]
b
ICD9 BTL [25–30]; ICD10 [I00–I99]
c
ICD9 BTL [08–14]; ICD10 [C00–C97]
d
ICD9 BTL [E47–E56]; ICD10 [V01–X59, Y40–Y86, Y88]
The risk of dying by the age of 65 amongst adult males is highest amongst those in the Slavic republics. In
particular, the risk of dying from diseases of the circulatory system and injuries is very high in Slavic 3. Data source:
Authors analyses using WHO mortality database
2.3 Uses of Cause Specific Rates
Knowing that absolute differences in mortality are greatest in adult males does not make
mortality differences in adult females uninteresting. If we wish to seek out the ‘‘underlying’’
(e.g., dietary) causes of the massive differences in vascular mortality risks, we may be concerned
that the male rates are more affected by ‘‘noise’’ – for example, from the different timing of the
smoking epidemics (which have had bigger absolute effects on males) (Didkowska et al., 2005)
and, in the comparisons of interest here, from culturally-based differences in binge drinking
(Didkowska et al., 2005; Rehm et al., 2007). The evolution of vascular mortality rates in middle
aged females in Europe is therefore of potential interest and is shown in > Figure 30‐2.
Here age and cause-specific rates provide perhaps the clearest picture of how the biggest
component of the East/West mortality gap has evolved – at least in relation to those causes of
vascular disease that are most fully shared by males and females – for example, composition of
the diet. In the 1950s female vascular mortality rates for all European countries formed a single
cluster. By the 1990s there are two clusters – one for the western countries and one for the
eastern countries. The gap was created by falls in vascular risks in the western countries that
were not matched by similar falls in the eastern countries. It appears, for females at least, that
the gap was created not so much by things going wrong in the east as by things going right in
. Figure 30‐2
Age-standardized death rates per 100,000 person years from all- vascular causes in females aged
45–64, 37 European countries (including former Soviet republics), 1950s to 1990s (log scale). The
upper heavy broken line is for Hungary and the lower one is for France. There is a steady decline
in vascular mortality amongst women in Western countries over the years while those in Eastern
countries have remained high. Data source: Authors analyses using WHO mortality database
the west that were not matched in the east. Other evidence suggests that changes in the
nutritional/physiological risk factors for vascular disease are the leading suspects (Bennett
et al., 2006; Capewell et al., 2000; Critchley et al., 2004; Ford et al., 2007; Unal et al., 2004).
Rates and risks are capable of characterizing both absolute and relative differences in
mortality. They are, however, limited in their ability to express these differences in a way that
reflects the social importance of death at different ages. This is well illustrated by deaths due to
intentional and unintentional injury. Injuries make up a large proportion of deaths in
those aged 5–35, especially in males. Although total deaths from vascular diseases are much
more numerous, they are concentrated towards the end of the lifespan, so the loss of expected
life per death is much smaller than in the case of injury. Rates and risks can’t really capture
mortality levels in a way that reflects the losses they incur. Time-based metrics generated by
life tables can help fill this gap.
3 Life Expectancies and Health Gap Measures
Life tables summarize mortality levels in an intuitively simple way and their method of
calculation gives more weight to events that result in bigger losses of potential life years
lived. > Table 30‐3 compares life expectancies at birth (e0) – sensitive to losses at all ages – and
at 15 (e15), reflecting only losses in the adult years. The East West gap in life expectancy is
almost as big at 15 as it is at birth, again emphasizing the dominant contribution of risk
differences in the adult years.
Expectancies can be made more informative by decomposing the contribution of different
age groups to the overall differences in life expectancy (> Figure 30‐3).
. Table 30‐3
Life expectancies in 2000 at birth and at age 15, by sex: EU15, EU10 and 3 Slavic Republics
Males Females
EU15 EU10 Slavic EU15 EU10 Slavic
e0 75.9 68.9 59.9 81.8 77.2 72.4
e15 61.5 55.1 46.4 67.4 63.2 58.8
The differences in life expectancy at the age of 0 between Eastern and Western European countries are similar to
the differences in expectancies at age 15. Data source: Authors analyses using WHO mortality database
. Figure 30‐3
The percentage contribution of different life stages to the difference in life expectancy at birth:
pair-wise comparisons between the EU 15, EU1O and the Slavic republics – 2000. Amongst males
the age range between 15 and 64 contributes most to the differences in life expectancy between
EU15, EU1O and Slavic 3. Amongst women, those over 65 contribute more to the difference in life
expectancy (except in the EU1O/Slavic 3 comparison). Data source: Authors analyses using WHO
Statistical Information System – Mortality
This form of decomposition of life expectancy differences illustrates nicely how differences
in mortality during the working ages make a dominant contribution to inter-regional differ-
ences in male life expectancy at birth. For females, perhaps surprisingly, it is differences in
mortality levels beyond age 65 that make the largest contribution in two of the three
comparisons.
3.1 Decomposition of Life Expectancy Differences by Cause
It is also possible to use life table methods to summarize the contribution of different causes
to differences in life expectancy between populations. This can be done using life expectancy
at birth as the summary indicator or using just the expectation of years lived within a specific
age range.
In addition to calculating expectancies of total life, it is possible to calculate ‘‘health
adjusted’’ expectancies e.g., HALE (Health Adjusted Life Expectancy) (Mathers et al., 2003a)
and ‘‘Healthy life expectancy.’’ These include an adjustment that reduces the value of time lived
in less than perfect health. The adjusted figure expresses the total expected life span in the
equivalent number of years in perfect health. For example, a year lived in a state equivalent to
80% of perfect health counts as equivalent to 0.8 years of perfect health.
Health expectancies of this kind are straightforward to calculate but have rather demand-
ing data requirements – unless survey data on self-rated health is used more or less directly as
in the ‘‘Healthy life expectancy’’ favored by the European Union (http://ec.europa.eu/health/
ph_information/indicators/lifeyears_en.htm accessed 21/4/08) and the UK (Kelly et al., 2000).
Data of this latter kind is fairly readily available but lacks comparability across age groups and
across cultures. For example, with increasing age one’s expectations for bodily functioning
decrease, so subjective ratings of health will be more favorable than more objectively based
ratings would be. Across cultures there are major unsolved problems arising from the way
persons rate their health in response to similar questions. An alternative more ‘‘objectivist’’
approach is embodied in the HALE favored by the WHO. Here average health levels are
assessed by synthesizing information from a wide variety of sources, including modeled
disease prevalences and their associated disability levels as well as self-reported health states.
The replicability of these assessments is unclear (Mathers et al., 2003a).
Health expectancies summarize information on both mortality and morbidity levels into a
single index value. As such they constitute one family of ‘‘Summary measures of average
population health.’’ The other family are the ‘‘Health gap’’ measures, of which the best known
is the ‘‘Disability Adjusted Life Year (lost)’’ – the DALY.
3.1.1 DALYs
DALYs have two advantages:

1. Like health expectancies, they combine information on health losses from premature death
with information on health losses among the living.
2. Unlike the health expectancies, health gaps can be readily decomposed into the diseases
and injuries that contribute to them. These in turn can be attributed to the risk factors that
cause them (Ezzati et al., 2004). This ability to quantitatively attribute health losses to their
cause is of great value for public health assessments.
DALYs are usually incidence-based, in which case they add together losses of life years arising
from deaths with losses from onsets of non-fatal disease and injury during the period of
interest (usually a calendar year). Losses are calculated relative to lives lived in perfect health
with the survival functions of reference life tables with a life expectancy at birth of 80 for males
and 82.5 for females (Mathers et al., 2003b).
Here we illustrate how DALYs can be used to work backwards from the health gap to its
contributing diseases and injuries and from those to the underlying responsible exposures,
concentrating – in this illustration – just on the role of alcohol (> Figure 30-4).
. Figure 30-4
Total DALYs/l00,000 person years at ages 15–69 attributed to alcohol, by cause, males and
females in EU 15, EU10 and Slavic republics, 2002. The majority of the difference in DALY’s lost/
100,000 person years between EU15, EU10 and Slavic 3 is loss of healthy life due to injury. Data
source: Authors analyses of country estimates from WHO, evidence and information for policy
> Figure 30-4 depicts the total health losses (DALYs) per 100,000 person-years attributed
to alcohol in the three population groups of interest.

1. In each of the populations, losses attributed to alcohol are several times higher in males than
in females (4.5, 12.3 and 6.8 times higher respectively in the EU15, EU10 and Slavic 3).
2. Among males, losses in the EU10 and (especially) in the Slavic 3 are much higher than in
the EU15 – respectively 1.8 and 4.8 times higher.
3. In the EU15 males and females, losses from (non-fatal) neuropsychiatric conditions
(mostly alcohol dependence syndrome and depression) comprise a large proportion
(72.5%) of the total health losses from alcohol. Such losses show only a modest gradient
across the three regions (22.6% greater in Slavic 3).
4. In the EU15 males, alcohol confers a net protective effect on vascular disease – because of the
prevalence of the protective pattern of frequent drinking. In the EU10 and Slavic 3 the net
effect of alcohol on vascular risk is adverse probably because of the dominance of the binge
drinking pattern (which actually seems to increase vascular risk) (Britton and McKee, 2000).
5. The most dramatic gradient west to east for deaths attributed to alcohol is for deaths
from injury: The male rates being 2.7 and 11.7 times higher in the EU10 and Slavic 3 than
in the EU15.
. Table 30‐4
Taxonomy of metrics of disease occurrence: strengths and weaknesses when used to
characterize the East/West health gap in Europe
Metric type Examples Advantages Disadvantages Comments

Rates
Crude rates Crude death Low data Sensitivity to age
rate for all requirements structure, hence
causes non-comparable
Age- Age Characterizes disease Absolute and Useful for
standardized standardized occurrence in a relative magnitudes ‘‘epidemiological’’
rates death rates – comparable way are not readily characterization of
for all causes across groups of interpretable by disease occurrence
or for major interest persons not in relation to other
groups regularly working attributes
with them
Risks
Risks of Infant As probabilities, scale Risks over wide age
death from mortality is easily interpreted span are not
all causes ‘‘rate’’; Adult by non-expert users sensitive to whether
mortality deaths occur earlier
‘‘rate’’ (45q15) or later i.e., don’t
fully reflect quantity
of lost life
Risks of Risk of death As probabilities, scale Need to assume no
death from from vascular is easily interpreted competing risks i.e.,
specified causes by non-expert users ‘‘if no other causes
causes between 15 (but see note on were operating’’
and 65 competing risks)
Time-based:
Life
expectancies
Expectation Weights deaths by Cannot be readily
of life; at their effects on decomposed by
birth, exact average time lived disease or risk
age 15 etc factors
Time-based: health gaps
Years of life Total and Can be decomposed Only counts deaths Requires use of
lost (YLL) cause-specific to losses by age, reference life table
YLL per causes and by risk
100,000 factors
population
East/West Differences in Health in Europe: Rates, Expectancies and DALYs

30 515
Metric type Examples Advantages Disadvantages Comments

Disability DALYs lost Can be decomposed Metric not yet widely
Adjusted Life per 100,000 to losses by causes understood or used;
Years Lost population and by risk factors; substantial
(DALYs) Includes health losses uncertainties in YLD
among the living estimates because of
from disease and inadequacies in
injury losses (Years epidemiological
Lived with Disability, information;
YLD) disability weights
sometimes
controversial
All metrics have advantages and disadvantages and all are potentially useful in characterizing population health.
The choice of metric should be deliberate and matched to purpose
The data summarized in > Figure 30-4 thus convey a good deal about the way in which both
the quantity of alcohol consumed and the temporal pattern of consumption in the Slavic 3
contribute to their much higher health losses. (It is of interest to note that some rural
Mediterranean populations consume equal quantities of ethanol per month but have nothing
like the Russian pattern of associated vascular and injury mortality (Powles and Day, 1997)).
DALYs can thus offer a much fuller picture of reasons for variation in health losses (Powles
et al., 2005). They do however require comprehensive Burden of Disease studies and these are
hindered by the quantity and quality of available descriptive epidemiology. Furthermore,
DALYs entail their own set of assumptions and methods of calculation.
4 Conclusion
Here we have shown that the health gap between East and West Europe can be characterized in
a number of ways. By choosing different metrics it is possible to illuminate more and more of
the situation we are trying to understand. Using rates and risks we were able to illustrate higher
mortality rates in adult males in EU10 and in particular the Slavic 3 countries and to identify
Slavic 3 males as being especially high risk of dying from injuries and diseases of the
circulatory system. Life table methods can be used to confirm the contribution of differences
in mortality levels at different life stages and differences in risks for specific diseases to overall
survival differences. DALYs provide a > summary measure of health differences that allows
such differences to be decomposed back to the contributing diseases and injuries and then
further to the risk factors responsible.
Differing health metrics have different strengths and weaknesses, and each comes with its
own set of assumptions. No metric is capable of being all things for all purposes. The use of a
wider range of metrics can add depth to our understanding of the health of populations and to
our understanding of the causes of health differences between populations (> Table 30-4).
The choice of metrics in public health assessments should be deliberate and it should be
informed by the nature of the question being addressed.
Summary Points
There exists a large gap in health indicators between East and West Europe.
Rates and risks can be useful for identifying the age-sex groups where risks are highest, and
for identifying the leading causes of death.
Life tables can help elucidate the contribution of different age groups and causes to the
observed differences in life expectancy between populations.
Summary measures sum health losses from mortality and morbidity; gap measures, like
the DALY, can be used to attribute losses to diseases and to the risk factors that cause them.
Choice of metrics needs to be informed by the question they are being used to address.
References
Bennett K, Kabir Z, Unal B, Shelley E, Critchley J, Perry I, Mathers C, Murray CJL, Salomon JA, Murray CJL, Evans
Feely J, Capewell S. (2006). J Epidemiol Commun DB (eds.) (2003a). Methods for Measuring Healthy
Health. 60: 322–327. Life Expectancy. Health Systems Performance
Britton A, McKee M. (2000). J Epidemiol Commun Assessment: Debates, Methods and Empiricism.
Health. 54: 328–332. World Health Organization, Geneva, pp. 437–470.
Capewell S, Beaglehole R, Seddon M, McMurray J. Mathers CD, Bernard C, Moesgaard Iburg K, Inoue M,
(2000). Circulation. 102: 1511–1516. Ma Fat D, Shibuya K, Stein C, Tomijima N, Xu H.
Critchley J, Liu J, Zhao D, Wei W, Capewell S. (2004). (2003b). Global Burden of Disease in 2002: Data
Circulation. 110: 1236–1244. Sources, Methods and Results. World Health Orga-
Didkowska J, Manczuk M, McNeill A, Powles J, nization, Geneva.
Zatonski W. (2005). Br Med J. 331: 189–191. Powles JW, Day NE. (1997). Lancet. 350: 956–956.
Ezzati M, Lopez AD, Rodgers A, Murray CJL. (2004). Powles JW, Zatonski W, Vander HS, Ezzati M. (2005).
Comparative Quantification of Health Risks: Global BMC Public Health. 5: 116.
and Regional Burden of Diseases Attributable to Rehm J, Sulkowska U, Manczuk M, Boffetta P, Powles J,
Selected Major Risk Factors. World Health Organi- Popova S, Zatonski W. (2007). Int J Epidemiol. 36:
zation, Geneva. 458–467.
Ford E, Ajani UAA, Croft JB, Critchley JA, Labarthe DR, Unal B, Critchley JA, Capewell S. (2004). Circulation.
Kottke TE, Giles WH, Capewell S. (2007). N Engl J 109: 1101–1107.
Med. 356: 2388–2398.
Kelly S, Baker A, and Gupta S. Health Statistics Quarterly
2000(7): 32–37.
31 The Burden of Neglected
Diseases in Developing
Countries
A. Boutayeb
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
2 Neglected Diseases: A Succinct Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520

2.1 Lymphatic Filariasis (LF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
2.2 Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
2.3 Schistosomiasis and Soil-Transmitted Hemlinthiasis (Hookworm, Ascariasis,
Trichuriasis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
2.4 African Trypanosomiasis (Sleeping Sickness) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
2.5 American Trypanosomiasis (Chaga’s Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
2.6 Dengue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
2.7 Buruli Ulcer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
2.8 Trachoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
2.9 Leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
2.10 Dracunculiasis (Guinea-Worm Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
2.11 Onchocerciasis (River Blindness) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
2.12 Neuropsychatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
2.13 Other Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
3 Why Neglected Diseases are Given So Little Attention? . . . . . . . . . . . . . . . . . . . . . . . . . . 526
4 Global Burden of Neglected Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528

518 31 The Burden of Neglected Diseases in Developing Countries
Abstract: Although with low mortality rates, neglected diseases are causing severe and
permanent disabilities and deformities affecting approximately 1 billion people in the world,
yielding millions of > Disability Adjusted Life Years. Unfortunately, despite scientific and
technological advances realized during the last century and the evidence of possible research
output in the biomedical field, a large population living in developing countries, do not have
access to adequate affordable treatment against infectious diseases. The reasons why the so-
called neglected diseases have been given very little attention are local, national and interna-
tional. First of all, these diseases affect almost exclusively extremely poor populations living in
remote areas beyond the reach of health services. Secondly, they occur in developing countries
where few governments are putting science, technology, and innovation at the centre of their
strategies and, in the meantime, war and conflicts are financed at the expense of health
services. Thirdly, little (or no) research is currently dedicated to the most neglected diseases
because they offer negligible marketable and profitable issues, getting less than 10% of the
global spending on health research in spite of being among diseases or conditions that account
for 90% of the global disease burden. New initiatives are needed and coordination for a
better efficiency should strengthen the existing projects such as > Drug for Neglected Diseases
Initiative, Global Alliance for Vaccines and Immunization, The > Human Hookworm Vaccine
initiative and the > Foundation for Innovative New Diagnostics.
List of Abbreviations: AIDS, acquired immune defense system; DALY, disability adjusted
life years; DF, dengue fever; DHF, dengue hemorrhagic fever; DNDi, drug for neglected
diseases initiative; DSS, dengue shock syndrome; EU, European union; FIND, foundation
for innovative new diagnostics; FL, filariasis lymphatic; GAVI, global alliance for vaccines and
immunization; HHVI, human hookworm vaccine initiative; HIV, human immunodeficiency
virus; MDG, millennium development goals; ND, neglected disease; OCDE, organization for
economic cooperation and development; OCP, > Onchocerciasis Control Program; UNDP,
United Nations Development Program; USAID, United States Agency for Development; VL,
visceral leishmaniasis; WHO, World Health Organization; YLD, years lived with disability;
YLL, years of life lost
1 Introduction
Despite scientific and technological advances realized during the last century and the evidence
of possible research output in the biomedical field, a large population living in developing
countries, do not have access to adequate affordable treatment against infectious diseases.
The fact that the so-called neglected diseases have been given very little attention is now
recognized at different levels. The European Parliament stressed that ‘‘to our shame, Neglected
Diseases have not received the attention they deserve from EU actions’’ (EP, 2005). The World
Health Organization (WHO) explains that these diseases are hidden because they affect almost
exclusively extremely poor populations living in remote areas beyond the reach of health
services (WHO, 2003a), whereas other non governmental organizations like doctors without
borders are criticizing the ‘‘inertia’’ and the delay taken in the response to the infectious
diseases, and trying to attract the international attention to stimulate more interest in the
development and provision of treatments for the most neglected diseases. Meanwhile, at a
time where human rights and health equity are on all international agendas, millions of poor
people are daily suffering from neglected diseases (NDs) such as lymphatic filariasis (LF),
The Burden of Neglected Diseases in Developing Countries 31 519
leishmaniasis, schistosomiasis, Buruli ulcer, cholera, cysticercosis, dracunculiasis (guinea-

worm disease), foodborne trematode infections, hydatidosis, soil-transmitted helminthiasis
(ascariasis, trichuriasis, hookworm diseases), trachoma, trypanosomiasis (sleeping sickness),
onchocerciasis, Chagas disease, dengue and others (Boutayeb, 2007) (> Table 31-1).
In order to assess the impact of these diseases and to facilitate meaningful comparisons of
the disease burden across world regions, economic costs are often expressed in > international
dollars and diseases are evaluated according to their burden in terms of mortality and
disability. The most frequent method that has been used during the last decade is the approach
that measures the disease burden in terms of disability adjusted life years (DALY) which is a
combination of years of life lost (YLL) due to premature mortality, and years lived with
disability (YLD). Thus, one DALY is thought of as one lost year of healthy life (either through
death or illness/disability). Other metrics for disease burden can be found in the chapters
Calculating QALYs and DALYs by F. Sassi, QALYs Gained in antiviral treatment of chronic
hepatitis C – a decision-analytic approach by U. Siebert and The global tuberculosis burden by
N. Ishikawa.
An average disability weight is affected to each disease according to the severity of its
impact. As indicated in > Table 31-2, the weights vary between 0 (indicating full health) and 1
(meaning death or equivalent). Details, critics and expected improvement of the DALY
measure can be found in the recent paper by Mathers et al. (2007) (> Table 31-2).
. Table 31-1
Deaths caused by neglected diseases in developing countries, in thousands, in 2002 (WHO,
2003b)
Eastern South-East
Africa America Mediterranean Asia World
Trypanosomiasis 47 0 1 0 48
Chagas disease 0 15 0 0 15
Schistosomiasis 2 1 9 0 15
Leishmaniasis 8 0 5 36 51
Lymphatic filariasis 0 0 0 0 0
Onchocerciasis 0 0 0 0 0
Leprosy 0 1 1 3 6
Dengue 0 2 1 12 19
Japanese encephalitis 0 0 2 8 14
Trachoma 0 0 0 0 0
Intestinal nematode 3 1 1 5 12
infections
Ascariasis 1 0 0 1 3
Trichuriasis 0 0 0 2 3
Hookworm disease 2 0 0 1 3
Reproduced by kind permission of the World Health Organization. In developing countries, the so-called neglected
are responsible for about 500,000 deaths every year
. Table 31-2
Disability weight by disease cause (WHO, 2004)
Disability Disability
Disease/cause weight Disease/cause weight
Onchocerciasis/blindness 0.600 Leprosy/disabling 0.152
Onchocerciasis/itching 0.068 Dengue hemorrhagic fever 0.075
Onchocerciasis/low vision 0.260 Ascariasis/contemporaneous 0.006
cognitive deficit
Trachoma/blindness 0.600 Ascariasis/cognitive impairment 0.463
Trachoma/low vision 0.278 Ascariasis/intestinal obstruction 0.024
Leishmaniasis/visceral 0.243 Trichuriasis/contemporaneous 0.006
cognitive deficit
Leishmaniasis/cutaneous 0.023 Trichuriasis/massive dysentery 0.116
syndrome
Schistosomiasis/infection 0.006 Trichuriasis/cognitive impairment 0.024
Lymphatic filariasis/hydrocele 0.073 Trichuriasis/high intensity 0.000
>15 cm infection
Lymphatic filariasis/Bancroftian 0.106 Hookworm/anemia 0.024
lymphoedema
Lymphatic filariasis/Brugian 0.116 Hookworm/cognitive impairment 0.024
lymphoedema
Reproduced by kind permission of the World Health Organization. Average disability weight indicates the power
of each neglected disease to cause disability and morbidity
2 Neglected Diseases: A Succinct Overview

Although neglected diseases are not causing high mortality rates, their socio-economic cost is
important and their global impact can be measured by severe and permanent disabilities and
deformities affecting approximately 1 billion people in the world and causing millions of
Disability Adjusted Life Years (DALYs), mainly in Africa and Latin America. Indeed, lymphatic
filariasis (LF), leishmaniasis, schistosomiasis, sleeping sickness, Chaga disease, Buruli ulcer,
dengue and others are responsible for impaired childhood growth, mental retardation,
blindness, amputation and diverse disability conditions (> Table 31-3).
Neglected diseases are almost exclusively affecting developing countries. These illnesses
thrive in Africa, Asia and Latin America (> Table 31-4). However, most of the so-called
neglected diseases are endemic in African countries. A brief overview of each disease and
its impact, essentially based on the estimates of the World Health Organization (WHO), is
given below.
2.1 Lymphatic Filariasis (LF)
Lymphatic filariasis is caused by thread-like parasitic worms and transmitted by mosquitoes.

It is also known as Elephantiasis because it results in the grossly enlarged limbs. Currently
. Table 31-3
The burden of disease in DALYs by cause in developing countries, in thousands, in 2002 (WHO,
2003b)
Eastern South-East
Africa Americas Mediterranean Asia World
Trypanosomiasis 1,494 0 39 0 1,535
Chagas disease 0 662 0 0 667
Schistosomiasis 1,334 74 227 7 1,702
Leishmaniasis 383 44 248 1,358 2,090
Lymphatic filariasis 2,011 10 122 3,219 5,777
Onchocerciasis 470 2 10 0 484
Leprosy 23 18 25 118 199
Dengue 5 69 30 381 616
Japanese encephalitis 0 0 83 306 709
Trachoma 1,212 164 283 168 2,329
Intestinal nematode infections 1,138 168 225 804 2,951
Ascariasis 858 62 158 409 1,817
Trichuriasis 233 71 60 368 1,006
Hookworm disease 46 0 2 9 59
Reproduced by kind permission of the World Health Organization. Although with relatively low rates of mortality,
neglected diseases constitute a real threat and impediment to development by their extravagant burden
. Table 31-4
Prevalence of selected neglected diseasesa
Number endemic Population infected Population at risk

Disease countries (millions) (millions)
Lymphatic filariasis 80 40 1,300
Leishmaniasis 88 12 350
Schistosomiasis 76 200 600
African trypanosomiasis 36 18 100
Dengue 100 50 2,500
Chagas disease 21 20 100
Trachoma 100 150 600
a
Author’s estimation
Altogether, neglected diseases affect more than one sixth of the world population, exclusively living in developing
countries
ranking as the second leading cause of disability worldwide, this disease has been causing
severe disability and immense suffering for centuries. Endemic in over 80 countries, where 120
million people are infected and 1.3 billion people are at risk, LF is seriously incapacitating and
disfiguring at least 40 million people worldwide (Perera et al., 2007).
. Table 31-5
Poverty and lymphatic filariasis (WHO, 2003a)
Number of LF Population living in

Number of endemic endemic countries Population at risk
Countries countries countries (millions) for LF (millions)
Least developed 38 32 86.0 289.5
Other Low-income 21 11 75.6 633.3
Lower-middle-income 19 10 4.3 39.7
Upper-middle-income 3 1 0.3 1.3
Reproduced by kind permission of the World Health Organization. Like most of neglected diseases, lymphatic
filariasis can be seen both as a cause and a consequence of poverty
African and Asian populations living in Least-developed, > low-income countries, and
lower-middle-income countries represent nearly 100% of people at risk for LF (> Table 31-5).
According to a 1998 estimate, economic gains following LF elimination are expected to
approach US$4 billion per year (WHO, 2003a).
Treatment is by a once-yearly administration of single doses of albendazole plus either
dietthylcarbamazine or ivermectin carried out for 4–6 years. Reduction in the frequency of
acute episodes of inflammation and improvement of the patient’s quality of life may be
obtained by rigorous hygiene of the affected limbs, combined with measures to minimize
infection and promote lymph flow.
2.2 Leishmaniasis
Leishmaniasis is a parasitic infection transmitted by the bite of a tiny sand-colored fly that
feeds and breeds in forest areas, caves, or the burrows of small rodents. The parasite can reside
for decades in asymptomatic individuals (humans or animals) who provide an important
reservoir of infection. The disease thrives in impoverished urban areas and refugee camps, and
malnutrition is a well-known risk factor for visceral leishmaniasis in particular. According to
WHO estimates, this disease is endemic in 88 countries, where 12 million people are currently
affected and 350 million people are at risk. However, as a disease of poverty that causes high
morbidity but relatively low mortality, its burden remains difficult to evaluate. With a rising
trend, about 1.5–2 million new cases occur annually but only around 600,000 infections are
officially reported each year (WHO, 2003a).
Leishmaniasis is a complex disease ranging in severity from self-healing cutaneous ulcers
to severe life-threatening infection. The most life-threatening form is Visceral Leishmaniasis
(VL) (also known as kala-azar or black fever) which attacks the immune system, with the most
severe damage occurring in the liver, spleen, and bone marrow. According to WHO estimates,
VL affects around 500,000 each year, compared with 1–1.5 million cases of the cutaneous
forms. In 1999, VL caused 57,000 deaths.
The most widely prescribed drug to treat this disease is pentavalent antimony, discovered a
century ago. The drug has serious side effects, needs prolonged treatment and is loosing
efficacy in some regions due to parasite resistance. Newer treatments have problems of
toxicity, high price, and/or difficulty of administration.
It should be stressed that AIDS and VL reinforce one other and co-infection poses
additional problems. AIDS increases the risk of VL by 100–1,000 times in endemic areas.
2.3 Schistosomiasis and Soil-Transmitted Hemlinthiasis

(Hookworm, Ascariasis, Trichuriasis)
These ancient diseases continue to cause misery and disability to millions of poor people
in developing countries. It is thought that 2 billion people are affected, of whom 300 million
suffer severe morbidity. In 1999, WHO estimated that these two diseases represented
more than 40% of the disease burden due to all tropical diseases, excluding malaria (WHO,
2003a).
In school-age children, intestinal parasites cause anemia, poor growth and poor cognitive
performance and other subtle forms of morbidity, whereas, schistosomiasis is known to cause
irreversible damage to the liver, kidney and urinary tract. Despite the success of ongoing
control programs in certain Asian and North African countries, where mortality, morbidity
and transmission have been reduced, the global number of infected people has not changed for
50 years, mainly due to dramatic increases in sub-Saharan Africa. Indeed, in 2000, 85% of all
people affected by this disease were living on the African continent.
Treatment with praziquantel exists but the emergence of resistant parasites may complicate
the task. There is a need for alternative therapies.
2.4 African Trypanosomiasis (Sleeping Sickness)
Sleeping sickness is an old parasitic disease that ravaged sub-Saharan Africa in waves of
> epidemics for at two centuries. Thought to be virtually eliminated from Africa in the
mid-1960s, the disease was back by 1970 with a growing > prevalence. It is now endemic in
36 sub-Saharan African countries where 60 million people are at risk. Although the disease is
underreported, an estimated 300,000–500,000 people are thought to be infected, most of them
are living in remote rural areas on less than US$150 per year. Proper treatment reaches only
10% of patients needing it and the disease is having devastating consequences on the
development in Africa, affecting health, education and socio-economic development in
general. African trypanosomiasis causes over 3 million livestock deaths each year and an
annual loss of US$ 4.5 billion in agriculture, impeding development and accentuating poverty
(Boutayeb, 2007; WHO, 2003a).
The limited choice of available drugs, their toxicity (causing mortality in 5% of patients),
and the disease’s growing unresponsiveness to drugs, make it imperative that new treatments
are urgently developed.
2.5 American Trypanosomiasis (Chaga’s Disease)
According to WHO estimates, about 100 million people are at risk of acquiring Chagas’ disease
in Latin America, representing about 25% of the population of whom 18 million people are
infected by the parasite and 50,000 people die annually. Only two drugs (nifurtimox and
benznidazole) exist but there is no treatment for chronic Chaga’s disease.
2.6 Dengue
Dengue is a re-emergent disease that is sweeping the world, hitting countries with tropical
and warm climates. It is transmitted to man by the mosquito of the genus Aedes and exists
in two forms: Dengue Fever (DF) or classic dengue and Dengue Hemorrhagic Fever
(DHF) which may evolve toward a severe form known as Dengue Shock Syndrome (DSS).
The major problem with dengue is the fact that the disease is caused by four distinct serotypes
known as DEN1, DEN2, DEN3 and DEN4. A person infected by one of the four serotypes
looses immunity to the three other serotypes. The disease is endemic in more than 100
countries and its > incidence has increased fourfold since 1970, putting half the world’s
population (2.5–3 billion) at risk. It is estimated that more than 50 million people are infected
annually of which a million are affected by the more severe form Dengue Hemorrhagic Fever.
WHO estimates that dengue causes a burden of 0.7 million DALYs but according to other
sources, the burden is much higher (Derouich et al., 2006). No treatment or vaccine is
available at the moment.
2.7 Buruli Ulcer
Buruli ulcer is a severely and disabling bacterial disease reported from 30 countries throughout
the tropical world. The disease has emerged dramatically over the past decade especially in
West Africa, by far the most affected region. WHO estimates that, prevalence rates reach 16%
in some communities in Ghana and 20% or more in Côte d’Ivoire.
The disease is now the second most prevalent mycobacterial disease after tuberculosis. It
can be cured if detected early. However, in Africa less than 10% of cases are seen at this stage
because, for many reasons, most infected people do not seek care until the disease is far
advanced. Consequently, most infected people will end up with irreversible deformity and
sometimes with life-threatening infection. Buruli ulcer is most common in children under
the age of 15, who account for 70% of all cases. With an average cost of treatment estimated
at US$780 per patient, this disease exacerbates health problems in many African countries
(WHO, 2003a).
At present, the only treatment available is surgery to remove the lesion and a skin graft if
necessary. This is both costly and dangerous, with loss of tissues or permanent disability.
2.8 Trachoma
Trachoma is the leading cause of preventable blindness. In developing countries, about 80

million people are affected, of whom some eight million are visually impaired and nearly 10%
of the population is at risk of blindness with more than 150 million people needing treatment.
But its impact goes beyond vision, it affects seriously productivity and development in general.
Indeed, as indicated in > Table 31-3, the disease burden due to Trachoma is around 2.3 billion
DALYs with 53% occurring in Africa. In some regions, pre-school children are particularly
affected with prevalence rates as high as 60–90%.
Poor hygiene conditions, crowded households, flies and water shortage constitute potential
risk factors for this disease caused by a microorganism (Chlamydia trachomatis) which spreads
through contact with eye discharge from infected people. It is estimated that, improving access
to water and better hygiene can reduce trachoma morbidity by 27% (Bartram, 2005).
2.9 Leprosy
Among the diseases that continue to challenge humanity, leprosy is one of the most known for
causing disability, deformity and fear. Considered highly contagious, the disease was thought
to be incurable. On top of their physical suffering, the victims were exposed to discrimination
and stigma. The sole option of control was the isolation of patients in colonies or leprosaria.
Fortunately, according to WHO, 14.5 million patients have been cured from leprosy since
1985, through multidrug therapy and less than a million people are affected by the disease
today (WHO, 2003a).
2.10 Dracunculiasis (Guinea-Worm Disease)
Dracunculiasis, commonly known as guinea worm disease is a painful and disabling parasitic
disease caused by Dracunculus medinensis. The disease thrives in rural communities lacking
access to safe drinking-water and adequate health care. Guinea worm affects agricultural
activity, food availability, and school attendance. In highly endemic areas, over 30% of village’s
population can be disabled by infection coinciding with the planting or harvest season. In the
mid-1980s, in south-eastern Nigeria, rice farming lost about US$20 million per year due to
outbreaks of guinea worm disease.
Before eradication program started in early 1980s, about 3.5 million people in 20 endemic
countries were infected. In 2005, only about 10,000 cases were reported in nine endemic
countries (WHO, 2003a).
2.11 Onchocerciasis (River Blindness)
Onchocerciasis (known as river blindness) is a parasitic disease caused by the bite of the black
fly, Simulium damnos. In 1974, when WHO, the World Bank, UNDP, and their partners
launched the Onchocerciasis Control Program (OCP) in West Africa, 10% of the population
in some African communities was blind, 20–30% suffered from serious visual handicap and
some regions have seen 40% of their men over the age of 40 years blinded by the disease. In the
1970s, the annual economic losses were estimated at US$30 million. More than 25 million
hectares of land available for settlement and agricultural cultivation which are now disease-
free, improving thereby the development in Africa and Latin America, were previously
infected.
2.12 Neuropsychatric Disorders
Mental illnesses are affecting developing countries with an increasing trend. Worldwide,
it is estimated that 450 million people suffer from mental, neurological or behavioral
problems. About 120 million people currently live with depression and some 900,000 people
commit suicide each year. In 2000, depression was the fourth leading cause of disease burden
(Moussavi et al., 2007). Schizophrenia affects 24 million people and nearly 40 million people
live with dementia. In particular, with ageing populations, the prevalence of Alzheimer’s
disease is rising rapidly. More than 80% of the 50 million affected by epilepsy live in
developing countries. It is thought that at least 70% of people affected can be seizure-free
if treated with antiepileptic drugs. However, the vast majority remain untreated (in Africa,
80% receive no treatment). More generally, cost-effective treatments can be made available for
most disorders but at least two-thirds of people who are mentally ill receive no treatment
(Thornicroft, 2007). The reader can find more details in the series of articles devoted by Lancet
in its volume 370 to mental disorders under the title ‘‘why do we invest so little in our mental
health care?’’. As indicated in > Table 31-4, mental illnesses are affecting developed and
developing countries alike. However, due to lack of budget and human resources, the impact
is more pronounced in > low-income countries and middle-income countries where
neglected mental illnesses are causing important economic costs and impeding human
development. It should be stressed that, in developing countries, children and adolescents
are particularly affected by mental or behavioral problems due to injuries, childhood infec-
tions and lack of oxygen at birth (> Table 31-6).
2.13 Other Diseases
Although with less impact, other NDs are affecting poor populations in developing countries.
These include cholera, cysticercosis, foodborne trematode infections and hydatidosis.
3 Why Neglected Diseases are Given So Little Attention?
In developing countries, very few governments are putting science, technology, and innovation
at the centre of their strategies and, in the meantime, war and conflicts are financed at the
expense of health services (Boutayeb, 2007; Mashelkar, 2005; Morel et al., 2005). In parallel,
. Table 31-6
Neuropsychiatric disorders: disability weight (WHO, 2004)
Disability Disability
Disease/cause weight Disease/cause weight
Unipolar depressive disorders: Episodes 0.398 Alzheimer and other dementias 0.666
Unipolar depressive disorders: Dysthymia 0.140 Parkinson disease 0.351
Bipolar affective disorder 0.367 Multiple sclerosis 0.411
Schizophrenia 0.528 Drug use disorders 0.252
Epilepsy 0.113 Insomnia (primary) 0.100
Alcohol use disorders 0.155 Panic disorder 0.165
Reproduced by kind permission of the World Health Organization. Neuropsychiatric disorders are causing a huge
burden in developing countries
in developed countries, there is a chronic shortage of investment in research and development

in poverty-related diseases (EP, 2005). Consequently, little (or no) research is currently dedi-
cated to the most neglected diseases which occur almost exclusively in poor developing
countries where they offer negligible marketable and profitable issues. Indeed, it is estimated
that less than 10% of the global spending on health research is devoted to diseases or conditions
that account for 90% of the global disease burden (Morel, 2003). The majority of research and
development of new drugs being mainly carried out by private pharmaceutical companies
based on profit making, it seems too costly and risky to invest in drugs for neglected diseases
occurring almost exclusively in developing countries and especially in low-income and least
developed ones, where public spending on drugs is less than US$6 (sub-Saharan Africa)
compared to around US$ 240 spent in countries of the Organization for Economic Coopera-
tion and Development (OECD) (Trouiller et al., 2002). This disproportionate deal is also
illustrated by the fact that of all drugs in development for all neglected diseases in 1999–2000,
18 R&D projects were clinical development, compared to 2,100 compounds for all other
diseases (WHO, 2002; EP, 2005). Similarly, between 1975 and 2004, among the 1,556 new
molecules of drugs marketed in the world, only 21 were intended for the neglected diseases
(eight for malaria, three for tuberculosis and only ten for the whole set of most neglected
diseases) (MSF, 2007). According to another study on the market of new chemical entities
between 1975 and 1999, only 16 among 1,393 new chemical entities were for tropical diseases
and tuberculosis, implying that there is a 13-fold greater chance for a drug to be marketed for
central-nervous-system disorders or cancer than for a neglected disease (Trouiller et al., 2002).
4 Global Burden of Neglected Diseases

According to WHO estimates, neglected diseases cause about 150,000 deaths annually. How-
ever, because of unreported cases and unreliable data, estimates are sometimes very different
and some sources assume that more than 500,000 deaths occur annually almost totally in
developing countries. Moreover, beyond mortality figures, the burden of these diseases is more
apparent when expressed in terms of disability.
Obviously, neglected diseases constitute an impediment to economic and human develop-
ment by increasing poverty, reducing productivity and affecting childhood growth and educa-
tion. Interference with other diseases like HIV/AIDS, tuberculosis and malaria worsens the
global impact of diseases. Conversely, conditions of poverty like unsafe water, poor sanitation
and refuse disposal sustain transmission cycles and favor the proliferation of vectors that
transmit neglected diseases (Bartram, 2005; Boutayeb, 2007; Franco-Paredes, 2007; Holveck
et al., 2007; Molyneux et al., 2005; Saxena et al., 2007). Studies have shown that controlling
neglected diseases is cost-effective and treatment can be provided for less than one dollar per
capita per year. For instance, in Brazil, one dollar invested in the control of Chagas disease
produces a return of $7.16, whereas in China, one dollar invested in the control of lymphatic
filariasis produces a return of $15. Similarly, onchocerciasis control in West Africa has been
described by the World Bank as one of the most effective investments in any development sector.
Unfortunately, despite this striking evidence, policymakers seemed to ignore that invest-
ment against neglected diseases is cost-effective. Indeed, these diseases receive 1/100th of the
funding devoted to the ‘‘big three’’ (HIV/AIDS, TB, malaria). It should be stressed, however,
that policymakers and their partners have recently showed a renewed interest in these diseases
(Perera et al., 2007).
5 Conclusion
At the dawn of the third millennium, while regular meetings are daily held worldwide to
discuss human rights and various forms, causes and consequences of health inequities, poor
populations living in developing countries are denied access to adequate and affordable
treatment against neglected diseases. In the era of advanced science and high technology,
there is growing evidence that treatments can be obtained but good will and incentive
measures should be enhanced. Consequently, urgent actions are necessary to develop new
drugs and vaccines that are efficient and accessible. New initiatives are needed and coordina-
tion for a better efficiency should strengthen the existing projects such as Drug for Neglected
Diseases Initiative (DNDi), Global Alliance for Vaccines and Immunization (GAVI), The
Human Hookworm Vaccine initiative (HHVI), the Foundation for Innovative New Diagnos-
tics (FIND), the USAID funded program on integrated control of seven of the most prevalent
neglected tropical diseases (trachoma, hookworm, ascariasis, trichuriasis, onchocerciasis,
schistosomiasis and lymphatic filariasis) and others (Boutayeb, 2006; Boutayeb, 2007;
EP, 2005; Molyneux, 2004; WHO, 2003a).
Summary Points
Neglected Diseases is the name given to a multitude of diseases, including lymphatic

filariasis, leishmaniasis, schistosomiasis, sleeping sickness, dengue, Chagas disease, Buruli,
ulcer, trachoma and others.
Dengue disease is endemic in more than 100 countries and its incidence has increased
fourfold since 1970, putting half the world’s population (2.5–3 billion) at risk.
Buruli ulcer is a severely and disabling bacterial disease reported from 30 countries
throughout the tropical world.
The disease burden due to Trachoma is around 2.3 billion DALYs with 53% occurring in
Africa.
Lymphatic filariasis is endemic in over 80 countries, where 120 million people are infected
and 1.3 billion people are at risk.
Leishmaniasis is endemic in 88 countries, where 12 million people are currently affected
and 350 million people are at risk.
Sleeping sickness is having devastating consequences on the development in Africa. It
causes over 3 million livestock deaths each year and an annual loss of US$ 4.5 billion in
agriculture.
More than 80% of the 50 million affected by epilepsy live in developing countries.
It is estimated that less than 10% of the global spending on health research is devoted to
diseases or conditions that account for 90% of the global disease burden.
According to a study on the market of new chemical entities between 1975 and 1999, only
16 among 1,393 new chemical entities were for tropical diseases and tuberculosis.
In sub-Saharan Africa, public spending on drugs is less than US$6 per capita compared to
around US$ 240 spent in countries of the Organization for Economic Cooperation and
Development.
One dollar invested in the control of Chagas disease produces a return of $7.16, and one
dollar invested in the control of lymphatic filariasis produces a return of $15.
Acknowledgments
This work is partially funded by the Program Global de Recherche of the university Mohamed
Ier.
References
Bartram J, Lewis K, Lenton R, Wright A. (2005). Lancet. Morel C, Broun D, Dangi A, Elias C, Gardener C, Gupta
365: 810–812. RK, Haycock J, Heher T, Hoetz P, Kettler H,
Boutayeb A. (2006). Trans R Soc Trop Med Hyg. 100: Keusch G, Krattiger A, Kreutz F, Lee K, Mahoney
191–199. R, Mashelkar RA, Min H, Matlin S, Mzimba M,
Boutayeb A. (2007). Developing countries and neglected Oehler J, Ridley R, Senanayake P, Thorsteinsdottir H,
diseases: Challenges and perspectives. Int J Equity Singer PA, Yun M. (2005). Innov Strat Today. 1:
Health. doi: 10.1186/1475–9276–6–20. 1–15.
Derouich M, Boutayeb A. (2006). Appl Math Comput. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V,
177: 528–544. Ustun B. (2007). Lancet. 307: 851–858.
European Parliament (EP). (2005). Report on Major and Perera M, Witehead M, Molyneux D, Weerasooriya M,
Neglected Diseases in Developing Countries. http:// Gunatilleke G. (2007). PLOS Negl Trop Dis. 1: e128.
www.europarl.europa.eu. Cited 20 Jan 2008. Saxena S, Thornicroft G, Whiteford H. (2007). Lancet.
Franco-Paredes C, Jones D, Rodrigues-Morales AJ, 370: 878–889.
Santos-Preciado JI. (2007). BMC Public Health. Thornicroft G. (2007). Lancet. 370: 807–808.
7: 11. Trouiller P, Olliaro P, Torreele E, Orbinski J, Laing R,
Holveck JC, Ehrenberg JP, Ault SK, Rojas R, Vasquez J, Ford N. (2002). Lancet. 359: 2188–2194.
Cerquiera MT, Ippolito-Shepherd J, Genovese MA, World Health Organization. (2003a). Global Defence
Periago MR. (2007). BMC Public Health. 7: 6. Against the Infectious Diseases Threat. World
Mashelkar RA. (2005). Innov Strat Today. 1: 16–32. Health Organization, Geneva.
Mathers CD, Ezzati M, Lopez AD. (2007). PLOS Negl WHO. (2002). World Health Organization Annual
Trop Dis. 1: e114. Report. http://www.who.int/whr/2002/en. Cited
Mèdecins Sans Frontières (MSF). (2007). Report on Drugs 20 Dec 2007.
for Neglected Diseases. [http://www.accessmed-msf. WHO. (2003b). World Health Organization annual
org/dnd/dndi.asp]. Accessed June 18, 2007. Report. http://www.who.int/whr/2003/en. Cited 20
Molyneux DH. (2004). Lancet. 364: 380–383. Jan 2008.
Molyneux DH, Hotez PJ, Fenwick A. (2005). PLOS Med. WHO. (2004). World Health Organization annual
2: e336. Report. http://www.who.int/whr/2004/en. Cited 20
Morel CM. (2003). EMBO Rep. 4: S35–S38. Jan 2008.
32 The Burden of Communicable
and Non-Communicable
Diseases in Developing
Countries
A. Boutayeb
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
2 NonCommunicable Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536

2.1 Cardio-Vascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
2.2 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
2.3 Chronic Respiratory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
2.4 Mental Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
2.5 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
2.6 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
3 Communicable Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539

3.1 Major Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
3.2 HIV/AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
3.3 Diarrheal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
3.4 Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
3.5 Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
3.6 Preventable Sexually Transmitted Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
3.7 Respiratory Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
3.8 Neglected Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
4 Discussion and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545

532 32 The Burden of Communicable and Non-communicable Diseases in Developing Countries
Abstract: Worldwide, developed and developing countries are facing the double burden of
communicable and > noncommunicable diseases. However, developing countries are more
exposed and more vulnerable due to a multitude of factors, including geographic, demo-
graphic and socio-economic factors. Noncommunicable diseases like cardio-vascular diseases,
cancer, diabetes, chronic obstructive pulmonary disease and mental disorders are affecting
developing countries with an increasing trend. In parallel, > communicable diseases such as
HIV/AIDS, malaria, tuberculosis, acute respiratory infections and diarrheal disease are caus-
ing high mortality rates especially in low and middle income countries. Other diseases like the
so-called neglected diseases are exclusively afflicting developing countries. Low-income
countries are particularly affected by lymphatic filariasis, leishmaniasis, schistosomiasis, Bur-
uli ulcer, cholera, cysticercosis, dracunculiasis, foodborne trematode infections, hydatidosis,
soil-transmitted helminthiasis (ascariasis, trichuriasis, hookworm diseases), trachoma, sleep-
ing sickness, onchocerciasis, Chagas disease, dengue and others. Beyond the high mortality
and morbidity rates caused by communicable and/or noncommunicable diseases in develop-
ing countries, the global burden includes economic losses due to care for diseases and
disabilities but also as a lack of productivity. More generally, communicable and noncommu-
nicable diseases are impeding human development in developing countries by their negative
impact on education, income and life expectancy and other health indicators. In sub-Saharan
African countries, devastating consequences are already strikingly apparent in terms of life
expectancy and > human development index (HDI) in general.
A large part of the burden caused by noncommunicable diseases like cardio vascular diseases,
cancer, diabetes, obesity and others can be avoided by preventive measures, early diagnosis and
detection and mainly by controlling risk factors such as smoking, alcohol, diet, and physical
inactivity. Similarly, the impact of communicable diseases can be alleviated by efficient strategies,
including affordability of treatments, development of new vaccines and medicines, improvement
of environmental conditions and general incentives and sensitization.
List of Abbreviations: AIDS, acquired immune defense system; BMI, > body mass index; CD,
communicable disease; COPD, chronic obstructive pulmonary disease; CVD, cardio vascular
disease; DALY, disability adjusted life years; DOTS, > directly observed therapy strategy; HDI,
human development index; HIV, human immunodeficiency virus; NCD, noncommunicable
disease; ND, neglected disease; SARS, severe acute respiratory syndrome; STD, sexually
transmitted disease; UNAIDS, United Nations AIDS; UNESCO, United Nations Educational,
Scientific and Cultural Organization; UNICEF, United Nations Children’s Fund; WHO, World
Health Organization; YLD, years lived with disability; YLL, years of life lost
1 Introduction
By the dawn of the third millennium, the developing world’s population is facing the double
burden of communicable and noncommunicable diseases. Although at different stages and
degrees, developed and developing countries alike, are struggling against the alarming trends
of diseases such as cardiovascular diseases (CVDs), diabetes, cancer, chronic respiratory
diseases, mental conditions, HIV/AIDS, malaria, tuberculosis and a multitude of other
known existing, emerging or re-emerging diseases like measles, hepatitis, cholera, meningitis,
Ebola, SARS and others (> Figure 32‐1).
. Figure 32‐1
Deaths attributable to 16 leading causes in developing countries, 2002 (WHO, 2003b). This figure shows that developing countries are exposed to the
double burden of communicable and noncommunicable diseases (reproduced by kind permission of the World Health Organisation)
The Burden of Communicable and Non-communicable Diseases in Developing Countries
32
533
According to the World Health Organization report (WHO, 2002), it has been estimated
that, in 2001, approximately 60% of the 56.5 million total reported deaths in the world and
approximately 46% of the global burden of disease is attributable to chronic diseases and
cardiovascular disease in particular. Deaths caused by noncommunicable diseases dominate
the mortality statistics in five out of six regions of the World Health Organization. The
exception is Africa where deaths caused by HIV/AIDS, malaria, tuberculosis and other
communicable diseases are predominant (> Table 32‐1).
In 2007, nearly 60 million deaths occurred worldwide with the large part in developing
countries. Three-quarters of adult deaths are due to noncommunicable diseases, with coro-
nary heart disease causing 7.6, stroke responsible for 5.7 million deaths, and hypertensive and
other heart conditions causing an additional 4 million deaths. In the meantime, infectious
diseases continue to cause millions of deaths and disabilities especially in Africa (see the
Chapter The impact of infectious disease in Africa in this book). Acute respiratory infections,
HIV/AIDS, diarrhea, malaria and tuberculosis are the biggest infectious killers in the world
and particularly in Africa. These five diseases are causing some 13 million deaths per year, but
besides mortality figures, they also engender a high burden in terms of > disability and
morbidity, affecting individuals, families and entire societies. A multitude of other diseases,
including the so-called neglected diseases like lymphatic filariasis, leishmaniasis, schistosomi-
asis, Buruli ulcer, cholera, cysticercosis, dracunculiasis, foodborne trematode infections,
hydatidosis, soil-transmitted helminthiasis (ascariasis, trichuriasis, hookworm diseases), tra-
choma, trypanosomiasis, onchocerciasis, Chagas disease, dengue and others are affecting low
and middle income countries in exclusivity (WHO, 2003a) (See the Chapter The burden of
neglected diseases in developing countries in this book).
Beyond mortality statistics, different methods can be considered to quantify the burden
of disease expressed in terms of socio-economic costs such as productivity losses, care
. Table 32-1
Deaths by causes in WHO regions, estimates for 2002 (WHO, 2003b)
Communicable
diseases,
maternal and perinatal
conditions and Noncommunicable
Cause WHO regions nutritional deficiencies diseases Injuries
Africa 7,779 2,252 747
The Americas 875 4,543 540
Eastern Mediterranean 1,746 2,030 391
Europe 567 8,112 803
South-East Asia 5,730 7,423 1,467
Western Pacific 1,701 9,000 1,231
World 18,416 33,424 5,188
Percentage of total 32.3% 58.6% 9.1%
deaths
This table shows that three out of four deaths caused by communicable diseases occurred in Africa and South-East
Asia. Developing countries are seriously affected by the double burden of communicable and noncommunicable
diseases (reproduced by kind permission of the World Health Organisation)
The Burden of Communicable and Non-communicable Diseases in Developing Countries 32 535
and treatment, hospitalization and handicap. In order to overcome the specific problems of
each country, the most used method during the last decade is the approach that measures
the global burden of disease in terms of Disability Adjusted Life Years (DALYs) which is
a combination of Years of Life Lost (YLL) through premature death, and Years Lived
with Disability (YLD). Thus, DALY is thought of as one lost year of healthy life (WHO,
2003b) (> Table 32‐2).
In Low-income and middle-income countries, diseases are generally affecting people at
a younger age compared to their counterparts in the developed world. Consequently, the
double burden of communicable and noncommunicable diseases constitutes a major impedi-
ment to economic and human development in developing countries (> Figure 32‐2).
Different studies have been devoted to the disease impact on economic and human
development. Curiously and fortunately, all the studies conclude that a large part of
the disease burden can be avoided by preventive and curative strategies. According to a series
of studies published recently by the Lancet, 80% of the 35 million deaths caused by cardiovas-
cular diseases, cancer, chronic respiratory diseases, diabetes and other noncommunicable
diseases in 2005, occurred in low-income and middle-income countries. Achievement of
the global goal of reducing chronic disease death rates by 2% every year would save billions
of dollars and avert 36 million deaths between 2005 and 2015 mainly in developing
countries (Abegunde et al., 2007). A report of the World Bank, concentrating on the economic
benefit of tuberculosis control in the 22 countries with the highest burden of TB, has shown
that, moving from no DOTS to sustained DOTS in a global plan strategy between 2006
and 2015, will yield a benefit of US$ 129 billion quasi-totally in developing countries
(Laxminarayan et al., 2007). Similarly, the impact of HIV/AIDS and other diseases on
economic and human development was considered by several authors (Boutayeb, 2006;
Dzenovska et al., 2005; UNAIDS, 2006).
. Table 32-2
Burden of diseases in DALYs by cause in WHO (2002, 2003b)
Communicable diseases,
maternal and perinatal
conditions and nutritional Noncommunicable Injuries (in
Cause WHO region deficiencies (in thousands) diseases (in thousands) thousands)
Africa 268,240 64,851 31,008
The Americas 26,677 99,080 19,863
Eastern 64,817 57,233 17,477
Mediterranean
Europe 14,170 114,289 21,315
South-East Asia 183,563 186,376 55,547
Western Pacific 54,129 173,466 37,003
Total 612,194 696,632 182,591
Percentage of total 41.1% 46.7% 12.2%
deaths
Whereas the burden of noncommunicable diseases is shared between developed and developing countries, the
quasi-totality of the burden of communicable diseases is afflicting developing countries (reproduced by kind
permission of the World Health Organisation)
. Figure 32‐2
Disease burden (DALYs) among adults (aged 15 years and over) By broad cause, selected
epidemiological subregions, 2002 (WHO, 2003b). Deaths caused by noncommunicable diseases
dominate the mortality statistics in five out of six regions of the World Health Organization. The
exception is Africa where deaths caused by communicable diseases are predominant
(reproduced by kind permission of the World Health Organisation)
2 NonCommunicable Diseases
2.1 Cardio-Vascular Diseases
Cardio-Vascular Disease is the name for the group of disorders of the heart and blood vessels
and includes: hypertension (high blood pressure), coronary heart disease (heart attack),
cerebrovascular disease (stroke), peripheral vascular disease, heart failure, rheumatic heart
disease, congenital heart disease and cardiomyopathies. An estimated 17.5 million deaths were
caused by these diseases in 2005, representing 30% of all deaths occurring in the world.
Ischemic heart disease and cerebrovascular disease together, caused more than 13 million
deaths, whereas hypertensive and other heart conditions were responsible for an additional
4 million deaths. If the present trend is not reversed or at least stopped, some 20 million people
will die from CVDs by 2015. Once associated with rich and industrialized nations, CVDs are
now seriously affecting developing countries. Nearly 80% of CVD deaths occur in developing
countries where they are expected to be the leading cause of death by 2010. In some countries
of the East Mediterranean Region 40% of all deaths are caused by CVDs (Alwan, 1997;
Boutayeb and Boutayeb, 2005; Tazi et al., 2003). Among the 20 ‘‘lucky’’ million people who
survive annually heart attacks and stroke, a number of ‘‘unlucky’’ survivals are living in
developing countries where they cannot afford the continuing costly treatment and clinical
care. Beyond mortality figures, CVDs are also imposing a huge disease burden. More than 85%
of the global CVD burden happens in developing countries. In general, theses diseases strike
people in their mid-life years, affecting their productivity, undermining the family budget
and impeding the economic and human development of the whole society. Moreover, studies
have shown that lower socio-economic groups have greater > prevalence of risk factors, higher
> incidence and higher mortality (Reddy, 2002; Yusuf et al., 2001).
2.2 Cancer
Cancer is a major cause of mortality and morbidity worldwide but its trend is more pro-
nounced in developing countries and especially in those with middle-income economies.
Over 50% of the 10 million new cases and 56% of the 7 million deaths caused by cancer in
2000, occurred in developing countries. The future is more alarming since it is predicted that,
between 2000 and 2020, the number of cases will increase by 73% in developing countries
compared to a 29% increase in developed countries. While the incidence and prevalence of
some sites of cancer such as breast and cervical cancer have regressed in developed countries,
they still have devastating consequences in developing countries mainly due to late detection.
Other types such as lung cancer are exponentially exploding as a consequence of increase in
the use of tobacco and alcohol. Finally, many types of cancer such as colorectal, stomach and
liver cancer are ‘‘flourishing’’ in developing countries due to the multidimensional transition,
in which most developing countries are completely or partially engaged, and its corollaries on
inadequate diet and physical inactivity (Boutayeb and Boutayeb, 2005).
2.3 Chronic Respiratory Diseases
Chronic respiratory diseases constitute a major burden for health systems in developing
countries suffering from lack of standards protocols for assessing and managing respiratory
diseases such as asthma and chronic obstructive pulmonary disease (COPD) (Ait-Khaled
et al., 2001). According to the World Health Organisation, chronic obstructive pulmonary
disease causes 2.5 million deaths and some 25 million DALYs every year. Despite its chronic
nature affecting some 600 million people, and the fact that it is the fifth and sixth leading cause
of death in high and low- income countries respectively, COPD is thought to be overlooked,
under-diagnosed, under-treated and under-funded, and also neglected by the public, phar-
maceutical industry and physician alike when compared to other major killers such as
cardiovascular disease and stroke (The Lancet, 2007). If urgent and efficient actions are not
taken, COPD will be the third leading cause of death by 2020. This exponentially growing
trend is partly explained by the ageing of the world’s population and the sustained use of
tobacco, which is the most important risk factor for this disease (Buist et al., 2007). Different
authors have attempted to quantify its incidence, prevalence and global burden.
2.4 Mental Diseases
Mental illnesses are affecting all countries with an increasing trend. Worldwide, it is estimated
that 450 million people suffer from mental, neurological or behavioral problems. About 120
million people currently live with depression and some 900,000 people commit suicide each
year. In 2000, depression was the fourth leading cause of disease burden (Moussavi et al., 2007).
Schizophrenia affects 24 million people and nearly 40 million people live with dementia. In
particular, with ageing populations, the prevalence of Alzheimer’s disease is rising rapidly.
More than 80% of the 50 million affected by epilepsy live in developing countries. It is thought
that at least 70% of people affected can be seizure-free if treated with antiepileptic drugs.
However, the vast majority remain untreated (in Africa, 80% receive no treatment). More
generally, cost-effective treatments can be made available for most disorders but at least two-
thirds of people who are mentally ill receive no treatment (Thornicroft, 2007). The reader can
find more details in the series of articles devoted by Lancet in its volume 370 to mental disorders
under the title ‘‘why do we invest so little in our mental health care?’’. Mental illnesses are
affecting developed and developing countries alike. However, due to lack of budget and human
resources, the impact is more pronounced in low and middle-income countries where neglected
mental illnesses are causing important economic costs and impeding human development.
It should be stressed that, in developing countries, children and adolescents are particularly
affected by mental or behavioral problems due to injuries, childhood infections and lack of
oxygen at birth.
2.5 Diabetes
Worldwide, in 20 years, diabetes has had a sixfold increase, jumping from 30 million in 1985 to
around 180 million in 2005. If the trend is maintained, the figure is expected to reach 370 million
in 2030.
Diabetes is no more a disease of the ‘‘rich’’. It is now sweeping the whole globe with a
particular increase in developing countries. By 2025, 80% of all new cases of diabetes will take
place in low and middle income countries (Boutayeb et al., 2004). Moreover, diabetes affects
people of developing countries at a younger age compared with their counterpart in developed
countries. Although the disease impact is comparable to that of HIV/AIDS, it remains under-
evaluated, continuing silently to cause a high burden.
In developing countries, more than 50% of people living with diabetes ignore that they have
the disease. Consequently, most of them will rapidly end up with irreversible complications and
morbidity.
In 2007, about 3.5 million deaths were caused by diabetes as a consequence of increasing
incidence and prevalence which are now reaching alarming thresholds. Worldwide, every year
some 6 million join the group of diabetics, whereas, in many countries in Asia, the Middle
East, Oceania and the Caribbean, the prevalence reaches 12–20% of the adult population.
Although type 2 diabetes is the most frequent, representing 90–95% of the global number
of diabetics, > insulin-dependent diabetes is particularly attracting attention in some African
countries where lack of > insulin is causing premature deaths.
Beyond, high rates of mortality, diabetes is responsible for an excessive burden due
essentially to micro- and macro-vascular complications such as blindness, kidney failure,
amputations and heart diseases. As a chronic disease, diabetes is asking a large toll at all levels.
It is estimated that the disease causes annually more than one million amputations, about 5%
of blindness due to diabetic retinal disease and a large number of renal failures. Economically,
about 300 billion US$ (215–375) were spent worldwide in care for diabetes and its complica-
tions in 2007. In developing countries where four out of five people pay for their own
treatments and medicines, as much as 25% of family income may be devoted to diabetes
care (WHO, 2007).
2.6 Obesity
According to the World Health Organisation, obesity is defined as ‘‘a condition of abnormal or
excessive fat accumulation in adipose tissue, to the extent that health may be impaired.’’ A
convenient measurement of obesity is given by the Body Mass Index (BMI) which is a simple
weight to (square) height ratio (kg/m2). Worldwide, obesity and overweight affect 1.2 billion
people of which 300 million are clinically obese. In some developed countries, the prevalence
of overweight and obesity reaches 60% (Drewnowski and Specter, 2004). However, obesity is
no more a feature of rich countries alone. It is affecting more and more seriously developing
countries. A special interest should be paid to the growing prevalence of obesity in children
and the concern about the co-existence of under- and overweight people in developing
countries in general and in African countries in particular.
Obesity and overweight lead to adverse metabolic changes such as insulin resistance,
increasing blood pressure and cholesterol. Considered as a disease, obesity diminishes both
quality of life and life expectancy, but it is also a common risk factor for other diseases like
CVDs, diabetes, arthritis and many types of cancer. Besides genetic, gender and socio-
economic factors, the alarmingly increasing trend of obesity is principally linked to the
many transition forms (demographic, epidemiological (> epidemiology), geographic, demo-
cratic and economic). In particular, the transition from a rural to an urban lifestyle and its
corollary of nutrition transition characterized by a higher energy density diet with a greater
role for fat and added sugar in foods, greater saturated fat intake mostly from animal sources,
reduced intakes of fiber, fruit and vegetables (WHO, 2003c).
3 Communicable Diseases
3.1 Major Infectious Diseases
With malnutrition as a common contributor, the five biggest infectious killers in the world are
acute respiratory infections, HIV/AIDS, diarrhea, malaria and tuberculosis, responsible for
nearly 80% of the total infectious disease burden and claiming about 12 million people per
year mainly in developing countries (> Table 32‐3 and > 32‐4).
. Table 32-3
Estimates of the COPD burden worldwide
Author Age category Prevalence

Ezzati and Lopez (2000) 40 years or older (9–10%)
Lopez et al. (2007) 30 years or older Men (0.6–4%) Women (0.2–3.2%)
Buist et al. (2007) (BOLD study) 40 years or older Men 11.8%, Women 8.5%
Menezes et al. (2005) (PLATINO study) 60 years or older 18.4–32.1%
Yin et al. (2007) 40 years or older 7.2%
Several authors have tried to estimate the prevalence of COPD in different age categories. The various estimates
produced are another indication proving that this disease needs more attention. BOLD burden of lung disease;
PLATINO Latin-American project for investigation of pulmonary obstruction
. Table 32-4
Main causes of Mortality due to infectious diseases, 2001 (WHO, 2003b)
Deaths per year Deaths per year

Disease (Worldwide, in million) (developing countries, in million)a
Respiratory infections 3.9 3.2 (82%)
AIDS 3.0 2.7 (90%)
Diarrheal diseases 1.9 1.8 (95%)
Tuberculosis 1.6 1.5 (95%)
Malaria 1.1 1.08 (98%)
a
Author’s estimation
The five biggest infectious killers in the world and in Africa are acute respiratory infections, HIV/AIDS, diarrhea,
malaria and tuberculosis. These diseases contribute not only to high mortality rate, they also engender a high
burden in terms of disability and morbidity (reproduced by kind permission of the World Health Organisation)
. Table 32-5
Leading causes of deaths in children in developing countries, 2002 (WHO, 2003b)
Condition Numbers (in thousands) Percentage of all deaths (%)

Perinatal conditions 2,375 23.1
Lower respiratory infections 1,856 18.1
Diarrheal diseases 1,566 15.2
Malaria 1,098 10.7
Measles 551 05.4
Congenital anomalies 386 03.8
HIV/AIDS 370 03.6
Pertussis 301 02.9
Tetanus 185 01.8
Protein-energy malnutrition 138 01.3
Other causes 1,437 14.0
Total 10,263 100
Lower respiratory infections, malaria, diarrhea, measles, AIDS and other infectious diseases are the leading causes
of child mortality in developing countries. Almost all child deaths occur in developing countries and about half of
them especially in Africa (reproduced by kind permission of the World Heath Organisation)
Despite the success of vaccination programs for polio and many childhood diseases,
malaria, tuberculosis, HIV/AIDS and others are still out of control in the majority of African
countries. Children remain at high risk. Indeed, in 2002, of the 57 million deaths reported
worldwide, 10.5 million deaths were among children of less than 5 years of age, of which 98%
were in developing countries in general and in Africa in particular (WHO, 2003a, 2003b, 2004)
(> Table 32‐5). Consequently, while life expectancy at birth reached 78 years for women in
developed countries, it fell back to less than 46 years in sub-Saharan Africa (> Figure 32‐3).
. Figure 32‐3
Child mortality in the six WHO regions, 2002 (WHO, 2003b). This figure shows clearly the gap
existing between developed and developing countries in child mortality. Almost all child deaths
are occurring in developing countries with about 50% of deaths taking place in Africa
(reproduced by kind permission of the World Heath Organisation)
3.2 HIV/AIDS
HIV/AIDS is an infectious disease that emerged a quarter of century ago, causing so far about
40 million deaths and leaving millions of orphan children and disabled adults. If the present
trend is maintained, by 2020 AIDS will have caused more deaths than any other disease
> epidemics in history. Beyond the fact that the disease is now recognized as a major health
emergency, it has also imposed its burden on the whole development of societies. In the most
affected countries of Africa, devastating consequences are already strikingly apparent not only
on health systems and health indicators but also in terms of income and productivity,
education and knowledge, human rights and gender equality (UNAIDS, 2006). It is know
commonly admitted that HIV/AIDS is impeding the development of many countries, espe-
cially in sub Saharan Africa were lived 80% of the 3 million people killed by HIV/AIDS in
2002. Many countries have a 20% or more prevalence of HIV. Consequently, life expectancy is
decreasing and the future is more alarming if nothing is done to reverse or at least to stop the
present trend of HIV/AIDS (> Figure 32‐4) (Dzenovska et al., 2004).
3.3 Diarrheal Disease
It is well known that diarrheal disease is among the leading causes of mortality and morbidity
in children and that the quasi-totality of deaths caused by diarrhea occurs in developing
countries. Using different methods and sources of information, several authors have
attempted to evaluate the burden of this disease. Despite the differences existing between
estimates, they all show a declining trend in mortality figures but a relatively stable morbidity
(Bern et al., 1992; Kosek et al., 2003; Murray et al., 2001; NVD, 1986; Rohde and Northrup,
1976; Snyder and Merson, 1982; WHO, 2003a) (> Table 32‐6).
542
32
. Figure 32-4
Estimated impact of AIDS on under-five mortality rates 2002–2005, selected countries in sub-Saharan Africa (UNAIDS, 2006). This figure shows the
devastating impact of AIDS on child mortality in the most affected African countries (reproduced by kind permission of UNAIDS)
The Burden of Communicable and Non-communicable Diseases in Developing Countries
. Table 32-6
Disease burden due to diarrhea worldwide
Period covered and data used in the

Authors Deaths per year review
Rohde and Northrup (1976) 5 million Author’s data, 1976
Snyder and Merson (1982) 4.6 million Review of data published between
1954 and 1979
NVD-US Institute of Medicine (1986) 3.5 million Based on published data and field
experience
Bern et al. (1992) 3.3 million Using data published between 1980
and 1990
Murray et al. (2001) 1.4 million Data analysis in 2000
Kosek et al. (2003) 2.5 million Using data published between 1992
and 2000
WHO (2003a) 1.9 million Report: Global defence against the
infectious disease threat, data 2001
Various estimates provided by different authors who have tempted to evaluate the disease burden caused by
diarrhea diseases. They all show a declining trend in mortality but morbidity remains relatively stable
3.4 Malaria
In developing countries, every year, malaria affects some 300 million people and kills more
than a million of them. A large proportion of those who survive will end up with disability.
The quasi-totality of people suffering from malaria lives in developing countries. It should be
noted that the most exposed and vulnerable people are among children, pregnant women and
those already weakened by other health and socio-economic conditions like malnutrition,
pulmonary infections and lack of water and sanitation. Countries in tropical Africa bear the
brunt of malaria, accounting for more than 90% of all cases occurring worldwide each year
(Ruxin et al., 2005).
3.5 Tuberculosis
About 95% of deaths caused by tuberculosis (TB) take place in developing countries. Being
among the top ten causes of global mortality, TB is the second leading cause of adult death due
to infectious disease (Borgdorff et al., 2002; Dye, 1999; Laxminarayan et al., 2007). It has been
estimated that approximately one-third of the world’s population is infected with tuberculosis
bacillus, and that each year nearly 9 million people develop tuberculosis disease and about
2 million die of it. South-East Asia and Africa are the most affected. It should be stressed that
HIV/AIDS epidemic and multi-drug resistance have worsened the tuberculosis situation over
the last two decades. Tuberculosis is a leading killer of people with HIV, and 80% of tubercu-
losis patients are HIV positive in countries with high prevalence of HIV (Dye, 1999; Ruxin
et al., 2005). The most devastating impact of tuberculosis is death; without treatment, two-
thirds of smear-positive cases die within 5 years, with most dying within 18 months of being
infected (Laxminarayan et al., 2007).
3.6 Preventable Sexually Transmitted Diseases
In the era of AIDS and the high level of politicization and priority given to HIV, other sexual
transmissible diseases may receive less attention. It is the case of preventable sexually trans-
mitted diseases (STD) which caused in 1999, about 350 million infections in the population
aged 15–49. However, knowing the correlation existing between STD and HIV/AIDS, health
policy makers should be very careful. An illustrative example is given by the case of North
African countries, known to have high prevalence of STD and, so far, relatively saved from
high prevalence of HIV/AIDS but the increasing trend may explode rapidly (Boutayeb, 2006).
Congenital syphilis is still endemic in many African countries. An estimated 4 million cases
occurred in 1999 among adults in sub-Sahara Africa, a similar number of cases was recorded in
south and south-east Asia and 3 million cases took place in Latin America and the Caribbean
(Berman, 2003; Hawkes et al., 2003; Peeling and Ye, 2003; Schmidt, 2003). It is worth stressing
that all these cases are happening while tools of prevention have been available for decades.
3.7 Respiratory Infections
According to WHO estimates, Respiratory infectious diseases were the first cause of mortality
from infectious diseases in 2001, responsible for nearly 4 million deaths principally in
developing countries. In 2002, lower respiratory infections caused nearly 2 million deaths in
children, ranking at the second leading cause.
3.8 Neglected Diseases
An exhaustive deal with all communicable diseases in developing countries is beyond the scope
of this chapter. However, we cannot overlook the multitude of infectious diseases which are
so-called ‘‘neglected diseases’’ due to the little consideration they have been given at national
and international levels. Indeed, lymphatic filariasis, leishmaniasis, schistosomiasis, sleeping
sickness, dengue, Chagas disease, Buruli ulcer and others are responsible for impaired child-
hood growth, mental retardation, blindness, amputation and diverse disability conditions
almost exclusively in developing countries (Boutayeb, 2007; Derouich and Boutayeb, 2006; See
details in the Chapter The burden of neglected diseases in developing countries of this book).
4 Discussion and Conclusion
In developing countries nearly 3 billion people live with less than 2 dollars a day, 1.2 billion live
with one dollar a day, 1.3 billion live on fragile and often remote rural ecosystems, and about
2 billion people have inadequate or no access to life-saving treatments. On top of natural
catastrophes, poverty, wars and conflicts, these countries are exposed to a double burden of
communicable and noncommunicable diseases with alarming trends. Some diseases like tuber-
culosis are both causes and consequences of poverty. Other diseases like diabetes and cardio
vascular diseases are more associated with different transition forms (demographic, economic,
geographic and epidemiological) in which middle income countries are engaged. Globally,
however, the double action of communicable and noncommunicable diseases constitute serious
impediments to economic development by reducing productivity, setting aside saving possibi-

lities and slowing economic growth in general. They also obstruct human development by their
negative action on life expectancy, education and socio-economic status in general. The econom-
ic cost of care for noncommunicable diseases such as CVDs, diabetes, COPD and cancer is huge.
The adequate treatment for communicable diseases like HIV/AIDS, tuberculosis and malaria is
beyond the capacity of most developing countries. In the main time, diseases are causing the loss
of billions of dollars in terms of non productivity, absenteeism and skill. The global disease
impact has a special feature in developing countries since most of the diseases affect either
children or adults in their most productive part of life. Consequently, life expectancy, education,
income and all human development components are affected by communicable and/or non-
communicable in developing countries. The disease burden is a major problem for health public
and a real global concern for the whole economic and human development (Malawi, 2005; South
Africa, 2003; UNESCO, 2007; UNICEF, 2005; Zimbabwe, 2003).
Summary Points
In developing countries, nearly 50% of the disease burden is caused by deaths under age
15, compared to 10% in developed countries.
The five biggest infectious killers in the world and in Africa are acute respiratory infections,
HIV/AIDS, diarrhea, malaria and tuberculosis.
Diabetes is a disorder in which the body becomes unable to control the amount of sugar
in the blood.
Type2 diabetes is the most frequent, representing 85–90% and characterized by a partial
lack of insulin or its efficiency. It generally affects people aged 40 years and plus, generally
treated with diet and tablets.
Type1 diabetes is characterized by a total lack of insulin due the destruction of beta cells
producers of this vital hormone. This type of diabetes affects children and young adults,
for this reason it is also called juvenile diabetes or insulin-dependent diabetes. It’s
treatment necessitate the daily injection of insulin.
Hyperglycemia occurs when the blood sugar is higher then the usual threshold. It indicates
the onset of diabetes and/or its bad control in known diabetic people.
Hypoglycemia is the state where blood sugar is lower than the normal concentration which
is around one gram per liter or 6 mmol.
In 2007, about 300 billion US$ (215–375) were spent worldwide in care for diabetes and its
complications.
Body Mass Index (BMI) is the ratio given in kg/m2 and obtained by dividing the weight of
a person by the square of its height. A person is said to be obese if its BMI is greater than
30 kg/m2.
Chronic obstructive pulmonary disease (COPD) causes 2.5 million deaths and some
25 million DALYs every year.
An estimated 17.5 million deaths were caused by CVDs in 2005, representing 30% of all
deaths occurring in the world.
In 2000, 53% of the 10 million new cases and 56% of the 7 million deaths caused by cancer,
occurred in developing countries.
Directly Observed Therapy Strategy (DOTS) is the most efficient strategy so far to control
tuberculosis and limit its burden.
References
Abegunde DO, Mathers CD, Adam T, Ortegon M, Peeling RW, Ye H. (2003). Bull World Health Organ. 82:
Strong K. (2007). Lancet. 370: 1929–1932. 439–446.
Ait-Khaled N, Enarson D, Bousquet J. (2001). Bull World Reddy K. (2002). Public Health Nutr. 5: 231–237.
Health Organ. 79: 971–979. Rohde JR, Northrup RS. (1976). In: Ciba Foundation
Alwan A. (1997). East Mediterr Health J. 3: 6–16. Symposium (ed.) Acute Diarrhoea in Children.
Berman SM. (2003). Bull World Health Organ. 82: Elsevier, Amsterdam, pp. 339–365.
433–438. Ruxin J, Paluzzi JE, Wilson PA, Tozan Y, Kruk M,
Bern C, Martines J, de Zoysa I, Glass RI. (1992). Bull Teklehaimanot A. (2005). Lancet. 365: 618–621.
World Health Organ. 70: 705–714. Schmidt G. (2003). Bull World Health Organ. 82:
Borgdorff MW, Floyd K, Broekmans JF. (2002). Bull 402–409.
World Health Organ. 80: 217–227. Snyder JD, Merson MH. (1982). Bull World Health
Boutayeb A. (2006). Trans R Soc Trop Med Hyg. 100: Organ. 60: 605–613.
191–199. South Africa. (2003). Human Development Report.
Boutayeb A. (2007). Int J Equity Health. doi: 10.1186/ http://www.undp.org.za Cited 8 Dec 2007.
1475-9276-6-20. Tazi M, Abirkhalil S, Chaouki N, Cherkaoui S, Lahmouz F,
Boutayeb A, Boutayeb S. (2005). Int J Equity Health. doi: Srairi J, Mahjour J. (2003). J Hypertens. 21: 897–903.
10.1186/1475-9276-4-2. The Lancet. (2007). The Lancet. 370: 713–713.
Boutayeb A, Twizell EH, Achouyab K, Chetouani A. Thornicroft G. (2007). Lancet. 370: 807–808.
(2004). BioMed Eng. doi: 1186/1475-925X-3-20. UNAIDS. (2006). The Impact of AIDS on People and
Buist AS, McBurine MA, Vollmer WM, BOLD group. Societies. http://data.unaids.org Cited 20 Dec 2007.
(2007). Lancet. 370: 741–750. UNESCO. (2007). Education for All in Least Developed
Derouich M, Boutayeb A. (2006). Appl Math Comput. Countries. http://unesdoc.unesco.org Cited 20 Dec
177: 528–544. 2007.
Drewnowski A, Specter SE. (2004). Am J Clin Nutr. 79: UNICEF. (2005). The State of the World’s Children. The
6–16. United Nations Children’s Fund, New York.
Dye C (1999). Int J Tuberc Lung Disease. 4: 146–152. WHO. (2002). World Health Organization Annual Re-
Dzenovska D, Rasheed N, Sandkjaer B. (2005). HIV/ port. http://www.who.int/whr/2002/en Cited 20 Dec
AIDS and Human Development Thematic Guidance 2007.
Note. UNDP, New York, NY. WHO. (2003a). Global Defence Against the Infectious
Ezzati M, Lopez AD. (2000). Lancet. 362: 847–852. Diseases Threat. World Health Organization,
Hawkes S, Miller S, Rechenbach L, Nayyar A, Buse K. Geneva.
(2003). Bull World Health Organ. 82: 417–423. WHO. (2003b). World Health Organization annual Re-
Kosek M, Bern C, Guerrant RL. (2003). Bull World port. http://www.who.int/whr/2003/en Cited 20 Dec
Health Organ. 81: 197–204. 2007.
Laxminarayan R, Klein E, Dye C, Floyd K, Dareley S, WHO. (2003c). Diet, Nutrition and the Prevention of
Adeyi O. (2007). Economic Benefit of Tuberculosis Chronic Diseases. World Health Organisation,
Control. The World Bank, Washington DC. Geneva.
Lopez AD, Shibuya K, Rao C, Mathers CD, Ezzati M, WHO. (2004). World Health Organization Annual Re-
Lopez AD. (2007). PLOS Negl Trop Dis. doi: port. http://www.who.int/whr/2004/en Cited 20 Dec
10.1371/journal.pntd.0000114. 2007.
Malawi HDR. (2005). Reversing HIV/AIDS in Malawi. WHO. (2007). World Health Organization Annual Re-
United Nations Development Programme, port. http://www.who.int/whr/2007/en. Cited 20
Washington, DC. Dec 2007.
Menezes AMB, Perez-Padilla R, Jardim JRB, PLATINO Yin P, Jiang CQ, Cheng KK, Lam TH, Miller MR,
team. (2005). Lancet. 366: 1875–1881. Zhang WS, Thomas GN, Adab P. (2007). Lancet.
Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, 370: 751–757.
Ustun B. (2007). Lancet. 307: 851–858. Yusuf S, Reddy KS, Ounpus S, Anand S. (2001). Circula-
Murray CJL, Lopez AD, Mathers CD, Stein C. (2001). tion. 104: 2746–2753.
The Global Burden of Disease 2002 Project. Word Zimbabwe HDR. (2003). Redirecting our Responses to
Health Organization, Geneva. HIV and AIDS. United Nations Development
NVD. (1986). Establishing Priorities Volume 2. Institute Programme, Washington, DC.
of Medicine, Washington, DC.
33 Economic Evaluation of
Health Interventions:
Tanzania Perspectives
B. Robberstad . Yusuf Hemed
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548
1.1 Major Trends in Burden of Disease in Tanzania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
1.2 The Health Gap and Rationale for Economic Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . 550
2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
3 Economic Evaluation of Health Interventions in Tanzania . . . . . . . . . . . . . . . . . . . . . . . 552

3.1 Overview of Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
3.2 Malaria Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
3.3 HIV-AIDS Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
3.4 Maternal and Perinatal Health Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
3.5 Interventions Targeting Intestinal Worms and Parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
3.6 Tuberculosis Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
3.7 Childhood Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
3.8 Primary Prevention of Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
4 Research Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583

4.1 Infectious Diseases and Reproductive Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
4.2 Non-communicable Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584

548 33 Economic Evaluation of Health Interventions: Tanzania Perspectives
Abstract: The life expectancy of Tanzania has declined since 1990, and the health care services
are facing immense challenges. The two single most important sources of burden of disease in
the country are HIV/AIDS and malaria. Cardiovascular and other non-communicable diseases
are also becoming increasingly important causes of disease burden. This chapter reviews the
available > economic evaluation literature for all types of health interventions in Tanzania.
Economic evaluation is useful for setting health care priorities when decision makers are
concerned about producing as much health benefits as possible within the limits of scarce
health care resources.
A total of 23 studies were found reporting costs and benefits for health interventions
in Tanzania. The studies included in the review can roughly be sorted into the disease
groups malaria, HIV/AIDS, maternal and perinatal health, intestinal parasites and worms,
tuberculosis (TB), childhood diseases and cardiovascular disorders. The economic evaluation
evidence for Tanzania is generally very scarce. Evidence is relatively good for malaria inter-
ventions and interventions against intestinal worms and parasites. Within these disease
groups economic evaluation can be particularly useful to inform implementation policy. For
all other disease groups, evidence is either vastly insufficient or totally missing. Lack of
evidence is particularly striking for treatment and care of patients with HIV/AIDS, and for
non-communicable diseases. Economic evaluation can in most cases not be used efficiently
and consistently to set health care priorities in Tanzania. More research is needed to improve
this situation.
List of Abbreviations: AIDS, acquired immunodeficiency syndrome; AL, artemether-
lumefantrine; AMMP, adult mortality and morbidity project; AQ, amodiaquine; ARV, antire-
troviral; AS, artesunate; ASA, aspirin; BET, betablocker; BOD, burden of disease; CAB, calcium
channel blocker; CER, cost-effectiveness ratio; CMH, commission on macroeconomics
and health; CV, cardiovascular; DALY, disability adjusted life year; DEC, diethylcarbamazine;
DIU, diuretic; DOT, directly observed treatment; EbyC, evacuation by curettage; EPI, expanded
programme for immunization; GDP, gross domestic product; HIV, human immunodeficiency
virus; ICER, > incremental cost-effectiveness ratio; IMCI, integrated management of child-
hood illness; ITN, insecticide treated bednets; LY, life year; MVA, manual vacuum aspiration;
NBS, National Bureau of Statistics; ORS, oral rehydration solution; PMTCT, prevention of
mother to child transmission; POC, point of care testing; RPR, rapid plasma reagin testing; SP,
sulfadoxine-pyrimethamine; SSA, Sub Saharan Africa; STA, statin; STD, sexually transmitted
diseases; TB, tuberculosis; TNVS, Tanzania National Voucher Scheme; USD, United States
dollars; VCT, voluntary counseling and testing; WHO, World Health Organization
1 Introduction
The United Republic of Tanzania has socioeconomic, demographic and epidemiological

characteristics that are typical for many countries in sub-Saharan Africa (SSA). The popula-
tion of the country in the 2002 census was 34.5 million, with an annual growth rate of 2.9%
(Tanzania 2002 census, 2008). Life expectancy at birth in Tanzania improved gradually from
1955 to a peak in 1990 of 51.3 years, but has subsequently declined to 43.3 years in 2005
(Globalis, 2008). Life expectancy is now back at the level of the late 1960s. This illustrates
clearly the immense challenges facing the Tanzanian health care services.
Economic Evaluation of Health Interventions: Tanzania Perspectives 33 549
1.1 Major Trends in Burden of Disease in Tanzania
Understanding Burden of Disease is fundamental for health planning and for setting evidence
based health care priorities. In addition, knowledge of the magnitude of burden of specific
diseases in different age groups, sexes and in different geographical areas is important for
assessing the coverage of targeted preventive and treatment interventions, and for budgeting of
scale up exercises. Most developing countries lack such information on burden of disease, and
the Tanzanian Ministry of Health in 1992 therefore established the Adult Morbidity and
Mortality Project (AMMP) in partnership with the UK University of Newcastle upon Tyne
to answer such questions. With support from the UK, AMMP provided information about the
leading causes of death and ill health for nearly a decade. The project focused on three different
socio-economic and geographic areas of the country.
Tanzania has been classified as a ‘‘high mortality–high fertility’’ country with a morbidity
and mortality profile dominated by infectious disease. The AMMP project revealed that
malaria and HIV/AIDS are the two most important conditions causing mortality and disability
in the country. National burden of disease estimates showed that HIV-AIDS was responsible
for 31% of total mortality, while malaria accounted for 30%. About 50% of the malaria burden
is in children under the age of 5 years (AMMP, 2004). More recently, non-communicable
diseases have been documented to be rising and present major challenges to the health services
(Setel et al., 2001).
A major trend is that maternal mortality in Tanzania remains high despite some improve-
ments between 1990 and 2001, but it is good news that the reduction has been more
pronounced in the poorest sections of the community (AMMP, 2004). Between 1994 and
2001 a decrease in maternal mortality rate of 60% from 934 to 543 (per 100,000) was recorded
in AMMP surveillance areas (AMMP, 2004). This development could be related to the
observed increase in births taking place in health facilities, and a drop in fertility rates during
the same period. Improved availability of maternity and antenatal clinic services to areas that
were previously poorly served could also be a contributory factor. A striking finding was that a
1-year increase in education of household heads was associated with 62% lower maternal
mortality at the community level (AMMP, 2004).
Perinatal mortality is an important indicator of the quality and coverage of antenatal care
and delivery. Despite increased perinatal mortality in the first half of the last decade, perinatal
mortality rates including still births declined in the later part of the period. On the other hand,
child and infant mortality rates dropped in both the poorest and in the least poor groups
(AMMP, 2004). It is important to note that despite dramatic improvements in mortality rates,
large disparities in health persist both within and between the surveillance areas, between
males and females and between different socioeconomic strata. Further scaling up prenatal
care and maternity and emergency obstetric care services may help to further roll back
maternal and perinatal mortality.
Malaria and diarrheal diseases cause high mortality in Tanzanians at all ages, in all areas,
and particularly in the poorest quarters (AMMP, 2004). Between 1994 and 1999 declines in
both infant and child mortality rates have been noted in all three sentinel areas. Diarrheal
diseases mortality rates have shown marked and steady declines in all socioeconomic groups
and geographic locations in all areas under AMMP surveillance. The proportion of children
under the age of 5 who died from diarrheal diseases declined from 10 to 3% (AMMP, 2004).
During the same period the coverage of clean water supplies improved, and the supply of
Vitamin A to children was scaled up. Despite these improvements, much remains to be done to
improve child health in Tanzania.
The levels and trends of acute febrile illness and malaria mortality rates have been erratic,
declining in some years and increasing in others, but overall there was a decline in proportion
of deaths from malaria (AMMP, 2004). The malaria mortality rates have persistently been
shown to be higher in the poorest sections of the community and in children. This observation
had prompted policy makers to subsidize and target ITNs use to pregnant mothers and to
mothers with small children.
HIV/AIDS has been a leading cause of adult deaths in the 15–59 age groups throughout the
1990s and possibly thereafter. The HIV/AIDS mortality rates have been fairly stable between
1994 and 2001 (AMMP, 2004). However sero-prevalence and HIV indicator surveys has shown
some decline HIV prevalence between the 1990s and the recent past. Females have consistently
experienced higher mortality rates than their male counterparts. Interestingly, AMMP data
shows the HIV/AIDS mortality rates was higher in the least poor compared to the poorest
women (350 compared to 500/100,000 HIV/AIDS related mortality rates) (AMMP, 2004).
AMMP developed the concept of acute (or episodic) and broad care needs based on
whether the condition could be cured within 1 month or longer. Adults and the elderly need
long-term care and management of highly burdening chronic conditions which are likely to
lead to death. HIV/AIDS and tuberculosis was found to account for 75% of all broad care
needs, while 20% was for cancer and cardiovascular (CV) diseases.
Despite excessively high burden of mortality from many familiar infectious diseases,
including HIV/AIDS and malaria, Tanzanians have a very high risk of dying from non-
communicable diseases including heart disease, high blood pressure, asthma, cancer and
diabetes (Setel et al., 2001). The AMMP estimated that as many as 27% of all adult deaths
are due to non-infectious causes. Death rates from non-communicable diseases such as stroke
are several times higher than in parts of Western Europe, with women in urban areas
particularly at risk. Mortality from cardiovascular diseases and cancers has been rising. The
mortality rates for CV disorders for example rose from 50 to 70 per 100,000 between 1994 and
2002, and the increase was noted in both sexes and all socioeconomic groups (AMMP, 2004).
Similar trends for diabetes and cancers have been recorded. The main cancers are of the female
reproductive organs, skin, breast, lymphomas and prostate.
1.2 The Health Gap and Rationale for Economic Evaluation
To cope with the situation described above, Tanzania has a public health expenditure
corresponding to only 7 US dollars (USD) per capita per year and another five USD of
expenditure in the private health care sector (WHO, 2006). These funds cover primary and
referral health care services, prevention and treatment programs, administration and outreach
services, as well as antenatal services and terminal palliative care. It has been pointed out by the
Commission on Macroeconomics and Health (CMH) that an increase in health expenditure
of only 22 USD per capita per year in the least developed countries would be sufficient to
improve the coverage rates of essential health interventions (Commission on Macroeconomics
and Health and WHO, 2001). It is obvious that the discrepancy between available resources
and health care needs in Tanzania remains immense.
Where resources are insufficient to meet even the most basic health care needs for a large
proportion of the population, a process of prioritization is necessary. It is not untypical that
such processes are implicit, also in Tanzania. For example, the ‘‘first come – first served’’
principle. Most scholars within the field of priority setting in health care would argue that it is
fairer to base priority setting on pre-defined criteria derived from principles of equity and
efficiency (Brock and Wikler, 2006). The aims of evidence based health policy should be to
contribute towards reaching national health goals such as reducing the burden of disease and
promoting a more equitable distribution of health and health care.
Economic evaluations have been used to inform priority setting in health care in indus-
trialized countries since the 1970s, and have since then become increasingly important. The
breakthrough for using economic evaluations as a priority-setting tool in developing countries
came with the 1993 World Development Report, Investing in Health, which suggested that
addressing those diseases of high burden with the most > cost-effective interventions could do
much to reduce disease in the population (WorldBank, 1993). The major advantage of
economic evaluation techniques, such as > cost-effectiveness analyses or > cost-utility ana-
lyses, is that they enable the analyst to compare both the costs and the > health outcomes of
different health interventions. In this way, it is possible to maximize the health benefits from
limited resources. The major disadvantage of economic evaluations is that the distribution of
health benefits across population groups is ignored. A policy based solely on economic
evaluation may lead to increased inequity in health. Distributive questions are therefore
usually considered in addition to the economic evidence.
At policy level, the efficient use of economic evaluations requires a reasonable amount of
evidence on a number of different policies. For low income countries, the availability of health
economic evidence can generally be described as poor. A few global initiatives, such as the
Word Health Organization project ‘‘Choosing Interventions that are Cost-Effective’’ (WHO
CHOICE), have attempted to address these knowledge gaps (WHO, 2008). Another example is
the project ‘‘Disease Control Program in Developing Countries,’’ in which cost-effectiveness
evidence for a wide range of interventions and disease groups was collated (Jamison et al., 2006).
These initiatives are all valuable contributions to the knowledge base. But for decision makers in
Tanzania it is a great disadvantage that there is no overview of economic evaluations specifically
targeting local conditions in terms of epidemiology, health care infrastructure and socioeco-
nomic situations. For this reason, the local value of global initiatives can always be questioned.
The main objective of this chapter is to provide a literature review of the economic
evaluation evidence currently available in Tanzania, and relate this to the current situation
and trends of burden of disease. We will also suggest a few areas in which the need for further
research is particularly evident. An overview of our approach to this task is given in the
methods section. In the following chapter the findings of the literature review is presented,
both as text and in tables. We present the findings in general terms in the text, while more
details are provided in the tables. Finally, we attempt to extract research challenges and a few
conclusions based on the available evidence.
2 Methods
We searched for literature in the database EmBase using the key words ‘‘Tanzania’’ AND ‘‘exp
economic evaluation/’’ for the years 1980–2008 (week 5) limited to English articles and
humans. PubMed was also searched using the Mesh words > Cost-Benefit Analysis AND
‘‘Tanzania’’ for all available years. The Cochrane library was browsed using the search
term ‘‘Tanzania’’ in the whole NHS economic evaluation database. Finally, we looked for
relevant studies from other sources like lists of references, or studies that were too recent to
have been indexed in the databases. The abstracts of the reports we found were screened for
eligibility. Then we considered the entire reports for the studies which appeared to be eligible
from the abstract. Only original economic evaluations for health care interventions in Tanza-
nian settings were included in the literature review. We excluded studies which were not
economic evaluations or did not include assessment of both costs and health effects. Studies in
which results were available only for larger geographical areas such as sub-Saharan Africa were
also excluded, as were review studies.
The included studies were screened and key assumptions, major findings and conclusions
were extracted. To improve comparability, all monetary values have been converted into 2006
USD using GDP-deflator rates (Bureau of Economic Analysis, 2008). We also assessed major
strengths and weaknesses of the studies in the light of recent developments and discussions
within the respective fields of research. Whether or not interventions should be considered to
be cost-effective was assessed using the definition proposed by the Commission on Macroeco-
nomics and Health. Interventions costing less than one Gross Domestic Product per capita per
disability adjusted life year (DALY) averted is considered to be very cost-effective (Commis-
sion on Macroeconomics and Health and WHO, 2001). The GDP in Tanzania was 390 USD
per capita in 2006 (Tanzania, 2007).
3 Economic Evaluation of Health Interventions in Tanzania
3.1 Overview of Evidence
The literature search revealed a total of 161 hits. After exclusion of non-eligible studies and
pairing of studies that were found in several databases, we were left with a total of 26
manuscripts reporting economic evaluation evidence for health interventions in Tanzania.
This process is shown in more detail in > Figure 33‐1. The most important reason for non
inclusion was that studies turned out not to be economic evaluations with simultaneous
consideration of costs and health benefits. A few studies were excluded because they reported
findings from a grater geographical area than Tanzania, or because they were review studies
with no original data. Since some of the original articles reported findings from the same
studies (double publications), the total number of studies turned out to be only 23.
The studies included in the review can roughly be sorted into the disease groups malaria,
HIV-AIDS, maternal and perinatal health, intestinal parasites and worms, tuberculosis (TB),
childhood diseases and cardiovascular disorders. The earliest studies considered tuberculosis
interventions, while studies on intestinal parasites, reproductive health and childhood diseases
followed in later years. The most recent additions to the literature include evaluations on
preventive cardiology and several approaches to malaria control.
In the following we present the major findings of all included studies. More details and
comments are provided in > Tables 33‐1–33‐5.
3.2 Malaria Interventions
Malaria and febrile illness remains the most important disease burden in Tanzania for all age-
groups except adults between 15 and 59 years. This is particularly so for children under 5 years
. Figure 33-1
The literature search of the systematic review. (Robberstad_Fig 1.doc). The literature search
resulted in a total of 23 economic evaluations for Tanzania published in 26 different manuscripts.
The figure illustrates how the manuscripts were identified
(AMMP, 2004). An overview of the five economic evaluations addressing malaria in Tanzania
is given in > Table 33‐1. These interventions as a group can be labeled as highly cost-effective.
They range from ‘‘> cost-saving and improving health outcomes,’’ up to ‘‘costing a little over
200 USD per DALY averted’’ after all monetary values have been converted to 2006 USD.
It is well known that over half the children in developing countries suffer from anemia
caused primarily by iron deficiency and malaria. Alonso Gonzàlez and colleagues considered
the costs and effects of supplementing routine case management of new cases either with daily
iron supplementation to infants between 2 and 6 months, weekly malaria prophylaxis with
Deltaprim (pyrimethamine and dapsone) to infants between 2 and 12 months, or a combina-
tion of the two (Alonzo Gonzalez et al., 2000). From a > societal perspective, they found that
all the alternatives they considered are more cost-saving and improve the health of infants
more compared to routine care. They recommended that a combination of iron supplemen-
tation and Deltaprim should be provided through the expanded programme for immuniza-
tion (EPI) (Alonzo Gonzalez et al., 2000).
Two recent studies considered promotion of insecticide treated bednets (ITNs) to reduce
the malaria burden. Hanson et al. (2003) evaluated a programme for social marketing of
insecticide treated bednets. Using a community perspective, they found that a social marketing
programme would cost between 50 and 76 USD per DALY averted depending on the assumed
protectivity of bednets without retreatment. They concluded that such interventions may have
a significant role in national malaria programs (Hanson et al., 2003), but it seems that more
information about the cost-effectiveness in areas where malaria is less prevalent would have
been useful. In an evaluation of the Tanzania National Voucher Scheme of ITNs, which was a
trial of much larger scale than the previous study, a voucher scheme for distribution of nets to
pregnant women attending antenatal care was evaluated. The researchers were concerned
about finding a trade-off between the need for immediate impact through free distribution,
and the long-term sustainability of increased coverage through supporting development of a
554
. Table 33‐1
Economic evaluation of malaria interventions in Tanzania
Target Intervention and Source

population comparator CER (2006 USD) Major assumptions Authors conclusion Comments [ref.]
33
Prevention Iron supplementation and Costs per DALY Costing was done from a The authors conclude Since the interventions (Alonzo
of anemia chemoprophylaxis averted: > societal perspective, that the combination of are all cost-saving at the Gonzalez
and malaria compared to standard case Not applicable. All including both costs to malaria same time as averting et al.,
among management: interventions were health care providers and chemoprophylaxis and more DALYs compared to 2000)
infants cost saving and costs to families. Results iron supplementation is standard case
Iron
averted more only from the provider cost-effective and cost- management, the
Deltaprim
DALYs compared perspective were also saving in Tanzania. It is support for introducing
Deltaprim + Iron
to standard case presented in the paper. recommended that a them is strong. But the
management combination of relevance of Deltaprim as
prophylaxis and iron is prophylaxis should be
provided to infants reassessed for whether or
through the expanded not the resistance
programme for situation has changed
immunization (EPI). since data collection in
1996.
The study presents cost
per averted DALY
separately for malaria and
anemia, but it would have
been highly relevant to
see the aggregate results
for all effects from the
Economic Evaluation of Health Interventions: Tanzania Perspectives
same intervention, since

this is a major part of the
underlying idea of using
such a generic measure of
population health.
Prevention Social marketing of Costs per DALY Costing was done from Social marketing of bed The geographic area of (Hanson
of malaria insecticide-treated averted: project and community nets is clearly a feasible the study was Kilombero, et al.,
among the bednets compared to no perspectives, and a 3% method of saving lives. It which is an area where 2003)
general net use discount rate was used undoubtedly has a Malaria is the most
population for both future costs and significant role to play in important disease
Baseline 76
(in health effects. national strategies for burden. Less attractive
assumptions
particular Prospective collection of scaling up the use of cost-effectiveness results
Assuming some 50
infants) cost (Prospective Costing) these nets. should be expected in
protective effect from
and outcome data in an areas of lower disease
untreated nets
area where the prevalence. It would be
Costs per treated
prevalence of malaria is useful to analyze this
net year:
high. aspect before a national
18
scale up of social
marketing.
33
555
556
33

Prevention Tanzania National Voucher Costs per ITN Costing was done In Tanzania there has The study present (Mulligan
of malaria Scheme (TNVS): A voucher delivered: retrospectively from a been a mixed approach average figures on costs- et al.,
among the scheme for distribution of 7.57 societal perspective, and to delivering ITNs: and effects compared to 2008)
general insecticide treated bednets Costs per treated net utilization data were combining social no intervention. The
population (ITNs) to pregnant women net year: based on a household marketing techniques authors mention different
(in attending antenatal care 4.23 survey. Health outcome with the targeting of alternatives approaches
particular Costs per malaria data were taken from the vulnerable groups with to deliver ITN, but
infants) case averted: literature. subsidies. The results attempts were not made
13 presented here suggest to calculate incremental
that the TNVS, a key part costs and outcomes
of that strategy, is a cost– compared to these.
effective method of Costs per DALYs averted
delivering subsidized ITNs not reported, but since
to targeted groups the costs per treated net
year is less than one third
in this study compared to
the Hanson study
(Hanson et al., 2003), it

can be assumed that the
cost per DALY averted
would be between USD
15 and 25 in this study.
Treatment Three antimalarial drug Gross costs per Costs were calculated In an area of high drug The authors themselves (Wiseman
of malaria combinations compared to case averted from both a provider and resistance, there is raise the issue of et al.,
(Teule monotherapy with (provider the societal perspective. evidence that AL and diagnostic procedures, 2006)
Hospital in amodiaquine (AQ): perspective, Discounting of costs at AQ + AS are the most and that treatment of
Tanga 28 days after 3%. Results are presented cost-effective drugs many false positive cases
district) treatment): both as gross costs and as despite being the most may reduce the cost-
AQ + sulfadoxine- 11 net costs including expensive, because they effectiveness drastically.
pyrimethamine (SP) resource savings. are significantly more They cite studies from
AQ + artesunate (AS) 7.5 effective than other Tanzania demonstrating
Artemether- 5.9 options and so reduce the that between 23 and 70%
lumefantrine (AL) need for further of people with false tests
Net costs per case treatment. will be given treatment in
averted: All Findings must be primary health care
combinations cost- interpreted with caution facilities. A model
saving and more in areas with different integrating the cost-
effective resistance patterns, in effectiveness of different
compared to settings with less treatment options with
monotherapy accurate diagnostic the empirical evidence on
routines and if real world alternative screening
compliance is poorer than procedures might be a
for the trial setting. more appropriate way to
analyze this issue than the
one-way sensitivity
analysis presented in this
paper.
33
557
558
33

Prevention Introduction of a Costs per DALY The study applies a A price range of 1–20 USD This study models the (Tediosi
of malaria hypothetical pre- averted: societal perspective, per dose of the vaccine is cost-effectiveness of a et al.,
among erythrocytic malaria including costs of vaccine explored, and the cost per hypothetical vaccine. All 2006)
children vaccine into the expanded delivery, case DALY averted increases clinical input is therefore
programme on management costs and almost proportionally purely assumptive, and it
immunization (EPI). economic impacts from with the vaccine price. Up could have been more
Compared to case the intervention. to a vaccine price of USD strongly emphasized that
management of malaria: Costs and DALYs 10 per dose, the cost per this is in fact a threshold
discounted at 3%. discounted DALY averted analysis asking the
Vaccine price 1 USD per 14
Alternative discounting remains less than USD question ‘‘What would
dose
and age-weighting 100. have been needed in
scenarios were also For the vaccine prices terms of costs and clinical
dose
explored. towards the lower end of effectiveness for a malaria
Costs and outcomes are the range, malaria vaccine to be cost-
dose
estimated using a vaccination compares effective?’’
stochastic simulation favourably with other A reassessment of this
model. The single most malaria control initiatives. analysis using data from
important assumption is a Results are highly sensitive clinical trials, whenever
vaccine efficacy of 52%, to assumptions about the made available, would
with the range 30–80% epidemiological setting considerably strengthen

explored in sensitivity and vaccine characteristics the basis for a routine
analysis. including the transmission scale up of the
intensity, the efficacy, and intervention through
duration of protection. the EPI.
Diagnostic Rapid diagnostic test Net costs per 1,000 Costing included provider Improving diagnostic This is the only cost- (Lubell
testing of compared to microscopy patients (including costs and the monetary methods, including rapid benefit analysis of health et al.
malaria in and presumptive the monetary value of years of life lost diagnostic tests, can interventions found for 2008)
the general treatment: value of years of because of incorrect reduce costs and enhance Tanzania, and the
population life lost to Malaria: diagnosis and the benefits of effective findings are presented as
Low prevalence 5,518 inappropriate treatment. antimalarial drugs, but net societal costs from
(50% consistent A year of life was assigned only if the consistency of different policies,
response rate) a value of USD 150, and clinicians’ response to the including the monetary
High prevalence 3,714 life expectancies were test results is also value of years of life lost.
(50% consistent taken from a Tanzanian improved. It is difficult to use these
response rate) life table. Outcome data findings to inform
were obtained from a decision making about
randomized controlled resource allocation across
clinical trial of 2,425 groups of interventions
patients. and diseases, as
comparison cannot be
made directly between
the net costs presented in
this study and cost-
effectiveness estimates. It
would have been very
useful if the results also
were presented as costs
per DALY. Furthermore,
results are not presented
in a sufficiently
disaggregated way to
enable readers to make
their own assessment of

costs per LY or costs per
DALY.
A total of six studies were found reporting costs, health outcomes and cost-effectiveness in a Tanzanian context. Four of the studies considered interventions to prevent malaria, while
diagnostics and treatment were considered in two studies. All the studies found that malaria interventions are either cost saving or cost-effective according to usual definitions. CER:
Cost-Effectiveness Ratio; USD: United States Dollars; EPI: Expanded Programme for Immunization; DALY: Disability Adjusted Life Year; TNVS: Tanzania National Voucher Scheme; ITN:
Insecticide Treated Bednets; AQ: Amodiaquine; SP: Sulphadoxine Pyrimethamine; AS: Artesunate; AL: Artemether Lumefantrine; LY: Life Year
33
559
560
33
. Table 33‐2
Economic evaluation of HIV-AIDS interventions in tanzania
Intervention and CER (2006 Source

Target population comparator USD) Major assumptions Authors conclusion Comments [ref.]
Prevention of HIV Hospital-based blood Average cost The costing perspective For a low-income This study suggests that (Jacobs
infection through banking using voluntary per life year is not stated, but there country like Tanzania, hospital based blood and
infected blood donors, compared to saved: are no indications of provision of safe blood banking should be Mercer,
transfusion to the blood donation by 5.6–5.8 patient costs being transfusion services introduced, but the 1999)
general population relatives. Benefit-cost included so we assume through a hospital– authors rely on benefit
(in particular ratio: only provider costs are based blood banking estimates that are now
children < 5 years and 15–37: 1 included. Future health system is a feasible out of date. Since the
pregnant women) benefits discounted horizontal alternative to publication of these,
at 5%. the more costly vertical much has happened in
approach. the area of treatment
and care of HIV/AIDS
patients, both with
respect to procedures
and prices. This is likely
to affect cost-
effectiveness.
A reassessment of the
model taking these
things into consideration
would be useful before
results are used to
inform policy.
General adult Syndromic management Costs per HIV The study appeared to Improved STD treatment The results from this (Gilson
population of sexually transmitted transmission apply a programme in a rural African economic evaluation are et al.,
diseases compared to averted: perspective on the costs, population was highly reported in two papers, 1997,
usual primary level STD 432 but this is not clearly effective in reducing HIV but in somewhat more Mayaud
services stated. incidence and compared detail in the first of these. et al.,
Costs per Clinical data were taken favourably with other The cost-effectiveness 1998)
DALY from a large community cost-effective results are based on a
averted: randomized study, and interventions. The simple static model,
18–20 the prevalence of HIV syndromic approach was rather than a life cycle
and other STDs are also highly acceptable to model which is typically
based on a 2 year follow both staff and patients, applied in more recent
up period. Standard and proved highly research. The costs and
assumptions from BOD effective in curing STDs. impacts of ART are not
study (Murray and included, which means
Lopez, 1996) applied for that the relevance of the
DALY estimation, results can be
including discounting questioned in
and age-weighting. contemporary Tanzania.
Nor are the effects of
reduced morbidity
attributable to the cured
cases of STDs.
33
561
562

Infants Prevention of Mother to Costs per Costs were calculated These programs should It is an interesting (Sweat
33
Child Transmission DALY from a programme be considered cost- finding that the cost per et al.,
(PMTCT) of HIV using averted: perspective, including effective, although less DALY averted is 2004)
single dose Nevirapine costs of enhancing the so than previously significantly higher in
compared with no health system, pre-test reported, because of the this study compared to
antiretroviral prophylaxis counseling, HIV testing high societal value previous studies from
in eight African and post-test counseling placed on infant survival other settings. The
countries: and drug costs. and the potential for authors point out that
Tanzania 103 The efficacy assumptions severe long-term this is because previous
were based on the well demographic and studies underestimated
known HIVNET 012 economic harm from the cost of necessary
study, life expectancies high infant mortality enhancements of current
were based on country rates. health systems in Africa
specific demographic Small reductions in in order to deliver this
data, while disease maternal HIV prevalence treatment effectively.
weights for DALY or unintended It is possible that the
calculations were taken pregnancy by HIV- costing perspective
from the BOD study infected women have makes the cost-
(Murray and Lopez, equivalent impacts on effectiveness estimates
1996). infant HIV incidence and conservative. General
should be part of an antenatal care services
overall strategy to lessen are also likely to benefit
numbers of infant from the improvements
infections. of the health system to
provide counseling with

subsequent health gains
for mothers and babies.
Such an improvement
has not been included in
the calculations.
General population Voluntary Counseling Costs per Costs were calculated Overall, HIV VCT is highly The model relies heavily (Sweat
and Testing (VCT) DALY from a programme cost-effective in urban on an overall transmission et al.,
compared to no averted: perspective, and the East African settings, but rate of 0.0172 per sexual 2000)
intervention: study site was at slightly less so than act. The study has been
Muhimbili Hospital in interventions such as criticized because this
Overall all clients 27
Dar es Salaam. improvement of STD rate is relevant only for
HIV positive men 4.5
The modeling of HIV services and PMTCT with people particularly at risk,
enrolled as couple
infections and DALYs nevirapine. for example people co-
HIV negative women 231
averted is based on a VCT was most cost- infected with STDs. The
enrolled as individual
three year study where effective in Tanzania for favorable results, it is
participants were HIV positive men enrolled argued, do not therefore
randomized either to as part of a couple, while reflect the true cost-
VCT or general health it was least attractive for effectiveness of providing
education. Key HIV negative women VCT to the general
assumptions include a enrolled as individuals. population, as a lower
0.0172 overall infectivity Furthermore, cost- infectivity rate would lead
rate per sex act and an effectiveness improved to fewer modeled
observed improvement when VCT was targeted infections and fewer
in condom use from 26% to populations with high infections averted.
before the intervention HIV-prevalence and when The study was
to 88% after the VCT. people were targeted as conducted in an urban
Costs and benefits were couples. area. It remains to be
discounted at 3%, and seen whether these
DALY estimates were highly favorable findings
based on disease can be replicated in the
weights from the burden more transparent rural
of disease study. societies which
represent 80% of the
Tanzanian population.
Finally, this VCT study was
undertaken before the
initiation of wide-spread
of scale-up programs for
ART, and the potential
interactions between VCT
33
and access to ART are

563
therefore not included.

564
General population Voluntary Counseling Costs per Cost estimates and data The provision of free VCT This study applied the (Thielman
and Testing (VCT) with DALY on VCT uptake were enhances both the previous estimates of et al.,
33
different user fees averted: based on an number of clients testing Sweat et al. (2000) for 2006)
profiles compared to no observational study on a per day and its cost- HIV infections averted by
intervention. community-based AIDS effectiveness in VCT. In other words, the
service organization. resource-limited main contribution of this
No free VCT (user fees) 10.5
Costs were estimated settings. study is in terms of
Free VCT campaign 6.5
from a programme VCT with free campaigns alternative estimates of
(user fees when no
perspective. or the provision of programme costs and of
campaign)
Costs and benefits were sustained free VCT VCT uptake in a general
Sustained free VCT (no 5.7
discounted at 3%, and should be adopted into population. The
user fees)
DALY estimates were national HIV control objections made to the
based on disease policies. original Sweat study
weights from the burden about infectivity and
of disease study. changes in sexual
behaviour also apply to
this study.
Only average cost-
effectiveness ratios are
provided in the report.
When we observe the
incremental costs and
effects of these three
mutually exclusive VCT
strategies, in turns out
that both alternatives

are dominated by the
strategy of providing
sustained free VCT.
Five studies report costs, effects and cost-effectiveness of interventions to prevent HIV in Tanzania. All studies conclude that HIV preventions is highly cost-effective, but several of
them are so old that the impact of ARV treatment has not been included into the models. This warrants reassessment. No economic evaluations were found assessing treatment or
care of people with HIV/AIDS. CER: Cost-Effectiveness Ratio; USD: United States Dollars; STD: Sexually Transmitted Disease; BOD: Burden of Disease; DALY: Disability Adjusted Life Year;
ART: Antiretroviral Treatment; PMTCT: Prevention of Mother to Child Transmission; VCT: Voluntary Counseling and Testing
. Table 33‐3
Economic evaluation of maternal and perinatal health interventions and interventions targeting STDs in tanzania

Pregnant Management of Cost-savings of The costing was done Assuming post This is actually a cost- (Magotti
women incomplete abortions by MVA for an annual from a partial facility procedures outcomes are minimization study, et al., 1995)
manual vacuum aspiration cohort of 1,432 perspective, and only the same for both patient although the total cost
(MVA) compared to evacuations: costs assumed to be groups, available data including waiting time
evacuation by curettage different between the from this study has shown and hospitalization was
Reduced
(EbyC) alternatives were that there is solid not valued and
treatment cost:
included. objective evidence to aggregated.
7721
suggest that MVA in a The costing excluded all
Reduced
poor developing country costs that were assumed
waiting time:
health care delivery to be equal between the
280.5 days
system is more cost- groups, such as
Reduced
effective compared to overheads, transport and
hospital stay:
EbyC. a number of other articles.
439.7 days
Only the cost differential
between the two
procedures is computed,
whereas the absolute
costs are unknown. The
study is not therefore
suitable for informing
allocative decision
making between different
disease and patient

groups.
If an assumption about
equal treatment outcomes
holds, the conclusion that
MVA is more cost-effective
33
than EbyC is supported.

565
566
33

Pregnant On-site rapid syphilis Costs per DALY Costs were estimated On-site syphilis screening The study presents cost- (Terris-
women screening with rapid averted (low birth from a provider and treatment are effectiveness with and Prestholt
and infants plasma reagin (RPR) test weight only perspective, including extremely good value for without stillbirths. As the et al., 2003)
(Mwanza) and treatment with a adverse event): both financial and money and important authors point out,
single dose of benzathine 143 economic costs. The synergies between stillbirth has previously
penicillin into routine DALY estimates are based antenatal syphilis not been included in
antenatal care, compared on data from a 26 month screening and HIV DALY calculations, as life
to routine antenatal care prospective cohort study. prevention can be has been considered to
without the intervention. exploited. begin at birth. Since
Costs per DALY Syphilis screening is stillbirth is the most
averted (low birth shown to be at least as important adverse
weight + cost-effective as PMTCT, outcome of untreated
stillbirth): and more cost-effective maternal syphilis,
14 than many widely improving the cost-
implemented effectiveness ratio
interventions. ten-fold, it seems highly
relevant to put more
weight on figures which

include this effect. As a
result, this intervention
appears to be highly
attractive in terms of cost-
effectiveness.
Pregnant Compares four syphilis Costs per DALY Costs are calculated from The RPR test is likely to be This study combines the (Vickerman
women point of care (POC) tests averted (test done a programme perspective the best choice in settings model and treatment et al., 2006)
and infants with rapid plasma reagin on blood serum): and take into account the with good facilities and outcomes of the Terris-
(Mwanza) (RPR) test in the diagnosis reduced demand for well trained staff, while Prestholt et al (2003) with
of syphilis in antenatal training and equipment POC tests are likely to data from an evaluation
care: of the POC tests improve coverage in of four RPR tests. No
compared to the RPR test. resource poor settings as incremental analyses
RPR test 12.7
DALYs were calculated they can be used on were performed between
POC tests:
including stillbirths using whole blood rather than the five mutually
Determine 18.0
the same methodology as serum, and require no exclusive syphilis tests.
Visitect 15.2
in the Terris-Presthold electrical equipment. Average cost-
Syphcheck 15.0
(2003) study. effectiveness ratios
Bioline 11.8
support the previous
finding that syphilis
screening should be a
highly attractive
intervention for decision
makers, although this is
not surprising given that
the results are based on
the same model and
evidence as the Terris-
Prestholt et al. (2003)
study.
Three studies were found addressing maternal and perinatal health in Tanzania. One study considered procedures for management of incomplete abortions, while the other two
addressed syphilis screening and treatment. Addressing syphilis in pregnant women appears to be highly cost-effective, while MVA seems to be a more cost-effective alternative to
manage incomplete abortions than EbyC. CER: Cost-Effectiveness Ratio; USD: United States Dollars; MVA: Manual Vacuum Aspiration; EbyC: Evacuation by Curettage; DALY: Disability
Adjusted Life Year; PMTCT: Prevention of Mother to Child Transmission; POC: Point of Care; RPR: Rapid Plasma Reagin
33
567
568
33
. Table 33‐4
Economic evaluation of interventions targeting parasite infections and intestinal worms in Tanzania
Target Intervention and CER (2006 Source

population comparator USD) Major assumptions Authors conclusion Comments [ref.]
High risk groups Chemotherapy with Costs per Provider perspective on Schistosomiasis control is The disease specific (Guyatt
(school children) quaziprantel compared infected costs. cheaper and more outcome measure (infected et al.,
and general to no intervention. person Economic and sustainable when person treated) makes 1994)
population in treated: epidemiological data from integrated into routine comparison with
areas where Mass treatment of 9.9 Kilombero in Tanzania primary health services than interventions targeting
schistosomiasis is school children previous estimates of other diseases difficult. The
endemic. Reagents strip testing 8.4 vertical strategies. BOD study (Murray and
by school teachers Passive testing with Lopez, 1996) gives a disease
Passive testing and 4.1 integration of screening weight of 0.005 for
treatment at local and treatment at primary schistosomiasis. With the
dispensary health care facilities is additional crude
affordable and more cost- assumptions that this is a
effective than the two chronic condition, and that
alternatives. LEs for school children and

the general population are
45 and 25 years,
respectively, CERs are in the
range 31–43 USD per DALY.
School children Three simple diagnostic Cost per The study applied a narrow The use of self reported The study applies a (Ansell
in areas where tests compared to urine infection programme perspective, schistosomiasis or self somewhat narrow costing and
schistosomiasis is filtration and correctly including both fixed and reported blood in urine perspective, meaning that Guyatt,
endemic. microscopical identified: variable costs. could be supported as a the costs might be higher if 2002)
examination Costs for overhead simple, cheap and cost- a broader set of cost-
programme management effective tool for identifying variables were to be
Self reporting through 0.8
and training of personnel schools at high-risk of included.
interview
were not included. schistosomiasis. Only average costs per case
Reagent strip testing 1.3
Clinical data from 15 With a prevalence of 68%, are reported. It would have
of urine
schools in Muheza district in self reported been relevant if the authors
Examination of urine 3.9
Tanzania. schistosomiasis to identify had also presented
for visible blood
high-risk schools for mass incremental costs per
Filtration of urine and 2.6
treatment and high-risk incremental case between
microscopical
children for selective this set of mutually
examination for eggs
treatment in low-risk exclusive interventions.
schools is twice as cost-
effective as using urine
filtration at a cost of around
1.8 USD per child treated.
33
569
570
33
Target Intervention and CER (2006 Source

population comparator USD) Major assumptions Authors conclusion Comments [ref.]
School children School health package, Costs per Although not clearly stated, Deworming programmes Although results are (Guyatt
in areas with high including albendazole anemia it appears that costs were should be included in public presented in terms of a et al.,
prevalence of and praziquantel case calculated from a health strategies for the disease specific outcome 2001)
hookworm and treatment, and health prevented: programme perspective. control of anemia in measure, it seems likely that
schistosomiasis education. Compared to Prevalences were assessed schoolchildren where there a scale up of such treatment
no school health in cross-sectional studies of are high prevalences of is reasonable even
package. large school samples hookworm and compared to other health
including a baseline and schistosomiasis. interventions competing for
Hemoglobin 12
follow up studies. resources.
threshold < 110 g/l
The authors write that the
Hemoglobin 246
most traditional approach
threshold < 70 g/l
to improving iron balance
and reducing anemia is to
use iron supplementation,
but that they found no
studies presenting cost per
anemia case prevented.
However, Alonzo Gonzales
et al present cost-
effectiveness results for iron
supplementation in the
context of malaria, so some
comparison should have
been possible.
General Four different mass Average Provider perspective on The most cost-effective DEC The study also reports (Michael
population in diethylcarbamazine cost per costs, including direct based chemotherapy is incremental cost- et al.
communities (DEC) chemotherapy case financial costs and costs of using a low monthly dose. effectiveness ratios, but this 1996)
where regimens compared to cured: treating side-effects. Future Standard dose strategy is is done in a non-standard
bancroftian no intervention: benefits discounted at 6% dominated by strategies II format. The authors failed to
filariasis is and III. Findings are very report that strategy II
I. Standard dose 46
endemic sensitive to programme should be excluded in the
II. Semi-annual single 9.3
design parameters. There base case scenario because
dose
are great potentials for of extended dominance by
III. Low monthly dose 8.9
economies of scale, which a combination of
IV. DEC-medicated 31
may significantly influence intervention III and the null
cooking salt
the results. intervention. After this
adjustment, the ICER of III is
8.9 compared to no
intervention, while the ICER
of moving from III to IV is
USD 355 per cured case.
Four evaluations address interventions against intestinal worms and parasite infections in Tanzania. All studies apply disease specific outcome measures, with the consequence that
comparison is difficult to make with interventions targeting other types of diseases. The studies conclude that control of intestinal worms and parasites are cost-effective ways to
improve health of school children. CER: Cost-Effectiveness Ratio; USD: United States Dollars; DALY: Disability Adjusted Life Year; LE: Life Expectancy; DEC: Diethylcarbamazine; ICER:
Incremental Cost-Effectiveness Ratio
33
571
572
33
. Table 33-5
Economic evaluation of interventions targeting tuberculosis, cardiovascular disease and childhood diseases in tanzania
Target Intervention and

population comparator CER (2006 USD) Major assumptions Authors conclusion Comments Source [ref.]
Patients with Chemotherapy. Costs per LY saved Provider perspective on Chemotherapy for The outcomes of this (de Jonghe
pulmonary Comparator not (Costs per cure): costs. smear-positive economic evaluation are et al., 1994,
sputum-smear- clearly stated, but Outcome data from the tuberculosis is the most reported in three Murray,
positive assumed to be no national tuberculosis cost-effective health papers, but most 1991,
tuberculosis (TB) chemotherapy program. intervention in detailed by de Jonghe Murray
developing countries. et al. (de Jonghe et al., et al., 1991)
Short course with 5.1 (486)
Short-course therapy is 1994). This is an early
hospital admission
cheaper and has higher study assuming low HIV-
Standard with 7.5 (650)
cure rate than standard prevalence, which may
hospital admission
12-month therapy. lead to life years gained
Ambulatory short 2.6 (243)
When feasible, being overestimated.
course
ambulatory therapy is The study is criticized for
Ambulatory 2.9 (257)
much cheaper than using some of the best
standard
hospital therapy. treatment outcomes
ever achieved (Borgdorff
et al., 2002).
Average CERs only. No

incremental CERs
calculated between
mutually exclusive
interventions.
Patients with Directly Observed Costs per patient Societal perspective on Community DOT The study only presents (Wandwalo
sputum-smear- Treatment (DOT) successfully treated: costs. Outcome data improves the costs per successfully et al., 2005)
positive, smear- compared to no from a randomized affordability and cost- treated patient, which
negative and treatment controlled study, with effectiveness of TB makes comparison with
extra-pulmonary prospective collection of treatment, and may interventions targeting
Community based 161
tuberculosis (TB) cost data. reduce congestion in other diseases difficult.
DOT (average all)
Applies cure rates of overburdened TB clinics. The facility based DOT
Facility based DOT 256
74% and 72% for option in this study
(average all)
community and facility corresponds roughly to
Community based 183
DOT, respectively. Takes the ambulatory short
DOT (smear
into account the rates of course option in the
positive only)
self cure without previous study (de
Facility based DOT 325
treatment. Jonghe et al., 1994,
(smear-positive
Murray, 1991, Murray
only)
et al., 1991). This means
that in comparison, the
costs per patient cured/
successfully treated is
roughly in the same area
in the two studies, and
so the cost per LY saved
should be roughly the
same.
33
573
Target Intervention and 574

Children under 5 Integrated Costs per unit of Costs were collected IMCI improved the This study directly (Bryce et al.,
years at risk of management of health not from a societal quality and efficiency of targets the millennium 2005)
33
childhood childhood illness presented, but IMCI perspective, including child health care relative development goal of
diseases (IMCI) compared to had both reduced national- and district to routine child health reducing mortality
(pneumonia, routine care. costs and reduced level authorities, facility care, and the total costs among children under 5
diarrhea, malaria, child mortality level costs and per child were also years by two-thirds
measles and compared to household costs. lower. We can therefore within 2015, and the
undernutrition) routine care. Data on effectiveness conclude that IMCI is findings are therefore of
were taken from a non- more cost-effective than particular relevance to
Reduced child
randomized routine care for policy.
mortality: 13%
observational study improving child health The finding that IMCI is
(3.8 fewer deaths
from two districts with outcomes. both cost-saving and at
per 1,000
IMCI and two districts the same time saves
children per year)
with routine care. more life years makes
Reduced total
the argument in favor of
costs per child of
IMCI a strong one, even
care: 7.86 USD
if observational studies
(IMCI) compared
are not generally
to 8.34 USD
considered to be the
(routine care)
gold standard for
measuring clinical
effectiveness.
It may be noted that
IMCI is more costly than
routine care at the
household level. This

implies that IMCI would
be even more cost-
effective if a pure health
systems perspective had
been applied.
Children 1–5 Zinc as adjunct Incremental costs The study applies a Treatment strategies I The table of incremental (Robberstad
years at risk of therapy for childhood per DALY averted: societal perspective and II are extendedly CERs does not contain et al., 2004)
diarrhea diarrhoea compared including both costs to dominated by a all relevant values, and is
with standard oral the health system and combination of no presented in a slightly
rehydration solution some patient cost. treatment and strategy non-traditional fashion,
(ORS) treatment and Epidemiological and III. The optimal case but this does not
with no treatment: clinical effectiveness management is influence the
data were based on a therefore to provide zinc conclusions. It is
0. No treatment 0–I: 147
review of the available in addition to ORS to all assumed that the only
I. Standard I–II: 52
literature, while cost diarrhea patients, incremental cost from
treatment with
data were based on a irrespective of whether zinc treatment is the
ORS
Tanzanian costing study or not they have price of the dispersible
II. ORS + zinc in II–III: 14
and recent drug prices. dysentery. tablets, which perhaps is
non-dysenteric
Costs and outcomes Zinc used as adjunct a bit optimistic as some
diarrhea
were discounted at 3%, therapy to standard case training and awareness
III. ORS + zinc to all 0–III: 95
while DALYs in addition management of acute campaigns would
diarrhea cases
were age-weighted. diarrhoea represents probably be needed
including
Other scenarios were good value for money, during a scale up
dysentery
explored in sensitivity as well as representing exercise.
analyses. an equitable resource
allocation.
33
575
576
Target Intervention and
Adults at risk of Medical interventions Average costs per Costing was done from a Diuretic given as The study does not (Robberstad
cardiovascular of primary DALY for patients societal perspective, monotherapy is the drug include saved treatment et al., 2007)
33
disease (stroke prevention: with very high CV including health yielding the lowest cost- costs or avoided
and coronary risk (incremental provider costs and direct effectiveness ratio, while productivity losses from
heart disease) costs per DALY): patient costs. Costs and the Polypill has the averted cases of stroke
Aspirin (ASA) 173 outcomes were highest potential for or coronary heart
Diuretic (DIU) 90 (90) discounted at 3%, while averting DALYs. Primary disease. This makes the
Betablocker (BET) 349 DALYs were age- prevention is most perspective a semi-
Calcium channel 1,162 weighted. Other favorable in patients societal one. Since both
blocker (CAB) scenarios were explored with very high CV risk, the above effects
Statin (STA) 573 in sensitivity analyses. while the cost- increase the benefits to
ASA + DIU 118 (152) Effect sizes were derived effectiveness ratios society, the findings in
ASA + BET 193 from systematic reviews gradually increase for this study are likely to be
DIU + BET 132 or meta-analyses, drug lower risk levels. conservative.
ASA + DIU + BET 146 (336) costs were taken from Primary prevention of
ASA + DIU + STA 457 international price lists CV disease is supported
DIU + BET + STA 459 and other costs were for patients with very
ASA + BET + STA 510 taken from a Tanzanian high risk when policy
ASA + DIU + BET + 467 (1,060) costing study. makers are willing to
STA pay at least 90 USD to
Polypill 591 (1,566) avert one DALY. The
most likely drug is a
diuretic like
Hydrochlorothiazide,
either given alone or
together with aspirin.
Two studies were found reporting cost-effectiveness of tuberculosis treatment in Tanzania, two evaluations look at childhood diseases, while one study consider primary prevention
of cardiovascular disorders with pharmaceuticals. Both of the TB studies indicate that the DOT strategy is highly cost-effective, while the study on IMCI concluded that the
intervention is cost-saving. Diarrhea treatment with ORS appears to be a little less cost-effective than previously believed, but the cost effectiveness improves with the
supplementation of zinc. Preventive cardiology is most cost-effective when given to patients with very high risk, and is for these patients likely to be considered good value for
money in Tanzania. CER: Cost-Effectiveness Ratio; USD: United States Dollars; TB: Tuberculosis; LY: Life Year; DALY: Disability Adjusted Life Year; CER: Cost-Effectiveness Ratio; DOT:
Directly Observed Treatment; IMCI: Integrated Management of Childhood Illness; ORS: Oral Rehydration Solution; ASA: Aspirin; DIU: Diuretic; BET: Betablocker; CAB: Calcium Channel
Blocker; STA: Statin; CV: Cardiovascular
domestic market for ITNs. This study concluded that a voucher scheme is a cost–effective
method of delivering subsidized ITNs to targeted groups (Mulligan et al., 2008). By comparing
figures (> Table 33‐1) it appears that this set-up is roughly three times more cost-effective than
the social marketing program evaluated in the previous study.
Tediosi and colleagues (2006) modeled the impacts of introducing a hypothetical malaria
vaccine into the expanded programme of immunization (EPI). The malaria vaccine costs
between 14 and 215 USD per DALY averted depending on assumptions about vaccine price.
The authors found that the vaccine compares favorably with other malaria interventions for
the lower price ranges (Tediosi et al., 2006), but it is difficult to use this information to inform
implementation policy because the vaccine remains hypothetical and is not yet available for
scaling up.
Two recent studies address the issues of how to diagnose and treat new cases of malaria.
Wiseman et al. evaluate the cost-effectiveness of changing first line treatment from mono-
therapy with amodiaquine to three alternative combination therapies (Wiseman et al., 2006).
When resource savings from averted cases were included, they found that all combination
therapies were cost-saving, while at the same time being significantly more effective than
monotherapy (Wiseman et al., 2006). Without savings from averted cases, they found cost-
effectiveness ratios between 5.9 and 11 USD per case averted. The authors raise the concern
that treatment of many false positive cases can reduce the cost-effectiveness dramatically. This
issue is directly targeted by Lubell and colleagues, who observed that in areas in Tanzania with
low transmission, over 90% of all antimalarials are given to patients with a negative test result.
They were therefore worried about the sustainability of new artemisinin based combination
therapies (Lubell et al., 2008). In a cost-benefit analysis, they evaluated the response of
clinicians to rapid diagnostic tests as an alternative to testing with microscopy, which is not
available in most primary health care facilities. They found that rapid diagnostics test could
reduce the costs and enhance the benefits of antimalarial drugs, but only if improvements are
also made in how clinicians respond to test results (Lubell et al., 2008). This is a cost-benefit
analysis expressing health outcomes in monetary values, and the results are not presented in
a way which allows us to assess cost per DALY averted. This makes it difficult to compare
the results directly with the rest of the literature, although the main conclusion appears
reasonably firm.
3.3 HIV-AIDS Interventions
While malaria and febrile illnesses are the most important sources of disease burden in
Tanzania in general, HIV-AIDS is the most important among the adult population aged
15–59 years (AMMP, 2004). This pandemic is also the most important explanation for the
drop in life expectancy since 1990. Given the tremendous impacts of this disease, it is strange
that no studies have yet been published reporting the costs and effects of treatment and care
interventions for AIDS in Tanzania. As for interventions to prevent the transmission of HIV,
we found a total of 5 different studies including safe blood transfusion procedures, manage-
ment of sexually transmitted diseases (STDs), prevention of mother to child transmission and
voluntary counseling and testing. The reported cost-effectiveness ratios summarized in
> Table 33‐2 were in the range from 5 USD to 230 USD after conversion to 2006 values.
These can all be characterized as very cost-effective since this is lower than GDP per capita per
DALY averted (Commission on Macroeconomics and Health and WHO, 2001, Tanzania,
2007). But several of these studies are so old that their adequacy can be questioned after the
scale up of antiretroviral treatment in recent years.
Jacobs and Mercer evaluated improvement in the safety of blood transfusion by using
hospital-based blood banking rather than blood donation from relatives. They found this to be
an effective way of reducing HIV infection through transfusion of infected blood. They also
argued that a strategy of hospital-based blood banking is cheaper than centralized alternatives.
With cost-effectiveness ratios of 5.6–5.8 USD per year of life saved, and > benefit-cost ratios in
the range 15:1 and 37:1, they concluded that hospital-based blood banking is a feasible
alternative for low income countries like Tanzania (Jacobs and Mercer, 1999). However,
contrary to the evidence presented in their paper, a model of centralized blood banking has
since been selected for Tanzania. This is recommended by the World Health Organization,
partly because a centrally coordinated system is able to do more thorough screening of the
donated blood than a hospital based system (WHO, 1999).
In the so-called Mwanza trial, the cost-effectiveness of syndromic management of STDs
was explored. The results of the study were reported first by Gilson and colleagues (Gilson
et al., 1997), and later by Mayaud et al. (1998). Compared to usual primary level STD services,
they found the incremental costs of syndromic management to be in the range 18–20 USD
per DALY averted. The driving force behind this result appeared to be that transmission of
HIV increases in the presence of STDs, and that effective management of these is an effective
way of controlling HIV (Mayaud et al., 1998). The sustainability of the intervention was
later questioned because no change in sexual behavior was observed in the Mwanza study
(Kumaranayake and Watts, 1998). Retrospectively, however, the most important limitation of
the study is probably that is was carried out before the introduction of ARV treatment, and
therefore does not take into account the costs and health effects of AIDS management in
contemporary Tanzania. It is difficult to foresee without formal analysis how the introduction
of ARV treatment is likely to influence the cost-effectiveness of STD management.
Prevention of mother to child transmission (PMTCT) of HIV from infected mothers to
their babies using single dose nevirapine is one of the most well documented health interven-
tions in terms of cost-effectiveness in sub-Saharan Africa. One such study is also available for
Tanzania. Sweat and colleagues reported the cost-effectiveness of this intervention for eight
African countries, including estimates based on Tanzanian epidemiological and cost data
(Sweat et al., 2004). They found that PMTCT with nevirapine in Tanzania would cost 103
USD per DALY averted compared to no prophylaxis. The authors conclude that the interven-
tion is cost-effective, but that nevirapine should be part of an overall strategy to lessen the
numbers of infant infections since small reductions in maternal HIV prevalence or unintended
pregnancies by HIV-infected women have equivalent impacts on infant HIV incidence (Sweat
et al., 2004).
Voluntary counseling and testing (VCT) is a research area that has been debated widely
during the last 8 years, primarily because experiences with such programs have varied consid-
erably across settings. The most commonly cited study has been the one by Sweat and colleagues
from Muhimbili Hospital in Dar es Salaam (Sweat et al., 2000), in which remarkably good
improvements in condom use were observed. With incremental cost-effectiveness ratios be-
tween 4.5 and 231 USD per DALY averted, they found that VCT is highly cost-effective,
particularly when the intervention is targeted at couples in high prevalence populations
(Sweat et al., 2000). This study has been criticized for applying a very high transmission rate,
and it’s relevance for a general population has therefore been questioned (Moses et al., 2000).
The study does not incorporate the outcomes and costs of ARV treatment, nor does it model
the potential interactions between ARV and sexual behavior (Sherr et al., 2007). A reassessment
of VCT in the light of the new treatment situation in Tanzania would therefore be useful.
Thielman et al. recently applied the estimates of behavioral change and infectivity from the
Muhimbili study to see how different levels of user fees influence cost-effectiveness. With observa-
tional data from Moshi town, they found that VCT is most cost-effective at 5.7 USD per DALY
averted when it is provided without user fees. It is concluded that free VCTshould be adopted into
national HIV control policies, but it should be noted that the objections made to the Muhimbili
study about infectivity and sustainability of behavior change also applies to this later paper.
3.4 Maternal and Perinatal Health Interventions
Improving maternal health has been given high priority in the global health agenda through
the inclusion of millennium development goal number 5: reducing maternal mortality by
three-quarters by 2015 (Wagstaff and Claeson, 2004). This high priority is by no means
reflected in the health economic literature available on Tanzania, as only three studies were
found which indirectly target this goal. One study considered management of incomplete
abortions, while the other two evaluated syphilis interventions among pregnant women. These
are summarized in > Table 33‐3, and presented briefly below.
Magotti and colleagues considered the appropriateness of two alternatives for management
of incomplete abortions at Muhimbili Hospital. They compared manual vacuum aspiration with
evacuation by curettage, and concluded that the former is more cost-effective than the latter
procedure (Magotti et al., 1995). This is a partial > cost-minimization analyses reporting the
differential for a sub-set of costs assuming of equal post procedural outcomes. No attempts were
made to report costs per life year (LY) saved or DALYs averted, and the findings are therefore not
suitable for comparison with the other interventions included in this review.
Two recent studies target the issue of screening and treatment of pregnant women for
syphilis, and both conclude that such interventions are likely to be extremely good value for
money. Terris Prestholt et al. considered including on-site syphilis screening with rapid plasma
reagin (RPR) testing and treatment in routine antenatal care. They found that the intervention
costs were 14 USD per DALY averted (Terris-Prestholt et al., 2003). Most of the benefit was
from reduction in stillbirths, but there was also reduced incidence of low birth weight. The
model and treatment outcomes of this study were combined with new evidence from an
evaluation of four alternative point of care (POC) testing procedures in a study by Vickerman
and colleagues (Vickerman et al., 2006). The cost-effectiveness of the POC tests and the RPR
test were in the range 11–18 USD per DALY averted, which are all in the same range as the
result found by Terris-Presthold et al. They conclude that POC tests are likely to be the best
choice in resource poor settings as they are less demanding on infrastructure (Vickerman et al.,
2006). The current coverage of syphilis screening in antenatal women is only 38% in Tanzania,
so the potential for reduced child mortality and progress towards millennium development
goal number four appear to be good using this intervention.
3.5 Interventions Targeting Intestinal Worms and Parasites
The literature of economic evaluations on interventions targeting intestinal worms and

parasites is relatively rich compared to other health conditions. We identified four studies,
but none of them reported results in > commensurable units such as costs per DALY averted.
It is therefore difficult to compare and rank the interventions, or to use the results to inform
priority setting across disease groups. Nevertheless, these studies appear to have had some
impact, as Tanzania in 2005 launched the National Schistosomiasis Day targeting 4 million
school children (WHO, 2004). Intestinal worms and parasites are major health problems in
the country, with prevalence rates among school children in high endemic areas of for example
87% for intestinal parasites such as hookworm or schistosomiasis (Guyatt et al., 2001), and
20% for filariasis (Michael et al., 1996). The four studies are summarized in > Table 33‐4.
In a paper from 1994, Guyatt and colleagues compared three different case detection and
treatment strategies for schistosomiasis control to the alternative no intervention. With costs
between 4.1 and 9.9 USD (2006 values) per infected person treated, they found that integra-
tion of schistosomiasis control into routine primary health services is more affordable and
sustainable than previous estimates of vertical mass treatment strategies, and that a strategy
aiming at the general population is more cost-effective than strategies specifically targeting
school children (Guyatt et al., 1994). As mentioned, this outcome measure is not commensu-
rable and cannot be used for comparison with other types of treatment and prevention. By
assuming normal life expectancy (Lopez et al., 2001), assuming that this is a chronic condi-
tion, and applying a disease weight of 0.005 (Murray and Lopez, 1996), it is possible to suggest
that the cost per DALY averted is likely to be in the range USD 31–43 for these interventions,
which should be very favorable.
Mass treatment of schistosomiasis in children has been recommended at schools where the
prevalence is higher than 50% (Ansell and Guyatt, 2002). This is one of the alternatives
investigated in the Guyatt study above. But in order to identify high risk schools, or to identify
infected individuals in areas where the disease has lower prevalence, diagnostic tests are
needed. Ansell and Guyatt therefore compared the costs and effects of three simple diagnostic
tests with the gold standard, which is filtration of urine and microscopical examination. They
found a range of costs from 0.8 to 3.9 USD per infection correctly identified for the four
alternatives, and concluded that self-reported schistosomiasis or self-reported blood in urine
are the cheapest and most cost-effective tools for identification of schistosomiasis (Ansell and
Guyatt, 2002). These figures are for identification of infected cases only, and can not be
compared with the costs per infected person treated in the study above.
While the two previous studies looked solely at diagnosis and treatment of schistosomiasis,
Guyatt and colleagues in 2001 published the results of a campaign to reduce anemia through
mass treatment of both schistosomiasis and hookworm. The campaign targeted school
children, and it was found that the cost was 12 USD per case of anemia prevented using a
threshold of 110 g hemoglobin per liter blood. For severe anemia (<70 g/l) the cost was 246
USD per averted case. It was concluded that de-worming should be implemented in public
health strategies to control anemia in areas with high prevalence of schistosomiasis and
hookworm (Guyatt et al., 2001). If the results had also been presented as costs per DALY
averted, the conclusion may have had a firmer standing.
Bancroftian filariasis is a significant problem in many areas of Tanzania. Michael and
colleagues considered four different mass treatment strategies with diethylcarbamazine che-
motherapy (Michael et al., 1996). The cost-effectiveness ratios of these alternatives varied
between 8.9 and 46 USD per case cured, with a low monthly dose being the most attractive.
The standard treatment, with daily doses for 12 consecutive days was the least cost-effective.
The authors are not explicit about whether or not such campaigns should be promoted, but
point out that the results are sensitive to design parameters such as the scale of the programme
(Michael et al., 1996). It is necessary to mention the recent discovery that antibiotic treatment
of filariasis with doxycycline is highly effective (Debrah et al., 2007, Taylor et al., 2005), and the
relevance of this diethylcarbamazine study therefore needs to be reassessed.
3.6 Tuberculosis Interventions
Tuberculosis (TB) is the most important opportunistic infection in patients with HIV-AIDS,
and the disease has therefore received renewed interest in the recent years. But a study
comparing short course with standard course chemotherapy to patients with sputum smear
positive TB was also the first cost-effectiveness study ever of a health intervention in Tanzania.
The results from this multi-country study were presented in three publications by Murray
(1991), Murray et al. (1991), and de Jonghe and colleagues (1994). They found some of the
most favorable cost-effectiveness ratios ever recorded, varying between 2.6 and 7.5 USD per
life year (LY) saved (2006 USD), and the World Bank 1993 estimate that tuberculosis
treatment cost USD 1–3 per DALY gained was based on these results (WorldBank, 1993).
The costs per cure were in the range 243–650 USD. The authors concluded that chemotherapy
for smear positive TB is the most cost-effective health intervention in developing countries.
They also found that short course is cheaper and has higher cure rates than the old standard
therapy, and that ambulatory therapy is much cheaper than hospital therapy when feasible
(de Jonghe et al., 1994; Murray, 1991; Murray et al., 1991). The two TB studies are presented in
more detail in > Table 33‐5.
Wandwalo and colleagues applied data from a recent randomized controlled study with
prospective collection of cost data to compare different treatment delivery options of directly
observed treatment (DOT) to patients with sputum smear positive, smear negative and extra-
pulmonary TB. It was found that community based DOT is more cost-effective than facility
based DOT, both for all TB patients as a group, and when only the smear positive patients were
considered (Wandwalo et al., 2005). The cost-effectiveness ratios were from 161 to 325 USD
per patient successfully treated. In the Murray and de Jonghe studies (de Jonghe et al., 1994;
Murray, 1991; Murray et al., 1991), the intervention called ‘‘ambulatory short course’’ roughly
corresponds to the contemporary term ‘‘facility based DOT’’ in the Wandwalo study (Wand-
walo et al., 2005). The cost per cure/per patient successfully treated for this intervention is
surprisingly similar for these two studies, given that the analyses are based on totally different
clinical and cost data sets. But it should be kept in mind that the most recent study also
includes patient costs, which accounted for 30% of the total costs for the facility based strategy
(Wandwalo et al., 2005).
3.7 Childhood Diseases
Very little is known about the cost-effectiveness of interventions targeting typical childhood
diseases in Tanzania, despite the fact that Tanzania, like other typical low income countries,
has a high under-five mortality rate. Two studies, presented in > Table 33‐5, consider this
population group specifically. One study addresses childhood diarrhea, while another con-
siders the implementation of Integrated Management of Childhood Illness (IMCI). In addi-
tion, the studies of malaria interventions and interventions targeting intestinal worms and
parasites are of specific relevance to children. These studies have already been covered above,
and this evidence altogether suggest that few things are more attractive in terms of cost-
effectiveness than addressing childhood diseases.
IMCI is a response to the evidence that the major causes of under-five deaths in
low income countries are caused by a few disease groups including pneumonia, diarrhea,
malaria, measles and undernutrition, and that there are many missed opportunities for
prevention and treatment with effective and cheap drugs (Bryce et al., 2005). This publicat-
ion by Bryce and colleagues directly targets the millennium development goal of reducing
mortality among children under 5 years by two-thirds by 2015 (Wagstaff and Claeson, 2004),
and the findings are therefore of particular policy relevance. Bryce and colleagues evalua-
ted IMCI by comparing it to routine care at primary health facilities. This is not a
> cost-effectiveness analysis, since costs were not presented for any unit of health improvem-
ent. But the authors document that IMCI both has lower costs and results in reduced
child mortality compared to routine care. This is sufficient to support the authors’ conclus-
ion that IMCI is more cost-effective than routine care for improving child health (Bryce
et al., 2005).
While IMCI includes oral rehydration solution (ORS) for diarrhea management, the
recent evidence that zinc has additional benefits for recovery has not so far been used
in routine implementation. Robberstad and colleagues considered the use of zinc as adjunct
therapy to standard treatment with ORS and to no therapy (Robberstad et al., 2004). They
found that ORS is somewhat less cost-effective than previously believed, with a cost
of 147 USD per DALY averted. Supplementing ORS with zinc to both the dysenteric and
non-dysenteric cases of diarrhea resulted in the average cost-effectiveness being reduced to
95 USD per DALY averted. The authors conclude that zinc used as adjunct therapy to
standard case management of acute diarrhea represents good value for money (Robberstad
et al., 2004).
3.8 Primary Prevention of Cardiovascular Diseases
All the economic evidence found for health interventions in Tanzania, with the exception of
management of incomplete abortions (Magotti et al., 1995), cover diseases that are commu-
nicable. Nearly all the evidence ignores the fact that non-communicable diseases are among
the most important for the adult and elderly population of the country (Setel et al., 2001).
Robberstad and colleagues recently published an economic evaluation of medical interven-
tions to prevent cardiovascular diseases such as stroke and coronary heart disease, which
are the two most important cardiovascular disorders in Tanzania. They explored the cost-
effectiveness of 14 different drugs and drug combinations, given to people with risk profiles
ranging from low risk to very high cardiovascular risk (Robberstad et al., 2007). They found
that preventive cardiology is most cost-effective when given to people with very high risk of
cardiovascular disease, while the cost-effectiveness ratios gradually increase for lower risk
levels. They conclude that the most likely drug candidate in a country like Tanzania is a
diuretic like Hydrochlorothiazide, either given alone or together with aspirin (Robberstad
et al., 2007). The incremental cost-effectiveness ratios varied between 90 and 1,566 USD per
DALY averted for the very high risk group. More details about this study are provided in
> Table 33‐5.
4 Research Challenges
This literature review reveals that few existing and potential health interventions in Tanzania
have been assessed by economic evaluation, and there are large knowledge gaps in the relevant
literature. This limited evidence strongly limits the usefulness of economic evaluation as a
guide for setting health care priorities in the country, because whenever an intervention is
implemented which is assumed to be cost-effective, no-one know whether other interventions
would have yielded even better value for money in terms of improved population health.
There are large research gaps both within infectious diseases and non-communicable diseases.
4.1 Infectious Diseases and Reproductive Health
The research gaps are particularly evident for some areas. As mentioned, no evidence is
available for HIV-AIDS treatment and care in Tanzania. Literature from other settings suggests
that antiretroviral treatment of AIDS is likely to be much less cost-effective than prevention
(Canning, 2006; Creese et al., 2002; Marseille et al., 2002), but these findings rely on specific
assumptions about prevalence, modes of delivery, and the cost of alternative care for patients.
These assumptions don’t necessarily reflect the typical situation in Tanzania. Given the
importance of this pandemic in the country, and the amount of resources currently being
channeled into treatment through vertical scale-up programs, more economic evidence in this
area is desperately in need.
Malaria, together with intestinal worms and parasites, is probably the disease group with
best evidence for Tanzania. Existing economic evaluations cover both important preventive
and treatment alternatives. Still the evidence is not complete, and it would have been useful for
decision making if more research were available, particularly on presumptive treatment of
pregnant women against malaria.
Maternal and perinatal conditions are responsible for much of the disease burden in
Tanzania, in particular among the least well-off population groups. Given the meagre results
from our literature review, it seems safe to conclude that the discrepancy between the level of
disease burden and the amount of economic evidence available is larger for this disease cluster
than for any other group of communicable diseases. Important maternal and perinatal policy
options which have not been covered by evidence from Tanzanian include improved coverage
of routine maternity care, improved basic and comprehensive emergency obstetric care
services, and nutritional supplementation.
While there is relatively good evidence available for treatment of active tuberculosis, little
is known about alternative preventive interventions in a Tanzanian setting. For example,
prevention of TB through vaccination, or stopping progression from infection to active disease
with the inexpensive drug isoniazid, are alternatives which may be of great importance but
they have not yet been evaluated.
The literature review revealed a handful of studies evaluating interventions targeting
young children, including prevention and treatment of malaria, diarrhea treatment, integrated
management of childhood illness and campaigns against intestinal worms. But there is no
available evidence on, for example, the cost-effectiveness of increasing the coverage for the
immunization programme in Tanzania, or the cost-effectiveness of adding new vaccines to the
programme. Other gaps appear to be research on newborn care packages, and on interventions
to improve infant and child nutrition through improved breastfeeding, supplementation of

nutrients such as vitamin A, zinc or iodine, or safe water supplies.
4.2 Non-communicable Diseases
Above we have seen that there are large knowledge gaps for almost all groups of communicable
diseases, but this literature is in fact relatively rich in comparison with the available evidence
on non-communicable diseases in Tanzania. Apart from the study on preventive cardiology
(Robberstad et al., 2007), we found no other economic evaluation covering typical non-
communicable diseases. This is a striking finding, since both general studies (Lopez et al.,
2006) and studies specific to Tanzania (Setel et al., 2001) suggest that the so called epidemio-
logical transition is becoming increasingly challenging to the country.
The evidence available covers primary prevention of cardiovascular diseases, but evidence is
not available for care, treatment and secondary prevention in people who have already suffered a
cardiovascular disorder. Evidence is missing for all other important groups of non-communicable
diseases, including diabetes, cancers, mental and neurological disorders, kidney and urinary
diseases and injuries. Furthermore, there is an evidence vacuum for interventions targeting
important risk factors such as tobacco and alcohol, and for the treatment of manifest complica-
tions resulting from excess use of these substances. Finally, no evidence was found targeting dental
problems, vision and hearing impairment or musculoskeletal conditions.
5 Conclusions
A literature review reveals that the available economic evidence for health interventions in
Tanzania is reasonably sufficient to advice health care priority setting only for the areas malaria
and intestinal worms. Within these disease groups economic evaluation can be particularly
useful to inform implementation policy. For all other disease groups, evidence is either vastly
insufficient or totally missing. It is clear that for economic evidence to be used in an efficient
and consistent manner for setting health care priorities in Tanzania, much more knowledge
must be made available through a targeted scale up of research activities.
Summary Points
The United Republic of Tanzania has had a reduction of life expectancies since 1990, and
the two most important sources of burden of disease are malaria and HIV/AIDS.
Resources available for health care in Tanzania are extremely scarce, with a public health
expenditure of only USD 7 per capita per year.
Economic evaluation is useful for setting health care priorities when decision makers are
concerned about producing as much health benefits as possible within the limits of scarce
health care resources.
The economic evaluation evidence for Tanzania is scarce, with only 23 studies covering the
areas malaria, HIV-AIDS, maternal and perinatal health, child health, tuberculosis and
non-communicable diseases.
Evidence is relatively good for malaria interventions and interventions against intestinal
worms and parasites.
For all other disease groups, evidence is either vastly insufficient or totally missing. Lack
of evidence is particularly striking for treatment and care of patients with HIV/AIDS and
for non-communicable diseases. Economic evaluation can in most cases not be used
efficiently and consistently to set health care priorities in Tanzania, without more research
becoming available.
Acknowledgments
We thank Ole Frithjof Norheim and Kjell Arne Johansson for peer review of the manuscript
and Julia Norman for proofreading.
References
Alonzo Gonzalez M, Menendez C, Font F, Kahigwa E, Mabey D, Mills A, Hayes R. (1997). Lancet. 350:
Kimario J, Mshinda H, Tanner M, Bosch-Capblanch 1805–1809.
X, Alonso PL. (2000). Bull World Health Organ. 78: Globalis. (2008) (web-page), http://Globalis.gvu.unu.
97–107. edu (accessed 2008).
AMMP. (2004). AMMP Final Report–The Policy Implica- Guyatt H, Evans D, Lengeler C, Tanner M. (1994). Health
tions of Tanzanias Mortality Burden: A 10 year Policy Plan. 9: 385–395.
Community-Based Perspective. Adult Mortality and Guyatt HL, Brooker S, Kihamia CM, Hall A, Bundy DA.
Morbidity Project–Ministry of Health, Dar es Salaam. (2001). Bull World Health Organ. 79: 695–703.
Ansell J, Guyatt HL. (2002). Ann Trop Med Parasitol. 96: Hanson K, Kikumbih N, Armstrong Schellenberg J,
145–153. Mponda H, Nathan R, Lake S, Mills A, Tanner M,
Borgdorff MW, Floyd K, Broekmans JF. (2002). Bull Lengeler C. (2003). Bull World Health Organ. 81:
World Health Organ. 80: 217–227. 269–276.
Brock D, Wikler D. (2006). In: Jamison DT, Breman JG, Jacobs B, Mercer A. (1999). Health Policy Plan. 14:
Measham AR, Alleyne G, Claeson M, Evans DB, 354–362.
Jha P, Mills A, Musgrove P (eds.) Disease Control Jamison DT, Breman JG, Measham AR, Alleyne G,
Priorities in Developing Countries. Oxford Univer- Claeson M, Evans DB, Jha P, Mills A, Musgrove P.
sity Press and the World Bank, New York. (2006). Disease Control Priorities in Developing
Bryce J, Gouws E, Adam T, Black R, Schellenberg J, Manzi Countries. The World Bank and Oxford University
F, Victora C, Habicht J. (2005). Health Policy Plan. Press, New York.
20(Suppl 1): i69–i76. Kumaranayake L, Watts C. (1998). Lancet. 351: 989–990.
Bureau of Economic Analysis (web-page), http://www. Lopez AD, Ahmad OB, Guillot M, Inoue M, Ferguson
bea.gov/national/nipaweb (accessed 2008). BD, Salomon JA. (2001). Life Tables for 191
Canning D. (2006). J Econ Perspect. 20: 121–142. Countries for 2000: Data, Methods, Results (GPE
Commission on Macroeconomics and Health & WHO. Discussion Paper No. 40), Evidence and Information
(2001). Macroeconomics and Health: Investing in for Policy (EIP). World Health Organisation,
Health for Economic Development. WHO, Geneva. Geneva.
Creese A, Floyd K, Alban A, Guinness L. (2002). Lancet. Lopez AD, Mathers CD, Ezzati M, Jamison DT,
359: 1635–1643. Murray CJ. (2006). Lancet. 367: 1747–1757.
de Jonghe E, Murray CJ, Chum HJ, Nyangulu DS, Lubell Y, Reyburn H, Mbakilwa H, Mwangi R, Chonya S,
Salomao A, Styblo K. (1994). Int J Health Plann Whitty CJ, Mills A. (2008). Br Med J. 336: 202–205.
Manage. 9: 151–181. Magotti RF, Munjinja PG, Lema RS, Ngwalle EK (1995).
Debrah AY, Mand S, Marfo-Debrekyei Y, Batsa L, Pfarr K, East Afr Med J. 72: 248–251.
Buttner M, Adjei O, Buttner D, Hoerauf A. (2007). Marseille E, Hofmann PB, Kahn JG. (2002). Lancet. 359:
Trop Med Int Health. 12: 1433–1441. 1851–1856.
Gilson L, Mkanje R, Grosskurth H, Mosha F, Picard J, Mayaud P, Ka-Gina G, Grosskurth H. (1998). Int J STD
Gavyole A, Todd J, Mayaud P, Swai R, Fransen L, AIDS. 9(Suppl 1): 11–14.
Michael E, Meyrowitsch DW, Simonsen PE. (1996). Trop Tediosi F, Hutton G, Maire N, Smith T A, Ross A, Tanner
Med Int Health. 1: 414–426. M. (2006). Am J Trop Med Hyg. 75: 131–143.
Moses S, Plummer FA, Nagelkerke NJ. (2000). Lancet. Terris-Prestholt F, Watson-Jones D, Mugeye K,
356: 1602–1603. Kumaranayake L, Ndeki L, Weiss H,
Mulligan JA, Yukich J, Hanson K. (2008). Malar J. 7: 32. Changalucha J, Todd J, Lisekie F, Gumodoka B,
Murray C, Lopez A. (1996). The Global Burden of Mabey D, Hayes R. (2003). Sex Transm Infect. 79:
Disease. A Comprehensive Assessment of Mortality 375–381.
and Disability from Diseases, Injuries, and Risk Fac- Thielman NM, Chu HY, Ostermann J, Itemba DK,
tors in 1990 and Projected to 2020. The Harvard Mgonja A, Mtweve S, Bartlett JA, Shao JF, Crump
School of Public Health. JA. (2006). Am J Public Health. 96: 114–119.
Murray CJ. (1991). Bull Int Union Tuberc Lung Dis. 66: Vickerman P, Peeling RW, Terris-Prestholt F, Changalu-
149–156. cha J, Mabey D, Watson-Jones D, Watts C. (2006).
Murray CJ, DeJonghe E, Chum HJ, Nyangulu DS, Sex Transm Infect. 82(Suppl 5): v38–v43.
Salomao A, Styblo K. (1991). Lancet. 338: Wagstaff A, Claeson M. (2004). The Millennium Devel-
1305–1308. opment Goals for Health. Rising to the Challenges.
Robberstad B, Hemed Y, Norheim OF. (2007). Cost Eff The World Bank, Washington DC.
Resour Alloc. 5: 3. Wandwalo E, Robberstad B, Morkve O. (2005). Cost Eff
Robberstad B, Strand T, Black RE, Sommerfelt H. (2004). Resour Alloc. 3: 6.
Bull World Health Organ. 82: 523–531. WHO. (1999). Report of the Meeting of Experts in Blood
Setel P, Hemed Y, Whiting D, Masanja H, Lewanga M, Transfusion Services. World Health Organization.
Mswia R, Kitange H. (2001). Insights Health, Department of Blood Safety and Clinical Technology,
(2001). Geneva.
Sherr L, Lopman B, Kakowa M, Dube S, Chawira G, WHO. (2004). Devorming for Health and Development.
Nyamukapa C, Oberzaucher N, Cremin I, Gregson S. Report of the Third Global Meeting of the Partners
(2007). AIDS. 21: 851–860. for Parasite Control. World Health Organization,
Sweat M, Gregorich S, Sangiwa G, Furlonge C, Balmer D, Geneva.
Kamenga C, Grinstead O, Coates T. (2000). Lancet. WHO. (2006). World Health Report 2006. World Health
356: 113–121. Organisation, Geneva.
Sweat MD, O’Reilly KR, Schmid GP, Denison J, de Zoysa I. WHO (web-page), http://www3.who.int/choice/(accessed
(2004). AIDS. 18: 1661–1671. 2008).
Tanzania. (2002). Census (web-page), http://www.tanzania. Wiseman V, Kim M, Mutabingwa TK, Whitty CJ. (2006).
go.tz/census/census/index.html (accessed 2008). PLoS Med. 3: e373.
Tanzania. (2007). Tanzania in Figures 2006, National WorldBank. (1993). World Development Report 1993:
Bureau of Statistics, Ministry of Planning, Economy Investing in Health. Oxford University Press,
and Empowerment. Dar es Salaam. New York.
Taylor MJ, Makunde WH, McGarry HF, Turner JD,
Mand S, and Hoerauf A. (2005). Lancet. 365:
2116–2121.
34 The Burden of Disease and
Injury in Serbia
S. Janković . H. Vlajinac . V. Bjegović . J. Marinković . S. Šipetić-Grujicić .
Marković-Denić . N. Kocev . M. Šantrić-Milićević . Z. Terzić-Šupić .
N. Maksimović . U. Laaser
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
2 Summary Measures of Population Health and Their Uses . . . . . . . . . . . . . . . . . . . . . . . 589

1.1 Uses of Summary Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
1.2 Advantages and Disadvantages of Summary Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
2 Serbian Burden of Disease Study (SBDS) as an Example of the

DALY’s Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
2.1 Disability Weights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
2.2 Discounting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
2.3 Age Weighting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
2.4 Mortality and Disability Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
2.5 DALY Calculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
2.6 YLL Calculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
2.7 YLD Calculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
3 Main Results of the Study and Methodological Consideration . . . . . . . . . . . . . . . . . . . 592
4 The New Global Burden of Disease Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599

588 34 The Burden of Disease and Injury in Serbia
Abstract: The > epidemiological transition, characterized by a progressive rise in the average
age of death in all populations, has necessitated a serious reconsideration of how to measure
the health of populations. In the last decade of twentieth century, a considerable effort has
been put into the development of > summary measures of population health that combine
information on mortality and non-fatal health outcomes.
The burden of disease in Serbia, caused by 19 selected conditions was calculated using
DALY (> disability adjusted life years) which combines premature mortality (measured using
years of life lost – YLLs) and disability (measured using years lived with disability – YLDs).
The total burden of selected disorders in Serbia in 2000 was estimated at 652,260 DALYs or
86.4 DALYs lost per 1,000 population. There were more relevant YLLs for observed conditions
than YLDs (77%: 23%) with the exception of non-fatal health outcomes (unipolar major
depression, vision and hearing loss), and low birth weight and asthma, the burden of which
was mainly caused by lengthy period of disability. The leading five causes of DALYs were
ischemic heart disease (20.0 per 1,000), cerebrovascular diseases (18.0 per 1,000), lung cancer
(7.8 per 1,000), unipolar major depression (7.0 per 1,000), and diabetes mellitus (4.9 per
1,000). The total male burden of selected health problems was 32% higher than the total
female burden (99.8 per 1,000 males and 73.7 per 1,000 females).
The Serbian burden of disease study is a first step towards exploring the usefulness of
burden of disease methods for Serbia in providing information to assist in health planning and
priority setting in the health sector.
List of Abbreviations: AIDS, > acquired immuno deficiency syndrome; COPD, > chronic
obstructive pulmonary disease; DALE, disability adjusted life expectancy; DALY, disability
adjusted life year; DFLE, disability free life expectancy; > DisMod, disease model; EURO A,
Andorra, Austria, Belgium, Croatia, Czech Republic, Denmark, Finland, France, Germany,
Greece, Iceland, Ireland, Israel, Italy, Luxemburg, Malta, Monaco, Netherlands, Norway,
Portugal, San Marino, Slovenia, Spain, Sweden, Switzerland, United Kingdom; EURO B,
Albania, Armenia, Azerbaijan, Bosnia and Herzegovina, Bulgaria, Georgia, Kyrgyzstan Poland,
Romania, Slovakia, The Former Yugoslav Republic of Macedonia, Tajikistan, Turkey, Turkmenistan,
Serbia and Montenegro; EURO C, Belarus, Estonia, Hungary, Kazakhstan, Latvia, Lithuania,
Republic of Moldavia, Russian FederationUkraine; GBD, global burden of disease; HALE,
healthy adjusted life expectance; HIV, > human immunodeficiency virus; IHD, ischemic heart
disease; SBDS, serbian burden of disease study; SMPH, summary measures of population
health; YLD, years lived with disability; YLL, years of life lost
1 Introduction
The regular assessment of population health, its causes, and its distribution is a key compo-
nent of the public policy process to improve health levels and reduce health inequalities in all
countries across the world (Murray et al., 2002).
The epidemiological transition, characterized by a progressive rise in the average age
of death in all populations, has necessitated a serious reconsideration of how the health of
populations is measured. With the majority of the population living into old age and so
increasingly at risk of chronic disease and disability, the need for information on quality as
well as quantity of life has become more pressing (Tobias et al., 2001). In addition, given
the obvious incongruence between available resources and technological as well as human
potential in health care, the setting of priorities for investment in health is mandatory in all
The Burden of Disease and Injury in Serbia 34 589
societies. This is likely to lead to demands for more reliable and useful evidence about
population health problems, and for affordable and effective measures to address them
(Lopez, 2003).
2 Summary Measures of Population Health and Their Uses
Summary measures of population health (SMPH) are measures that combine information on
mortality and non-fatal health outcomes to represent the health of a particular population as a
single number. They may be divided into two broad families: health expectancies and health
gaps (Murray et al., 2000).
Health expectancies are population indicators that estimate the average time that a person
could expect to live in a defined state of health. As summary measures of the overall level of
health of population, health expectancies have two advantages over other summary measures:
they are measured in time units (expected years of life), and it is relatively easy to explain the
concept of an equivalent healthy > life expectancy to an audience. Some of them are DFLE
(disability free life expectancy), HALE (healthy adjusted life expectance) and DALE (disability
adjusted life expectancy) (Mathers et al., 2001).
Health gaps measure the difference between actual population health and some specified
norm or goal. The best known of the health gaps, developed for use in burden of disease studies is
DALY (disability adjusted life year). It measures the gap between current health and an ideal
situation where everyone lives to old age, free of disease and disability. The DALYexpresses years of
life lost (YLL) due to premature death together with years lived with disability (YLD). One DALY
is equivalent to the loss of 1 year of “healthy” life (Mathers et al., 2001). DALY provides a broader
picture of community health needs than traditional measures of mortality and morbidity.
1.1 Uses of Summary Measures
There are many uses of SMPH. Some of the most important are:
Comparison of health between different populations;

Monitoring changes in the health of a given population;
Identifying and quantifying overall health inequalities within populations;
Providing appropriate attention to the effects of non-fatal health outcomes on overall
population health;
Informing debates on priorities for health service delivery, planning and research;
Improving curricula for professional training in public health;
Analyzing the benefits of health interventions for use in cost-effectiveness analyses
(Murray et al., 2000).
1.2 Advantages and Disadvantages of Summary Measures
SMPH are useful analytical aids to priority setting in the health sector, but their limitation
should also be recognized. Understanding the composition of disease burdens and identifying
the main causes of illness are not all that is required for priority setting. Data on the relative
effectiveness and efficiency of different interventions to improve the public’s health are
additional considerations to set priorities for the organization and delivery of health care
services (Mahaparta, 2002). Reducing the burden of disease requires a coordinated effort of
public programs, policies, and priorities.
A principal advantage of burden of disease approach is that it entails a data audit, whereby
the completeness and reliability of routinely collected health data are assessed. The periodic
quality assessment of routine data ought to be done to ensure their relevance and reliability for
public policy. Another might be a need for a more rational assessment of priority data for the
healthcare sector, placing greater emphasis on data collection from surveys and relevant
longitudinal studies (Lopez, 2003).
2 Serbian Burden of Disease Study (SBDS) as an Example of

the DALY’s Use
The Serbian burden of disease study (SBDS) has provided an assessment of the health status
of the Serbian population through estimates of contribution of fatal and non-fatal health
outcomes to the total burden of disease and injury in Serbia. It is largely based on the methods
developed for the global burden of disease (GBD) study (Murray and Lopez, 1996a).
The GBD study has pioneered new approaches to health priority setting since its findings
were first published in 1993 (World Bank, 1993). A fundamental outcome of this research has
been a change in the paradigm for health accounting, from measuring death to measuring
population health, using a new single time-based metric, the disability adjusted life year
(DALY). The use of DALY allowed researchers to combine in a single indicator years of life
lost from premature death and years of life lived with disabilities (Murray, 1996; Murray and
Lopez, 1996a).
The SBDS commenced in October 2002 and ran for approximately 12 months. The
reference year for the analysis was 2000. Kosovo and Metohia were not included in the
study because relevant data for this part of Serbia were not available for the period observed.
Eighteen conditions were selected which covered a range of severity and different dimen-
sions of disability and were relevant for the Serbian population. Factors influencing restriction
of total burden estimates in SBDS on 18 diseases and injuries were: relatively short study
period, results of other national burden studies, share of selected disorders in total mortality in
Serbia, and availability and reliability of data. After completion of the study, using the same
methodology, chronic obstructive pulmonary disease (COPD) was added, as the 19th condi-
tion. Each condition was subdivided into stages with respect to functional health status,
treatment and prognosis, validated by the health experts from Serbia.
2.1 Disability Weights
In the absence of Serbia specific values (social preferences for health states), SBDS 2000 project
adopted GBD > disability weights (Mathers and Boschi-Pinto, 2003; Murray and Lopez, 1996a,
b). The GBD study used the same values for all regions of the world. In particular, it used the
same life expectancy for all population subgroups, whether or not their current life expectancy
was lower than that of other groups, it used the same “disability weight” for everyone living
a year in a specified health state. Only for some conditions we used Duch weights, e.g., for
HIV/AIDS and vision and hearing loss (Stouthard et al., 1997).
2.2 Discounting
The > discounting factor quantifies the perception that a year of life is more valuable the
closer it is to the present. As in the GBD study and other national studies the discounting
factor applied is 3% per year, a rate used in many economic analyses. This means that a YLL
one year into the future is valued at 3% less than a YLL in the current year (Murray and Lopez,
1996a,b).
2.3 Age Weighting
The > age weighting factor quantifies the widely held perception that a year of life is valued
more heavily at some ages than at others. A GBD study weighted a year of healthy life lived at
young and older ages lower than for others ages. This choice was based on a number of studies
which have indicated that there is a broad social preference to value a year lived by a young
adult more highly than a year lived by young child or at older ages. Although the influence of
age weighting on the ranking of conditions is not very great and the latter are controversial in
literature, we have decided to use it for comparison with other studies. Recommended values
of C = 0.1658, and b = 0.04 were applied.
2.4 Mortality and Disability Data
We collected mortality data for selected conditions for 2000 from the Serbian office of statistics
mortality database.
For the majority of conditions, the numbers of > incidence cases were available directly
from disease registers, routine databases or epidemiological studies, but for some conditions
only > prevalence data were available (e.g., for diabetes mellitus and sense organ disorders).
Where insufficient Serbian data were not available to run the model, the incidence estimates
developed in other studies were used, like for asthma, COPD, unipolar depression and injuries
(Murray and Lopez, 1996b).
2.5 DALY Calculation
DALYs were obtained from the addition of two components: YLL and YLD at the population
level and thus reflect the burden of disease in population (DALY = YLL + YLD).
2.6 YLL Calculation
YLL, the mortality component of DALY, was determined by the average life expectancy at age
of death while discounting future years by 3%. YLL were calculated by multiplying age-specific
mortality rates by age-specific standard expected YLL and population numbers. Standard
expected YLL were derived from the standard life table West 26 with a life expectancy at birth
of 82.5 years for women in Japan (Coale and Guo, 1989). The male-female “biological”
difference in survival potential was chosen as 2.5 years. As there is no male schedule with a
life expectancy of 80 years, life table West 25 for females was used for men with life expetancy
at birth of 80 years (Coale et al., 1983). These tables were chosen to match the life expectancies
used in the global burden of disease (GBD) study and reflect the highest national life
expectancies observed worldwide. Actual life expectancies at birth in Serbia are lower: 75.2
years for females and 69.7 years for males in 2001 (Atanasković-Marković et al., 2003).
The burden of disease method does not calculate YLLs individually for each death. Instead,
each death is assigned to one of 21 age groups (<1 year, 1–4 years, 5–9 years, 10–14 years,
15–19 years, 20–24 years . . .50–54 years. . . 90–94 years, 95+ years), and the midpoint of the
age group is taken as the average age at death for every person in that group (Atanasković-
Marković et al., 2003).
2.7 YLD Calculation
The calculation of YLDs takes into account the severity of disability due to a given disease as
well as the average length of time the disability persists.
For most conditions YLD were estimated by multiplying age-specific incidence rates by
average duration of each incident case and average disability weight. Only for diabetes mellitus
and sense organ disorders YLD were calculated on the basis of prevalence. In some cases, a
software program, DisMod (DisMod version, 1994) was used to model disease incidence and
duration from estimates of prevalence, remission, case fatality and background mortality (e.g.,
for nephritis and nephrosis). To estimate YLD for each disease, the SBDS estimated the
amount of time lived in each of the disease stages, severity levels and with various sequelae.
For most disease and injury groups experts were consulted during the development and
revision of YLD estimates.
For comparisons between populations and over time, DALY rates per 1,000 population
were calculated and age standardized by direct method, using WHO world population as
standard (Ahmad et al., 2000). In addition we calculated YLD/YLL ratios.
Calculations were realized using STATISTICA, MORTPAK-LITE version 3.0/CP, NCSS,
DisMod II, Microsoft Excel, and @Risk (Atanasković-Marković et al., 2003).
3 Main Results of the Study and Methodological

Consideration
The total burden of selected disorders in Serbia in 2000 was estimated at 652,260 DALYs. The
relative contributions of premature mortality (YLLs) and disability (YLDs) for each of the 19
selected causes of DALYs are shown in > Figure 34-1.
Ischemic heart disease, cerebrovascular diseases, lung cancer, unipolar major depression,
and diabetes mellitus were responsible for two thirds (67%) of the total burden of selected
disorders. There were more relevant YLLs for observed disorders than YLDs (77%: 23%) with
the exception of non-fatal health outcomes (unipolar major depression, vision and hearing
loss), and low birth weight and asthma, the burden of which was mainly caused by lengthy
. Figure 34-1
Burden of selected diseases (YLL, YLD and total DALYs) in Serbia, 2000. YLD years lived
with disability; YLL years of life lost; DALY disability adjusted life years; COPD chronic
obstructive pulmonary disease
period of disability. For HIV/AIDS contribution of YLL and YLD in DALYs was almost
the same. These 19 selected conditions caused 500,164 YLLs or approximately 60% of the
total mortality burden in Serbia.
The rank for the 19 selected conditions accounting for number of deaths, YLLs and DALYs,
and their corresponding ranks are shown in > Table 34-1.
Considerable variation is apparent in the ranking of conditions based on the number of
deaths (crude mortality) versus YLLs and DALYs. For example, although COPD is the sixth
leading cause of death based on crude mortality, it was the 10th leading cause of premature
death based on YLLs and 7th leading cause of premature death and disability based on DALYs.
Ischemic heart disease was the leading cause of YLLs (136,151 years) and DALYs (150,886
years), followed by cerebrovascular disease (122,170 YLLs and 136,090 DALYs) and lung
cancers (56,434 YLLs and 59,088 DALYs). Some of the leading causes of disease burden on
the DALYs list are ranked considerably lower based on crude mortality and YLLs. For example,
depression is ranked fourth based on DALYs but it is, together with vision and hearing loss, at
the end of the list based on both YLLs and crude mortality. These disparities highlight the
importance of these conditions as sources of disability and their relatively minimal impacts on
mortality.
The DALY and YLD rates (per 1,000 population) and YLD/DALY ratio for 19 selected
conditions are shown on > Table 34-2.
Non-fatal outcomes (YLD) were responsible for 23% of the total burden. The greatest YLD
ratios are for major depression and vision and hearing loss.
Comparing health problems by gender, it appears that the burden of the majority of
selected conditions was higher for males (> Figure 34-2).
. Table 34-1
Number of death, YLLs and DALYs of selected causes and their corresponding ranks in Serbia
in 2000
No. of YLLs DALYs

Cause death Rank (years) Rank (years) Rank
Cerebrovascular disease (Stroke) 18,785 1 122,170 2 136,090 2
Ischemic heart disease 18,583 2 136,151 1 150,886 1
Trachea, bronchus and lung 5,491 3 56,434 3 59,088 3
cancers
Colorectal cancer 2,835 4 24,222 5 26,007 9
Diabetes mellitus 2,731 5 20,721 7 37,336 5
COPD 2,379 6 15,172 10 30,267 7
Breast cancer 1,978 7 21,734 6 23,868 10
Self-inflicted injuries 1,908 8 26,835 4 27,938 8
Stomach cancer 1,734 9 15,903 9 16,487 11
Nephritis and nephrosis 1,530 10 12,835 12 14,215 12
Road-traffic accidents 849 11 17,233 8 30,468 6
Asthma 703 12 4,895 14 12,988 14
Cervix uteri cancer 605 13 7,701 13 8,230 15
Birth asphyxia and birth trauma 390 14 12,910 11 13,520 13
Tuberculosis 284 15 2,848 15 3,236 17
Low birth weight 45 16 1,477 16 4,759 16
HIV/AIDS 41 17 923 17 1,742 19
Unipolar major depression 0 18 0 18.5 52,901 4
Vision and hearing loss 0 19 0 18.5 2,236 18
YLL years of life lost; DALY disability adjusted life years; COPD chronic obstructive pulmonary disease
The burden of breast cancer, depressive disorders, diabetes mellitus and cerebrovascular
diseases expressed in DALY was higher for females, and the burden of hearing and vision loss
was almost the same for both sexes.
The DALY rates (crude and age-standardized) for men and women are shown in
> Table 34-3 and > Table 34-4.
The leading five causes of DALYs for males in the Serbia were ischemic heart disease (26.1
DALY per 1,000), stroke (17.9 per 1,000), lung cancer (12.7 per 1,000), road traffic injuries (6.5 per
1,000), and COPD (5.7 per 1,000). For females, the leading five causes were stroke (18.1
per 1,000), ischemic heart disease (14.1 per 1,000), depression (8.7 per 1,000), breast cancer
(6.1 per 1,000), and diabetes mellitus (5.2 per 1,000).
The total male burden of selected health problems was 32% higher than the total female
burden (99.8 per 1,000 males and 73.7 per 1,000 females).
The SBDS represents an important step in improving the Serbia’s ability to assess health needs
more accurately at the population level. DALYs provide a tool for refining health improvement
priorities based on total burden of disease. The burden of non-fatal or low-fatality conditions
. Table 34-2
DALYs and YLDs (rates per 1,000 population) and YLD/DALY (%)
Cause DALYs per 1,000 YLDs per 1,000 YLD/DALY (%)

Ischemic heart disease 20.0 1.9 10
Cerebrovascular disease (Stroke) 18.0 1.8 11
Trachea, bronchus and lung cancers 7.8 0.4 4
Unipolar major depression 7.0 7.0 100
Diabetes mellitus 4.9 2.2 44
COPD 4.0 2.0 50
Road-traffic accidents 4.0 1.7 43
Self-inflicted injuries 3.7 0.1 4
Colorectal cancer 3.4 0.2 7
Breast cancer 3.2 0.3 9
Stomach cancer 2.2 0.1 3
Nephritis and nephrosis 1.9 0.2 10
Birth asphyxia and birth trauma 1.8 0.1 5
Asthma 1.7 1.1 62
Cervix uteri cancer 1.1 0.1 6
Low birth weight 0.6 0.4 69
Tuberculosis 0.4 0.1 12
Vision and hearing loss 0.3 0.3 100
HIV/AIDS 0.2 0.1 45
DALY disability adjusted life years; YLD years lived with disability; COPD chronic obstructive pulmonary disease
such as depression, asthma, and vision and hearing loss, has been overlooked in an analysis based
solely on mortality data.
Ranking of total burden in Serbia based on DALYs differ substantially from ranking based
on the number of deaths only (Atanasković-Marković et al., 2003; Vlajinac et al., 2008). In
particular, it was found that unipolar major depression accounted for a substantial health
burden which was not captured by mortality data alone (Janković et al., 2007). The impor-
tance of unipolar depressive disorders, even if it does not generate deaths in Serbia, was one
of the key findings of this study, like in similar studies worldwide (Mathers et al., 1999;
WHO, 2001).
In terms of specific conditions, according to DALYs, the total burden in Serbia was highest
for heart disease, followed by stroke, like in many other developed and developing countries
(Mathers et al., 2000; McKenna et al., 2005; Murray and Lopez, 1996a; Schopper et al., 2000).
Cardiovascular disease is the number one killer in Europe, causing more than half of all deaths
across the European region, with heart and stroke being the leading cause of deaths in all
52 member states (WHO, 2006). The DALY rate for ischemic heart disease in Serbia was higher
in comparison with the DALY rates in EURO regions (A, B and C). The greatest part of the
total burden caused by heart disease and stroke was the result of premature deaths. Heart
disease accounts for 16.7%, and stroke for 15.0% of the total YLL in the Serbian population.
. Figure 34-2
Burden of selected diseases by sex (DALYs) in Serbia, 2000. Males – disability adjusted
life years in males; Females – disability adjusted life years in females; DALY disability adjusted
life years; COPD chronic obstructive pulmonary disease
The proportion of YLD in DALY for IHD was higher than in EURO region, while the
proportion of YLD in DALY for stroke was half of that in EURO B, and even lower when
compared with EURO C (Vlajinac et al., 2006a).
Among cancers which were selected for analysis, lung cancer was at the first place, followed
by colorectal cancer. In overall rankings of selected diseases and injuries, lung cancer had the
third rank. The greatest proportion of lung cancer burden in Serbia was associated with use of
tobacco: more than 80% of total DALYs caused by lung cancer for males, and 90% for females
(Vlajinac et al., 2006b). A comprehensive public health approach to tobacco control (preven-
tion of the beginning of tobacco use and promotion of its cessation) as proposed by WHO
(WHO, 2003) is urgently needed in Serbia. It must include young people and women and
reach the entire population. The proportion of YLD in DALY for lung and stomach cancers in
Serbia was similar to that estimated for the EURO region. For colorectal, breast and cervical
cancer, the proportion of YLD in DALY was lower even in comparison to EURO B and EURO
C regions (Mathers and Boschi-Pinto, 2003; Vlajinac et al., 2006b). This can be explained by
the fact that possibilities for early detection of mostly cervical and breast cancers, have not
been sufficiently utilized yet.
As one could expect, on the basis of the previous studies (Mathers et al., 2001; Murray and
Lopez, 1996a; Schopper et al., 2000) the SBDS found depression as the leading cause of non-
fatal disease burden in Serbia 2000, and put it into priority area for policy makers and health
care providers. Depressive disorders were the fourth leading cause of global burden of disease
in the year 2000, and they caused a large amount of non-fatal burden, accounting for almost
. Table 34-3
Disability Adjusted Life Years (DALYs) in men, Serbia, 2000, by selected causes
Rank Cause DALYs years DALYs per 1,000 DALYs per 1,000a
1 Ischemic heart disease 96,023 26.1 18.1
2 Cerebrovascular disease 65,795 17.9 12.4
3 Lung cancer 46,543 12.7 8.8
4 Road traffic injuries 24,038 6.5 6.7
5 COPD 20,942 5.7 3.8
6 Self-inflicted injuries 20,308 5.5 5.0
7 Unipolar major depression 19,073 5.2 5.3
8 Diabetes mellitus 17,137 4.7 3.2
9 Colorectal cancer 15,525 4.2 3.0
10 Stomach cancer 10,802 2.9 2.1
11 Birth asphyxia and birth trauma 8,077 2.2 3.9
12 Nephritis and nephrosis 7,417 2.0 1.5
13 Asthma 7,317 2.0 2.1
14 Low birth weight 2,519 0.7 1.2
15 Tuberculosis 2,431 0.7 0.5
16 HIV/AIDS 1,227 0.3 0.3
17 Vision and hearing loss 1,054 0.3 0.2
18 Breast cancer 327 0.1 0.1
COPD chronic obstructive pulmonary disease
a
According to WHO world standard population (Ahmad et al., 2000)
12% of total years lived with disability worldwide (McKenna et al., 2005; Üstün et al., 2004).
Depression, once considered to be of little importance to policy makers has now become an
area of national concern.
SBDS showed that diabetes mellitus was on the fifth place in Serbia in 2000, although it
was 20th leading cause of DALYs at the global level in the same year. The proportion of YLD in
DALY is lower than in EURO region (Mathers et al., 2002). The results obtained suggest that
only an early diagnosis of the disease, adequate treatment and continuous follow-up of
diabetic patients may reduce early death from this condition and undesired complications
contributing to burden of disease.
During the time available for SBDS no new data were collected, but rather existing
resources were used. Although substantial efforts were made to identify and use the best
information available for each disease and injury category, and although wide consultations in
the relevant fields were undertaken, the estimates made in this study should be regarded only
as a subject for further refinement. In the course of this study, like in the other studies (Murray
and Lopez, 1996a; WHO, 2003), a number of methodological issues have emerged, which
require further development and refinement in order to improve the validity and applicability
of the DALY metric. One of the major areas where methods need to be improved is numerical
valuation of health states – disability estimates. However, developing direct population-
based measures of all relevant disabilities and incorporating these measures into the DALY
. Table 34-4
Disability Adjusted Life Years (DALYs) in women, Serbia, 2000, by selected causes
Rank Cause DALYs years DALYs per 1,000 DALYs per 1,000a
1 Cerebrovascular disease 70,295 18.1 10.3
2 Ischemic heart disease 54,866 14.1 7.9
3 Unipolar major depression 33,828 8.7 8.8
4 Breast cancer 23,541 6.1 4.3
5 Diabetes mellitus 20,199 5.2 3.0
6 Lung cancer 12,545 3.2 2.2
7 Colorectal cancer 10,482 2.7 1.7
8 COPD 9,325 2.4 1.4
9 Cervical cancer 8,230 2.1 1.6
10 Self-inflicted injuries 7,630 2.0 1.4
11 Nephritis and nephrosis 6,798 2.0 1.1
12 Road traffic injuries 6,430 1.7 1.8
13 Stomach cancer 5,685 1.5 0.9
14 Asthma 5,672 1.5 1.2
15 Birth asphyxia and birth trauma 5,443 1.4 2.7
16 Low birth weight 2,240 0.6 1.1
17 Vision and hearing loss 1,182 0.3 0.3
18 Tuberculosis 805 0.2 0.1
19 HIV/AIDS 514 0.1 0.1
COPD chronic obstructive pulmonary disease
a
According to WHO world standard population (Ahmad et al., 2000)
calculations for Serbia would require a large effort. Such refinements are an important
research challenge, but other studies suggest that direct measurement of disability would
have a limited impact on the findings (McGinnis and Foege, 1993; Üstün et al., 1999).
Although the use of DALYs represents a substantial improvement over previous methods
of assessing the burden of disease and injuries, there are several important limitations of the
DALYs measure and its YLD component.
The main limitation of this study is the lack of morbidity data for some diseases, which
forced us to use estimates obtained from the scientific literature. If disability rates within the
country are significantly different from the rates used in this analysis, the YLDs and DALYs
reported here may be overstated or understated for specific health conditions. The study
points to the need for consistent long-term data collection, particularly for those conditions
where mortality plays a minor part in the attributable disease burden. Agenda setting for the
collection of epidemiological data is perhaps the most important issue to emerge from burden
of disease estimation (Essink-Bot et al., 2002). In the absence of information from disease
registers or notification systems, population health surveys should provide useful self-reported
information on disabilities, impairments and diseases and they are urgently needed. The
mental health of communities should be monitored by including mental health indicators
in health information and reporting system. For a number of diseases a population-based
epidemiological studies, particularly longitudinal ones, which can provide a wealth of infor-
mation on the incidence, average duration, levels of severity, remission and case fatality,
should be very useful.
The SBDS is a first step towards exploring the usefulness of burden of disease methods for
Serbia in providing information to assist in health planning and priority setting in the health
sector. The results coming from the SBDS analysis are not only of relevance for the decision
makers in the government, but also in all key institutions related to health. The better
depiction of disease burden in Serbia will be used to help allocate funding for public health
services and programs. The analysis presented in this paper provides a framework for
completion of DALY estimates for all conditions that are not covered in SBDS; for more
detailed analysis of particular conditions; for burden of disease estimates for sub-populations
and for analysis of the impact of risk factors and health determinants to inform health policy
making and priority setting. These first results can serve as baseline against which the future
evolution of the health status of population in Serbia can be compared in a more complete way
than using only mortality data.
It is early to comment on the policy impact of the study’s results. However, it is important
to note that Ministry of Health of the Republic of Serbia supported this study. Also, a wide
range of opinion leaders among clinicians took part in repeated consultations particularly
concerning the estimates of the burden due to non-fatal diseases and injury. As a routine tool
for present and future policy makers in Serbia, the SBDS will be judged by its impact in
making a difference in terms of health policy and the pattern of health service delivery
(Janković, 2005).
4 The New Global Burden of Disease Study
The GBD study is an evidence-based and scientific pursuit. Since 1996 there has not been yet a
comprehensive and systematic revision of the original GBD study. As a result some burden
estimates are out of date and inconsistent. Besides that, patterns of disease and their risk
factors have changed dramatically in the past decade. Researches have improved methods for
burden assessment since the original GBD, particularly for ranking risk factors and disabilities.
The new comprehensive GBD study commencing in 2007, will stand to revise our compre-
hension of global health, while providing information in a way that is maximally useful for
funders and policy-makers. A thorough GBD reassessment will ensure that the global health
community bases its research and policies on complete, valid, and reliable information.
Summary Points
Summary measures of population health are measures that combine information on

mortality and non-fatal health outcomes to represent the health of a particular population
as a single number.
DALY provides unique and desirable health information on non fatal health outcomes that
is essential for determining appropriate health priorities and for improving the quality or
impact of health policy decisions.
Serbian burden of disease study was the first detailed assessment using DALY as a common
metric of the disability and mortality associated with health conditions in Serbia.
The main results of SBDS: ischemic heart disease, cerebrovascular desease, lung cancer,
road traffic injuries and COPD exacted the greatest burden in men, while cerebrovascular
disease, ischemic heart disease, unipolar major depression, breast cancer and diabetes
mellitus were the leading five causes of burden in women.
The SBDS points to the need for consistent long-term data collection, particularly for
those conditions where mortality plays a minor part in the disease burden.
Acknowledgments
The authors would like to acknowledge the Oxford University Press for copyright permission
to reproduce parts of the article: Janković S et al. The Burden of Disease and Injury in Serbia.
Eur J Public Health 2007; 17(1): 80–85. The authors would also like to acknowledge the
assistance provided by the Ministry of Health of the Republic of Serbia and European Agency
for Reconstruction.
References
Ahmad O, Boschi-Pinto, Lopez A, Murray C, Lozano R, Mahaparta P. (2002). In: Murray CJL, Salomon JA,
Inoue M. (2000). Age Standardization of Rates: A Mathers CD, Lopez AD. (eds.) Summary Measures
New WHO Standard. GPE Discussion Paper Series of Population Health: Concepts, Ethics, Measure-
No. 31. World Health Organization, Geneva. ment and Applications. World Health Organization,
Atanasković-Marković Z, Bjegović V, Janković S, Geneva, pp. 83–89 (http://www.who.int/pub/smph/
Kocev N, Laaser U, Marinković J, Marković-Denić en/ index/index.html)
Lj, Pejin-Stokić Lj, Penev G, Stanisavljević D, Mathers C and Boschi-Pinto C. (2003). Global Burden of
Šantrić-Milićević M, Šaulić A, Šipetić-Grujicić S, Cancer in the Year 2000: Version 1 Estimates. WHO,
Terzić-Šupić, Vlajinac H. (2003). Burden of Disease Geneva.
and Injury in Serbia. Ministry of Health of the Mathers C, Stein C, Ma Fat D, et al. (2002). Global
Republic of Serbia, Belgrade. Burden of Disease 2000: Version 2 Methods and
Coale A, Guo G. (1989). Popul Index. 55: 613–643. Results. GPE Disccussion Paper No. 50. WHO,
Coale A, Demeny P, Vaughan B. (1983). Regional Model Geneva. Available at: www.who.int./evidence
Life Tables and Stable Populations, 2nd ed. Academic Mathers CD, Vos ET, Stevenson CE, Begg SJ. (2000).
Press, New York. MJA. 172: 592–596.
DisMod version 1.0. Cambridge, MA, Harvard University, Mathers CD, Vos ET, Lopez AD, Salomon JA, Ezzati M.
1994. Available at: www.hsph.harvard.edu/organiza- (eds.) (2001). National Burden of Disease Studies: A
tions/bdu/dismod/index.html Practical Guide. Edition 2.0. Global Program on
Essink-Bot ML, Pereira J, Packer C, Schwarzinger M, Evidence for Health Policy. World Health Organiza-
Burstrom K. (2002). Bull World Health Organ. 80: tion, Geneva.
644–652. Mathers CD, Vos ET, Stevenson CE. (1999). The Burden
Janković S. (2005). In: Scintee GS, Galan A (eds.) Public of Disease and Injury in Australia. Australian Insti-
Health Strategies: A Tool for Regional Development. tute of Health and Welfare, Canberra. Available at:
Hans Jacobs Editing Company, Lage, Germany, www.aihw.gov.au
pp. 190–207. Mathers CD, Vos ET, Stevenson CE, Begg SJ. (2001).
Janković S, Vlajinac H, Bjegović V, Marinković J, Šipetić- Bull World Health Organ. 79: 1076–1084.
Grujicić S, Marković-Denić Lj, Kocev N, Šantrić- McGinnis JM, Foege WH. (1993). JAMA. 270:
Milićević M, Terzić-Šupić Z, Maksimović N, 2207–2212.
Laaser U. (2007). Eur J Public Health. 17: 80–85. McKenna MT, Michaud CM, Murray CJL, Marks JS.
Lopez AD. (2003). MJA. 179: 396–397. (2005). Am J Prev Med. 28: 415–423.
Murray CJL. (1996). In: Murray CJL, Lopez AD. (eds.) No.1. Ministry of Health, Wellington, New Zealand.
The Global Burden of Disease. Harvard University Available at www.moh.govt.nz
Press, Cambridge. Üstün TB, Ayuso-Mateos JL, Chatterji S, Mathers C,
Murray CJL, Lopez AD. (eds.) (1996a). The Global Bur- Murray CJ. (2004). Br J Psychiatry. 184: 386–392.
den of Disease: A Comprehensive Assessment of Üstün TB, Rehm J, Chatterji S, Saxena S, Trotter R, Room
Mortality and Disability from Diseases, Injuries R, Bickenbach J. (1999). Lancet. 354: 111–115.
and Risk Factors in 1990 and Projected to 2020. Vlajinac H, Marinkovic J, Kocev N, Sipetic S, Bjegovic V,
Global Burden of Disease and Injury Series, vol. 1. Jankovic S, Stanisavljevic D, Markovic Denic Lj,
Harvard University Press, Cambridge. Maksimovic J. (2008). Public Health. 122: 277–284.
Murray CJL, Lopez AD. (eds.) (1996b). Global Health Vlajinac H, Sipetic S, Saulic A, Atanaskovic Z, Marinkovic
Statistics: A Compendium of Incidence, Prevalence J, Bjegovic V. (2006a). Eur J Cardiovasc Prev
and Mortality Estimates for Over 200 Conditions. Rehabil. 13: 753–759.
Global Burden of Disease and Injury Series, vol. 2. Vlajinac H, Šipetić-Grujicić S, Jankovic S, Marinkovic J,
Harvard University Press, Cambridge. Kocev N, Marković-Denić Lj, Bjegović V. (2006b).
Murray CJL, Salomon JA, Mathers CD. (2000). Bull Croat Med J. 47: 75–90.
World Health Organ. 78: 981–984. WHO. (2006). Gaining Health. The European Strategy
Murray CJL, Salomon JA, Mathers CD, Lopez AD. (eds.) for the Prevention and Control of Noncommu-
(2002). Summary Measures of Population Health: nicable Diseases. World Health Organization,
Concepts, Ethics, Measurement and Applications. Copenhagen, pp. 7.
World Health Organization, Geneva. Available at: World Bank. (1993). World Development Report 1993:
http://www.who.int/pub/smph/en/ index/index.html Investing in Health. World Bank, Washington.
Schopper D, Pereira J, Torres A, Cuende N, Alonso M, World Health Organization. (2001). The World Health
Baylin A, Ammon C, Rougemont A. (2000). Int J Report 2001 – Mental Health: New Understanding.
Epidemiol. 29: 871–877. New Hope. World Health Organization, Geneva.
Stouthard M, Essink-Bott M, Bonsel G, Barendreght J, World Health Organization. (2003). The World Health
Kramers P. (1997). Disability Weights for Diseases in Report 2003 – Shaping the Future. World Health
the Netherlands. Erasmus University, Rotterdam. Organization, Geneva.
Tobias M, Borman B, Forbes G, Hemona P. (2001). The
Burden of Disease and Injury in New Zealand.
Public Health Intelligence Occasional Bulletin
35 Disease Burdens and
Disability-Adjusted Life
Years in Aboriginal and
Non-Aboriginal Populations
Y. Zhao
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
1.1 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
1.2 Sources of Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
2 Years of Life Lost Due to Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608

2.1 Mortality Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
2.2 Time Trend in Mortality Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
3 Years Lived with Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
4 Disability Adjusted Life Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616

4.1 Patterns of DALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
4.2 Burden of Disease by Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
4.2.1 Children Aged 0–14 Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
4.2.2 Young Adults Aged 15–24 Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
4.2.3 Adults Aged 25–64 Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
4.2.4 Older Territorians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
5 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
5.1 Main Findings and Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
5.2 Accuracy of the Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
5.3 Strengths and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626

604 35 Disease Burdens and DALYs in Aboriginal and Non-Aboriginal Populations
Abstract: This chapter presents the methodology and some detailed results from the burden
of disease and injury study, undertaken in 2000 by the NT Department of Health and
Community Services, Australia (Zhao et al., 2004). In the disease and injury categories for
which the data was available, this study followed closely the methods developed by WHO in
Global Burden of Disease Study (Murray and Lopez, 1996) and AIHW in the Australian
Burden of Diseases and Injury Study 1996 (Mathers et al., 1999). In the categories for which
the data was unavailable, a hierarchical approach was adopted to choose the most appropriate
method. This study provides a comprehensive assessment of the amount of ill health for both
Aboriginal and non-Aboriginal people in the NT during the period 1994–1998.
Population mortality and morbidity attributive to 176 disease and injury categories were
quantified by using a common currency – disability adjusted life years (DALYs). One DALY
equals to 1 year lost due to premature death (YLL) or equivalent one healthy life year lost due
to disability (YLD). YLL measures the mortality burden, whereas YLD gauges the disability
burden.
The strength of using DALYs is that it summarizes both mortality and morbidity informa-
tion, and facilitates meaningful comparisons when setting health care service priorities,
identifying disadvantaged population groups and evaluating health interventions. Assessment
of burden of disease estimates indicated that the YLL estimates were robust, as they were based
on good quality mortality data. The quality of YLD data sources varied from ‘‘excellent’’ in
disease surveillance systems to ‘‘reasonable’’ for the extrapolation method of national averages.
The accuracy and precision of YLD estimates were not quantifiable, and therefore should be
regarded as provisional and developmental.
List of Abbreviations: ABS, Australian Bureau of Statistics; AIHW, Australian Institute of
Health And Welfare; BEACH, bettering the evaluation and care of health: a study of general
practice activity; COPD, chronic obstructive pulmonary disease; DALY, disability adjusted life
years; DISMOD II, a disease modeling software; HIV/AIDS, human immunodeficiency virus
or acquired immunodeficiency syndrome; ICD-9, International Classification of Diseases,
ninth revision; ICD-9-CM, International Classification of Diseases, ninth revision, Clinical
Modification; ICD-10, International Statistical Classification of Diseases And Related Health
Problems, tenth revision; IHD, ischemic heart disease; LRTI, low respiratory tract infections;
NT, northern territory, Australia; PYLL, potential years of life lost; RTA, road traffic accident;
SIDS, sudden infant death syndrome; WHO, World Health Organisation; YLD, years lived
with disability; YLL, years of life lost
1 Introduction
Over 13% of Aboriginal Australians live in the NT, a federal territory in northern Australia.
The NT has the lowest population density in all States/Territories in Australia, with only 1% of
the total national population and a vast landmass of 1.3 million square kilometers (17% of the
total). The NT has the highest proportion of Aboriginal people (29% compared with 2.4% for
Australian average) (ABS, 2001, 2002a, b).
Aboriginal people in the NT, as elsewhere in Australia, carried a disproportionate burden
of poor health (Condon et al., 2001). Aboriginal Australians born in 1999–2001 had a life
expectancy of 56.3 years for males and 62.8 years for females, proximately 20 years shorter
compared with the total population (ABS, 2002d). This was a similar level of life expectancy
Disease Burdens and DALYs in Aboriginal and Non-Aboriginal Populations 35 605
experienced by non-Aboriginal Australians in the first quarter of last century. The poor health
status of the Aboriginal population exerted extraordinary pressure to the public system of
health services in the NT.
The study focused on developing a standard process of estimating burden of disease and
injury for the Aboriginal and non-Aboriginal population in order to
Quantify burden of disease and injury in the NT
Estimate impact of key chronic diseases on the health and welfare
Monitor the changes in the burden over time
Prioritize health care services to effectively reduce the burden in the NT
1.1 Methods
Mortality rate and life expectancy were often used to reflect health care needs in population.
They were not accurate, because they did not take into account the burden of disease due to
disability. In order to include the impact of both premature death and disability, a common
metric is required. The disability adjusted life years (DALYs) use time as a common currency
and extends the concept of potential years of life lost (PYLL) to non-fatal equivalent years of
‘‘healthy’’ life lost resulting from disability. DALYs for a disease or health condition are
calculated as the sum of the years of life lost (YLL) due to premature death plus the years
lived with disability (YLD) caused by disease or injury:
DALY ¼ YLL þ YLD
The YLL is obtained by summing the life expectancy lost at the age of death for each death.
Calculations of YLD require estimation of the incidence or prevalence of the condition. The
YLD is derived by multiplying the average duration by a disability weight, a measure for
severity valued between 0 and 1 (see details in Murray and Lopez, 1996).
The NT studies followed closely the methodology used in the Burden of Disease and Injury
in Australia study (Mathers et al., 1999) except for the following areas:
Due to the high proportion of Aboriginal persons in the NT population and different
disease pattern in Aboriginal population, the analysis was done for Aboriginals and Non-
Aboriginals separately
Due to small population in the NT, 5 years data were combined to undertake the analysis
The YLL analysis was done for two different time ranges, 1989–1993 and 1994–1998, to
identify the time trends
The burden of disease and injury was estimated for a comprehensive set of 176 disease and
injury categories. Following the classifications for the national study, the diseases and injuries
were categorized into three broad groups:
Group I: Communicable, maternal, neonatal and nutritional conditions
Group II: > Non-communicable diseases
Group III: Injuries
Each of these groups was then subdivided into subcategories (22 in total), most of which
corresponded to chapter-level groups of the Ninth Revision of the International Classification
of Diseases (ICD-9) codes.
In keeping with the national study, DALYs were calculated with a 3% discount rate to
measure the future stream of the burden. An incidence-based measure was used. All results in
this study used uniform age weights.
The YLL was the mortality component of DALYs. The study calculated YLL at a given age
of death using the standard cohort life expectancy taken from the national study (with life
expectancy at birth 82.5 years for females and 80.0 years for males).
The NT study used exactly the same disability weights and disease sequelae as the national
studies. This study also precisely followed the case definition, disease stage and severity level
used in the national study, in order to make a consistent and meaningful comparison with the
national results. Australian total population in 1996 was used for age standardization, being
consistent with the national study.
A comprehensive literature search was undertaken to identify all the key disease areas that
were found more or less common among Aboriginals. By using DisMod II, separate disease
models were established for Aboriginals and non-Aboriginals to summarize available epide-
miological information of each specific condition with internally consistent measures of
incidence, prevalence, remission, mortality and duration.
1.2 Sources of Data
The estimated resident population between 1989 and 1998 was obtained from Australian
Bureau of Statistics (ABS). The Aboriginal population was derived using ABS Experimental
Estimates of the Aboriginal and Torres Strait Islander Population.
Mortality data for the period 1989–2000 was sourced from the Registrar of Births, Deaths
and Marriages in each State or Territory. The analysis was based on year of death. The
underlying cause of death was coded using ICD-9 between years of registration 1989 and
1998. Since 1999, underlying causes of death have been coded in ICD-10. About 9% of the
deaths in 1998 were coded to ICD-10 due to late registration. Backward mapping was used to
recode the causes of death to ICD-9.
Other data sources used in this study are summarized in > Table 35‐1. During YLD
analysis, for each specific disease a checking list was followed to prioritize which dataset to
use should multiple datasets coexist. The checking list consisted of six questions as follows in a
descending priority order:
Is there a local disease register or surveillance system?
Is there a local epidemiological survey or other study?
Are there local > service activity data?
Is there a national or interstate disease register or surveillance system?
Is there a national or interstate epidemiological survey or other study?
Is there an international epidemiological study?
Hospital morbidity data comprised unit records of inpatient episodes from all NT public
hospitals. Demographic information (> Demographics) was included such as age, sex, Abor-
iginality and usual place of residence. Clinical data covered both principal diagnosis and
secondary diagnoses, which were coded using ICD-9-CM (Clinical Modification). In the NT, a
unique patient identifier (Hospital Registration Number) was used to follow-up patient across
all public hospitals and health clinics. Multiple separations due to the same condition were
identified and eliminated when estimating incidence or prevalence.
. Table 35‐1
Summary of main data sources in estimating Aboriginal YLD
Data source Accuracy Disease and injury categories

Disease surveillance Excellent Cancers, communicable diseases, malnutrition, low birth
system or registry weight and congenital malformations
Local epidemiological Excellent Nephritis/nephrosis, type 2 diabetes, substance abuse and
studies otitis media
Hospital inpatient Good Circulatory diseases, injuries, maternal and neonatal
episode data conditions, benign brain tumors, majority of digestive
system diseases, benign prostatic hypertrophy, slipped disc
Hospital admission Fair Chronic obstructive pulmonary disease, liver cirrhosis,
rate ratio deficiency anemia, periodontal disease, congenital heart
disease, eczema, schizophrenia, dementias, hypertensive
and rheumatic heart diseases, osteoarthritis, spina bifida,
cleft lip or palate
Interstate Fair Sense organ disorders, asthma, infertility, multiple sclerosis,
epidemiological eating disorders, cystic fibrosis, hemophilia and non-
studies melanocytic skin cancer
Extrapolation of Reasonable Affective disorder, anxiety disorders, borderline personality
national averages disorder, childhood conditions, Parkinson’s disease and
epilepsy, peripheral arterial disease, chronic back pain,
osteoporosis, repetitive strain injury, respiratory tract
infections, peptic ulcer, stress incontinence, dental caries,
edentulism, uterine myomas, chronic fatigue syndrome, and
residual categories of systems
YLD years lived with disability
The YLD is derived by multiplying the average duration by a disability weight for each patient (see details in
Murray and Lopez, 1996)
The main source for YLD estimates (51 disease or injury categories) was disease registry or
surveillance system data (> Table 35‐1). Information from local or interstate epidemiological
studies was applied to 12 disease categories while 38 disease categories relied on hospital
inpatient episode data. Hospital admission rate ratios were applied to 13 disease categories
(including chronic obstructive pulmonary disease and deficiency anemia) to derive YLD
estimates for Aboriginals. These hospital admission rate ratios were derived from NT hospital
and population data between 1994 and 1998. The Hospital Registration Number was available
for each individual admitted to any NT public hospital, and this was used to eliminate repeated
admissions of the same patient to NT hospitals at different times and locations for the same
condition. A rate ratio greater than one indicates hospital admission rates of Aboriginals are
higher than those of non-Aboriginals. Both principal diagnosis and associated multiple sec-
ondary diagnoses were used to identify a specific condition. This method assumes that the NT
non-Aboriginal incidence is consistent with the national average incidence and that the
likelihood of admission for a given disease is similar between Aboriginals and non-Aboriginals.
For the remaining (62) disease categories no conclusive evidence was found that Abori-
ginals have a different incidence or prevalence. Therefore, a national ‘‘average’’ incidence,
duration and prevalence from the national study were applied.
2 Years of Life Lost Due to Mortality
2.1 Mortality Burden
The YLL is a measure for premature deaths based on life expectancy at age of death. In terms of
YLL, as shown in > Figure 35‐1, nearly half of the total mortality burden in NT Aboriginal
males was attributable to cardiovascular disease (25%) and injuries (23%). Cancers accounted
for 10% of total YLL for NT Aboriginal males. In NT non-Aboriginal males, three quarters of
. Figure 35‐1
The total years of life lost is derived by summing the life expectancies at the age of death, which
individual deaths have lost (see details in Murray and Lopez, 1996). Mortality burden (Years of
life lost) by sex, Aboriginality and broad disease group, northern territory, 1994–1998
the total mortality burden were attributed to injuries (33%), cancers (23%) and cardiovascular
diseases (19%). Cardiovascular disease, injuries and cancers accounted for 23%, 14% and 11%
of the total mortality burden for NT Aboriginal females respectively. In NT non-Aboriginal
females, the mortality burden largely resulted from cancers (30%), cardiovascular diseases
(17%) and injuries (16%).
Fatal communicable and nutritional diseases affected mainly children aged 0–4 years. Injuries
mainly caused death in young adults aged 15–44 especially for males. Non-communicable
diseases dominated the mortality burden in NT Aboriginals aged 25 and over, and in NT non-
Aboriginals aged 35 and over (> Figure 35‐2).
> Table 35‐2 showed that ischemic heart disease (IHD) and road traffic accidents (RTA)
remained the leading causes for mortality burden in both Aboriginals and non-Aboriginals.
. Figure 35-2
The total years of life lost is derived by summing the life expectancies at the age of death, which individual deaths have lost (see details in Murray and
Lopez, 1996). Distribution of years of life lost by age, sex, Aboriginality and broad disease group, northern territory, 1994–1998
Disease Burdens and DALYs in Aboriginal and Non-Aboriginal Populations
35
609
. Table 35‐2
Top twenty causes of the mortality burden (Years of life lost), by Aboriginality, northern territory,
1994–1998
Aboriginal YLL Non-Aboriginal YLL Persons YLL

1 IHD 4,255 IHD 3,305 IHD 7,560
2 RTA 2,970 RTA 3,287 RTA 6,256
3 LRTI 2,166 Self-inflicted injuries 2,815 Self-inflicted injuries 3,716
4 Diabetes 1,902 Lung cancer 2,361 Lung cancer 3,481
5 Stroke 1,823 Stroke 1,339 Stroke 3,162
6 COPD 1,423 COPD 1,117 LRTI 2,713
7 Rheumatic heart 1,254 Colorectal cancer 991 COPD 2,541
disease
8 Homicide and 1,233 Cirrhosis of the liver 838 Diabetes 2,380
violence
9 Lung cancer 1,120 Substance abuse 796 Homicide and 1,898
disorders violence
10 Inflammatory heart 976 Homicide and violence 665 Cirrhosis of the liver 1,786
disease
11 Cirrhosis of the liver 948 Breast cancer 575 Substance abuse 1,608
disorders
12 Self-inflicted injuries 901 Drowning 563 Rheumatic heart 1,575
disease
13 Nephritis/nephrosis 887 LRTI 547 Inflammatory heart 1,394
disease
14 SIDS 839 Diabetes 478 Colorectal cancer 1,269
15 Substance abuse 812 Low birth weight 460 Low birth weight 1,112
disorders
16 Low birth weight 652 Inflammatory heart 418 Drowning 1,073
disease
17 Drowning 511 Falls 394 Nephritis/nephrosis 1,021
18 Birth trauma and 498 Congenital heart 388 SIDS 996
asphyxia disease
19 Congenital heart 459 Leukemia 375 Congenital heart 846
disease disease
20 Falls 381 Mouth and oropharynx 361 Falls 775
cancer
All causes 36,833 All causes 32,777 All causes 69,610
IHD ischemic heart disease; RTA road traffic accidents; COPD chronic obstructive pulmonary disease; LRTI lower
respiratory tract infections; SIDS sudden infant death syndrome
The total years of life lost is derived by summing the life expectancies at the age of death, which individual deaths
have lost (see details in Murray and Lopez, 1996)
Lower respiratory tract infections (LRTI), diabetes and stroke ranked between the third and
fifth leading causes for Aboriginals, and self-inflicted injuries, lung cancer and stroke rank
between the third and fifth for non-Aboriginals.
The Australian Burden of Disease and Injury study showed that NT mortality bur-
den was significantly higher than those of other States and Territory (Mathers et al., 1999).
> Figure 35‐3 compared the age standardised YLL rates by major disease categories between
. Figure 35‐3
individual deaths have lost (see details in Murray and Lopez, 1996). Years of life lost per 1,000
population by broad disease group, northern territory 1994–1998 and Australia 1996
NT 1994–1998 and Australia 1996. It appeared that the NT mortality burden measured in YLL
rate was higher than the national average for all disease categories except cancer and neonatal
causes. > Figure 35‐4 further illustrated that the mortality burden of NT Aboriginals was con-
siderably higher for all disease categories than national average including cancer and neonatal
causes. The disparity was mainly attributable to urinary-genito disorder (10 times), infectious
disease (9 times), diabetes (7 times), chronic respiratory disease (4 times), mental, digestive
and cardiovascular diseases (3 times), and injuries (2 times).
2.2 Time Trend in Mortality Burden
It was shown in > Figure 35‐5 that there had been substantial reductions in mortality burden
in NT Aboriginal population over the study periods. The reduction stemmed mainly from
. Figure 35‐4
population by broad disease group, northern territory Aboriginal 1994–1998 and Australia 1996
. Figure 35‐5
population by Aboriginality and age, northern territory, 1989–1993 and 1994–1998
. Figure 35‐6
The total years of life lost is derived by summing the life expectancies at the age of death,
which individual deaths have lost (see details in Murray and Lopez, 1996). Years of life lost
per 1,000 population by top ten major disease categories, northern territory, 1989–1993
and 1994–1998
improvement in COPD, IHD, RTA and LRTI, as shown in > Figure 35‐6. Further analysis of
single year data revealed there had been sustained declines in the mortality burdens for both
NT Aboriginals and non-Aboriginals over the period 1989–1999. It appeared that the imbal-
ance between Aboriginals and non-Aboriginals in mortality burden had been improved slowly,
although a significant gap still existed (> Figure 35‐7).
3 Years Lived with Disability
Non-fatal burden of disease was measured by YLD on the basis of duration and severity for the
condition. This study indicated that mental disorders were the leading disease category in
disability burden of disease in the NT, followed by chronic respiratory diseases and nervous
system and sense organ disorders.
Substance abuse disorders, affective disorders, asthma, anxiety disorders and otitis media
were among the most common causes for the disability burden in NT males. The disability
burden in NT females was attributed mainly to affective disorders, anxiety disorders, asthma,
otitis media and type 2 diabetes. Distribution of YLD showed that NT had significantly higher
proportions for substance abuse disorders, otitis media, type 2 diabetes, birth trauma and
asphyxia than Australia did (> Figure 35‐8).
. Figure 35‐7
The total years of life lost is derived by summing the life expectancies at the age of death,
which individual deaths have lost (see details in Murray and Lopez, 1996). Time trend in years of
life lost by Aboriginality, northern territory, 1989–1999
. Figure 35‐8
The years lived with disability is derived by multiplying the average duration by a disability
weight for each patient (see details in Murray and Lopez, 1996). Years lived with disability for
major disease groups, northern territory 1994–1998 and Australia 1996
. Table 35‐3
Percentage of years lived with disability by main disease category, Aboriginality and sex,
northern territory, 1994–1998
Aboriginal Non-aboriginal
Disease category Persons Male Female Male Female
A Infectious and parasitic diseases 2.5 2.2 2.7 2.6 2.3
B Acute respiratory infections 6.1 14.1 12.7 1.1 1.2
C Maternal conditions 0.5 0.0 1.9 0.0 0.6
D Neonatal causes 4.6 5.8 4.3 4.7 4.0
E Nutritional disorders 2.9 5.6 6.9 0.4 0.7
F Malignant neoplasms 3.4 1.3 1.5 4.9 4.6
G Other neoplasms 0.1 0.1 0.1 0.0 0.1
H Diabetes mellitus 5.7 7.8 8.8 4.2 3.6
I Endocrine and metabolic disorders 0.5 0.7 0.5 0.4 0.3
J Mental disorders 28.9 21.3 21.0 32.3 36.7
K Nervous system and sense organ 7.7 6.2 6.5 9.4 7.6
L Cardiovascular disease 7.0 7.5 6.6 8.1 5.6
M Chronic respiratory disease 9.8 10.6 8.4 10.1 10.0
N Diseases of the digestive system 1.5 1.0 1.1 1.6 1.9
O Genito-urinary diseases 3.0 1.8 2.4 3.0 4.1
P Skin diseases 0.4 0.4 0.5 0.2 0.5
Q Musculoskeletal diseases 4.7 1.5 2.9 5.0 8.1
R Congenital abnormalities 2.2 3.0 2.5 1.8 2.0
S Oral health 2.4 2.9 3.6 1.9 1.9
T Unintentional injuries 5.2 4.4 3.2 7.8 4.0
U Intentional injuries 1.1 2.1 2.0 0.5 0.3
X Ill-Defined conditions 0.0 0.0 0.0 0.0 0.0
Total 100.0 100.0 100.0 100.0 100.0
The years lived with disability is derived by multiplying the average duration by a disability weight for each patient
(see details in Murray and Lopez, 1996)
It was shown in > Table 35‐3 that for Aboriginals the disability burden of disease was
associated with mental disorders (21%), acute respiratory diseases (about 13%) and chronic
respiratory diseases (males 11% and female 8%). For non-Aboriginals, the non-fatal burden of
disease was caused mainly by mental disorders (32% for males, 37% for females), and chronic
respiratory diseases (10%).
> Figure 35‐9 illustrated disability burden measured in YLD rate by Aboriginality and age
group in the NT. The analysis showed the disability burdens in NT Aboriginals were signifi-
cantly higher than those in non-Aboriginals for all age groups. These differences were more
remarkable for nutritional disorder (15 times), acute respiratory diseases (13 times) and
intentional injury (10 times), as shown in > Table 35‐4. In general, non-fatal burden of disease
among Aboriginals was 1.7 times higher than the non-Aboriginal counterpart.
. Figure 35‐9
The years lived with disability is derived by multiplying the average duration by a disability
weight for each patient (see details in Murray and Lopez, 1996). Years lived with disability per
1,000 population by age and Aboriginality, northern territory, 1994–1998
4 Disability Adjusted Life Years
During the period 1994–1998, there were totally 127 871 DALYs lost due to communicable and
nutritional diseases (13.8%), non-communicable diseases (70.9%) and injuries (15.3%) in the
NT. It was shown that the leading causes for the total burden of disease and injury in the NT
during 1994–1998 were cardiovascular disease (14.9%), mental disorders (14.5%), malignant
neoplasms (11.2%), unintentional injuries (10.4%) and chronic respiratory disease (7.7%).
Male to female sex ratio for the total burden was 136:100, disproportionate to the population
sex ratio (111:100). This clearly indicated that males were imposed a heavier burden of disease
and injury than females. After age standardization for DALYs lost per 1,000 population, the
burden of disease and injury for males was higher than that of females by 17% (> Table 35‐5).
Overall burden of disease and injury in the NT during 1994–1998 was 183.2 DALYs lost per
1,000 population, exceeding the Australian rate by 34% (27% for males, 39% for females).
Burden of disease and injury was estimated to be 339.9 DALYs lost per 1,000 Aboriginals,
2.5 times the Australian rate. Non-Aboriginal rate was very similar to the Australian rate.
4.1 Patterns of DALYs
The leading causes for burden of disease and injury in descending order were IHD, RTA,
depression, substance abuse and stroke in the NT, followed by diabetes and COPD. This
. Table 35‐4
Years lived with disability per 1,000 population by major disease category, sex and Aboriginality,
northern territory, 1994–1998
Aboriginal Non-aboriginal Rate ratio

Person Male Female Person Male Female Person Male Female
Infectious and 2.07 1.87 2.29 1.25 1.39 1.13 1.65 1.35 2.03
parasitic diseases
Acute respiratory 7.77 7.60 7.95 0.62 0.62 0.61 12.60 12.20 13.03
infections
Maternal conditions 0.70 0.00 1.40 0.12 0.00 0.25 6.09 1.00 5.68
Neonatal causes 2.53 2.69 2.36 2.12 2.43 1.79 1.20 1.11 1.32
Nutritional disorders 3.94 3.01 4.84 0.27 0.21 0.34 14.70 14.47 14.37
Malignant 2.58 2.59 2.60 3.92 4.25 3.51 0.66 0.61 0.74
neoplasms
Other neoplasms 0.08 0.07 0.08 0.03 0.03 0.03 2.32 2.16 2.51
Diabetes mellitus 9.99 9.32 10.63 2.38 2.54 2.18 4.20 3.67 4.87
Endocrine and 0.68 0.76 0.61 0.20 0.23 0.17 3.38 3.24 3.64
metabolic disorders
Mental disorders 18.35 17.66 18.97 16.80 16.11 17.67 1.09 1.10 1.07
Nervous system and 16.04 14.75 17.04 8.64 8.90 8.02 1.86 1.66 2.12
sense organ
Cardiovascular 12.58 13.78 11.58 6.38 7.19 5.36 1.97 1.91 2.16
disease
Chronic respiratory 8.86 9.58 8.18 5.37 5.61 5.05 1.65 1.71 1.62
disease
Diseases of the 1.14 1.10 1.18 0.95 0.93 0.97 1.20 1.18 1.22
digestive system
Genito-urinary 2.80 3.01 2.69 1.94 1.99 1.83 1.44 1.51 1.47
diseases
Skin diseases 0.36 0.27 0.45 0.16 0.11 0.22 2.27 2.46 2.07
Musculoskeletal 3.58 2.36 4.63 4.16 3.19 5.47 0.86 0.74 0.85
diseases
Congenital 1.36 1.38 1.35 0.90 0.94 0.87 1.51 1.47 1.56
abnormalities
Oral health 4.40 4.25 4.57 1.05 1.05 1.05 4.20 4.06 4.35
Unintentional 3.93 4.03 3.76 3.23 4.15 2.14 1.22 0.97 1.76
injuries
Intentional injuries 1.98 2.12 1.87 0.19 0.27 0.11 10.17 7.90 17.12
Ill-defined 0.00 0.00 0.00 0.00 0.00 0.00 1.00 1.00 1.00
conditions
Total 105.74 102.19 109.04 60.68 62.14 58.76 1.74 1.64 1.86
The years lived with disability is derived by multiplying the average duration by a disability weight for each patient
(see details in Murray and Lopez, 1996)
. Table 35‐5
Total burden of disease and injury by Aboriginality and sex, northern territory, 1994–1998
Number NT crude DALY rate NT AS DALY rate Australia DALY rate

Aboriginal
Males 32,369 250.8 371.2 –
Females 28,182 217.0 311.1 –
Total 60,552 233.8 339.9 –
Non-Aboriginal
Males 41,209 117.9 153.3 –
Females 26,110 86.7 118.2 –
Total 67,320 103.5 137.7 –
Northern territory
Males 73,579 153.8 196.3 155.0
Females 54,293 125.9 167.8 121.0
Total 127,871 140.6 183.2 137.1
Rate per 1,000 population; AS age-standardization using 1996 Australian population; DALY disability adjusted life
years
The DALYs are calculated as the sum of the years of life lost due to premature death and the years lived with
disability caused by disease or injury. The DALYs use time (year) as a common currency to measure both fatal and
non-fatal burden of disease and injury (see details in Murray and Lopez, 1996)
pattern was different from that of Australia as a whole, largely due to a heavier burden in RTA
and substance abuse. Males suffered more from RTA, substance abuse disorders and self-
inflicted injuries. Females tended to be more vulnerable to depression, type 2 diabetes and
anxiety disorder.
> Figure 35‐10 demonstrated the distributions of burden of disease and injury by Abor-
iginality for NT between 1994 and 1998. Cardiovascular diseases were responsible for 18% of
the total disease and injury burden for NT Aboriginals, mental disorders 10%, unintentional
injuries 10%, acute and chronic respiratory diseases 9% and 8% respectively. For NT non-
Aboriginals, mental disorders accounted for 20% of the total burden of disease and injury,
malignant neoplasms for 15%, cardiovascular diseases 13%, followed by unintentional injuries
(11%) and chronic respiratory diseases (8%).
Apart from IHD and RTA shared by both Aboriginal and non-Aboriginal population in
the top five major disease categories, type 2 diabetes, otitis media and stroke were more
common among Aboriginals, whereas depression, substance abuse and anxiety disorder were
more common in non-Aboriginals (refer to > Table 35‐6).
NT Aboriginals suffered a higher proportion of disease burden in the young age
group (0–14 years) than NT non-Aboriginals. NT non-Aboriginals experienced a higher
proportional disease burden in older age groups (25–64 and 65 plus) than NT Aboriginals
(see > Table 35‐7).
The analysis showed Aboriginals bore a higher burden of disease and injury per population
than non-Aboriginals for all age groups by 2.5 times on average. Aboriginal people aged 35–54
bore a disease burden 4.1 times higher than the non-Aboriginal counterpart. Aboriginal
people aged 45–54 were equivalent to non-Aboriginal people aged 65–74 in terms of disease
. Figure 35‐10
The disability adjusted life years are calculated as the sum of the years of life lost due to
premature death and the years lived with disability caused by disease or injury. The disability
adjusted life years use time (year) as a common currency to measure both fatal and non-fatal
burden of disease and injury (see details in Murray and Lopez, 1996). Disability adjusted life years
by Aboriginality and major disease groups, northern territory, 1994–1998
burden and the need for health care. This indicated that the NT Aboriginals were 25 years
ahead of the general population in terms of ageing. This difference, as demonstrated in
> Figure 35‐11, was caused by 4.8 times higher burden from communicable and nutritional
diseases, 2.3 times higher non-communicable diseases and 2.1 times higher injury burden.
4.2 Burden of Disease by Age
4.2.1 Children Aged 0–14 Years
Pattern of disease burden for boys was broadly similar to that of girls. There was a remarkable
differential in pattern of disease burden between Aboriginal and non-Aboriginal children.
Otitis media and birth trauma accounted for about 19% and 10% of the total burden of
disease for Aboriginal boys and girls aged 0–14 years. Asthma, low birth weight and sudden
infant death syndrome were also major causes for the burden of disease for Aboriginal
children, each accounting for 5–8% of the total disease burden.
For non-Aboriginal children, asthma was the leading cause of disease burden, representing
17% and 15% of the total disease burden for boys and girls respectively. Birth trauma and low
birth weight accounted for 14–15% and 7–10% of the disease burden for non-Aboriginal
children (see details in > Table 35‐8).
. Table 35‐6
The leading causes of disease burden: disability adjusted life years by Aboriginality, northern
territory, 1994–1998
Aboriginal DALY % Non-Aboriginal DALY %

1 IHD 4,658 7.7 1 Depressions 4,286 6.4
2 Type 2 diabetes 3,684 6.1 2 IHD 4,098 6.2
3 RTA 3,172 5.2 3 Substance abuse disorders 3,999 6.0
4 Otitis media 3,034 5.0 4 RTA 3,763 5.7
5 Stroke 2,850 4.7 5 Anxiety disorders 2,890 4.3
6 Substance abuse disorders 2,434 4.0 6 Self-inflicted injuries 2,830 4.3
7 COPD 2,423 4.0 7 Stroke 2,573 3.9
8 LRTI 2,264 3.7 8 Lung cancer 2,540 3.8
9 Homicide and violence 1,660 2.7 9 Asthma 2,447 3.7
10 Depressions 1,615 2.7 10 COPD 2,394 3.6
11 Asthma 1,549 2.6 11 Type 2 diabetes 1,588 2.4
12 Birth trauma and asphyxia 1,366 2.3 12 Osteoarthritis 1,467 2.2
13 Rheumatic heart disease 1,281 2.1 13 Sense organ disorders 1373 2.1
14 Nephritis/nephrosis 1,196 2.0 14 Birth trauma and asphyxia 1,358 2.0
15 Lung cancer 1,172 1.9 15 Colorectal cancer 1,216 1.8
16 Anxiety disorders 1,071 1.8 16 Dementias 891 1.3
17 Inflammatory heart disease 1,053 1.7 17 Cirrhosis of the liver 864 1.3
18 Cirrhosis of the liver 976 1.6 18 Breast cancer 862 1.3
19 Self-inflicted injuries 965 1.6 19 Homicide and violence 793 1.2
20 Low birth weight 947 1.6 20 Low birth weight 766 1.2
respiratory tract infections; DALY disability adjusted life years
4.2.2 Young Adults Aged 15–24 Years
Mental disorders made up nearly 50% of the total disease burden for young adults aged 15–24
years in the NT. Unintentional and intentional injuries accounted for 19% and 10% of the
disease burden. Mental disorders, unintentional and intentional injuries together made up
over three-quarters of the total burden of disease and injury for young Territorians.
As indicated in > Table 35‐9, the top five major causes of the disease and injury burden
were substance abuse disorders (20%), RTA (14%), self-inflicted injuries (9%), depression
(6%) and homicide and violence (6%) for Aboriginal males aged 15–24 years. For Aboriginal
females aged 15–24, depression (14%), substance abuse disorders (13%), anxiety disorders
(9%), RTA (6%) and otitis media (5%) were listed as the top leading causes of burden of
disease and injury.
. Table 35‐7
Distribution of DALYs (disability adjusted life years) by age and Aboriginality, northern territory,
1994–1998
Aboriginal Non-aboriginal
Age in years DALY % DALY %
0–14 14,216 23.5 9,327 13.9
15–24 7,334 12.1 8,169 12.1
25–64 33,016 54.5 38,740 57.5
65+ 5,985 9.9 11084 16.5
Total 60,552 100.0 67,320 100.0
. Figure 35‐11
The DALYs are calculated as the sum of the years of life lost due to premature death and the
years lived with disability caused by disease or injury. The DALYs use time (year) as a common
currency to measure both fatal and non-fatal burden of disease and injury (see details in Murray
and Lopez, 1996). Age standardized disability adjusted life years per 1,000 population by broad
disease classification, Aboriginal versus non-Aboriginal, northern territory, 1994–1998
The top five causes of disease and injury burden for non-Aboriginal males aged 15–24
years covered substance abuse disorders (23%), RTA (18%), depression (11%), self-inflicted
injuries (9%) and anxiety disorders (9%). The five leading causes of disease and injury burden
for non-Aboriginal females aged 15–24 involved depression (22%), substance abuse disorders
(16%), anxiety disorders (14%), RTA (11%) and schizophrenia (5%).
. Table 35‐8
Leading causes of burden of disease and injury in children aged 0–14 years: disability adjusted
life years by sex and Aboriginality, northern territory, 1994–1998
Aboriginal boys DALYs % Aboriginal girls DALYs %

1 Otitis media 1,353 18 1 Otitis media 1,285 19
2 Birth trauma and asphyxia 739 10 2 Birth trauma and asphyxia 627 9
3 Asthma 571 8 3 SIDS 468 7
4 Low birth weight 490 7 4 Low birth weight 457 7
5 SIDS 370 5 5 Asthma 414 6
6 Protein-energy malnutrition 338 5 6 Other neonatal causes 342 5
7 Congenital heart disease 324 4 7 Protein-energy malnutrition 332 5
8 Deficiency anemia 265 4 8 Deficiency anemia 250 4
9 LRTI 203 3 9 Congenital heart disease 241 4
10 Other neonatal causes 186 3 10 LRTI 233 3
Non-Aboriginal boys DALYs % Non-Aboriginal girls DALYs %
1 Asthma 847 17 1 Asthma 635 15
2 Birth trauma and asphyxia 772 15 2 Birth trauma and asphyxia 586 14
3 Low birth weight 338 7 3 Low birth weight 428 10
4 Other neonatal causes 304 6 4 Congenital heart disease 301 7
5 Drowning 271 5 5 Other neonatal causes 185 4
6 RTA 228 5 6 Other chromosomal 176 4
anomalies
7 Congenital heart disease 221 4 7 SIDS 157 4
8 Vaccine-preventable cluster 210 4 8 Affective disorders 142 3
9 Other chromosomal 177 4 9 RTA 133 3
anomalies
10 Other congenital 120 2 10 Neonatal infections 106 2
abnormalities
SIDS sudden infant death syndrome; LRTI lower respiratory tract infections; RTA road traffic accidents; DALYs
disability adjusted life years
4.2.3 Adults Aged 25–64 Years
Cardiovascular disease was the leading cause of disease burden for adults aged 25–64
years in the NT, accounting for 19% of the total DALYs. The second leading cause was
mental disorders (15%), closely followed by malignant neoplasms (14%) and unintentional
injuries (10%).
IHD, type 2 diabetes, RTA, stroke and COPD were the major disease categories that led to
poor health status in Aboriginal adults aged 25–64 years. These five diseases represented about
40% of the total disease burden for both males and females. Aboriginal males were more likely
to suffer from IHD. Aboriginal females were more prone to type 2 diabetes (> Table 35‐10).
. Table 35‐9
Leading causes of burden of disease and injury in young people aged 15–24 years: disability
adjusted life years by sex and Aboriginality, northern territory, 1994–1998
Aboriginal males DALYs % Aboriginal females DALYs %

1 Substance abuse disorders 857 20 1 Affective disorders 434 14
2 RTA 576 14 2 Substance abuse disorders 393 13
3 Self-inflicted injuries 398 9 3 Anxiety disorders 276 9
4 Affective disorders 260 6 4 RTA 189 6
5 Homicide and violence 259 6 5 Otitis media 150 5
6 Rheumatic heart disease 216 5 6 Maternal sepsis 143 5
7 Anxiety disorders 210 5 7 Schizophrenia 133 4
8 Otitis media 147 3 8 Asthma 116 4
9 Suffocation and foreign bodies 113 3 9 Homicide and violence 109 4
10 Type 2 diabetes 89 2 10 Type 2 diabetes 95 3
Non-Aboriginal males DALYs % Non-Aboriginal females DALYs %
1 Substance abuse disorders 1113 23 1 Affective disorders 733 22
2 RTA 880 18 2 Substance abuse disorders 539 16
3 Affective disorders 504 11 3 Anxiety disorders 465 14
4 Self-inflicted injuries 417 9 4 RTA 363 11
5 Anxiety disorders 407 9 5 Schizophrenia 154 5
6 Schizophrenia 206 4 6 Asthma 144 4
7 Falls 165 3 7 Self-inflicted injuries 114 3
8 Other unintentional injuries 121 3 8 Eating disorders 114 3
9 Borderline personality disorder 119 2 9 Borderline personality 113 3
disorder
10 Other transport accidents s 113 2 10 Genital prolapse 60 2
RTA road traffic accidents; DALYs disability adjusted life years
There was a significant difference in pattern of disease burden between non-Aboriginal males
and females. IHD, self-inflicted injuries, substance abuse disorders, RTA were on the top of
disease category list, responsible for disease burden in non-Aboriginal males. These were
compared with the top list of depression, anxiety disorders, breast cancer and osteoarthritis
for non-Aboriginal males.
4.2.4 Older Territorians
The leading cause of disease burden for Territorians aged 65 years and over was cardiovascular
disease, explaining 32% of the total disease burden. The second leading cause was malignant
neoplasms (22%). Nervous system and sense organ disorder, chronic respiratory disease and
diabetes mellitus were the third to fifth leading causes accounting for 13%, 10% and 4% of the
total disease burden respectively. The disease patterns among different groups of older
. Table 35‐10
Leading causes of burden of disease and injury in adults aged 25–64 years: disability adjusted life
years by sex and Aboriginality, northern territory, 1994–1998

1 IHD 2,547 14 1 Type 2 diabetes 1768 12
2 RTA 1,432 8 2 IHD 1249 8
3 Type 2 diabetes 1,352 7 3 Stroke 935 6
4 Stroke 1,157 6 4 COPD 900 6
5 COPD 942 5 5 RTA 699 5
6 LRTI 940 5 6 Homicide and violence 650 4
7 Substance abuse disorders 789 4 7 Nephritis/nephrosis 563 4
8 Cirrhosis of the liver 564 3 8 LRTI 495 3
9 Trachea/bronchi/lung cancer 559 3 9 Rheumatic heart disease 494 3
10 Homicide and violence 543 3 10 Affective disorders 426 3
1 IHD 1,989 8 1 Affective disorders 1,406 10
2 Self-inflicted injuries 1,913 8 2 Anxiety disorders 1,105 8
3 Substance abuse disorders 1,752 7 3 Breast cancer 713 5
4 RTA 1,708 7 4 Osteoarthritis 650 5
5 Affective disorders 1,352 5 5 COPD 587 4
6 Trachea/bronchi/lung cancer 1,030 4 6 Type 2 diabetes 554 4
7 COPD 976 4 7 Trachea/bronchi/lung 550 4
cancer
8 Stroke 900 4 8 Stroke 537 4
9 Anxiety disorders 771 3 9 Substance abuse 529 4
disorders
10 Type 2 diabetes 709 3 10 RTA 527 4
respiratory tract infections; DALYs disability adjusted life years
Territorians were broadly similar, dominated by IHD (13–17%), followed by stroke, COPD,
sense organ disorder, lung cancer and dementias (> Table 35‐11).
5 Discussion
5.1 Main Findings and Implications
Overall burden of disease and injury measured in the NT during 1994–1998 was 183 DALYs
lost per 1,000 population, exceeding the Australian rate by 34% (137 DALYs per 1,000).
The total burden of disease and injury in the NT during 1994–1998 was attributive to
. Table 35‐11
Leading causes of burden of disease and injury in older people aged 64 years and over: disability
adjusted life years by sex and Aboriginality, northern territory, 1994–1998

1 IHD 335 13 1 IHD 452 13
2 Stroke 318 13 2 Sense organ disorders 374 11
3 COPD 264 10 3 Stroke 335 10
4 Trachea/bronchi/lung cancer 206 8 4 COPD 314 9
5 Sense organ disorders 166 7 5 Type 2 diabetes 218 6
6 Type 2 diabetes 143 6 6 LRTI 199 6
7 LRTI 118 5 7 Alzheimer and other dementias 127 4
8 Nephritis/nephrosis 95 4 8 Nephritis/nephrosis 118 3
9 Liver cancer 82 3 9 Hypertensive heart disease 95 3
10 Alzheimer and other dementias 78 3 10 Trachea/bronchi/lung cancer 91 3
1 IHD 1096 17 1 IHD 636 14
2 Trachea/bronchi/lung cancer 735 11 2 Stroke 528 11
3 Stroke 570 9 3 Alzheimer and other dementias 337 7
4 COPD 539 8 4 COPD 262 6
5 Alzheimer and other dementias 256 4 5 Sense organ disorders 233 5
6 Sense organ disorders 243 4 6 Trachea/bronchi/lung cancer 225 5
7 Prostate cancer 242 4 7 Colon and rectum cancer 189 4
8 Colon and rectum cancer 220 3 8 Breast cancer 145 3
9 Type 2 diabetes 165 3 9 Osteoarthritis 139 3
10 Larynx cancer 129 2 10 Type 2 diabetes 132 3
IHD ischemic heart disease; COPD chronic obstructive pulmonary disease; LRTI lower respiratory tract infections;
DALYs disability adjusted life years
cardiovascular diseases by 14.9%, mental disorders by 14.5%, malignant neoplasms (11.2%),

unintentional injuries (10.4%) and chronic respiratory disease (7.7%). Major leading causes
for burden of disease in descending order were IHD, RTA, affective disorders (mainly
depression), substance abuse and stroke, followed by diabetes and COPD. This pattern was
different from that of Australia as a whole, largely due to a heavier burden in RTA, substance
abuse and type 2 diabetes.
Burden of disease and injury for NT Aboriginals was estimated to be 339.9 DALYs lost per
1,000 Aboriginal people, 2.5 times the Australian rate. This difference was caused by 3.0 times
higher mortality burden and 1.7 times higher disability burden, or from a disease category
point of view, 4.8 times higher burden from communicable and nutritional diseases, 2.3 times
higher non-communicable diseases and 2.2 times higher injury burden. NT Non-Aboriginal
rate was very similar to or slightly over the Australian rate.
The DALY has the capacity to answer questions about the health care need and equity.
It provides a more equitable base than the crude ‘‘number of deaths’’ method in health need
assessment and resource equalization. Linking burden of disease data with expenditure data
for the financial year 1996–1997 (AIHW, 2002) indicates that the total health expenditure in
Australia in the financial year 1996–1997 was estimated to be $18,000 per DALY. The
corresponding NT health expenditure was $18,700 per DALY, marginally higher than the
national average. The Commonwealth health funding for the whole Australia was estimated at
$7,890 per DALY in the financial year 1996–1997. NT received only $6,413 per DALY, almost
20% below the national average. Taking into account the high costs in delivering health care
services in NT due to remoteness, culture and language diversity and scale of diseconomy, it
appeared that the health care system in NT was significantly under-resourced in 1996.
5.2 Accuracy of the Estimates
There are a number of issues that may have contributed to possible underestimation of the
true burden of disease and injury for the NT Aboriginal population. The estimation of
the contribution of mortality in the burden of disease study is straightforward and based
on the standard mortality data. However, the disability component requires estimation of the
contribution of a relatively large number of disease and injury categories, and this relies on a
wide range of data sources. For some data sources, contestable assumptions have to be made
during data analysis. One of the most obvious discrepancies is probably in mental health
services, in which there was a lack of information and severe social and emotional stress of
Aboriginal population cannot be translated into a proportionally high rate of mental condi-
tion. A second area for possible underestimation is the compounding burden of multiple
chronic conditions, a factor that is not accommodated in the current method.
Providing a better approach to assessing health care needs, this study is instrumental for
more effective and efficient management of health care information. Nevertheless, this study
remains exploratory because of potential inaccuracies of the data used. The quality of data
sources varied from ‘‘excellent’’ in disease surveillance systems to ‘‘reasonable’’ for the extrap-
olation method of national averages.
5.3 Strengths and Limitations
The strength of using DALYs is that DALYs summarize both mortality and morbidity
information, and change health care need measurement from ‘‘number of deaths’’ to ‘‘number
of years’’ lost due to either death or disease.
However, there are clear limitations in the burden of disease and injury study. First, the
estimation of YLDs is complicated and often overwhelmed by disease model assumptions.
Second, the hospital admission rate ratio assumed that the NT non-Aboriginal incidence was
consistent with the national average incidence and that the likelihood of admission for a given
condition was similar between Aboriginal and non-Aboriginal people. These assumptions may
not always hold. Third, like other statistics, the quality of the burden of disease and injury
measures totally depends on the quality of data analyzed.
References
ABS. (2001). Migration, Australia 1999–2000 (Catalogue Mathers C, Vos T, Stevenson C. (1999). The Burden of
No. 3412.0). Disease and Injury in Australia, Canberra. AIHW
ABS. (2002a). Australian Demographic Statistics, (Catalogue No. PHE 17).
December Quarter 2001 (Catalogue No. 3101.0). Murray CJ, Lopez AD. (1996). The Global Burden of
ABS. (2002b). Population Distribution, Aboriginal and Disease: a comprehensive assessment of mortality
Torres Strait Islander Australians 2001 (Catalogue and disability from diseases, injuries and risk factors
No. 4705.0). in 1990 and projected to 2020. Volume 1, Global
ABS. (2002c). Australian Social Trends 2002 (Catalogue Burden of Disease and Injury Series. Harvard School
No. 4102.0). of Public Health, Harvard.
ABS. (2002d). Deaths, Australia (Catalogue No. 3302.0). Victorian Department of Human Services. (1999). The
AIHW. (2002). Health expenditure Australia 2000–2001 Victorian Burden of Disease Study: Mortality, Mel-
(Catalogue No. HWE 20). bourne.
Commonwealth Department of Health and Aged Care. WHO. (1996). The Global Burden of Disease. Harvard
(1997). Priority Setting Methodologies in Health, University Press, Boston.
Canberra. WHO. (2000). DisMod Manual. Department of Public
Condon J, Warman G, Arnold L. (2001). The Health and Health, Erasmus University.
Welfare of Territorians, Epidemiology Branch. Ter- Zhao Y, Guthridge S, Magnus A, Vos T. (2004). Med
ritory Health Services, Darwin. J Aust. 180: 498–502.
36 The Relationship Between the
National Health Insurance
Expenditures and the
Burden of Disease Measures
in the Iran
M. Russel . H. R. Jamshidi
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630
2 Methods to Identify Costs and GBD Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
3 Type of Data Gathered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
4 An Analysis and Results for Decision Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
5 Considerations and Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640

630 36 The Relationship Between the NHI Expenditures and the Burden of Disease Measures in the Iran
Abstract: The Iranian government has considered using Disability Adjusted Life Years
(DALYs) as an indicator to priorities health service expenditures to reduce the burden of
disease for the public.
A cross-sectional study was designed to compare several measures of the burden of disease
with the actual amounts of National Health Insurance (NHI) (the statute requiring persons to
join a sickness fund and requiring employers and employee to pay premiums) expenditures, in
one province of Iran (Semnan) for a period of 2 months (September 2000 & February 2001).
Furthermore, on the basis of the research findings, a questionnaire was designed and
distributed to stakeholders at the in local and national levels to explore their ideas about the
gap between the expenditures of the diseases group and their burden. A semi-structured
interview was conducted to elicit participants’ views on the research findings.
The results of this study have revealed that, currently, there is no strong relation between
the NHI expenditures and DALY (r = 0.41, p = 0.09), but that there are stronger relationships
between the amounts of NHI reimbursements with YLL (r = 0.52, P < 0.05), Mortality
(r = 0.67, P < 0.01) and hospital days (r = 0.90, P < 0.01). Comparing each group of
disorders’ DALY with the resources allocated to them (cost per DALY) it was shown that
Diabetes mellitus, musculoskeletal diseases, maternal conditions, sense organ disorders
received considerably generous funding; and, perinatal conditions, congenital abnormalities,
nutritional deficiencies were relatively under-funded in Iran.
The qualitative research results showed that the majority of respondents agreed that the
differences presently existing between disorders’ burden and NHI expenditures cannot be
justified; and, further that, reducing the overall burden of disease must be one of the most
important objectives for the Iranian NHI.
List of Abbreviations: DALY, disability adjusted life years; GBD, global burden of disease;
ICD, international classification of diseases; MEC, Middle Eastern Crescent; MSIO, medical
service insurance organization; NHI, National Health Insurance; PBO, Plan and Budget
Organization; WB, World Bank; WHO, World Health Organization; YLD, years lived with
disability; YLL, years of life lost
1 Introduction
The Global Burden of Disease Study (GBD) has been introduced as a quantitative indicator,
and used as a mechanism to influence the allocation of resources within any county’s health
care system (Fox-Rushby, 2002). Its main concept is that of Disability Adjusted Life Years
(DALYs), which expresses years of healthy life lost alongside the quality of those years
(disability adjusted) (Murray and Lopez, 1996).
One of the goals of this kind of work is to then quantify the burden of disease using a
measure that could also be used for cost-effectiveness and for the re-allocation of resources
(Murray and Lopez, 1996; Fox-Rushby and Hanson, 2001).
Nowadays, health insurance has become a major source of funding source for the health
sector, in large number of countries (Glaser, 1991; Abel-Smith, 1992; Normand, 1999). Based
on the insurance concepts, providing safeguard against loss and declining financial and
economical damage is the main objective for insurance carriers (Follman, 1963; Criel, 1998;
Folland et al., 2003). Reallocation and redistribution of health financial resources, in order to
increasing the efficiency and effectiveness of the health sector to decrease economic burden of
The Relationship Between the NHI Expenditures and the Burden of Disease Measures in the Iran 36 631
risks arising from diseases, injuries and disabilities, can be a significant task for insurance
carriers. In this direction, social insurance carriers need to follow robust approaches and
methods to prioritize their coverage, in terms of benefit packages (Soderlund, 1998).
The Islamic Republic of Iran is seeking to reform its health care system, throughout the
national health insurance development. Iran has considered using DALYs as a mechanism to
prioritise health service delivery (PBO, 1999).
Accordingly, this study has attempted to find out the relationship presently existing
between funding by NHI and the GBD in Iran. The concept of combining mortality and
morbidity into a single indicator to aid decision makers in its priority setting for is a key issue
for Iran, as a developing country, with serious limitation of resources.
What is the relationship presently between disbursements from the NHI fund and the
burden of disease in Iran? It was important to determine the correlation between the resources
allocated e.g., through NHI, and the different indicators of the burden of disease; to do so,
because it will address how the resources have been allocated (direction of expenditures) and
prompt questions about what may the health care thereby achieve in future (results or
outcomes).
2 Methods to Identify Costs and GBD Measures
The main method of this research is a cross-sectional study. This cross-sectional study has
related several measures of the burden of disease (six independent variables) with the
magnitude of Medical Service Insurance Organisation (MSIO) (the organization, in Iran
responsible for medical insurance of civil servants, self-employed, villagers and the needy)
expenditures, in one province of Iran (Semnan), for a period of 2 months, September 2000 &
February 2001.
The sampling frame employed in this research is the number of people who used inpatient
and outpatient services through the MSIO, in one province of Iran (Semnan) in September
2000 & February 2001.
There are 19 general groups of diseases, according to Global Burden of Disorders classifi-
cation, which this survey embarked upon in order to compare their expenditures and their
burden of disease indicators.
The insurance documentation related to those inpatient and outpatient services delivered
in September 2000 & February 2001 were gathered from the MSIO, Iran. Then, according to
the history of patients and other reports existing, patients’ diagnoses were identified, checked
and sorted into 19 major groups according to Global Burden of Disease classification.
To clarify the results of the study (first phase), a qualitative research element has been
designed to bring experts’ ideas into account, to explore their ideas about the gap between the
expenditures of the diseases group and their burden. In the questionnaire, participants were
invited to use a five-point scale to indicate whether they agreed or disagreed with specific
aspects of the research findings. They could choose, to: strongly agree, agree, neither agree/
disagree, disagree, and strongly disagree. The question began with the following observation:
‘‘on the basis of the data available, it would appear that diabetes mellitus, musculoskeletal
diseases, maternal conditions, sense organ disorders (first group) received considerably more
generous funding as compared with their DALY; while, perinatal conditions, congenital
abnormalities, nutritional deficiencies (second group) were under-funded compared with
their DALY.’’
A semi-structured interview was conducted to elicit participants’ views on the research

findings.
3 Type of Data Gathered
Primary data was collected in two main groups, those of inpatient and out patients’ services
reimbursed by MSIO in Semnan (Semnam, 2001). Mortality and YLL data were extracted
from the ‘‘figures of death in Semnan in year 2000–2001’’ (Naghavi, 2000). As there is no
information available on DALYs in Iran at the time of study (year 2000), data from the Middle
Eastern Crescent (MEC) region was adopted from the Global Burden of Disease study.
All inpatient and outpatients bills received by the MSIO in Semnan in September 2000 and
February 2001 were assessed. Based on inpatients bills submitted by 11 hospitals in Semnan
province, inpatient costs including NHI and Co-payment were obtained. As > Table 36-1
. Table 36-1
Research sample size and number of cases
Health services
Month Inpatient cases Outpatient cases Total
September 2000 (Mehr 1379) 981 18,656 19,637
January 2001 (Bahman 1379) 1,164 25,505 26,669
Total 2,145 44,161 46,306
points out, in total 2,145 inpatient bills were assessed, 981 bills related to September and the
rest to services delivered in February. Based on outpatients’ bills submitted by outpatient
services, outpatient cost data was also gathered. The numbers of hospital days were also
determined from the data collection process.
A questionnaire was distributed to stakeholders (30 people) at the local and national levels.
They were familiar with the financing of the health sector, particularly the NHI scheme and
planning of health and curative programmes. Their responses also collected and analyzed.
4 An Analysis and Results for Decision Making
The data were entered in SPSS program for statistical analysis. The dependent variables were
total cost, inpatient &outpatient expenditures, NHI funding, and co-insurance payments.
The independent variables were DALY, YLL, hospital days and mortality. With the use of
the correlation coefficient test (Spearman’s) the relation between these measures and NHI
expenditures was calculated; and, with the use of the regression test, predicted funds were
calculated and compared with actual expenditures.
Data were also gathered from questionnaire and interview, and entered and analyzed using
SPSS statistical software.
The relationship between GBD measures and expenditures in several categories is shown in
> Table 36-2.
Although there are positive correlation coefficients between DALY and expenditures, none
of the nine expressions of the dependent variable ‘‘expenditure’’ has a significant correlation
with DALY. Hence, the evidence is in favor of the hypothesis, which suggested, ‘‘there is likely
to be a weak relation (currently) between DALYs and NHI funding in Iran.’’
The results show that YLL had significant correlations with: total inpatient expenditures
(r = 0.53, p < 0.05); total NHI reimbursements (r = 0.51, p < 0.05); and, with inpatient NHI
reimbursement (r = 0.54, p < 0.01). Indeed, the correlation between YLL and NHI funding is
more statistically significant than with the DALY. In contrast with the size of the correlation
coefficient between the DALY and outpatient expenditures, YLL had less of a correlation with
outpatient expenditures. Yet, YLL correlation is more statistically significant with inpatient
services expenditures; and, in particular, with NHI payments. This suggests that inpatient
services might lead NHI to reimburse more hospital services, perhaps without close affinity to
those long term disabilities with a high burden.
. Table 36-2
Regression and correlation results for GBD measures in association with expenditures in Iran
Correlation
GBD coefficient Adjusted
measures Total Coefficient (Beta) R square P value
DALY Expenditure 51,169.20 0.39 0.10 0.09
Inpatient expenditure 31,963.45 0.32 0.05 0.17
Outpatient expenditure 19,205.74 0.43 0.14 0.06
NHI reimbursement 42,688.59 0.41 0.11 0.09
Inpatient NHI reimbursement 28,284.28 0.33 0.05 0.16
Outpatient NHI 14,404.30 0.43 0.14 0.06
reimbursement
Family payment (co-insurance) 8,480.60 0.38 0.09 0.10
Inpatient cost sharing 3,679.17 0.25 0.01 0.28
Outpatient cost sharing 4,801.43 0.43 0.14 0.06
YLL Expenditure 142,124.00 0.49 0.20 <0.05
Inpatient expenditure 117,392.00 0.53 0.24 <0.05
NHI reimbursement 121,758.50 0.51 0.21 <0.05
Inpatient NHI reimbursement 103,208.80 0.54 0.25 <0.01
Outpatient NHI 18,549.67 0.24 0.00 0.32
reimbursement
Family payment (co-insurance) 20,366.41 0.41 0.11 0.09
Inpatient cost sharing 14,183.19 0.44 0.15 0.06
Correlation
GBD coefficient Adjusted
measures Total Coefficient (Beta) R square P value
Hospital Expenditure 233,356.00 0.91 0.82 <0.01
days Inpatient expenditure 177,640.90 0.90 0.81 <0.01
Outpatient expenditure 55,715.16 0.63 0.37 <0.01
NHI reimbursement 193,979.80 0.90 0.82 <0.01
Inpatient NHI reimbursement 152,193.40 0.90 0.80 <0.01
Outpatient NHI 41,786.37 0.63 0.37 <0.01
reimbursement
Family payment (co-insurance) 39,376.26 0.89 0.78 <0.01
Inpatient cost sharing 25,447.47 0.89 0.79 <0.01
Outpatient cost sharing 13,928.79 0.63 0.37 <0.01
Mortality Expenditure 195,3791.00 0.65 0.38 <0.01
Inpatient expenditure 1,535,607.00 0.66 0.41 <0.01
NHI reimbursement 1,669,973.00 0.67 0.41 <0.01
Inpatient NHI reimbursement 1,356,335.00 0.68 0.44 <0.01
Outpatient NHI 313,637.90 0.39 0.10 0.10
reimbursement
Family payment (co-insurance) 283,817.70 0.54 0.25 <0.05
Inpatient cost sharing 179,271.80 0.54 0.25 <0.05
Mortality has a statistically significant correlation with Total expenditure (r = 0.65,

P < 0.01); Total Inpatient expenditures (r = 0.66, p < 0.01); Total NHI reimbursement
(r = 0.67, p < 0.01); Inpatient NHI reimbursement (r = 0.68, p < 0.01); Total family payments
(r = 0.54, p < 0.05); and, Inpatient co-insurance (r = 0.54, p < 0.05).
The correlations between mortality and the expenditure variables show the same patterns
as the YLL correlations.
The ‘‘numbers of hospital days’’ were shown to have a significant correlation with all forms
of expenditures (p < 0.01). It is maybe predictable that ‘‘hospital days’’ might have a significant
and direct relation with inpatient services expenditures, but this correlation was extremely
statistically significant, while that related to outpatient service expenditures was also high.
Overall, all expenditures in association with YLL and mortality are shown to have higher
coefficients. This means that a slight change in mortality, compared with other dependent
variables, might affect the expenditures significantly. In contrast, DALY has less effect on
expenditures compared with other dependent variables.
Among the four independent variables, total expenditure in association with mortality has
the maximum coefficient (1,953,791). It is almost 40 times more than the total expenditure
coefficient in association with DALY, and 14 times more than the total expenditure coefficient
in association with YLL.
Overall, all expenditures in association with mortality are shown to have higher coeffi-
cients. It means that a slight change in mortality, as compared with other independent
variables, might affect the expenditures significantly. In contrast, DALY has less effect on
expenditures compared with other independent variables.
The low value of the Adjusted R Square in the regression test when applied on the
data indicates that, despite the statistically significant associations between some expenditures
and some GBD measures, the majority of the variability in expenditures might not explained
by variations in GBD measures. Or, expressed differently, the so-called independent
variables selected on the basis of ‘‘burden of disease’’ are not proving significant predictors
of actual expenditures (whether from NHI or household sources). In terms of Adjusted
R Square, hospital days in association with expenditures show the closer relationships. It
supports the view that hospital days do explain actual expenditures more precisely, when
compared with other independent (i.e., epidemiological) variables. Hospital days do have
significant associations with expenditures; and, therefore, high Adjusted R Square endorses
its correlations.
The amount of predicted and actual Iranian NHI expenditures in association with DALY is
shown in > Figure 36-1. The line represents the amount of NHI funding that would be predicted
if the DALY was the exclusive criterion for funding (on the basis of the evidence available).
The data shows the amount of funds disbursed on each diseases group and their correla-
tions with GBD measures on the basis of the data, it is then possible to determine the amount
that had been spent for one DALY in every disease, total cost per DALY, and total NHI cost
per DALY.
As can be seen in > Table 36-3, noncommunicable conditions received more aggregate
funds compared with the two other groups. However, in terms of total cost per DALY, there
were fewer differentials between noncommunicable conditions with communicable diseases
. Figure 36-1
DALY correlation with Iranian NHI Funding in 2000
. Table 36-3
Expenditure per DALY in 1379 (2000–2001): Semnan
Total Total NHI

expenditure per expenditure per
Disorders classification DALY DALY
I. Communicable diseases, maternal and perinatal 94,168 74,990
conditions and nutritional deficiencies
Infectious and parasitic diseases 66,464 54,042
Respiratory infections 90,900 70,512
Maternal conditions 1,002,037 791,590
Perinatal conditions 18,060 15,051
Nutritional deficiencies 50,439 40,606
II. Noncommunicable conditions 200,192 165,261
Malignant neoplasms 69,887 58,663
Diabetes mellitus 1,124,589 945,638
Nutritional/endocrine disorders 99,722 77,226
Neuropsychiatric disorders 84,867 68,619
Sense organ disorders 893,934 743,532
Cardiovascular diseases 191,181 160,746
Respiratory diseases 151,361 126,427
Digestive diseases 279,733 230,981
Diseases of the genitourinary system 326,510 275,505
Musculoskeletal diseases 1,012,985 785,187
Congenital abnormalities 42,375 31,874
Oral diseases 161,654 121,241
III. Injuries 70,211 56,644
Unintentional 128,979 104,287
Intentional injuries 9,716 7,601
and injuries. Expenditures on noncommunicable conditions were 4% more than on commu-

nicable diseases, and 2.8 times more than on injuries.
In contrast, the total NHI cost per DALY illustrated wider differentials, between noncommu-
nicable conditions and communicable diseases. NHI had disbursed 1.87 times more to non-
communicable conditions than to communicable diseases, and 2.94 times more than to injuries.
In terms of communicable diseases, maternal conditions show the highest cost per DALY.
The category of infection and parasitic diseases was in second place, and respiratory infection
in third place in terms of total cost per DALY, while these positions were reversed in terms of
total NHI cost per DALY.
In respect of Noncommunicable conditions, Diabetes mellitus, musculoskeletal diseases
and sense organ disorders are found to have the highest cost per DALY, and then, diseases of
the genitourinary system, digestive diseases and cardiovascular diseases. Malignant neoplasms
and neuropsychiatric disorders received fewer funds than other disorders in this group (on a
cost per DALY calculation).
The minimum NHI expenditures per DALY was for perinatal conditions (Intentional
injuries was ignored because it receives other funds as well as NHI monies) with 14,458 Rials
per DALY, and the maximum was for Diabetes Mellitus with 905,601 Rials per DALY.
Consequently, there is about 891,143 Rials differentials between these two categories (see
> Figure 36-2 for a more complete picture).
. Figure 36-2
Total NHI expenditures per DALY in Semnan in year 1379 (2000–2001)
It also shows that more than 50% of respondents agreed that the following were important
factors influencing expenditure patterns between groups of diseases:
new technologies, techniques and medicines are influencing these expenditure patterns.
difficulties in access to some health care services.
health providers, particularly physicians, play a significant role in influencing expenditures.
health decision making (either at a national or local level) has a significant role in
influencing expenditures.
All respondents agreed that there is a need to change resource allocation ‘‘formula’’ to one
based on cost-effectiveness treatment.
To compare the associations between the respondents’ position in the hierarchy and their
responses to the questions, the Spearman correlation coefficient test was applied. A compari-
son between the respondents in national positions, and respondents working at the local levels,
revealed that respondents in national positions were more likely to support the idea that new
technologies, techniques and medicines are influencing actual expenditures patterns
(P < 0.05); while respondents who were working at the local levels were more likely to support
the view that difficulties in access to some health care services was a significant factor in
creating difference levels of expenditures (P < 0.05). No significant differences were found
between respondents’ positions and their responses to other questions.
Interviews with key stakeholders revealed that the majority also believed that the differ-
ences between the expenditures of first and second groups of disorders could not be justified
based on this study. They also emphasised that, although the burden of disease measures are
necessary to take into account to distinguish the gap between the expenditures of the diseases
group and their burden, it was not sufficient to judge about overall circumstances, and that
they needed more information to make a decision on resource reallocation.
Regarding health providers’ influence upon expenditure patterns, some interviewees
acknowledged that some medical professionals do tend to generate demands for some health
care services, and provide services of questionable value (from a societies point of view).
5 Considerations and Challenges
This research demonstrates the importance of examining the actual relationship between
resources allocated and different indicators of burden of disease, simply because it will address,
how the resources have been allocated (direction of resources) and how these may be in future
(results or outcomes o health gain). Obviously, it is an aspiration that the health care system
will reallocate resources in the direction to cover the main burden of disease to reduce the
whole society burden. But, as has emerged in many debates, DALY cannot be the only
indicator for resources allocation, due to its restriction. It means that resources cannot simply
be allocated solely based on DALY; the expenditures and cost-effectiveness of treatments must
be of concern too. Then, a model to integrate the results of a GBD study with effective
treatments existing and the new technologies and medicine gradually introduced to health
services, might be useful. However, it can be acknowledged that Iranian policy makers would
be faced with some conceptual and methodological challenges when choosing DALYas a factor
to influence priority setting in NHI coverage. One of the immediate issues is the poor or non-
availability and quality of relevant data currently in Iran on this subject. A second, is how to
incorporate social values into the other measures like DALY. Finally, how policy makers in
the health sector might deal with external pressures, which influence priority setting based
on economic indicators other than the DALY, would have to be addressed, given the fact
that incorporating the DALY into the resource allocation formula would necessarily influence
(i.e., change) existing patterns of expenditure and of professional workloads.
In contrast, as at present, the results of this research show that NHI payments are
uninformed by, and insensitive to, the DALY mechanism. Further, although they are more
sensitive to mortality and YLL at the time of the research, these do not fully reflect the burden
of disease and its alleviates, and cannot be judged to be adequate proxies for so doing.
However, all groups of disorder expenditures have been analyzed, and their relationships
with four measures of the burden of disease have been assessed (incidence and prevalence data
were exempted from assessment, due to their unavailability).
NHI disbursements show a closer correspondence with death indicators (mortality) rather
than with disability indicators (morbidity). Evidence gained from stakeholders concurs that there
is a need to change present policy and reallocate resources through NHI in directions that
will cover a greater burden of disease and reduce the societal economic burden. Regression
analysis showed that YLL was currently less predictive of NHI expenditures than total mortality.
Taken literally, this result suggests that all deaths were treated and expenditures reimbursed,
regardless of the age of patients at death, or of the quality of life prior to death.
Turning to the results themselves, the regression analysis shows that cardiovascular disorders
received more funding than might has been predicted on the basis of the various ‘‘burden of
disease’’ measures. One of the reasons that NHI dispersed remarkably more of its funding on
cardiovascular diseases, than other disorders, is that cardiovascular disorders cause many acute
. Table 36-4
Results of questionnaire
Neither agree/
Questions Agree disagree Disagree
These differences between the first and second groups 8 (35%) 3 (13%) 12 (52%)
can be justified
It is new technologies, techniques and medicines that 12 (52%) 3 (13%) 8 (35%)
are mainly influencing these expenditure patterns
There are problems of access to some of these services 17 (74%) 2 (9%) 4 (17%)
Providers have a significant role, particularly physicians 17 (75%) 1 (4%) 5 (21%)
in influencing the different levels of expenditures (per
DALY)
Decision makers (at national or local level) have 15 (66%) 4 (17%) 4 (17%)
considerable influence on expenditure patterns and are
able to create such differentiations between several
disease groupings
Prospective expenditures need to be changed through 23 (100%) – –
resource reallocation on the basis of cost-effectiveness
treatments
Note: N = 23
emergency admissions. In fact, high percentages of emergency unit patients have a cardiovascu-
lar complaint. Furthermore, cardiovascular treatments (e.g., open heart surgery) have developed
rapidly in recent years in Iran, based on the new technologies, which mostly are expensive.
Summary Points
Burden of disease measures (DALY) have been developed as an evaluation tool to serve two
main purposes.
First, as a unit for measuring the magnitude of premature death and non-fatal health
outcomes attributable to proximal biological causes, including supply factors
As an outcome measure for interventions that could reduce the burden of either the
proximal biological causes or the more distal risk factors and socio-economic deter-
minants
There was a weak relation between DALYs and NHI expenditures in Iran.
There was a significant positive correlation between YLL and NHI funding in Iran.
There was a strong positive correlation between the number of deaths (mortality) and NHI
expenditures in Iran.
There was a strong positive correlation between hospital days and NHI funding in Iran.
There is a perceived need to establish a new NHI benefit package to prioritize health service
coverage based on the burden of disease measures.
Although it has been confirmed that ‘‘burden of disease’’ and ‘‘cost-effectiveness’’ measures be
considered principal criteria for informing the NHI benefit packages, other social, political
and individual factors do need to be considered in determining the NHI benefit package.
Appendix
Acknowledgments
The author gratefully thanks Professor K. Lee, the Director of the Centre for Health Planning
and Management of Keele University, UK, for his guidance and support. Many thanks to the
friends who encouraged and supported me, especially to Dr A. Ferdosipor, Chancellor of
Semnan Medical University and Dr H. Tajalli General Director of MSIO of Semnan for
remarkable help in collecting the data from Semnan district.
References
Fox-Rushby J. (2002). Disability Adjusted Life Years Studies in Health Services Organisation & Policy’’,
(DALYs) for Decision-Making? An Overview of the paper 9. Antwerp Institute of Tropical Medicine,
Literature. Office of Health Economics, OHE, London. Netherlands, pp. 149.
Murray CJL, Lopez AD. (1996). The Global Burden of Folland S, Goodman AC, Stano M. (2003). The Econom-
Diseases. WHO/WB/Harvard School of Public ics of Health & Health Care. Prentice Hall, New
Health, Cambridge, MA. Jersey.
Fox-Rushby J, Hanson K. (2001). Health Policy Plan. Soderlund N. (1998). Health Policy. 45: 195–208.
16(3): 326–331. PBO. (1999). Third Iranian Development Program.
Glaser WA. (1991). Health Insurance in Practice. Jossey- Iranian Plan and Budget Organization, Tehran, Iran.
Bass Inc, CA. Semnam MSIO. (2001). Semnan MSIO Financial Report
Abel-Smith B. (1992). Health Policy Plan. 7(3): 215–226. for year 1379(2000–2001), Semnan MSIO, Semnan,
Normand C. (1999). Soc Sci Med. 48(7): 865–869. Iran.
Follman JF. (1963). Medical Care and Health Insurance. Naghavi M. (2000). Figure of deaths in four provin-
Richard D. Irwin, Inc. Homewood, Illions. ces of Iran in 1999. WHO Representative Office in
Criel B. (1998). ‘‘District-based Health Insurance in Sub- I.R. Iran. Tehran.
Saharan Africa: Part I, From Theory to Practice,
37 The Burden of Maternal
Mortality and Morbidity in
the United States and
Worldwide
C. T. Lang . J. C. King
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
2 The Burden of Maternal Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651

2.1 The Partner’s Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
2.2 The Child’s Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
2.3 The Physician and Hospital’s Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
2.4 The Scientific Community’s Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
2.5 Society’s Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
3 The Burden of Maternal Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654

3.1 Pregnancy Weight Gain/Weight Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
3.2 Reduced Self-Esteem/Sexuality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
3.3 Gestational Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
3.4 Postpartum Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
3.5 Perineal Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
3.6 Bedrest-Related Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
3.7 Operative-Related Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
3.8 Multiple Pregnancy-Related Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657

648 37 The Burden of Maternal Mortality and Morbidity in the United States and Worldwide
Abstract: There is an extensive literature exploring maternal mortality and morbidity in the
United States and worldwide in terms of epidemiology, etiologies, clinical associations, and
preventability. A particularly novel approach to this subject, however, concerns the > burden
that both maternal mortality and morbidity represent. Although various studies use the word
burden in their titles, it is used as a descriptive or metamorphical term. Looking upon both
mortality and morbidity as burdens is akin to a stone falling into a still pond, with the mother at
the epicenter and the ripples emanating outward to affect her partner, children, and family, as well
as the physician, hospital, scientific community, society as a whole, and in cases of morbidity,
back to the mother herself for years after the inciting event. From the perspective of these
parties, the impact felt is individual to each, whether it is on an economic, medical/psychological,
developmental, medicolegal, or macrostructural level. Although the individual prevalences of
maternal mortality and severe morbidity are low enough especially in developed countries to not
be considered significant problems, the > total prevalent burden they can and do represent
along with minor morbidity is on a much grander scale, and not well-represented in the
literature. It is in this light that efforts to reduce maternal mortality and morbidity become
especially laudable.
List of Abbreviations: ACOG, American College of Obstetricians and Gynecologists; AIDS,
acquired immunodeficiency syndrome; CDC, Centers for Disease Control and Prevention;
> DALY, disability adjusted life years; HIV, human immunodeficiency virus; ICD, international
classification of diseases; > QALY, quality adjusted life years; WHO, World Health Organiza-
tion; YLD, years lost due to disability; YLL, years of life lost due to premature mortality
1 Introduction
The Sixth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom
features a cover depicting a little boy sitting by himself and not in the arms of his mother
(Lewis, 2004). The emotional impact of his mother’s death is clear by the forlorn look on his
face. One eventually wonders about the downstream consequences for his development as he
grows up in a single-parent household. The cover could have just as easily depicted the father
meeting with a funeral director or raising his son by himself, the physician and hospital
officials heatedly discussing substandard care or system breakdowns, or the woman’s employer
struggling to replace lost productivity. In cases of mortality, clearly the burden falls on the
survivors. In cases of morbidity, on the other hand, the burden is borne also by the mother,
such as with severe morbidity that could leave her with irreversible injury, and less-severe
morbidity such as postpartum depression and incontinence.
> Figure 37-1 is a graphical representation of the distribution and quality of burden
following an event of maternal mortality or morbidity, as in order to fully define burden one
must also define who bears it and how. This chapter is built around > Figure 37-1, with any
given case of mortality or morbidity presented as the focal point and the available literature
cited to support and understand the resulting “ripple effect.” To further complete the defini-
tion, > Table 37-1 lists the most common > sources of worldwide maternal mortality and
severe morbidity, while > Table 37-2 lists the common > sources of less-severe morbidity.
Before discussing this subject further, it is helpful to first consider some background
information in an effort to define a burden in an epidemiological and medical sense, and
not in a metamorphical sense. Burden is, in fact, a measurable entity, whether one is
considering mortality or morbidity. The World Health Organization (WHO) defines disability
The Burden of Maternal Mortality and Morbidity in the United States and Worldwide 37 649
. Figure 37-1
Distribution and quality of burden following an event of maternal mortality or morbidity
adjusted life years (DALY) as the sum total of the years of life lost due to premature mortality plus
the years of life lost due to disability secondary to a disease or health condition (WHO. int/en).
Each of these individual entities, in turn, is also measurable, allowing for a separate analysis of
mortality and morbidity. > Figure 37-2 presents a schematic illustrating these concepts.
> Table 37-3 presents 2002 WHO burden of disease statistics specific to death as well as
DALY associated with “maternal conditions,” both in the United States and in Somalia as an
example of a developing country.
Another means of measuring disease burden is by considering quality adjusted life years
(QALY), or the quality and quantity of life lived (Wikipedia.org). This is employed as a means
of determining the benefit of a medical intervention, based on the number of years that would
be added to a person’s life by virtue of undergoing such an intervention. A full QALY (i.e., a
value of 1.0) corresponds to a year lived in perfect health (the definition for which is a matter
of debate, and a limitation of QALYs). Years lived in less than perfect health are graded on a
scale of less than one (and in some models, to include negative numbers), with zero being the
equivalent of death, and a negative value the equivalent of a condition considered worse than
even death. Unfortunately, there is no way for the impact of less-than-optimal health of an
individual woman on her family to be figured into these calculations.
Maternal mortality has been defined in a number of ways, depending upon the source. The
WHO’s 2003 definition is “the death of a woman while pregnant or within 42 days of
. Table 37-1
Most common sources of worldwide maternal mortality and severe morbidity
Hemorrhage
Hypertensive disorders and associated complications
Embolism
Sepsis
HIV/AIDS
Abortion
Obstructed labor
Cardiac complications
Anesthesia complications
This table depicts the most common sources of maternal death and serious injury from a worldwide perspective
(Khan et al., 2006)
. Table 37-2
Common sources of less-severe maternal morbidity
Pregnancy weight gain/weight retention

Reduced self-esteem/sexuality
Gestational diabetes
Postpartum depression
Perineal trauma, urinary/fecal incontinence
Bed rest-related morbidity
Operative-related morbidity
Multiple pregnancy-related morbidity
This table depicts the more common sources of less-severe maternal injury, or that which is not life-threatening
termination of pregnancy, irrespective of the duration and the site of pregnancy, from any
cause related to or aggravated by pregnancy or its management, but not from accidental or
incidental causes” (Geller et al., 2006; WHO, 2003). The American College of Obstetricians
and Gynecologists (ACOG) along with The Centers for Disease Control and Prevention
(CDC) define maternal mortality as either pregnancy-associated or pregnancy-related, with
the former referring to the death of a woman during or within a year of the end of pregnancy
regardless of the cause of death, and the latter referring to the death of a woman during or
within a year of the end of pregnancy from any cause related to or aggravated by pregnancy or
its management, but not from accidental or incidental causes (Berg et al., 2001; Geller et al.,
2006). The International Classification of Diseases 10th edition (ICD-10) further distinguishes
between late maternal deaths (those secondary to direct or obstetric causes greater than
42 days but less than 1 year following pregnancy) and pregnancy-related deaths (those
secondary to any cause within 42 days of the end of pregnancy) (Geller et al., 2006).
> Maternal morbidity also has multiple definitions, ranging from very broad to specific scoring
systems, and is also subdivided into less severe and so-called “near-miss,” or life-threatening,
. Figure 37-2
Schematic illustrating DALY concepts
. Table 37-3
WHO burden of disease statistics, 2002
Burden secondary to “maternal conditions” United States Somalia

Deaths 500 4,400
DALY 194,000 203,000
Death rates 0.2/100,000 population 46.9/100,000 population
DALY rates 67/100,000 population 2,142/100,000 population
This table depicts total deaths and DALY, and both as rates, in the United States (an example of a developed
country) and in Somalia (an example of a developing country), secondary to conditions related to pregnancy in
2002 (http://www. who.int/evidence/bod/en/). WHO World Health Organization; DALY disability adjusted life years
varieties. In a broad sense, morbidity may include any instance in which a woman’s physical health
is adversely affected beyond what would be considered normal (Danel et al., 2003; Geller et al.,
2006), while in a more specific sense, any given case of morbidity is scored as forwarded by Geller
et al. (2004a), allowing for greater detection and proper categorization of morbidity of varying
severity.
2 The Burden of Maternal Mortality
2.1 The Partner’s Burden
Clearly a significant amount of burden will fall upon the shoulders of the woman’s partner, left
to raising children and managing finances alone compounded by the loss of a loved one. Aside
from the acute consequences of a maternal death, there are longer-term effects on the partner, as
well. Janzen et al. (2006) performed a secondary analysis of a national health survey including
15,662 men in Canada. Single fathers were found to have poorer self-rated health as compared to
those men who were still with their partners. Single men understandably experienced socioeco-
nomic disadvantages by virtue of being a single parent typically compounded by older age and
unemployment. Poorer paternal health was concluded to be a downstream consequence of these
factors. Ringback Weitoft et al. (2004) in an analysis of 682,919 men in Sweden concluded that
lone fathers with custody of their children were at increased risk for mortality as compared to
cohabitating fathers with a child in their household. Long-term lone custodial fathers were at
significantly increased risk for total mortality, ischemic heart disease, and addiction. In addition,
a significant financial burden exists soon after the maternal death with funeral and burial
arrangements typically exceeding $5,000 (Banks, 1998). Over the longer term, raising children
and preparing for their future exacts a financial toll, as well (Waldman, 1997).
2.2 The Child’s Burden
Perhaps the most noteworthy burden is that borne by the woman’s child, as alluded to in the
introduction. Obed et al. (2007) in an analysis of 64 live-born infants of 76 deceased mothers
in Nigeria, found that 44 (68.6%) did not survive to age 5 years. Not surprisingly, survival was
associated with proper care from the sister or mother of the deceased. Strikingly, Anderson
et al. (2007) found that a family had a 55% increased risk of experiencing the loss of a child less
than 12 years of age if a maternal death had occurred as opposed to a non-maternal death,
following an analysis of maternal and non-maternal deaths in Haiti. Pavard et al. (2005) also
found an increase in childhood mortality especially in older daughters following an analysis of
the early French Canadian population of Quebec. Lastly, Masmas et al. (2004) in an analysis
of 320 total motherless children in Guinea-Bissau found that there was excess mortality prior
to 2 years of age even after controlling for multiple confounders. Similar to the findings of
Obed et al. (2007), surrogate breastfeeding was associated with survival. Although this
evidence is largely derived from developing countries, a child’s dependence on his or her
mother is unmistakable no matter the cultural or socioeconomic milieu.
2.3 The Physician and Hospital’s Burden
Given that a significant proportion of cases of maternal mortality are secondary to substan-
dard care and/or breakdowns in the system as a whole (Geller et al., 2004b; Lewis, 2001;
Wildman and Bouvier-Colle, 2004), medicolegal concerns arise. Although there appears to be
no literature among obstetricians and gynecologists, among 51 emergency medicine interns
in California, 48% declared a substantial loss of enjoyment of practicing medicine as com-
pared to graduates because of malpractice concerns (Rodriguez et al., 2007). In addition, it
seems logical that defensive medicine practices are likely to follow at least in the short term for
any physician experiencing a maternal death, especially when a disciplinary complaint has
been forwarded (Cunningham and Dovey, 2000). Another potential downstream consequence
for physicians is depression. In a questionnaire study, 131 general practitioners from the
University of Leeds associated a variety of stressors with depression such as relationships with
other physicians and patients, making mistakes, and turning blame inward (Firth-Cozens,
1998), each of which is likely associated with a maternal mortality.
From the perspective of the hospital, the issue of preventability becomes apparent partic-
ularly in cases of maternal mortality (WHO, 2005). In this light, the burden becomes especially
heavy, as a potentially preventable death has occurred. Geller, et al. presented “strategies for
change” in a 2006 publication, speaking to the importance of proper identification and
recording of maternal mortality and severe morbidity such that data can be analyzed to
learn from mistakes and remedy physician and system-related deficits (Geller et al., 2006).
Such efforts extend beyond the walls of the hospital to include what Geller, et al. refer to as
“stakeholders” – health agencies, public health officials, and federal agencies – in the name of
reducing maternal mortality.
2.4 The Scientific Community’s Burden
In the eyes of some, there exists a “knowledge gap” in the literature with regards to maternal
mortality, especially among developing countries (Gil-Gonzalez et al., 2006). This places a
burden upon the shoulders of the scientific community to consider aspects other than clinical
decision-making in cases of maternal mortality, and to dedicate resources to those sources of
maternal mortality which previous literature supports being the most likely culprits.
Gil-Gonzalez et al. (2006) in a systematic review of 2,250 studies on maternal mortality
were able to identify only 27 that explored “macrostructural” determinants including socio-
economic, political, and cultural factors. Of those excluded, more than 1,600 were either
letters or editorials, or focused solely on clinical intervention or technology. From the
perspective of these investigators, this literature does not allow for a full understanding of
the problem, and therefore potentially fails to uncover targets for intervention. Despite there
being a clinical intervention available to keep a woman safer or to save her life, macrostruc-
tural barriers may exist preventing this intervention from becoming reality on a regular basis
and available to all women.
The same investigators also presented a frequency distribution of published scientific
papers according to prevalence of cause of death, and uncovered a seemingly reduced scientific
interest in the larger sources of maternal mortality. Specifically, preeclampsia, eclampsia, and
indirect causes were over-represented, while obstructed labor, unsafe abortion, and most
notably hemorrhage were under-represented. Another concerning finding was that literature
from developing countries was more likely to be authored by investigators from developed
countries, introducing an inherent disconnect between the sources of maternal mortality and a
personal appreciation for their underlying significance. Akin to the remarks made in the last
section, herein lies “adding insult to injury” to the overall burden of maternal mortality, in
that healthcare professionals and the scientific community are aware of the predominant
sources of mortality but direct a significant proportion of their attention elsewhere.
2.5 Society’s Burden
The last burden to consider concerns society as a whole, in terms of economics, the layperson’s
perspective, and racial disparity. Examining the cost of a maternal death is perhaps disingen-
uous as the loss of a mother is arguably priceless (Callaghan, 2008 – personal communication),
especially from the perspective of the woman’s surviving family. Nonetheless, there is data
available regarding inpatient care for pregnancy complications, which in many cases of
maternal mortality would act as a surrogate measure. According to Geller et al. (2006),
$34.7 billion was spent in 2002 on pregnancy inpatient care regardless of pregnancy outcome.
Put into the context of overall national health care expenditures, inpatient maternal care
accounted for 5%. The concept of DALYdescribed above also allows for a better understanding
of the economic impact of a maternal death in terms of the years of productivity lost, with
each individual case being weighted according to the woman’s occupation and contribution to
society. Thus, a burden falls upon society to fill the void left behind.
From the perspective of the layperson “looking from the outside in” it is understandable that
the prevailing feeling may be one of distrust or anger. Especially in developed countries such as
the United States with a maternal mortality ratio of 11.8 per 100,000 live births over the 9-year
period 1991–1999 (Chang et al., 2003), pregnancy is seldom looked upon as a potentially life-
threatening event in a woman’s life. This places a burden upon families to value the importance of
regular prenatal care and to seek prompt attention for any complications, rather than looking
upon pregnancy as “a natural event which needs little healthcare attention” (Elu, 1995).
Lastly, a word regarding racial disparity is in order. At least in the United States, the burden
of racism is undoubtedly compounded and strained with each loss of a mother of African or
Hispanic ancestry. In comparison with pregnancy-related mortality for Caucasian women,
black women experience up to a 5.5-fold greater increase in risk, especially as they grow older
(Chang et al., 2003). There is clearly a burden upon society to remedy the fact that minorities
tend to receive substandard care in obstetrics and other medical disciplines (Freeman and
Payne, 2000), and to place greater emphasis on early and thorough prenatal care for minorities
insomuch as they are more likely to present with more significant underlying disease and
potentially at later stages (Brett et al., 1994).
3 The Burden of Maternal Morbidity
Maternal morbidity can either be life-threatening (i.e., severe morbidity, see > Table 37-1),
or of a less serious nature (see > Table 37-2). Callaghan et al. (2008) very recently presented
National Hospital Discharge Survey data from 1991–2003 regarding maternal life-threatening
diagnoses. Over this time frame in the United States, the severe morbidity rate was 5.1 per
1,000 deliveries. Looked at in another way, for every maternal death, approximately 50 women
experience severe morbidity – an additional way in which the burden of maternal mortality
becomes manifest. Danel et al. (2003) also reviewed National Hospital Discharge Survey data
from 1993–1997, but specifically considered morbidity (some life-threatening, including
eclampsia and hemorrhage) during labor and delivery. Forty-three percent (approximately
1.7 million women per year) experienced some form of maternal morbidity, including
obstetric complications, preexisting medical conditions, and/or a cesarean delivery.
Perhaps a novel approach to the subject of maternal morbidity involves an analysis of the
comparatively much more common forms of non-life-threatening morbidity, as listed in
> Table 37-2. As mentioned previously, although the individual burdens of these more
minor forms of morbidity are less in that they do not entail loss of life or require months of
treatment in an intensive care unit, the sum total burden they potentially represent in the day-
to-day life of women is significant. This section will concentrate on the last interaction
depicted in > Figure 37-1 – between the event and the mother herself over the long-term –
but will also reference literature supporting other interactions, as well.
3.1 Pregnancy Weight Gain/Weight Retention
Women may enter pregnancy already overweight or obese, or may gain an excess amount of weight
during the pregnancy itself. In either case, or even in women who enter pregnancy with an ideal
weight and gain an appropriate amount during their pregnancies, shedding weight in the
postpartum period can be a formidable challenge. More importantly, there is a strong body of
evidence linking excessive weight gain during pregnancy and/or failure to lose pregnancy-related
weight in the postpartum period with long-term obesity and the downstream consequences.
Specifically, Amorim et al. (2007) found that gestational weight gain was directly related to body
mass index at a 15-year follow-up even after accounting for multiple confounders. Similarly,
Rooney et al. (2005), Linne et al. (2004), and Crowell (1995) found associations between
pregnancy weight gain and failure to lose weight with obesity in the midlife, along with diabetes
and heart disease. Gore et al. (2003) found this to be especially true with minority women. In terms
of the effects on offspring, children of obese parents clearly are at risk for obesity and the attendant
complications (Reece, 2008), and in the immediate neonatal period are at risk for lower Apgar
scores, seizures, hypoglycemia, polycythemia, and meconium aspiration (Stotland et al., 2006).
3.2 Reduced Self-Esteem/Sexuality
In a similar light to the previous section, postpartum women (especially African-American

women) tend to be dissatisfied with their body size (Boyington et al., 2007) and tend to perceive
themselves as larger than they actually are (Morin et al., 2002). Not surprisingly, this may have a
detrimental effect upon sexuality both during pregnancy and afterwards (Fischman et al., 1986;
Reamy and White, 1987), along with other factors including depression and fatigue (DeJudicibus
and McCabe, 2002; Fischman et al., 1986), episiotomy discomfort, vaginal bleeding, dyspareunia,
insufficient lubrication, fear of neglecting the infant, and fear of injury (Reamy and White, 1987).
3.3 Gestational Diabetes
There is of course an extensive body of literature exploring the morbidities associated with
gestational diabetes. For the mother herself, there is clearly an association with the development
of persistent insulin resistance and frank diabetes mellitus later in life (Hunger-Dathe et al., 2006;
Kim et al., 2002; Russell et al., 2008; Verma et al., 2002; Wein et al., 1997), metabolic syndrome
(Albareda et al., 2005), and even cancer (Dawson, 2004; Perrin et al., 2007). In terms of the effects
on offspring, there appears to be an increased risk for impaired glucose tolerance and overweight
status (Malcolm et al., 2006), metabolic syndrome (Boney et al., 2005; Wang et al., 2007),
precocious atherosclerosis (Skilton, 2008), and even aneuploidy (Moore et al., 2002). There are
of course a multitude of potential complications seen in the neonatal period, as well, including
macrosomia and birth trauma.
3.4 Postpartum Depression
Depression in the postpartum period has gained attention in recent years as the morbidity it
represents has become more and more appreciated. It is not surprising that it is associated with
suboptimal maternal behavior such as smoking, not providing vitamins to children, and not
restraining children properly in motor vehicles (Leiferman, 2002). Studies have also found a
variable impact on subsequent cognitive development in the offspring of depressed mothers,
with Grace et al. (2003) demonstrating small effects on language and intelligence quotient, and
Hay et al. (2001) demonstrating significantly lower intelligence quotient scores and attention
problems and difficulty with mathematics. In keeping with the first section above, Carter et al.
(2000) found measures of body mass index were associated with depressive and anxiety
symptoms at both 4 and 14 months postpartum. Lastly, mean cost differences between
women with and without postnatal depression are significant in terms of community care
services, with costs becoming higher with extended periods of depression (Petrou et al., 2002).
3.5 Perineal Trauma
Trauma to the maternal perineum, whether it is spontaneous or intentional in the form of

episiotomy, can also be a significant source of morbidity. Williams et al. (2007) performed a
retrospective cross-sectional community survey of 2,100 postnatal women and found that
those having experienced perineal trauma as compared to those with an intact perineum were
more likely to report dyspareunia, a delayed return to sexual intercourse, urinary inconti-
nence, and fecal incontinence. Surprisingly, a significant proportion of women with an intact
perineum also reported enduring morbidity, especially stress urinary incontinence. Williams
et al. (2005) also described emotional and psychological morbidity associated with a third-
degree perineal injury, compounded by poor support and counseling from the health care
team, in a focus-group qualitative study. In a secondary cohort analysis of 697 women, Klein
et al. (1994) found that those with midline episiotomy were more likely to suffer perineal pain,
pelvic floor weakness, and decreased sexual functioning, as compared to those with an intact
perineum or those who experienced spontaneous injury. Understandably, those women left
incontinent of urine and/or stool may experience tremendous physical and psychological
morbidity, with management of these conditions requiring extensive resources (Dolan et al.,
2004; Thornton and Lubowski, 2006).
3.6 Bedrest-Related Morbidity
Bed rest is commonly a part of the management of women with a variety of obstetrical
complications, especially preterm labor and placenta previa, despite the lack of evidence
supporting the utility of this. Bed rest appears to be associated with musculoskeletal decompen-
sation (Kaji et al., 2007; Maloni et al., 1993), maternal and familial stress (Gupton et al., 1997),
persistent symptoms into the postpartum period including fatigue, mood changes, tenseness,
difficulty concentrating, backache, dry skin, and headache (Maloni and Park, 2005), and
lost productivity of up to billions of dollars per year (Goldenberg et al., 1994). From the
perspective of offspring, those born to mothers on bed rest during pregnancy are potentially
more likely to suffer allergies, motion sickness, and require rocking to fall asleep (Bellieni et al.,
2003), and to weigh less at birth (Maloni et al., 2004). From the perspective of family, emotional
and financial distress may arise (Maloni et al., 2001; May, 2001). Lastly, bed rest may very well
be associated with an increased risk for thromboembolic disease, particularly given that this
can be seen even in healthy, nonpregnant women (Slipman et al., 2000). Especially in cases
of underlying thrombophilia does thromboembolic disease become likely with bed rest in
pregnancy (Sikovanyecz et al., 2004). Ultimately, however, in a review of 265 women on

antepartum hospital bed rest and not on anticoagulation therapy, Carr et al. (1997) demon-
strated no cases of deep venous thrombosis.
3.7 Operative-Related Morbidity
As the cesarean delivery rate has risen over the last decade, the morbidity (and potential
mortality) associated with it as opposed to a vaginal birth has become apparent. One of the
most recent analyses in this regard is from Declercq et al. (2007). In a retrospective study of
244,088 low-risk mothers from Massachusetts from 1998–2003, rehospitalization within 30 days
of discharge was 2.3 times more likely following a planned cesarean delivery when compared with
a planned vaginal delivery, most commonly for wound complications and hematoma formation
(Declercq et al., 2007). The average hospital cost associated with a planned cesarean delivery was
$4,372, and for a planned vaginal delivery, $2,487. In a study from Canada, Liu et al. (2007)
performed a retrospective study of 2,339,186 women from 1991–2005, and found that although
absolute risks were low, odds ratio increases were significant in the planned cesarean delivery
group for cardiac arrest, hematoma, hysterectomy, major infection, anesthesia complications,
thromboembolic disease, hemorrhage, and hospital stay, when compared to the planned vaginal
delivery group. Deneux-Tharaux et al. (2006) performed a population-based case-control study
in France from 1996–2005, which included 65 cases of maternal mortality. After controlling for
confounders, the risk of postpartum death was 3.6 times higher following a cesarean rather than a
vaginal delivery, secondary to anesthesia complications, infection, and thromboembolic disease.
Also, disorders of placental implantation (e.g., placenta accreta, increta, percreta) become more
likely following uterine surgery, including cesarean deliveries (Oyelese and Smulian, 2006). The
associated morbidity in these cases is largely related to hemorrhage and the resulting blood
product transfusions and possible hysterectomy. Of course, these events have the potential to be
life-threatening, especially in developing countries or at institutions with limited blood banking
and lack of 24-h interventional radiology. Cesarean delivery has also been associated with
neonatal morbidity, as well, including infectious disease, digestive and circulatory diseases, and
respiratory distress syndrome (Chang et al., 2006; Miller, 1988).
3.8 Multiple Pregnancy-Related Morbidity
It is well-known that women carrying twins or higher-order multiples are at greater risk as
compared to women carrying singletons for a variety of complications, including preeclamp-
sia, anemia, hemorrhage, and mortality (Kinzler et al., 2000). Not surprisingly, the economic
burden is substantial, given that in addition to management of maternal complications, one
must also take into account neonatal interventions which are often involving preterm infants
and associated with lengthy hospital stays (Henderson et al., 2004; Luke et al., 2005).
Summary Points
Burden is a measurable entity in the realm of maternal mortality and morbidity.

In addition to the mother herself, the partner, children, physician, scientific community,
and society as a whole are affected in unique ways following a maternal mortality or
instance of morbidity.
Examples of ways in which the aforementioned parties may be affected include those on an
economic, medical/psychological, developmental, medicolegal, or macrostructural level.
Disability adjusted life years (DALY) are determined by adding years lost due to premature
death and years of life lost due to disability.
Although the absolute risk for a maternal mortality or instance of severe morbidity is low
in developed countries, the total prevalent burden they can and do represent after the fact is
on a much grander scale.
Even in cases of minor maternal morbidity, the potential long-term burden may signifi-
cantly impact quality of life.
References
Albareda M, Caballero A, Badell G, Rodriguez-Espinosa J, Deneux-Tharaux C, Carmona E, Bouvier-Colle MH,
Ordonez-Llanos J, de Leiva A, Corcoy R. (2005). Breart G. (2006). Obstet Gynecol. 108: 541–548.
Met Clin Exp. 54: 1115–1121. Dolan LM, Walsh D, Hamilton S, Marshall K,
Amorim AR, Rossner S, Neovius M, Lourenco PM, Thompson K, Ashe RG. (2004). Int Urogyn J. 15:
Linne Y. (2007). Obesity. 15: 1278–86. 160–164.
Anderson FW, Morton SU, Naik S, Gebrian B. (2007). Elu MC. (1995). WHO Q. 48: 47–49.
Mat Child Health J. 11: 395–401. Firth-Cozens J. (1998). Br J Gen Pract. 48: 1647–1651.
Banks DA. (1998). Death Stud. 22: 269–285. Fischman SH, Rankin EA, Soeken KL, Lenz ER. (1986).
Bellieni CV, Bagnoli F, Perrone S, Caparelli N, JOGNN. 15: 58–63.
Cordelli DM, Melissa B, Buonocore G. (2003). Biol Freeman HP, Payne R. (2000). N Engl J Med. 343:
Neonate. 84: 147–151. 1045–1047.
Berg C, Danel I, Atrash H, Zane S, Bartlett L. (2001). Friedlander Y, Paltiel O, Harlap S. (2007). BMC Med.
Strategies to reduce pregnancy-related deaths: from 5: 25.
identification to review and action. Centers for Geller SE, Rosenberg D, Cox S, Brown M, Simonson L,
Disease Control and Prevention, Atlanta. Kilpatrick S. (2004a). J Clin Epid. 57: 716–720.
Boney CM, Verma A, Tucker R, Vohr BR. (2005). Ped. Geller SE, Rosenberg D, Cox S, Brown ML, Simonson L,
115: e290–296. Driscoll CA, Kilpatrick SJ. (2004b). Am J Obstet
Boyington J, Johnson A, Carter-Edwards L. (2007). Gynecol. 191: 939–944.
JOGNN. 36: 144–151. Geller SE, Cox SM, Callaghan WM, Berg CJ. (2006).
Brett KM, Schoendorf KC, Kiely JL. (1994). Am J Obstet Womens Health Issues. 16: 176–188.
Gynecol. 170: 41–46. Gil-Gonzalez D, Carrasco-Portino M, Ruiz MT. (2006).
Callaghan WM, MacKay AP, Berg C. (2008). Am J Obstet Bull WHO. 84: 903–909.
Gynecol. 199: 133.e1–133.e8. Goldenberg RL, Cliver SP, Bronstein J, Cutter GR,
Carr MH, Towers CV, Eastenson AR, Pircon RA, Iriye Andrews WW, Mennemeyer ST. (1994). Obstet
BK, Adashek JA. (1997). J Mat Fet Med. 6: 264–267. Gynecol. 84: 131–136.
Carter AS, Baker CW, Brownell KD. (2000). Psychosom Gore SA, Brown DM, West DS. (2003). Ann Behav Med.
Med. 62: 264–270. 26: 149–159.
Chang J, Elam-Evans LD, Berg C, Herndon J, Flowers L, Grace SL, Evindar A, Stewart DE. (2003). Arch Womens
Seed K, Syverson C. (2003). MMWR. 52: 1–8. Ment Health. 6: 263–274.
Chang JH, Hsu CY, Lo JC, Chen CP, Huang FY, Yu S. Gupton A, Heaman M, Ashcroft. (1997). JOGNN.26:
(2006). Acta Ped. 95: 1561–1566. 423–430.
Crowell DT. (1995). J Nurse Midwifery. 40: 418–423. Hay DF, Pawlby S, Sharp D, Asten P, Mills A, Kumar R.
Cunningham W, Dovey S. (2000). NZ Med J. 113: (2001). J Child Psychol Psych Allied Disciplines. 42:
464–467. 871–889.
Danel I, Berg C, Johnson CH, Atrash H. (2003). Am J Henderson J, Hockley C, Petrou S, Goldacre M,
Pub Health. 93: 631–634. Davidson L. (2004). Arch Dis Child Fet Neonat Ed.
Dawson SI. (2004). Cancer. 100: 149–155. 89: F542–545.
Declercq E, Barger M, Cabral HJ, Evans SR, Kotelchuck Hunger-Dathe W, Mosebach N, Samann A, Wolf G,
M, Simon C, Weiss J, Heffner LJ. (2007). Obstet Muller UA. (2006). Exp Clin Endo Diab. 114:
Gynecol. 109: 669–677. 11–17.
DeJudicibus MA, McCabe MP. (2002). J Sex Res. 39: Janzen BL, Green K, Muhajarine N. (2006). Can J Pub
94–103. Health. 97: 440–444.
Kaji T, Yasui T, Suto M, Mitani R, Morine M, Uemura H, Pavard S, Gagnon A, Desjardins B, Heyer E. (2005).
Maeda K, Irahara M. (2007). Bone. 40: 1088–1094. J Biosoc Sci. 37: 209–227.
Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look Perrin MC, Terry MB, Kleinhaus K, Deutsch L, Yanetz R,
PFA. (2006). Lancet. 367: 1066–1074. Tiram E, Calderon R, Friedlander Y, Paltiel O,
Kim C, Newton KM, Knopp RH. (2002). Diab Care. 25: Harlap S. (2007). BMC Med. 5: 25.
1862–1868. Petrou S, Cooper P, Murray L, Davidson LL. (2002). Br J
Kinzler WL, Ananth CV, Vintzileos AM. (2000). J Soc Psych. 181: 505–512.
Gynecol Investig. 7: 321–327. Reamy KJ, White SE. (1987). Arch Sex Behav. 16:
Klein MC, Gauthier RJ, Robbins JM, Kaczorowski J, 165–186.
Jorgensen SH, Franco ED, Johnson B, Waghorn K, Reece EA. (2008). Am J Obstet Gynecol. 198: 23–27.
Gelfand MM, Guralnick MS. (1994). Am J Obstet Ringback Weitoft G, Burstrom B, Rosen M. (2004).
Gynecol. 171: 591–598. Social Sci Med. 59: 1449–1459.
Leiferman J. (2002). Health Ed Behav. 29: 596–607. Rodriguez RM, Anglin D, Hankin A, Hayden SR,
Lewis G. (ed.) (2001). Why mothers die 1997–1999:report Phelps M, McCollough L, Hendey GW. (2007).
from the confidential enquiries into maternal deaths in Acad Emerg Med. 14: 569–573.
the United Kingdom. RCOG Press, London. Rooney BL, Schauberger CW. (2002). Obstet Gynecol.
Lewis G. (ed.) (2004). Why mothers die 2000–2002: 100: 245–252.
report on confidential enquiries into maternal deaths Rooney BL, Schauberger CW, Mathiason MA. (2005).
in the United Kingdom. RCOG Press, London. Obstet Gynecol. 106: 1349–1356.
Linne Y, Dye L, Barkeling B, Rossner S. (2004). Obesity Russell C, Dodds L, Armson BA, Kephart G, Joseph KS.
Res. 12: 1166–1178. (2008). BJOG. 115: 253–259.
Liu S, Liston RM, Joseph KS, Heaman M, Sauve R, Sikovanyecz J, Orvos H, Pal A, Katona M, Endreffy E,
Kramer MS. (2007). CMAJ. 176: 455–460. Horvath E, Szabo J. (2004). Fet Diag Ther. 19:
Luke B, Brown MB, Alexandre PK, Kinoshi T, O’Sullivan 275–277.
MJ, Martin D, Misiunas RB, Nugent C, Skilton MR. (2008). Ped. 121: 570–574.
van de Ven C, Newman RB, Mauldin JG, Witter Slipman CW, Lipetz JS, Jackson HB, Vresilovic EJ.
FR. (2005). Am J Obstet Gynecol. 192: 909–915. (2000). Arch Phys Med Rehab. 81: 127–129.
Malcolm JC, Lawson ML, Gaboury I, Lough G, Keely E. Stotland NE, Cheng YW, Hopkins LM, Caughey AB.
(2006). Diab Med. 23: 565–570. (2006). Obstet Gynecol. 108: 635–643.
Maloni JA, Alexander GR, Schluchter MD, Shah DM, Thornton MJ, Lubowski DZ. (2006). Aust NZ J Obstet
Park S. (2004). Biol Res Nurs. 5: 177–186. Gynaecol. 46: 468–473.
Maloni JA, Brezinski-Tomasi JE, Johnson LA. (2001). Verma A, Boney CM, Tucker R, Vohr BR. (2002). J Clin
JOGNN. 30: 165–173. Endo Met. 87: 3227–3335.
Maloni JA, Chance B, Zhang C, Cohen AW, Betts D, Waldman HB. (1997). J Dent Child. 64: 287–290.
Gange SJ. (1993). Nurs Res. 42: 197–203. Wang X, Liang L, Junfen FU, Lizhong DU. (2007). Ind J
Maloni JA, Park S. (2005). JOGNN. 34: 163–171. Ped. 74: 561–565.
Masmas TN, Jensen H, da Silva D, Hoj L, Sandstrom A, Wein P, Beischer NA, Sheedy MT. (1997). Aust NZ J
Aaby P. (2004). Acta Ped. 93: 99–105. Obstet Gynaecol. 37: 420–423.
May KA. (2001). Health Care Wom Int. 22: 29–47. Wildman K, Bouvier-Colle MH. (2004). Br J Obstet
Miller JM. (1988). Obstet Gynecol Clin N Am. 15: Gynaecol. 111: 164–169.
629–638. Williams A, Lavender T, Richmond DH, Tincello DG.
Moore LL, Bradlee ML, Singer MR, Rothman KJ, (2005). Birth. 32: 129–136.
Milunsky A. (2002). Am J Epid. 155: 719–724. Williams A, Herron-Marx S, Hicks C. (2007). Midwifery.
Morin KH, Brogan S, Flavin SK. (2002). MCN. 27: 23: 392–403.
20–25. WHO. (2003). Maternal mortality in 2000: estimates
Obed JY, Agida ET, Mairiga AG. (2007). Nig J Clin Pract. developed by WHO, UNICEF, and UNFPA. WHO,
10: 35–40. Geneva.
Oyelese Y, Smulian JC. (2006). Obstet Gynecol. 107: WHO. (2005). World health report 2005: make every
927–941. mother and child count. WHO, Geneva.
38 The Financial Implications of
Pancreas Transplant
Complications
J. A. Cohn . M. J. Englesbe
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
2 The Role of Pancreas Transplantation in the Clinical Management of

Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
3 Complications of Pancreas Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664

3.1 How the Complications of Pancreas Transplantation Determine the
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
3.2 Surgical Complications of Pancreas Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
4 The Financial Implications of Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666

4.1 Who Pays for Pancreas Transplant Complications? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
4.2 The High Costs of Complications Invite Investment in
Quality Improvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668

662 38 The Financial Implications of Pancreas Transplant Complications
Abstract: Diabetes mellitus is associated with profound morbidity and mortality. For a small
subset of diabetics, > pancreas transplantation offers a cure for diabetes. Unfortunately,
pancreas transplantation is associated with its own risks. These risks include > graft thrombosis
and peri-operative infections in the short-term, and renal failure, malignancy, and infections
related to the long-term effects of immunosuppression (> immunosuppression medications).
Surgical complications of pancreas transplantation are associated with significant costs for
the patient, the payer, the hospital, and the physician. For example, a patient with a surgical
complication following pancreas transplantation will cost an insurer an additional $17,363.
Quantifying the costs of surgical complications is important as payers and hospitals consider
future investment in > quality improvement initiatives. Our work in pancreas transplantation
suggests that payers bear the majority of the financial burden of pancreas transplant complica-
tions. Within this context, focused quality improvement initiatives in pancreas transplantation
seem like a reasonable investment for large payers, such as > Medicare.
List of Abbreviations: BCBSM, blue cross and blue shield of Michigan; PAK, pancreas after
kidney transplant; PTA, pancreas transplant alone; QI, quality improvement; SPK, simulta-
neous kidney-pancreas transplant; USD, United States dollar
1 Introduction
Diabetes mellitus is a leading public health concern around the world. Diabetes is associated with
numerous devastating complications and high mortality rates. In the United States, the total
annual economic cost of diabetes in 2007 was estimated to be $174 billion. Medical expenditures
totaled $116 billion and were comprised of $27 billion for diabetes care, $58 billion for chronic
diabetes-related complications, and $31 billion for excess general medical costs. Indirect costs
resulting from increased absenteeism, reduced productivity, disease-related unemployment,
disability, and loss of productive capacity due to early mortality totaled $58 billion (2008).
Within the context of the remarkable morbidity, mortality, and costs associated with diabetes
mellitus, significant efforts have been made to provide b-cell replacement for Type 1 diabetics.
Type 1 diabetics can become euglycemic following either pancreas transplantation or islet-cell
transplantation. Islet cell transplantation is not yet mainstream therapy for these patients. In
contrast, pancreas transplantation is done to treat > Type 1 diabetes mellitus.
Though pancreas transplantation offers significant potential benefits for Type 1 diabetics,
medical and surgical complications are common following pancreas transplantation. These
complications may not only affect patient quality of life, but also affect patient survival.
In addition, these complications have significant financial implications for patients, payers,
hospitals, and surgeons. Within the context of rising health care costs, the financial implica-
tions of pancreas transplant complications is having direct policy implications on the avail-
ability of pancreas transplantation for Type 1 diabetics. In addition, careful accounting of
the costs of surgical complications is critical in order to assure appropriate levels of investment
in quality improvement activities.
2 The Role of Pancreas Transplantation in the Clinical

Management of Diabetes Mellitus
In the United States, it is estimated that there over 20 million diabetics, which represents
approximately 7% of the population (2008). While only 0.22% of Americans under the age 20
The Financial Implications of Pancreas Transplant Complications 38 663
of have diabetes, greater than 20% of Americans over the age of 60 are diabetic. Diabetes
affects both men and women equally, but is more prevalent in nonwhite populations within
the United States.
Diabetes is associated with a number of serious and potentially life-threatening complica-
tions. Within this context, diabetes was the seventh leading cause of death listed on death
certificates in the United States in 1996, and middle aged Americans with diabetes have twice the
death rate compared to non-diabetic, middle aged Americans (1997). Heart disease and stroke
account for approximately 65% of deaths among patients with diabetes (2008). Diabetes is the
leading cause of kidney disease and blindness in the United States, and is the most common
diagnosis among kidney transplant recipients (Danovitch et al., 2005). In addition, 60–70%
of diabetic Americans have some form of nervous system damage. Sadly, in 2002, 82,000
non-traumatic amputations were performed on diabetics in the United States (Mitka, 2007).
Patients coping with the restrictions of a diabetic lifestyle and concerned about the
secondary complications of diabetes occasionally are referred for pancreas transplantation.
A pancreas transplant releases insulin and provides euglycemia to Type 1 diabetics. Type 2
diabetics have a dysfunction in insulin utilization, and as a result, pancreas transplantation
will unlikely provide significant benefit.
Many pancreas transplant recipients are free from the diabetic lifestyle and enjoyed
a significantly improved quality of life compared to their pre-transplant lifestyle. Inter-
estingly, improved quality of life is not considered an adequate outcome goal for pan-
creas transplantation. This observation is related to the significant risks associated with
pancreas transplantation, both related to the surgical procedure and to the long-term
effects of immunosuppression (> Table 38‐1).
Transplant physicians frequently disagree on the indications for pancreas transplantation.
Pancreas transplants can be done in three settings: as a pancreas transplant alone (PTA), as a
> simultaneous kidney-pancreas transplant (SPK), and as a pancreas transplant after kidney
transplant (PAK). Within the United States in 2005, SPK was performed in 895 patients, PAK
was performed in 343 patients, and PTA was performed in 129 (Andreoni et al., 2007).
Most surgeons agree that SPK is beneficial to the majority of Type 1 diabetics with renal
insufficiency. In contrast, opinions regarding the role for PAK and PTA vary widely. This debate
. Table 38‐1
Important features of pancreas transplantation
1. Only Type 1 diabetics are potential pancreas transplant recipients

2. Pancreas transplantation can cure Type 1 diabetes
3. Pancreas transplantation involves a major operation with significant risks of severe
complications
4. Pancreas transplantation improves the lifestyle of many Type 1 diabetics, but has never been
shown to extend the life of Type 1 diabetics
5. Type 1 diabetics in renal failure frequently receive a simultaneous kidney and pancreas
transplant
6. All transplant recipients need to take daily immunosuppressive medications. These medications
have significant potential to cause adverse effects
Type 1 diabetics who receive a pancreas transplant non longer need insulin and are no longer diabetic. Unfortu-
nately, pancreas transplant are associated with significant potential complications and as a result, are only offered
to higher selected Type 1 diabetics
has been ongoing for 20 years, and as the management of Type 1 diabetes mellitus conti-
nues to improve, the role for a solitary pancreas transplant is becoming more controversial.
Pancreas transplantation is a treatment option for very small number of diabetics world-
wide. This is, in part, related to the fact that pancreas transplantation is primarily offered to
patients within the United States and some countries within Western Europe. More specifi-
cally, as of 2004, 23,043 pancreas transplants were reported to the International Pancreas
Transplant Registry (2007). Despite the fact that <8% of the Type 1 diabetics in the world live
in the United States, pancreas transplants were reported in 17,127 patients in the United
States, and 5,916 patients from outside of the United States (2007). The fact that most
pancreas transplants are done within United States is related, in part, to be highly developed
transplant system within United States. In addition, it is also likely that pancreas transplanta-
tion is not offered to many Type 1 diabetics outside of the United States because of physician
concerns about whether patients benefit from the operation (> Table 38‐2).
. Table 38‐2
Clinical outcomes and complications of pancreas transplants
Simultaneous pancreas-kidney Pancreas only

recipients (N = 46) recipients (N = 31)
90 day graft function 87.3% 91.1%
Technical graft loss (30 day) 8.5% 11.9%
Pancreatic leak or abscess 8.8% 17.2%
Re-operations (first 90 days) 25.9% 26.4%
Readmissions (first 180 days) 1.1 0.8 1.3 0.9
Length of stay (days) 7.9 6.2 8.5 7.9
Rejection first 180 days 12.3% 31.5%
Pancreas transplant outcomes (Pancreas only combines the results of pancreas after kidney transplants and
pancreas alone transplants) among pancreas transplant recipients within the State of Michigan between 1 January
2002 and 15 November 2004
3 Complications of Pancreas Transplantation

3.1 How the Complications of Pancreas Transplantation Determine
the Indications
Pancreas transplantation has not received mainstream acceptance for the treatment of Type 1
diabetes, in part, related to the severity of pancreas transplant complications. Unlike kidney
transplantation, a large number of pancreas transplant recipients have severe surgical compli-
cations (Englesbe et al., 2006b). In addition, maintenance of the pancreas allograft requires
long-term immunosuppression, which is also associated with significant short and long term
complications.
Assessment of the benefit of pancreas transplantation requires careful consideration
regarding the risks and benefits of the transplant operation, compared to the risks of Type 1
diabetes. In general, transplant professionals do not suggest pancreas transplantation for
well controlled Type 1 diabetics unless they have renal dysfunction. In patients with renal
failure, SPK is offered to patients who do not have other severe complications of diabetes
mellitus (i.e., severe vascular disease, coronary artery disease, etc.). PAK and PTA are generally
reserved for Type 1 diabetics with life-threatening > hypoglycemic unawareness. Even though
a solitary pancreas transplant is a smaller operation than a SPK, surgical complications are
more common with PAK and PTA. The reasons for this are largely unknown.
3.2 Surgical Complications of Pancreas Transplantation
The medical complications of pancreas transplantation are primarily related to long-term

immunosuppression. Considering that the majority of pancreas transplant recipients also have
a kidney transplant, it is difficult to assess the specific implications of long-term immunosup-
pression on pancreas transplant recipients. In addition, the morbidity associated pancreas
transplantation is largely related to the transplant operation. As a result, we will focus on
pancreas transplant surgical complications.
The two most common surgical complications of pancreas transplantation are thrombosis
and infection. This is related to specific technical aspects of the pancreas transplant operation.
When a pancreas transplant is done, it is usually done through a midline laparotomy incision.
The pancreas is placed in the intra-peritoneal cavity. Arterial inflow is generally obtained from
the recipient iliac artery. Venous outflow is usually to either the recipient iliac vein or the
recipient portal vein. Historically, the duodenal segment of the allograft was sewn to the
recipient bladder (bladder drainage). Now more commonly, the duodenal segment is sewn to a
loop of small intestine (enteric drainage). Enteric drainage seems to be associated with fewer
complications including less cystitis and dehydration.
Pancreas allograft thrombosis occurs at approximately 10% of pancreas transplants (2007).
Thrombosis is generally related to technical failure, cold ischemia time, and donor selection. In
one study completed by our group, technical pancreas allograft loss was associated with
significantly longer cold ischemia times ((11.7 1.5 h vs. 8.0 3.8 h, p < 0.05) (2007)). In
addition, a donor pancreas with fatty infiltration, fibrosis, or other advanced age will have an
increased risk of thrombosis. Allograft thrombosis is thought to be more common with PAK
and PTA. This is potentially related to the anti-platelet effects of uremia (present in SPK
patients). Some centers administer peri-operative and post-operative intravenous heparin in
order to minimize the risk of thrombosis (Sutherland et al., 2001). This practice pattern is
associated with high rates of bleeding, transfusion, and re-operation (Troppmann et al., 1998).
Nonetheless, allograft thrombosis is rarely salvageable, and such high complication rates from
bleeding may be acceptable within this context.
Management of the exocrine secretions of the pancreas (> pancreas exocrine secretions) is
frequently problematic. Generally, enteric drainage to the pancreas is thought to have fewer
complications. Nonetheless, completion of a surgical entero-enterostomy in the setting of
chronic illness and profound immunosuppression is associated with significant surgical
complications. In general, 10% of pancreas transplants result in a peri-pancreatic leak or
abscess (Englesbe et al., 2006b; Troppmann et al., 1998). These complications can have
devastating implications and potentially be associated with mortality. Peri-pancreatic leaks
are generally managed with percutaneous drainage and antibiotics. Surgeons focus signifi-
cantly on the well-being of the transplanted kidney in patients with septic complications of the
pancreas transplant. As a result, early transplant pancreatectomy may be needed in order to
mitigate deleterious effects on the kidney transplant of aggressive therapies used to manage
the complications of the pancreas transplant.
4 The Financial Implications of Complications
Hospital administrators and insurance providers are well aware of the high cost of surgical
complications. Data involving general surgery cases at the University of Michigan reported
median hospital costs (adjusted for case mix) were lowest for patients without complications
(4,487 dollars) compared with those with minor (14,094 dollars) and major complications
(28,356 dollars) (p < 0.001) (Dimick et al., 2004; Dimick et al., 2006). In the United States
Veteran’s Health Care System, reductions in post-surgical pneumonias alone have resulted in
annual savings of $9.3 million (Arozullah et al., 2000; Arozullah et al., 2001). Most impor-
tantly, surgical complications are costly for the patient, with associated suffering, delayed
return to normal function, and long-term disability. These costs have not specifically been
quantified. Overall, considering the therapeutic benefit of pancreas transplantation (which is
questionable for many patients), a close assessment of the financial implications of surgical
complications is important. Moreover, pancreas transplantation in the United States may be
utilizing excessive resources relative to the benefit it provides for patients.
4.1 Who Pays for Pancreas Transplant Complications?
Obviously, the patient pays the highest price for pancreas transplant complications. These
complications are common (reported as 38% in the largest series) and very morbid (Cohn
et al., 2007; Englesbe et al., 2006b). In addition, these complications are associated with high
rates of re-operation and prolonged lengths of stay. These complications may affect future
productivity, with associated costs to the patient and to society, in general.
The insurance provider also pays for pancreas transplant complications. In the United
States, approximately 60% of pancreas transplant recipients have Medicare as their primary
insurer (2007). Medicare is the national healthcare system within United States and it pays
for approximately 1,000 pancreas transplants per year. Though hospitals are paid by Medicare
a fixed rate for the care of a pancreas transplant patient, when patients have complications,
they frequently qualify for “outlier” payments. > Outlier payments protect hospitals from
significant financial loss when hospital charges are significantly in excess of the Medicare
prospective payment. Without outlier payments, hospitals might avoid caring for high-risk
patient populations.
Pancreas transplant recipients frequently qualify for outlier payments. Our group has
previously documented that insurers pay hospitals and additional $17,363 (2004 USD),
for care administered to patients with complications following pancreas transplant
(> Table 38‐3) (Cohn et al., 2007). As expected, complications were associated with more
hospital days immediately following the procedure (mean difference 5.7 days, P = 0.005) and a
trend toward more readmissions in the first 6 months.
Complications also affect the financial “bottom-line” for the hospital. In pancreas trans-
plantation, this effect is minimal (> Table 38‐2). Moreover, hospital costs increase when
patients have complications following pancreas transplantation, but reimbursements also
increase a similar amount. Surgical complications have been noted to be associated with
. Table 38‐3
The financial implications of pancreas transplant complications
No surgical Surgical
complication complication Difference
(N = 30) (N = 19) in median P-value
Total cost to hospital 92,917 108,431 15,514 0.03
Estimated hospital reimbursement 91,429 107,148 15,719 0.001
Estimated hospital margin (Profit) 1,488 1,283 205 0.21
Reimbursement for physician 2,512 2,921 409 0.14
services
Estimated total insurance liability 93,497 110,860 17,363 0.001
Financial data of patients with no surgical complication versus those with a surgical complication following
pancreas transplantation at the University of Michigan between 2002 and 2004 (Cohn et al., 2007)
significantly decreased profit margins for hospitals in liver transplantation and in general
surgery (Dimick et al., 2006; Englesbe et al., 2006a). Even though the direct effects on hospital
profit margins are less obvious in pancreas transplantation, complications among these patients
likely have deleterious effects on hospital finances. Moreover, direct financial calculations fail to
quantify opportunity costs for a medical center. If a medical center runs at capacity, having a
pancreas transplant patient occupying a bed for management of their surgical complications
prevents another, potentially “profitable” patient from occupying that bed. Thus, the perceived
increase in cost from complications may be higher for the medical center and the profit lower.
Pancreas transplant complications also have financial implications for the surgeon. Sur-
geons are paid modestly ($409) more for managing a patient that has a complication following
their pancreas transplant (Cohn et al., 2007). It is difficult to quantify true “costs” of care
administered by the surgeon. More specifically, it remains unclear how much additional time
is required for a surgeon to care for a patient following a pancreas transplant complication. In
addition, the opportunity costs of this additional surgeon time are almost impossible to
quantify. Nonetheless, it seems clear that there is a financial incentive for the surgeon to
avoid pancreas transplant complications.
4.2 The High Costs of Complications Invite Investment in Quality

Improvement
Quantifying and attributing the costs of surgical complications is important as payers and
hospitals consider future investments in quality improvement initiatives. Our work concludes
that, besides the patient, the payers bear the majority of the financial burden of pancreas
transplant complications. Within this context, focused quality improvement initiatives in
pancreas transplantation seem like a reasonable investment for large payers, such as Medicare.
Briefly, we will attempt to quantify the total insurer costs from pancreas transplant
complications in United States. Previous work reports a surgical complication rate of 38%
following pancreas transplantation. If we applied this complication rate to all pancreas trans-
plants performed in the U.S. during the year 2004 (N = 1,484), there were approximately
564 pancreas transplants with surgical complications across the country (2007). Using our
data, hospitals spent an additional $8.8 million, and insurance carriers reimbursed medical
centers an additional $9.8 million as a result of surgical complications associated with pancreas
transplantation. These large amounts of insurer pay-outs suggest a potential for significant cost
savings by insurers. Moreover, even though improvements in postoperative morbidity rates are
sufficient benchmarks for quality improvement, investment in efforts to improve surgical
quality may be financially beneficial for some large insurers, such as Medicare.
In the United States, data documenting the high costs of surgical complications has
compelled payers to become actively involved in quality improvement efforts. Even though
the total costs of complications to payers from pancreas transplant complications is rather
modest, it is easy to appreciate how surgical complications with common procedures will have
significant affects on insurer costs. In the state of Michigan, the primary private health insurer,
Blue Cross and Blue Shield of Michigan (BCBSM), has initiated an aggressive quality
improvement initiative in surgery (Englesbe et al., 2007). In contrast to more widely dis-
cussed “pay-for-performance” initiatives, the BCBSM program uses a novel format called “pay
for participation.” Hospitals willing to participate in the program receive a bonus on their
procedure specific reimbursement rates. The additional reimbursements more than cover the
costs of QI program participation for the hospital. Participation requires participation in
the American College of Surgeons-National Surgical Quality Improvement Program. Partici-
pating hospitals collect detailed data on the peri-operative characteristics and outcomes of
their patients. Hospital specific, risk-adjusted, outcome reports are made four times year.
These reports allow a single hospital to assess their performance relative to other hospitals
within the state of Michigan. In addition, results are discussed among a consortium
of surgeons representing each participating hospital, and best practice initiatives are shared
by the best performing institutions.
Among the 15 Michigan hospitals initially participating in this program, BCBSM reim-
bursed these hospitals and additional $89 million to pay for surgical complications. Clearly,
even modest reductions in surgical complication rates will have significant cost savings for
large insurers. BCBSM has invested heavily in quality improvement initiatives with a goal of
improving the healthcare of their patients, while at the same time reducing the costs of care.
Our initial experience with this cooperative model of quality improvement between the
hospitals and the payers has yielded encouraging results.
Summary Points
Pancreas transplantation offers a cure for diabetes mellitus for a subset of Type 1 diabetics.
Worldwide, pancreas transplantation has not received mainstream acceptance as treatment
of Type 1 diabetes, in part related to the severity of pancreas transplant complications.
The two most common surgical complications following pancreas transplantation include
infection and graft thrombosis.
Pancreas transplant complications are expensive for the patient, the payer, the hospital,
and the physician.
The payer bears the primary financial burden for pancreas transplant complications.
Quantifying and attributing the costs of surgical complications is important as payers and
hospitals consider future investments in quality improvement initiatives.
Investment in comprehensive quality improvement initiatives in pancreas transplantation
may offer significant return on investment for large payers, such as Medicare.
References
International Pancreas Transplant Registry. (2007). Dimick JB, Weeks WB, Karia RJ, Das S, Campbell DA Jr.
http://www.med.umn.edu/IPTR/annual_reports/ (2006). J Am Coll Surg. 202: 933–937.
2004_annual_report.html. Accessed 3/2008. Englesbe MJ, Dimick J, Mathur A, Ads Y, Welling TH,
Andreoni KA, Brayman KL, Guidinger MK, Sommers CM, Pelletier SJ, Heidt DG, Magee JC, Sung RS, Punch
Sung RS. (2007). Am J Transplant. 7: 1359–1375. JD, Hanto DW, Campbell DA Jr. (2006a) Am J
Arozullah AM, Daley J, Henderson WG, Khuri SF. Transplant. 6: 2978–2982.
(2000). Ann Surg. 232: 242–253. Englesbe MJ, Dimick JB, Sonnenday CJ, Share DA,
Arozullah AM, Khuri SF, Henderson WG, Daley J. Campbell DA Jr. (2007). Ann Surg. 246: 1100–1103.
(2001). Ann Intern Med. 135: 847–857. Englesbe MJ, Moyer A, Kim DY, Granger DK, Pietroski R,
Cohn JA, Englesbe MJ, Ads YM, Paruch JL, Pelletier SJ, Yoshida A, Arenas JD, Oh H, Pelletier SJ, Campbell
Welling TH, Sonnenday CJ, Magee JC, Punch JD, DA Jr., Punch JD, Magee JC, Gruber SA, Sung RS.
Campbell DA Jr., Sung RS. (2007). Am J Transplant. (2006b). Transplantation. 82: 136–139.
7: 1656–1660. Mitka M. (2007). Jama. 297: 2337–2338.
Danovitch GM, Cohen DJ, Weir MR, Stock PG, Sutherland DE, Gruessner RW, Dunn DL, Matas AJ,
Bennett WM, Christensen LL, Sung RS. (2005). Humar A, Kandaswamy R, Mauer SM, Kennedy WR,
Am J Transplant. 5: 904–915. Goetz FC, Robertson RP, Gruessner AC, Najarian JS.
Dimick JB, Chen SL, Taheri PA, Henderson WG, (2001). Ann Surg. 233: 463–501.
Khuri SF, Campbell DA Jr. (2004). J Am Coll Surg. Troppmann C, Gruessner AC, Dunn DL, Sutherland DE,
199: 531–537. Gruessner RW. (1998). Ann Surg. 227: 255–268.
39 The Use of
Pharmacoepidemiological
Databases to Assess Disease
Burdens: Application to
Diabetes
H. Støvring
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
2 What is a Pharmacoepidemiologic Database? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
3 Gross Volume Studies: Diabetes Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
4 Individual Level Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676

4.1 Individual Treatment Status Ascertainment Based on Decision Rules . . . . . . . . . . . . . . 676
4.2 Waiting Time Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
4.3 Beyond Prevalence: Incidence and Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
5 Summary and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683

672 39 The Use of Pharmacoepidemiological Databases to Assess Disease Burdens
Abstract: Assessing the disease burden of diabetes in general populations is important for
planning and monitoring public health initiatives. > Prevalence is the relative frequency of
diseased subjects in a population, and is the default measure of disease burden. Traditional
epidemiological methods for estimating prevalence are however costly, and so it has been
suggested to exploit the advent of large scale pharmacoepidemiological databases for estimat-
ing diabetes prevalence, as these databases are available at nominal costs. In this paper we
review how information on either gross volume sales of anti-diabetic agents or on prescription
redemptions have been used to estimate the prevalence of diabetes, as well as > incidence and
> mortality among treated. For studies based on gross volume sales, the critical prerequisite is
to obtain valid estimates of average drug consumption among treated diabetics. Studies based
on individual level information on prescription redemptions requires determination of
treatment status, either explicitly via decision rules or implicitly via a stochastic model. For
the latter, the > Waiting Time Distribution has been suggested. While prevalence estimates
based on > pharmacoepidemiologic databases are found to underestimate overall prevalence
of diabetes – by definition, they only concern diabetics treated pharmacologically – good
agreement is found with respect to trend estimates of both prevalence, incidence, and
mortality among diabetics. Pharmacoepidemiologic databases can therefore be a valuable
source of data for cost-effective monitoring of developments in the disease burden of diabetes.
List of Abbreviations: > ATC, anatomic-therapeutic-chemical; > CDD, consumed daily
doses; > DDD, defined daily doses; NHANES, national health and nutrition examination
> survey; > PDD, prescribed daily doses; UKPDS, United Kingdom prospective diabetes study
1 Introduction
> Diabetes mellitus – or just diabetes – is a metabolic disorder with chronic > hyperglycemia
caused by defects in > insulin secretion, insulin action, or both. A readable, general descrip-
tion of the disease is given by World Health Organization Department of Noncommunicable
Disease Surveillance (1999). Diabetes has severe consequences for afflicted individuals in the
form of excess mortality (Saydah et al., 2002) and elevated comorbidity with cardiovascular
disease, kidney disease and eye complications as prominent examples (Stratton et al., 2000).
But also as diverse diseases as tuberculosis (Stevenson et al., 2007) and depressions (Ludman
et al., 2004) have been linked to diabetes, as well as loss of active everyday life, occurrence of
disability, and unemployment (Korff et al., 2005).
From the perspective of society, diabetes has severe consequences in the form of increased
costs, both due to loss of productive work years (Vijan et al., 2004) and the need for health care
services (Chaturvedi, 2007). This cost increase has been found in many different countries, see
for example (Bradshaw et al., 2007; Dawson et al., 2002; Hogan et al., 2003; Khowaja et al.,
2007; Köster et al., 2006). Furthermore, the burden is estimated to continue its increase
globally at least 20 years into the future with a projected doubling in prevalence from year
2000 to 2030 (Wild et al., 2004). For the United States, Honeycutt et al. (2003) projected an
increase until at least 2050 with an increase from 4.4% in year 2000 to 9.7% in 2050, even when
assuming constant incidence and constant relative mortality due to diabetes. Both assump-
tions are likely conservative, in that incidence will realistically increase and relative mortality
decline – both of which will lead to even higher prevalence (Narayan et al., 2006).
The Use of Pharmacoepidemiological Databases to Assess Disease Burdens 39 673
Given the severe consequences diabetes has on individuals and societies, the disease
has been the focus of much epidemiologic research trying to measure its magnitude and
development in general populations, as is partly reflected in references above. While preva-
lence is the primary measure of disease burden, incidence and mortality are at least as
important when focus is on describing and understanding changes in disease burden over
time. The efforts of measuring the disease burden can roughly be grouped into three distinct
types of studies: Surveys on a random sample of the population, cohort studies with follow-
up, and studies based on routinely collected data of health care events. Pharmacoepidemio-
logic databases are examples of the latter category.
Advantages and challenges of each of these study methodologies follow common knowledge
of traditional epidemiology. Well conducted surveys give reliable information on the prevalence
of diabetes, typically accompanied by detailed information on patients regarding clinical, socio-
economic, and demographic characteristics. Examples of such surveys are the study by Green
et al. (1981), and the National Health and Nutrition Examination Survey (NHANES) (Cowie
et al., 2006). The primary limitation of surveys is that by definition they provide a snapshot
only of the situation at a single point in time. This makes it difficult to analyze trends over
time, although sometimes for example date of first diagnosis from a survey can be combined
with external data to allow analysis of past trends in incidence (Keiding et al., 1989). Cohort
studies do not suffer from this shortcoming, as they follow a well-defined group of subjects
over a given time period. It is important to distinguish between two general types of cohort
studies characterized by whether or not members of the cohort all suffer from diabetes
at inclusion. The United Kingdom Prospective Diabetes Study (UKPDS) is an example of a
> cohort study which follows diabetics, and so is primarily useful for studies of comorbidity,
secondary prevention and mortality among diabetics, cf. (UKPDS Study Group, 1991). The
study by Jagger et al. (2003) included subjects above age 75, both with and without diabetes in
a survey and then followed them up via registers which allowed studying comorbidity and
mortality relative to the general population. Both types of studies are costly and time
consuming, and so cannot be conducted widely on a regular basis. This limitation is overcome
by routinely collected data of health care events, typically in the form either of physician
contacts labeled with a diagnosis of diabetes, or consumption of certain drugs indicative of
diabetes. As such data are often routinely collected electronically for administrative purposes
(allocating fees for services rendered and/or reimbursement of patients) they are available at a
nominal cost, allows near continuous updating of analyses, and provide wide coverage of the
general populations. Utilizing such data does, however, present unique challenges, as we will
review below.
In this paper we review the results obtained with pharmacoepidemiologic databases
in measuring the population burden of diabetes with particular focus on the associated
methodological challenges. The review is organized as follows: Section 2 introduces and
defines pharmacoepidemiologic databases, and gives examples on the types of data
collected. Next, Section 3 reviews studies on prevalence based on aggregated, gross
volume sales data, before Section 4 reviews studies based on pharmacoepidemiologic data-
bases with information at the individual level. The final Section 5 briefly summarizes
results and outlines main challenges in using pharmacoepidemiologic databases for monitor-
ing the diabetes burden in general populations, possibly in combination with other data
sources.
2 What is a Pharmacoepidemiologic Database?
Pharmacoepidemiologic databases can loosely be defined as registers containing information

on medication dispensing for large groups of individuals, even populations. Considerable
variation exist between databases in the type and detail of information collected, but three
main types can be identified according to their content: Gross volume sales databases,
databases with individual prescription histories only, and databases integrating prescription
events with other health care events.
Gross volume sales databases record the total amount of drugs sold within a well-defined area
and time period. For example, such data are available for most OECD countries (OECD
Publishing, 2007). Data are available for subclasses of drugs defined by the so-called Anatomic-
Therapeutic-Chemical (ATC) code. Maintained by the World Health Organization, the ATC
system identifies drugs by a five level code consisting of seven digits (The WHO Collaborating
Centre for Drug Statistics Methodology, 2001). The first three levels indicate the anatomic system
targeted by the drug, the intended therapeutic effect of the drug, and its chemical composition,
respectively. For our purposes it suffices to know that all anti-diabetic drugs are identified by the
first three characters in the ATC code being ‘‘> A10.’’ Insulin drugs all have the code ‘‘> A10A’’ as
their initial four characters, while oral anti-diabetic drugs are uniquely identified by the initial
ATC code of ‘‘> A10B.’’
Pharmacoepidemiologic databases of individual prescription histories are found mostly
in Scandinavia, and are currently operative in Denmark, Finland, Iceland, Norway, and
Sweden. The first national database to be established was the Danish, which started in 1990,
but data are only available for research from 1995 and onwards. From 1992, the Danish data has
also been available in independent regional databases, each covering several hundred thousand
inhabitants. The Scandinavian registers all record dates of individual prescription redemptions
at pharmacies, together with a unique person identification number, information on drug type
and amount dispensed, and often some information on prescribing physician. The drug type is
recorded by ATC code. The registers do generally not contain reliable information on indica-
tion (> indication for treatment) and prescribed daily dose. A more thorough presentation of
the Danish register(s) – which is representative of the Scandinavian pharmacoepidemiologic
databases – and the ATC code system can be found in Hallas and Nissen (1994) and Gaist et al.
(1997). Note, that although these registers only record prescription redemptions, the unique
subject identifier key is also used in other official registers, such as for example hospitalization
records, disease specific registers, sociodemographic registers, and cause of death registers. The
pharmacoepidemiologic databases can thus be linked with these registers.
The integrated pharmacoepidemiologic databases have a wider scope than the purely
medication oriented databases. The primary example of such a database is the General Practice
Research Database (GPRD) of the UK (Walley and Mantgani, 1997), but also claims databases
of American Health Maintenance Organizations (Strom et al., 1985) belongs to this class of
databases. They are characterized by collecting information on all types of health care events
for associated subjects. This allows for studying use of particulars drugs among subjects with a
specific diagnosis. Further, these databases by default provide detailed clinical profiles on all
individuals. Thus, diabetics can in these databases be identified not only from their redemp-
tions of specific drugs, but also from laboratory tests or an explicit diagnosis. From this
perspective, integrated pharmacoepidemiologic databases requires no specific methodology
for analysis. They can be analyzed directly with respect to diagnosis data as in (Evans et al.,
2007), or with methods similar to those for pharmacoepidemiologic databases with prescrip-
tion events only. We will therefore not go into further detail for this class of databases.
3 Gross Volume Studies: Diabetes Prevalence
The fundamental idea of studies based on gross volume sales is to estimate prevalence from a
division of the total amount sold within a given population and a specified time period by
the average consumption of a diabetes patient. This strategy was most prominently applied
by the EURODIAB Subarea C study group in the early 1990s (Papoz, 1993; Walckiers et al.,
1992), but also more recently by Duarte-Ramos and Cabrita (2006).
The critical step in these studies is getting a good estimate of average drug consumption
for the relevant population and for the relevant drug classes. Three different measures of
consumption have been suggested, Defined Daily Doses (DDD), Prescribed Daily Doses
(PDD), and Consumed Daily Doses (CDD). While CDD in principle may be considered the
most meaningful measure, since it directly represents actual consumption, it can only be
obtained by asking patients – which may make it subject to recall bias – or by observation of
patients – which is infeasible and may induce changes in compliance. DDD is on the other
hand a theoretical construct, as it is defined by international experts in the field to be the
average dose used by adults with the main indication for the drug. This may not represent
actual, average drug use well – for example, Papoz (1993) found substantial variation between
countries in the daily dose used of oral anti-diabetic agents. The PDD is a reasonable
alternative which can be obtained from physician’s medical records with relative ease. Further,
for a disease as severe as diabetes, prescribed medications are most likely redeemed and
consumed, and so PDD will be close to CDD.
The main study using this approach is the EURODIAB Subarea C study reported by
Papoz (1993). They obtained total sales volumes from samples of pharmacies and information
on PDD from a variety of country-specific sources in 11 countries. Two countries, Spain
and Italy, were only represented with a small region each, not representative of their respec-
tive country. The data obtained from Romania was considered unreliable, which made
the methodology inadequate for this country. Papoz (1993) estimated PDD for three
subgroups of drugs, Insulin, > Sulfonylureas, and > Biguanides, as well as the fraction of
patients treated with combinations of the three. They finally estimated the fraction of patients
not receiving pharmacological treatment, i.e., treated with diet alone. In some countries
it was also possible to get direct estimates of diabetes prevalence which allowed validation
of the approach.
While prevalence was rather homogeneous for insulin treated diabetes, variation
between countries was found for orally treated diabetes (Sulfonylureas and Biguanides com-
bined) and diabetes treated with diet only. Total prevalence of diabetes varied from 1.6% in
Northern Ireland and Switzerland to 4.7% in Malta. Reasonable agreement with direct
estimates was found in all four countries where this was possible, although the pharmacoe-
pidemiologic approach consistently underestimated prevalence. Papoz (1993) did not report
gender and/or age specific estimates, which would have required average consumption for
gender and age specific strata, as well as estimates of gender and age composition of the
studied population.
Subsequently, Sartor and Walckiers (1995) presented a more detailed analysis of diabetes
prevalence in Belgium in 1990 built on the same data. This paper also contains a thorough
exposition of the methodology and an excellent discussion of its potential and challenges.
The most recent study using this methodology was made in Portugal by Duarte-Ramos
and Cabrita (2006), who found a diabetes prevalence of 2.52% when using DDD as
measure of average consumption, and 2.72% when instead using PDD.
4 Individual Level Data
When individual level data is available on drug dispensing, it in principle becomes possible to
count subjects instead of drug units. If the size of the source population is known either from
within the pharmacoepidemiologic database or from external sources, then prevalence can be
estimated directly from a count of drug users. The key challenge is how to identify a subject as
user of a drug at a given time point, since information on actual, daily treatment status is not
available, but only dates of prescription redemptions. While this may seem simple, it is actually
surprisingly difficult (Hallas and Stovring, 2006). The problem has been tackled using two
different approaches: decision rules (Mantel-Teeuwisse et al., 2001; Støvring et al., 2003, 2007),
and the Waiting Time Distribution method (Hallas et al., 1997; Støvring and Vach, 2005).
Recent reviews of these methods were given by Hallas (2005) and Hallas and Stovring (2006).
4.1 Individual Treatment Status Ascertainment Based

on Decision Rules
All methods based on decision rules try to establish treatment status at a given date based on a
fixed algorithm applied to the observed redemptions. The approaches can be further sub-
divided into two types according to whether or not they take into account the dose dispensed
at the prescription redemption.
Let us first consider the method which does not take account of the dispensed dose, the
so-called > run-in period method. The run-in period method can be described as in the graph
of > Figure 39-1. Among all present throughout the run-in period, treatment status at the
> index date (t0) is determined by observation of prescription redemptions during the run-
in period. In the graph there are thus two prevalent subjects and three non-prevalent subjects,
of which one initiates treatment after the index date.
The crucial aspect of determining treatment status with the run-in method is thus how
to choose an appropriate length of the run-in period. Two strategies exist for choosing
this length.
The first method is to use all available information prior to the index date, cf. for example the
papers by Lipworth et al. (2004) and Vestergaard et al. (2004). Several more examples exist of
papers using this approach, although many of them will not state explicitly the use of this method.
Typically, not all individuals are under observation for equal lengths of time, and so one may view
this approach as using individual run-in periods. The implicit rationale is to maximize precision
in determining treatment status, since it maximizes the chance of observing an individual’s
prescription redemptions, if any. But, since observation periods vary between individuals, so does
the chance of observing eventual events, which leads to differential misclassification of subjects.
Consider for example an individual who moves into the capture area 1 week before the index date.
Even though the individual may be a regular user of anti-diabetics, the chance of observing a
prescription redemption is much smaller than for another regular user who has been present
since start of the database, say, 5 years before. In particular, when calendar time trends are of
interest, this method cannot be recommended as it will bias any trend estimates: Even absent
any true trend in prevalence, estimates of prevalence will increase, since the chance of observing
a prescription redemption will increase with time.
The second method for choosing the length of the run-in period uses a combina-
tion of clinical reasoning and observed patterns of redemption events (Glynn et al., 1999;
. Figure 39-1
Graphical presentation of the run-in method. Treatment status at the index date, t0, is
defined from observation of prescription redemptions during the run-in period (gray area).
Only black events are observed
Støvring et al., 2003, 2007). For example, Green et al. (1981) found that for insulin dependent
diabetes, very good agreement existed between treatment status at a given date and observa-
tion of prescription redemptions of insulin within a preceding 6-month run-in period. Glynn
et al. (1999), however, found a low agreement between use of anti-diabetic agents within
120 days preceding hospitalization and the discharge diagnosis. Another approach which does
not require observation of actual treatment status at the index date, is to examine the individual
patterns of prescription redemptions, often by visualizing a random sample of patients. From
this it may become apparent that most regular users will renew their prescriptions within
some given time period, the length of which can then be used for the run-in period. Another
variant of this approach is more indirect as it considers the resulting prevalence estimates. An
example of this approach was given by Støvring et al. (2007), who compared prevalence
estimates based on run-in periods of length 1 and 2 years, respectively. With a run-in period
of 1 year, it became apparent that stockpiling was taking place during year 2000, as there was an
artificial jump in prevalence in 2001 with a subsequent fall in 2002. This could be explained by
a change in reimbursement policy in year 2000. When instead a 2-year period was used, the
jump was smoothed out, as prevalence then increased steadily over the calendar years studied,
1994–2003. While prevalence differed depending on the length, estimates of calendar time
trend in prevalence were unaffected.
The other type of fixed decision rules are based on dispensed doses, and attaches what
Mantel-Teeuwisse et al. (2001) termed a > legend duration to each prescription redemption.
Assuming an average daily dose, the period is calculated for which the redeemed prescription
provides medication, as illustrated in > Figure 39-2.
. Figure 39-2
Methods for determining legend duration. Schematic representation of the four different
methods used for data handling before estimating point prevalence of cholesterol-lowering
drug use by using pharmacy records. In this example, a patient filled three prescriptions for the
same drug (same strength and prescribed daily dose). Legend duration for each prescription is
30 days. Method 1: no data handling was applied. Method 2: legend duration was arbitrarily
multiplied by a factor 1.1. Method 3: subsequent prescriptions were ‘‘pasted.’’ The new
dispensing date of the second drug was artificially reset to the theoretical end date of the
first drug. Method 4: because the time-span between two subsequent periods of drug use was
<30 days after pasting, an episode of drug use was constructed. On point A in time, this patient
is a prevalent user according to methods 2, 3 and 4. On point B in time, this patient is a prevalent
user according to all methods (from Mantel-Teeuwisse et al. (2001) (http://www.sciencedirect.
com/science/journal/08954356))
Mantel-Teeuwisse et al. (2001) evaluated four different strategies of this type, although not
in relation with diabetes. It was concluded that differences were small between all four
strategies with respect to estimated prevalence of treatment with cholesterol-lowering drugs.
Mantel-Teeuwisse et al. (2001) finally considered period prevalence which they found to
differ substantially from the point prevalence estimated by their other approaches. By definition,
period prevalence makes no distinction between incident use, continued and discontinued use, as
long as it occurs within the study period, and so this difference is hardly surprising. From an
epidemiological point of view, point prevalence is the preferred measure of disease burden, as it is
more readily interpretable.
Results of applying a run-in period to estimate diabetes prevalence were reported by
Støvring et al. (2003, 2007) and Støvring (2007), all studies based on a database covering the
Danish County of Fyn with a population of approximately 470,000 subjects. With a 1-year run-
in period, prevalence was found to increase steadily with approximately 4% per year (Støvring
et al., 2007) from 14.2 per thousand in 1993 to 21.6 per thousand, 10 years later in 2003.
The two main problems with all variants of decision rules is first that they do not allow for
the inherent uncertainty in assignment of treatment status in subsequent prevalence estimates,
and second that they mandate exclusion of subjects migrating into the capture area during the
run-in period to avoid differential misclassification.
4.2 Waiting Time Distribution
It was in the context of identifying new users that Hallas et al. (1997) first considered the
Waiting Time Distribution, as a graphical tool to assist in this process. Briefly, the idea of
Hallas et al. (1997) was to look at time from a fixed date until the first prescription redemption
of each individual. A histogram of these times will peak initially due to regular users renewing
their prescriptions, but eventually it will level off and approach a more or less constant level
representing subjects who initiate treatment. The method is, however, also useful for estimat-
ing prevalence of drug use. Hallas et al. (1997) suggested using a graphical approach based on
relative areas of the histogram, whereas Støvring and Vach (2005) suggested formalizing the
approach to allow parametric, statistical analysis of the distribution. An example of a Waiting
Time Distribution is shown in > Figure 39-3.
As the method does not require a run-in period and can accommodate censoring after the
index date, the prevalence at the index date can be estimated for the entire population. This
feature was exploited by Støvring (2007) to study if the use of a run-in period lead to selection
bias in studies of diabetes prevalence. While the overall bias was small, it was found to be
substantial for ages 20–40, but could in older age categories be controlled by accounting for
age in prevalence estimates, i.e., conditional on age, the subjects arriving in the run-in period
had a prevalence similar to the remaining population. Støvring (2007) found a small bias in
uncertainty estimates when using the run-in period.
4.3 Beyond Prevalence: Incidence and Mortality
While prevalence is the primary measure for diseases burden, it is governed by in- and outflow,
ie., incidence and discontinuance of treatment. If treatment was regular and lifelong, then
onset of treatment would correspond to ordinary incidence and only death would terminate
treatment. However, even for a chronic disease as diabetes, pharmacological treatment is for
some patients with type II diabetes periodic. While this is not the case for type I diabetes – who
depend upon continued insulin treatment throughout life – these cannot be identified with
any reasonable level of confidence, as most users of insulin are type II diabetics – Sartor and
Walckiers (1995) found 67% of all treated with insulin to have type II diabetes. Analyses
trying to understand shifts in prevalence due to changes in incidence and mortality should
take this into account. A natural model for studying the relations between incidence of
treatment, discontinuance, and death on the one hand and prevalence on the other, is thus
the model shown in > Figure 39-4.
This model was applied to data from Odense PharmacoEpidemiologic Database on
the population in Fyn County, Denmark, in the period 1993–2003 by Støvring et al. (2007).
. Figure 39-3
Waiting Time Distribution for redemption of anti-diabetic agents, Fyn County, Denmark, 2003.
Data from Odense PharmacoEpidemiologic Database, n = 472, 672, and analyzed as described in
(Støvring, 2007). The histogram represents observed counts, the smooth curve the fitted Waiting
Time Distribution. Prevalence was estimated at 19.5 per 1,000, 95% confidence interval
(19.1; 20.0)
. Figure 39-4
Illness death model with recovery. Conceptual model for analyzing how prevalence depends on
incidence, discontinuance, and death
They found that age specific prevalence and incidence increased approximately 4–5% per year
for both genders, while age specific mortality among treated declined approximately 2.5% per
year, again for both genders, cf. > Figure 39-5. The decline in mortality among treated
exceeded the contemporaneous decline among non-treated of approximately 1.5%.
. Figure 39-5
Prevalence, incidence and mortality for treatment of diabetes, Fyn County, Denmark,
1994–2003. Prevalence, incidence and mortality estimates stratified by gender and age.
Line-styles indicates age-categories in years: – 0–14, 15–39, 40–64, 65+. Data from Odense
PharmacoEpidemiologic Database. Reprinted from Støvring et al. (2007), published by
BioMed Central
Framing the analysis in the model depicted in > Figure 39-4 makes it clear that prevalence
is a secondary measure in the sense, that it is controlled by incidence, discontinuance and
death among treated. Further, the model suggests to study the relative importance of changes
in incidence and/or mortality on concurrent prevalence. Støvring et al. (2007) used this
approach to study how prevalence would have developed over the period 1994–2003 on
Fyn, if either age specific incidence or mortality rates had been held constant over the period,
cf. > Figure 39-6.
. Figure 39-6
Observed and predicted prevalences with respect to use of anti-diabetic drugs, Fyn County,
Denmark, 1994–2003. Predicted prevalence is based on fixation of the indicated rates with
respect to their 1994-level. Data from Odense PharmacoEpidemiologic Database. Reprinted from
Støvring et al. (2007), published by BioMed Central
The primary result was that even if both incidence and mortality had been constant,
then prevalence would have increased over the period, although not as much as observed.
This was due to incident cases consistently outnumbering cessation and deaths among treated,
a consequence of the diabetes population not being in epidemiological equilibrium. The
second finding was that increasing incidence was more influential than declining mortality.
These findings coincide with those of Evans et al. (2007) and Lipscombe and Hux (2007), who
both based their analyses on diagnosis data.
5 Summary and Perspectives

Diabetes is a unique disease from a pharmacoepidemiologic perspective as it can only be treated
pharmacologically with drugs of a very specific type, and these drugs are not used for other
diseases. While it is not a new idea to use this link for assessing disease burden of diabetes, the
emergence of large scale pharmacoepidemiologic databases with individual level information has
created new possibilities for routine monitoring of diabetes burden and associated trends. Even
when individual level data are not available, the unique link allows using data on gross volume
sales of anti-diabetic drugs together with sampled information on average consumption to
estimate prevalence. Although the latter method requires a sample of diabetic subjects to estimate
average consumption, it is still a more cost-effective study design than traditional epidemiological
designs. In one aspect, studies based on gross volume sales is even superior to studies on
individual level data, as it will also estimate the prevalence of non-pharmacologically treated
diabetes. Individual level data do, however, give more detailed information, and in particular
allow studying trends not only in prevalence, but also in incidence, discontinuance, and mortality
among treated.
The main problem of all pharmacoepidemiologic studies on disease burden of diabetes, is
the inherent dependence on prescribing patterns. If, for example, diabetes becomes more
aggressively treated by physicians over a period of time – as documented by Walley et al.

(2005) – then this will in itself cause an increase in both incidence and prevalence of
pharmacologically treated diabetes. One must therefore be careful in interpreting estimates
pertaining to pharmacologically treated diabetes with respect to all diabetes. This is, however,
not a problem only for pharmacoepidemiologic studies, but is equally relevant to studies based
on other routinely collected health events, such as for example diagnosis coded contacts with a
physician.
While pharmacoepidemiologic databases with individual level data have provided a signifi-
cant step forward in allowing surveillance of diabetes on general populations, they may well be
obsoleted for this purpose in the coming years. Recently, several new databases have emerged
which integrate pharmacy-records with other kinds of health events. In such databases, the use of
actual diagnoses should supersede data on pharmacological treatment. On the other hand
pharmacoepidemiologic data will remain valuable for studies of disease progression and treat-
ment, both with respect to quality improvement and adherence.
Summary Points
Diabetes is a severe disease which increases risk of disability and mortality for afflicted
individuals.
Diabetes is costly to society due to patient’s needs for medical treatment and health care,
and loss of productive life-years.
A unique set of pharmaceutical drugs (anti-diabetic drugs) are used exclusively to treat
diabetes.
Pharmacoepidemiologic databases provide a cost-effective alternative to traditional stud-
ies of the disease burden of diabetes.
Valid analysis of data from pharmacoepidemiologic databases require dedicated methods
for assessment of treatment status.
Disease burden of diabetes is growing rapidly throughout the world.
Incidence of diabetes is currently rising.
Mortality among diabetics is currently declining.
Appendix
Key Facts of Pharmacoepidemiology

Pharmacoepidemiology measures drug utilization in general populations and its effects.
Pharmacoepidemiologic databases collects information on dispensed medications within a
defined region and time period.
Pharmaceutical drugs are classified according to their targeted anatomical system,
intended therapeutic effect, and chemical composition in the ATC system.
Electronic pharmacoepidemiologic databases with individual level information covering
entire populations have been established in Scandinavian countries since 1990.
References
Bradshaw D, Norman R, Pieterse D, Levitt NS. (2007). Mantel-Teeuwisse A, Klungel O, Verschuren W,

South African Comparative Risk Assessment Colla- Porsius A, de Boer A. (2001). J Clin Epidemiol.
borating Group. S Afr Med J. 97: 700–706. 54:1181–1186.
Chaturvedi N. (2007). Diabetes Res Clin Pract. 76 Narayan KMV, Boyle JP, Geiss LS, Saaddine JB,
(Suppl. 1): S3–12. Thompson TJ. (2006). Diabetes Care. 29:
Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, 2114–2116.
Flegal KM, Engelgau MM, Saydah SH, Williams DE, OECD Publishing. (2007). OECD Health Data 2007:
Geiss LS, Gregg EW. (2006). Diabetes Care. 29: Statistics and Indicators for 30 Countries. URL
1263–1268. http://www.oecd.org/health/healthdata
Dawson KG, Gomes D, Gerstein H, Blanchard JF, Papoz L. (1993). Epidemiology. 4: 421–427.
Kahler KH. (2002). Diabetes Care. 25: 1303–1307. Sartor F, Walckiers D. (1995). Am J Epidemiol. 141:
Duarte-Ramos F, Cabrita J. (2006). Pharmacoepidemiol 782–787.
Drug Saf. 15: 269–274. Saydah SH, Eberhardt MS, Loria CM, Brancati FL.
Evans JMM, Barnett KN, Ogston SA, Morris AD. (2007). (2002). Am J Epidemiol. 156: 714–719.
Diabetologia. 50: 729–732. Stevenson CR, Critchley JA, Forouhi NG, Roglic G,
Gaist D, Sorensen H, Hallas J. (1997). Dan Med Bull. 44: Williams BG, Dye C, Unwin NC. (2007). Chronic
445–448. Illn. 3: 228–245.
Glynn RJ, Monane M, Gurwitz JH, Choodnovskiy I, Støvring H. (2007). Pharmacoepidemiol Drug Saf. 16:
Avorn J. (1999). Am J Epidemiol. 149: 541–549. 681–686.
Green A, Hauge M, Holm N, Rasch L. (1981). Støvring H, Andersen M, Beck-Nielsen H, Green A,
Diabetologia. 20: 468–470. Vach W. (2003). Lancet. 362: 537–538.
Hallas J. (2005). Pharmacoepidemiol Drug Saf. 14: Støvring H, Andersen M, Beck-Nielsen H, Green A,
455–463. Vach W. (2007). Popul Health Metr. 5: 2.
Hallas J, Gaist D, Bjerrum L. (1997). Epidemiology. 8: Støvring H, Vach W. (2005). Stat Med. 24: 3139–3154.
666–670. Stratton I, Adler A, Neil H, Matthews D, Manley S,
Hallas J, Nissen A. (1994). Eur J Clin Pharmacol. 47: Cull C, Hadden D, Turner R, Holman R. (2000).
367–372. BMJ. 321: 405–412.
Hallas J, Stovring H. (2006). Basic Clin Pharmacol Strom BL, Carson JL, Morse ML, LeRoy AA. (1985). Clin
Toxicol. 98: 260–265. Pharmacol Ther. 38: 359–364.
Hogan P, Dall T, Nikolov P, Association AD. (2003). The WHO Collaborating Centre for Drug Statistics
Diabetes Care. 26: 917–932. Methodology. (2001). ATC Index with DDDs and
Honeycutt AA, Boyle JP, Broglio KR, Thompson TJ, Guidelines for ATC Classification and DDD Assign-
Hoerger TJ, Geiss LS, Narayan KMV. (2003). Health ment, Oslo.
Care Manag Sci. 6: 155–164. UKPDS Study Group. (1991). Diabetologia. 34: 877–890.
Jagger C, Goyder E, Clarke M, Brouard N, Arthur A. Vestergaard P, Rejnmark L, Mosekilde L. (2004). Epilep-
(2003). J Public Health Med. 25: 42–46. sia. 45: 1330–1337.
Keiding N, Holst C, Green A. (1989). Am J Epidemiol. Vijan S, Hayward RA, Langa KM. (2004). Health Serv
130: 588–600. Res. 39: 1653–1669.
Khowaja LA, Khuwaja AK, Cosgrove P. (2007). BMC Walckiers D, der Veken JV, Papoz L, Stroobant A. (1992).
Health Serv Res. 7: 189. Eur J Clin Pharmacol. 43: 613–619.
Korff MV, Katon W, Lin EHB, Simon G, Ciechanowski P, Walley T, Hughes D, Kendall H. (2005). Pharmacoepide-
Ludman E, Oliver M, Rutter C, Young B. (2005). miol Drug Saf. 14: 769–773.
Diabetes care. 28: 1326–1332. Walley T, Mantgani A. (1997). Lancet. 350: 1097–1099.
Köster I, von Ferber L, Ihle P, Schubert I, Hauner H. Wild S, Roglic G, Green A, Sicree R, King H. (2004).
(2006). Diabetologia. 49: 1498–1504. Diabetes Care. 27: 1047–1053.
Lipscombe LL, Hux JE. (2007). Lancet. 369: 750–756. World Health Organization Department of Noncommu-
Lipworth L, Friis S, Blot WJ, McLaughlin JK, nicable Disease Surveillance. (1999). Definition,
Mellemkjaer L, Johnsen SP, Nørgaard B, Olsen JH. Diagnosis and Classification of Diabetes Mellitus
(2004). Am J Ther. 11: 156–163. and its Complications; Part 1: Diagnosis and Classi-
Ludman EJ, Katon W, Russo J, Korff MV, Simon G, fication of Diabetes Mellitus. URL http://whqlibdoc.
Ciechanowski P, Lin E, Bush T, Walker E, Young B. who.int/hq/1999/WHO_NCD_NCS_99.2.pdf
(2004). Gen Hosp Psychiatry. 26: 430–436.
40 Years of Life Lost Due to
Air Pollution in Switzerland:
A Dynamic Exposure-
Response Model*
M. Röösli
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686
2 Description of the Dynamic Exposure-Response Model . . . . . . . . . . . . . . . . . . . . . . . . . . . 687

2.1 Derivation of the Exposure-Response Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
2.2 Derivation of the Decay Constant K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
2.3 Application to Switzerland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
3.1 Association Between Air Pollution and Mortality: Exposure
Response Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
3.2 The Decay Constant K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
3.3 Years of Life Lost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
4 Methodological Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694

4.1 Strengths and Weaknesses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
4.2 Comparison with Other Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
* (Update for 2005)

686 40 Years of Life Lost Due to Air Pollution in Switzerland: A Dynamic Exposure-Response Model
Abstract: There is debate on how the effect of air pollution should be assessed. The dynamic
exposure-response model integrates data from long-term epidemiological studies and studies
of interventions to reduce pollution to estimate the impact of air pollution on adult and infant
mortality. Based on this method > years of life lost (YLL) attributable to air pollution during 1
year in Switzerland were calculated.
A dynamic exposure-response model was implemented, which uses an exponential func-
tion (expkt) to model the change in mortality after cessation of air pollution. The model was
populated with relative risk estimates and estimates of decay constant k from the literature. Air
pollution exposure in Switzerland was modeled using data from emission inventories. YLL
attributable to air pollution were calculated by taking the difference between observed survival
probabilities in Switzerland in 2005 and modified survival probabilities, assuming a low
> PM10 level of 7.5 mg/m during the year 2005.
3
Meta-analyses of three studies of adult mortality and five studies of infant mortality gave
relative risks of 1.059 (95% confidence interval (CI): 1.031–1.088) and 1.056 (95% CI 1.026–
1.088) per 10 mg/m3 increase in PM10 concentration. Decay constants k derived from two
studies of the effects of closing down a steel mill in the Utah Valley and of the coal ban in
Dublin were 0.88 and 0.11 per year. Assuming a decay constant k of 0.5 per year resulted in
48,200 (95% CI 25,600–72,000) YLL, with 3.6% being ascribed to infant deaths. Thirty-nine
percent of the effect occurred in the same year and 78% within 3 years.
In contrast to traditional steady-state models the dynamic model allows changes in
mortality following short-term increases or decreases in air pollution levels to be quantified.
This type of information is of obvious interest to policy makers.
List of Abbreviations: BS, black smoke; CI, confidence interval; DM, change in mortality in
percent years; ERR, > excess relative risk (¼RR-1); k, decay constant; PM, particulate matter;
PM10, Particulate matter with an aerodynamic diameter of <10 mm; RR, relative risk; t, time
(in years); TSP, total suspended particles; mg, microgram; YLL, years of life lost
1 Introduction
Although there is clear evidence that outdoor air pollution is a determinant of mortality at the
population level, it is less clear how exactly its impact should be assessed. Reliable estimation
of air pollution’s burden on the health of the public is essential to inform environmental
policy. Seminal early work focused on quantifying the acute, short-term effects of ambient air
pollution (Ostro, 1994). However, it has been widely recognized that, by design, > time series
studies are concerned with effects following exposure within a few days only (Künzli et al.,
2001). Thus, they are not suitable to quantify long term health impact. Effect estimates are an
order of magnitude lower than those obtained from cohort studies. Today, health impact
assessments are generally based on estimating morbidity and premature deaths (Boldo et al.,
2006; Cohen et al., 2005; Künzli et al., 2000; Mestl et al., 2007) as well as the number of years of
life lost (YLL) (Forsberg et al., 2005; Leksell and Rabl, 2001; Miller and Hurley, 2003; Rabl,
2003), using concentration-response functions derived from cohort studies with long-term
follow up. These studies assume that levels of air pollution vary across different population
groups but remain constant over time within groups. Thus, they are basically steady state
comparisons. However, there are situations when steady state information is not enough and
information about the change in risk after a change in the exposure is needed. For instances
policy makers may want to predict the health benefits before introducing a new air pollution
Years of Life Lost Due to Air Pollution in Switzerland: A Dynamic Exposure-Response Model 40 687
regulation. Information about the time course of the risk change is also needed for the
monetarily quantification of the external costs from air pollution if discount rates are taken
into account. Events that occur in the far future will have a different monetary value than
events at present.
Information about the temporal change in risk would be best obtained from studies that
investigated the health effects of an intervention that leads to sustained increases or decreases
in air pollution levels in a large population. Such interventions could be a change in laws or
regulations, or the start or end of operation of an air-polluting facility. Typically, an > inter-
vention study occupies the middle ground between cohort and time-series studies as effects
over a few months or years are investigated. Unfortunately, such studies are too rare to derive a
robust effect estimate.
For that reason I propose an approach to estimating the years of life lost, which integrates
data from long-term epidemiological studies and air pollution intervention studies.
This approach was developed to quantify years of life lost in Switzerland for the year 2000 (Röösli
et al., 2005). In this chapter I will describe the model and apply it to the estimation of the number
of years of life lost attributable to traffic related air pollution in Switzerland in the year 2005.
2 Description of the Dynamic Exposure-Response Model
Based on work by Leksell and Rabl (2001), I developed a concentration-response model, which
estimates the course of mortality after a sudden reduction of air pollution exposure. A
reference scenario based on observed survival probabilities with the actual PM10 levels, was
compared with a hypothetical scenario where PM10 levels in Switzerland were reduced to
7.5 mg/m3 during 1 year (2005). Estimates of concentration-response associations between air
pollution and mortality were obtained from the literature and used to modify the observed
survival probabilities, taking into account that the effect of reduced levels during 1 year will
extend over a longer period but wane with time. Life tables for the Swiss population were
calculated using the observed and the modified survival probabilities. The difference between
the two life tables is interpreted as the years of life lost (YLL) due to the population’s exposure
to air pollution during the year 2005.
2.1 Derivation of the Exposure-Response Association
Meta-analytic techniques were used to derive the exposure-response association. I aimed to

identify all population based cohort studies of air pollution and adult mortality that estimated
the association between mortality and exposure to particulate matter (PM2.5, PM10, TSP or
black smoke). Cohort studies capture both short and long-term effects of exposure to air
pollution. When several analyses from the same cohort were available, the most recent results
were considered. For infant mortality at age below 1 year, effects of long-term exposure are less
relevant by definition, and effect estimates were derived from cohort studies as well as from
case-control and time-series studies. I searched Medline and Embase from inception to July
2003, and checked review articles, conference abstracts and the LUDOK specialist database
(http://www.unibas.ch/ispmbs/LuG/welcome.html) for eligible studies.
I extracted estimates of the relative risk of death from all non-violent causes from studies
in adults aged 30 years or older and studies of infant mortality. No studies were identified for
age group 1–30 years. For each study, risk ratios were standardized to a change of 10 mg/m3 in
PM10 exposure. PM2.5 concentration was converted into PM10 concentration using a
conversion factor of 1.33; for black smoke a factor of 1.0 was used (Gehrig and Buchmann,
2003; Roemer and van Wijnen, 2001). Standardized risk ratios from different studies were
combined using random-effects or fixed-effects > meta-analysis. I2 statistic, which describes
the percentage of total variation across studies that is due to heterogeneity rather than chance,
and standard tests of heterogeneity were performed (DerSimonian and Laird, 1986; Higgins
and Thompson, 2002).
2.2 Derivation of the Decay Constant K
For infant mortality the effect of air pollution was by definition assumed to occur within 1 year
and thus no dynamic model was applied. For adult mortality the pooled risk ratio from cohort
studies served as the basis for the development of a dynamic model. Studies that reported the
effect on mortality of a sudden sustained change in particulate matter (PM2.5, PM10, TSP or
black smoke) were considered eligible ‘‘intervention studies.’’ I assumed an exponential
decrease of the risk after termination of the exposure as proposed by Leksell and Rabl
(2001) in view of the repair processes of the body (> Figure 40-1). The relative risk from air
pollution (RR) at a given time point (t) after reduction of air pollution can then be calculated
. Figure 40-1
Risk decrease after sustained decrease in air pollution at t = 0. According to the dynamic
exposure-response model, health risk decreases exponentially after a sustained decrease in air
pollution at t = 0. R+ refers to the risk with air pollution and R0 to the baseline risk without air
pollution
from the total long term excess relative risk attributable to air pollution (ERR = RR- R0),
as follows:
RRðtÞ ¼ ERR ekt þ R0 ð1Þ
where R0 is the baseline relative risk in the absence of air pollution (R0 = 1) and k refers to the
decay constant. After cessation of exposure mortality will start to decline exponentially
(> Figure 40-1). The observed change in mortality (DM) in percent during a given time
period (0-t) can be derived from > equation (1) as follows:
Zt
DM ¼ ERR t ERR ekt dt ð2Þ
0
The unit of DM is percent-years: the percentage change in mortality is multiplied with the
time period (e.g., 3% reduction of mortality during 2 years equals 0.06). Estimates of the
change in mortality (DM) per 10 mg/m3 decrease in PM10 levels can be obtained from
intervention studies. Integrating > equation (2) gives:

DM ¼ ERR t þ ERR=k ekt 1 ð3Þ
From > equation (3) k was iteratively determined by entering the combined relative risk
from the meta-analysis of cohort studies (RR) and the observed change in mortality (DM)
from studies of the effect of interventions on air pollution and mortality during a given time
period (t). I calculated k for each available intervention study, and the results informed the
choice of a range of constants k for calculating YLLs.
2.3 Application to Switzerland
I used the model described above to estimate the number of YLL attributable to air pollution in
Switzerland in 2005. In 2005, the Swiss population size was 7,459,100; thereof 72,500 were
infants (0–1 year). Population exposure to PM10 was estimated using a dispersion model which
considers primary particulate matter, secondary particles formed in the atmosphere from
precursor emissions, and transboundary large-scale PM10 (Filliger et al., 1999). Population
exposure distribution was modeled at a spatial resolution of 0.04 km2, i.e., 200 m 200 m grid
(Sommer et al., 2004). Model inputs were emission inventories of PM10 as well as emission
inventories or modeled exposure distributions of the precursor substances (NO2, SO2, VOC)
for the year 2000, which allowed traffic source specific exposure modeling. The change in
population exposure between 2000 and 2005 was derived from ambient PM10 measurements
from 16 different measurements sites within Switzerland (National Air Pollution Monitoring
Network, NABEL). The lowest exposure level in populated areas was 7.5 mg/m3. The possible
health impact of air pollution exposure below this concentration was not considered.
YLLs due to air pollution were calculated based on life tables, using the observed survival
probabilities in Switzerland in the year 2005 as the reference scenario. Using modified survival
functions the alternative scenario assumed that the population was not exposed to air
pollution above 7.5 mg/m3 during the year 2005, thereafter air pollution levels returned to
previous values. For calculation of traffic related YLLs, I used modified survival functions
omitting air pollution from the corresponding traffic sources. I considered emissions from
road and rail traffic separated by the purpose of the traffic (passenger vs. freight). According to
the steady state model reduction of air pollution will result in increased survival probabilities
exclusively in the respective year. With the dynamic model survival probabilities will also be
affected in subsequent years (> Figure 40-2). The steady state model was used for infant
mortality and the dynamic model for adult mortality. The difference between the life tables
obtained from the reference and the alternative scenario is interpreted as the YLL attributable
to air pollution during the year 2005.
3 Results
3.1 Association Between Air Pollution and Mortality: Exposure
Response Association
I identified four cohort studies on the effect of air pollution on adult mortality: the Six-Cities
study (Krewski et al., 2000), the American Cancer Society (ACS) study (Pope et al., 2002), the
Netherlands > Cohort study on Diet and Cancer (NLCS) (Hoek et al., 2002) and the
Adventists study (Abbey et al., 1999). The latter study was performed in non-smoking
California Seventh-day Adventists who are not representative of the general population and
was therefore excluded. > Table 40-1 shows the characteristics of the three included cohort
studies. > Figure 40-3 presents the meta-analysis of estimates of the relative risk of death.
. Figure 40-2
Time course of relative risk of death after a sudden decrease in air pollution for the steady state
(bold dashed line) and the dynamic model (solid line). According to the steady state model (bold
dashed line) reduction of air pollution will result in increased survival probabilities exclusively in
the respective year. With the dynamic model (solid line) survival probabilities will also be
affected in subsequent years. The thin dashed line refers to the reference scenario
. Table 40-1
Characteristics of primary studies (from Röösli et al., 2005)
First author Study Number of

(year) Design Location period deaths Age range Pollutant
Studies of adult mortality
Krewski (2000) Cohort USA 1974–1991 1,430 25–74 PM10
years
Pope (2002) Cohort USA 1982–1998 Not reported >30 years PM2.5
Hoek (2002 Cohort The 1986–1994 489 55–69 Black
Netherlands years smoke
Studies of infant mortality
Woodruff Cohort USAa 1989–1991 12,841 1–12 PM10
(1997) months
Bobak (1999) Case- Czech 1989–1991 2,006 <1 year TSP
control Republic
Loomis (1999) Time Mexico city 1993–1995 2,798 <1 year PM2.5
series
Lipfert (2000) Cohort USA 1990 13,041 <1 year PM10
Ha (2003) Time Seoul 1995–1999 1,045 1–12 PM10
series months
Intervention studies
Pope (1992) Time Utah Valley 1985–1989 1,736 All ages PM10
series
Clancy (2002) Time Dublin 1984–1996 58,086 All ages Black
series smoke
a
Excluding eight states (California, Indiana, Louisiana, Nebraska, New York, Oklahoma, South Dakota, Washington)
Studies of adult mortality are cohort studies with long-term follow up. Studies of infant mortality considered
mortality at age <1 year. Intervention studies investigated the health effects of an intervention that leads to
sustained increase or decrease in air pollution levels in a large population
There was moderate between study heterogeneity (I-squared ¼ 51%, p ¼ 0.13 from test of
heterogeneity). The combined relative risk from fixed-effect analysis was 1.059 (95% CI 1.031–
1.088) per 10 mg/m3 increase in average PM10 concentration. For infant mortality I identified
two time series studies (Ha et al., 2003; Loomis et al., 1999), two cohort studies (Lipfert et al.,
2000; Woodruff et al., 1997) and one > case control study (Bobak and Leon, 1999)
(> Table 40-1). All were included in the meta-analysis. Results were heterogeneous
(I-squared ¼ 85%, p < 0.001), which was mainly due to the study by Lipfert et al. (2000),
which showed a greater relative risk than the other studies (> Figure 40-4). The combined
relative risk from random-effect meta-analysis was 1.056 (95% CI 1.026–1.088) per 10 mg/m3
increase in average PM10 exposure.
3.2 The Decay Constant K
Three potentially eligible air pollution intervention-type study were identified. One study
(Hedley et al., 2002) was excluded because SO2 but not particulate matter was studied.
The first of the included studies examined the effect of shutting down a steel mill in the
692
40
. Figure 40-3
Fixed-effects meta-analysis of cohort studies of the effect of air pollution on mortality in adults. The combined relative risk is 1.059 (95% confidence
intervals 1.031–1.088) per 10 mg/m3 increase in average PM10 concentration. ES refers to the effect estimate including confidence intervals. The last
column gives the weight in percent that each study contributed to the overall estimate (proportional to the size of the squares). The solid horizontal
line represents the 95% confidence interval of each study. The solid vertical line marks the baseline risk (RR = 1). The scattered line represents the
pooled estimate from all studies. The edges of the diamonds show the 95% confidence intervals of the pooled estimate
Years of Life Lost Due to Air Pollution in Switzerland: A Dynamic Exposure-Response Model
. Figure 40-4
Random-effects meta-analysis of cohort, case-control and time-series studies of the effect of air pollution on infant mortality. The combined relative
risk is 1.056 (95% CI 1.026–1.088) per 10 mg/m3 increase in average PM10 concentration. ES refers to the effect estimate including confidence
intervals. The last column gives the weight in percent that each study contributed to the overall estimate (proportional to the size of the squares).
The solid horizontal line represents the 95% confidence interval of each study. The solid vertical line marks the baseline risk (RR = 1). The scattered
line represents the pooled estimate from all studies. The edges of the diamonds show the 95% confidence intervals of the pooled estimate
40
693
Utah Valley on mortality during the following year (Pope et al., 1992). The average PM10
exposure level decreased by 15 mg/m3 and mortality by 3.2%. The second study investigated
the impact of introducing the coal ban in Dublin (Clancy et al., 2002). Following the new
legislation the black smoke levels declined by 35.60 mg/m3 and mortality by 5.7%.
A linear approximation of the results from the steel mill study yielded a 2.1% decrease
in mortality per 10 mg/m3 decrease in PM10 during 13 months. Therefore DM from
> equation (3) corresponds to 0.23 percent-years (396/365*0.021). Using this figure and the
combined excess relative risk (ERR) of 0.059 from the meta-analysis of cohort studies,
> equation (3) gave a decay constant k of 0.88 per year. The coal ban study showed a 1.6%
decrease in mortality per 10 mg/m3 PM10 during 6 years corresponding to DM = 0.096

percent-years (=6*0.016). This corresponded to a decay constant k of 0.11 per year. Based
on these results a decay constant k of 0.5 per year was determined. > Table 40-2 shows the
effect on all cause mortality between 2005 and 2014, assuming a k of 0.5. In this case, 39% of
the effect of air pollution during 2005 occurs in the same year and 63% within 2 years. The risk
ratios for each year reflect the reduction in risk after reducing PM10 exposure by 10 mg/m3
during 2005, with exposure returning to the previous level in the following year. Multi-
plying the relative risks for each year yields the steady state relative risk of 0.944 (¼1/1.059)
per 10 mg/m3 reduction in average PM10 exposure.
3.3 Years of Life Lost
Modeling PM10 exposure in Switzerland yielded a population weighted average of 19.8 mg/m3
for adults aged 30 years or older. The weighted exposure for children below the age of one
was 19.2 mg/m3. With the choice of 7.5 mg/m3 for the ‘‘no pollution’’ alternative, the impact
of a contrast of 12.3 ug/m3 (adults) and 11.7 ug/m3 (children) was therefore quantified. For
a decay constant k of 0.5 per year, life table calculations resulted in 48,200 (95% CI
25,600–72,000) YLL due to air pollution exposure in the year 2005, with 3.6% attributable
to infant deaths (> Table 40-3). This corresponds to 6,500 (95% CI 3,400–9,700) YLL per
million of Swiss population. About a third of the YLLs were due to emissions from road traffic.
Emissions from trail traffic contributed about 2% of the total YLLs attributable to air
pollution.
Data from population-based cohort studies were used to obtain an average concentration-
response function describing the steady state. The decrease in risk following termination of an
exposure was derived from intervention studies. These data were used to populate a dynamic
model which allows estimation of the change in mortality following increases or decreases in
air pollution levels. The dynamic model builds on external evidence from interventions that
reduce pollution. It allows more solid assessments of likely changes in mortality following
defined reductions (or increases) in air pollution levels than the widely used models assuming
steady-state conditions. It is this type of information that policy makers often need, for
example when deciding on whether an air polluting facility should be allowed to be built, or
closed down.
. Table 40-2
Distribution of the effect of a hypothetical reduction of 10 mg/m3 PM10 in 2005 on all cause mortality 2005–2014 in Switzerland (from Röösli et al., 2005)
Year 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Proportion of total effect – 39.3% 23.9% 14.5% 8.8% 5.3% 3.2% 2.0% 1.2% 0.7% 0.4%
Relative risk (per 10 mg/m3 reduction in PM10) 1.0 0.9775 0.9863 0.9917 0.9950 0.9969 0.9981 0.9989 0.9993 0.9996 0.9997
Table 34-2 shows the time course of the effect on all cause mortality between 2005 and 2014, assuming a k of 0.5. In this case, 39% of the effect of air pollution during 2005 occurs in
the same year and 63% within 2 years. The risk ratios for each year reflect the reduction in risk after reducing PM10 exposure by 10 mg/m3 during 2005, with exposure returning to
the previous level in the following year. Multiplying the relative risks for each year yields the steady state relative risk of 0.944 (¼1/1.059) per 10 mg/m3 reduction in average PM10
exposure
40
695
. Table 40-3
Years of life lost in 2005 in Switzerland due to air pollution as well as different traffic sources
(population size 7,450,100)
Years of life lost (reasons) Number of years Lower 95% CI Upper 95% CI
Total air pollution 48,200 25,600 72,000
Road traffic 17,200 9,100 25,700
Road traffic, passenger 9,800 5,200 14,600
Road traffic, freight 7,400 3,900 11,000
Rail traffic 1,100 600 1,700
Rail traffic, passenger 500 300 800
Rail traffic, freight 600 300 900
48,200 YLL are attributable to air pollution. About one third is due to road traffic (17,200) and 2% due to rail traffic
(1,100). The 95% CI reflects the statistical uncertainty of the exposure-response association
4.1 Strengths and Weaknesses
In general, data from prospective cohort studies are considered the gold standard for health
impact assessment (Burnett et al., 2003; Künzli et al., 2001; Rabl, 2006). However, cohort
studies do not provide information about the change of the risk after a sustained increase or
decrease of air pollution level, if each person is assigned a single long-term exposure value as it
is usually done. Intervention-type studies could provide this information; however, such data
are scarce and vulnerable to bias from secular time trends of other health risk factors. Thus, any
exposure-response association based on intervention-type studies only is likely to be imprecise
and inaccurate. The strength of this dynamic exposure-response model is the combination of
cohort data with data from intervention-type studies. In such a way a robust exposure-response
association is obtained and predictions about the time course of the health risk can be made.
The dynamic model and its application also has a number of limitations. Most
importantly, little empirical data exist that could ultimately confirm the accuracy of the
dynamic model. For example, although an exponential decrease is often observed in biological
systems, I cannot prove that assuming an exponential form of the curve is appropriate. Its
shape may differ for different outcomes, for example coronary heart disease and lung cancer
(Leksell and Rabl, 2001). In principle the decrease function could be examined empirically in
very large intervention studies by estimating changes in risk at different time points and for
different outcomes. For instances such information may be obtained from several recent
intervention studies that analyzed the effect of smoking bans on acute myocardial infarction
(Barone-Adesi et al., 2006; Bartecchi et al., 2006; Juster et al., 2007; Khuder et al., 2007; Sargent
et al., 2004). An analysis of the association between particulate pollution and daily mortality
over 17 years in Dublin concluded that within 3 days mortality increased by 0.4% per 10 mg/m3
increase in the black smoke concentration (Goodman et al., 2004). This result is in line with
most time series studies. Within 40 days the corresponding increase in Dublin was 1.1%.
A recent analysis of an extended follow up of the six cities studies found that effects of changes
in exposure on mortality are seen within 2 years (Schwartz et al., 2008). According to these
results, it seems likely that a substantial proportion of the benefit of reducing pollution
levels manifests itself within a relatively short period after the reduction has taken place.
This is in line with our calculations.
There is uncertainty regarding the choice of an appropriate decay constant. The calcula-
tion of the decay constant is highly sensitive to the assumed long term air pollution risk. The
approach I used to determine the decay constant can only produce a solution if the interven-
tion studies report smaller effect estimates than the cohort studies (see > equation 3), which
has not to be necessarily the case for all populations. I found relatively large differences in the
decay constant between the two intervention studies (0.11 and 0.88). This can be expected
because small variations in the relative risk estimates (e.g., due to chance) can have major
effect on the estimated decay constant. However, sensitivity analyses showed that the choice of
the decay constant does not materially influence the estimated YLL. Only the distribution of
the YLL in time will be affected by the choice of the decay constant (Röösli et al., 2005).
In the case study for Switzerland, I assumed that levels of PM10 of 7.5 mg/m3 or below are
not harmful, however, for low and very low concentrations of PM10, the concentration-
response function is uncertain, and there is no evidence for a no-effect threshold (Schwartz
et al., 2008). For the Swiss population natural background PM10 exposure was estimated to
be 1.3 mg/m3. Finally, I did not consider the impact of air pollution on mortality of age groups
1–30 years but it is clear that in this age group the non-violent mortality is so low that the
effect of pollution can be assumed to be negligible. Although response functions were very
similar for adult and infant mortality, and YLL are large for an infant death, infant mortality
contributed only 3.6% of all YLL. This is due to the low infant mortality rate in Switzerland.
4.2 Comparison with Other Studies
Previous assessments of the impact of air pollution on health have generally been based on
steady state models (Boldo et al., 2006; Cohen et al., 2005; Künzli et al., 2000; Mestl et al., 2007;
Miller and Hurley, 2003). For Switzerland a previous assessment with a dynamic exposure-
response model yielded 42,400 YLLs for the year 2000 (Röösli et al., 2005). The observed
difference of 14% between the estimates for 2000 and 2005 is because of an increase in the
population size, an increase in survival probability and an increase in the mean PM10
exposure by 0.5 mg/m3. The only other impact assessment that used a dynamic model is the
study by Leksell and Rabl (2001), who estimated the loss of life expectancy due to air pollution
for the European Union. Interestingly, the decay constant was estimated from smoking
cessation studies, rather than studies of air pollution. Results were nevertheless comparable:
Leksell and Rabl reported 0.22 days lost per 1 mg/m3 increase in PM2.5 per person and year
of exposure. The corresponding figure for my impact assessment is 0.26 days, taking into
account the size of the Swiss population and the different type of particulate matter (PM10).
These similar figures underline that the choice of the decay constant has little impact on the
total number of YLL estimated by the model. US Studies estimated about 22,000 smoking-
attributable YLL per million population (From the Centers for Disease Control and Preven-
tion, 2002; Max et al., 2004), which is four times higher than my estimate for outdoor
air pollution. In contrast to smoking the whole population including children is exposed
to air pollution, and air pollution cessation is not a choice available to the individual.
5 Conclusions
This case study for Switzerland illustrates that the dynamic exposure-response model can be
used to estimate the total impact of air pollution during a defined period of time, using a
scenario and framework that may facilitate communication with policy makers and the public
at large. In general the dynamic model will produce similar estimates of the total YLL as steady-
state models. Thus, if one is interested exclusively in the number of YLL, the simpler steady-
state approach will generally be appropriate. However, in many health impact assessment
contexts the date of the prevented event is of interest. For example, the monetary value of a
prevented death in the future will differ from the value of a death that is prevented in the
present. Clearly, more data are needed from large epidemiological studies of mortality and air
pollution, and particularly from studies of interventions that reduced or increased pollution
levels. Future studies of interventions should ideally report results for the same indicators of
total air pollution used in the studies that provide the concentration-response functions.
Summary Points
Results from cohort studies suggest a 6% increase in mortality per 10 mg/m3 increase in
long term exposure to PM10.
Results from time-series studies suggest a 0.5% increase in mortality per 10 mg/m3 increase
in PM10 exposure within three days.
Data from long-term epidemiological studies and studies that examined sudden changes
in exposure levels can be used to assess the health impact of ambient air pollution.
A dynamic exposure-response model based on an exponential function was developed to
estimating years of life lost attributable to ambient air pollution in Switzerland.
According to the dynamic exposure-response model, 39% of the cases occur within 1 year
and 78% within 3 years.
In Switzerland an estimated 6,500 years of live lost per million population are attributable
to air pollution each year.
About a third of the YLL due to air pollution are attributed to road traffic emissions and
about 2% are attributed to rail traffic emissions.
The total number of YLL was insensitive to different assumptions regarding the course of
mortality after cessation of air pollution.
References
Abbey DE, Nishino N, McDonnell WF, Burchette RJ, Clancy L, Goodman P, Sinclair H, Dockery DW. (2002).
Knutsen SF, Lawrence Beeson W, Yang JX. (1999). Lancet. 360: 1210–1214.
Am J Respir Crit Care Med. 159: 373–382. Cohen AJ, Ross Anderson H, Ostro B, Pandey KD,
Barone-Adesi F, Vizzini L, Merletti F, Richiardi L. (2006). Krzyzanowski M, Kunzli N, Gutschmidt K, Pope A,
Eur Heart J. 27: 2468–2472. Romieu I, Samet JM, Smith K. (2005). J Toxicol
Bartecchi C, Alsever RN, Nevin-Woods C, Thomas WM, Environ Health A. 68: 1301–1307.
Estacio RO, Bartelson BB, Krantz MJ. (2006). Circu- DerSimonian R, Laird N. (1986). Control Clin Trials. 7:
lation. 114: 1490–1496. 177–188.
Bobak M, Leon DA. (1999). Epidemiology 10: 666–670. Filliger P, Puybonnieux-Texier V, Schneider J. (1999).
Boldo E, Medina S, LeTertre A, Hurley F, Mucke HG, Health Costs Due to Road Traffic-Related Air
Ballester F, Aguilera I, Eilstein D. (2006). Eur J Pollution – PM10 Population Exposure. Federal
Epidemiol. 21: 449–458. Department of Environment, Transport, Energy
Burnett RT, Dewanji A, Dominici F, Goldberg MS, and Communications, Bern.
Cohen A, Krewski D. (2003). Environ Health Per- Forsberg B, Hansson HC, Johansson C, Areskoug H,
spect. 111: 1170–1174. Persson K, Jarvholm B. (2005). Ambio. 34: 11–19.
From the Centers for Disease Control and Prevention. Loomis D, Castillejos M, Gold DR, McDonnell W,
(2002) JAMA. 287: 2355–2356. Borja-Aburto VH. (1999). Epidemiology. 10:
Gehrig R, Buchmann B. (2003). Atmos Environ. 37: 118–123.
2571–2580. Max W, Rice DP, Sung HY, Zhang X, Miller L. (2004).
Goodman PG, Dockery DW, Clancy L. (2004). Environ Tob Control. 13: 264–267.
Health Perspect. 112: 179–185. Mestl HE, Aunan K, Seip HM. (2007). Environ Int. 33:
Ha EH, Lee JT, Kim H, Hong YC, Lee BE, Park HS, 831–840.
Christiani DC. (2003). Pediatrics. 111: 284–290. Miller BG, Hurley JF. (2003). J Epidemiol Commun
Hedley AJ, Wong CM, Thach TQ, Ma S, Lam TH, Health. 57: 200–206.
Anderson HR. (2002). Lancet. 360: 1646–1652. Ostro B. (1994). Estimating the health effects of air
Higgins JP, Thompson SG. (2002). Stat Med. 21: pollutants. A method with an application to Jakarta.
1539–1558. Policy Research Working Paper No. 1301, World
Hoek G, Brunekreef B, Goldbohm S, Fischer P, Brandt Bank, Washington DC.
van den PA. (2002). Lancet. 360: 1203–1209. Pope CA, 3rd, Burnett RT, Thun MJ, Calle EE, Krewski D,
Juster HR, Loomis BR, Hinman TM, Farrelly MC, Ito K, Thurston GD. (2002). JAMA. 287: 1132–1141.
Hyland A, Bauer UE, Birkhead GS. (2007). Am J Pope CA, 3rd, Schwartz J, Ransom MR. (1992). Arch
Public Health. 97: 2035–2039. Environ Health. 47: 211–217.
Khuder SA, Milz S, Jordan T, Price J, Silvestri K, Butler P. Rabl A. (2003). J Air Waste Manag Assoc. 53: 41–50.
(2007). Prev Med. 45: 3–8. Rabl A. (2006). Environ Health. 5: 1.
Krewski D, Burnett RT, Goldberg MS. (2000). Reanalysis Roemer WH, van Wijnen JH. (2001). Environ Health
of the Harvard Six Cities Study and American Can- Perspect. 109: 151–154.
cer Society Study of Particulate Air Pollution and Röösli M, Künzli N, Braun-Fahrländer C, Egger M.
Mortality: Special Report. Health Effect Institute, (2005). Int J Epidemiol. 34: 1029–1035.
Cambridge, MA, pp. (Available at http://www. Sargent RP, Shepard RM, Glantz SA. (2004). Br Med J.
healtheffects.org/pubs-special.htm). 328: 977–980.
Künzli N, Kaiser R, Medina S, Studnicka M, Chanel O, Schwartz J, Coull B, Laden F, Ryan L. (2008). Environ
Filliger P, Herry M, Horak F, Jr., Puybonnieux- Health Perspect. 116: 64–69.
Texier V, Quenel P, Schneider J, Seethaler R, Sommer H, Lieb C, Heldstab J, Künzle T, Braun-
Vergnaud JC, Sommer H. (2000). Lancet. 356: Fahrlander C, Röösli M. (2004). Externe
795–801. Gesundheitskosten durch verkehrsbedingte Luft-
Künzli N, Medina S, Kaiser R, Quenel P, Horak F, Jr., verschmutzung [External costs due to traffic related
Studnicka M. (2001). Am J Epidemiol. 153: air pollution]. Bundesamt für Raumentwicklung,
1050–1055. Bern.
Leksell I, Rabl A. (2001). Risk Anal. 21: 843–857. Woodruff TJ, Grillo J, Schoendorf KC. (1997). Environ
Lipfert FW, Zhang J, Wyzga RE. (2000). J Air Waste Health Perspect. 105: 608–612.
Manag Assoc. 50: 1350–1366.
41 Quantification of Deaths and
DALYs Due to Chronic
Exposure to Arsenic in
Groundwaters Utilized for
Drinking, Cooking and
Irrigation of Food-Crops
D. A. Polya . D. Mondal . A. K. Giri
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
2 Health Impacts of Chronic Arsenic Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705

2.1 Nature of Health Impacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
2.2 Magnitude of Health Impacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
3 Arsenic Hazard in Groundwater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
4 Exposure Routes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709
5 Dose–Response Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710

5.1 Incidence Rates and Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
5.2 Mortality Rates and SMRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
6 Deterministic and Probabilistic Risk Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720

6.1 Reasons and Basis for Assessment of Risk Arising from
Environmental Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
6.2 Deterministic vs. Probabilistic Assessment Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
6.3 Quantitative Risk Assessment of Arsenic-Induced Deaths and DALYs in
Bangladesh . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
7 Remediation Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
8 Relative Magnitude of Arsenic-Related and Water-Borne Pathogen

Related Health Impacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 724
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726

702 41 Quantification of Deaths and DALYs due to Chronic Exposure
Abstract: > Groundwaters with arsenic concentrations higher than the WHO provisional
guide value of 10 mg/L are found in many parts of the world. Widespread utilization of these
groundwaters for drinking, irrigation of food crops and cooking over the past few decades has
resulted in chronic exposure to tens of millions of people, annual excess deaths of the order of
thousands and annual DALYs of the order of hundreds of thousands in Bangladesh, the worst
impacted country. Chronic exposure to arsenic may result in a wide range of cancerous and
non-cancerous deleterious health impacts; particularly for cancers, these health impacts may
not manifest themselves until decades after the exposure. Many health end-points are non-
fatal but nevertheless result in considerable loss of quality of life. Calculation of arsenic-
attributable DALYs is therefore important to inform policy-makers.
Assessing the overall risk of utilization of arsenic-bearing groundwaters may be achieved,
in principle, by quantifying (1) dose–response relationships; (2) exposure routes; and (3)
groundwater arsenic hazard.
There is a clear association between chronic arsenic exposure and various cancers, partic-
ularly skin and lung cancers, at drinking water concentrations above 100 mg/L but there is
considerable argument over the nature of dose–response relationships at concentrations much
below this. Nutritional status, including intake of selenium and folate, genetic disposition,
smoking habits, age and gender are all contributory factors to the risk of acquiring arsenic-
related diseases as a result of a given chronic exposure.
The major exposure routes for arsenic from groundwaters are: (1) drinking groundwater;
(2) eating rice and other food-crops irrigated with groundwater; and (3) indirectly through
cooking rice with high arsenic groundwater.
Assessing the impact of various arsenic remediation options needs to explicitly consider
potential risk-substitution and, in particular, the balance between DALYs arising from arsenic-
related health impacts and those related to water-borne pathogens.
List of Abbreviations: As, arsenic, DALY, disability adjusted life year; DG, dug well; DTW,
deep > tubewell; GBD, global burden of disease study; PAF, > population attributable fraction;
ppb, parts per billion; ppm, parts per million; PSF, pond sand filter; mg/L, micrograms/liter;
RWH, rainwater harvesting; SMR, > standardized mortality ratio; STW, shallow tubewell;
WHO, World Health Organization
1 Introduction
Arsenic is commonly thought of an acute poison, utilized in homicides, or as a chronic poison

associated with long-term occupational exposure, however quantitatively the most serious
known health impacts of arsenic are associated with the extensive long-term use of ground-
waters with hazardously high concentration of arsenic. Key facts about chronic arsenic
exposure from groundwater are summarized in > Table 41-1.
In many parts of the world, most notably in Bangladesh, groundwaters are found with
arsenic concentrations higher than the WHO provisional guide value of 10 mg/L (also
equivalent to the USEPA MCL and the standard required by European Union Drinking
Water Directive (98/93/EC) for arsenic) (> Figure 41-1).
Widespread utilization of these groundwaters for drinking, irrigation of food crops and
cooking, has resulted in chronic exposure to tens of millions of people (> Table 41-2).
This has resulted in annual excess deaths on the scale of thousands (Yu et al., 2003) and
annual DALYs on the scale of at least hundreds of thousands (Lokuge et al., 2004).
Quantification of Deaths and DALYs due to Chronic Exposure 41 703
. Table 41-1
Key facts: health impacts of chronic exposure to arsenic in wellwaters
Arsenic is a metalloid widely distributed in the Earth’s crust and present at an average
concentration of 2 mg/kg
Groundwaters with arsenic concentrations higher than the WHO provisional guide value of 10 mg/L
are found in many parts of the world
Widespread utilization of these groundwaters for drinking, irrigation of food crops and cooking
over the past few decades has resulted in chronic exposure to tens of millions of people
Cancers impacts of chronic arsenic exposure include: skin, lung, bladder and liver cancers
Non-cancerous endpoints include arsenicosis – hyperpigmentation and keratoses of the skins,
and – although this is currently subject to some debate – ischemic heart disease, hypertension and
diabetes mellitus
Chronic exposure to arsenic in groundwaters has resulted in annual excess deaths of the order of
thousands and annual DALYs of the order of hundreds of thousands just in Bangladesh, the worst
impacted country
Many health end-points are non-fatal but nevertheless result in considerable loss of quality of life
Assessing the overall risk of utilization of arsenic-bearing groundwaters may be achieved, in
principle, by quantifying (1) health impact response to known exposure doses; (2) exposure routes;
and (3) arsenic hazard in the groundwater source
There is a clear association between arsenic exposure and various cancers, particular skin and lung
cancers, at high concentrations but below 100 mg/L there is considerable argument over the nature
of the dose–response relationships
Nutritional status, genetic disposition, smoking habits, age and gender all contribute to the risk of
acquiring arsenic-related disease as a result of a given exposure
The major exposure routes for arsenic from groundwaters are: (1) drinking groundwater; (2) eating
rice irrigated with groundwater; (3) cooking rice with high arsenic groundwater
Arsenic hazard in groundwater is highly heterogeneous – and therefore predictions of arsenic
hazard on a well-by-well basis are typically associated with very high uncertainty and poor
confidence limits
Assessing the impact of various remediation options needs to explicitly consider risk-substitution,
including the balance between DALYs arising from arsenic-related health impacts and those
related to water borne pathogens, however, with good practice there is no reason in principle why
both risks may not be simultaneously addressed
In this article, we outline the currently known associations between chronic arsenic
exposure from groundwater and deleterious health outcomes; and then briefly describe the
key three elements required for determining the risks to human populations of chronic
exposure to groundwater arsenic, viz. (1) dose–response relationships for key health out-
comes; (2) the nature and relative importance of human exposure routes; and (3) the nature
and distribution of arsenic in groundwaters exploited as a water resource. Lastly, we show
these elements may be combined in > probabilistic risk assessments and how, using examples
from West Bengal (India) and Bangladesh, these may address the critical issues of (1) the
relative importance of arsenic-related and water-borne-pathogen-related end-points; and (2)
the relative merits of various groundwater arsenic remediation/mitigation strategies.
. Figure 41-1
Sketched global distribution of known major high arsenic groundwater regions as of 2008. After
Ravenscroft (2007); with additional information from Polya et al., 2005; and Lenny Winkel,
Michael Berg and Nayarini Estiningsih, personal communications. Recent discoveries of high
arsenic shallow groundwaters in the middle and upper reaches of the Ganges plain suggest that
this map is likely to change in the next 5–10 years. This map is only indicative and should not be
used as a hazard map
. Table 41-2
Major exposure of populations worldwide to groundwater with (1) >50 ppb and (2) >10 ppb
arsenic. The table refers to peak exposures. In several countries mitigation efforts are reducing
exposure from peak levels (?) indicates population exposed is unknown or poorly quantified
(After Ravenscroft, 2007; and Lenny Winkel, Michael Berg, Micky Sampson and Nayarini
Estiningsih, personal communication)
Peak Exposure (in millions)

Country > 50 ppb > 10 ppb
Bangladesh 27 50
India 11 30
China 5.6 15
USA 3.0 30
Myanmar 2.5 (?) (?)
Pakistan 2.0 5.0
Argentina 2.0 (?)
Vietnam 1.5 (?)
Nepal 0.5 2.5
Mexico 0.4 2.0
Cambodia 0.1 0.3
The scope of this review is necessarily restricted. We confine ourselves to the consideration
of human health risks related to groundwater derived arsenic, hence occupational exposures
and those from arsenic-bearing soils and air-borne dusts are not within the scope of this
article, except where such hazards are the direct result of the utilization of high arsenic
groundwaters. There are several different types of high arsenic groundwaters, here we focus
primarily on shallow reducing groundwaters, utilization of which have the by far the largest
known human health impacts, and in particular on those in Bangladesh.
Furthermore, the published literature on arsenic in groundwater and its health impacts
numbers several thousand papers and a comprehensive review of all of these is beyond the
scope of this article. The reference limit to this article means that many excellent published
studies have not been explicitly included. However, detailed reviews, with more comprehen-
sive reference lists, of health impacts of chronic exposure to groundwater arsenic may be found
in NRC (1999), NRC (2001), WHO (2001), Brown (2004), USEPA (2005), Cantor and Lubin
(2007) and references therein. Charlet and Polya (2006) provide a brief review and key
references on the biogeochemistry of arsenic in groundwaters of some of most impacted regions
of the world. Smedley and Kinniburgh (2002) detail the abundance, form and origin of arsenic in
many geological media – notably different rock-types, soils and waters – whilst Cullen and Reimer
(1989) provide an authoritative account of the chemical speciation of arsenic.
Despite the volume of published work on this subject, at the time of writing, there
remains considerable debate about: (1) the modes of action of arsenic within the body,
(2) the range of sequelas which may be reliably determined to be caused by chronic arsenic
exposure, (3) dose–response relationships – particularly for exposures to drinking water with
less than 100 mg As/L, (4) genetic controls on susceptibility to developing arsenic-related
diseases for a given level of exposure; (5) the relative importance of various human exposure
routes; (6) the controls on abundance of arsenic in groundwaters and in particular (7) the
impact of human activities on future changes in this hazard.
Thus much of what is written here is likely to be superseded as ongoing and future studies
are published. Furthermore, the current theoretical uncertainties and variability in individual
responses to exposure and in the distribution of arsenic groundwater hazard, means that
application of generalized statements to individual cases is strongly discouraged and should
not be undertaken without a suitable range of expert input. We hope, however, that this article
will serve as a useful starting point for those with an interest in this subject.
2 Health Impacts of Chronic Arsenic Exposure
2.1 Nature of Health Impacts
Soluble inorganic arsenic is toxic with both cancer and non-cancer health impacts. Long-term
ingestion of inorganic arsenic from water is an established cause of lung, bladder, kidney, liver
and skin cancer but the database is not strong and confirmatory studies would be needed to
establish arsenic as an underlying cause of other cancers (Brown, 2004; NRC, 2001). The most
clearly established non-cancer health impacts are skin changes, notably hyperkeratosis and
pigmentation changes. Though conclusions on the causality of the relationship between
arsenic exposure and other health effects are less clear-cut, the evidence is strongest for
hypertension and cardiovascular disease, suggestive for diabetes and reproductive effects and weak
for cerebrovascular disease, long-term neurological effects, and cancer at sites other than lung,
bladder, kidney and skin (WHO, 2001). Some evidence also suggests that the ingestion of arsenic
can have effects on the immune and respiratory systems and pregnancy outcome (NRC, 2001).
2.2 Magnitude of Health Impacts
The magnitude of health impacts arising from chronic exposure to arsenic from groundwater
have been estimated by direct health surveys and also indirectly by the application of
epidemiological data from small and medium sized cohort studies. They may be expressed
in a variety of measures including: excess mortality, > prevalence or > incidence, or DALYs
(> Figure 41-2).
. Figure 41-2
Estimates of prevalence of arsenicosis in Bangladesh based upon direct surveys and indirect
techniques. Data from Yu et al. (2003). The figure illustrates different types of bias to which such
surveys or calculations are prone – the high prevalences found for the smaller surveys are likely
the result of bias in selecting non-representative highly at-risk sub-populations of study; the low
prevalences found for the larger surveys reflect the difficulties in obtaining unambiguous
diagnosis of early stage arsenicosis and other systemic biases of such surveys
Smith et al. (2000) estimate that several tens of millions of Bangladeshis exposed to
groundwater derived drinking water with greater than 50 mg/L As, and that such a level of
chronic exposure is likely to lead to arsenic-attributable deaths to around 1% of the popula-
tion. In Chile Region II, Marshall et al. (2007) estimate that such cancers – largely resulting
from exposure to nearly 900 mg/L As in drinking water over a decade around the 1960s – are
now responsible for approximately 10% of all male deaths and 5% of all female deaths.
Yu et al. (2003) suggest prevalences for arsenicicosis and skin cancer in Bangladesh to be
1,900,000 and 125,000 respectively. The incidence of internal cancers attributable to arsenic
exposure is more difficult to determine, not least of all because of the long latency periods
and multiple other causes of such cancers (Smith et al., 2000), but are nevertheless estimated
by Yu et al. (2003) to be of the order of 3,000 per year.
Estimated mortality rates in Bangladesh from both cancer and non-cancer end-points are
summarized in > Table 41-5. However, as Smith et al. (2000) points out, the long latency
periods of skin and other cancers – of the order of tens of years – means that peak excess
mortality due to the development of these arsenic-related cancers may not take place until
several decades after peak exposures. Furthermore, there remains considerably uncertainty
over dose–response relationships for arsenic-related health outcomes for chronic exposures
much below 100 mg/L. Brown (2004) notes that mortality from both cancer and non-cancer
end-points are important to quantify.
Many health end-points are non-fatal but nevertheless result in considerable loss of quality
of life. Calculation of arsenic-related DALYs is therefore important to enable policy-makers to
determine fully the importance of health impacts arising from chronic arsenic exposure.
Given the difficulties in formulating direct surveys to determine some health impacts,
many of which have long latency periods, risk assessment models based on quantifying
groundwater arsenic hazard, exposure routes and dose–response relations may be a useful
policy tool for those with the wherewithal or responsibility to put mitigation measures
into place.
3 Arsenic Hazard in Groundwater
Most shallow (typically 5–150 m) groundwaters contain arsenic concentrations below the
WHO provisional value for drinking water of 10 mg/L. However, medium hazard (defined here
as 10–50 mg As/L) and high hazard (defined here as > 50 mg As/L) groundwaters are common
and are found in many parts of the world (Smedley and Kinniburgh, 2002). Ravenscroft
(2007), who summarizes several hundred separate areas of occurrence in over 70 countries
and 6 continents, classifies these occurrences into four major types according to the major
mechanism by which arsenic is mobilized (that is transferred from the solid > aquifer
framework, where it constitutes negligible risk to humans, to the aqueous phase, where it
may constitute a major risk to humans exploiting the groundwater via wells):
1. Reducing groundwaters, characterized by near neutral pH, low Eh, high Fe, Mn, HCO3,
NH4 and low SO4, NO3; and in which arsenic is mobilized through the reductive dissolu-
tion of arsenic-bearing phases (Nickson et al., 1998), such as Fe(III) oxyhydroxides by
indigenous metal-reducing bacteria (Islam et al., 2004). In terms of areal extent and
human health impacts, these are the most significant and are the groundwater type
prevalent in the major arsenic-impacted areas of Bangladesh (Nickson et al., 1998),
India (Rahman et al., 2003), Pakistan and South-East Asia (Polya et al., 2005), amongst
other places.
2. Relatively oxidized groundwaters, characterized by slightly alkaline pH, intermediate-high
Eh, low Fe, high NO3. In these groundwaters, common in parts of Argentina and Inner
Mongolia, desorption of arsenic under oxic conditions is thought to be the principle
mechanism of mobilization of arsenic. In terms of areal extent and human health impacts,
these are second in rank to reducing groundwaters.
3. Acid sulfate waters, characterized by low pH and high SO4. These are most commonly
associated with coal or metalliferous ore deposits, in which the iron sulfide, pyrite (FeS2) is
abundant. Such pyrite may contain 100s or even 1,000s ppm of arsenic and, unstable under
oxidizing conditions at or near the Earth’s surface, will release arsenic into surface and
groundwater systems. Such occurrences are widespread, but tend be closely associated with
known mining areas.
4. Geothermal waters, characterized by high temperatures and chloride ion concentrations.
Such waters may contain 1,000s mg/L of arsenic. Their occurrence is restricted in areal
extent to geothermal areas, such as those of the USA, northern New Zealand, Japan and the
Philippines.
High arsenic hazard groundwaters are particularly found in the deltaic regions of large rivers
draining the Himalayas in Bangladesh, India, Pakistan, China and Indo-China, but the arsenic
groundwater hazard is also found in non-deltaic regions, and also in other countries, including
USA and parts of the European Union, notably Hungary, Romania and Slovakia (Lindberg
et al., 2006).
Arsenic hazard in groundwater is well documented in some key regions of the world (e.g.,
Bangladesh, West Bengal) with the total number of measurements of arsenic concentration in
wells exploiting groundwaters being of the order of millions. Nevertheless, such high numbers
of analyses are small compared to the total number of wells, of the order of tens of millions,
installed world wide, and therefore robust techniques are required to predict the arsenic
hazard in wells which have not been currently included in surveys. To this end, geostatis-
tical techniques, such as > kriging, are being increasingly used to predict the spatial variability
of arsenic concentrations in exploited groundwaters, although the meaningful spatial
resolution of such techniques is limited by the spatial distribution of samples upon which it
is based.
Limitation to the spatial resolution of kriging techniques may be overcome, to a certain
extent, by > regression-kriging, utilizing suitably selected auxiliary variables that are known at
a much finer spatial resolution than the arsenic groundwater concentration data. Rodriguez-
Lado et al. (2008), for example, first correlated arsenic concentrations in groundwaters in
Cambodia with geology and satellite-derived auxiliary variables including topographic slopes,
topographic wetness index, hydrological flux length and normalized difference vegetation
index, the use of which was justified as proxies for factors considered to be important in
controlling arsenic concentrations in shallow reducing groundwaters in Cambodia and else-
where. The spatially distributed residuals of this regression analysis were then subjected to
kriging to produce a regression-kriging model, which is more robustly predictive than a simple
kriging model because (1) of the finer scale meaningful resolution; and (2) the residuals from
the regression modeling are, at least in this case, approximately normally distributed whereas
the raw arsenic concentrations in groundwater data were not.
However, the distribution of arsenic concentrations in groundwaters is, due to a variety of
geological and geo-microbiological reasons, highly heterogeneous. High arsenic concentra-
tions and low arsenic concentrations may frequently be found in wells only tens of meters
apart. Thus, large scale arsenic hazard predictions on a well-by-well basis are typically
associated with high degrees of uncertainty and poor confidence limits. Ultimately, the best
and perhaps only reliable estimates of arsenic hazard in groundwaters tapped by newly
installed wells (or older wells where no reliable exists) is from suitably quality assured
sampling and chemical analysis.
There is currently widespread debate over whether or not there are significant cyclic or
secular changes in the arsenic concentrations in groundwaters, particularly in shallow reduc-
ing groundwaters in Pakistan, India, Bangladesh and South-East Asia. Several groups have
independently observed seasonal changes in such concentrations, particularly in wells close to
rivers, possibly due to natural changes in groundwater flow directions between the monsoon
and post-monsoon seasons. Harvey et al. (2002) further suggested that human activity
through massive groundwater abstraction is, of itself, likely to contribute to accelerated arsenic
mobilization in shallow reducing groundwaters and hence led to a secular increase in ground-
water arsenic concentrations over a period of decades.
4 Exposure Routes
The major exposure routes for arsenic from groundwaters are: (1) directly drinking ground-
water; (2) indirectly through eating rice irrigated with groundwater; (3) indirectly through
cooking rice and other food-crops with high arsenic groundwater (> Figure 41-3).
Among the many possible pathways of arsenic ingestion, drinking water has implicitly
been considered as the most significant as epidemiological data that has been accumulating
. Figure 41-3
Schematic diagram illustrating direct and indirect routes of exposure to arsenic from
groundwater
during last couple of years has mainly relied on the concentration of arsenic in the drinking
water as the proxy for exposure (e.g., Ahsan et al., 2006; Smith et al., 2000).
But the chronic arsenic toxicity symptoms recorded in Bangladesh, West Bengal and
elsewhere in the world, may reflect exposure pathways other than the consumption of water.
A number of studies have reported the presence of arsenic in rice (e.g., Williams et al., 2006;
Mondal and Polya, in press) and have implicated arsenic contaminated groundwater used
extensively for crop irrigation, particularly in the dry season, to be the cause. Thus, even if
arsenic-safe drinking-water is assured, the question of irrigating soils with arsenic-laden
groundwater will continue for years to come, accumulating arsenic in soils and its subsequent
entry into the food-chain through soil-crop-food transfer (Huq et al., 2006). Roberts et al.
(2007) suggest that the arsenic content of soils in rice-growing areas irrigated by arsenic-
bearing groundwaters may be undergoing a secular increase, suggesting that arsenic exposure
from rice might become even more significant in the future.
Cooking of rice with arsenic contaminated water has been found to lead to an increase in
the arsenic content of the rice (Rahman et al., 2006) and thereby increase of chronic arsenic
exposure. Mondal and Polya (2008) calculated that rice cooking contributes around 10% of
the median exposure to a study population in West Bengal – whilst this is a comparatively
small proportion of the total exposure, it represents an exposure that can be cheaply and
quickly minimized through education about appropriate rice cooking methods.
Measuring arsenic exposure histories through food frequency questionnaires and other
questionnaire based methods are notoriously difficult (Roychowdhury et al., 2002), not least
of all because of the challenges in obtaining accurate answers from volunteers, large degrees of
variability in diet on both a cyclic and secular basis, and seasonal and other temporal
variations in the arsenic content of foodstuffs. Measurement of arsenic > biomarkers in
nails, hair or urine, however, provides an objective measure of arsenic exposure, albeit over
short-periods of time. Gault et al. (2008) is one recent example of numerous studies which
have sought to obtain a working relationship between arsenic concentrations in nails (or hair)
with arsenic exposure via drinking water. Nail and hair arsenic concentrations were to found
vary between around 0.1 and 10 mg/g over the range of drinking water arsenic concentrations
of around 0.1–1,000 mg/L (ibid.). However, whilst they found a significant relationship
between these biomarkers and arsenic concentration in known drinking water supplies, the
relationships were rather poor, confounded by many factors, possibly including the use of
multiple water sources and arsenic exposure via food.
5 Dose–Response Relationships
There is a clear association between arsenic exposure and various cancers at concentrations in
drinking water at or above 100 mg/L but much below this concentration there is considerable
uncertainty and discussion about the nature of dose–response relationships – a clear area for
ongoing and future research. However, as Smith et al. (2000) points out, the complex series of
health end-points, multiple causes and confounding factors means that enormous cohorts
would be required to be studied over a period of decades in order to establish dose–response
relationships at arsenic drinking water concentrations much less than 100 mg/L.
Confounding factors include: nutritional status (Vahter, 2007) including of selenium
(Chen et al., 2007a) and folate (Chen et al., 2007b), genetic susceptibility (Ahsan et al.,
2007; Smith and Smith, 2004), smoking (Smith and Smith, 2004) and dietary habits.
Studies on populations from different parts of the world exposed to comparable levels of
arsenic in drinking water show varying degree of individual susceptibility to arsenic induced
genetic damage, metabolism, methylation capacity and other health effects (Brown, 2004;
NRC, 1999, 2001). Also, within the same population exposed to arsenic, only about 15–20%
actually develops arsenic-induced skin lesions that are considered to be the hallmarks of
> arsenicosis. This observation suggests that genetic composition is an important factor
that determines individuals’ susceptibility or resistance to arsenic toxicity. Consequently, it

is of utmost importance to understand the underlying molecular mechanisms that render a
person susceptible to arsenic toxicity.
Amongst others, the IICB in West Bengal has long been involved in deciphering the roles
played by > genetic polymorphisms with respect to arsenic susceptibility. Probable associa-
tions of several candidate genes, including arsenic metabolism pathway genes (GSTT1,
GSTM1, GSTP1, GSTO1, GSTO2, PNP) and DNA repair pathway genes (p53, ERCC2)
have been tested. GSTs encode for phase II detoxification enzymes that help in the excretion
of arsenic; PNP encodes for an enzyme that reduces inorganic arsenate to arsenite; p53 plays
a pivotal role in DNA repair, while protein product of ERCC2 is responsible for local
unwinding of DNA duplex, a primary prerequisite for proper repair of damaged DNA. The
> polymorphisms of all these genes have been showed to be associated with different types
of human maladies, especially cancers. In their studies, GSTM1 positive > genotype
(þ þ . þ ) and the three exonic SNPs in PNP gene (His20His, Gly51Ser, Pro57Pro)
were found to be associated with increased risk of developing arsenic-induced skin lesions
(Ghosh et al., 2006). For all three PNP polymorphisms, any genotype having at least one
minor allele was found to impart increased risk of developing arsenic-induced skin lesions.
p53 polymorphisms (p53 codon 72 Arg/Arg genotype and homozygous absence of 16 bp
duplication at Intron 3) and also ERCC2 > codon 751 Lys/Lys genotype were found to
impart increased risk of developing premalignant hyperkeratosis (Banerjee et al., 2007; De
Chaudhuri et al., 2006). The other candidate polymorphisms were found not to be asso-
ciated with arsenic toxicity in the West Bengal population.
5.1 Incidence Rates and Prevalence
Incidence rate is the rapidity with which new cases of a disease develops. Prevalence refers to
the proportion of a specified population exhibiting a given end-point during a given period of
time. > Table 41-3 summarizes, largely as prevalence ratios, some of the non-cancer health
effects observed from exposure to arsenic, notably dermal effects, cardiovascular effects,
cerebrovascular effects and diabetes mellitus. Incidence rates and prevalence of cancer health
outcomes have been modeled by NRC (1999) as follows.
The NRC (1999) estimated a dose response function that predicts the incidence rate
Il,g(x,t) for a given end point, l and gender, g, as a function of arsenic concentration and age
for arsenic induced lung, bladder and liver cancer expressed by the > Equation (1):
k 1
Il;g ðx; tÞ ¼ kl;g q0 ;l ;g q1;l;g x þ q2;l;g x2 t ml;g l;g H t ml;g ð1Þ
where t is the age in years, x is the arsenic concentration in mg/l, H = Heaviside function,
namely, H(t m) = 0 for t < m and H(t m) = 1 for t m and q0,l,g, q1l,g, q2l,g, kl,g, ml,g are
non negative age and gender dependent empirical parameters evaluated by NRC (1999) for
lung, bladder and liver cancer.
712
41
. Table 41-3
Selected studies of prevalence of non-cancer health outcomes of chronic arsenic exposure. Based in part of reviews by Navas-Acien et al. (2005, 2006). See
text for discussion of prevalence and incidence rates of cancer health outcomes
Health Type of No. of cases/

outcome Study area study Exposure total cases Risk estimate (95% CI) Comments Reference
Cardio- Taiwan Cross- High Arsenic 139 (stroke Relative risk: 2.69 (1.35–5.38) Age, gender, smoking, Chiou et al. (1997)
vascular sectional area prevalence)/ alcohol and cited by Navas-Acien
effect 7,963 hypertension adjusted et al. (2005)
risk estimates.
Taiwan Cross- High Arsenic 39 (Coronary Relative risk: 4.90 (1.36–17.7) Age, gender, smoking, Chen et al. (1996)
sectional area heart disease)/ BMI, lipids and cited by Navas-Acien
2,517 hypertension adjusted et al. (2005)
Quantification of Deaths and DALYs due to Chronic Exposure
risk estimates.
Diabetes Taiwan Cross- High Arsenic 27,543/ Relative risk: 2.69 (2.65–2.73) Age and gender Wang et al. (2003)
mellitus sectional area 678,791 adjusted risk estimates cited by Navas-Acien
et al. (2006)
Bangladesh Cross- High Arsenic 263/1,332 Relative risk: 2.10(1.10–4.20) Age and gender Rahman et al. (1999)
sectional area adjusted risk estimates cited by Navas-Acien
et al. (2006)
Respiratory West Cross- Arsenic 211/6,864 Prevalence Odds Ratio: m = 2.2 Age adjusted POR for Mazumder et al.
effect Bengal, sectional conc > 500 (non smokers) (1.3–4.1) f = 2.5(1.4–4.4) abnormal chest sound in (2000) cited by
India ppb compared non smokers Navas-Acien et al.
to <50 ppb (2006).
Dermal West Cross- Dose/body wt Hyper- Prevalence/100 Age adjusted prevalence Mazumder et al.
effects Bengal, sectional (g/kg/d) 0–3.2 pigmentation: Hyperpigmentation: m = 0.4, for the studied (1998)
India 3.2–14.9 14.9– 361 Keratosis: f = 0.0 m = 6.9, f = 2.9 m = 15.2, population
73.9 156/7,683 f = 5.9 Keratosis: m = 0.8, f = 0.8
m = 4.6, f = 2.2 m = 11.0, f = 3.5
Araihazar, Longitudinal As conc (ppb) 714/11,746 Prevalence odds ratios (PORs) PORs were adjusted for Ahsan et al. (2006)
Bangladesh study 8.1–40 40.1– (Skin lesions) for skin lesions: 1.91 (1.26,-2.89) age, gender, body mass
91 91.1–175 3.03 (2.05–4.50) 3.71 (2.53– index, education hukka
175.1–864 5.44) 5.39 (3.69–7.86) smoking, sun exposure
Compared and land ownership
with As
conc < 8.1
ppb
41
713
The NRC (1999) estimated a dose response function that predicts the prevalence ratio of
arsenic induced skin cancer as a function of arsenic concentration and age expressed by the
> Equation (2):
k
Pl;g ðx; tÞ ¼ 1 exp ðq0;l;g þ q1;l;g x þ q2;l;g x2 t ml;g l;g H t ml;g Þ ð2Þ
where the symbols have the same meanings as for > Equation (1).
5.2 Mortality Rates and SMRs
Several studies have been completed that contribute to establish the cancer and non-cancer
dose response relationships for arsenic exposure leading to death. Some of these epidemiolog-
ical studies are summarized in > Table 41-4. The evaluation criteria for citing the studies is
largely sample size as stated by NRC (2001) who note that findings from small studies, even
those with excellent methodology, are of limited utility.
SMRs provide a popular approach to summarize the observed patterns of mortality by
comparing mortality in a specific population with mortality from a suitable comparison
population. The SMRs reported in > Table 41-4 correspond to ratios of observed and expected
number of events and are calculated by > Equation (3):
P
Oi
SMR ¼ P ð3Þ
Ei
where Oi is the observed number of deaths in the ith age group and Ei is the corresponding
expected number of deaths, calculated by multiplying the study population size (Pi) by the
age-specific cancer death rate (Mi) in a comparison population (i.e., Ei = Pi. Mi) (Morales
et al., 2000).
The detailed mechanism for arsenic carcinogenicity being unknown and sub-linearity for
arsenic dose response relationship being speculative in spite of arsenic being known to cause
point mutations (Brown, 2004), the USEPA’s default to a linear extrapolation in the absence of
adequate mode-of-action data (USEPA, 2005) is, in part, a policy decision (NRC, 2001).
Several models can be used to calculate the dose response relationship resulting in deaths from
arsenic exposure.
Mortality rates may be calculated from incidence rates by taking into account case fatality
rates. Various models may be used to estimate case fatality rates. End member models are
exemplified by (1) Yu et al. (2003) who implicitly assume incidence rates to be equal to
mortality rates for lung, bladder and liver cancers; and of (2) NRC (1999, 2001) who, in one
model, implicitly assume that death rates for non-cancer end-points, such as diabetes mellitus
and ischemic heart diseases, are the same as background death rates, corrected for the
prevalence of this end-point in the population; whilst NRC (2001) also estimate case fatality
rates for lung and bladder cancer to be 100 and 80% respectively.
Similarly mortality rates may be calculated from prevalence, taking into account both
case fatality rates and estimates of duration of disease – thus Lokuge et al. (2004) estimate
skin cancer mortality from estimated case fatality rates of 14.3% over a 5 year duration
of disease.
More detailed reviews of dose–response relationships may be found in NRC (1999),
Morales et al. (2000), NRC (2001), Brown (2004) and Marshall et al. (2007) and refer-
ences therein.
. Table 41-4
Selected studies of fatal health outcomes of chronic arsenic exposure. All risks refer to mortality rather than prevalence of disease. Based in part on review
by NRC (2001). Studies cited by NRC (2001) included here but not cited in the reference list are: Hopenhayn-Rich C, Bigg ML, Smith AH (1998) Int.
J. Epidemiology 27: 561–569; Smith AH, Goycolea, Haque R, Bigg ML (1998) American Journal of Epidemiology 147: 660–669; Tsai SM, Wang TN, Ko YC
(1999) Archives Environmental Health 54: 186–193; Wu MM, Kuyo TL, Hwang YH, Chen CJ (1989) American Journal of Epidemiology 130: 1123–1132
Health out Type of No. of

come Study area study Exposure cases Risk estimate (95% CI) Comments Reference
Lung cancer Chile Ecological Highest 307,541 Peak mortality risk ratio: Mortality of region II compared Marshall
(50 year population deaths m = 3.61(3.13–4.16) f = 3.26 with region V et al. (2007)
study) weighted from (2.50–4.23)
average As region II
conc: 569ppb and V
Lung cancer Bangladesh Cohort Arsenic effected 65,876 Lifetime excess risk per 100,000: Age and gender adjusted lifetime Chen and
area (Study m = 175.92 f = 48.3 excess relative risks computed for Ahsan
population) the population of Bangladesh (2004) cited
by NRC
(2001)
Lung cancer Taiwan Cohort Arsenic Deaths: SMR: m = 2.64 (2.45–2.84) SMRs calculated from total Tsai et al.
(external endemic area m-699, f = 3.50 (3.19–3.84) observed death and expected (1999) cited
comparison) f-471 death between 1971 and 1994 by NRC
from National mortality data. (2001)
Lung cancer Northern Ecological 5 year average Deaths: SMR: m = 3.8 (3.5–4.1) f = 3.1 SMRs calculated from total Smith et al.
Chile m-544, (2.7–3.7) observed death and expected (1998) cited
f-154 death calculated from National by NRC
mortality data. (2001)
41
715
716

41
Lung cancer Corboda Ecological As Conc: Low Deaths: m- SMR: m = 0.92(0.88–0.98); SMRs calculated from total Hopenhayn-
Province, Medium High 826, f-154 f = 1.24(1.06–1.42) m = 1.54 observed death and expected Rich et al.
Argentina m-914, f- (1.44–1.64); f = 1.34(1.12–1.58) death between 1986 and 1991 for (1998) cited
154 m-708, m = 1.77(1.63–1.90); f = 2.16 all Argentina as the reference by NRC
f-154 (1.83–2.52) population (2001)
Lung cancer Taiwan Cohort Average Deaths: m- Age standardized mortality: Age standardized mortality per Wu et al.
(external As: < 0.30ppm, 53, f-43 m- m = 49.16, f = 36.71 m = 100.67, 100,000 against 1976 World (1989) cited
comparison) 0.30–0.59ppm, 62, f-40 m- f = 60.82 m = 104.08, f = 122.16 population by NRC
0.60 ppm 32, f-38 (2001)
Bladdercancer Chile Ecological Highest 307,541 Peak mortality risk ratio: Mortality of region II compared Marshall
(50 year population deaths m = 6.10(3.97–9.39) f = 13.8 with region V et al. (2007)
study) weighted from (7.74–24.5)
average As region II
conc: 569ppb and V
Bladdercancer Bangladesh Cohort Arsenic effected 65,876 Lifetime excess risk per 100,000: Age and gender adjusted lifetime Chen and
by NRC
(2001)
Bladdercancer Taiwan Cohort Arsenic Deaths: m- SMR: m = 10.50(9.37–11.73) SMRs calculated from total Tsai et al.
(external endemic area 312, f-295 f = 17.65(5.70–19.79) observed death and expected (1999) cited
comparison) death between 1971 and 1994 by NRC
Bladdercancer Northern Ecological 5 year average Deaths: m- SMR: m = 6.0(4.8–7.4) f = 8.2 SMRs calculated from total Smith et al.
Chile 93, f-64 (6.3–10.5) observed death and expected (1998) cited
death calculated from National by NRC
Bladdercancer Corboda Ecological As Conc: Low Deaths: m- SMR: m = 0.80(0.66–0.96); SMRs calculated from total Hopenhayn-
Province, Medium High 113, f-39 m- f = 1.22(0.86–1.67) m = 1.28 observed death and expected Rich et al.
Argentina 116, f-29 m- (1.05–1.53); f = 1.39(0.93–1.99) death between 1986 and 1991 for (1998) cited
131, f-27 m = 2.14(1.78–2.53); f = 1.81 all Argentina as the reference by NRC
(1.19–2.64) population. (2001)
Bladdercancer Taiwan Cohort Average Deaths: m- Age standardized mortality: Age standardized mortality per Wu et al.
(external As: < 0.30ppm, 23, f-30 m- m = 22.64, f = 25.60 m = 61.02, 100,000 against 1976 World (1989) cited
0.60 ppm 26, f-30 (2001)
Kidney cancer Taiwan Cohort Arsenic Deaths: m- SMR: m = 6.80 (5.49–8.32) SMRs calculated from total Tsai et al.
(external endemic area 94, f-128 f = 10.49 (8.75–12.47) observed death and expected (1999) cited
Kidney cancer Northern Ecological 5 year average Deaths: m- SMR: m = 1.6 (1.1–2.1) f = 2.7 SMRs calculated from total Smith et al.
Kidney cancer Corboda Ecological As Conc: Low Deaths: m- SMR: m = 0.87(0.66–1.10); SMRs calculated from total Hopenhayn-
Province, Medium High 66, f-38 m- f = 1.00(0.71–1.37) m = 1.33 observed death and expected Rich et al.
Argentina 66, f-34 m- (1.02–1.68); f = 1.36 (0.94–1.89) death between 1986 and 1991 for (1998) cited
53, f-27 m = 1.57 (1.17–2.05); f = 1.81 all Argentina as the reference by NRC
(1.19–2.64) population. (2001)
Kidney cancer Taiwan Cohort Average As: Deaths: m- Age standardized mortality: Age standardized mortality per (Wu et al.
(external <0.30ppm, 9, f-4 m-11, m = 8.42, f = 3.42 m = 18.90, 100,000 against 1976 World (1989) cited
comparison) 0.30–0.59ppm, f-13 m-6, f = 19.42 m = 25.26, f = 57.98 population by NRC
0.60 ppm f-16 (2001)

Liver cancer Bangladesh Cohort Arsenic effected 65,876 Lifetime excess risk per 100,000: Age and gender adjusted lifetime Chen and
by NRC
(2001)
41
717
718
41

Liver cancer Northern Ecological 5 year average Deaths: m- SMR: m = 1.1(0.8–1.5) f = 1.1 SMRs calculated from total Smith et al.
Liver cancer Taiwan Cohort Average As: Deaths: m- Age standardized mortality: Age standardized mortality per Wu et al.
(external < 0.30ppm, 54, f-25 m- m = 47.78, f = 21.40 m = 67.62, 100,000 against 1976 World (1989) cited
0.60 ppm 27, f-10 (2001)
Skin cancer Northern Ecological 5 year average Deaths: m- SMR: m = 7.7(4.7–11.9) f = 3.2 SMRs calculated from total Smith et al.
Skin cancer Taiwan Cohort Average As: Deaths: m- Age standardized mortality: Age standardized mortality per Wu et al.
(external < 0.30ppm, 2, f-2 m-8, f- m = 2.03, f = 1.73 m = 14.01, 100,000 against 1976 World (1989) cited
comparison) 0.30–0.59ppm, 10 m-9, f-5 f = 14.75 m = 32.41, f = 18.66 population by NRC
0.60 ppm (2001)
Prostate Taiwan Cohort Average As: Deaths: m- Age standardized mortality: Age standardized mortality per (Wu et al.
cancer (external < 0.30ppm, 1, m-5, m-3, m = 0.95 m = 9.00 m = 9.18 100,000 against 1976 World (1989) cited
comparison) 0.30–0.59ppm, population by NRC
0.60 ppm (2001)
Stomach Taiwan Cohort Arsenic Deaths: SMR: m = 0.96(0.83–1.11) SMRs calculated from total Tsai et al.
cancer (external endemic area m-195, f = 1.01(0.83–1.22) observed death and expected (1999) cited
comparison) f-111 death between 1971 and 1994 by NRC
Stomach Taiwan Cohort Average As: Deaths: m- Age standardized mortality: Age standardized mortality per Wu et al.
cancer (external < 0.30ppm, 26, f-8 m- m = 25.66, f = 6.71 m = 17.82, 100,000 against 1976 World (1989) cited
0.60 ppm 10, f-2 (2001)
Colon cancer Taiwan Cohort Arsenic Deaths: m- SMR: m = 1.35(1.09–1.66) SMRs calculated from total Tsai et al.
(external endemic area 91, f-83 f = 1.20(0.96–1.49) observed death and expected (1999) cited
Colon cancer Taiwan Cohort Average As: Deaths: m- Age standardized mortality: Age standardized mortality per Wu et al.
(external < 0.30ppm, 8, f-11 m-6, m = 7.94, f = 9.05 m = 8.30, 100,000 against 1976 World (1989) cited
comparison) 0.30–0.59ppm, f-5 m-3, f-5 f = 8.16 m = 12.51, f = 17.21 population by NRC
0.60 ppm (2001)
Diabetes Taiwan Cohort Arsenic Deaths: m- SMR: m = 1.14(0.98–1.31) SMRs calculated from total Tsai et al.
mellitus (external endemic area 188, f-343 f = 1.23(1.11–1.37) observed death and expected (1999) cited
Ischem-ic Taiwan Cohort Arsenic Deaths: m- SMR: m = 1.50(1.36–1.64) SMRs calculated from total Tsai et al.
heart disease (external endemic area 445, f-283 f = 1.23(1.09–1.39) observed death and expected (1999) cited
41
719
6 Deterministic and Probabilistic Risk Assessments
6.1 Reasons and Basis for Assessment of Risk Arising from

Environmental Hazards
Objectively assessing health risks, either as excess mortality or DALYs, as a result of chronic
exposure to groundwater arsenic, is necessary to inform policy makers and other groups as to
the extent of the problem, to identify particular at risk groups and to assess the relative merits
of various remediation strategies. Assessing the overall risk of utilization of arsenic-bearing
groundwaters may be achieved, in principle, by quantifying (1) arsenic hazard in the ground-
water source; (2) exposure routes; (3) health impact response to known exposure doses.
Quantitative risk assessments are associated with uncertainties and variabilities – these may
be dealt with following either deterministic or probabilistic methodologies.
6.2 Deterministic vs. Probabilistic Assessment Methods
The traditional deterministic approach to risk assessment is to deal with variability and
uncertainty by successively adding safety factors or selecting parameter estimates that will
almost certainly overestimate the risks involved (Paustenbach, 2000). This gives a distinct
estimate of maximum exposure, which can subsequently be compared with reference values
for health and environmental effects. It is not possible, however, to obtain an indication of the
uncertainty in this value or the margin of safety (NRC, 1999).
Probabilistic risk assessment, on the other hand, provides a method to deal with these
problems. Variability and uncertainty in input parameters are described by probability
distributions, and output is likewise presented as a probability distribution. Probabilistic
analysis addresses the main deficiencies of point estimates because it imparts more informa-
tion and uses all of the available data. The purpose of probabilistic methods is to find a rational
and scientifically justifiable method of dealing with uncertainty and variability. The selection
of probability distributions for input variables is the single most important factor determining
the outcomes of a probabilistic risk assessment – mostly standard probability distributions are
used for factors that do not vary greatly between different sites (Paustenbach, 2000). The
results of probabilistic risk assessment can facilitate sensitivity analysis and will ultimately have
particular relevance to determining high risk sub-groups of the population.
6.3 Quantitative Risk Assessment of Arsenic-Induced Deaths and

DALYs in Bangladesh
Two methods of calculating arsenic-attributable deaths and DALYs are illustrated schemati-
cally in > Figure 41-4. Both methods utilize the same exposure data. Both methods may be
implemented in a deterministic or probabilistic mode. Method (I), previously utilized by
Lokuge et al. (2004) and Adamson and Polya (2007), uses previously published SMRs to
determine the arsenic-related population attributable fraction (PAF) of identified health
impacts. The estimation of the disease burden is then made from arsenic-related PAF of the
disease combined with background rates, for example as published by the Global Burden of
Disease study. Method (II), previously utilized by Howard et al. (2006, 2007), is based on the
determination of the disease burden as a continuous function of arsenic concentration by
. Figure 41-4
Conceptual model for risk assessment calculations of deaths and DALYs associated with chronic
exposure to arsenic derived from groundwater
using dose-response models given, for example, by Yu et al. (2003) based on a NRC (2001)
model, assuming case fatality rates, and then combining these with the empirical formulae for
DALYs by Murray and Lopez (1996).
DALYs may be calculated as the sum of the years of life lost (YLL) due to premature death
and the equivalent ‘‘healthy’’ years lost due to disability (YLD):
DALY ¼ YLL þ YLD ð4Þ
YLL for a given end-point, l, gender, g, and age class interval, tc, may be calculated from the
incidence multiplied by the years of life lost due to a death at the age at which death occurs:

YLLl;g;tc ¼ Deathl;g;tc Yg;tc ð5Þ
where Yg,tc = years of life lost due to death at the age at which death occurs, values provided by
Murray and Lopez (1996).
YLD may be calculated for non-zero discounting and non-uniform age weighting as
follows (Murray and Acharya, 1997):
Certc
YLDl;g;tc ¼ Deathl;g;tc ðDWl Þ ½eðbþrÞðLl þtc Þ ððb þ rÞðLl þ tc ÞÞ
ðb þ rÞ2 ð6Þ
ðbþrÞtc
e ððb þ rÞtc 1Þ
where DWl = disability weight (e.g., 0.146 for lung cancer, 0.085 for bladder cancer and 0.239
for liver cancer) (Murray and Lopez, 1996), C = age-weighting correction constant (GBD
standard value is 0.1658), r = discount rate (GBD standard value is 0.03), b = parameter from
the age-weighting function (GBD standard value is 0.04), and Ll = duration of disability, data
(e.g., 1.7 years for lung cancer, 4 years for bladder cancer and 3.6 years for liver cancer)
(Murray and Lopez, 1996).
Because the risk of dying from arsenic exposure is age and gender dependent, risk is
expressed as age and gender adjusted excess lifetime risk and can be calculated by integrating
the death hazard over the typical lifetime in the population of interest:
c ¼22 X
tX g¼f
DALYl ¼ DALYl;g;tc
tc ¼1 g¼m
where the summations are over all age groups and both genders.
> Tables 41-5 and > 41-6 summaries the risk estimates in terms of deaths and DALYs
respectively for the population of Bangladesh based broadly on these methods.
. Table 41-5
Estimated cancer deaths per year from chronic groundwater-derived arsenic exposure in Ban-
gladesh. The skin cancer deaths from Yu et al. (2003) were calculated from their prevalence data
assuming exposure for 20 years. Case fatality rates used here were 100% for lung cancers (NRC,
2001); 80% for bladder cancers (NRC, 2001); 100% for liver cancers; 14.3% for skin cancers
(Lokuge et al., 2004); Values calculated by Mondal et al. (2008) were done using the methodology
and data-sources cited by Adamson and Polya (2007) with population exposure data from
Lokuge et al. (2004), with the exception of the value for skin cancer, which is based on the data of
Yu et al. (2003) corrected for both case fatality rate for just the population exposed to greater
than 50 ppb arsenic in drinking water
Yu et al. Yu et al. (2003)

(2003) corrected for case Lokuge et al. (2004) Mondal et al (in prep)
Whole fatality rate whole Population exposed Population exposed
population population to >50 ppb As to >50 ppb As
Lung 1,840 1,840 2,100 3,696
cancer
Bladder 900 720 1,346 131
cancer
Liver 510 510 NA 140
cancer
Skin 6,280 898 126 728
cancer
Ischemic Not Not reported 5,128 3,588
heart reported
disease
Diabetes Not Not reported 351 327
mellitus reported
The risk estimates are highly dependent on the model choice. Risk estimates can be based on a
Poisson regression model or SMR approach and may or may not include an external comparison
population (NRC, 2001). Morales et al. (2000), amongst others, highlighted the substantive
differences that may accrue in calculated arsenic-attributable health risks depending upon the
nature of the external comparison population. Furthermore, care needs to be taken in the
application of dose–response models derived from populations in which the exposure duration
. Table 41-6
Estimated DALYs per year from chronic groundwater-derived arsenic exposure in Bangladesh.
Values calculated by Mondal et al. (2008) were done using the methodology and data-sources
cited by Adamson and Polya (2007) with population exposure data from Lokuge et al. (2004),
with the exception of the value for skin cancer, hyperpigmentation and keratosis, which are
calculated as follows: skin cancers – product of total mortality from Table > 41-4 and YLL (years
of life lost) based on age at death of 55 years; hyperpigmentation and keratosis – based on YLD
(years of life lost due to disability) only with prevalence from Yu et al. (2003) and severity
weighting from Fewtrell and Kay (2005) which is based on the data of Yu et al. (2003) corrected
for both case fatality rate for just the population exposed to greater than 50 ppb arsenic in
drinking water
Lokuge et al. (2004) Lokuge et al. (2004) Mondal et al (2008)

Population exposed Population exposed Population exposed
to >50 ppb As to >50 ppb As to >50 ppb As
(undiscounted) (discounted at 3%) (discounted at 3%)
Lung cancer 39,759 28,921 37,427
Bladder cancer 25,432 17,121 11,823
Liver cancer NA NA 1,936
Skin cancer 3,379 2,120 10,5851
Ischemic heart 91,616 67,380 39,803
disease
Diabetes mellitus 10,524 7,628 6,186
Hyperpigmentation Not reported Not reported 187,7552
Keratosis Not reported Not reported 91,8452
may be different from the populations to which the data are being applied. Differences between
risks calculated using Method (I) and Method (II) approaches emphasise how dose–response
relationships may not be the same in the different regions, as result of different background rates
and different environment-dependent and genetic-dependent (cf. Ahsan et al., 2007; Mahata
et al., 2003; Smith and Smith, 2004) susceptibility to arsenic-induced diseases. Lastly, more
sophisticated models need to be developed to account for systematic variations in excess
mortality and DALY rates as function of time elapsed since peak exposure, such models being
particularly important for health end-points with long latency periods.
7 Remediation Options
Many types of remediation options have been proposed and implemented in regions of the
world impacted by high arsenic groundwaters—these broadly falls into six classes, relating to
(1) treatment of exposed individuals; (2) provision of alternative water supplies; (3) treatment
of groundwater in the ground; (4) treatment of groundwater after extraction; (5) modification
of rice cooking methods; and (6) modification of agricultural practices.
Which options are the most appropriate depends upon a number of factors including: how
advanced arsenic-related diseases have progressed; the nutritional and economic status of
those impacted; the availability of nearby alternative water supplies; local mores impacting the
likelihood or otherwise of alternative water supplies being routinely accessed by householders,

particularly women; short-term vs. long-term solution requirements; and regional or national
economic circumstances. Ultimately, a combination of options is most likely to be more
comprehensively effective than any single option.
The effectiveness of many mitigation measures depend critically upon educating water-
users and those responsible for operating mitigation technologies, whether simple or complex.
Many technologies depend upon regular monitoring and maintenance in order to maintain
their long-term effectiveness.
Modification of agricultural practices, including changing rice-growing methods to lower
soil-plant arsenic transfer rates and utilizing rice varieties which exhibit lower rates of arsenic
uptake from soils, are the subject of on-going research and will become increasingly important
as remediation of drinking water supplies and contamination of rice paddy field sites increases
the relative importance of rice as an arsenic exposure route (Mondal and Polya, 2008).
Cooking in arsenic-free water, ensuring a substantial excess of water throughout the cooking
process and discarding the gruel are all cheap easy-to-implement measures that can further
reduce arsenic exposure from consumption of rice.
In situ treatment methods in shallow reducing groundwater are largely based on reversing
the reductive processes that lead to arsenic mobilization in the first place. Bioremediation
treatments are currently being investigated. Direct injection of oxygen has been found to be
very effective, but is also prohibitively expensive.
In contrast, several ex situ treatment options are relatively cheap. George Mason Uni-
versity’s Abul Hussam, recently won the US$ 1,000,000 Grainger Gold Challenge Award for
arsenic treatment methodology, which is reported to have the capability of filtering 20 L of
water per hour at a total cost of around US$35 and may last up to 5 year without replacement.
The treatment is based on a three bucket system with Fe(III)-phases and charcoal as the active
arsenic removal components.
In Bangladesh and West Bengal, India, the major emphasis for the mitigation of arsenic is
the provision of alternative water sources. In West Bengal, for example, of the order of US$
500,000,000 is being spent over the next few years on major water engineering (piped surface
water supply schemes, arsenic treatment plants) works to provide sustainable safe water
supplies to over 11 million people. A number of alternative water-supply technologies have
been identified and tested on a pilot basis in several areas of Bangladesh and West Bengal.
Options include improved dugwells (DG), deep tubewells (DTW), pond-sand filters (PSF),
and rainwater harvesting (RWH) (Howard et al., 2006).
8 Relative Magnitude of Arsenic-Related and Water-Borne

Pathogen Related Health Impacts
It is imperative that mitigation of arsenic in groundwaters does not result in the substitution
of arsenic-related health risks by other health risks. Howard et al. (2006), for example, points
out that, where surface water or dug wells are used as alternative water supplies, health-risks
from water-borne pathogens, notably viruses, bacteria and protozoa, potentially massively
out-weigh those of arsenic-related health risks.
Arsenic-related disease due to chronic exposure through drinking water has a relatively
low incidence and a latency of up to decades for most end points significant to a burden of
disease assessment (NRC, 2001) However, case fatality rates for arsenic-related cancers in
countries such as Bangladesh or India where access to health care is limited are high (Lokuge
et al., 2004). In contrast, diarrheal and other diseases arising from water-borne pathogens,
have relatively high incidence, short latency but comparatively low case fatality rates (Lokuge
et al., 2004). Explicit quantitative comparison of DALYs arising from arsenic-related health
impacts and those related to water borne pathogens are therefore required to assess the relative
impacts of these two contrasting sets of health impacts.
DALY calculations have been carried out by several groups to estimate the relative impor-
tance of (1) groundwater arsenic and (2) surface- and shallow-water pathogens in impacting
human health, thus providing an insight into the relative benefits of various groundwater
arsenic mitigation strategies (Adamson and Polya, 2007; Howard et al., 2006, 2007; Lokuge
et al., 2004). Howard et al. (2006, 2007), in particular, has calculated the excess death and DALYs
related to both arsenic and pathogens for various proposed groundwater arsenic mitigation
options. Lokuge et al. (2004) have calculated the health impacts of substitution of arsenic-
bearing groundwater supplies, explicitly taking into account the health impacts estimated to
arise from the use of waters containing pathogens. Adamson and Polya (2007) extended this
study by determining the sensitivity of these calculations to uncertainties in published dose–
response relationships for arsenic and both ischemic heart disease and diabetes mellitus.
These various studies have essentially used two different approaches to calculate arsenic-
related disease burden. Lokuge et al. (2004) and Adamson and Polya (2007) used a Method (I)
(see > Figure 41-4) approach based upon the use of the Global Burden of Disease study –
reported deaths and DALYs as the background rates for the endpoints under consideration,
whereas Howard et al. (2006, 2007) used a Method (II) (see > Figure 41-4) approach based on
the use of empirical formulae for death and DALY estimates.
Lokuge et al. (2004) demonstrated that substitution of alternative water supplies for
arsenic-bearing groundwaters from DTWs may lead to an increase in overall negative health
impacts, depending upon the concentrations of arsenic in the replaced DTWs, and particularly
in regions or districts where sanitation is poor. There is considerable discussion over the
appropriateness of the figure used by Lokuge et al. (2004) to estimate the potential increase in
water-borne diseases in such areas, but irrespective of this there is clearly as cross-over point in
terms of arsenic concentration in groundwater, below which increased DALYs from water-
borne diseases will inevitably exceed those saved from arsenic mitigation (Adamson and Polya,
2007) (> Figure 41-5).
Howard et al. (2006, 2007) further identified which alternative water sources were most
susceptible to contamination by pathogens by measuring – in the field – the abundance of
thermally tolerant colliforms (as a proxy for the concentrations of key viral, bacterial and protozoan
pathogens) in various remediation schemes. They found that: (1) in most cases calculated DALYs
due to water-borne pathogens were much higher than DALYs attributable to arsenic; (2) dug wells
and pond sand filter were particularly susceptible to contamination by pathogens; and (3)
pathogen contamination was strongly seasonally dependent with RWH schemes being particularly
prone to contamination during the dry season because of prolonged storage.
Of course, if alternative water supplies are adequately protected from pathogens then this risk-
substitution is no long is a key issue. Clasen and Cairncross (2004) note that the nature of drinking
water sources is not the dominant factor in determining the prevalence of waterborne diseases in
developing countries; rather the nature of sanitary facilities and water handling procedures,
particularly within the household, is the dominant factor. Chlorination is a very effective method
for deactivating water-borne pathogens, but this must be done on a frequent and regular basis and
be accompanied by appropriate monitoring in order for its effectiveness to be assured. Dipankar
. Figure 41-5
Sketch showing qualitative impact of replacing high arsenic groundwaters with alternative
water supplies. DALYs arising from exposure to arsenic in groundwater and water-borne
pathogens are sketched as a function of groundwater arsenic concentration. The qualitative
impact of various interventions are also shown. After Adamson and Polya (2007)
Chakraborti from SOES at Jadavpur University further notes (personal communication) the
importance, for dug wells, of locating away from sanitary pits, preventing contamination by the
use of fine net or fiber-glass coverings, enabling direct sunlight into the wells or using UV
sterilization, and regularly removing bottom sediments in the wells. Thus, ultimately, remediation
of arsenic exposure requires several parallel approaches to be implemented.
Improving the economic and educational status of those exposed, particularly in develop-
ing countries, is likely to lead to better nutrition, better sanitation and better understanding of
arsenic-related and other water-borne risks – all of which would concomitantly reduce health
risks arising both from groundwater arsenic and other water-borne diseases.
Summary Points
Groundwaters with arsenic concentrations higher than the WHO provisional guide value
of 10 mg/L are found in many parts of world, and widespread utilization of these ground-
waters for drinking, irrigation of food crops and cooking over the past few decades has
resulted in chronic exposure to tens of millions of people, annual excess deaths of the order
of thousands and annual DALYs of the order of hundreds of thousands in Bangladesh, the
worst impacted country.
Cancers impacts of chronic arsenic exposure include: skin, lung, bladder and liver cancers.
Non-cancerous endpoints include arsenicosis – hyperpigmentation and keratoses of the
skins, and – although this is currently subject to some debate – ischemic heart disease,
hypertension and diabetes mellitus.
Many health end-points are non-fatal but nevertheless result in considerable loss of quality
of life.
Assessing the overall risk of utilization of arsenic-bearing groundwaters may be achieved,
in principle, by quantifying (1) health impact response to known exposure doses; (2)
exposure routes; and (3) arsenic hazard in the groundwater source.
There is a clear association between arsenic exposure and various cancers, particular skin
and lung cancers, at high concentrations but below 100 mg/L there is considerable
argument over the nature of the dose–response relationships.
Nutritional status, genetic disposition, smoking habits, age and gender all contribute to the
risk of acquiring arsenic-related disease as a result of a given exposure.
The major exposure routes for arsenic from groundwaters are: (1) drinking groundwater;
(2) eating rice irrigated with groundwater; (3) cooking rice with high arsenic groundwater.
Arsenic hazard in groundwater is highly heterogeneous – and therefore predictions of
arsenic hazard on a well-by-well basis are typically associated with very high uncertainty
and poor confidence limits.
Assessing the impact of various remediation options needs to explicitly consider risk-
substitution, including the balance between DALYs arising from arsenic-related health
impacts and those related to water borne pathogens, however, with good practice there is
no reason in principle why both risks may not be simultaneously addressed.
Acknowledgments
This work is a joint output of the PRAMA and AquaTRAIN projects. PRAMA is a UKIERI
(UK India Education and Research Initiative) project funded by the British Council, the UK
Department for Innovation, Universities and Skills (DIUS), Office of Science and Innova-
tion, the FCO, Department of Science and Technology, Government of India, The Scottish
government, Northern Ireland, Wales, GSK, BP, Shell and BAE for the benefit of the India
Higher Education Sector and the UK Higher Education Sector. AquaTRAIN is funded by
the European Commission Sixth Framework Programme (2002–2006), Marie Curie
Actions – Human Resources and Mobility Activity Area, Research Training Networks. DM
acknowledges the receipt of an NERC Dorothy Hodgkins Postgraduate Award. We thank
George Adamson, Dipankar Chakraborti, Tony Fletcher, Guy Howard, D.N. Guha Mazumder,
Ross Nickson, Luis Rodriguiz-Lado and Allan Smith for discussions. The views expressed
here are not necessarily those of any of the funding bodies or any of the individuals
acknowledged here.
References
Adamson GCD, Polya DA. (2007). J Environ Sci Health., Banerjee M, Sarkar J, Das JK, Mukherjee A, Sarkar AK,
Part A. 42: 1909–1917. Mondal L, Giri AK. (2007). Carcinogenesis. 28:
Ahsan H, Chen Y, Parvez F, Zablotska L, Argos M, 672–676.
Hussain I, Momotaj H, Levy D, Cheng Z, Brown J. (2004). Public Health Goal for Arsenic in
Slavkovitch V, van Geen A, Howe GR, Graziano Drinking Water. Office of Environmental Health
JH. (2006). Am J Epidemiol. 163: 1138–1148. Hazard Assessment, California Environmental Pro-
Ahsan H, Chen Y, Kibrita MG, Slavkovich V, Parvez F, tection Agency.
Jasmine F, Gamble MV, Graziano JH. (2007). Epi- Cantor KP, Lubin JH. (2007). Toxicol Appl Pharmacol.
demiol Biomar Prevent. 16: 1270–1278. 222: 252–255.
Charlet L, Polya DA. (2006). Elements. 2: 91–96. Murray CJL, Acharya AK. (1997). J Health Econ. 16:
Chen Y, Hall M, Graziano JH, Slavkovich V, van Geen A, 703–730.
Parvez F, Ahsan H. (2007a). Cancer Epidemiol Pre- Murray CJL, Lopez AD. (1996). In: Global Health Statis-
vent. 16: 207–213. tics. Global Burden of Disease and Injury
Chen Y, Factor-Litvak P, Howe GR, Graziano JH, Brandt- Series, Vol. I and II. WHO/Harvard University
Raul P, Parvez F, van Geen A, Ahsan H. (2007b). Am Press, 1996.
J Epidemiol. 165: 541–552. Navas-Acien A, Sharrett AR, Silbergeld EK, Schwartz BS,
Clasen TF, Cairncross S. (2004). Trop Med Int Health. 9: Nachman KE, Burke TA, Guallar E. (2005). Am J
187–191. Epidemiol. 162: 1037–1049.
Cullen WR, Reimer KJ. (1989) Chem Rev. 89: 713–764. Navas-Acien A, Silbergeld EK, Streeter RA, Clark JM,
De Chaudhuri S, Mahata J, Das JK, Mukherjee A, Burke TA, Guallar E. (2006). Environ Health Per-
Ghosh P, Sau TJ, Mondal L, Basu S, Giri AK, spect. 114: 641–648.
Roychoudhury K. (2006). Mutat Res. 601: 102–112. Nickson R, McArthur J, Burgess W, Matin Ahmed K,
Fewtrell FR, Kay D. (2005). J Water Health. 3: 101–107. Ravenscrof P, Rahman M. (1998). Nature 395: 338.
Gault AG, Rowland HAL, Charnock JM, Wogelius RA, NRC. (1999). In: Arsenic in Drinking Water. National
Gomez-Morilla I, Vong S, Leng M, Samreth S, Academy, Washington, DC.
Sampson ML, Polya DA. (2008). Sci Total Environ. NRC. (2001). In: Arsenic in Drinking water. 2001 Up-
393: 168–176. date. National Academy, Washington, DC.
Ghosh P, Basu A, Mahata J, Basu S, Sengupta M, Das JK, Paustenbach DJ. (2000). J Toxicol Environ Health. 3:
Mukherjee A, Sarkar AK, Mondal L, Ray K, Giri AK. 179–291.
(2006). Int J Cancer. 118: 2470–2478. Polya DA, Gault AG, Niebe N, Feldmann P, Rosenboom
Harvey CF, Swartz CH, Badruzzaman ABM, Keon-Blute JW, Gilligan E, Fredericks D, Milton AH,
N, Yu W, Ali MA, Jay J, Beckie R, Niedan V, Sampson M, Rowland HAL, Lythgoe PR, Jones JC,
Brabander D, Oates PM, Asfaque KN, Islam S, Middleton C, Cooke DA. (2005). Mineral Mag. 69:
Hemond HF, Ahmed MF. (2002). Science. 298: 807–823.
1602–1606. Rahman MA, Hasegawa H, Rahman MA, Rahman MM,
Howard G, Ahmed MF, Shamsuddin A, Mahmud SG, Miah MAM. (2006). Sci Total Environ. 370: 51–60.
Deere D. (2006). J Health Popul Nutr. 24: 346–355. Rahman MM, Mandal BK, Chowdhury TR, Sengupta
Howard G, Ahmed MF, Teunis P, Mahmud SG, MK, Chowdhury UK, Lodh D, Chanda CR, Basu
Davison A, Deere D. (2007). J Water Health. 5: GK, Mukherjee SC, Saha KC, Chakraborti D. (2003).
67–81. J Environ Sci Health., Part A. 38: 25–59.
Huq SMI, Joardar JC, Parvin S, Correll R, Naidu R. Ravenscroft P. (2007). Royal Geographical Society Annu-
(2006). J Health Popol Nutr. 24: 305–316. al Meeting 2007 http://www.geog.cam.ac.uk/re-
Islam FS, Gault AG, Boothman C, Polya DA, Charnock search/projects/arsenic/symposium/S1.2_P_Raven-
JM, Chatterjee D, Lloyd JR. (2004). Nature. 430: scroft.pdf; accessed 28/3/2008.
68–71. Roberts LC, Hug SJ, Dittmar J, Voegelin A, Saha GC, Ali
Linberg A-L, Goessler W, Gurzau E, Koppova K, MA, Badruzzanian ABM, Kretzschniar R. (2007)
Rudnai P, Kumar R, Fletcher T, Leonardi G, Environ Sci Technol. 41: 5960–5966.
Slotova K, Gheorgiu E, Vahter M. (2006). J Environ Rodriguez-Lado L, Polya DA, Winkel L, Berg M, Hegan A
Monitor J Environ Monitor. 8: 203–208. (2008). Appl. Geochem. in press.
Lokuge KM, Smith W, Caldwell B, Dear K, Milton A. Roychowdhury T, Uchino T, Tokunaga H, Ando M.
(2004). Environ Health Perspect. 112(11): (2002). Food Chem Toxicol. 40: 1611–1621.
1172–1177. Smedley P, Kinniburgh D. (2002). Appl Geochem. 17:
Mahata J, Basu A, Ghoshal S, Sarkar JN, Roy Ak, Poddar 517–568.
G, Nandy AK, Banerjee A, Ray K, Natarajan AT, Smith AH, Smith MMH. (2004). Toxicology 198: 39–44.
Nilsson R, Giri Ak (2003). Mutation Res. 534(1-2): Smith AH, Lingas E, Rahman M. (2000). B World Health
133–143 Organ. 78: 1093–1103.
Marshall G, Ferreccio C, Yuan Y, Bates MN, Steinmaus C, USEPA. (2005) In: Issue Paper: Inorganic Arsenic Cancer
Selvin S, Liaw J, Smith AH. (2007). J Natl Cancer Slope Factor, Final Draft, July 22, 2005
Inst. 99: 920–928. Vahter ME. (2007) J Nutr. 137: 2798–2804.
Mazumder DNG, Haque R, Ghosh N, De BK, Santra A, WHO. (2001) In: Environmental Health Criteria 224.
Chakraborty D, Smith AH. (1998). Int J Epidemiol. Arsenic and Arsenic Compounds. World Health
27: 871–877. Organization. Geneva.
Mondal D, Adamson GCD, Nickson R, Polya DA. Williams PN, Islam MR, Adomako EE, Raab A, Hossain
(2008). Appl Geochem in press. doi:10.1016/j. SA, Zhu YG, Feldmann J, Meharg AA. (2006). Envi-
apgeochem.2008.06.009 ron Sci Technol. 40: 4903–4908.
Morales KH, Ryan L, Kuo TL, Wu MM, Chen CJ. (2000). Yu WH, Harvey CM, Harvey CF. (2003). Water Resour
Environ Health Perspect. 108: 655–661. Res. 39: 1146–1162.
Impacts
2.2 Early Life Stages and Aging
42 Disability-Adjusted Life Years
in Children and Adolescents
in Europe
F. Valent . S. Di Bartolomeo
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 732
1.1 The Concept of Burden of Disease and the DALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 732
1.2 The Burden of Disease in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733
1.3 Estimating Dalys Among Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
2 The Burden of Disease Among Children and Adolescents in Europe . . . . . . . . . . . . . 735

2.1 The Burden of Disease in the WHO European Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
2.2 Differences in the Burden of Disease in the Three WHO European Subregions . . . 743
2.3 National Studies of Child Burden of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
2.4 The Environmental Burden of Disease Among Children and Adolescents
in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745
2.5 The Value of Child Burden of Disease Studies in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749

732 42 Disability-Adjusted Life Years in Children and Adolescents in Europe
Abstract: Measures of burden of disease such as the DALYs provide useful indications for
identifying health priorities in a population, improving resource allocation, assessing the
progress in performance over time in a region or comparing performances across regions.
DALYs represent the healthy years of life lost due to mortality or to disability and therefore
allow to quantify of the impact of diseases and conditions on health in a more complete
way than mortality or incidence alone. This measure is particularly important in children,
whose long life-expectancy makes any loss of healthy years more considerable. We present
some burden of disease estimates among children and adolescents in Europe from the WHO
Global Burden of Disease 2002. The estimates are also described by European subregion,
because the rate and distribution of DALYs varied depending on the subregion. In addition, we
present the results of the few European studies that assessed the burden of diseases specifically
among children. Some of these studies regarded the burden of disease attributable to environ-
mental factors. These studies have proved useful to raise awareness of issues, such as the
impact of certain environmental risks, to highlight health gaps across the region, and to
estimate the effect of prevention programs. However, more research is needed because
the conditions and factors studied so far are only a small number and therefore not sufficient
to provide policy makers with a clear and complete picture of the relative magnitude of all the
main conditions potentially affecting children.
List of Abbreviations: AIDS, acquired immune deficiency syndrome; ASD, Autism spectrum
disorders; CEHAPE, Children’s Environment and Health Action Plan for Europe; COPD,
chronic obstructive pulmonary disease; DALY, disability adjusted life years; EUR, European
subregion; GBD, global burden of disease; HIV, human immunodeficiency virus; MMR, mild
mental retardation; STD, sexually transmitted diseases; WHO, World Health Organization;
YLD, years lived with disability; YLL, years of life lost due to premature mortality
1 Introduction
1.1 The Concept of Burden of Disease and the DALYs
The concept of Burden of Disease has to do with a quantitative assessment of the relative
magnitudes of diseases, > injuries, and their risk factors. In order for such an assessment to
serve purposes such as identifying health priorities in a population, improving resource
allocation, assessing the progress in performance over time in a region or comparing perfor-
mances across regions, the estimates should be valid and internally consistent, and reflect the
public health impact of diseases and conditions. Burden of Disease studies should be based on
the best available information, obtained after screening for validity and completeness and
integrating all sources of potentially useful health data.
One of the most commonly used measures of Burden of Disease is the DALY (Disability
Adjusted Life Year), which is a health gap measure that combines potential years of life lost due
to premature death and equivalent years of healthy life lost because of poor health or disability
(Murray and Lopez, 1996). In short, one DALY represents one lost year of healthy life and the
Burden of Disease can be thought of as a measure of the gap between current health status of a
population and an ideal situation where everyone lives into old age free from disease and
disability. One unquestionable advantage of using the DALY as a measure of Burden of Disease
is that it allows a comparison of the public health impact of fatal and non-fatal conditions,
which otherwise would be impossible using only deaths or incidence.
Disability-Adjusted Life Years in Children and Adolescents in Europe 42 733
DALYs for a disease or health condition in a population are calculated as the sum of the
years of life lost (YLL) and the years lived with disability (YLD) for incident cases of the health
condition. YLL is calculated from the number of deaths at each age multiplied by the life
expectancy for the age at which death occurs. YLD is calculated from the number of incident
cases in a certain period multiplied by the average duration of the disease and a weight factor
that reflects the severity of the disease on a scale from 0 (perfect health) to 1 (dead). > Time
discounting and non-uniform > age weights are sometimes used in calculating the DALYs
(Murray and Lopez, 1996).
Throughout this chapter, only information that make use of DALY are considered.
1.2 The Burden of Disease in Europe
Europe is a heterogeneous region from both the cultural, the environmental, and the economic
point of view. The WHO divided the European region into three subregions (EUR A, EUR B,
and EUR C) characterized by different child and adult mortality levels, which correspond
approximately to western Europe, eastern Europe, and the former Soviet Union states (WHO,
2002). The countries within each subregion are listed in > Table 42-1. Analogously, the World
Bank classified the European states according to income; therefore, 30 low- and middle-
income countries belong to the so-called ‘‘Europe and Central Asia’’ region, whereas the
remaining are in the high-income countries group, together with the USA, Canada, and
Japan (The World Bank. Countries & Regions. http://go.worldbank.org/FFZ0CTE2V0). The
whole European region, as defined by WHO, bears a relatively low disease burden as compared
with other regions. In fact, Europe represents 14% of the world population, but bears ‘‘only’’
10% of the worldwide disease burden (WHO, 2004a). However, even within Europe, the
burden of disease varies in different subregions, being higher in the Europe and Central Asia
region than in high-income countries. The distribution of DALYs by cause group is also
different. In particular, infectious, cardiovascular, and accidental causes determine a higher
proportion of burden of disease in the Europe and Central Asia region than in high-income
countries (Lopez et al., 2006a).
Powles et al. (2005), investigated the health differences across Europe, analyzing the
distribution of the burden of disease due to 15 leading diseases and 10 leading risk factors
in the three WHO European subregions. Overall, the two main contributors to disease burden
in Europe were vascular diseases and injuries, and the two strongest risk factors were alcohol
and tobacco use. The crude annual rates of DALYs were similar across Europe for certain
diseases, such as depressive disorders, adult onset hearing loss, COPD, osteoarthritis, and lung
cancer, however, for most conditions large differences were found: for ischemic heart disease,
cerebrovascular disease, and unintentional injuries the lowest rate of DALYs was in EUR A and
the highest in EUR C; for lower respiratory infections the lowest rate of DALYs was in EUR A
and the highest in EUR B; EUR A had the highest rate of DALYs for Alzheimer and other
dementias; EUR C featured the highest rate of DALYs regarding self-inflicted injuries, while
the highest rate of DALYs for alcohol use disorders was in EUR A and C. Similarly, disparities
exist in the disease burden associated with all the examined risk factors (high blood pressure,
cholesterol, body mass index, low fruit and vegetable intake, physical inactivity, tobacco
and alcohol use, unsafe sex, and lead exposure), with an increasing A–B–C gradient, the
only exception being illicit drug use (Powles et al., 2005). The authors of the study pointed
out how differences in prevention strategies, policy, regulations, economy, infrastructures,
. Table 42-1
Subregions in the WHO European region
Child (<5 years) and

adult mortality Child
(15–59 years) population
Subregion Countries criterion (thousands)
EUR A Andorra, Austria, Belgium, Croatia, Czech Very low child, very 0–4 years:
Republic, Denmark, Finland, France, Germany, low adult 21,974
Greece, Iceland, Ireland, Israel, Italy, 0–14 years:
Luxembourg, Malta, Monaco, Netherlands, 69,195
Norway, Portugal, San Marino, Slovenia, Spain,
0–19 years:
Sweden, Switzerland, United Kingdom
94,994
EUR B Albania, Armenia, Azerbaijan, Bosnia and Low child, low adult 0–4 years:
Herzegovina, Bulgaria, Georgia, Kyrgyzstan, 17,576
Poland, Romania, Slovakia, Tajikistan, The 0–14 years:
former Yugoslav Republic of Macedonia, 57,240
Turkey, Turkmenistan, Uzbekistan, Yugoslavia
0–19 years:
79,467
EUR C Belarus, Estonia, Hungary, Kazakhstan, Latvia, Low child, high adult 0–4 years:
Lithuania, Republic of Moldova, Russian 10,859
Federation, Ukraine 0–14 years:
41,314
0–19 years:
64,846
WHO classifies countries according to child and adult mortality levels (very low, low, high, very high). The European
region is divided into three subregions (WHO, 2002). The child population in each subregion is provided by age
group (United Nations Population Division, 2003). WHO World Health Organization; EUR European subregion
combinations of multiple risks, level of scientific activity and public information through mass
media may account for the observed health inequalities across Europe.
1.3 Estimating Dalys Among Children
It has been shown that child mortality in the age group 0–4 years declined between 1990 and
2001 in all regions of the world (Lopez et al., 2006a). In 2001, however, deaths among children
0–4 years still accounted for almost 20% of deaths worldwide, despite the fact that children in
this age group represent approximately 10% of the population (Lopez et al., 2006b). Most of
these child and infant deaths occurred in low-income countries, such as those in Sub-Saharan
Africa. However, in the Europe and Central Asia region child mortality in the age group 0–4
still accounted for about 3% of all deaths of the region, while in high-income countries for less
than 1%, despite a similar representation of this age-category (6% and 5.9% respectively).
Measures such as mortality, however, take into account neither the YLL, which are high in
case children are involved, nor the YLD, which result from non-fatal diseases and injuries and
usually represent a relevant share of disease burden. In fact, in the age group 0–4 years they
represented more than 8% of all the regional DALYs in Europe and Central Asia in 2001, and
4.5% of DALYs in high-income countries (Lopez et al., 2006b). The fact that the DALY takes
into account the years of healthy life lost explains why such a measure is particularly
informative when studying disease burdens among children, in addition to the fact that it
allows a comparison of the public health impact of fatal and non-fatal conditions.
2 The Burden of Disease Among Children and Adolescents

in Europe
2.1 The Burden of Disease in the WHO European Region
According to the Global Burden of Disease (GBD) 2002 estimates (WHO, 2004a), every year in
the WHO European region approximately 15,500,000 DALYs are lost among children 0–14
years of age, with a rate of 9,312 DALYs/100,000 children. Of these DALYs, two thirds are in the
age group 0–4 (annual rate: 20,049 DALYs/100,000 children) and one third in the age group
5–14 (annual rate: 4,699 DALYs/100,000 children). 44% are due to communicable, maternal,
or > perinatal diseases, 40% to > non-communicable diseases, and 15% to injuries. A more
detailed distribution of DALYs in the European region in 2002 is provided in > Tables 42-2–
42-4, along with the annual rate of DALYs, the proportional contribution of different causes
to the overall DALYs in the > EURO region, and the contribution of DALYs among European
children to all DALYs in the world.
With respect to > communicable diseases, respiratory and other infectious diseases share
approximately the same amount of burden. Within non-respiratory infections, the highest
number of DALYs was attributed to diarrheal diseases, childhood-cluster diseases (especially
measles and pertussis), and meningitis. No or negligible burden of disease was associated with
poliomyelitis, diphtheria, tetanus and some of the > tropical-cluster diseases such as trypano-
somiasis, Chagas disease, and schistosomiasis, leprosy, dengue, trachoma. Maternal conditions
were also scarcely represented, as were some nutritional deficiencies, such as vitamin A
deficiency. On the contrary, iodine deficiency was responsible for a high number of DALYs,
corresponding to almost 20% of the World’s burden of disease due to this cause among
children 0–14. Regarding noncommunicable diseases, the greatest burden was caused by
congenital anomalies, in particular heart anomalies, and neuropsychiatric conditions, partic-
ularly lead-related mental retardation. Of DALYs due to injuries, almost all were related to
unintentional mechanisms.
DALYs lost by children in the EURO region represent less than 3% of all the burden of
disease in the age group 0–14 in the world. This figure should be interpreted in the light of the
fact that the EURO population 0–14 represents more than 9% of the world population in
the same age group. The child burden of disease in Europe appears to be much lower than in
the world as a whole. However, for certain conditions, the burden of disease in Europe
represents a large share of the world’s burden. For example, the burden of disease due to
sexually transmitted diseases other than syphilis, chlamydia, and gonorrhea among the
European children corresponds to 14.5% of the world’s DALYs for this cause, and particularly
among children 5–14 years of age (9.7% of the world’s population in the same age group), for
which the percentage rises to 26.6%. Similarly, the DALYs lost because of iodine deficiency in
Europe correspond to 19.7% of the world’s burden of disease for this cause. As compared with
736
42
. Table 42-2
Child burden of disease by age group and disease cause in the European region (communicable, maternal, perinatal, and nutritional conditions)
Distribution of
causes of burden
DALYs annual rate of diseases in Percentage of
(DALYs/100,000 EURO region (% of worldwide DALYs
Total annual DALYs child-years) all EURO causes) by cause
Age group 0–4 5–14 0–14 0–4 5–14 0–14 0–4 5–14 0–14 0–4 5–14 0–14
All causes 10,106,205 5,514,190 15,620,395 20,049 4,699 9,312 100.0 100.0 100.0 2.3 5.0 2.9
Communicable, maternal, perinatal and nutritional 6,059,878 809,074 6,868,952 12,022 690 4,095 60.0 14.7 44.0 1.7 1.8 1.7
conditions
Infectious and parasitic diseases 1,360,946 219,386 1,580,332 2,700 187 942 13.5 4.0 10.1 0.8 0.8 0.8
Tuberculosis 7,863 14,149 22,013 16 12 13 0.1 0.3 0.1 0.5 0.9 0.7
STDs excluding HIV 14,191 4,807 18,998 28 4 11 0.1 0.1 0.1 0.4 3.9 0.6
HIV/AIDS 18,502 17,313 35,815 37 15 21 0.2 0.3 0.2 0.2 0.5 0.2
Diarrhoeal diseases 487,203 36,828 524,031 967 31 312 4.8 0.7 3.4 0.9 2.4 0.9
Childhood-cluster diseases 309,404 38,440 347,844 614 33 207 3.1 0.7 2.2 0.8 1.3 0.8
Meningitis 341,977 27,062 369,039 678 23 220 3.4 0.5 2.4 10.8 2.0 8.2
Disability-Adjusted Life Years in Children and Adolescents in Europe
Hepatitis B 118,25 5,103 16,928 23 4 10 0.1 0.1 0.1 4.0 2.6 3.4
Hepatitis C 5,906 1,916 7,823 12 2 5 0.1 0.0 0.1 5.5 2.4 4.1
Malaria 3,986 7,570 11,556 8 6 7 0.0 0.1 0.1 0.0 0.6 0.0
Tropical-cluster diseases 1,634 2,921 4,555 3 2 3 0.0 0.1 0.0 0.3 0.1 0.1
Intestinal nematode infections 124 88 211 0 0 0 0.0 0.0 0.0 0.0 0.0 0.0
Other intestinal infections 16 0 16 0 0 0 0.0 0.0 0.0 0.0 0.0 0.0
Other infectious diseases 158,331 63,188 221,519 314 54 132 1.6 1.1 1.4 0.8 0.9 0.9
Respiratory infections 1,206,536 280,868 1,487,405 2,394 239 887 11.9 5.1 9.5 1.9 2.1 2.0
Lower respiratory infections 1,105,814 188,210 1,294,025 2,194 160 771 10.9 3.4 8.3 1.8 1.6 1.8
Upper respiratory infections 85,020 15,334 100,353 169 13 60 0.8 0.3 0.6 8.7 5.4 8.0
Otitis media 15,702 77,324 93,026 31 66 55 0.2 1.4 0.6 5.9 6.9 6.7
Maternal conditions 0 936 936 0 1 1 0.0 0.0 0.0 0.0 0.4 0.4
Perinatal conditions 2,746,326 356 2,746,682 5,448 0 1,637 27.2 0.0 17.6 2.8 14.0 2.8
Low birth weight 1,051,553 0 1,051,553 2,086 0 627 10.4 0.0 6.7 2.3 0.0 2.3
Birth asphyxia and birth trauma 1,015,298 100 1,015,398 2,014 0 605 10.0 0.0 6.5 2.9 7.3 2.9
Other perinatal conditions 679,475 256 679,731 1,348 0 405 6.7 0.0 4.4 4.1 23.5 4.1
Nutritional deficiencies 746,070 307,528 1,053,598 1,480 262 628 7.4 5.6 6.7 3.6 6.8 4.2
Protein-energy malnutrition 159,146 1,707 160,853 316 1 96 1.6 0.0 1.0 1.1 0.1 1.0
Iodine deficiency 490,784 201,160 691,944 974 171 412 4.9 3.6 4.4 19.0 21.8 19.7
Vitamin A deficiency 250 309 559 0 0 0 0.0 0.0 0.0 0.0 0.2 0.1
Iron-deficiency anemia 88,634 92,051 180,685 176 78 108 0.9 1.7 1.2 4.3 4.3 4.3
Other nutritional disorders 7,256 12,301 19,557 14 10 12 0.1 0.2 0.1 1.5 12.8 3.3
The Table shows DALYs, DALYs rate, distribution of disease causes in the WHO EURO region, and contribution to the World’s burden of disease among children 0–14 years of age in
2002. DALYs rate, distribution, and contribution to the World’s burden were calculated by the authors from the WHO (2002) estimates of DALYs in the EURO region (WHO, 2004a). In
the EURO region, children 0–14 years represent 9.2% of the population (children 0–4: 8.2%; children 5–14: 9.7%). WHO World Health Organization; EURO European; DALY disability
adjusted life year; STD sexually transmitted disease; HIV human immunodeficiency virus; AIDS acquired immune deficiency syndrome
42
737
738
. Table 42-3
Child burden of disease by age group and disease cause in the European region (noncommunicable diseases)
42
Distribution of
causes of burden of
DALYs annual rate diseases in EURO Percentage of
(DALYs/100,000 region (% of all worldwide DALYs
Total annual DALYs child-years) EURO causes) by cause
Age group 0–4 5–14 0–14 0–4 5–14 0–14 0–4 5–14 0–14 0–4 5–14 0–14
All causes 10,106,205 5,514,190 15,620,395 20,049 4,699 9,312 100.0 100.0 100.0 2.3 5.0 2.9
Noncommunicable diseases 3,291,599 3,105,857 6,397,457 6,530 2,647 3,814 32.6 56.3 41.0 5.6 8.9 6.8
Malignant neoplasms 84,384 183,789 268,173 167 157 160 0.8 3.3 1.7 6.4 9.8 8.4
Other neoplasms 9,782 9,587 19,368 19 8 12 0.1 0.2 0.1 6.8 6.1 6.4
Diabetes mellitus 2,815 11,605 14,420 6 10 9 0.0 0.2 0.1 2.5 5.8 4.6
Endocrine disorders 131,274 71,173 202,447 260 61 121 1.3 1.3 1.3 5.4 12.1 6.7
Neuropsychiatric conditions 728,463 1,831,556 2,560,019 1,445 1,561 1,526 7.2 33.2 16.4 5.2 11.0 8.4
Unipolar depressive disorders 64 630,247 630,311 0 537 376 0.0 11.4 4.0 8.4 10.4 10.4
Bipolar disorder 3 61,137 61,141 0 52 36 0.0 1.1 0.4 0.8 8.5 8.5
Schizophrenia 832 258,808 259,639 2 221 155 0.0 4.7 1.7 54.2 15.8 15.8
Epilepsy 23,213 80,752 103,965 46 69 62 0.2 1.5 0.7 2.4 4.7 3.9
Alcohol use disorders 2,001 39,788 41,788 4 34 25 0.0 0.7 0.3 64.0 15.8 16.4
Alzheimer and other dementias 51,977 32,350 84,327 103 28 50 0.5 0.6 0.5 11.2 14.3 12.2
Parkinson disease 2,760 2,165 4,925 5 2 3 0.0 0.0 0.0 23.9 24.2 24.0
Multiple sclerosis 881 16,600 17,481 2 14 10 0.0 0.3 0.1 43.3 10.4 10.8
Drug use disorders 876 22,279 23,155 2 19 14 0.0 0.4 0.1 87.0 12.6 13.0
Post-traumatic stress disorder 12 5,250 5,262 0 4 3 0.0 0.1 0.0 40.6 8.9 8.9
Obsessive-compulsive disorder 0 946,87 94,687 0 81 56 0.0 1.7 0.6 - 15.4 15.4
Panic disorder 0 23,248 23,248 0 20 14 0.0 0.4 0.1 - 10.1 10.1
Insomnia (primary) 0 9,055 9,055 0 8 5 0.0 0.2 0.1 – 10.2 10.2
Migraine 18,474 285,524 303,998 37 243 181 0.2 5.2 1.9 7.7 9.3 9.1
Mental retardation, lead-caused 379,552 3,319 382,871 753 3 228 3.8 0.1 2.5 3.9 7.7 3.9
Other neuropsychiatric disorders 247,819 266,346 514,165 492 227 307 2.5 4.8 3.3 10.4 16.2 12.7
Sense organ diseases 1,831 4,371 6,202 4 4 4 0.0 0.1 0.0 2.5 1.1 1.3
Glaucoma 80 1,455 1,536 0 1 1 0.0 0.0 0.0 0.6 1.9 1.7
Cataracts 63 834 897 0 1 1 0.0 0.0 0.0 0.2 0.4 0.3
Vision disorders, age-related 525 1,845 2,370 1 2 1 0.0 0.0 0.0 3.5 2.3 2.5
Other sense organ disorders 1,162 237 1,399 2 0 1 0.0 0.0 0.0 17.1 4.9 12.0
Cardiovascular diseases 105,746 93,105 198,850 210 79 119 1.0 1.7 1.3 3.6 4.1 3.8
Rheumatic heart disease 928 4,512 5,440 2 4 3 0.0 0.1 0.0 0.2 0.9 0.5
Hypertensive heart disease 2,372 1,425 3,797 5 1 2 0.0 0.0 0.0 4.5 2.5 3.5
Ischemic heart disease 1,016 14,709 15,725 2 13 9 0.0 0.3 0.1 0.5 2.9 2.3
Cerebrovascular disease 30,141 31,676 61,817 60 27 37 0.3 0.6 0.4 7.3 8.8 8.0
Inflammatory heart diseases 30,696 13,720 44,415 61 12 26 0.3 0.2 0.3 6.4 6.5 6.4
Other cardiovascular diseases 40,594 27,062 67,656 81 23 40 0.4 0.5 0.4 3.2 4.3 3.6
Respiratory diseases 262,662 437,596 700,258 521 373 417 2.6 7.9 4.5 6.1 8.4 7.3
Chronic obstructive pulmonary disease 4,259 27,023 31,282 8 23 19 0.0 0.5 0.2 3.4 48.8 17.3
Asthma 125,482 328,212 453,694 249 280 270 1.2 6.0 2.9 6.6 7.4 7.2
Other respiratory diseases 132,922 82,361 215,282 264 70 128 1.3 1.5 1.4 5.8 10.9 7.1
Digestive diseases 149,505 81,877 231,382 297 70 138 1.5 1.5 1.5 2.6 3.3 2.8
Peptic ulcer disease 490 5,094 5,584 1 4 3 0.0 0.1 0.0 0.2 3.3 1.6
Cirrhosis of the liver 4,490 15,466 19,957 9 13 12 0.0 0.3 0.1 0.5 2.7 1.3
Appendicitis 1,133 5,708 6,840 2 5 4 0.0 0.1 0.0 8.8 8.9 8.9
Other digestive diseases 143,391 55,610 199,001 284 47 119 1.4 1.0 1.3 3.1 3.3 3.2
Genitourinary diseases 30,566 38,844 69,410 61 33 41 0.3 0.7 0.4 3.4 4.6 3.9
42
739
740
42
Distribution of
causes of burden of
DALYs annual rate diseases in EURO Percentage of
(DALYs/100,000 region (% of all worldwide DALYs
Total annual DALYs child-years) EURO causes) by cause
Age group 0–4 5–14 0–14 0–4 5–14 0–14 0–4 5–14 0–14 0–4 5–14 0–14
Skin diseases 8,293 13,063 21,355 16 11 13 0.1 0.2 0.1 2.0 2.9 2.5
Musculoskeletal diseases 13,914 140,705 154,619 28 120 92 0.1 2.6 1.0 5.4 10.3 9.5
Rheumatoid arthritis 3,571 62,624 66,195 7 53 39 0.0 1.1 0.4 10.0 15.6 15.1
Osteoarthritis 76 555 631 0 0 0 0.0 0.0 0. 15.4 5.7 6.2
Gout 23 280 303 0 0 0 0.0 0.0 0.0 57.1 46.0 46.7

Low back pain 6,151 36,090 42,242 12 31 25 0.1 0.7 0.3 5.2 6.6 6.4
Other musculoskeletal disorders 4,093 41,155 45,249 8 35 27 0.0 0.7 0.3 3.9 10.1 8.8
Congenital anomalies 1,711,094 57,064 1,768,158 3,394 49 1,054 16.9 1.0 11.3 6.7 7.2 6.7
Abdominal wall defect 9,015 92 9,107 18 0 5 0.1 0.0 0.1 7.3 11.9 7.4
Anencephaly 11,848 92 11,940 24 0 7 0.1 0.0 0.1 2.0 5.3 2.0
Anorectal atresia 2,050 12 2,061 4 0 1 0.0 0.0 0.0 7.2 4.6 7.2
Cleft lip 5,155 1 5,156 10 0 3 0.1 0.0 0.0 3.7 0.7 3.7
Cleft palate 5,344 1 5,345 11 0 3 0.1 0.0 0.0 3.5 0.5 3.5
Esophageal atresia 5,675 213 5,888 11 0 4 0.1 0.0 0.0 15.9 29.3 16.1
Renal agenesis 10,363 285 10,649 21 0 6 0.1 0.0 0.1 15.5 24.8 15.7
Down syndrome 245,602 1,855 247,457 487 2 148 2.4 0.0 1.6 6.4 2.5 6.3
Congenital heart anomalies 935,073 25,176 960,249 1,855 21 572 9.3 0.5 6.1 6.6 5.6 6.6
Spina bifida 61,211 3,265 64,476 121 3 38 0.6 0.1 0.4 3.7 14.7 3.8
Other congenital anomalies 419,757 26,073 445,829 833 22 266 4.2 0.5 2.9 9.1 11.1 9.2
Oral conditions 51,272 131,524 182,795 102 112 109 0.5 2.4 1.2 6.1 9.5 8.2
adjusted life year
42
741
742
. Table 42-4
Child burden of disease by age group and disease cause in the European region (injuries)
42
Distribution of causes
DALYs annual rate of burden of diseases Percentage of
(DALYs/100,000 in EURO region (% of worldwide DALYs by
Total annual DALYs child-years) all EURO causes) cause
Age group 0–4 5–14 0–14 0–4 5–14 0–14 0–4 5–14 0–14 0–4 5–14 0–14
All causes 10,106,205 5,514,190 15,620,395 20,049 4,699 9,312 100.0 100.0 100.0 2.3 5.0 2.9
Injuries 754,728 1,599,258 2,353,986 1,497 1,363 1,403 7.5 29.0 15.1 4.5 5.0 4.9
Unintentional injuries 724,516 1,394,515 2,119,032 1,437 1,188 1,263 7.2 25.3 13.6 4.5 4.9 4.7
Road traffic accidents 76,934 268,093 345,027 153 228 206 0.8 4.9 2.2 3.0 3.6 3.5
Poisonings 36,494 32,933 69,428 72 28 41 0.4 0.6 0.4 6.6 4.3 5.3
Falls 126,717 263,919 390,636 251 225 233 1.3 4.8 2.5 6.4 6.2 6.3
Fires 73,764 65,589 139,352 146 56 83 0.7 1.2 0.9 3.3 2.6 2.9
Drownings 64,645 107,336 171,981 128 91 103 0.6 1.9 1.1 3.2 3.3 3.3
Other unintentional injuries 345,964 656,644 1,002,608 686 560 598 3.4 11.9 6.4 5.1 6.2 5.8
Intentional injuries 30,211 204,743 234,954 60 174 140 0.3 3.7 1.5 4.7 7.0 6.5
Self-inflicted injuries 188 110,473 110,661 0 94 66 0.0 2.0 0.7 4.7 10.8 10.8
Violence 20,476 66,380 86,856 41 57 52 0.2 1.2 0.6 4.1 4.3 4.3
War 7,755 27,653 35,408 15 24 21 0.1 0.5 0.2 6.8 7.6 7.4
Other intentional injuries 1,792 237 2,028 4 0 1 0.0 0.0 0.0 5.6 0.9 3.4
adjusted life year
the population share, European children have a much higher burden of disease due
to schizophrenia, alcohol and drug use disorders, especially those in the age group 0–4:
despite the fact that they represent approximately 8% of the world’s population of the
same age, the share of DALYs is 54.2%, 64.0%, and 87.0%, respectively for the three conditions
listed above.
2.2 Differences in the Burden of Disease in the Three WHO

European Subregions
The European child population 0–14 years of age is distributed among the three European
subregions approximately as follows:
EUR A: 41%
EUR B: 34%
EUR C: 25%
The burden of disease is not uniformly distributed among the children of the three regions.
In fact, EUR B contributes to half of the DALYs among children of the whole region,
whereas EUR A ‘‘only’’ contributes to 20%, as shown in > Figure 42-1. Only for asthma the
. Figure 42-1
Child burden of disease by European subregion and major causes. The Figure shows the
contribution of the three WHO European subregions to the total regional burden of disease in
terms of DALYs among children 0–14 years of age. The percentages were calculated by the
authors from the WHO (2002) estimates of DALYs in the European region (WHO, 2004a). EUR
European subregion; DALY disability adjusted life year
contribution of EUR A to the regional child burden of disease (56%) is greater than expected
on the sole basis of the population distribution. EUR C contributed to the regional burden
more than expected for the following major causes of infectious diseases: tuberculosis (45%),
syphilis (33%), HIV and AIDS (57%); for nutritional (particularly iodine) deficiencies (52%);
for malignant neoplasms (32%); for some neuropsychiatric conditions (schizophrenia:
48%, alcohol use disorders: 37%, obsessive-compulsive disorders: 41%, lead-related mental
retardation: 35%); for chronic obstructive pulmonary disease (65%); for most congenital
anomalies (35.1%); and for all intentional (58%) and unintentional injuries (41%). In EUR B
the contribution to the regional burden of disease was higher that expected for virtually
all major conditions. EUR B has also the highest representation of children in the popula-
tion (children/total population: EUR A 17.4%, EUR B 26.4%, EUR C 18.8%), showing
that interventions targeted at this age- category are likely to be particularly effective in
this area.
In EUR A the annual DALYs rate was similar between boys and girls for most conditions,
the only exceptions being migraine (98 DALYs/100,000 child-years among boys and 211
DALYs/100,000 child-years among girls) and unintentional injuries (627 DALYs/100,000
child-years among boys and 439 DALYs/100,000 child-years among girls). Analogous patterns
were noticed in EUR B, where the difference between boys and girls in the annual DALYs rate
due to unintentional injuries was much stronger: 2,038 DALYs/100,000 child-years among
boys and 986 DALYs/100,000 child-years among girls. On the contrary, in EUR C the DALYs
rate for migraine did not substantially differ between males and females, whereas in this
subregion there was a marked difference in the rate of schizophrenia: 412 DALYs/100,000
child-years among boys and 185 DALYs/100,000 child-years among girls. In EUR C, the DALYs
rate due to both intentional and unintentional injuries was much higher among males than
among females: respectively 418 and 240 DALYs/100,000 child-years for intentional and 2,892
and 1,315 DALYs/100,000 child-years for unintentional injuries. The DALYs rate due to
congenital anomalies and perinatal conditions was slightly higher among boys than among
girls in all three subregions.
2.3 National Studies of Child Burden of Disease
WHO periodically estimates the burden of disease by country for over 100 major diseases and
conditions (WHO, 2004a), making this valuable information publicly available. National
studies are nevertheless needed because that they can be much more detailed, for example
because they can look into narrower age categories, quantify the burden of rare diseases of
particular interest in certain countries, and don’t have to rely on the assumptions adopted in
the GBD study if valid and complete local data are available.
In Europe, very few studies have been published that estimated the burden of disease
among children at a national level. One of these (Sánchez-Valle et al., 2007) estimated the
DALYs due to autism spectrum disorders among children 0–14 years of age in Spain in 2003.
The authors estimated that approximately 44,000 DALYs (95%CI: 28,453–58,347) were due to
ASD among Spanish children 0–14 years in 2003, with a rate of 727 DALYs/100,000 child-
years. The DALY rate was higher among children 0–4 years of age (1,345 DALYs/100,000
child-years) than among those 5–9 years (628 DALYs/100,000 child-years) and those 10–14
years (275 DALYs/100,000 child-years). This study is interesting because it was aimed at
quantifying in Spain the impact of a specific disease category not routinely investigated by
WHO. However, since reliable data on disease incidence were not available in Spain,
the researchers adapted the rates from an Australian study whose results they considered
generalizable to all Western countries, and applied them to the Spanish child population 0–14
years of age. Similarly, since no deaths had occurred in Spain due to ASD in the study year, the
researchers used mortality rate from another study. Therefore, the study may yield invalid
estimates if the rates that were used differed significantly from the true Spanish ones.
Another national study was performed in Spain and it estimated the child burden of
disease due to diseases that could be prevented through vaccination (Cortés et al., 2004). Using
various national sources of information on the diseases incidence, the authors estimated the
proportion of overall DALYs among children 0–14 years of age that is due to infectious
diseases included in the vaccination schedule (diphtheria, tetanus, pertussis, poliomyelitis,
measles, rubella, mumps, hepatitis B) and to some not included in the vaccination schedule at
the time of the study (meningococcal infection, meningococcal meningitis, chicken pox).
The proportion of DALYs due to diseases in the first group was close to zero in all age groups
(<1 year, 1–4, 5–14 years). Poliomyelitis accounted for 0.01% of total DALYs among children
<1 year of age; mumps for 0.01% of DALYs among those 5–14. No burden of disease was
attributed to any of the other diseases included in the vaccination schedule. Among diseases
not included in the vaccination schedule, meningococcal infection was responsible for 0.5%
of child DALYs (3.3% of DALYs among children <1 year of age and 0.4% among those
1–4 years), meningococcal meningitis for 0.2% of DALYs (0.7% in the age group <1 year and
0.06% in the age group 1–4), chicken pox for 0.1% of DALYs in the age group <1 year
and 0.2% among those 1–4. This study showed that the immunization programs in Spain have
been successful and underlines the importance of the DALY as a useful indicator to be used
when programming and evaluating immunization activities in a country.
2.4 The Environmental Burden of Disease Among Children and

Adolescents in Europe
Children are particularly susceptible and sometimes more exposed than adults to environ-
mental factors such as chemical and microbiological contamination of air, water, food, unsafe
and unhealthy homes, noise, radiation (Bruckner, 2000; Tamburlini et al., 2002). This is
reflected by the fact that over 40% of the > environmental burden of disease regards children
<5 years of age (Smith et al., 1999). In the last years, therefore, the child environmental health
issues have been taken into serious consideration at an international level (WHO, 1999,
2004b) and a children’s environment and health action plan has recently been developed for
the European region (CEHAPE) (WHO, 2004c). A quantification of the child burden of
disease attributable to environmental exposures is necessary for setting health priorities
correctly, and for assessing improvements over time.
Two different approaches, direct and indirect, can be used to estimate the environmental
burden of disease in a population. In the first approach, the burden of disease attributable to
a certain risk factor is calculated directly starting from the exposure distribution in the
population, the incidence rate of disease associated with different exposure levels, age at
onset, duration, and disability weight. This approach is rarely used due to the difficulty
of collecting all the necessary information. On the other hand, in the indirect approach,
for each outcome of interest an impact fraction is calculated from the distribution of risk
factor exposure within the study population and the exposure-response relationship for the
risk factor. Such impact fraction is then multiplied by the total DALYs for the outcome of
interest, to quantify the DALYs that could be attributed to the exposure under study. In
this process, the exposure-response relationship can be described by a continuous numerical
relationship or through the definition of exposure scenarios associated with known risks of
disease.
Few studies have been conducted so far to estimate the burden of disease attributable to
environmental exposures among children in Europe. One of these (Valent et al., 2004a, b) was
restricted to four major environmental risk factors (outdoor air pollution, indoor air pollu-
tion, inadequate water and sanitation, lead) and injuries, representing the main environmental
risk factors globally (Ezzati et al., 2003) and at the same time those for which available data
were sufficient for large scale estimates. The health impact of outdoor air pollution was only
quantified in terms of deaths and is not described here. On the contrary, for the other factors,
DALYs were calculated. The study only estimated the burden of disease for selected outcomes
for which, in particular age groups, strong evidence existed of an association: lower respiratory
infections attributable to indoor air pollution among children 0–4 (Desai et al., 2004);
diarrheal disease due to inadequate water and sanitation among children 0–14 (Huttly et al.,
1997; Prüss et al., 2002); mild mental retardation (MMR) due to lead among children 0–4
(Fewtrell et al., 2003); injuries among children 0–19.
A mix of direct and indirect methods and of exposure- and scenario-based approaches were
used depending on the factor of interest. Exposure estimates in the European child population
were obtained from recent published scientific literature. The total DALYs for each outcome of
interest were extracted from the Global Burden of Disease 2001 study (WHO, 2003). Using
counterfactual analysis (Prüss-Üstün et al., 2003), the study estimated the contribution of a risk
factor to the burden of disease by comparing the disease burden in the study period with what
would have been realistically achievable after interventions and/or with the theoretical mini-
mum. > Table 42-5 shows the child environmental burden of disease in Europe and in each of
the three subregions as estimated by Valent et al. (2004a, b). Children in EUR A had the lowest
DALY rates. In EUR B the rate of DALYs attributable to indoor air pollution (household solid
fuel use) and to inadequate water and sanitation was much higher than in the other two
subregions. The highest rate of DALYs due to injuries was noticed in EUR C.
In the age group 0–4 years, in which the burden of disease was estimated for all the factors
and outcomes of interest, approximately one fifth of all-cause DALYs resulted attributable to
the exposure to indoor air pollution due to household solid fuel use (3.1%), inadequate water
and sanitation (7.9%), lead (1.4–4.4%), and to injuries (7.3%).
This study highlighted the enormous impact on the health of European children of
these few environmental exposure, showing that a substantial proportion of the burden
of disease could be eliminated through the implementation of prevention programs addres-
sing these factors. It also confirmed the role of injuries as a leading cause not only of child
mortality but also the loss of years of healthy life.
Following an analogous methodology, the impact on children’s health of the exposure to
second hand smoke is now being studied in the European region and subregions (Öberg et al.,
2007) and soon it will be possible to compare the magnitude of the effect of this exposure with
those previously studied.
In the same way, a study was conducted in Poland (Jarosińska et al., 2006) to estimate the
burden of disease arising from mild mental retardation due to lead in the urban center of
the Province of Upper Silesia. Lead exposure data were collected in the context of a local
. Table 42-5
Child burden of disease attributable to selected environmental factors and injuries in Europe
DALYs per
Risk factor, disease Percentage of DALYs 100,000
outcome, and age group Region DALYs from all causes children
Acute lower respiratory EUR A 0 0 0
infections due to indoor EUR B 321,483 5.0 1,789
air pollution (age 0–4)
EUR C 19,335 0.7 170
EURO 340,818 3.1 661
Diarrhoeal disease due to EUR A 25,946 0.8 37
inadequate water and EUR B 446,763 5.2 757
sanitation (age 0–14)
EUR C 77,231 1.6 170
EURO 549,940 3.5 316
Mild mental retardation EUR A 14,092–39,458 0.8–2.3 63–178
due to lead (age 0–4) EUR B 54,711–300,913 1.9–4.5 304–1,674
EUR C 87,816–142,521 3.1–5.0 774–1,256
EURO 156,619–482,892 1.4–4.4 301–937
Injuries (age 0–19) EUR A 894,947 14.9 942
EUR B 1,528,037 13.8 1,925
EUR C 2,370,573 29.1 3,656
EURO 4,793,557 19.0 2,004
The Table shows DALYs and DALYs rate attributable to main environmental exposures and injuries by subregion.
Age groups were chosen based on the scientific evidence of the relation between outcomes and exposures. For
mild mental retardation two estimates are provided: the former was obtained by combining studies reporting
urban and rural sample means, the latter by analyzing separately urban and rural blood lead levels. Data from
Valent et al. (2004a,b) EUR European subregion; EURO European; DALY disability adjusted life year
biomonitoring and prevention program focusing on urban young children of the Province
living outside the direct impact of the many industries (lead mining and processing, coal
mining, heavy industry) located in the area. Within this program, more than 14,000 children
2–7 years of age were tested for lead in blood between 1993 and 2000. To maximize compara-
bility with the estimates of the European study (Valent et al., 2004a, b), the Polish study
estimated DALYs in the age group 0–4 for the year 2001; in addition, the environmental
burden of disease was assessed with projection to the year 2005. In 2001, the estimated DALYs
due to lead exposure were 136 (with a rate of 445 DALYs/100,000 child-years); in 2005, thanks
to the estimated effect of lead prevention activities, the burden of disease due to lead was
approximately halved (66 DALYs; 216 DALYs/100,000 child-years). This study has several
merits. Since it relied entirely on blood lead measures collected at a local level, it did not have
to extrapolate exposure data from one area to others, as was done in the European study
(Valent et al., 2004a, b), thus eliminating one potential source of uncertainty or bias in the
results. In addition, it estimated the impact of lead prevention activities on the health of
children living in a relatively small area, by comparing the burden of disease in different years
thus providing useful information for local policy makers.
A recent study (Polinder et al., 2007) attempted to compare the DALY burden of injury
among six European countries, all belonging to Eur A. As for the 0–14 years category, it
showed that there are conspicuous differences, the burden being higher in Austria and Ireland,
though the authors themselves acknowledge that the findings may be due in part to limitations
in data sources.
2.5 The Value of Child Burden of Disease Studies in Europe
Since the first publications of studies that presented the DALYs as a health outcome measure,
the use of such a measure has been greatly debated (Barker and Green, 1996). In fact, the
conceptual and technical basis for DALYs has been considered flawed by some authors, who
have also questioned its assumptions and value judgments, such as those implied in age-
weighting and discounting (Anand and Hanson, 1997). Age-weighting, in particular, might be
considered particularly unethical when children are studied, because years lost at early ages are
valued less than years lost in adulthood. However, the choice of weighing ages differentially
reflects the social preference to value a year of life in adulthood more than a year in infancy. In
addition, Murray and Acharya (1997) believe that the weights are not inequitable, because
everyone in theory is expected to live through every age.
In addition, an important feature of the DALY methodology is that choices and valuations
are made explicit and are therefore open to discussion.
In a recent study (Lapostolle et al., 2007), sensitivity analyses were conducted using
different mortality data sets and various life tables as mortality norms, and calculations
were also performed with and without discounting and age-weighting. The study showed
that depending on the mortality data set and the choice of social values used for calculation,
results could be very different and that the validity of results depends heavily on the validity of
the input data. The importance of good data had already been stressed by the authors of a
previous national study (Melse et al., 2000), who highlighted that even in a country like the
Netherlands, with well-developed registration systems and surveys, improvement in epidemi-
ologic data collection was still needed.
Despite the potential limitations and uncertainties, burden of disease studies have proved
helpful tools. As an example, a French study (Granados et al., 2005) showed how DALYs can
illuminate debates about public health priorities, informing the population about health
conditions and providing decision makers with helpful health indicators. The mentioned
study by Melse et al. (2000) also concluded that the DALY was a potentially useful tool in
public health and that further development and application at the national level of the DALY
approach should be supported.
In Europe, there is a scarcity of burden of disease studies with a specific focus on children.
Although these studies have proved useful to raise awareness of issues, such as the impact of
certain environmental risks, to highlight health gaps across the region, and to estimate the
effect of prevention programs (Valent et al., 2004a, b; Jarosińska et al., 2006), the conditions
and factors that have been studied so far are only a small number and therefore not sufficient
to provide policy makers with a clear and complete picture of the relative magnitude of all the
main conditions potentially affecting children. More research is warranted, both at a national
and at a regional level, which implies that a greater effort is put on a more complete and valid
collection of health-related data.
Summary Points
The DALY is a measure of disease burden which is particularly important in studies on

children because it quantifies the years of health life lost because of mortality or disability,
which may be considerable when diseases occur at early ages.
Measuring in DALYs the impact on health of different fatal and non-fatal conditions and
risk factors may help policy makers setting priorities in prevention programs regarding
children’s health.
In Europe, few ad-hoc studies have estimated disease burdens among children using the
DALY.
Data from the WHO Global Burden of Disease project show that every year in the WHO
European region approximately 15,500,000 DALYs are lost among children 0–14 years of
age.
Two thirds of the child DALYs in Europe are in the age group 0–4 (annual rate: 20,049
DALYs/100,000 children) and one third in the age group 5–14 (annual rate: 4,699 DALYs/
100,000 children).
44% of child DALYs in Europe are due to communicable, maternal, or perinatal diseases,
40% to noncommunicable diseases, and 15% to injuries.
The child burden of disease in Europe is much lower than in the world as a whole.
The child burden of disease in Europe is not uniformly distributed: western European
(‘‘EUR A’’) countries have the lowest rate of DALYs, whereas eastern counties (‘‘EUR B’’)
have the highest.
The relative frequency of different causes of disease also vary among children of different
European subregions.
A few studies have assessed in Europe the child disease burden attributable to major
environmental factors: among children 0–4 years of age, exposure to indoor air pollu-
tion, lead, poor water and sanitation, and injuries determine about 20% of all-cause
DALYs.
Children of eastern Europe (‘‘EUR B’’) have the highest disease burden due to indoor air
pollution and to poor water and sanitation, whereas those of the Former Soviet Union
(‘‘EUR C’’) have the highest disease burden due to injuries.
Despite the possible limitations related to the estimation of DALYs, policy-makers should
value the information provided by studies of burden of disease, particularly when they
regard children.
In Europe, very few conditions that may affect children have been examined in terms of
DALYs; therefore, more burden of disease studies are needed with a specific focus on the
youngest age groups.
References
Anand S, Hanson K. (1997). J Health Econ. 16: 685–702. Cortés M, Pereira J, Peña-Rey I, Génova R, Amela C.
Barker C, Green A. (1996). Health Policy Plan. 11: (2004). Gac Sanit. 18: 312–320 (Spanish).
179–183. Desai MA, Mehta S, Smith KR. (2004). Indoor Smoke
Bruckner J. (2000). Regul Toxicol Pharmacol. 31: from Solid Fuels: Assessing the Environmental Bur-
280–285. den of Disease at National and Local Levels. World
Health Organization (WHO Environmental Burden Sánchez-Valle E, Posada M, Villaverde-Hueso A, Touriño E,

of Disease Series, No. 4), Geneva. Ferrari-Arroyo MJ, Boada L, Martı́n-Arribas MC,
Ezzati M, Hoorn SV, Rodgers A, Lopez AD, Mathers CD, Canal R, Fuentes-Biggi J. (2008). J Autism Dev
Murray CJ. (2003). Lancet. 362: 271–280. Disord. 38(2): 288–296.
Fewtrell L, Kaufmann R, Prüss-üstün A. (2003). Lead: Smith KR, Corvalan CF, Kjellstrom T. (1999). Epidemi-
Assessing the Environmental Burden of Disease at ology. 10: 573–584.
National and Local Levels. World Health Organiza- Tamburlini G, von Ehrenstein OS, Bertollini R. (eds.)
tion (WHO Environmental Burden of Disease (2002). Children’s Health and Environment: A
Series, No. 2), Geneva. Review of Evidence. Environmental Issue Report
Granados D, Lefranc A, Reiter R, Grémy I, Spira A. No. 29. World Health Organization Regional
(2005). Rev Epidemiol Sante Publique. 53: 111–125 Office for Europe, European Environment Agency,
(French). Copenhagen.
Huttly SRA, Morris SS, Pisani V. (1997). Bull WHO. 75: United Nations Population Division. (2003). World Pop-
165–174. ulation Prospects – The 2002 Revision. United
Jarosińska D, Biesiada M, Muszyńska-Graca M. (2006). Nations, New York.
Sci Total Environ. 367: 71–79. Valent F, Little D, Bertollini R, Nemer LE, Barbone F,
Lapostolle A, Lefranc A, Gremy I, Spira A. (2007). Eur J Tamburlini G. (2004a). Lancet. 363: 2032–2039.
Public Health. 18(2): 192–200. Valent F, Little D, Tamburlini G, Barbone F. (2004b).
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray Burden of Disease Attributable to Selected Environ-
CJL. (2006a). Lancet. 367: 1747–1757. mental Factors and Injuries Among Europe’s Chil-
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray dren and Adolescents. World Health Organization
CJL. (eds.). (2006b). Global Burden of Disease and (WHO Environmental Burden of Disease Series,
Risk Factors. The World Bank, Washington, and No. 8), Geneva.
Oxford University Press, New York. WHO (1999). Declaration of the Third Ministerial Con-
Melse JM, Essink-Bot ML, Kramers PG, Hoeymans N. ference on Environment and Health (London,
(2000). Am J Public Health. 90: 1241–1247. 16–18 June 1999). World Health Organization
Murray CJ, Acharya AK. (1997). J Health Econ. 16: Regional Office for Europe, Copenhagen.
703–730. WHO (2002). The World Health Report 2002: Reducing
Murray CJL, Lopez AD. (eds.) (1996). The Global Risks, Promoting Healthy Life. World Health Orga-
Burden of Disease. Harvard University Press, nization, Geneva.
Cambridge, MA. WHO (2003). Burden of Disease Project: 2001 Mortality
Öberg M, Jaakkola MS, Woodward A. (2007). Burden of and DALYs. World Health Organization, Geneva.
Childhood Disease Attributable to Second Hand WHO (2004a). Revised Global Burden of Disease (GBD)
Smoke in the WHO European Region. World Health 2002 Estimates. Incidence, Prevalence, Mortality,
Organization (WHO Environmental Burden of Dis- YLL, YLD and DALYs by Sex, Cause and Region,
ease Series, draft version), Geneva. Estimates for 2002 as Reported in the World
Polinder S, Meerding WJ, Mulder S, Petridou E, Health Report 2004. http://www.who.int/
van Beeck Ed & EUROCOST Reference Group. healthinfo/bodgbd2002revised/en/index.html.
(2007). Bull WHO. 85: 27–34. WHO (2004b). Fourth Ministerial Conference on Envi-
Powles JW, Zatonski W, Vander Hoorn S, Ezzati M. ronment and Health. Budapest, Hungary, 23–25
(2005). BMC Public Health 5: 116. June 2004. Final conference report. http://www.
Prüss A, Kay D, Fewtrell L, Bartram J. (2002). Environ euro.who.int/document/eehc/ereport.pdf.
Health Perspect 110: 537–542. WHO (2004c). Fourth Ministerial Conference on Envi-
Prüss-üstün A, Mathers C, Corvalán C, Woodward A. ronment and Health. Budapest, Hungary, 23–25
(2003). Introduction and Methods: Assessing the June 2004. Children’s Environment and Health
Environmental Burden of Disease at National and Action Plan for Europe. http://www.euro.who.int/
Local Levels. World Health Organization (WHO document/e83338.pdf.
Environmental Burden of Disease Series, No. 1),
Geneva.
43 Disease Burden of Diarrheal
and Respiratory Disorders in
Children: Hong Kong
Perspectives
E. A. S. Nelson
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752
2 Diarrheal and Respiratory Disease Burden Based on Passive

Surveillance Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
3 Linking of CMS with Laboratory Data for One Hospital . . . . . . . . . . . . . . . . . . . . . . . . . . 755
4 Active Sentinel Hospital-Based Surveillance of Diarrheal Disease . . . . . . . . . . . . . . . . . 756
5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760

752 43 Disease Burden of Diarrheal and Respiratory Disorders in Children: Hong Kong Perspectives
Abstract: Diarrheal and respiratory infections are leading causes of pediatric hospital admis-
sion in Hong Kong. Since 1996, all Hong Kong government hospitals routinely collect
computerize information on all admissions, enabling disease burden of diarrheal and respira-
tory disorders to be estimated. These data showed that, for the 2-year period 1 July 1997 to 30
June 1999, diarrheal diseases accounted for 11.5% of general pediatric admissions under 5
years and that respiratory disorders accounted for 37.5% of general pediatric admissions
under 15 years. However linking these data to laboratory reports from one hospital showed
significant discrepancies between actual diagnoses and the specific pathogens identified,
emphasizing that there was significant under-reporting of diseases due to specific pathogens.
An active sentinel surveillance study for rotavirus and diarrheal diseases, involving four
hospitals from 1 April 2001 to 31 March 2003, confirmed these underestimates and high-
lighted the potential for establishing a sustainable surveillance system. Such a system would
require one or more sentinel hospitals routinely collecting and testing specimens from all
diarrheal and respiratory associated admissions for identification of specific viral and bacterial
etiological agents. These laboratory data would then need to be linked to routinely collected
> passive surveillance hospital admission data and with government census data to provide
reliable disease burden estimates. Such a system has the potential to meet the goals of the new
WHO initiative known as the Global Framework for Immunization Monitoring and Surveil-
lance, which aims to strengthen surveillance and program monitoring of vaccine preventable
diseases.
List of Abbreviations: ARSN, Asian rotavirus surveillance network; CMS, clinical manage-
ment system; GFIMS, global framework for immunization monitoring and surveillance; HA,
hospital authority; ICD, International Classification of Diseases; IR, interquartile range; MDG,
millennium development goals; PATH, program for appropriate technology in health; RSV,
respiratory syncytial virus; UNICEF, United Nations Children’s Fund; WHO, World Health
Organization
1 Introduction
In Hong Kong, as in most developed and developing countries, diarrheal and respiratory
disorders are leading causes of admission to general pediatric wards, especially for children
under 5 years of age. Increasing numbers of respiratory and diarrheal diseases are becoming
vaccine preventable, and immunization programs are seen as essential to achieving the
Millennium Development Goals (MDG), particularly MDG 4 (Dabbagh, 2007). In 2005, the
World Health Organization and the United Nations Children’s Fund (UNICEF) published a
Global Immunization Vision and Strategy and called for strong systems for disease surveil-
lance and program monitoring to achieve these immunization goals. Consequently the World
Health Organization (WHO) has launched a new initiative, the Global Framework for
Immunization Monitoring and Surveillance (GFIMS), to strengthen surveillance and program
monitoring of vaccine preventable diseases. GFIMS aims to sustainably build capacity to
incorporate high quality vaccine preventable disease surveillance and monitoring into national
public health systems (Dabbagh, 2007).
Since the 1980s, a number of Hong Kong studies have assessed the impact of respiratory
and diarrheal diseases (Chiu et al., 2002; Nelson et al., 2004; Sung et al., 1992, 1993). For
example bronchiolitis was shown to account for about 6% of all pediatric admissions
Disease Burden of Diarrheal and Respiratory Disorders in Children: Hong Kong Perspectives 43 753
(Sung et al., 1992), and admission rates for influenza were 3–10 fold higher than those
reported for the United States (Chiu et al., 2002). Rotavirus was consistently shown in a number
of studies to be the leading cause of diarrhea, accounting for about 30% of all pediatric
gastroenteritis (Biswas et al., 1996; Chan et al., 1998; Tam et al., 1986). From 1996, a central
computerized database known as the Clinical Management System (CMS) was introduced to
collect uniform discharge and other information on all patients admitted to all publicly funded
government hospitals in Hong Kong, referred to as Hospital Authority (HA) hospitals. The
information collected through this system includes patient identifiers, date of birth, sex, a
maximum of 15 diagnoses and 15 procedures (classified according to the International Classifi-
cation of Diseases [ICD9-CM] codes), and admission and discharge dates. Pediatric patients
with medical and surgical conditions are admitted to separate wards of government hospitals in
Hong Kong. Twelve of these HA hospitals have pediatric beds. It has been estimated that 90% of
all in-patient care in Hong Kong occurs within HA (Chiu et al., 2002).
With the aim of improving disease burden estimates of potentially vaccine preventable
diarrheal and respiratory diseases, this passive CMS data source was analyzed to estimate the
disease burden for these conditions as a proportion of all general pediatric admissions for
children under the age of 5 years (diarrheal disorders) and under the age of 15 years
(respiratory disorders), over a 2-year period 1 July 1997 to 30 June 1999 inclusive (Nelson
et al., 2002, 2004, 2007). Recognizing that discharge coding was of variable quality, further
analyses from a single hospital were undertaken to link actual laboratory results to discharge
diagnostic codes provided by the CMS. This enabled incidence rates for rotavirus, influenza
and bronchiolitis to be estimated for children under 5 years old (Nelson et al., 2004, 2007).
Finally further > active surveillance of diarrheal diseases was undertaken, which enabled
linkage of the active and passive surveillance data sources to make estimates of rotavirus
and diarrheal disease burden for Hong Kong (Nelson et al., 2005a), and its economic impact
(Nelson et al., 2005b). Details of the methods and results of these analyses are discussed in
further detail.
2 Diarrheal and Respiratory Disease Burden Based on Passive

Surveillance Data
A database of all general pediatric patients hospitalized in the medical wards at the 12
government HA hospitals admitting such patients from 1 July 1997 to 30 June 1999 was
provided. Neonatal admissions were not included in the analysis. During the 2-year study
period, 169,082 children were admitted to HA medical pediatric wards; 94% (159,677) were
under the age of 15 years and 63% (106,919) were under the age of 5 years. A total of 2,720
different ICD codes were used.
The following ICD9-CM codes were used to define diarrhea hospitalizations: 001–005,
excluding 003.2, and 008.0–008.5 (bacterial diarrheas); 006–007, excluding 006.2–006.6 (par-
asitic diarrheas); 008.61 (rotavirus diarrhea); 008.6–008.8 (other viral diarrheas); 009.0–009.3
(diarrhea of undetermined etiology, including that presumed to be infectious); and 558.9 and
787.91 (other non-infectious diarrheas) (> Table 43-1). Although children with gastroenteritis
who have no pathogen isolated should be correctly coded as ICD 009.0–009.3, it was apparent
that the ICD codes 559.9 and 787.91 were often used instead. Diarrheas of undetermined and
non-infectious etiology were grouped as ‘‘non-specified diarrhea.’’ Classification into one of
these groups was made if any of these codes were listed as the primary diagnosis.
. Table 43-1
Diarrhea hospitalizations by reported diagnosis among 106,919 children aged 1–59 months,
Hong Kong government hospitals from 1 July 1997 to 30 June 1999 (Nelson et al., 2004)
Etiology of diarrhea hospitalization ICD codes Primary diagnosis no. (%) Male: Female
Non-specified diarrheas
Presumed infectious 009.0–009.3 5,753(46.9) 57:43
Presumed non-infectious 558.9, 789.91 3,358(27.4) 57:43
Viral excluding rotavirus 008.6–008.8 183(1.5) 48:52
Rotavirus 008.61 1,270(10.4) 58:42
Cholera 001–001.9 1(0) 100:0
Salmonella species 002–003.9 1,347(11.0) 53:47
Shigella 004–004.9 66(0.5) 59:41
Food poisoning 005–005.9 38(0.3) 59:41
Escherichia coli and others 008–008.5 241(2.0) 62:38
Total diarrhea 12,257(11.5%) 57:43
Total of all other diseases 94,662(88.5%) 58:42
The ICD9-CM codes classified respiratory-associated hospitalizations into upper respira-

tory tract infections, pharyngitis and tonsillitis, croup and laryngitis, otitis media, bronchitis
and non-specific chest infection, bronchiolitis, bronchiolitis due to respiratory syncytial virus
(RSV) infection, pneumonia, influenza, asthma and allergic rhinitis (> Table 43-2). Classifi-
cation into one of these groups was made if any of these codes were listed as the primary
diagnosis. A second classification for both the diarrheal and respiratory admissions was made
if any of these codes were listed as any of the 15 possible diagnostic codes (data not shown).
Children with bacterial diarrheas had a median hospital stay of 4 days (interquartile range
[IR], 2–7), a period similar to that for rotavirus hospitalizations but longer than that for
children with viral diarrheas or other non-specified diarrheas (3 days; IR, 2–4). Of all the
respiratory sub-categories, children with a diagnosis of bronchiolitis, influenza, and pneumo-
nia had the longest median stay in hospital of 3 days (IR, 2–5 days), whereas the other sub-
categories had a median stay of 2 days.
Incidence rates for diarrhea coded as rotavirus were estimated using total Hong Kong
births as denominators.(Nelson et al., 2002) For primary diagnosis only, rates per 100,000
were 437 and 440 for infants less than 1 year, and 171 and 221 for children less than 5 years for
1997 and 1998 respectively. The annual incidence (hospitalization) rates per 100,000 for
respiratory illnesses (primary diagnosis only) were estimated for the same period: bronchioli-
tis 887–979 (<5 years) and 3,551–3,949 (<1 year); RSV bronchiolitis 90–259 (<5 years) and
381–1,134 (<1 year); influenza 222–381 (<5 years) and 415–528 (<1 year) (Nelson et al.,
2007).
Recognized limitations of these passive CMS surveillance data include the absence of data
from private hospitals and the potential unreliability of the ICD coding. Absence of private
hospital data will impact on estimates of incidence, as will the movement back-and-forth of
Hong Kong born children between Hong Kong and Mainland China and the arrival of new
immigrant children to Hong Kong from Mainland China. The variable reliability of the ICD
. Table 43-2
Respiratory-associated hospitalizations by reported diagnosis among 159,626 children aged
0–15 years in government hospitals from 1 July 1997 to 30 June 1999 (Nelson et al., 2007)
Etiology of diarrhea Primary Male:

hospitalization ICD codes diagnosis no. (%) Female
Upper respiratory infection 460–461.9, 465–465.9, 18,046(30.1) 55:45
786.2
Tonsillitis/pharyngitis 462–463.9, 034.0, 474.11 6,311(10.5) 59:41
Croup/laryngitis 464–464.9, 786.1 1,394(2.3) 68:32
Acute otitis media 381–382.9 1,625(2.7) 63:37
Bronchitis/chest infection 466–466.09, 490–490.9, 1,546(2.6) 62:38
519.8
Bronchiolitisa 466.1–466.9 6,081(10.2) 66:34
Pneumonia 480–486.9, 507.0 12,541(20.9) 55:45
Influenza 487–487.9 2,418(4.0) 58:42
Asthma/allergic rhinitis 493–493.9, 477–477.9 9,908(16.5) 66:34
Total respiratory diseases All above codes 59,870(37.5) 59:41
All other diseases All other codes 99,756b(62.5) 55:45
a
No. of primary diagnosis of respiratory syncytial virus bronchiolitis = 1,125 (1.9% of all respiratory-associated
admissions)
b
715 admissions were not coded
coding practices was highlighted by significant inter-hospital variation in disease burden of the
different diarrheal and respiratory etiological groups (Nelson et al., 2004, 2007). ICD codes are
entered by the doctor responsible for writing the discharge summary and will depend on the
laboratory information available at the time of discharge and on the doctors’ choice of code
from the CMS. A further way to highlight discrepancies in ICD coding is to link the laboratory
results to CMS discharge diagnoses. This process indicates which admissions are associated
with a specific potential etiological agent and enable more accurate estimates to be made of
disease burden for specific diarrheal and respiratory pathogens. To explore the potential for
this linkage and to better understand the limitations of the passive ICD codes, the next step in
the analysis was to link the passive CMS data with laboratory data for both diarrheal and
respiratory pathogens from one hospital.
3 Linking of CMS with Laboratory Data for One Hospital

All admissions from one of the HA hospitals, Prince of Wales Hospital, were matched with a
unique hospital number with identifier information available within the pediatric depart-
ment’s audit system (based on the CMS data). A total of 16,844 general pediatric admissions
under the age of 15 years (10,231 under the age of 5 years) that had been admitted during the
corresponding period could be matched. The final number of laboratory tests available for
matching was 25,058 from a total of 4,160 subjects under 15 years (41% of general pediatric
admissions). The normal laboratory practice would be to test stool specimens for rotavirus
and bacterial culture and nasopharyngeal aspirate specimens for influenza A, influenza B, and
RSV by immunofluorescence followed by virus isolation for respiratory viruses. These labora-
tory results were then linked with the CMS discharge diagnoses. This showed significant
discrepancies between the actual diagnoses and laboratory results. There were 15% of the
10,231 general pediatric admissions under the age of 5 years that had a primary diagnosis of
diarrhea, but only 40% of these children had had a stool specimen sent for rotavirus testing, as
did 3.1% of children with non-diarrhea primary diagnoses. Of all specimens sent from
patients with a primary diagnosis of diarrhea, 37% were positive for rotavirus. A total of 76
children had a diagnosis of rotavirus diarrhea and a positive laboratory identification of
rotavirus. An additional 172 children had rotavirus identified on a stool specimen but did
not have any discharge diagnosis code that indicated a diagnosis of rotavirus diarrhea. In
addition, 69 children had a diagnosis listed as rotavirus diarrhea but had no laboratory
confirmation. Thus a CMS diagnosis of rotavirus diarrhea had a positive predictive value of
52% that the laboratory result was positive for rotavirus. Extrapolating from these data, it was
estimated that almost 6% of all general pediatric admissions could have been associated with
rotavirus infection (Nelson et al., 2004). Similar discrepancies were noted for the 34% (n =
5,639) of general pediatric admissions with a primary respiratory-associated diagnosis. Of 161
children with a primary or secondary CMS discharge diagnosis of influenza, there was
laboratory confirmation in only 77. Overall, the laboratory identified influenza in 507
children, of which 126 had a non-respiratory primary diagnosis. Similar discrepancies were
noted with the diagnosis of RSV bronchiolitis, with the laboratory identifying RSV in 319
admissions, of which only 76 were coded as RSV bronchiolitis. A CMS influenza discharge
diagnosis had a positive predictive value of 48% that the laboratory result would be positive
for influenza and a negative predictive value of 93% that the result would be negative or not
reported. Extrapolating from these data, almost 7% of all general pediatric admissions could
have been associated with influenza infection (Nelson et al., 2007).
These analyses of passive surveillance data and linkage of routine laboratory data with
passive CMS discharge data show that not only are diarrheal and respiratory disorders very
important causes of hospitalization of children in Hong Kong, but that passive HA hospital
discharge data are likely to underestimate the true disease burden of conditions caused by
specific pathogens. This emphasizes the importance of undertaking active surveillance to
provide a more precise estimate of such disease burdens. Designating sentinel hospitals
to undertake active surveillance by doing routine virology and bacteriology testing on
all diarrheal and respiratory admissions, and then linking these data to denominator
CMS discharge and census birth data could provide reliable estimates of disease burden of
specific diarrheal and respiratory pathogens in a sustainable way.
4 Active Sentinel Hospital-Based Surveillance of Diarrheal

Disease
The WHO and other international institutions such as the GAVI Alliance have identified
rotavirus vaccine as a priority, and funding has been provided to fast-track vaccine develop-
ment and introduction into developing countries (McCarthy, 2003). To this end, WHO
recommended the use of simple, generic protocols for surveillance, as well as the establishment
of regional surveillance networks, for rotavirus infection. The first such network, the Asian
Rotavirus Surveillance Network (ARSN), was established in February 1999 as an initiative of

the US Centers for Disease Control and Prevention, WHO, PATH and partners from industry
(GlaxoSmithKline and Merck & Co., Inc.) (Bresee et al., 2004). The first phase of the ARSN
included nine countries (with 36 centers) (GAVI-eligible countries in italics): China (7), Hong
Kong (4), Indonesia (3), Malaysia (2), Myanmar (1), South Korea (3), Taiwan (4), Thailand (6)
and Vietnam (6). A second phase of the ARSN was launched in 2005 and included 14 countries
(with 37 centers): Bangladesh (2), Cambodia (1), Kyrgyzstan (2), Laos PDR (1), Mongolia (2),
Nepal (1), Pakistan (2), Philippines (7), Sri Lanka (1), Uzbekistan (2), China (8), Indonesia (5),
Myanmar (1), Thailand (2) (Bresee et al., 2005).
The Hong Kong active surveillance study was undertaken in partnership with the ARSN to
obtain accurate estimates of rotavirus disease burden. As it was also believed that the CMS data
has the potential to provide long-term low cost surveillance of rotavirus disease in Hong Kong,
a secondary aim of the study was to explore the issue of under-reporting of rotavirus by the
CMS data by comparing active surveillance data collection with the passive CMS data
collection.
The overall study design of the active surveillance study was based on a WHO Generic
Protocol for conducting rotavirus surveillance in developed and developing countries (WHO,
2002). Twelve HA and ten private hospitals provide pediatric services in Hong Kong and four
HA hospitals, one in each of Hong Kong’s four main geographic districts, were selected for
active surveillance. At the time of the study it was estimated that 90% of inpatient care in Hong
Kong takes place in HA hospitals (Chiu et al., 2002). Ward log books of participating hospitals
were viewed weekly to record patient identifiers and admission diagnoses. A ‘‘Childhood
Diarrhea Admission Form’’ was used to help standardize the clinical data collection and data
abstraction after discharge. All children less than 5 years of age, that had either a primary or
secondary diagnosis of diarrhea, and/or had a stool specimen sent to the laboratory were
included. Children who did not pass any stool or were discharged within 48 h of admission
without any bowel evacuation were considered as non-diarrheal admissions. All participating
hospitals routinely sent stool specimens for bacterial culture and rotavirus testing on all
children admitted with diarrhea. Participating hospitals entered laboratory results into a
computer database which was regularly collated with the clinical data being collected. The
CMS data for all 12 HA hospitals from July 1999 to June 2003 were provided by the HA Data
Centre to enable the active surveillance data to be compared with the passive CMS data. The
classification of CMS ICD discharge diagnoses into different etiological groups was the same
as undertaken previously (ICD codes shown in > Table 43-1). The Hong Kong Census
Department provided details of all Hong Kong births and numbers of new immigrant children
to enable incidence estimates to be calculated.
Detailed analysis focused on data collected during the 24-month study period from 1 April
2001 to 31 March 2003. This period was selected as the rotavirus season in Hong Kong peaks
from November to February. During this 24-month period there were 7,391 cases eligible for
inclusion. A primary admission diagnosis that included gastroenteritis, diarrhea, gastritis,
vomiting was noted in 70% and 11% had had a previous admission within the past 2 weeks
(one third of these due to diarrhea). Overall, 80% of subjects had a stool specimen sent for
rotavirus testing and rotavirus antigen was identified in 30% of samples tested (24% of all
diarrhea-associated admissions). Stool specimens were sent for bacterial culture in 87% of the
patients and a pathogen was identified in 24% of samples tested (21% of all diarrhea-associated
admissions). Of the positive samples, Salmonella was identified in 44%, Campylobacter
in 11%, Shigella in 1%, other pathogens in 33%, and more than one organism in 11%.
Co-infections with rotavirus and a bacterial pathogen was noted in 12% of rotavirus positive
children. Cumulative percentage of admissions by age in months showed that rotavirus
positive children tended to be admitted at an older age than the rotavirus negative group
(> Figure 43-1). The seasonality of admissions for rotavirus-positive and -negative diarrhea
was examined over three rotavirus seasons during a 28-month period of the 1 December 2000
to 31 March 2003 (> Figure 43-2).
The surveillance data were compared with CMS data for the 24-month period 1 April 2001
to 31 March 2003. In the four surveillance hospitals, 13% of all admissions had a primary
diarrhea code, 15% had either a primary or secondary code indicating diarrhea, 1.7% of all
admissions had a primary code for rotavirus (008.61), and 2.0% had any code indicating
rotavirus (> Table 43-3). However the active surveillance data identified rotavirus in 4.6% of
all general pediatric admissions to the four surveillance hospitals. On the basis of these active
surveillance data over this 24-month period, incidence rates of rotavirus hospitalizations were
calculated to be between 8.1 and 8.8 per 1,000 children <5 years of age and between 15.4 and
18.4 per 1,000 children <1 year of age (Nelson et al., 2005a).
These active surveillance data showed that diarrhea was extremely common, with 20% of
all general pediatric admissions to the four surveillance hospitals being associated with
diarrhea (either primary or secondary diagnosis). The active surveillance results also con-
firmed previous concerns about under-estimating disease burden when routine CMS data
alone is used (Nelson et al., 2002, 2004) By combining the active surveillance data with the
CMS discharge data for all HA hospitals, it was possible to improve estimates of rotavirus
incidence, which was significantly higher than that derived from CMS data alone. However
. Figure 43-1
Cumulative percentage of rotavirus-positive and -negative diarrhea admissions by age of the
patient. Percentage of children admitted with diarrhea due to rotavirus according to age
compared to percentage admitted with diarrhea not due to rotavirus
. Figure 43-2
Number of children admitted with diarrhea due to rotavirus according to season of the year
compared to number admitted with diarrhea not due to rotavirus during the period 1 December
2000 to 31 March 2003
. Table 43-3
Comparison of passive Clinical Management System (CMS) and active surveillance data from four
Hong Kong government hospitals participating in a surveillance study (n = 37,829 admissions)
and eight hospitals not participating in the surveillance study (n = 57,382 admissions) during the
24-month period 1 April 2001 to 31 March 2003.(Nelson et al., 2005a)
Diarrhea as % of all Rotavirus as % of diarrhea- Rotavirus as % all

admissions associated admissions admissions
Surveillance study data at four surveillance hospitals
Any diagnosis (clinical 20% (7,391) 24% (1,758)a 4.6%a
or laboratory)
CMS data at four surveillance hospitals
Primary diagnosis 13% (4,927) 13% (634) 1.7%
b
Any diagnosis 15% (5,660) 13% (745) 2.0%
CMS data at eight non-surveillance hospitals
Primary diagnosis 10% (5,654) 12% (661) 1.2%
b
Any diagnosis 12% (7,097) 11% (793) 1.4%
a
If all diarrheal stool specimens had been tested for rotavirus, and if the proportion positive were the same as those
actually tested (i.e., 30%), then 5.9% of all general pediatric admissions would have been due to rotavirus
b
Diarrhea associated International Classification of Disease code in any of 15 possible discharge codes
even these improved incidence estimates do not fully take into account the number of children
admitted to private hospitals in Hong Kong, which may vary over time. The incidence
estimates also cannot easily account for movements of Hong Kong born children between
Hong Kong and Mainland China, although the potential impact of new immigrant children
was estimated. It is also important to emphasize that this analysis did not determine the
proportion of patients who were readmitted for the same diarrheal episode, a factor that
would result in the overestimation of the true incidence of diarrheal illness. Acknowledging
these limitations the overall risk of a child being admitted to hospital with rotavirus by the age
of 5 years was estimated to be 1 in 24 (excluding new immigrant children) or 1 in 27 if these
children are included in the calculation (Nelson et al., 2005a).
The CMS system has the potential to be a low-cost surveillance tool but issues such as the
reliability of ICD coding needs to be addressed. Although strategies can be explored to
improve actual quality of ICD coding e.g., computer prompts, it is unlikely that the CMS
ICD codes alone can be used to provide reliable disease burden estimates. Therefore other
strategies are required. The most feasible and sustainable option could be establishing a
sentinel hospital system where all participating hospitals are required to send appropriate
specimens on all diarrheal and respiratory associated admissions for identification of specific
viral and bacterial etiological agents. These laboratory data could then be linked routinely with
CMS and census data to provide sustainable disease burden estimates.
5 Conclusion
These studies have demonstrated the potential of using routinely collected discharge diagnosis
data (CMS data) and routinely collected laboratory data with actively collected sentinel
surveillance data and census data to derive reliable estimates of disease burden for diarrheal
and respiratory diseases. This experience could be used to establish a network of active sentinel
surveillance hospitals to monitor disease burden for a number of vaccine preventable diseases
in Hong Kong. Outstanding issues include absence of private hospital data and more infor-
mation is required to better understand health utilization practices of those children that move
regularly between Hong Kong and Mainland China. Economic analyses could help determine
whether such an active sentinel hospital surveillance system could be sustainable to meet the
goals of GFIMS.
Summary Points
Diarrheal and respiratory infections are leading causes of pediatric hospital admission in
Hong Kong.
Increasing proportions of diarrhea and respiratory infections are becoming vaccine pre-
ventable.
Surveillance and monitoring of vaccine preventable diseases is a WHO priority.
WHO has launched a new initiative known as the Global Framework for Immunization
Monitoring and Surveillance to strengthen surveillance and program monitoring of
vaccine preventable diseases.
Since 1996, Hong Kong government hospitals routinely collect computerize information
on all admissions providing passive disease burden surveillance data.
Using these passive surveillance data, significant discrepancies were noted between actual
diagnoses and specific pathogens identified from laboratory investigations.
These passive surveillance data significantly under-reported disease burden of diarrheal
and respiratory infections due to specific pathogens e.g., rotavirus, influenza.
A surveillance system that utilizes both active sentinel surveillance combined with passive
data collection has the potential to provide reliable and sustainable disease burden
information for important vaccine preventable diarrheal and respiratory pathogens.
Acknowledgments
The Statistics and Research Section, Hospital Authority provided the pediatric hospitals
admission dataset, from the HA data warehouse, used in these analyses.
References
Biswas R, Lyon DJ, Nelson EA, Lau D, Lewindon PJ. Nelson EA, Tam JS, Yu LM, Glass RI, Parashar UD,
(1996). Trop Med Int Health. 1(5): 679–683. Fok TF. (2004). Epidemiol Infect. 132(4): 619–626.
Bresee J, Fang ZY, Wang B, Nelson EA, Tam J, Soenarto Y, Nelson EA, Tam JS, Yu LM, Li AM, Chan PK, Sung RY.
Wilopo SA, Kilgore P, Kim JS, Kang JO, Lan WS, (2007). Hong Kong Med J. 13(2): 114–121.
Gaik CL, Moe K, Chen KT, Jiraphongsa C, Nelson EA, Tam JS, Yu LM, Ng YC, Bresee JS, Poon KH,
Ponguswanna Y, Nguyen VM, Phan VT, Le TL, Ng CH, Ip KS, Mast TC, Chan PK, Parashar UD,
Hummelman E, Gentsch JR, Glass R, Asian Rotavi- Fok TF, Glass RI. (2005b). J Infect Dis. 192(Suppl 1):
rus SN. (2004). Emerg Infect Dis. 10(6): 988–995. S64–S70.
Bresee JS, Hummelman E, Nelson EA, Glass RI. (2005). J Sung RY, Chan RC, Tam JS, Cheng AF, Murray HG.
Infect Dis. 192(Suppl 1): S1–S5. (1992). Epidemiol Infect. 108(1): 147–154.
Chan PK, Tam JS, Nelson EA, Fung KS, Adeyemi-Doro Sung RY, Cheng AF, Chan RC, Tam JS, Oppenheimer SJ.
FA, Fok TF, Cheng AF. (1998). Epidemiol Infect. 120 (1993). Clin Infect Dis. 17(5): 894–896.
(3): 321–325. Tam JS, Kum WW, Lam B, Yeung CY, Ng MH. (1986).
Chiu SS, Lau YL, Chan KH, Wong WH, Peiris JS. (2002). J Clin Microbiol. 23(3): 660–664.
N Engl J Med. 347(26): 2097–2103. WHO. (2002). Generic Protocol for (i) Hospital-Based
Dabbagh A. (2007). Bull World Health Organ. 85(12): Surveillance to Estimate the Burden of Rotavirus
901–980. Gastroenteritis in Children and (ii) A Community-
McCarthy M. (2003). Lancet. 361(9357): 582. Based Survey on Utilization of Health Care Services
Nelson EA, Tam JS, Bresee JS, Poon KH, Ng CH, Ip KS, for Gastroenteritis in Children. Field test version
Mast TC, Chan PK, Parashar UD, Fok TF, Glass RI. (WHO/V&B/02.15). WHO publication, WHO/
(2005a). J Infect Dis. 192(Suppl 1): S71–S79. V&B/02.15.
Nelson EA, Tam JS, Glass RI, Parashar UD, Fok TF.
(2002). Pediatr Infect Dis J. 21(7): 701–703.
44 Burden of Disease in Elderly
Mexican Population
B. Rico-Verdı́n . G. Rodriguez-Abrego . I. Villaseñor-Ruiz .
J. L. Torres-Cosme
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
2 Epidemiological Overview of Ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
3 Demographic Overview of Ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
4 Social and Economic Overview of Ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774
5 Profile of Medical and Social Care Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775
6 What are we Doing for Our Elderly Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
7 Final Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780

764 44 Burden of Disease in Elderly Mexican Population
Abstract: We live in an aging society in which at birth people can expect to live into their 70s
or 80s, compared to 40s in the beginning of the twentieth century. People are living longer and
they are living more of their years in good health; however, the fast growth of the elderly
population worldwide is creating an unprecedented global demographic revolution. At pres-
ent, the magnitude of aging in the world shows that developed countries have aged gradually
throughout the whole century; whereas developing countries will age in less than 30 years.
Mexico, as well as other Latino American countries, has a noticeable tendency to aging. In
an intermediate development society with a young population structure, there is an underly-
ing presence of a highly heterogeneous demographic and epidemiological process, in addition
to a lengthier population > life expectancy, which poses enormous challenges. Rather than
demographic progress, it constitutes a challenge for current population policies, social
planning and development of governmental programmes, since demands of the populations
exceed the capacity of the productive system.
Mexico is not yet facing a health crisis related to demographic aging. We are just at the right
time to develop health care and prevention policies and programmes based on the research and
experiences of developed countries. On the other hand, effective national and local social and
economic population interventions are needed. In a the short time, we will have to provide good
answers towards the improvement of the pension system and promote joint citizen participation
and governmental networks to keep the elderly integrated and active in our society.
List of Abbreviations: CONAPO, National Council of Population; CONAPO, Consejo
Nacional de Población; ECLAC, Economic Commission for Latin America and the Caribbean;
ENSA, National Health Survey; IMSS, Mexican Institute of Social Security; IMSS, Instituto
Mexicano del Seguro Social; INEGI, National Institute of Statistics, Geography and Informat-
ics; INEGI, Instituto Nacional de Estadı́stica, Geografia e Informática; ISSSTE, Institute of
Services of Social Security to Civil Servants; ISSSTE, Instituto de Servicios de Seguridad Social
de los Trabajadores del Estado; PAHO, Pan American Health Organization; SSA, Ministry of
Health of Mexico; SSA, Secretaria de Salud; SABE, Survey on Health, Welfare and Ageing;
SABE, Encuesta sobre Salud, Bienestar y Envejecimiento; NBD, National Burden of Disease;
DALY, Disability-adjusted life years; DFLE, > Disability free life expectancy; LED, > Life
expectancy with disability; LE, life expectancy; YLL, years of life lost due to mortality; YLD,
years lived with disability; WHO, World Health Organization; UN, United Nations; MLSP,
Maximum lifespan potential; DALY, List of Abbreviations of Tables and Figures: disability-
adjusted life years; DFLE, disability-free life expectancy; LED, life expectancy with disability;
LE, life expectancy; YLL, years of life lost due to mortality; YLD, years lived with disability
1 Introduction
Discussions of aging invariably begin by establishing satisfactory definitions for the term of
‘‘aging’’ and its related word ‘‘senescence.’’ Although the term ‘‘aging’’ is commonly used to
refer to post-maturational processes that lead to diminished homeostasis and increased
organismic vulnerability, the more correct term for this is ‘‘senescence.’’
There is enough evidence supporting at least five common characteristics of aging in
mammals: increased mortality with age after maturation; changes in tissue biochemical
composition with age; progressive decrease in physiological capacity with age; reduced ability
to respond adaptively to environmental stimuli with age; and increased susceptibility and
Burden of Disease in Elderly Mexican Population 44 765
vulnerability to disease (Fogel, 1997; Troen, 2003). In an effort to adequately explain the
phenotype of aged organisms, many theories about the cause of aging have been proposed; yet,
no unifying theory may be valid, since aging mechanisms could be quite distinct in different
organisms, tissues, and cells.
Historically, aging theories have been divided into two general categories: stochastic and
developmental genetic. The first one includes the following: somatic mutation and DNA error-
catastrophe repair, protein modification and free-radical (oxidative stress)/mitochondrial
DNA theories. The developmental-genetic category is associated to theories of longevity
genes, accelerated aging syndromes, neuroendocrine, immunologic, cellular senescence and
cell death (Fogel, 1997; Troen, 2003).
Now, age is a biological process with its own dynamics, and each society has its own concept
of old age. In the developed world, for instance, the beginning of ‘old age’ is at ‘retirement’, at
the age of 60 or 65 years, while in many developing countries, the chronological time has little or
no importance for the definition of elderly age. Old age is defined as a state of dependency and
incapacity that is conceived as the point in time that begins when people cannot work more
(Fogel, 1997; HelpAge international, 2006). Ageing, which is merely a reflection of successful
human development processes resulting from lower mortality (together with the decrease
in fertility) and greater longevity, will have a deep effect on society and will get more and
more attention from policy makers in the 21st century.
According to the World Health Organisation (WHO), in the next 10 years a greater
proportion of population will be considered ‘‘old’’ because of the aging of worldwide
populations. Considering that health during life is a cumulative process, the life-cycle
perspective recognises that the health of aging people will depend to a great extent on
their life style and behaviours. Generally, a person is considered ‘‘elderly or old’’ when he/she
reaches the age of 60–65 years, irrespective of his/her clinical history and particular
situation.
At present, the magnitude of aging in the world shows that developed countries have
aged gradually throughout the century; whereas developing countries will age in less than 30
years. Latin America and the Caribbean countries, in contrasts to the developed world which
was affluent when it aged, will age while still poor and that aging process already is
heightening the differences between individuals as well as the current socio-economics
inequalities (Lloyd-Sherlock P, 2000). Reference to ‘‘aging societies’’ conjures imageries
that differ sharply. In some cases, they revolve around nearly bankrupt pension or social
security systems, or about families physically and economically overburdened with respon-
sibilities of simultaneously caring for very young children and very old ones. In other cases,
they point towards societies overloaded with unmet health care demands of the chronically
ill, functionally disabled, and mentally and physically impaired. (Palloni et al., 2002)
Currently, in Latin America and the Caribbean countries these are the realities faced with
respect to their aging populations.
The information available leads us to confirm that the Latin American population displays
a noticeable aging tendency, and Mexico is not an exception. Mexico is a society with interme-
diate development and a young population structure that is experiencing the existence of an
aging process that is highly heterogeneous. This situation places challenges to previously
defined nationwide plans, in addition to the fact that the elderly are living much longer
which is not only a demographic advance but rather a challenge for population policies, social
planning and programme development, since the demands of this aged population exceed the
system’s capacity (Salgado-de Snyder et al., 2005; SSA, 2001).
2 Epidemiological Overview of Ageing
Mexico experiences a transition that in health terms is characterised by two challenges: health
unmet demands and emergent risks. Health unmet demands affect mainly the poorest groups
and it is characterised by infectious, nutritional and reproductive diseases. This in itself is an
unacceptable burden for a country like ours. In this sense, the lack of preventive schemes in
previous aging stages places them at the risk of suffering chronic degenerative diseases when they
become older. With regard to the second challenge, emergent risks, Mexico is undergoing a phase
of fast changes in health profiles. The general characteristic of this process consists of a reduction
of typical under-development sufferings and an increase of diseases prevalent in industrialised
countries. This is caused, apart from other factors, by a fast growth of urban central areas, better
educational levels, basic sanitation, and better control of infectious diseases, as well as by changes
in the conditions and life styles of current societies (Gonzalez, 2007).
At the moment, around 7% of the Mexican society is 60 years old or more. In other Latin
American countries, as in Mexico, the proportion of elderly population will grow significantly
in the next decades, and so will the frequency of chronic degenerative diseases, amongst which
the most important are: cardiovascular diseases, diabetes mellitus, hypertension and cancer.
Additionally, there are three problems in the mental health field that have high priority:
depression, dementias and problems related to excessive alcohol intake and drug abuse
(CONAPO, 2005; Guzmán JM, 2002). The same phenomenon is different across the regions
and states of Mexico, but in general a polarised transition model is observed, where chronic
degenerative and infectious diseases coexist. The stratum of population with better well-being
levels is in an advanced phase of transition, while the poorest groups are lagging behind in this
process. The main causes of hospital morbidity are pneumonias and complications of arterio-
sclerosis, in particular, cerebrovascular and cardiac diseases.
Little is known about the magnitude of other apparently common afflictions of the aged,
like trauma, malnutrition, dementia, depression and other ailments that do not produce
deaths but cause disability, because of deficient diagnosis and a lack of a suitable registry
system (Wong R et al., 2007a; Barrantes-Monge et al., 2007). In 1996, a study by the Centre of
Economy and Health classified high-priority needs of Mexican older people in three cate-
gories, irrespective of gender and disability degree. The first category, high disability, includes
falls, dementias, rheumatoid arthritis and osteoarthritis; the next category includes losses
between premature deaths and disability, such as stroke, nephritis and nephrosis and hyper-
tensive heart disease; the third category is comprised of the needs that are generated when
losses are essentially by premature death, such as ischemic heart disease, diabetes mellitus,
cancer and pneumonias (Lozano-Ascencio R et al., 1996).
In 1999 Mexico participated in an international research project known as ‘‘Survey on
Health, Welfare and Ageing’’ (SABE) through its Ministry of Health. This study was carried
out in Latin America and the Caribbean with the main goal of evaluating the current health
status and life conditions of the elderly; in Mexico, this survey was applied only in Mexico City
and the metropolitan area (SSA, 2001). One finding of this survey showed that a phenomenon
occurs among elderly men who reach and pass 75 years of age. In the 75- to 80-year-old group,
there is considerable health deterioration, with cardiac, pulmonary, urinary incontinence and
depression as added sufferings. Those men who survive this stage and exceed the age of 80
seem to suffer less compared to other age groups. In the case of women, the most common
diseases were hypertension, arthritis and diabetes and their frequency, except for stoke and
hearing problems, are always higher than in men.
These findings are similar in the great majority of countries of Latin America and the
Caribbean where chronic diseases are currently the main cause of premature death and
disability. By 2002, they represented 44% of the deaths in men and women under the age of
70 and caused two of three deaths in the general population. Chronic diseases contributed to
almost 50% of the years of life lost based on disability in the region (OPS, 2006). Moreover,
from the gender perspective, Life Expectancy (LE) of women at birth is greater than in men,
but their health is more aggravated than that of men for many reasons, for example, deficient
nutrition, little care on their reproductive health, domestic violence and difficult life condi-
tions, which are exacerbated after menopause when there are greater risks of having breast,
cervical and uterine cancer, as well as osteoporosis. Poverty, loneliness and abandonment are
added to their aged condition (Gonzalez, 2007).
In 2005, non-communicable diseases increased significantly in the elderly group and
contributed with a greater number of years of healthy life lost. > Table 44-1 illustrates the
conditions that constitute the Mexican elderly group health profile that cause the loss of
healthy life years in the 60-year-old group. The data obtained in 2005 for beneficiaries of the
Mexican Social Security Institute (IMSS) identified the diseases with the highest prevalence
and the disease burden in disability adjusted life years, which pointed at diabetes as one of the
main causes in this age group, as well as conditions that are potentially capable of causing
premature death, such as ischemic heart disease and cerebrovascular disease. In contrast, there
are also conditions associated to disturbances of the functional status and disability attribut-
able to pain, cognitive disorders, dependency and so on. Chronic obstructive pulmonary
disease, depression, dementia, rheumatoid arthritis and Parkinson’s disease are among the
most important illnesses identified.
> Figure 44-1 shows, in a gender analysis, that for the year 2005 at the age of 60, women
had a life expectancy of 24.2 years, i.e. an average of 4.37 years more than males. After
analyzing the Disability-Free Life Expectancy (DFLE) in this age group, we found that in
women the DFLE is 13.4 years, which indicates that women live less than men without
disability, in average 1.8 years. In general, we could state that women tend to be sick for
longer periods of time than men, since after comparing the Life Expectancy with Disability
(LED) in women from this age group, they will live 6.7 years in average versus 4.7 in men. The
above tallies with the information found in most of the countries, where women have a higher
likelihood of experiencing the equivalent of two or three more years of poor health during the
course of their lives compared to men but mainly during the old age [sic] (OECD, 2003).
3 Demographic Overview of Ageing
Ageing is determined by fertility behaviour, life expectancy (LE) at birth, mortality and
migration. According to United Nations criteria, a population can consider itself aged when
more than 5% of their members are over the age of 65, or when more than 10% of their
population is 60 years old or over.
The age distribution of the global population is undergoing a deep transformation. As
mortality and fertility have descended, age distribution has been gradually modified in favour
of the more advanced countries; yet, all the regions in the world are undergoing that change
(HelpAge International, 2002). At present, there are more than 416 million of elderly in the
world and it is expected that for the year 2025, the 60 years old and over population will be
12% of the world’s inhabitants. From this total, 72% will live in developing countries. LE in
768
44
. Table 44-1
Burden of disease in Mexican population covered by IMSS: Comparative Analysis with DALY selected causes. México 1995–2005
Mortality Morbidity Burden of diseases

Rate per Prevalence Incidence Rate per Rate per
Disease/Disorder by order of DALYs Deaths YLLs 100,000 cases YLDs 100,000 DALY 100,000
Diabetes mellitus 26710 345866 7192 1264309 31558 656,2 377423 7848,0
Ischemic heart disease 19833 200077 4160 78710 10272 213,6 210349 4373,9
Burden of Disease in Elderly Mexican Population
Cerebrovascular disease 9925 97797 2034 36711 88648 1843,3 186446 3876,9
Glaucoma 0 0 0 277597 154815 3219,2 154815 3219,2
Chronic obstructive pulmonary 8168 69937 1454 457968 62235 1294,1 132173 2748,4
disease
Depression 18 119 2 377462 122548 2548,2 122667 2550,7
Cirrhosis of the liver 6139 78680 1636 142091 43555 905,7 122235 2541,7
Nephritis and nephrosis 3690 40901 850 126618 10965 228,0 51866 1078,5
Dementia 682 5530 115 3964 39753 826,6 45283 941,6
Rheumatoid arthritis 215 2442 51 441 37673 783,4 40114 834,1
Unintentional injuries 3635 33181 690 147859 6107 127,0 39288 816,9
Trachea, bronchus and lung cancers 3016 36580 761 879 242 5,0 36822 765,7
Lower respiratory infections 4325 35396 736 15399 125 2,6 35521 738,6
Osteoarthritis 0 0 0 516627 34000 707,0 34000 707,0
Parkinson disease 440 3853 80 62176 23018 478,6 26871 558,7
Liver Cancer 1886 23390 486 1881 313 6,5 23703 492,9
Prostate Cancer 2298 21020 437 3958 1751 36,4 22771 473,5
Stomach cancer 1623 19973 415 2644 1845 38,4 21818 453,7
Colon and rectum cancers 1280 15584 324 2916 2162 45,0 17746 369,0
Breast Cancer 1123 16411 341 11623 0,0 16411 341,2
Source: Health Needs Assessment Project. IMSS 2005
Population over age 60: 4.809.141 IMSS 2005
Number of deaths, life years lost, years lived with disability and disability-adjusted life years are shown for each of the selected disease in population over age 60. The rate per 100,000
persons year is also expressed and the importance of each disease as priorities of health are also evaluated either in absolute (number of DALYs) or relative (rate) terms
The main cases of healthy life years lost in the 60-years-old group are presented here. Diseases that could potentially lead to premature death occupy the first positions among the
elderly population health needs, such as diabetes, ischemic heart disease, cerebrovascular diseases; also the presence of disability-related conditions, such as chronic obstructive
pulmonary disease, depression, glaucoma, hypertension, rheumatoid arthritis, among others
Burden of Disease in Elderly Mexican Population
44
769
. Figure 44-1
Life expectancy, disability-free life expectancy and life expectancy with disability in the
population over 60 years old. In the 2005 gender analysis, there is evidence that women have
higher life expectancy, in average 4.27 years, than men. If we analyze the disability-free life
expectancy component, women have in average of 1.8 years less than men, indicating that, in
general, women live with longer periods of disease, with a life expectancy with disability of
almost 2 years higher than men
Latin America is expected to increase from 64.1 years in 1985, to 71.8 years for the year 2025
(United Nations, 2005).
The average/median lifespan (also known as life expectancy) is represented by the age at
which 50% of a given population survives, and the maximum lifespan potential (MLSP)
represents the longest-lived member(s) of the population or species. The average lifespan of
humans has increased dramatically over time; yet, the MLSP has remained approximately
constant and is usually 90–100 years. MLSP appears to be species-specific implying a signifi-
cant genetic component to the rate of aging. Some biodemographic estimates predict that the
elimination of most of the major killers, such as cancer, cardiovascular disease, and diabetes,
could add no more than 10 years to the average life expectancy, but would not affect MLSP
(Troen, 2003).
The demographic transition has three stages: first, age distribution renovates as the propor-
tion of children increases because of the growth in survival during the first year; second, fertility
reduction and increase in the number of working-age population; third, it normally arrives after
a long period of fertility and mortality reduction, as the proportion of children and working-age
adults fall, and only the elderly population increases (United Nations, 2007).
The fast growth of the elderly population anywhere in the world is creating an unprece-
dented global demographic revolution. During the twentieth century, progresses in hygiene,
water provision and control of infectious diseases have significantly reduced the risk of
premature death. Consequently, the proportion of 60 years old and over population in the
world is increasing more quickly than in any previous era. In 1950, there were approximately
200 million people over 60 years of age in the whole world. By 2000, there were 550 millions,
and by 2025, this population is expected to reach 1,200 millions (United Nations, 2007;
HelpAge International, 2002).
The 2005 population count survey in Mexico showed that the population was a little over
103 million inhabitants. It considers that by the year 2025 it will reach a population of
130 million inhabitants (CONAPO, 2005). According to the National Statistics, Geography
and Informatics Institute (INEGI) 2005 National Population Count, the number of people of
age 60 and over represented 7.5% of the inhabitants and the growth rate is raising rapidly
(3.8% in average). Currently, global LE in Mexico is 75.7 years; 73.2 in men and 78.1 in women
(CONAPO, 2005; INEGI, 2006). Since the year 1970, the population growth rate began to
decline in this country attributable to fertility reduction and changes in reproductive patt-
erns, which have resulted in a gradual decrease of the population growth rate (refer to
> Figure 44-2). On the other hand, the decrease in mortality has also contributed
. Figure 44-2
Annual Growth rate (%) trends in Mexican people. 1960–2025 Projection. The Mexican
population has shown a gradual reduction of the natural growth rate, from 3.32 in 1960 to 1.17 in
2005. The projections for the future indicate that by the year 2025 the growth proportion will be
reduced to even 0.81
to demographic aging processes that have translated into a change in the age composition
and a widening of the population pyramid.
As > Figure 44-3 and > 44-4 show, Mexico is experiencing an incipient aging process
compared to developed countries. This increasing proportion of elderly population will exert a
strong economic and social pressure in the coming years that should be attended to. Addition-
ally, according to the > aging index as the indicator of changes in the population structure, it
has been estimated that the population of this country will be tripled in the next 30 years
(United Nations, 2005). In this sense, Mexico displays today a polarised model of geographical
population distribution that becomes in itself significant in the case of the elder population: on
the one hand, there is an urban concentration in the 26 largest metropolitan areas of the country;
those with more than half a million inhabitants concentrate 46.9% of the total population
and almost three quarters of the 60 years old and more (73%). In contrast, highly dispersed
. Figure 44-3
Proportion of people of age 60 and over. 1950–2025 comparative data. Mexico shows an incipient
aging process compared to that observed in developed countries. For the population over
60 years of age, figure for 2005 in absolute numbers is 5,308132. This figure demands interventions
for the improvement of life conditions of the elderly within the current public policies context,
since growth trends of this group will pose enormous social and economical pressures
rural communities (more than 180,000 rural localities) are only inhabited by 23.5% of the total
population and 27.4% of the elderly population (INEGI, 2006; Sánchez-González, 2007; Wong R
et al., 2007a; Salgado-de Snyder et al., 2005). With regard to locality-size-based relative distribu-
tion of the age 60 and over population, it is clear that between the years 2000 and 2005 urban
localities had increased the relative weight of older adults from 6.8 to 7.8%. In contrast,
rural localities have undergone a more acute demographic aging, from 8.1 to 9.5%, in the same
period of time (INEGI, 2006).
Mexico is among the countries where a high > dependency ratio prevails, which means
that the effect of the demographic bond still prevails and allows for the containment of the
aging process; however, in the midterm these conditions will not be favorable anymore and the
elderly population will tend to show lower ratios of dependency, which In Mexico today have
no relevant relative significance within the global demographic dependency ratio, –i.e. the
current proportion of elderly, 7%, has not yet impacted the social and economic population
structure of the country. In 1950, this ratio was 7.2 and in 2005, it was 9.1 per 100 productive-
age persons (INEGI, 2006). Nevertheless, as the demographic transition advances, the depen-
dency ratio of the elderly will grow exponentially in the mid- and long-terms: it is possible to
anticipate that by 2050 it will have increased to nearly 35 people of 65 years old or more per
100 working-age persons. In that year, the 65 years old and over population will be close to
28 million, representing 21% of the total population in the country.
According to the 2005 National Population Count (INEGI), the decrease in the dependency
ratio in recent years has not only occurred at the national level, but also in each state of the
country. The most important reductions in young population dependency ratio has been
observed in the states of the Mexican Republic that are in an advanced phase of demographic
transition, like Mexico City, Nuevo Leon, Tamaulipas, South Baja California and Baja
California. On the other hand, three states, that in 2005 showed a greater ratio of young
. Figure 44-4
1997–2025 aging indexes in selected populations of America. An indicator of changes in
population structure is the aging index (people over age 60 per 100 young people under age 15).
For the countries of the Americas, the highest 1970 indicator corresponded to Canada, 82, and
the lowest to Nicaragua, 9: the index for Mexico was 17. The projection for 2025 shows an
increase to 176 in Canada, an index of 26 for Nicaragua and 50 for Mexico. In other words, in
some countries of the region the index will double or even triple in the next 30 years
population dependency ratio, were the poorest states of Guerrero, Chiapas and Oaxaca
(Sánchez-González, 2007; INEGI 2006).
The gradual aging process of the Mexican population entails tackling the increasing
demands for elderly care in the areas of safety and social protection, particularly in woman
who have higher LE than men, but also higher social vulnerability because of their limited
incorporation to the work force. They reach the old age with very little possibilities of access to
the State social security systems (medical care, pension and retirements) (Gonzalez, 2007).
The twentieth century has seen the largest massive population movement, either as
individuals alone or as complete populations, of all times in the human history. Many
characteristics of these migrations have had an impact in the life of the elderly because some
of them have become migrants, but many others remain in their places of origin. The expelling
of young generations of men and women has also had negative poverty impacts in rural
communities, since it is growingly transforming the age and sex structure of rural localities, as
well as the structure of family supports. Migration is the fundamental demographic compo-
nent of rural localities transformation in Mexico; 31% of the municipalities show demo-
graphic decrease. At present, it is quite frequent to see small villages inhabited only by women
and elderly people who are waiting for their relatives to come back (INEGI, 2006; Salgado-de
Snyder et al., 2005).
Mexico shares the same patterns of aging demographics with other Latin America and
Caribbean countries: demographic momentum of aging in the region is rooted in the patterns
of population growth experienced over the last 50 years or so. These patterns have led to
continuous increase of elderly population, to significant shifts in other indicators of aging,
such as the mean population age and, finally, to increases in the overall speed of aging in the
region. This process is mainly attributable to the sharp decline in mortality, experienced after
1940 (Palloni et al., 2002).
4 Social and Economic Overview of Ageing
The Americas is aging prematurely and the composition by health and disability status may
take a turn for the worse and become unfavourable sooner rather than later. Families and next
of kin are loosing ground while social mechanisms take too long to transfer the weight of these
support networks to institutions in an orderly and financing fashion. An important difference
between countries of the region and more developed countries is the relation between the
speed and size of the momentum towards aging, but also the social and economic contexts of
the societies where the process is taking place. The aging process in developed countries takes
place long after they achieve high standards of living, reduce social and economic inequalities,
and implement a number of mechanisms to offset the effects of residual inequalities, at least in
the area of access to health services (Wong et al., 2006).
No country in the Americas region is blessed with a similar development history seen in
developed countries. Quite the contrary is that in almost all cases a highly compressed aging
process begins to take place in the midst of fragile economies, rising poverty levels, expanding
rather than contracting social and economic inequalities, and contracting rather than expand-
ing access to collectively financed services and resources. Not long ago, the region was exposed
to a drastic and costly process of adjustment to response to a prolonged and deep economic
recession (‘‘debt crisis’’) that engulfed the economies of virtually all countries (Palloni
et al., 2002).
Changes in dependency of economic support sources to dependency of other sources
(such as support by relatives) tend to be faster for older men than for older women. The latter
are more capable in diversifying their activities in times of need, for example, if men cannot
leave the house there is a lower likelihood of their staying economically active; however, the
women still carry out small commercial activities (Palloni et al., 2002; Salgado-de Snyder et al.,
2005). The different economic rolls also give more flexibility to women. Older men have the
responsibility to provide for the house and to buy the main assets such as land and cattle, but
aged women handle family income and daily budget. As a result, women have generally more
capacity to save in difficult times or to invest when they have some savings (Salgado-de Snyder
and Wong, 2007). In general, greater longevity of women and older marriage age, ending with
widowhood, are quite often observed in older ages. A growth in the rate of divorces in many
societies also tends to leave women in a more precarious economic situation than men at the
same age (HelpAge International, 2002).
In December of 2001, WHO proposed that low and middle income countries encourage
health payment; this means that budgetary health expenditures increased one point of the
gross domestic product in 2007 and by the year 2015 it will increase two points with respect to
present levels. According to this, Mexico would have to reach 6.6% of the gross domestic product
in health after 2007 and 7.6% in 2015. However, tax collection has remained insufficient to
take care of the multiple needs of a developing country such as ours. Moreover, the World
Bank has suggested that both financial safety for the elderly and economic growth of countries
are built on three systems: a compulsory participation system managed by the public sector
that involves reduction of poverty in elderly; a mandatory savings system managed by the
private sector and a voluntary savings system. Therefore, the challenges for the governments
are grouped in four areas: pension, age of retirement, services for older adults and revision of
public policies (World Bank, 2005). According to International Labor Organization (ILO
2002), 80% of the elderly population have insufficient protection to face health, disability and
income-related risks. For those who lack protection, the notion of retirement does not exist, so
they have to continue their work activities and face the effects of aging, particularly after
age 80.
With respect to poverty in the elderly, the evidence available in Latin America shows that
the elderly population (over age 60) has less likelihood of becoming employed compared to
other groups. Thus, elders who are employed tend to work less hours and receive lower wages
than young adults. This is worsened because in developing countries the elderly have lower
education levels, and thus they receive lower income. The incidence of poverty in rural areas is
close to 3.5% (the line of poverty was defined as elders who receive 2 US dollars adjusted by the
current exchange rate); this figure reached 51% in the absence of such a benefit. In contrast,
the proportion of people over the age of 60 who receive pensions in Mexico is only 20%: in
urban areas, this percentage reaches 25% while in rural areas it is only 7%. When pensions at
the national level are included, the proportion of people in the line of poverty is 26%,
otherwise this proportions increases to 40%. Mexico is still way behind countries such as
Uruguay and Brazil, who grant pensions to more than 70% of the elderly population, or
Argentina and Chile, with pensions paid to a little over half of the elders. > Table 44-2 shows
the proportion of population that receives pension in the countries of the region. The fact that
apparently, elderly women do not participate in the labor market and, therefore, do not receive
a pension points towards a serious social problem, since women are usually poorer and sicker.
Thus, the pension coverage in Latin America has not improved in the past 15 years and the
highest growth in employment has been related to the informal sector. Therefore, the pension
system reform has failed in increasing said coverage.
5 Profile of Medical and Social Care Services
The health status of older adults is the result of three complex factors: health conditions in
childhood (perinatal, growth and development during the first five years of life); behavioural
risks profile (smoking, alcoholism, nutrition, physical activity) and the use and access to
health services (reflected by education level and participation in the labour market) (Ruı́z-
Pantoja and Ham-Chande, 2007).
A success of societies is the aging of their population, and this must be considered a
medical-social challenge since in less-developed countries their inhabitants aged faster, even
when poor. In most elders, health is affected in different ways than in the young people, either
because disease presentations are different, or because the elderly have often multiple con-
comitant disease, take more medications, and their daily functionality is altered, thus becom-
ing dependant on other people (Marı́n, 2007). Another aspect of health problems in this group
is the need to understand and anticipate the relevance of chronic diseases, and playing an
active role against these diseases is of the utmost and ever-growing importance. The increase in
. Table 44-2
Percent of population over 60 years old with pension; comparative data in selected countries
National Urban areas Rural areas

Proportion receiving pension Proportion receiving Proportion receiving
Country (UN 2007) pension pension
Uruguay 77.9 77.9 –
Brazil 77.3 75.7 85.2
Argentina 56.4 56.4 56.4
Chile 54.5 57.9 37.9
México 20.1 25.4 7.3
Venezuela 17.1 17.1 –
Jamaica 14.0 17.3 11.9
Dominican 11.2 13.9 7.0
Republic
Bolivia 11.1 19.4 2.7
Ecuador 10.7 17.6 4.2
Guatemala 10.6 15.1 5.9
Honduras 5.4 9.7 1.7
Haiti 0.9 2.5 0.1
In contrast to other Latin American countries, Mexico has lessened the proportion of elders who receive pension;
only 1 out of 5 elders receive this benefit of social security. Moreover, the inequality observed is even greater when
the indicator is evaluated in the rural areas, where only 7.3% of this population receives pension, situation that has
not only a direct impact on well-being of people, but also favors higher poverty
the aging population has likewise important consequences in health matters. Elders are one of
the most vulnerable groups to disease because of their long-life-related cumulative weakening
or because of the manifestation of long-term diseases; therefore, this population becomes a
high health service consumer (Duran-Arenas L et al., 1996).
Mexico has a National Health System integrated by the institutions and organisations of
the Health Care System (Ministry of Health, SSA), Social Security System (Mexican Institute
of Social Security, IMSS, and the Civil Servants Services and Social Security Institute,
ISSSTE), private services and charities which are mainly characterized by their fund raising
strategies (donations, private medical insurance, direct payment, and so on) and resource
allocation for specific populations (the poorest of the poor, the wealthier, for instance)
through certain type of services (SSA, 2001). This strongly treatment-oriented health system
causes the elderly to feel compelled to use this system almost as their only alternative, which
generates a vicious circle: there are not enough hospitals and hospitalization costs are high;
there are no daytime hospitals or ambulatory cares units, so elderly patients have a higher
likelihood of complications (Duran-Arenas L et al., 1996). Lozano et al. pointed out that
elderly over age 60 demanded one of every six medical consultations provided at IMSS
Family Medical Units and one of every five consultations in the second health care level. In
1994, the 65 years old and over population occupied 28% of hospital beds of the Mexican
State-owned Oil Industry Hospitals, 15% of hospital beds of the ISSSTE, 10% of the IMSS
and 5% of the SSA (Lozano et al., 1996).
Health expenditure in Mexico will grow faster during the 2004–2050 period, with an
average annual rate of 9%. In 2050, one third (32.2% 9 public health resources) would have
been spent, whereas individual contributions will have an average annual growth of 8.4% in
the same period (ENSA, 2000). By the year 2000, the hospital service utilization rate in the 60
and older age group was 11.4%, the highest one in all age groups (ENSA, 2000). In 2005, health
care services provided 19 million primary care consultations to the same age group. The first-
time consultation to subsequent consultation ratio was 1:9, with an approximate cost of
6.2 thousand million dollars (Villarreal Rios et al., 2007). Health care costs for the elderly
are expensive and social security covers only 50% of the population. Curative, ambulatory
services, ambulatory prevention and hospital utilization rates increase with age until age 80.
For women over 65 years, care cost is 60% higher compared to men (ENSA, 2000).
In Mexico, long-term care institutions have undergone different development to the rest of
the social and health services in Mexico. These types of services are not very often assumed by
government structures, in part, because of the high care costs. Long-term care facilities for the
elderly in Mexico are poorly developed and have multiple service quality deficiencies. Most
elderly people require the support and care of their family and neighbour networks. In
addition, there is a legal gap in the regulation of the existing facilities. This problem has two
main aspects: institutional regulatory scope (census of institutions, supply of services, bed
availability, etc.) and care services (trained personal, sanitary conditions, customer’s right and
liberties, professionalized health providers, etc.).
6 What are we Doing for Our Elderly Population

Life quality of the elderly depends on social and emotional factors. Those who have enough
economic resources have access to multiple kinds of services, including health and recreational
services. In contrast, elderly groups with low economic resources live through a series of needs
that, without the support of their relatives and families, are not resolved. One of the realities
in developing countries like Mexico is that many people have a long-life exposure to health
problems, suffering from chronic diseases and disabilities, and no suitable access to
health care. They are, therefore, functionally old when they reach their forties or fifties
(Ruı́z-Pantoja and Ham-Chande, 2007). In addition, most of the health care facilities are
concentrated in urban areas, while the most vulnerable elders in Mexico are concentrated in
dispersed rural areas; transport and treatment cost become additional barriers. From the
quality health care perspective, elders must face negative attitudes from medical staff who give
low priority to their treatment, while in the national level health care planners neglect aged-
group problems (Wong and Diaz, 2007b).
Examples of successful international efforts to reduce these disadvantages and gaps for the
elderly have been done, especially in the European Community and Nordic countries, and
Canada. Nowadays, they have national policies and well-organized networks to attend their
aged population (Andersson and Karlberg, 2000; Bowling and Llife, 2006; Leichsenring K,
2004; Van Faber et al., 2001). In contrast, the Latin America and Caribbean region have only
isolated programmes and policies and none of them with proven success so far. The lack of
economic resources, education policies and political agreements has been the most important
handicap to develop national policies in the region.
Phrases such as ‘‘> healthy aging’’, ‘‘successful aging’’ and ‘‘active aging’’ have become
increasingly common in research protocols and policy documents in the last two decades
(Bowling and Dieppe, 2005; Rowe JW, 1987; Swedish National Institute of public Health, 2006;
Vaillant and Mukamal, 2001). An example comes from the WHO that states: ‘‘Active Ageing is
the process of optimizing opportunities for health, participation and security in order to
enhance quality of life as people age’’. The fourth phase (2003–2007) of the WHO Healthy
Cities programme includes a definition of healthy aging. It adopts a rights-based approach that
recognises the rights to equality of opportunity and treatment in all respects, particularly as people
age (Kalache A et al., 2002; Kane RL, 2003). According to the contribution of the European
Commission to the Second World Assembly on Active Ageing, active aging involves ‘‘an
orientation towards active-aging policies and practices’’. Core active-aging practices include
life-long learning, working longer, retiring later and more gradually, being active after retire-
ment and engaging in capacity-enhancing and health-sustaining activities. Such practices aim
to raise the average quality of individual lives and at the same time, at societal level, contribute
to larger growth, lower dependency burdens and substantial cost savings in pensions and
health. They, therefore, represent win-win strategies for people of all ages’’ (Swedish National
Institute of public Health, 2006). For the Healthy Ageing project by the European Commission
and for WHO, healthy aging is the process of optimising opportunities for physical, social and
mental health to enable older people to take an active part in society without discrimination
and to enjoy an independent and good quality of life (Swedish National Institute of public
Health, 2006).
Recently, the Mexican government has been working towards healthy and successful aging
conditions in the population. Although there is a real expansion of health services and
coverage to the most poor and vulnerable populations, there is still much to be done. At
present, the country is working in feasible alternatives to tackle the problems of poor coverage,
social unequal access and quality of available services. In the short-term, Mexico is advancing
towards a national primary health care insurance with a national health prevention program,
there are multi-sectoral efforts being undertaken for social development where public and
private sectors of the economy jointly collaborate and a budget has been ensured for cata-
strophic health expenses of selected illnesses defined as such by the General Health Council
and aimed at the most vulnerable groups of the population. In the mid-term: a national
system of second health care services will be added (second-care-level hospitals). Therefore, in
the long-term the goal is to have a universal health system, a nationwide prevention
programme in all care levels and a strong multi-sectoral effort of social development, irre-
spective of the kind of social security and care service that each person in the country may have
(SSA, 2007; Presidencia de la Republica, 2008).
With regard to research in aging, Mexico is following the work agendas and recommenda-
tions of international agencies such as the United Nations and the International Association of
Geriatrics, among others, in order to apply some of their thematic directives: social participa-
tion and integration, economic welfare, social changes, healthy aging, health care access,
biomedics, physical and mental functioning, quality of life, health systems and family and
community structure changes (United Nations, 2007, SSA, 2001; Swedish National Institute of
public Health, 2006).
Some non-governmental organizations (NGOs) are also making efforts and some of them
have sum actions and coordination efforts with the Mexican government through the Min-
istries of Health, Education and Social Development, whether in research and advisory or in
health care, education and sustainable development matters. In 2007, the government signed a
national alliance with NGOs, and with many industries and service companies to jointly tackle
specific population priority, social and health needs. This agreement is known as ‘‘Alliance to
Healthy Mexico’’ (SSA, 2008).
7 Final Considerations
In the past two decades, plenty of information and knowledge have been obtained about aging
and successful interventions on the old-age group, but so far Mexico does not have a global
policy to face the challenges posed by the current and forthcoming problems of the population
in aging process. We already know that we have a valuable demographic bond to build a
successful aging society, but as a country we have not been able to produce enough good jobs
to absorb the demands of the economically active population, and hence to grow faster from
an economic perspective and produce enough welfare and better redistribution of wealth for
our population.
Mexico in the new millennium is undergoing an enormous process of change that implies
multiple transitions in the economic, social, political, urban, demographic and epidemiologi-
cal arenas. Quick changes in the size and age structure of the population involve challenges
that are not always solved or take long time to solve.
There is an international consensus that states that the most important aspect is to keep
functionality in daily living and this is the key factor to predict future dependency, utilization
of sanitary and economic resources or even death in aged adults. World Health Organization
promotes active aging based on three pillars: social participation, economic welfare and health.
The majority of the countries advance first in social participation, where non-
governmental organisations and churches usually play important roles. Reaching welfare is
complex and faces diverse ways to develop a worthy and viable pension system. Health aspects
are generally the slowest (OMS, 1989; OMS & Milbank Memorial Fund, 2002). The Mexican
health sector has to adopt changes to traditional approaches of prevention, diagnosis and
treatment of diseases, since these elements will have to be integrated with many other
components as part of an integral health promotion. The aging adults and their service
needs will probably make the health system focus on the search for solutions to a global
problem (Duran-Arenas L et al., 1996; SSA, 2001).
In order to get ‘‘healthy aging’’ or ‘‘successful aging’’ for our population, health services
will have to contemplate elderly care needs. Without neglecting general population services,
health services will have to think about how to integrate elderly services, create suitable social
and physical atmospheres and promote healthy life styles, as well as having physicians and
paramedical personnel specialised in a variety of services (SSA, 2001). As elderly individuals
increase, intensive care episodes in hospitals also increase, which imply a high-rate hospital
beds occupation per day. Rehabilitation services for the elderly are needed after strokes,
fractures, heart diseases, surgeries recovery, etc.; nevertheless, these services are not yet ready
to take care of elderly patients. Hence, one of the challenges for the health system will be to
develop interdisciplinary models of rehabilitation in all levels of care, adaptable to patients at
home, to communities and to other institutions (Barrantes-Monge et al., 2007; Duran-Arenas L
et al., 1996; SSA, 2001).
Today, In Mexico like in the rest of the world, family support continues being the main
form of survival used by the majority of elderly people; either in the context of extended
families or in co-residence of parents and sons/daughters, which provides emotional and
psychological support, and exchange that provides material goods (house cost, and food
share) to the older. With current patterns of urbanization and migration, in many Latin
America and Caribbean countries the trend moves towards more elderly people living alone
with negative consequences, which could worsen by an inadequate pension systems. So, we
also have to do something soon about this, otherwise we will face a social crisis with those
elderly living alone (Wong et al., 2007a). The political conditions and social policies around the
Mexican pension system are not yet cleared; there is no general agreement among workers, the
general population and the government and employers regarding the time for retirement,
pension amounts and social security and health access. The aspiration is towards a multi-pillar
system: minimum universal pension system financed with public funds; labor-activity oriented
basic pension under a distribution system, and mandatory individual savings accounts
and voluntary retirement contributions.
With respect to the health care system, the strategies to take care of illnesses in the elderly
population are the adjustment of resources, equipment and facilities, as well as the adoption of
other types of prevention and therapy programmes, goods and medicines. Mexico is not yet
facing a health crisis related to demographic aging. We are just in the right moment to develop
health-care and prevention policies and programmes based on the research and experiences of
developed countries and also reorient academic health programs. Likewise, effective national
and local social and economic population interventions are needed. In the short-term, we will
have to provide good answers towards the improvement of the pension system and promote
joint citizen and governmental participation networks to keep the elderly integrated and active
in our society. The consequences of our demographic past are still evident at present, but there
will be even more in the coming years when the aging process becomes severe. While we have
the demographic bond, we have an extraordinary window of opportunity to build a successful
aging process for our population.
Summary Points
Never before in the human history were there so many aging adults. Ageing population is
an indicator of successful development in the countries.
In the Americas, the increase of aging adults will take place faster than in Europe (instead
of 150 years, it will take 50 years for us to duplicate the proportion of aged adults).
The aging process is heterogeneous, but predominantly feminine.
The most important life-quality aspect of aging adults is not only the age or the number of
diseases and other traditional health markers, but their functionality.
Health during life is a cumulative process. The life-cycle perspective recognises that the
health of the elder population will depend to a great extent on their life styles and
behaviours.
Sanitary policies for elders must be formulated within the context of other age groups
because: the well-being of the elderly is based on the life conditions at younger ages.
Sanitary programmes for the aged are also used for young people, especially for those
suffering some disability.
Harm anticipation and promotion of healthy life styles among young populations are
needed to counteract the effects of long-term exposure to risk factors such as chronic
diseases and their sequelae: diabetes mellitus, cardiovascular diseases and cancer, among
others.
There is a need to develop comprehensive public policies aimed at the improvement of the
quality of life of the elderly in order to reduce the social and economic vulnerability
through national retirement plans.
There is also a need to develop long-term strategies to provide home-care services
and other similar care alternatives that have an impact on the quality of life and health-
care costs.
Ageing is a part of the life cycle and its contribution to societal development is very
valuable; therefore, we must recognize and eliminate stereotypes and prejudices about the
elderly.
References
Andersson G, Karlberg I. (2000). Int J Integr Care. 1: Kalache A, Aboderin I, Hoskins I. (2002). Bull World
1–10. Health Organ. 80(3): 243–244.
Barrantes-Monge M, Garcı́a-Mayo EJ, Gutierrez- Kane RL. (2003). Ann of Intern Med. 139: 460–462.
Robledo LM, Miguel-Jaimes A. (2007). Salud Pub- Leichsenring K. (2004). Int J Integr Med. 4: 1–10.
lica Mex. 49 supl. 4: S459–S466. Lloyd-Sherlock P. (2000). World Dev. 28(12): 2157–2168.
Bowling A, Dieppe P. (2005). BMJ. 331: 1548–1551. Lozano-Ascencio R, Frenk-Mora J, González-Block MA.
Bowling A, Iliffe S. (2006). Age Ageing. 35: 607–614. (1996). Salud Publica Mex. 38: 419–429.
CONAPO. (2005). Indicadores demográficos básicos Marı́n LPP. (2007). Rev Méd Chile. 135: 392–398.
1990–2030. At www.conapo.gob.mx/00cifras/ OECD. (2003). Bol inf Asoc Med Argent. 2(7): 8–9.
00indicadores.htm. OIT. (2002). Seguridad Social. Un nuevo consenso. Gine-
Duran-Arenas L, Sánchez R, Vallejo M, Carreón J, bra. Oficina Internacional del Trabajo.
Franco F. 1996. Salud Publica Mex. 38: 501–512. OMS & Milbank Memorial Fund. (2002). In: Chile:
ENSA. (2000). Encuesta Nacional de Salud 2000 Mexico. Hacia un consenso internacional sobre la polı́tica
At www.salud.gob.mx. de atención de salud a largo plazo en el envejeci-
Van Faber M, Bootsma-van der Wiel A, van Exel E, miento. Geneva, OMS.
Gussekloo J, Lagaay AM, van Dongen E, Organización Mundial de la Salud. (1989). Health of the
Knooh DL, Geest van der S, Westendorp RGJ. elderly. Washington, D.C.
(2001). Arch Intern Med. 161: 2694–2700. Organización Panamericana de Salud OPS. (2002).
Fogel RW. (1997). Philo Trans R Soc Lond B Biol Sci. 352: Chile: Guı́a clı́nica para atención primaria a las
1905–1917. personas adultas mayores. Washington DC.
Gonzalez CA, Ham-Chande R. (2007). Salud Publica OPS. (2006). 138 a Sesión de Comité Ejecutivo. Resolu-
Mex. 49 supl. 4: S448–S458. ción CE138.R1
Guzmán JM. (2002). Envejecimiento y desarrollo en Palloni A, Pinto Aguirre G, Pelaez M. (2002). Intern J
América Latina y el Caribe. Serie Población y Desar- Epidem. 31: 762–771.
rollo No. 28. Centro Latinoamericano y Caribeño de Presidencia de la republica. (2008). Plan Nacional de
Demografı́a (CELADE). Comisión Económica para Desarrollo 2001–2006 y Plan Nacional de Desarrollo
América Latina (CEPAL). 2007–2012 México. At www.presidencia.gob.mx
HelpAge international. (2002). State of the world’s older Rowe JW. (1987). Science. 237: 143–149.
people 2002. London UK. At www.helpage.org/ Ruı́z-Pantoja TE, Ham-Chande R. (2007). Salud Publica
Resources/Policyreports/main_content/1118337662– Mex. 49 supl. 4: S495–S504.
0–11/SOTWOPeng.pdf. Salgado-de Snyder NV, Gonzalez-Vazquez TT, Jauregui-
HelpAge international. (2006). The Ageing & Development Ortiz B, Bonilla-Fernández P. (2005). Salud Publica
Report: Poverty, Independence and the World’s Older Mex. 47: 294–302.
People London UK. At http://www.helpage.org. Salgado-de Snyder NV, Wong R. (2007). Salud Publica
INEGI. (2006). Instituto Nacional de Estadı́stica, Geogra- Mex. 49 supl 4: S515–S520.
fı́a e Informática. II Conteo Nacional de Población. Sánchez-González D. (2007). Envejecimiento demográ-
At: http://www.inegi.gob.mx/est/contenidos/espa- fico urbano y sus repercusiones socio espaciales en
nol/sistemas/conteo2005/localidad/iter/default.asp? México. Retos de la planeación gerontológica. Rev.
s = est&c = 10395. Geogr. Norte Gd., 38: 45–61.
SSA. (2001). Secretaria de Salud: Programa de Acción New York US. At http://www.un.org/esa/policy/
de Atención al Envejecimiento. Primera Edición. wess/index.html.
México pp. 19–21. Vaillant GE, Mukamal K. (2001). Am J Psychiatry. 158:
SSA. (2007). Programa Nacional de Salud 2001–2006 839–847.
México y 2007–2012. At: www.salud.gob.mx and Villarreal Rı́os E, Martı́nez González L, Galicia
SSA (2008) Alianza por un México Sano. At: Rodrı́guez L, Vargas Daza ER. (2007). In Costo
http://www.alianza.salud.gob.mx/. Anual per capita de la atención de enfermedades
Swedish National Institute of Public Health. (2006). crónicas degenerativas. IMSS, México.
Healthy Ageing: A Challenge for Europe. Wong R, et al. (2006). J Ageing Health. 18(2): 157–179
Troen BR. (2003). Mount Sinai J Med. 70(1): 3–20. Wong R, Espinoza M, Palloni A. (2007a). Salud Publica
United Nations. (2005). Expert Group Meeting on social Mex. 49 supl 4: S436–S447.
and economic implications of changing population Wong R, Diaz JJ. (2007b). Salud Publica Mex. 49 supl 4:
age structure. Population division department S505–S514.
of economic and social affairs. At www.un.org/esa/ World Bank. (2005). Social In: Security coverage in Latin
population/meetings/EGMPopAge/1_UNPD_ America. Human Development Network.
Trends.pdf.
United Nations. (2007). In: World Economic and Social
Survey 2007 Development in an Ageing World.
Impacts
2.3 Cancer
45 Years of Life Lost from
Cancer and Applications to
Research Funding
N. G. Burnet . S. J. Jefferies . F. P. Treasure
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786
2 Algorithm for Years of Life Lost (YLL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787

2.1 Calculation Algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
3 Comparing Different Parameters of Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789

3.1 Data for Calculation of YLL and AYLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
3.2 Years of Life Lost (YLL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
3.3 Average Years of Life Lost (AYLL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
3.4 YLL, AYLL and Morbidity from Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
4 YLL, AYLL and Research Spending on Different Cancers . . . . . . . . . . . . . . . . . . . . . . . . . 794

4.1 YLL and AYLL Compared to UK Research Spending on Cancer . . . . . . . . . . . . . . . . . . . 794
4.2 YLL and AYLL as Measures of Research Spending in Diseases other
than Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
5 Conclusions - YLL, AYLL and Research Spending . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800

786 45 Years of Life Lost from Cancer and Applications to Research Funding
Abstract: Different measures of mortality can be used to focus attention on different aspects
of disease. Cancer statistics provide a useful example of this. Crude mortality is a simple
method of expressing the proportion or percentage of deaths attributable to any particular
cancer type. It is relatively influenced by common tumours in older patients. ‘Years of life lost’
(YLL) provides a measure of disease burden to society, and > average years of life lost (AYLL)
represents the measure burden of disease to the individual patient. These different parameters
show different aspects of mortality, and are complementary. Calculation of YLL must be done
with an appropriate algorithm to avoid misleading results. Using these YLL and AYLL reveals
interesting and important differences in mortality from different tumours. Analysis of this
type can identify tumour types with extreme impact, either on society or individual patients.
YLL indicates a relatively higher burden of disease on society from cancers of the cervix
and CNS, despite a screening programme for cervix cancer, and a rather low burden from
prostate cancer. AYLL reveals striking differences between tumours. Prostate cancer has the
lowest individual burden of death, measured as AYLL, at only 6.1 years. Brain and CNS
tumours cause over 3 times as much loss of life per affected individual, at just over 20 years,
higher than any other adult cancer.
These parameters can be used for comparison to research spending. In the cancer area,
such a comparison demonstrates a mis-match between disease burden and funding. In the
UK, research spending is very high on leukaemia, colo-rectal (+ anus) and breast cancer, which
has the highest level of relative spending. By contrast, research spending is relatively low on
several tumour types, including lung cancer, which are typically the less well-publicised
cancers. The research spend per year of life lost is over thirty times higher for leukaemia
than it is for lung cancer, which is relatively under-funded. There is clear evidence of inequity
in research spending, which goes beyond the under-provision for lung cancer research. Better
levels of funding are typically associated with well-publicised cancers. Comparing AYLL to
research spending reveals 4 ‘Cinderella’ cancers, with individual burden of mortality higher
and spending lower than average. These are kidney, melanoma, cervix, and brain and CNS
cancers, and of these CNS is the most extreme. Such extreme tumour types, expressed by either
statistic, may need special consideration.
Measures of mortality and disease burden may have to develop to include a component
related to disease morbidity and treatment toxicity. Comprehensive use of mortality statistics,
including YLL and AYLL, would be useful in considering allocation of research funding, and in
debates on public health issues.
List of Abbreviations: AYLL, average years of life lost; CNS, central nervous system; IYLL, > in-
dividual years of life lost; NCRI, National Cancer Research Institute (in the UK); NIH, National
Institutes of Health (in the USA); NTCP, > normal tissue complication probability; OPCS, Office
of Population Censuses and Surveys; TCP, > tumour control probability; TYLL, > total years of
life lost; UK, United Kingdom; USA, United States of America; YLL, years of life lost
1 Introduction
Measures of mortality from all types of disease are important from many different viewpoints,
and can be represented in such a way as to focus attention on different aspects of disease.
Mortality statistics are essential in assessing the effects of cancer screening programmes and
also the effects of changes in public health policy with regard to environmental and other
Years of Life Lost from Cancer and Applications to Research Funding 45 787
causal factors, such as smoking. Measurements of mortality are also important in viewing
trend changes in outcomes as therapy develops (Horm and Sondik, 1989). This provides a
different perspective compared to the randomised control trial, and operates over a more general
framework with a much longer time frame. Mortality statistics for disease are also important for
commissioning services, including the development of specific patient pathways to improve
patient management. Mortality statistics may also be relevant to the allocation of research
spending (Burnet et al., 2005), which is discussed in more detail below. Finally, patients have
an interest in their own illnesses, and statistics can be helpful to patients and their carers.
Different measures of mortality can focus attention and extract very specific issues from
general mortality data. Cancer statistics provide a useful example of this. In considering how to
present such data, its purpose must be explicitly considered. Crude mortality is a simple method of
expressing the proportion or percentage of deaths attributable to any particular cancer type, with
respect to cancer deaths in the whole population. It is also easy to calculate, since it is given by the
number of deaths from an individual tumour type divided by the total number of deaths from
cancer. Crude mortality tends to be relatively influenced by common tumours in older patients.
An alternative method of describing mortality is the use of ‘years of life lost’ (YLL). This is
a population-based indicator of mortality which gives relatively more weighting to those
diseases that are incurable and affect younger patients. It is calculated from considering the
shortening of life attributable to the cancer compared to life expectancy derived from
appropriate life tables. The YLL for each individual dying of the cancer of interest is summed
to produce the overall YLL, and this can be expressed as a percentage of the YLL from cancer as
a whole. Used in this way YLL gives some measure of the impact of the disease on society, thus
representing the population burden for a specific tumour type.
The data used to derive YLL can be used in a slightly different way, to provide a measure of
the burden of cancer to the individual patient. This measure, the average years of life lost
(AYLL), is derived by dividing the total YLL by the actual number of deaths from the cancer of
interest over a defined time period. It represents the average shortening of life for a patient
affected by a specific cancer. Once again, like YLL, it gives relatively higher weighting to tumours
that are incurable and kill patients when they are young.
2 Algorithm for Years of Life Lost (YLL)
Mathematically, the method for the calculation of YLL is given below. Although confusion has
existed in the past with variations in the calculation methods (Gardner and Sanborn, 1990),
the method described here is explicit.
The years of life lost (YLL) for an individual patient diagnosed with cancer is defined as the
number of years from diagnosis that an individual is expected to survive less the number of
years that the individual actually did survive. This is represented in > Figure 45-1.
2.1 Calculation Algorithm
Algorithm for calculating total and average years of life lost (TYLL and AYLL) for a cancer site
S over a time period P using a cancer registry database:
Note: the death may be from any cause.
Step 1: select from the cancer registry database all individuals with diagnosis S who have died
in P. Denote the number of such individuals by nSP .
. Figure 45-1
Illness trajectory to show years of life lost in relation to diagnosis and death.
Pathway representing the years of life lost (YLL) for an individual patient diagnosed with cancer.
This is given by subtracting the number of years that the individual actually survived from
the number of years the individual would be expected to survive.
Step 2: for each individual calculate the individual years of life lost (IYLL).
The registry database provides for the ith individual:
ci the date of diagnosis with that cancer;
di the date of death;
and appropriate life-tables are used to find:
ei the expectation of life at the date of diagnosis for an individual of the same gender and age
as the ith individual.
The individual years of life lost for the ith individual is given by:
yi ¼ ei ðdi ci Þ
where all quantities are converted to years and decimals of a year
Example: an individual died in June 2006 after being diagnosed with cancer in May 2004. The
population expectation of life for an individual of that gender and age in May 2004 was 10
years and 3 months. The actual survival time was 2 years and 1 month. The years of life lost
is therefore 8 years and 2 months, or 8.17 years.
Note: occasionally, the years of life lost is calculated from the date of death of the individual
rather than the date of diagnosis. We cannot recommend this approach if the dates of
diagnosis are available. The burden of cancer falls on the individual at the moment
of diagnosis rather than the moment of death. (Suppose a new treatment extended
the life of young men suffering from an aggressive cancer by 12 months. We would expect
the years of life lost calculated from date of diagnosis to reduce by 12 months, but that
calculated at the date of death to reduce by rather less). Furthermore, the burden of a
cancer on mortality need not be completely reflected in the cause of death recorded on a
death certificate. However, if the dates of diagnosis are not available, then there is no
alternative but to calculate from the age at death (see chapter by Marshall: Years of life lost
as a measure of disease burden: an investigation of the model).
Note: in principle, the population expectation of life should be adjusted by removing
mortality due to the cancer being considered, since the IYLL is the difference between
the actual survival and the survival which would have been expected if the diagnosis had
not happened. In practice this adjustment is not made. An individual cancer site will not
have a high enough incidence to make a substantial numerical difference.
Note: it is usual if the diagnosis is more than a certain number of years previous to death
(typically 15) to set the IYLL to zero. This is to avoid difficulties with data ascertainment
from diagnoses relatively far back in the past. Effectively these patients are deemed to have
been cured. Clearly, as more reliable data is available from cancer registries over longer
time periods, then the ‘cure cut-off ’ can be extended.
Patients whose date of diagnosis is not available (because they were diagnosed before the
registry started or in a different catchment area) can be invisible to this calculation even if
cancer is mentioned on their death certificate.
Step 3: calculate TYLL, the total number of years of life lost for that site and period over the
cancer registry catchment population, by summing the individual years of life lost over
the individuals who have died in P having previously been diagnosed with cancer of site S:
X
TYLL ¼ yi :
SP
Note: this is a population-level measure and represents the burden of that cancer on a
population.
Step 4: calculate AYLL, the average number of years lost for that site and period over the
cancer registry catchment population, by dividing the TYLL by the number of individuals
who have died in the time period P, having previously been diagnosed with cancer of site S:
1 X
AYLL ¼ yi :
nsp SP
Note: this is an individual-level measure and represents the burden of that cancer on an
individual who has been diagnosed. Effectively it shows, on average, how much a patient’s
life is likely to be shortened by their diagnosis of cancer.
Note: performing a ranking of sites by AYLL within the same time period P ranks the sites by
the effect on a diagnosed individual.
Ranking the sites by TYLL takes into account incidence: so a higher incidence site with low
AYLL may have a higher TYLL than a low incidence site with a high individual burden.
Effectively AYLL shows, on average, how much a patient’s life is likely to be shortened by
their diagnosis of cancer. Patients diagnosed with brain cancer in East Anglia in 1990-4
experienced a higher AYLL than those diagnosed with prostate cancer (20.1 versus
6.1 years) (see below and (Burnet et al., 2005)), but prostate cancer contributed more to
that region’s TYLL as the incidence is so much higher.
3 Comparing Different Parameters of Mortality
3.1 Data for Calculation of YLL and AYLL
The results presented below relate to our calculations of the percentage mortality, YLL and
AYLL for adult cancers in our local population, using data from the East Anglian Cancer
Registry for the 5-year period 1990 to 1994. No cut-off for age was used for the calculations.
Although a cut-off at age 70 years has been suggested (Romeder and McWhinnie, 1977),
censoring patients over 70 years is clearly unhelpful in the context of cancer mortality. YLL was
evaluated for the population with cancer, irrespective of whether or not they died from the
cancer. The statistics used for the calculation of life expectancy were obtained from the 1990
East Anglia OPCS Life tables.
3.2 Years of Life Lost (YLL)
For some tumours, there is relatively little difference between percent mortality and percent
YLL. For other tumours, though, the differences can be quite marked, and the ratio between
these two gives some indication of frequency and age when affected. For example, using simple
mortality as a measure, brain tumours account for 2% of cancer deaths; this rises to 3% of
the years of life lost for the population as a whole (Burnet et al., 2005). In fact, the percentages
are 1.9% and 3.4% respectively, so there is a considerable difference depending on which
parameter is used.
> Figure 45-2 shows percentage YLL plotted against percentage mortality. The ratio can be
inferred from the proximity of the points to the line of equality (x = y). Those tumour sites
which lie above the line of equality show a higher burden of death measured by YLL compared
. Figure 45-2
% years of life lost (YLL) versus % mortality for 17 adult cancer sites. This is a graphical
representation of the data presented in > Table 45-1. These 17 sites account for 83.9% of the
years of life lost from cancer. YLL data for liver cancer, and head and neck cancers were not
available (East Anglian Cancer Registry data for the 5-year period 1990 to 1994). The line of
equality (dashed) where y = x is shown to guide the eye. The graph demonstrates the 2 measures
of mortality are similar but with subtle and important differences. Cancer sites above and to the
left of the dashed line have a higher mortality, described by years of life lost (YLL) than by crude
mortality. Note especially that breast cancer lies to the left, indicating higher YLL than crude
mortality, but prostate cancer lies to the right, indicating the opposite. The differences for cancer
sites near the origin are not easily assessed from this graph. YLL – years of life lost [Reproduced
with the kind permission of the editor, British Journal of Cancer]
to crude mortality. The differences are not very obvious for tumours at the lower left of the
diagram, and tabulation of the data is useful to highlight these.
> Table 45-1 shows the figures for percentage mortality and YLL, and also the ratio of these
two parameters. The disease sites are arranged in order according to this ratio. These diseases
. Table 45-1
Percentage mortality and percentage of Years of Life Lost (YLL) for 17 specific tumour sites
Site % YLL % Mortality % YLL/ % mortality

Brain + CNS 3.4 1.9 1.8
Cervix 1.7 1.1 1.5
Ovary 3.6 2.6 1.4
Melanoma 1.4 1.0 1.3
Leukaemia 3.0 2.6 1.2
Breast 13.0 10.9 1.2
NHL 3.5 3.0 1.2
Kidney 2.0 1.7 1.1
Pancreas 3.6 3.4 1.1
Lung 18.2 17.6 1.0
Oesophagus 2.7 2.7 1.0
Stomach 5.2 5.3 1.0
Uterus 1.4 1.4 1.0
Myeloma 1.6 1.7 0.9
Colon + rectum (+ anus) 12.0 13.9 0.9
Bladder 2.9 4.4 0.7
Prostate 4.7 8.9 0.5
Total 83.9 83.9
These 17 sites account for 83.9% of the years of life lost from cancer. YLL data for liver cancer, and head
and neck cancers were not available. (East Anglian Cancer Registry data for the 5-year period 1990 to 1994)
The ratio %YLL/%mortality indicates the relative difference between the two parameters
YLL – years of life lost
CNS – central nervous system
NHL – non-Hodgkin’s lymphoma
account for 83.9% of the cancer deaths in this data set, reflected in the total shown. In the
centre of the range, there is essentially no difference according to mortality measure, for
example for lung cancer. Breast cancer shows a ratio of 1.2, indicating that at least some
patients are affected when young and die from the disease. This figure does not bring out
the large proportion of patients with breast cancer who are cured of the disease nor that some
older patients may have a very long natural history.
Three tumour sites have a rather large difference depending on the parameter used, with
ratios 0.50 or 1.5, which is not apparent from > Figure 45-2. The population burden from
prostate cancer is rather less than that is suggested by percent mortality, resulting from a high
incidence of the disease at older age. On the other hand, the population burden of cancers of
the cervix and CNS is rather higher, despite the presence of a screening programme for cervix
cancer. In fact, the ratio is the highest of any tumour type for patients with brain and CNS
tumours, underlining the fact that these diseases include patients who are young and that the
commonest tumour type, glioblastoma, is largely incurable.
YLL may also be helpful in providing easily understandable statistics which individuals can
consider in relation to themselves. The YLL statistics gives a clear concept of loss of life which
is readily understood (Brunekreef et al., 2007). It may also be less open to misunderstanding
than descriptions of risk and risk factors in epidemiological studies (Brunekreef et al., 2007).
3.3 Average Years of Life Lost (AYLL)
> Table 45-2 shows the AYLL for the 17 cancer sites. The data are plotted graphically in
> Figure 45-3. There are striking differences between tumours in this parameter of mortality,
which represents the burden to the individual affected. Our data for AYLL show that brain and
. Table 45-2
Average years of life lost (AYLL) per affected individual for 17 tumour sites
Site AYLL
Brain + CNS 20.1
Cervix 17.3
Ovary 16.3
Melanoma 15.1
Leukaemia 13.6
Breast 13.5
NHL 13.3
Kidney 12.8
Pancreas 12.0
Lung 11.8
Oesophagus 11.2
Stomach 11.1
Uterus 11.0
Myeloma 10.3
Colon + rectum (+ anus) 9.8
Bladder 7.3
Prostate 6.1
The figures show the very large individual patient burden from brain and central nervous system (CNS) tumours
See text for further discussion
Data for liver cancer, and head and neck cancers were not available. (East Anglian Cancer Registry data for the
5-year period 1990 to 1994)
AYLL – average years of life lost
. Figure 45-3
Average years of life lost (AYLL) for the 17 commonest adult cancers. These 17 cancer sites
account for 83.9% of the total years of life lost from cancer. Data from the East Anglian
Cancer Registry for the 5-year period 1990 to 1994. The range of individual disease burden,
measured as average years of life lost (AYLL), is large. Brain and central nervous system
(CNS) cancers account for the largest AYLL, at just over 20 years per patient.
CNS tumours, including benign tumours, account for just over 20 years of life lost per affected
individual, higher than any other adult cancer. This figure is consistent with other studies as
well (Thuppal et al., 2006; Turini and Redaelli, 2001). It contrasts with, for example, prostate
cancer which accounts for only 6.1 years of life lost per patient. This reflects the relatively high
age at which this disease affects patients, and that some patients die with the disease from other
causes, rather than from the disease.
An important aspect of this type of analysis is that it can provide data to support
individual patients and patient groups. For example, since the AYLL is highest for patients
with brain and CNS tumours, it is difficult for a strong group of advocates to develop, because
of the high mortality. This might be compared, for example, with patients with breast cancer,
where advocacy is extremely strong, but where cure rates are also high. AYLL data may
therefore be valuable to small groups of dedicated individuals intent on promoting the issues
for their patient group. This type of argument has also been applied to other tumour types,
such as melanoma (Albert et al., 1990).
In 2007, the UK Government launched the Cancer Reform Strategy, dealing with plans for
cancer services over the next 5 years. In the Annex on Brain & CNS cancers, reference was
made to the poor overall outcome of this tumour type in terms of AYLL (UK Department of
Health, 2007). It is encouraging that alternative measures of disease mortality are being
considered by governmental institutions.
3.4 YLL, AYLL and Morbidity from Treatment
Such measures of disease burden could be applicable to non-cancer diagnoses, although each of
these measures uses death as the end point. It is generally assumed that death is the result of cancer,
or possibly the result of the cancer treatment. Although it is uncommon for treatments to cause
death, there are some well-known examples where this has happened (Duncan et al., 1987).
The mortality statistics cannot be used to show the burden on the individual of chronic
disability resulting from treatment. This has become an important issue in the management of
cancer patients more recently, as survival rates in general are improving, slowly but surely.
It applies especially to children. This survivorship requires the development of new methods
which might include improvement of AYLL on the positive side but a reduction in function-
ality or possibly quality of life on the negative side. However, it is possible to calculate ‘years
of disease-free life lost’, provided that appropriate data is available. Such data would have to
be collected through channels other than cancer registries, and very large data sets would
be needed to produce meaningful results. This might provide a mechanism for combining
the cancer death statistics, YLL and AYLL, with outcomes of the toxicity of cancer treatment.
In relation to radiotherapy as a specific treatment modality, some effort has been put in to
estimating ‘uncomplicated tumour control probability’, which is sometimes abbreviated as P+
(Ågren et al., 1990). This can be calculated on a population basis from the combination
of tumour control probability (TCP) and normal tissue complication probability (NTCP),
when each is plotted against radiation dose delivered. The simplest formula to calculate
> uncomplicated tumour control probability P+ is:
Pþ ¼ TCP ð1 NTCPÞ
As dose increases, so tumour control probability increases, and then (usually) at a slightly
higher dose normal tissue complications begin to occur. As the incidence of complications rises,
so the curve of P+ versus dose reaches a peak and then falls. Some argument can be made to select
the radiotherapy dose to match the peak of the P+ curve. However, there may be circumstances
when it is more appropriate to deliver a higher dose of radiotherapy, albeit with a higher risk of
normal tissue complications, in order to cure more patients. It is also essential to specify the
toxicity endpoint of interest, and the level of severity of that toxicity which is considered
clinically relevant. This latter decision may have an element of subjectivity. These population
considerations may be helpful in principle, but are not easily applied to an individual patient.
4 YLL, AYLL and Research Spending on Different Cancers
4.1 YLL and AYLL Compared to UK Research Spending on Cancer
We sought to compare this with published data on research spending by cancer site. Data were
available from the Cancer Registry for 17 tumour types, which account for 84% of the total
YLL from cancer. Specific YLL data for liver cancer, and head and neck cancers were not
available but they represent only 2% each of simple mortality (NCRI, 2002). Unspecified
‘other’ tumour types account for the remainder of cancer deaths, but these could not be
specifically addressed in comparison to per cent YLL because of the lack of detail. Details
of cancer research spending were obtained from the National Cancer Research Institute
(NCRI) Strategic Analysis published in 2002 (NCRI, 2002). The overall research budget was
approximately GB £250 million (approximately Euro 400 million) at that time (NCRI, 2002).
Analysis of the research spending in relation to mortality has important implications, both for
national strategy planning and for researchers, especially those who work on tumour types
which are under-resourced.
> Table 45-3 shows the data for %YLL and %NCRI spend. In column 2 (%NCRI
spending) the Table shows how much difference there is between spending on some tumour
. Table 45-3
Percentage of YLL and percentage of NCRI spending, for 17 tumour sites
Site % YLL %NCRI Spend %YLL/% NCRI Spend

Lung 18.2 3.5 5.2
Pancreas 3.6 1.0 3.6
Stomach 5.2 1.5 3.5
Uterus 1.4 0.5 2.8
Brain + CNS 3.4 1.5 2.3
Bladder 2.9 1.5 1.9
Kidney 2.0 1.5 1.3
Myeloma 1.6 1.5 1.1
Colon + rectum (+ anus) 12.0 12.0 1.0
Breast 13.0 18.0 0.7
NHL 3.5 5.5 0.6
Ovary 3.6 6.0 0.6
Prostate 4.7 8.5 0.5
Cervix 1.7 3.5 0.5
Melanoma 1.4 3.0 0.5
Leukaemia 3.0 17.5 0.2
Total 83.9 87.5
The ratio of the %YLL/%NCRI spend gives an indication of the difference between the population burden of deaths
from the individual cancers and the research spending on that tumour group. Sites are shown in order of this ratio
NCRI – National Cancer Research Institute (in the UK)
sites, with very low relative levels on many tumours types, typically the less well-publicised
cancers. Spending on leukaemia, by contrast, is very high. Although it can be argued that this
is a predominantly curable cancer, it is also possible that other cancers might be more curable
if the same level of funding expenditure was applied to them. As well as leukaemia, 2 other
tumour types have percent spending in double figures, namely colo-rectal (+ anus) and breast
cancers. Breast cancer in fact has the highest level of relative spending.
Column 3 shows the level of mortality in relation to research spending, expressed
as %YLL/%NCRI spending, and the tumour sites are shown in descending order of this
parameter. The higher the figure, the higher the burden of death per percentage unit of
research spending. There are clearly very big differences in mortality and research spending
for some of the tumour sites. Lung cancer now heads this list, and leukaemia has the lowest
death per unit of research spend. In fact, the research spend per year of life lost is over thirty
times higher for leukaemia than it is for lung cancer. Both breast and prostate cancer have
values below one, and colo-rectal (+ anus) cancer has a level of unity. The data in this column
suggest relatively lower levels of spending on less ‘popular’ diseases. One explanation is that
less publicity is afforded these tumour types.
In > Figure 45-4, the percentage of YLL has been plotted against the percentage of NCRI
research spend, for the 17 cancer sites. These 17 specific sites account for 84% of YLL from
cancer. Tumour sites above and to the left of the line of equality have greater YLL than research
spend, while those below and to the right have higher research spend relative to YLL.
The positions of breast and prostate cancer and leukaemia to the right of the figure
indicate a relatively higher research spend than the population burden of these cancers. In
. Figure 45-4
% YLL plotted against % National Cancer Research Institute (NCRI) spending on cancer research
for 17 (adult) cancer sites. The research spending is based on data from the NCRI (NCRI, 2002).
The figures for YLL are expressed as a percentage (83.9%) of the total YLL attributable to cancer.
The line of equality where y = x is shown to guide the eye. Those tumour sites below the line
receive relatively more funding compared to the associated YLL; those above the line are
under-resourced relative to their YLL.
NCRI – National Cancer Research Institute [Reproduced with the kind permission of the editor,
British Journal of Cancer]
fact, the relative spending on leukaemia is quite extreme. Prostate cancer has a lower per cent
YLL but apparently attracts a moderate amount of research spending. By contrast, lung cancer
attracts much less research spending than its cancer burden. The figures for research spending
include some but probably not all monies relating to smoking cessation. However, the figure of
5.2 for %YLL/%research spend suggests under-provision of lung cancer research funding
which is considerable. It also suggests that an increase in funding is appropriate, especially for
strategies to reduce exposure to the highest risk factor (smoking).
In > Figure 45-4, just as in > Figure 45-2, those tumour types which lie towards the origin
are difficult to interpret from the graph. Tabulation of data, as in > Table 45-3, presents the
most suitable method to compare data in these tumour sites.
> Figure 45-5 presents the AYLL, the individual burden of death, against NCRI research
spending. The dashed lines show the mean percentage of NCRI spending (5.2%) and the mean
. Figure 45-5
Average years of life lost (AYLL) plotted against % National Cancer Research Institute (NCRI)
spending on cancer research for 17 (adult) cancer sites (NCRI, 2002). The dashed lines show the
mean percentage of NCRI spending (5.2%) and the mean AYLL (12.5 years), for the tumour sites
shown. Those to the right of the vertical dashed line are relatively over-funded. The top left
quadrant, shaded grey, contains those cancers with the highest AYLL and the lowest research
spending, which might be considered ‘Cinderella’ cancers. These receive the least research
support against the worst individual disease burden.
[Reproduced with the kind permission of the editor, British Journal of Cancer]
AYLL (12.5 years), for the tumour sites shown. Those below the horizontal dashed line therefore
cause less burden of death to the affected individual than the average for cancer overall, and
those to the right of the vertical dashed line are relatively over-funded. This diagram has several
notable features, and tumour sites cluster rather differently from > Figure 45-4.
Prostate cancer has a relatively low AYLL, because it affects relatively older men and can run
an indolent course in some men. In fact, it has the lowest AYLL of any of the tumours shown,
at only 6.1 years. It is also relatively over-funded. By contrast, brain & CNS tumours cause over
3 times as much loss of life per affected individual, at 20.1 years. They are also relatively under-
funded. The positions of breast cancer and leukaemia, both of which have roughly the average
AYLL, lie to the extreme right of this figure, indicating a considerable excess of research
spending over individual cancer burden. A relatively high research spend relative to AYLL is
also directed at colo-rectal (and prostate) cancer.
The top left quadrant, shaded grey, contains those cancers with the highest AYLL and the
lowest research spending. These might therefore be considered ‘Cinderella’ cancer sites. Of the
four ‘Cinderella’ cancers, perhaps the most striking are tumours of the brain and CNS, which
have the highest AYLL of all 17 tumour sites, but a rather modest 1.5% of NCRI research
spending. Cervix cancer is notable because of the high AYLL despite cervical screening.
Melanoma is noteworthy because the percentage YLL is relatively modest for this tumour
type, accounting for only 1.4% of YLL, whereas the AYLL of just over 15 years indicates that
the impact per patient is rather high. It is also increasing in incidence.
The ratio of annual research spending to AYLL can also be instructive, and is obtained by
dividing the annual NCRI research spend (£million) by the AYLL (> Table 45-4). For brain &
CNS tumours this is almost the lowest, at 0.2 (£million per year of life lost per affected
individual). Only uterine cancer has a lower value, at 0.1. In contrast, the only tumour types
which receive relative funding higher than a value of unity are colo-rectal (+ anus), leukaemia,
breast and prostate.
4.2 YLL and AYLL as Measures of Research Spending in Diseases

other than Cancer
YLL has been included as an analysis parameter for allocation of research funding in Australia,
specifically to assess spending across different diseases (Aoun et al., 2004). The most effective
parameters were found to be YLL and disability-adjusted life years. The study demonstrated
that the use of different measures of disease burden can alter conclusions as to whether a
disease is over- or under-funded. This may not be surprising, since different parameters are
essentially highlighting different features of disease burden. Interestingly, cancer was regarded
as relatively over-funded, compared to several other diseases, including cardiovascular disease
and mental disorders.
In a similar exercise, six measures of disease burden were used to compare disease-specific
research funding by the National Institutes of Health (NIH) in the USA in 1996 (Gross et al.,
1999). These measures of disease burden included mortality and YLL, and also disability-
adjusted life-years. Overall, there was a relationship between research funding and measures of
disease burden for the different diseases. Mortality and YLL demonstrated a weak association
with levels of funding, whereas the measure of disability-adjusted life-years was strongly
predictive of funding level. The authors also noted that different measures of disease burden
may yield different conclusions about funding levels, as we would expect.
. Table 45-4
Annual National Cancer Research Institute (NCRI) research spending, with average years of life
lost (AYLL) for 17 adult tumour sites
Annual NCRI research Annual NCRI research

Site spend (£million) AYLL (years) spend/AYLL (£million/year)
Uterus 1.25 11.0 0.1
Brain + CNS 3.75 20.1 0.2
Pancreas 2.5 12.0 0.2
Kidney 3.75 12.8 0.3
Stomach 3.75 11.1 0.3
Myeloma 3.75 10.3 0.4
Cervix 8.75 17.3 0.5
Melanoma 7.5 15.1 0.5
Bladder 3.75 7.3 0.5
Lung 8.75 11.8 0.7
Ovary 15.0 16.3 0.9
NHL 13.75 13.3 1.0
Colon + rectum 30.0 9.8 3.1
(+ anus)
Leukaemia 43.75 13.6 3.2
Breast 45.0 13.5 3.3
Prostate 21.25 6.1 3.5
Other 33.75
Total ~£250
NCRI – National Cancer Research Institute (in the UK)
Comparison of the burden of disease from conditions other than cancer may be a
potentially valuable exercise. Marshall addresses some comparisons in an accompanying
chapter (see Marshall: Years of life lost as a measure of disease burden: an investigation of
the model). Although there are some specific differences in the methods of calculation of the
parameters used, SEYLLd most closely matches our AYLL. While SEYLLd (Standard expected
years of life lost per death) averages over all deaths of interest, AYLL is based on averaging the
loss of life over all diagnoses. Nevertheless, some comparisons may be usefully made.
It is likely that with chronic conditions in which complications cause disability, that a
mixed parameter is needed, which can incorporate information on both death and also burden
of disability. For cancer there is currently less necessity to incorporate a measure of disability.
However, survivorship issues are becoming more important. This is being driven from two
different directions. Firstly, survival rates are improving and treating clinicians are concentrating
on toxicity issues, especially those that relate to treatment complications. Secondly, patient
groups are also promoting the importance of survivorship issues.
It appears that future developments in measuring disease burden for cancer will need to go
beyond simple cancer mortality measures, even if these include YLL and AYLL, to include
measures of disability associated with the condition or its treatment.
5 Conclusions - YLL, AYLL and Research Spending
Mortality data can be used to provide measures of disease burden to both society, in the form
of YLL, and the individual patient, using AYLL. The different indicators show different aspects
of mortality, and are complementary.
Cancer provides an example disease in which these mortality parameters can be most
useful, although they can be applied across a wide range of disease types. These parameters can
be used for comparison to research spending. In the cancer area, such a comparison demon-
strates a mis-match between disease burden and funding. Inequity in research spending goes
well beyond the under-provision for lung cancer research.
Better levels of funding are typically associated with well-publicised cancers. Breast cancer,
leukaemia and colo-rectal cancers have high relative levels of funding. The research spend per
year of life lost is over thirty times higher for leukaemia than it is for lung cancer, which is
relatively under-funded. Prostate cancer has the lowest individual burden of death, measured as
AYLL, at only 6.1 years, because it affects relatively older men and can run an indolent course in
some. It is also relatively over-funded. By contrast, brain & CNS tumours cause over 3 times as
much loss of life per affected individual, at 20.1 years. They are also relatively under-funded.
Analysis of this type can identify tumour types with extreme impact, either on society, for
example through a high incidence, or on individual patients, as a result of relatively low cure
rates. Where these are also under-funded, they might be considered ‘Cinderella’ cancers. Such
extreme tumour types, expressed by either statistic, may need special consideration.
Measures of mortality and disease burden may have to be developed to include a compo-
nent related to disease morbidity and treatment toxicity.
Overall, this type of analysis suggests that a more subtle and comprehensive calculation of
mortality statistics would be useful in considering allocation of research funding, and in
debates on public health issues.
Summary Points
Mortality statistics are essential in health care.

Different measures of mortality provide a focus on different aspects of the effect of disease
and its burden, and are complementary.
Crude mortality is relatively influenced by common tumours in older patients.
Years of life lost (YLL) is a population-based indicator of mortality which gives relatively
more weighting to diseases that are incurable and affect younger patients. YLL gives some
measure of the impact of the disease on society, representing the population burden of the
disease.
Average years of life lost (AYLL) represents the average shortening of life for a patient
affected by specific disease. It gives relatively higher weight to tumours that are incurable
and kill patients when they are young. AYLL provides an estimate of the impact of the
disease on the individual, representing the individual burden of the disease to the affected
individual.
YLL and AYLL can be used for comparing disease burden to research spending.
In the field of cancer research in particular, YLL and AYLL demonstrate a mismatch
between mortality and spending, some cancers being over-funded while others are
under-funded, relative to measures of burden of disease.
Measures of mortality and disease burden may have to develop to include a component
related to disease morbidity and treatment toxicity.
Analysis of this type can identify ‘Cinderella’ tumour types with extreme impact, either on
society, or on individual patients.
A more subtle and comprehensive calculation of mortality statistics would be useful in
considering allocation of research funding, and in debates on public health issues.
References
Ågren A, Brahme A, Turesson I. (1990). Int. J. Radiat. Horm JW, Sondik EJ. (1989). Am. J. Public Health. 79:
Oncol. Biol. Phys. 19: 1077–85. 1490–3.
Albert VA, Koh HK, Geller AC, Miller DR, Prout MN, NCRI. (2002). National Cancer Research Institute Stra-
Lew RA. (1990). J. Am. Acad. Dermatol. 23: 308–10. tegic Analysis. London: NCRI.
Aoun S, Pennebaker D, Pascal R. (2004). Aust. N. Z. J. Romeder JM, McWhinnie JR. (1977). Int. J. Epidemiol.
Public Health. 28: 80–6. 6: 143–151.
Brunekreef B, Miller BG, Hurley JF. (2007). Epidemiology. Thuppal S, Propp JM, McCarthy BJ. (2006). Neuroepi-
18: 785–8. demiology. 27: 22–7.
Burnet NG, Jefferies SJ, Benson RJ, Hunt DP, Treasure FP. Turini M, Redaelli A. (2001). Int. J. Clin. Pract Review.
(2005). Br. J. Cancer. 92: 241–5. 55: 471–5.
Duncan W, Orr JA, Arnott SJ, Jack WJ, Kerr GR, UK Government Department of Health. (2007). http://
Williams JR. (1987). Int. J. Radiat. Oncol. Biol. www.dh.gov.uk/en/Publicationsandstatistics/Letter
Phys. 13: 171–8. sandcirculars/Dearcolleagueletters/DH_080975.
Gardner JW, Sanborn JS. (1990). Epidemiology. 1: 322–9.
Gross CP, Anderson GF, Powe NR. (1999). N. Engl. J.
Med. 340: 1881–7.
46 Worldwide Burden of
Gynecological Cancer
R. Sankaranarayanan . J. Ferlay
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804
2 Indices of Cancer Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805

2.1 Sources and Methods of Estimation of Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
3 The 2005 Estimates of Gynecological Cancer Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807

3.1 Cancer of the Uterine Cervix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807
3.2 Cancer of the Uterine Corpus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
3.3 Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 812
3.4 Other Gynecological Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 814
4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 814
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822

804 46 Worldwide Burden of Gynecological Cancer
Abstract: > Cancer incidence, mortality, and > prevalence are commonly used indicators of
cancer burden. Estimation of cancer burden is valuable for the formulation of cancer control
policies and planning health services. The sources and methods of estimation of global data
and the worldwide burden of gynecological cancers (malignant neoplasm of uterine cervix,
corpus, ovary, vagina, vulva, and placenta) are described. Cervical cancer accounted for
487,300 new cases and 269,500 deaths; uterine corpus cancer for 233,300 new cases and
61,400 deaths; ovarian cancer for 230,000 new cases and 140,100 deaths; cancers of the vagina,
vulva, placenta, and ill-defined sites together constituted 74,900 cases. Less developed
countries accounted for more than 80% of the cervical cancer cases while almost 60% of
uterine corpus cases occurred in the developed world. Earnest implementation of current
developments in screening and vaccination has the potential to dramatically reduce the
burden of cervical cancer. The differences in the outcome of cancer treatment across the
world are due to vast disparities in health service infrastructures, human resources, service
delivery, and accessibility to services. A significant proportion of patients are unable to access
and avail or complete preventive, diagnostic, and therapy services in many countries due to
inadequate health care services and financing. Formulation and translation of appropriate
cancer control policies and investments in awareness creation, human resources development,
and healthcare infrastructure are vital to reduce the current burden of gynecological cancer in
low- and medium-resource countries. On the other hand, attention should be focused on
emerging cost-effective options to sustain and further improve current control prospects in
the developed world.
List of Abbreviations: ACCP, Alliance for Cervical Cancer Prevention; ASR, age-standardized
rate; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; IARC, International
Agency for Research on Cancer; ICD-10, international statistical classification of diseases, 10th
edition; NCCP, National Cancer Control Programme; SEER, Surveillance, Epidemiology and
End Results Programme; TVS, transvaginal sonography; VIA, visual inspection with acetic
acid; WHO, World Health Organization
1 Introduction
Cancer incidence, mortality, and prevalence are the commonly used indicators of
cancer burden. Cancer incidence is the number of new cases arising in a given period in a
specified population. It can be expressed as an absolute number of cases per year or as a rate
per 100,000 persons per year. > Cancer mortality is the number of deaths occurring in a given
period in a specified population. It can be expressed as an absolute number of deaths per year
or as a rate per 100,000 persons per year. Prevalence refers to the absolute number, and relative
proportion of persons in a population affected by the disease in a defined period. Other
complex indices of disease burden used include ‘‘> person-years of life lost’’ defined as how
many years of normal life are lost due to death from a given disease; ‘‘> disability-adjusted
life years lost’’ attempts to give a numerical score to the years lived with a reduced quality of
life between diagnosis and death.
Estimation of cancer burden in terms of incidence, mortality, and prevalence is valuable
for the formulation of cancer control policies and planning health service investments for
optimum disease control. It is a valuable resource to assess demands of care and to define
priorities for preventive, diagnostic, therapeutic, and palliative care services and to evaluate
Worldwide Burden of Gynecological Cancer 46 805
the outcomes of targeted interventions to reduce disease burden. The comparison of disease
burden between different populations over time helps to define causal hypotheses, and
evaluate the underlying risk factors, thereby providing opportunities for prevention by risk
factor control. In this chapter, we describe the incidence, mortality, and prevalence of cancers
of the uterine cervix (International classification of disease (ICD)-10 code C53), uterine
corpus (corpus uteri, ICD-10 C54), ovary (ICD-10 C56) together with the incidence of vagina
(ICD-10 C51), vulva (ICD-10 C52) and malignant neoplasm of the placenta (ICD-10 C58) for
18 world regions, as defined by the United Nations Organization (UNO) population division,
in order to quantify the global gynecological cancer burden around the year 2005, and discuss
briefly the sources of data, data validity, methods of estimation and the implications for cancer
control and health services worldwide in general, and in developing countries in particular.
2 Indices of Cancer Burden
Incidence represents the average risk of developing a cancer in a population (Ferlay et al., 2004;
Parkin et al., 2005). When expressed as an absolute number of cases per year, it reflects the load
of new cancer patients diagnosed in a given region. Using incidence data, the risk of disease in
different ethnicities and populations within countries, regions, can be compared over different
time periods. The impact of prevention strategies based on modulating exposure of popula-
tions to risk factors (e.g., controlling tobacco use or preventing human papillomavirus (HPV)
infection or hepatitis B virus or improving physical activity, etc.) or early detection and
treatment of precancerous lesions (e.g., cervical cancer screening, colorectal cancer screening)
is measured in terms of reduction in incidence.
Mortality is the product of fatality and incidence, and provides an important and definite
measure of the outcome of disease (Ferlay et al., 2004; Parkin et al., 2005). Fatality refers to the
proportion of incident cancer cases that die. Cancer mortality rates measure the average risk of
dying from a given cancer in a given population, while fatality reflects the probability of an
individual with cancer dying from it. Mortality rates are influenced by the trends in incidence
rates as well as by the changes in natural history of the disease, the evolution, dissemination
and efficacy of treatment interventions, and efficiency of health services delivery. Mortality
rate should not be used as a proxy measure of cancer incidence when comparing different
populations, assuming equal > survival/fatality in the populations compared, which is rarely
true. Survival of a cancer patient refers to the time duration between the diagnosis and death.
Prevalence pertains to the number of persons in a defined population who have had cancer
diagnosed at some time in the past, during a given period of time (Ferlay et al., 2004; Parkin
et al., 2005). Prevalence of cancer cases diagnosed with in 1, 3 and 5 years provide useful
supplementary information to the requirements of different phases of cancer management,
such as initial treatment (1-year prevalence) and treatment of residual/recurrent disease and
clinical follow-up (3- or 5-year prevalence).
2.1 Sources and Methods of Estimation of Data
The data presented in this chapter are based on the data published in the ninth volume of the
‘‘Cancer Incidence in Five Continents’’ by the International Agency for Research on Cancer
(IARC) of the World Health Organization (WHO) (Curado et al., 2007), and on updated
estimates of the GLOBOCAN 2002 database (Ferlay et al., 2004).
A brief description of the methods of estimation is useful to understand the validity,

limitations, and applications of the data in national, regional, and global contexts. The
methods of estimation have been widely described elsewhere (Ferlay et al., 2004; Parkin
et al., 2001, 2005; Pisani et al., 2002). The building blocks of the data on worldwide burden
are the best and most up-to-date information on incidence, mortality, and survival in a given
country. The estimates of cancer burden for different countries vary in accuracy, depending
upon the extent and validity of the data available for each country and for several developing
countries from where no data are available (e.g., Cambodia, Democratic Republic of Congo,
etc.) the estimate is derived from neighboring countries.
Population-based cancer registries provide cancer incidence data by systematic and
continuing collection of data on all new cancer cases, in a defined resident population and
in a given geographical region, diagnosed by all means (histological or clinical) (Armstrong,
1992). Unfortunately, cancer registries are non-existent in many populations and countries,
particularly in sub-Saharan Africa, certain regions of Asia (e.g., Central Asia), and Latin
America (e.g., Central America). Where available, cancer registries may cover the entire
geographical regions of a country (national registries) in some instances (e.g., Singapore,
Oman, The Gambia, Finland, Costa Rica, etc.), or populations living in some regions in a
country (e.g., Metro Manila in the Philippines, Chennai in India, Kyadondo county in
Uganda, Bas-Rhin department in France, Trujillo in Peru, etc.). It is estimated that 18% of
the world population (comprising of 65% of developed and 7% of developing country
populations) were covered by population-based cancer registries in 2000. The latest volume
(volume 9) of the ‘‘Cancer Incidence in Five Continents’’ published by the International
Agency for Research on Cancer (IARC) contains comprehensive and comparable incidence
data from 225 population-based cancer registries and 300 populations in 60 countries during
the period 1998–2002 (Curado et al., 2007).
The country specific incidence rates for cervical, corpus uteri, and ovarian cancers
described in GLOBOCAN 2002 were updated whenever possible using more recent data
available in ‘‘Cancer Incidence in Five Continents’’ volume IX, or, for cervical cancer in
European countries, using the latest available estimates for 2004 (Arbyn et al., 2007). The
numbers of cases are computed by multiplying the estimated rates by the year 2005 population
estimates for the corresponding country (United Nations, 2006). Estimates for malignant
neoplasm of vagina, vulva, and placenta in the 18 world regions were calculated by the
population weighting average of the age-specific incidence rates observed in local cancer
registries in the area and published in ‘‘Cancer Incidence in Five Continents’’ volume IX.
For countries in Europe and Northern America, and for Japan, Australia, and New
Zealand, mortality rates from cervical, corpus uteri, and ovarian cancers were calculated
using the most recent data available in the WHO mortality database. The numbers of cancer
deaths were computed by multiplying these rates by the year 2005 population estimates for the
corresponding country. For the other countries, the number of cancer deaths was calculated by
multiplying the estimated number of new cancer cases in 2005 by the country specific
incidence to mortality ratio in 2002 from GLOBOCAN 2002.
Finally, the country specific number of 5-year prevalent cancer cases of cervical, corpus
uteri, and ovarian cancers were computed by multiplying the estimated number of 5-year
prevalent cancer cases in 2002 (Ferlay et al., 2004) by the ratio of the estimated number of
cancer cases in 2005 to that in 2002 (Ferlay et al., 2004).
Population-based cancer survival data are widely available for developed countries, but
only for limited regions in a few developing countries. Population-based survival rates reflect
the average prognosis from a given cancer in a given region and provide a valuable measure of
the efficiency of the local health services. The sources of population-survival data include the
population-based cancer registries under the Surveillance, Epidemiology and End Results
(SEER) programme covering 13% of the US population (Ries et al., 2007), the EURO-
CARE-3 project providing survival data for registries in several European countries (The
EUROCARE Working Group, 2003), the ‘‘Cancer Survival in Developing Countries mono-
graph’’ providing survival data for selected populations in China, Cuba, India, the Philippines
and Thailand (Sankaranarayanan et al., 1996, 1998), Singapore (Chia et al., 2001) and first
results from Uganda (Gondos et al., 2004) and Zimbabwe (Gondos et al., 2005).
3 The 2005 Estimates of Gynecological Cancer Burden
The burden of uterine corpus, uterine cervix, and ovarian cancer in terms of incident cases,
deaths and 5-year prevalence for 18 world regions and for developing and developed countries
is given in > Table 46-1. Developed countries include North America, Europe (including all of
Russia), Australia, New Zealand, and Japan. Those in the remaining regions constitute
‘‘developing countries.’’ The estimated number of incident cases in 2005 for malignant
neoplasm of vagina, vulva, and placenta are given in > Table 46-2.
New cases of vagina (ICD-10 C51), vulva (ICD-10 C52), uterine cervix (ICD-10 C53),
uterine corpus (ICD-10 C54), ovary ((CD-10 C56), malignant neoplasms’ of other and
unspecified female genital organs (ICD-10 C57) and malignant neoplasm of placenta (ICD-
10 C 58) together constituted 1,026,000 cases.
3.1 Cancer of the Uterine Cervix
Cancer of the cervix is the second most common cancer among women worldwide in 2002,
with an estimated 487,300 new cases and 269,500 deaths (> Table 46-1) around 2005. More
than 80% of the global burden is experienced in developing countries, where it is the most
common cancer among women in many regions. Being the most common gynecological
cancer in the developing world, it continues to be a serious health problem, accounting for
60% of all gynecological cancer cases in developing countries and 80–95% of cervical cancers
are squamous cell carcinomas worldwide (Curado et al., 2007).
The lowest and highest cervical cancer age-standardized incidence rates (ASR) observed in
populations in the five continents, including rates from selected populations, are given in
> Figure 46-1. There is more than 20-fold variation in the incidence rates of cervical cancer
worldwide and the highest incidence rates are observed in sub-Saharan Africa, Melanesia,
Latin America and the Caribbean, South-Central Asia, South-East Asia, and Eastern Europe
(Curado et al., 2007) (> Figure 46-1). The ASRs ranged from a lowest of 2.1 per 100,000
women in Gharbia, Egypt to the highest of 47.3 per 100,000 African women in Harare,
Zimbabwe (Curado et al., 2007). The incidence is generally low in developed countries, with
ASRs less than 10 per 100,000 women (> Figure 46-1), where as the incidence rates in most of
developed countries before the introduction of screening programmes were similar to those
found in developing countries today (Gustafsson et al., 1997). Rates lower than 7/100,000
women are observed in the Middle Eastern countries and China (> Figure 46-1) (Curado et al.,
2007).
808
46
. Table 46-1
Cancer of the uterine cervix, uterine corpus, and ovary. Incident cases, deaths and 5-year prevalence in 18 world regions in 2005
Cervix uteri Uterine corpus Ovary All

5-year 5-year 5-year 5-year
World regions Cases Deaths prevalence Cases Deaths prevalence Cases Deaths prevalence Cases Deaths prevalence
Worldwide Burden of Gynecological Cancer
World 487,300 269,500 1,396,500 233,300 61,400 899,900 230,000 140,100 604,900 950,600 471,000 2,901,300
More developed 82,200 35,100 289,400 137,100 29,600 538,200 101,900 62,700 259,400 321,200 127,400 1,087,000
countries
Less developed 405,100 234,400 1,107,100 96,200 31,800 361,700 128,000 77,400 345,500 629,300 343,600 1,814,300
countries
Eastern Africa 29,400 23,500 49,700 2,900 1,000 10,600 4,900 3,500 11,000 37,200 28,000 71,300
Middle Africa 10,900 8,900 18,600 600 200 2,700 1,800 1,300 4,100 13,300 10,400 25,400
Northern Africa 10,600 8,500 18,200 1,100 400 3,900 2,300 1,600 5,200 14,000 10,500 27,300
Southern Africa 7,100 4,100 12,200 400 200 1,600 700 400 1,600 8,200 4,700 15,400
Western Africa 30,600 24,600 52,300 1,200 400 4,200 3,400 2,400 7,600 35,200 27,400 64,100
Caribbean 4,200 2,000 12,100 1,500 700 4,900 1,000 600 2,400 6,700 3,300 19,400
Central America 14,200 6,700 41,000 3,200 1,400 11,800 2,900 1,400 7,400 20,300 9,500 60,200
South America 45,300 20,000 130,500 11,600 3,500 38,500 16,500 7,900 40,800 73,400 31,400 209,800
Northern America 17,000 6,700 67,500 43,900 5,400 190,300 25,600 16,300 76,000 86,500 28,400 333,800
Eastern Asia 100,100 51,300 314,400 38,600 8,900 152,800 44,400 21,700 127,800 183,100 81,900 595,000
South-Eastern Asia 48,900 26,000 152,600 13,200 4,700 46,800 2,100 1,100 5,600 64,200 31,800 205,000
South Central Asia 103,200 56,700 291,900 17,300 7,100 60,300 45,700 32,000 117,400 166,200 95,800 469,600
Western Asia 4,400 2,100 13,600 7,000 3,300 23,600 5,700 3,500 14,600 17,100 8,900 51,800
Eastern Europe 31,400 17,500 109,700 41,200 14,100 155,200 30,500 19,700 73,200 103,100 51,300 338,100
Northern Europe 6,100 2,600 22,800 11,000 2,300 41,600 10,100 6,900 23,900 27,200 11,800 88,300
Southern Europe 10,200 3,200 39,500 15,900 3,400 61,800 12,000 6,600 33,200 38,100 13,200 134,500
Western Europe 11,400 4,700 44,300 19,200 4,000 79,500 17,600 12,100 48,400 48,200 20,800 172,200
Oceania 1,500 400 5,600 2,500 400 9,800 1,800 1,100 4,700 5,800 1,900 20,100
Almost a million new cases of and half million deaths due to cancers of the female genital tract occur annually in the world
Worldwide Burden of Gynecological Cancer
46
809
. Table 46-2
Estimated numbers of malignant neoplasm of vulva, vagina, placenta and uterine adenexa
in 2005
Uterine adenexa and

World regions Vulva Vagina other ill-defined sites Placenta
Eastern Africa 574 288 231 748
Middle Africa 330 131 21 187
Northern Africa 119 253 224 39
Southern Africa 189 64 16 122
Western Africa 499 366 84 476
Caribbean 152 65 30 11
Central America 479 234 92 27
South America 2,254 1,364 1,018 317
Northern America 4,288 1,370 1,088 138
Eastern Asia 2,656 1,768 4,361 1,050
South-Eastern Asia 1,147 652 18,233 364
Southern Asia 2,167 3,188 868 759
Western Asia 595 199 266 68
Eastern Europe 4,683 1,035 1,318 126
Northern Europe 1,656 382 386 26
Southern Europe 2,248 558 792 45
Western Europe 3,115 826 1,007 46
Oceania 309 90 87 14
More developed countries 16,542 4,397 4,758 410
Less developed countries 10,918 8,435 25,362 4,153
World 27,460 12,832 30,120 4,564
Almost 75,000 new cases of cancer of the vulva, vagina, placenta and other ill-defined sites of female genital tract
occur in the world annually
Higher survival is observed in populations in developed countries as compared to selected

populations in developing countries from where survival data are available (> Table 46-3). The
5-year survival in the SEER registries, Europe, and Singapore are considerably higher than
those reported from sub-Saharan Africa, whereas survival rates are fair in India, China, and
Thailand. The 5-year prevalence is around 1.4 million cases in the world, with 1.1 million of
these cases being in the developing world (> Table 46-1).
3.2 Cancer of the Uterine Corpus
Cancer of the uterine corpus, a cancer of the postmenopausal women accounted for 233,300
new cases and 61,400 deaths worldwide around 2005 (> Table 46-1). Globally, it is the second
most common gynecological cancer. However, it is the most common gynecological cancer in
developed countries, which account for 60% of the global burden. Around 90% of the uterine
. Figure 46-1
Age-standardized incidence rates of cervical cancer in selected populations in each continent,
during 1998–2002. More than 18-fold difference is observed in the incidence rate of cervical
cancer across different regions of the world. A higher incidence is observed in sub-Saharan
Africa, South America, South and South-East Asia, and Eastern Europe
. Table 46-3
Gynecological cancers: 5-year relative survival around 1990
Region/country Uterine corpus Cervix uteri Ovary

USA, SEER 83 72 42
English registries 74 64 31
French registries 73 68 38
Italian registries 76 67 37
Finland 81 66 35
Singapore 68 57 51
India, Mumbai 51
India, Chennai 60
China, Shanghai 77 52F 44
Thailand, Chiang Mai 69 68 45
Thailand, Khon Kaen 79 57 36
Philippines, Rizal 29
Uganda, Kampala 18 16
Harare, Zimbabwe: black 30 38
Five-year survival from gynecological cancers in developing countries are lower than those observed in developed
countries. SEER surveillance, epidemiology and end results program
corpus cancers are endometrial adenocarcinomas. Papillary serous carcinoma, clear cell
carcinomas, papillary endometrial carcinoma, and mucinous carcinoma account for the
remaining cases.
There is more than 14-fold variation in the worldwide incidence during 1998–2002 and
ASRs exceeding 15 per 100,000 women are observed in Europe and North America where as
the incidence rates are less than 10 per 100,000 women in the rest of the world and rates are
generally lower than 5 per 100,000 in populations in most developing countries in South
America, Africa, and Asia (Curado et al., 2007) (> Figure 46-2). More than 90% of the cases
occur in women aged 50 years and over. Cancer of uterine corpus has a much more favorable
prognosis than those with ovarian and cervical cancer, with 5-year survival rates around 80%
in developed countries and 70% in the developing countries (> Table 46-3). The 5-year
prevalence is around 899,900 cases worldwide (> Table 46-1).
3.3 Ovarian Cancer
Ovarian cancer ranks as the sixth most common cancer in women in 2002 and accounted for
230,000 cases and 140,100 deaths worldwide around 2005 (> Table 46-1). In developed
countries, more than 90% of ovarian cancers are epithelial in origin, the remaining constituted
by germ cell tumors (2–3%) and sex cord-stromal tumors (5–6%). Germ cell tumors account
for 10–15% of ovarian cancers in Asian and African populations. Dysgerminoma accounts for
more than 70% of germ cell tumors, whereas granulosa tumors constitute the most common
sex cord-stromal tumor. The vast majority of epithelial ovarian cancers are diagnosed in
. Figure 46-2
Age-standardized incidence rates of uterine corpus cancer in selected populations in each
continent, during 1998–2002. A high incidence of uterine corpus cancer is observed in Europe
and North America
postmenopausal women, whereas germ cell tumors occur in young women with child bearing
potential, in their twenties.
There is more than 7-fold variation in the worldwide occurrence of ovarian cancer, with
the ASRs exceeding 8 per 100,000 women in most populations in Europe and North America
(Curado et al., 2007) (> Figure 46-3). The rates vary between 4 and 8 per 100,000 women in
most populations in Asia, Africa, and Latin America.
The high-proportion of deaths in relation to new cases reflects the much less
favorable prognosis of ovarian cancer, as compared to uterine corpus and cervical cancer
(> Tables 46-1 and > 46-3). The 5-year survival from ovarian cancer is mostly less than 50%
(> Table 46-3) and the 5-year prevalence is 604,900 cases worldwide (> Table 46-1).
3.4 Other Gynecological Cancers
Cancer of the vulva constitutes 2.7% of gynecological cancers. It accounted for an estimated
27,500 cases, of which 16,500 occurred in developed countries (> Table 46-2). The ASRs vary
between 0.2 and 3.5 per 100,000 women (Curado et al., 2007) (> Figure 46-4). The incidence
rates exceed 1.5 per 100,000 women in populations North America, South America
and Europe, while the rates are less than 0.5 per 100,000 in most developing countries
(> Figure 46-4). More than 50% of the cases are diagnosed in women over the age of 70.
Incidence rates peak in women aged 75 and above. Two-thirds or more of the vulva cancers
occur in the labia majora.
Cancer of the vagina is rare and constitutes 1.2% of gynecological cancers. It accounted for
an estimated 12,800 cases worldwide around 2005 (> Table 46-1); of these 8,400 occurred in
developing countries. The ASRs vary between 0.1 and 1.5 per 100,000 women world wide
(Curado et al., 2007) (> Figure 46-5). More than three-fourths of cases occur in women older
than 60 years. Except for clear cell carcinomas associated with maternal diethyl stilboestrol
(DES) exposure, vaginal cancer is rare in women younger than 40 years. Half of the tumors
occur in the upper third of vagina.
Malignant neoplasm of the placenta is a rare cancer constituting 0.5% of all gynecological
cancers. It accounted for an estimated 4,600 cases worldwide of which 4,200 occurred in
developing countries (> Table 46-2). Incidence rates in different regions vary between 0.1 and
0.9 per 100,000 women (Curado et al., 2007) (> Figure 46-6). An incidence rate of 1.7/100,000
women has been reported from Vietnam (Altieri et al., 2003).
4 Discussion
The estimates of global burden and the available information on incidence rates from selected
populations through population cancer registries indicate important variations in the burden
of different gynecological cancers, due to different levels of exposure to established and
suspected risk factors and due to the wide disparity and inequity in health care infrastructure
and accessibility in different populations across the world.
Cervical cancer remains as the most common gynecological cancer among women and the
incidence rates are two to five fold higher in less developed countries than that observed in
developed countries despite the slowly declining incidence rates in many populations in low-
and medium-resource countries with or without screening programmes. The high risk of
. Figure 46-3
Age-standardized incidence rates of ovarian cancer in selected populations in each continent,
during 1998–2002. A seven-fold difference in the incidence rate of ovarian cancer is observed
across the world. High rates are observed in Europe and North America
. Figure 46-4
Age-standardized incidence rates of vulva cancer in selected populations in each continent,
during 1998–2002. The incidence rates of vulva cancer are generally low in different world
regions
. Figure 46-5
Age-standardized incidence rates of vagina cancer in selected populations in each continent,
during 1998–2002. Vaginal cancer is rare in the world
. Figure 46-6
Age-standardized incidence rates of malignant neoplasm of placenta in selected populations in
each continent, during 1998–2002. Malignant neoplasms of the placenta are rare in the world
cervical cancer in these countries is due to lack of inefficient existing screening programmes,
combined with a high background prevalence of human papillomavirus (HPV) infection
(Bosch and de Sanjose, 2003; IARC, 2004; Sankaranarayanan et al., 2001). Persistent infection
with one or more of the high-risk HPV types is now accepted as a necessary cause of cervical
cancer and HPV DNA can be identified in more than 95% of cervical cancers (IARC, 2007;
Munoz et al., 2003). Of the more than 100 HPV types identified, one or more of the 15 high-
risk types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73 and 82), are associated with
cervical neoplasia (Munoz et al., 2003). Most HPV infections are transient and 80% of them
resolve within 2 years; but some women infected with one or more of the high-risk types
develop persistent infections.
The estimated cervical cancer cases and deaths have not shown an increase as compared to
the estimates for 2002 (492,800 cases, 273,200 deaths) (Ferlay et al., 2004). There has been a
substantial decline in the estimated cases of South-Central Asia (burden of which is mainly
contributed by India, a high-risk country) as compared to 2002 estimates (103,200 cases in
2005 vs. 157,700 cases in 2002). The estimated ASR in GLOBOCAN 2002 for cervix cancer
in India was 30.0/100,000. The combined ASR is 18.2/100,000 for the seven Indian registries in
the ninth volume of the ‘‘Cancer Incidence in Five Continents,’’ based on which these 2005
estimates have been made. This explains the drop in the number of cervical cancer cases in
South-Central Asia. It is not clear if the rate assumed for 2005 is rather low, given the fact that
higher incidence rates for cervical cancer are reported from rural areas and regions not
included in the ‘‘Cancer Incidence in Five Continents’’ volume 9 (Nandakumar et al., 2005).
In recent years there have been a number of research initiatives in India and other developing
countries to evaluate alternative screening methods such as visual screening and HPV testing
(Sankaranarayanan et al., 2001). Recently, HPV testing or visual screening with acetic acid
(VIA) followed by cryotherapy of screen positive women has been shown to reduce the
prevalence of high-grade CIN in a randomized trial in South Africa (Denny et al., 2005). A
single round of VIA screening has been shown to reduce cervical cancer incidence by 25% and
mortality by 36% in a randomized trial in South India (Sankaranarayanan et al., 2007). Results
from a randomized intervention trial in India comparing VIA, cytology, and HPV testing
indicate that all tests had similar detection rates of CIN 2–3 lesions (Sankaranarayanan et al.,
2005). These studies have catalyzed a number of screening initiatives in several regions of
India, Bangladesh, and Nepal and it is too early for these initiatives to have a population
impact and it is unlikely that these are responsible for the decline in the estimated cases for
2005 in the sub-continent. A commendable global effort in the context of reducing disease
burden in recent years has been the studies of the Alliance for Cervical Cancer Prevention
(ACCP) supported by the Bill & Melinda Gates Foundation (Alliance for Cervical Cancer
Prevention, 2004). The organization of screening programmes based on visual screening or the
newly developed, rapid, less expensive HPV test linked with VIA triage and treatment of CIN
can lead to substantial reduction in cervical cancer burden in underserved populations in less
developed countries (Denny et al., 2005; Sankaranarayanan et al., 2007).
Introduction population-based cytology screening has substantially reduced cervical can-
cer risk in developed countries of Western Europe, North America, Australia, and New
Zealand (IARC, 2004). Low burden of disease is experienced in developed countries with
screening programmes and in countries with high prevalence of male circumcision (e.g.,
countries of the Middle East). A lower risk of HPV infection in circumcised than in uncir-
cumcised males, with a corresponding lower incidence of cervical cancer in their female
partners has been reported (Castellsague et al., 2002). In countries where screening has
resulted in considerable decline in the burden of cervical cancer, when different histologic
types of cervical cancers are considered and trends are examined, it becomes apparent that
observed declines are reflective of squamous cell carcinomas predominantly and the rates for
adenocarcinomas continue to rise (Herzog and Monk, 2007; Smith et al., 2000; Vizcaino et al.,
1998). This may be due to the difficulty in screening for glandular precursor lesions that often
arise high within the endocervical canal. Reducing the incidence and mortality rates that are
associated with adenocarcinomas can be accomplished by using improved screening techni-
ques and possibly by future large-scale implementation of cervical cancer vaccines that target
the oncogenic HPV types that are associated with adenocarcinoma.
The recognition that infection with certain HPV types is a necessary cause of cervical
cancer has opened new fronts in the prevention of cervical neoplasia. Primary prevention is
now possible via immunization with HPV vaccines, and the possibility of using HPV-DNA
testing has a large potential to improve screening and prevention of cervical neoplasia (Franco,
2003; Franco and Ferenczy, 2007; Koliopoulos et al., 2007). Although, currently available HPV
vaccines targeting HPV types 16 and 18 offers HPV–naı̈ve women a very high-level of
protection (99%) from infections and cervical intraepithelial neoplasia (CIN) associated
with the HPV types included in the vaccine and the vaccines were safe and well tolerated with
relatively few side effects (Harper et al., 2006; Koutsky and Harper, 2006; The Future II Study,
2007) and universal vaccination of adolescent girls before sexual debut is a desirable policy,
still there are several challenges that need to be resolved before it can be widely implemented in
high-risk developing countries (Agosti and Goldie, 2007). These include: current high costs of
the vaccines, affordability, feasibility, acceptability, logistics of vaccine delivery (in view of the
need for three doses spread over 6 months, improved strategies and vaccine platforms to reach
out to pre- or early-adolescent girls), long-term immunogenicity and efficacy in preventing
cervical neoplasia, cross-protection against HPV types not targeted by the vaccine antigens
and the efficacy of different, more logistically feasible dose regimes in inducing and main-
taining immunogenicity, and long-term protection against cervical neoplasia. While prophy-
lactic vaccination is likely to provide important future health gains if vaccination is offered to
girls before onset of sexual activity, cervical screening should still be continued for the women,
as the risk of being already infected with the oncogenic HPV types or of acquiring CIN due to
an HPV type other than 16 or 18 remains. To achieve cost-effective reductions in cervical
cancer burden, prevention initiatives must consider screening and immunization as integrated
and organized approaches that take advantage of HPV testing as a primary screening test
followed by triage with cytology (Franco and Ferenczy, 2007). This strategy has the added
benefit of providing surveillance of vaccinated populations.
Estrogenic stimulation produces glandular proliferation in the endometrial epithelium,
which is balanced by the cyclical maturational effects of progesterone. Increased risk of
endometrial cancer, associated with factors such as oral intake of estrogens (without proges-
tins), early menarche, late menopause, low parity, extended periods of anovulation and
obesity can be related to long-term unopposed estrogenic stimulation, leading to proliferation
and neoplastic transformation of endometrial cells. In Canada, 22% of endometrial cancer is
attributed to obesity, where the prevalence of obesity has increased from 10% in 1970 to 23%
in 2004 (Luo et al., 2007). The association between long-term tamoxifen use and endometrial
cancer has been attributed to its estrogen agonist properties and women receiving tamoxifen
should be monitored carefully. Diabetes mellitus and hypertension have also been associated
with increased risk. A protective effect has been attributed to high parity, late age at last birth,
long-term use of combined oral contraceptives and physical activity. Increasing trends among
postmenopausal women have been observed in developed countries; in premenopausal

and perimenopausal women, endometrial cancer is relatively rare, and where long-term data
are available, incidence is decreasing (Bray et al., 2005; Somoye et al., 2005). The continuing
increases in obesity and decreases in fertility indicate that endometrial cancer will become a
more important public health problem in coming years. This is also evident in the case of less
developed countries, where the estimated burden for 2005 (96,200 cases) has increased by 50%
as compared to 2002 estimates (62,300 cases) (Ferlay et al., 2004).
Ovarian cancer incidence rates have been slowly increasing in most populations over the
last two decades (Marugame and Hirabayashi, 2007). Most ovarian cancers are diagnosed in
advanced clinical stages with poor prospects of long-term survival, particularly in less devel-
oped countries. The etiology and natural history of ovarian cancer are not well understood
and thus the means of primary prevention are not clear. Less than 20% of women with
advanced stage disease survive long-term. When diagnosed in stage I, up to 90% of patients
can be cured with conventional surgery and chemotherapy. Although early detection and
adequate treatment are the current methods of ovarian cancer control, at present, less than
25% of ovarian cancers are detected in stage I due, in part, to the absence of specific symptoms
and to lack of an effective screening strategy. Routine screening for asymptomatic ovarian
cancer is not currently recommended. Transvaginal sonography (TVS), serum markers and a
combination of the two modalities are being evaluated for early detection of ovarian cancer;
two stage screening strategies promise to be cost effective, where abnormal serum assays
prompt TVS to detect lesions that require laparotomy (Badgwell and Bast, 2007). Accrual
has been completed for a large trial of ovarian cancer screening in the United Kingdom that
will evaluate the ability of a rising CA125 to trigger TVS and subsequent exploratory surgery.
The relatively stable incidence of vulva cancer, despite a steady increase in the diagnosis of
vulva intraepithelial neoplasia (VIN), suggests that effective treatment of VIN has prevented a
significant increase in the incidence of invasive cancer in developed countries. It has been
reported that vulvar carcinoma in situ has increased by 411% during 1973–2000 in popula-
tions covered by the SEER programme in the US as opposed to a 20% increase in the incidence
of invasive vulva cancer (Judson et al., 2006). Vaginal cancers are rarer than vulva cancer and
association between HPV infection and vaginal cancer has been reported (IARC, 2007).
Malignant neoplasms of placenta are rare and the treatment has dramatically improved the
outcome for this disease that had previously resulted in the death of 60% of patients with
localized and 90% with disseminated disease. The 5-year survival rate among 450 gestational
choriocarcinoma cases in SEER registries during 1973–1999 was 90% (Smith et al., 2003). Reports
indicate that gestational choriocarcinoma incidence rates have declined, with an increase in old
fertile women in developed countries (Loukovaara et al., 2004; Smith et al., 2003).
In summary, establishing population-based cancer registries in countries/regions with no
or inadequate coverage will improve the accuracy and validity of data on global cancer burden.
While screening and vaccination prevent cervical cancer, early clinical diagnosis and
prompt multidisciplinary treatment involving surgery, radiotherapy, and chemotherapy are
important in reducing mortality from all gynecological cancers. Survival rates suggest that
early gynecological cancers have an excellent prognosis even in low- and medium-resource
settings. The health services infrastructure for screening, vaccine delivery, early diagnosis, and
treatment of cancers is poorly developed in many developing countries, and particularly in
sub-Saharan Africa. Trained human resources in cancer diagnosis and management are
distinctly inadequate in many regions. Day-to-day translation of cancer control plans require
adequate health care infrastructure as well as adequate trained human and financial resources.
Advocacy and political will to invest in the development of human resources and health care
infrastructure hold the key for effective gynecological cancer control and reducing the burden
of disease in several regions of the world. A National Cancer Control Programme (NCCP), as
advocated by the WHO, provides a suitable and realistic framework to improve cancer
preventive and management services in general (World Health Organization, 2002).
Summary Points
Gynecological cancers account for 1 out of every 5 women with cancer in the world.
Cervical cancer still accounts for 1 out of 2 women with gynecological cancer.
While HPV vaccination holds a great promise for cervical cancer prevention in future,
current advances in screening such as HPV testing and visual screening can dramatically
reduce cervical cancer burden.
Future increases in uterine corpus cancer are likely, particularly in low- and medium
resourced countries, in view of increase in risk factors such as obesity.
Early detection and prompt treatment is currently important for ovarian cancer control.
Malignant neoplasm in other gynecological sites such as vagina, vulva, and placenta are
uncommon and account for less than 5% of gynecological cancers.
Establishing population-based cancer registries in countries/regions with no or inadequate
coverage will improve the accuracy and validity of data on global cancer burden.
Estimating population-based cancer survival data will help to evaluate and improve the
efficiency of cancer health services in medically underserved countries/regions.
References
Agosti JM, Goldie SJ. (2007). N Engl J Med. 356: Chichareon S, Smith JS, Herrero R, Moreno V,
1908–1910. Franceschi S. (2002). N Engl J Med. 346: 1105–1112.
Alliance for Cervical Cancer Prevention (ACCP). (2004). Chia KS, Du WB, Sankaranarayanan R, Sankila R,
Planning and Implementing Cervical Cancer Pre- Seow A, Lee HP. (2001). Int J Cancer. 93: 142–147.
vention and Control Programs: A Manual for Man- Curado MP, Edwards B, Shin HR, Strom H, Ferlay J,
agers. ACCP, Seattle. Heanue M, Boyle P. (2007). Cancer Incidence in
Altieri A, Franceschi S, Ferlay J, Smith J, La VC. (2003). Five Continents, vol. 9. IARC Scientific Publications
Lancet Oncol. 4: 670–678. No. 160, IARC, Lyon.
Arbyn M, Autier P, Ferlay J. (2007). Ann Oncol. 18: Denny L, Kuhn L, De Sousa M, Pollack AE, Dupree W,
1423–1425. Wright TC Jr. (2005). JAMA. 294: 2173–2181.
Armstrong BK. (1992). Cancer Causes Control. 3: Ferlay J, Bray F, Pisani P, Parkin DM. (2004). GLOBO-
569–579. CAN 2002. Cancer Incidence, Mortality and Preva-
Badgwell D, Bast RC Jr. (2007). Dis Markers. 23: lence Worldwide. IARC Cancer Base No. 5 version
397–410. 2.0. IARC, Lyon.
Bosch FX, de Sanjose S. (2003). J Natl Cancer Inst Franco EL. (2003). J Natl Cancer Inst Monogr. 31: 89–96.
Monogr. 31: 3–13. Franco EL, Ferenczy A. (2007). Future Oncol. 3: 319–327.
Bray F, Dos Santos Silva I, Moller H, Weiderpass E. Gondos A, Brenner H, Wabinga H, Parkin DM. (2005).
(2005). Cancer Epidemiol Biomarkers Prev. 14: Br J Cancer. 92: 1808–1812.
1132–1142. Gondos A, Chokunonga E, Brenner H, Parkin DM, San-
Castellsague X, Bosch FX, Munoz N, Meijer CJ, Shah KV, kila R, Borok MZ, Chirenje ZM, Nyakabau AM,
de Sanjose S, Eluf-Neto J, Ngelangel CA, Bassett MT. (2004). Int J Cancer. 112: 860–864.
Gustafsson L, Ponten J, Bergstrom R, Adami HO. (1997). Cancer Survival Among Adults: U.S. SEER Program,
Int J Cancer. 71: 159–165. 1988–2001, Patient and Tumor Characteristics. NIH
Harper DM, Franco EL, Wheeler CM, Moscicki AB, Pub. No. 07–6215. NIH, Bethesda.
Romanowski B, Roteli-Martins CM, Jenkins D, Sankaranarayanan R, Esmy PO, Rajkumar R, Muwonge R,
Schuind A, Costa Clemens SA, Dubin G. (2006). Swaminathan R, Shanthakumari S, Fayette JM,
Lancet. 367: 1247–1255. Cherian J. (2007). Lancet. 370: 398–406.
Herzog TJ, Monk BJ. (2007). Am J Obstet Gynecol. 197: Sankaranarayanan R, Nene BM, Dinshaw KA, Mahe C,
566–571. Jayant K, Shastri SS, Malvi SG, Chinoy R, Kelkar R,
IARC. (2004). IARC Handbooks on Cancer Prevention, Budukh AM, Keskar V, Rajeshwarker R, Muwonge R,
vol. 10: Cervix Cancer Screening. IARC, Lyon. Kane S, Parkin DM, Chauhan MK, Desai S,
IARC. (2007). IARC Monographs on the Evaluation of Fontaniere B, Frappart L, Kothari A, Lucas E,
Carcinogenic Risks to Humans. vol. 90: Human Panse N. (2005). Int J Cancer. 116: 617–623.
Papillomaviruises. IARC, Lyon. Sankaranarayanan R, Budukh AM, Rajkumar R. (2001).
Judson PL, Habermann EB, Baxter NN, Durham SB, Bull World Health Organ. 79: 954–962.
Virnig BA. (2006). Obstet Gynecol. 107: 1018–1022. Sankaranarayanan R, Black RJ, Parkin DM. (1998).
Koliopoulos G, Arbyn M, Martin-Hirsch P, Kyrgiou M, Cancer Survival in Developing Countries. IARC
Prendiville W, Paraskevaidis E. (2007). Gynecol Scientific Publications No 15. IARC, Lyon.
Oncol. 104: 232–246. Sankaranarayanan R, Swaminathan R, Black RJ. (1996).
Koutsky LA, Harper DM. (2006). Vaccine. 24: Cancer. 78: 2461–2464.
S114–S121. Smith HO, Qualls CR, Prairie BA, Padilla LA, Rayburn
Loukovaara M, Pukkala E, Lehtovirta P, Leminen A. WF, Key CR. (2003). Obstet Gynecol. 102: 978–987.
(2004). Gynecol Oncol. 92: 252–255. Smith HO, Tiffany MF, Qualls CR, Key CR. (2000).
Luo W, Morrison H, de Groh M, Waters C, Gynecol Oncol. 78: 97–105.
DesMeules M, Jones-McLean E, Ugnat AM, Somoye G, Olaitan A, Mocroft A, Jacobs I. (2005).
Desjardins S, Lim M, Mao Y. (2007). Chronic Dis J Obstet Gynaecol. 25: 35–38.
Can. 27: 135–144. The EUROCARE Working Group. (2003). Ann Oncol.
Marugame T, Hirabayashi Y. (2007). Jpn J Clin Oncol. 37: 14: v61–118.
802–803. The Future II Study. (2007). N Engl J Med. 356:
Munoz N, Bosch FX, de Sanjose S, Herrero R, 1915–1927.
Castellsague X, Shah KV, Snijders PJ, Meijer CJ. United Nations. (2006). Population Division (http://
(2003). N Engl J Med. 348: 518–527. www.un.org/). World Population Prospects (The
Nandakumar A, Gupta PC, Gangadharan P, Visweswara 2006 revision).
RN, Parkin DM. (2005). Int J Cancer. 116: 740–754. Vizcaino AP, Moreno V, Bosch FX, Munoz N,
Parkin DM, Bray F, Ferlay J, Pisani P. (2005). CA Cancer J Barros-Dios XM, Parkin DM. (1998). Int J Cancer.
Clin. 55: 74–108. 75: 536–545.
Parkin DM, Bray FI, Devesa SS. (2001). Eur J Cancer. 37: World Health Organization. (2002). National Cancer
S4–S66. Control Programmes: Policies and Managerial
Pisani P, Bray F, Parkin DM. (2002). Int J Cancer. 97: Guidelines, 2nd ed. WHO, Geneva.
72–81.
Ries LAG, Young JL, Keel GE, Eisner MP, Lin YD,
Horner MJ. (2007). SEER Survival Monograph:
47 Years of Life Lost from Lung,
Stomach, Liver and Cervical
Cancers: An Evaluation of the
Top Cancer Killers
B. Y. Goldstein . F. I. Bray . D. M. Parkin . J. W. Sellors . Z. F. Zhang
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 826
2 What Are ‘‘Years of Life Lost?’’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827
3 Data Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827
4 Years of Life Lost Calculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 828
5 Years of Life Lost Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 828

5.1 Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
5.2 Stomach Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833
5.3 Liver Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834
5.4 Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
6 Controversy Surrounding Years of Life Lost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
7 Additional Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840

826 47 Years of Life Lost from Lung, Stomach, Liver, and Cervical Cancers
Abstract: Based on > GLOBOCAN 2002 data, lung, stomach, and liver cancers are the top
three cancer killers in both sexes worldwide; cervical cancer is the third most common cause of
deaths from cancer among women globally and the top cancer killer among women in
developing countries. In this evaluation the burden of lung, stomach, liver, and cervical
cancers are assessed using the > years of life lost (YLL) measure, which accounts for both
the number of deaths and the age at which death occurs. World mortality data for lung,
stomach, liver, and cervical cancers was obtained from GLOBOCAN 2002 by region and sex.
Poisson regression models were used to interpolate mortality rates by five-year age categories
from the broader GLOBOCAN categories. YLLs were calculated using a model with non-
uniform age weights and a > discount rate of 3%.
Each year, lung, stomach, liver, and cervical cancers are responsible for a loss of 29.5 million
(weighted and discounted) years of life (11 million from lung cancer, 7 million from stomach
cancer, 7.5 million from liver cancer, and 4 million from cervical cancer). The age-standar-
dized YLL rate for lung cancer in developed countries is over 1.5 times greater than in
developing countries (261 vs. 154 YLL per 100,000 persons per year), while the annual YLL
rates in developing countries is greater than developed countries for stomach (129 vs. 94 YLL
per 100,000), liver (153 vs. 47 per 100,000), and cervical (162 vs. 55 YLL per 100,000 females)
cancers. Given the existence of proven prevention strategies for lung, liver, and cervical
cancers, the potential for ‘‘saving’’ years of life is great. Furthermore, prevention is effective
and feasible in developing parts of the world, areas where interventions will have the largest
impact.
List of Abbreviations: AIDS, Acquired Immune Deficiency Syndrome; EURO, European
Region from the Global Burden of Disease study; GBD, Global Burden of Disease study;
HBV, Hepatitis B Virus; HPV, Human Papillomavirus; LEEP, > Loop Electrosurgical Excision
Procedure; SEARO, South Eastern Asian Region from the Global Burden of Disease study;
SSA, Sub-Saharan Africa; US, United States; WHO, World Health Organization; WPRO,
Western Pacific Region from the Global Burden of Disease study; YLL, Years of Life Lost
1 Introduction
Based on estimates from 2002, the top three causes of death from cancer – lung, stomach, and
liver cancers – are responsible for over one-third of all deaths from cancer. Annually, lung
cancer is the cause of 1.18 million deaths and is also estimated to be the most frequently
diagnosed cancer site globally (1.35 million new cases). Nearly 700,000 deaths result from
stomach cancer each year, and it is the fourth most common new cancer in the world (933,000
new cases). Although liver cancer is the sixth most common new cancer (626,000 new cases), it
is the third leading cause of death from cancer with an estimated 600,000 deaths annually.
Respectively 50%, 70%, and 82% of deaths from lung, stomach, and liver cancer occur in less
developed regions, where 81% (over 5 billion people) of the global population of 6.2 billion
live (based on 2002 data) (Ferlay et al., 2004; United Nations Population Division, 2004).
Among women, cervical cancer is estimated to be the second most common new cancer
(493,100 new cases) worldwide and the third most common cause of death from cancer
(273,500 deaths) in the year 2002. Cervical cancer is especially important in less developed
regions of the world, where 85% of the world’s cases occur; among women in these areas,
cervical cancer is the leading cause of death from cancer, constituting 15% of all neoplasms
Years of Life Lost from Lung, Stomach, Liver, and Cervical Cancers 47 827
(Ferlay et al., 2004). Based on 2000 estimates, cervical cancer was previously shown to be not
only the largest contributor of years of life lost (YLL) from cancer among women aged 25–65
years in parts of the developing world (including Sub-Saharan Africa and South Central Asia)
but also an equal if not larger contributor to YLL than other major causes of mortality,
including acquired immune deficiency syndrome (AIDS), tuberculosis, and maternal condi-
tions, in Latin American Countries (Yang et al., 2004). Because of the large burden associated
with cervical cancer in developing countries, cervical cancer is included in this evaluation.
2 What Are ‘‘Years of Life Lost?’’
The years of life lost (YLL) concept was introduced 60 years ago to assess disease burden using
an indicator that went beyond the simple count of deaths to account for the age at which those
deaths occurred (Dempsey, 1947). The present methods for calculating YLLs may include
some form of an > age-weighting function and discount rate. Uniform age-weights give the
same weight to all ages, while non-uniform age-weights give varying weights to different ages,
usually giving more weight to those ages of highest contribution to family, society, or
economic productivity. When a discount rate is applied, decreasing value is given to years of
life saved in the future relative to current life-years.
In addition to these two factors, the lifespan against which to compare premature death
has a large influence on the YLL estimates. The lifespan to which a premature death is
compared may have a fixed upper limit or be based on a life table expectation of life, where
the life expectancy varies with the number of years lived. The use of life tables is commonplace
since deaths beyond the upper age limit in the fixed upper limit calculation would be given no
weight (Haenszel, 1950; Kohn, 1951; Murray, 1994). In this evaluation we estimate the annual
years of life lost as a measure of lung, stomach, liver, and cervical cancer burden in the world.
3 Data Sources
Cancer-specific annual mortality data by region and sex was obtained from GLOBOCAN 2002
(Ferlay et al., 2004). For estimation of YLLs, rates by 5-year intervals are needed. Because data
from GLOBOCAN 2002 is given in five broad age-categories of 0–14, 15–44, 45–54, 55–64,
and 65+ years, we interpolated the midpoints of the five age categories using a simple log-
linear Poisson regression model. The final selected model was the most parsimonious of
models including age as a linear predictor only and those allowing a degree of curvature
(polynomials of age up to order 3). Models were selected based on 2002 mortality data for
selected countries from the World Health Organization (WHO) Mortality Database (World
Health Organization, 2007), which is given in 5-year age categories. Data from the WHO
Database were collapsed into the GLOBOCAN categories in order to simulate the interpola-
tion process that would be done on the GLOBOCAN data. The interpolated WHO mortality
data (in 5-year age categories and weighted to the number of deaths for each broad category)
from the various models were compared to the original WHO data (also in 5-year age
categories). The model for interpolating the GLOBOCAN data for each cancer was that
which fit best for the WHO data. For lung, stomach, and liver cancers, the age model
providing a linear interpolation gave the best fit, while a model including an age polynomial
of order 2 provided the most reasonable fit for cervical cancer.
The world population was divided into 14 regions that are similar to the geographic
regions defined by the United Nations for statistical purposes (United Nations Statistics
Division, 2007). ‘‘Developing’’ countries (used synonymously with ‘‘less developed’’
countries) include countries within the regions of Sub-Saharan Africa, Latin America/
Caribbean, Eastern Asia (excluding Japan), South Eastern Asia, South Central Asia, Middle
East/North Africa, and the Pacific Islands (including Melanesia, Micronesia, and Polynesia).
‘‘Developed’’ countries (or ‘‘more developed’’ countries) include Japan, Australia/New
Zealand, and countries within the regions of North America and Europe. Given its popula-
tion size and subsequent influence on results, China was separated from the other developing
Eastern Asian countries.
4 Years of Life Lost Calculation
Years of life lost from a single death were calculated according to the following formula:
KCera h ðrþbÞðLþaÞ ðrþbÞa
i
YLL ¼ e ½ ðr þ bÞðL þ a Þ 1 e ½ ðr þ bÞa 1
ðr þ bÞ2
1 K
þ 1 erL ;
r
where a is the age at death, L is the standard life expectancy at age a, r is the discount rate, and
K, b, and C are associated with the age-weighting function (Murray, 1994). K is the age-
weighting modulation factor, whereby ages could be given uniform or non-uniform weights
by giving K a value of 0 or 1, respectively; b controls the age at which the maximum value
occurs, and C is a constant that helps determine the value of the maximum point. Midpoints
of the 5-year age categories were used for the age at death; for the 65+ age category, the average
age of the general population for this age group was used. The standard life expectancy was
obtained from the Coale and Demeny West Life 26 life table (Coale and Guo, 1989), which has
a life expectancy at birth of 82.5 years for females and 80 years for males. A discount rate of
0.03 was used in the calculations, as recommended by the Global Burden of Disease (GBD)
study (Murray, 1994; Mathers et al., 2006). Also consistent with the GBD, a b of 0.04 and C of
0.1658, which give an approximate maximum relative-weight of 1.52 at 25 years of age, were
used. The YLL due to a single death at each age for females and males using the above values
are shown in > Figure 47-1.
Information on years of life lost is presented as absolute numbers of YLLs (in thousands)
and annual rates per 100,000 persons. In order to allow for comparisons between regions with
very different age distributions, age-standardized rates [using age weights of the world
standard population (Doll and Cook, 1967)] were calculated in addition to crude rates.
Rates given in the text are annual age-standardized rates unless specified otherwise.
5 Years of Life Lost Burden
Based on 2002 worldwide data, a combined 2.7 million annual deaths are due to
lung (1.2 million), stomach (697,000), liver (596,000), and cervical cancer (273,000)
(> Table 47-1). Lung cancer deaths are evenly distributed between developed and developing
. Figure 47-1
Years of life lost due to a death at each age by sex. This figure shows the weighted and
discounted years of life lost due to a single death between birth and 80 years of age for females
and males
countries, whereas 70%, 82%, and 86% of deaths from stomach, liver, and cervical cancer,
respectively, occur in developing parts of the world. Furthermore, deaths from these
cancers generally occur at earlier ages in developing countries compared to developed
countries (> Figure 47-2). The 2.7 million deaths from these four cancers result in a loss of
29.5 million (weighted and discounted) years of life (11 million from lung cancer, 7 million
from stomach cancer, 7.5 million from liver cancer, and 4 million from cervical cancer)
each year (> Table 47-2).
The annual total years of life lost in developed and developing countries for each of the
cancers is shown in > Figure 47-3. As expected, most years of life lost for these cancers are in
developing countries, especially for liver, stomach, and cervical cancer. Furthermore, the
proportional disease burden of developing countries increases when measured with years of
life lost rather than mortality; developing countries account for 57%, 75%, 88%, and 89% of
the world’s YLLs from lung, stomach, liver, and cervical cancers, respectively. Although, lung
cancer burden is distributed quite evenly between developed and developing populations, the
annual YLL rate for lung cancer in developed countries is over 1.5 times greater than in
developing countries (> Figure 47-4). The annual YLL rates for liver, stomach, and cervical
cancer, on the other hand, are higher in developing countries than developed countries,
roughly three times greater for cervical and liver cancers.
5.1 Lung Cancer
Worldwide, 7.8 million years of life are lost among males due to lung cancer per year,
and 3.2 million years of life are lost among females (> Table 47-2). Regions with the
largest contribution to years of life lost from lung cancer include China (32% of all areas),
North America (12%), Eastern Europe (11%), and North/Western Europe (10%). A large
contribution from China is not unexpected given the relative magnitude of its population;
. Table 47-1
Number of deaths (in thousands) and percentage of all areas of the world by cancer and sex, in
the year 2002
Cervical
Lung cancer Stomach cancer Liver Cancer cancer
Region Male Female Male Female Male Female Female
Sub-Saharan 7.7 3.2 10.6 10.1 32.9 15.2 55.1
Africa (0.9%) (1.0%) (2.4%) (4.0%) (7.9%) (8.4%) (20.2%)
Latin American 40.1 17.3 31.4 20.6 12.3 12.0 32.6
Countries (4.7%) (5.2%) (7.1%) (8.1%) (3.0%) (6.6%) (11.9%)
North America 105.7 72.6 9.1 6.2 9.2 5.3 5.8
(12.5%) (22.0%) (2.0%) (2.4%) (2.2%) (2.9%) (2.1%)
Eastern Asia 231.3 109.1 206.6 101.7 232.8 89.1 25.6
(China) (27.3%) (33.1%) (46.5%) (40.2%) (56.1%) (49.3%) (9.4%)
Eastern Asia 41.1 15.3 35.3 19.1 25.2 11.1 3.6
(Japan) (4.9%) (4.6%) (8.0%) (7.5%) (6.1%) (6.2%) (1.3%)
Eastern Asia 13.8 4.4 12.3 6.4 13.0 3.9 2.0
(Other) (1.6%) (1.3%) (2.8%) (2.5%) (3.1%) (2.1%) (0.7%)
South Eastern 46.1 17.5 13.6 8.3 33.5 11.6 22.6
Asia (5.5%) (5.3%) (3.1%) (3.3%) (8.1%) (6.4%) (8.3%)
South Central 56.9 12.0 31.7 17.1 13.9 8.0 86.7
Asia (6.7%) (3.6%) (7.1%) (6.7%) (3.3%) (4.4%) (31.7%)
Middle East/ 26.6 4.9 9.0 5.5 5.2 2.9 8.7
North Africa (3.1%) (1.5%) (2.0%) (2.2%) (1.3%) (1.6%) (3.2%)
Eastern Europe 109.0 22.1 46.2 31.6 10.7 7.8 17.2
(12.9%) (6.7%) (10.4%) (12.5%) (2.6%) (4.3%) (6.3%)
Southern Europe 59.5 11.3 16.0 10.6 12.5 7.0 4.1
(7.0%) (3.4%) (3.6%) (4.2%) (3.0%) (3.9%) (1.5%)
North/Western 102.3 37.4 21.1 15.5 12.9 6.5 8.5
Europe (12.1%) (11.3%) (4.7%) (6.1%) (3.1%) (3.6%) (3.1%)
Australia/New 5.8 2.8 1.0 0.6 0.6 0.3 0.3
Zealand (0.7%) (0.9%) (0.2%) (0.2%) (0.1%) (0.2%) (0.1%)
Pacific 0.2 0.1 0.2 0.1 0.4 0.2 0.5
Islands (0.0%) (0.0%) (0.0%) (0.0%) (0.1%) (0.1%) (0.2%)
Developed 423.5 161.5 128.7 83.5 71.2 38.1 39.5
Countries (50.0%) (48.9%) (29.0%) (33.0%) (17.1%) (21.1%) (14.5%)
Developing 422.9 168.5 315.2 169.8 344.0 142.7 233.7
Countries (50.0%) (51.1%) (71.0%) (67.0%) (82.9%) (78.9%) (85.5%)
All Areas 846.4 329.9 444.0 253.3 415.1 180.8 273.2
(100.0%) (100.0%) (100.0%) (100.0%) (100.0%) (100.0%) (100.0%)
This table gives the number of deaths (in thousands) by world region, development, and sex for lung, stomach, liver,
and cervical cancers. The percentages reflect the percentage of deaths from all areas of the world by sex and cancer
however, looking at China’s proportionate contribution to the world population (20.8%)

relative to those of mortality (28.9%) and YLL (31.9%), shows that its disease burden is still
large in relative terms (> Figure 47-5). The proportional lung cancer burden of North America
and all parts of Europe are also relatively sizable. While the relative proportion of YLL is less
. Figure 47-2
Age distribution of deaths in developing and developed countries by cancer, in 2002. This figure
shows the different age distribution of deaths from lung, stomach, liver, and cervical cancers for
developed countries and developing countries
than that of mortality for North America and North/Western Europe, the relative proportion
of YLL for China is greater than mortality, indicating that younger people are dying of lung
cancer in China compared to the other regions.
The areas with the highest annual rates for years of life lost among males include all parts
of Europe (592, 439, and 378 YLL per 100,000 males in Eastern, Southern, and North/Western
Europe, respectively) North America (391 per 100,000), China (353 per 100,000), and Eastern
. Table 47-2
Total years of life lost (in thousands) and percentage of all areas of the world by cancer and sex,
in 2002
Cervical
Lung cancer Stomach cancer Liver Cancer cancer
Region Male Female Male Female Male Female Female
Sub-Saharan 104.5 44.4 155.0 152.6 563.7 272.3 934.2
Africa (1.3%) (1.4%) (3.5%) (5.9%) (10.5%) (12.7%) (23.3%)
Latin American 372.3 176.7 303.7 209.4 125.1 121.7 483.0
Countries (4.8%) (5.6%) (6.9%) (8.1%) (2.3%) (5.7%) (12.0%)
North America 804.1 570.7 74.9 48.9 85.5 41.8 58.0
(10.3%) (18.0%) (1.7%) (1.9%) (1.6%) (1.9%) (1.4%)
Eastern Asia 2344.1 1163.3 2146.1 1086.3 3221.8 1126.2 349.5
(China) (30.0%) (36.6%) (48.6%) (42.1%) (60.1%) (52.3%) (8.7%)
Eastern Asia 279.1 109.9 262.8 149.5 199.8 73.7 36.0
(Japan) (3.6%) (3.5%) (5.9%) (5.8%) (3.7%) (3.4%) (0.9%)
Eastern Asia 120.8 40.9 122.9 69.1 160.4 41.2 24.8
(Other) (1.5%) (1.3%) (2.8%) (2.7%) (3.0%) (1.9%) (0.6%)
South Eastern 494.5 213.8 147.9 106.6 455.6 150.0 356.7
Asia (6.3%) (6.7%) (3.3%) (4.1%) (8.5%) (7.0%) (8.9%)
South Central 625.0 151.4 367.4 216.3 177.0 116.9 1269.8
Asia (8.0%) (4.8%) (8.3%) (8.4%) (3.3%) (5.4%) (31.7%)
Middle East/ 290.4 59.7 102.2 68.6 60.8 38.0 136.7
North Africa (3.7%) (1.9%) (2.3%) (2.7%) (1.1%) (1.8%) (3.4%)
Eastern Europe 1055.9 207.3 449.0 281.8 103.3 68.6 220.2
(13.5%) (6.5%) (10.2%) (10.9%) (1.9%) (3.2%) (5.5%)
Southern 476.0 96.3 123.0 77.5 93.3 48.2 47.5
Europe (6.1%) (3.0%) (2.8%) (3.0%) (1.7%) (2.2%) (1.2%)
North/Western 799.3 302.0 156.9 107.5 99.9 45.7 91.3
Europe (10.2%) (9.5%) (3.6%) (4.2%) (1.9%) (2.1%) (2.3%)
Australia/New 42.0 22.5 7.8 4.6 4.8 2.3 3.9
Zealand (0.5%) (0.7%) (0.2%) (0.2%) (0.1%) (0.1%) (0.1%)
Pacific 2.6 0.9 1.8 1.4 6.5 3.4 9.0
Islands (0.0%) (0.0%) (0.0%) (0.1%) (0.1%) (0.2%) (0.2%)
Developed 3457.2 1319.8 1066.2 663.6 585.7 279.5 455.2
Countries (44.2%) (41.5%) (24.1%) (25.7%) (10.9%) (13.0%) (11.4%)
Developing 4363.8 1858.5 3354.0 1917.2 4778.0 1872.1 3555.5
Countries (55.8%) (58.5%) (75.9%) (74.3%) (89.1%) (87.0%) (88.6%)
All Areas 7821.0 3178.3 4420.2 2580.8 5363.7 2151.6 4010.7
(100.0%) (100.0%) (100.0%) (100.0%) (100.0%) (100.0%) (100.0%)
This table gives the total years of life lost (in thousands) by world region, development, and sex for lung, stomach,
liver, and cervical cancers. The percentages reflect the percentage of years of life lost from all areas of the world by
sex and cancer
Asia (Other) (353 per 100,000) (> Table 47-3). Areas with the highest annual YLL rates among
females are North America (240 per 100,000 females), China (174 per 100,000), Australia/New
Zealand (132 per 100,000), and North/Western Europe (127 per 100,000).
. Figure 47-3
Cancer-specific total years of life lost (in thousands) in developed and developing countries, in
2002. This figure contrasts the total years of life lost (in thousands) from lung, liver, stomach, and
cervical cancers between developed countries and developing countries
. Figure 47-4
Age-standardized years of life lost rates (per 100,000 per year) for developed and developing
countries, in 2002. This figure contrasts the age-standardized rates of years of life lost
(per 100,000 persons per year) from lung, liver, stomach, and cervical cancers between
developed countries and developing countries. Rates are for males and females combined
except for cervical cancer, which are for females only
5.2 Stomach Cancer
Stomach cancer is responsible for the loss of 4.4 million and 2.6 million years of life among
males and females, respectively (> Table 47-2). The largest contributor to years of life lost from
. Figure 47-5
Population, death, and years of lost life distribution for lung cancer by sex and region, in 2002.
This figure compares the relative contribution of the different world regions to the world’s total
population, deaths, and years of life lost from lung cancer for males and females
stomach cancer is by far China, accounting for 46% of the world’s YLL from stomach cancer.
Taking into account the relative proportion of China’s population, the country carries a
disproportionate burden of stomach cancer in terms of both mortality and YLL
(> Figure 47-6). Other areas that have disproportionately high levels of burden are Japan,
Eastern Europe, and Eastern Asia (Other).
Although China is by far the largest contributor to the world’s YLL from stomach cancer,
the annual YLL rates for China (324 YLL per 100,000 males and 161 YLL per 100,000 females)
are slightly lower than those for Eastern Asia (Other) (343 per 100,000 males and 164 per
100,000 females) (> Table 47-3). Also, although Japan’s age-standardized annual YLL rate
is lower than China’s, Japan’s crude annual YLL rate is roughly 30% higher than China’s,
a difference which is mostly attributable to Japan’s ‘‘top heavier’’ (older) demographic
distribution.
5.3 Liver Cancer
Liver cancer is the cause of 5.4 million years of life lost among males and 2.2 million years of
life lost among females each year in the world (> Table 47-2). Although liver cancer is behind
stomach cancer in terms of number of annual deaths, it is a greater source of years of life lost
than stomach cancer because those dying from liver cancer are typically dying at an earlier age
relative to those dying from stomach cancer (> Figure 47-2). The largest contributor to YLL
from liver cancer is by far China (58% of all areas), though the contribution from Sub-Saharan
Africa is also high relative to the other regions (11%). As in the case of stomach cancer, China’s
large contribution to YLL from liver cancer is not fully attributable to its large population; the
country holds a severely disproportionate mortality and YLL burden of liver cancer even in
light of its population size (> Figure 47-7).
. Table 47-3
Crude and age-standardized years of life lost rates (per 100,000 per year) by cancer and sex, in 2002
Lung cancer Stomach cancer Liver cancer Cervical cancer

Male Female Male Female Male Female Female
Crude Std. Crude Std. Crude Std. Crude Std. Crude Std. Crude Std. Crude Std.
Region Rate Rate Rate Rate Rate Rate Rate Rate Rate Rate Rate Rate Rate Rate
Sub-Saharan Africa 32 59 14 23 48 80 47 74 174 264 83 117 286 442
Latin American 1409 186 66 75 115 147 78 87 47 59 45 51 179 192
Countries
North America 510 391 353 240 48 37 30 20 54 43 26 18 36 27
Eastern Asia (China) 354 353 185 174 324 324 173 161 486 458 180 166 56 50
Eastern Asia (Japan) 449 239 169 84 422 237 230 125 321 184 113 51 55 37
Eastern Asia (Other) 332 353 113 97 338 343 192 164 442 427 115 101 69 60
South Eastern Asia 184 252 80 96 55 73 40 46 170 210 56 67 133 152
South Central Asia 79 109 20 25 47 62 29 36 22 29 16 19 171 212
Middle East/North 152 224 32 42 53 75 37 47 32 45 20 26 74 92
Africa
Eastern Europe 745 592 131 86 317 250 178 113 73 58 43 28 139 105
Southern Europe 673 439 130 80 174 111 105 56 132 83 65 33 64 46
North/Western 585 378 213 127 115 73 76 40 73 47 32 18 64 46
Europe
Years of Life Lost from Lung, Stomach, Liver, and Cervical Cancers
Australia/New 363 265 192 132 67 50 39 26 41 31 20 13 34 26

Zealand
Pacific Islands 62 109 24 39 43 71 38 57 157 200 89 114 236 308
Developed 595 417 215 132 184 129 108 66 101 71 46 26 74 55
Countries
47
835
836
47
Lung cancer Stomach cancer Liver cancer Cervical cancer

Male Female Male Female Male Female Female
Crude Std. Crude Std. Crude Std. Crude Std. Crude Std. Crude Std. Crude Std.
Region Rate Rate Rate Rate Rate Rate Rate Rate Rate Rate Rate Rate Rate Rate
Developing 172 222 75 89 132 169 78 91 188 220 76 86 144 162
Countries
All Areas 250 283 103 103 141 158 84 83 172 183 70 70 130 132
This table gives the crude and age-standardized rates (labeled Std. Rate) of years of life lost per 100,000 persons per year by world region, development, and sex for lung, stomach,
liver, and cervical cancers
Years of Life Lost from Lung, Stomach, Liver, and Cervical Cancers
. Figure 47-6
Population, death, and years of life lost distribution for stomach cancer by sex and region, in
2002. This figure compares the relative contribution of the different world regions to the world’s
total population, deaths, and years of life lost from stomach cancer for males and females
. Figure 47-7
Population, death, and years of life lost distribution for liver cancer by sex and region, in 2002.
This figure compares the relative contribution of the different world regions to the world’s total
population, deaths, and years of life lost from liver cancer for males and females
China’s large burden of liver cancer is also reflected in the annual YLL rate, where it has the
highest rates (458 YLL per 100,000 males and 166 YLL per 100,000 females) (> Table 47-3).
Annual YLL rates for Eastern Asia (Other) are also as high as China’s among males. Other
areas with high annual YLL rates among males, though not as high as China, are Sub-Saharan
Africa, South Eastern Asia, the Pacific Islands, and Japan, with YLL rates around 200 per
100,000 males. These areas additionally have high age-standardized rates among females,
although Japan has a relatively lower rate, most likely attributed to its differing age structure
(comprised of a relatively older population).
5.4 Cervical Cancer
Over four million years of life are lost due to cervical cancer each year (> Table 47-2). The areas
that account for the most years of life lost from cervical cancer are South Central Asia (32% of
all areas), Sub-Saharan Africa (SSA) (23%), and Latin American Countries (12%). Further-
more, these areas have notably higher proportions of deaths and YLLs relative to their
population proportions (> Figure 47-8). Of these regions, SSA further has a higher proportion
of YLL relative to deaths, suggesting that not only does SSA have a higher risk of dying from
cervical cancer but also that younger populations are dying from cervical cancer in this region
relative to other parts of the world.
As expected, the annual YLL rates for Sub-Saharan Africa are highest (442 YLL per 100,000
females) (> Table 47-3). The Pacific Islands, however, also has a very high annual YLL rate
(308 per 100,000); due to its relatively smaller population, its contribution to the burden of
cervical cancer was previously overshadowed by other regions. Other areas with relatively high
annual YLL rates include South Central Asia (212 per 100,000), Latin American Countries
(192 per 100,000), and South Eastern Asia (152 per 100,000).
. Figure 47-8
Population, death, and years of life lost distribution for cervical cancer by region, in 2002. This
figure compares the relative contribution of the different world regions to the world’s total
female population, deaths, and years of life lost from cervical cancer
6 Controversy Surrounding Years of Life Lost
Although calculations for years of life lost seem straightforward, it has had its fair share of
controversy. The dominant issues under discussion include the use of the same standard life
table for all populations of the world, the age weights, and the discount rate. For these YLL
estimations, a single life table by sex [Coale and Demeny West Level 26 (Coale and Guo, 1989)]
was used. The argument against the use of a standardized life table is that it assumes that
prevention of diseases alone would increase life expectancies to the same level; calculations,
therefore, using a standardized life table would measure not only the burden of disease but also
the burden of underdevelopment (Anand and Hanson, 1997). Use of the same life table rather
than country- or region-specific life tables, on the other hand, prevents the placement of
different values on lives from different countries; the use of country-specific life tables would
result in giving the death of a 40-year old woman from the United States (US) more value than
the death of a woman of the same age from Zimbabwe, for example, since the life expectancy is
higher in the US (Murray, 1994). Although the arguments against the use of a standardized life
table are valid, we feel that equalizing the value of lives across development and socio-
economic levels is a more compelling reason for the use of a standardized life table.
Other topics of controversy include the use of non-uniform age weights and discounting,
which were originally included to capture social and economic values. The rationale for
including non-uniform age weights is to give higher weight to those ages that possess a larger
social role and upon which a society is assumed to be more dependent. The basis for including
a discount rate, which is common practice in economics, is to reflect the preference of
current benefits over future gains of the same order of magnitude. As previously explained,
the age-weighting and discount values were those recommended in the Global Burden of
Disease study; these values are arguably somewhat arbitrary, being a compromise between
different expert groups, including economists and public health specialists (Murray, 1994),
and continues to be a topic of debate (Anand and Hanson, 1997).
Even given its controversy, the YLL measure is undoubtedly useful, especially in high-
lighting the disproportional burden from early deaths caused by various cancers between
developing and developed countries. While the population ratio between developing and
developed countries is roughly 4:1, the mortality ratios for liver and cervical cancers are
respectively 4.5:1 and 6:1, and the YLL ratios for both cancers are nearly 8:1, indicating not
only that there are proportionately more deaths occurring in developing regions but also that
these deaths are occurring at younger ages.
7 Additional Considerations
Often in the estimation of age-specific mortality rates, a variety of assumptions are made,
especially in the calculation of disease burden in less developed parts of the world. For cancer,
there is fortunately an international network of cancer registries that make estimates of
mortality more widely available and of higher quality than for many other diseases, although
the precision of the absolute numbers has some uncertainty. It should be noted, however, that
although the estimates used in GLOBOCAN 2002 are for the year 2002, there is a time lag of
generally 2–5 years for the mortality rates, as these were based on the most recently available
mortality data (Ferlay et al., 2004).
In this evaluation, we used the same life tables, age-weights, and discount rate as those
used in the Global Burden of Disease study (Murray, 1994; Mathers et al., 2006), in part to aid
comparability. Our worldwide mortality and years of life lost estimates for lung and liver
cancers are very similar to those of the 2002 GBD study (World Health Organization, 2004),
while our estimates for stomach and cervical cancers, on the other hand, do differ quite a bit
from the GBD estimates. Our results differed most from the GBD study for regions where data
was less readily available, especially Sub-Saharan Africa. It should also be noted that although
our regions are very similar to the regions in the GBD study, they do not overlap perfectly,
especially for the GBD South Eastern Asian (SEARO) and Western Pacific (WPRO) regions,
making comparisons in these regions difficult. Fortunately, for areas that do overlap and have
more complete data, like the GBD European region (EURO), our results are very similar.
Mathers et al. (Mathers et al., 2006) suggest that mortality for a single cause is often over-
estimated; since our evaluation uses models different from the GBD study, it is difficult to
determine the accuracy of our estimates relative to those in the GBD.
8 Conclusion
The 29.5 million (weighted and discounted) years of life that are lost from lung, stomach, liver,
and cervical cancers each year is an alarming amount of lost life; yet many of these years of life
have the potential of being ‘‘saved,’’ with potential savings particularly high in low-resource
settings. The following are all feasible strategies that are minimally resource intensive: (1) anti-
smoking programs that promote smoking cessation and persuade adolescents not to start
smoking in order to prevent lung cancer; (2) improved nutrition (increased fresh fruits and
vegetables consumption and decreased salty foods consumption) hypothesized to prevent
stomach cancer; (3) vaccination against the hepatitis B virus (HBV), responsible for the
majority of liver cancers in developing areas, to fight against liver cancer; and (4) screening
of precursor lesions followed by appropriate treatment [with cryotherapy or loop electrosur-
gical excision procedure (LEEP)] in order to prevent cervical cancer. Although some strategies
are more feasible and have more supportive evidence than others, each of these prevention
methods have the potential of reducing the health disparity between developed and developing
countries, whether it be to decrease lung cancer mortality in developed countries or decrease
stomach, liver, and cervical cancer mortality in developing countries. Furthermore, as addi-
tional preventive measures become more supported and widely available [e.g., vaccination
against high-risk human papillomavirus (HPV) types to eliminate cervical cancer] or are
proven (e.g., effective therapy to eliminate Helicobacter pylori infection in the prevention
against stomach cancer), preventative interventions can provide an even greater prospect
of reducing the global burden by decreasing the number of cancer deaths from these
major killers.
Summary Points
In 2002, lung, stomach, and liver cancers were the major cancer killers in both sexes;
cervical cancer was the third most common cause of death from cancer among women
worldwide and the most common cause of cancer death among women in developing
parts of the world.
The 1.2 million estimated worldwide deaths from lung cancer result in 11 million years of
life lost each year. Although half of the YLL occur in developed countries, the annual
rate of YLL in developed countries is 1.7 times greater than in developing countries
(261 vs. 154 YLL per 100,000 persons).
Areas that contribute most to the worldwide YLL from lung cancer are China (32%),
North America (12%), Eastern Europe (11%), and North/Western Europe (10%). Areas
with the highest annual YLL rates are all of the European regions, North America, China,
and other parts of Eastern Asia.
Over seven million years of life are lost based on the estimated 700,000 worldwide deaths
caused by stomach cancer each year. Seventy-five percent of the YLL occur in developing
countries, where the annual YLL rate is 129 YLL per 100,000 persons (as compared to 94
YLL per 100,000 in developed countries).
The largest contributor to YLL from stomach cancer is by far China, accounting for 46% of
the world’s YLL from stomach cancer. Additional areas with high annual YLL rates include
other parts of Eastern Asia (including Japan) and Eastern Europe.
Worldwide, approximately 600,000 deaths from liver cancer result in the loss of over
7.5 million years of life each year, 88% of which are lost in developing countries. The
annual rate of YLL in developing countries is over three times that of developed countries
(153 vs. 47 YLL per 100,000 persons).
The largest contributor to years of life lost from liver cancer is again China, accounting for
58% of the world’s YLL from the cancer. Additional areas with high annual YLL rates
include China, other parts of Eastern Asia, and Sub-Saharan Africa.
From the 273,500 estimated worldwide deaths caused by cervical cancer, over four million
years of life are lost each year, nearly 90% of which occur in developing countries. The
annual rate of YLL in developing countries is nearly three times that of developed countries
(162 vs. 55 YLL per 100,000 females).
The regions that contribute most to the world’s YLL from cervical cancer are South Central
Asia (32%) and Sub-Saharan Africa (23%). In addition to these areas, high annual YLL
rates are also found in the Pacific Islands.
Given the documented and feasible prevention strategies for these major causes of cancer
mortality, the potential for ‘‘saving’’ years of life is large, particularly in developing areas of
the world where interventions are needed most.
References
Anand S, Hanson K. (1997). J Health Econ. 16: 685–702. Global Burden of Disease and Risk Factors. The
Coale A, Guo G. (1989). Popul Index. 55: 613–643. World Bank and Oxford University Press, New
Dempsey M. (1947). Am Rev Tuberc. 56: 157–164. York, NY, pp 45–240.
Doll R, Cook P. (1967). Int J Cancer. 2: 269–279. Murray CJ. (1994). Bull World Health Organ.
Ferlay J, Parkin DM, Bray F, Pisani P. (2004). GLOBO- 72: 429–445.
CAN 2002: Cancer incidence, mortality and prevalence United Nations Population Division, Department of
worldwide, Version 1.0. IARC Press, Lyon, France. Economic and Social Affairs. (2004). World Popula-
Haenszel W. (1950). Am J Public Health. 40: 17–26. tion Prospects (The 2002 Revision). United Nations,
Kohn R. (1951). Can J Public Health. 42: 375–379. http://www.un.org/.
Mathers CD, Lopez AD, Murray CJ. (2006). In: Lopez AD, United Nations Statistics Division. (2007). Compo-
Mathers CD, Ezzati M, Jamison DT, Murray CJ (ed.) sition of macro geographical (continental) regions,
geographical sub-regions, and selected economic World Health Organization. (2007). WHO Mortality
and other groupings. United Nations, http:// Database. World Health Organization, Geneva,
unstats.un.org. Switzerland.
World Health Organization. (2004). Revised Global Yang BH, Bray FI, Parkin DM, Sellors JW, Zhang ZF.
Burden of Disease (GBD) 2002 Estimates (from (2004). Int J Cancer. 109: 418–424.
the World Health Report 2004). World Health
Organization, Geneva, Switzerland.
48 Burden of Cancer in Serbia
H. Vlajinac . S. Sipetic-Grujicic . S. Jankovic . L. Markovic-Denic .
J. Marinkovic
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
2 Overall Cancer Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844

2.1 Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
2.2 Cancer Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
2.3 Cancer Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
2.4 Disability Adjusted Life Years (DALY) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
2.5 Temporal Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848
2.6 Patterns of Cancer Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853
2.6.1 Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853
2.6.2 Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
2.6.3 Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
2.6.4 Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
2.6.5 Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860
2.6.6 Stomach Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861

844 48 Burden of Cancer in Serbia
Abstract: The morbidity and mortality of cancers have a major impact on the population of
Serbia. During 5-year period (1999–2003), the average standardized > incidence rates for all
cancers (all sites but non-melanoma skin cancer) were 241.9/100,000 for men, and 215.4/
100,000 for women. In men, the most frequent was lung cancer, followed by colorectal,
prostate, bladder and stomach cancers. In women, the incidence was highest for breast cancer,
followed by cervical, colorectal, lung and corpus uteri cancers. The average standardized
> mortality rates for the same period were 159.5/100,000 for men, and 106.4/100,000 for
women. In men the highest mortality rates were for lung cancer, followed by colorectal,
stomach and prostate cancers. In women, breast cancer was on the first place as a cause of
death followed by lung cancer, colorectal, cervical and stomach cancers. Stomach, colorectal,
lung, breast and cervical cancers were responsible for 73,197 (19.9/1,000 population) disability
adjusted life years – DALYs in men and for 60,482 (15.6/1,000) DALYs in women, on a yearly
basis. The participation of years of life lost from premature mortality (> YLL) in > DALY was
95.2% in men and 93.2% in women. The greatest part of the DALY was caused by lung cancer
in men and by breast cancer in women. During the period 1985–2002 in Serbia, there was a
significant rise in the mortality from overall cancers, and among the most frequent cancers, for
lung, breast and cervical cancers. The increase in lung cancer mortality rates was more
pronounced in women. Increasing cancer mortality trends stress the importance of imple-
menting preventive measures that have proved effective in other countries, especially
> screening for cervical cancer, the incidence of which in Serbia (25.8/100,000) was the highest
in Europe.
List of Abbreviations: DALY, disability adjusted life years; > EURO, European countries; MR:
IR, mortality rate: incidence rate (mortality to incidence rate ratio); YLL, years of life lost;
> YLD, years lived with disability
1 Introduction
Cancers occupy second place as the cause of morbidity and mortality in most developed and in
some developing countries (Shibuya et al., 2002). They are an important public health
problem in Europe, although there are variations between countries in both the level and
trend of their morbidity and mortality (Boyle and Ferlay, 2005; Levi et al., 2004d). The
morbidity and mortality of cancers have a major impact on the population of Serbia. Over
several decades malignant neoplasms have occupied second place as a cause of death, and
mortality rates for some cancers have been slowly but steadily increasing (Adanja et al., 2000;
Vlajinac et al., 2000).
The aim of this report is to provide recent data on cancer incidence, mortality and mortality
trends in Serbia, as well as data on a comprehensive assessment of premature death and disability
attributable to cancers in Serbia by calculating disability adjusted life years (DALY).
2 Overall Cancer Estimates
2.1 Population
Serbia is composed of three regions: Central Serbia, Vojvodina, and Kosovo and Metohia.
The data presented cover Central Serbia, with the exception of DALY which was estimated both
Burden of Cancer in Serbia 48 845
for Central Serbia and Vojvodina. In the following text both Central Serbia, and Central Serbia
and Vojvodina, were designated as Serbia. According to the population census in 2002, there
were about 5.5 million inhabitants in Central Serbia (2,660,988 men and 2,805,021 women).
2.2 Cancer Incidence
The Serbian population-based cancer registry was established in 1970. With a view to applying
uniform Register implementation methodology, Guidelines for cancer registration and a Book of
Regulations were adopted in the year 1986. However, for several reasons, including imprecise
Guidelines, insufficient training of medical personnel and lack of informatics support, there was
under-registration of new cancer cases, and during the period 1986–1995 the number of registered
cases with malignant tumors was almost the same as the number of cases who died from cancer.
Thanks to reorganization, which began during 1996, the quality of data provided by the Cancer
Registry in Central Serbia greatly improved and, in 1998, the Cancer Registry was admitted to the
International Agency for Research on Cancer and the European Network of Cancer Registries.
According to data from the Cancer Registry (Institute of Public Health of Serbia, 2001–2006)
during a 5-year period (1999–2003), the average number of incidence cancer cases (all sites but
non-melanoma skin cancer) per year in Serbia was 10,446 for men and 9,943 for women. Average
incidence rates, standardized according to the World population (Jensen et al., 1991), were 241.9/
100,000 for men and 215.4/100,000 for women. In men, the most frequent was lung cancer,
followed by colorectal, prostate, bladder and stomach cancer. These five cancers accounted
for 62% of all incidence cancer cases. In women, incidence was highest for breast cancer, followed
by cervical, colorectal, lung and corpus uteri cancers. These cancers were responsible for 62%
of all new cancers (> Table 48-1, > Figure 48-1).
Overall cancer incidence for men in Serbia was similar to that in Central and Eastern
Europe, and lower than in other parts of Europe (> Table 48-2). Incidence rates in Europe
varied from 206.5/100,000 in Bulgaria to 386.8/100,000 in Hungary (Ferlay et al., 2004).
Overall cancer incidence for women in Serbia was similar to that in Southern Europe
(> Table 48-2). The lowest rate in Europe was in the Russian Federation (160.6/100,000)
and the highest was in Denmark (285.5/100,000) and Iceland (284.5/100,000) (Ferlay et al.,
2004). Incidence variations between countries can be caused by differences in: a) the
prevalence of > risk factors for cancer, b) the use of screening programs for some cancers,
and c) the quality of cancer registration.
2.3 Cancer Mortality
Data on cancer mortality were derived from official death statistics.

During the same period (1999–2003), an average of 12,753 subjects per year died from
cancer (all sites but non-melanoma skin cancer) in Serbia (7,251 men, and 5,502 women).
Average mortality rates, standardized according to world population (Jensen et al., 1991) were
159.5/100,000 for men, and 106.4/100,000 for women. In men, the highest mortality rates
were for lung cancer, then colorectal, stomach and prostate cancers, and these accounted for
55% of all cancer deaths. In women, breast cancer occupied first place as a cause of death
followed by lung, colorectal, cervical and stomach cancers. These five cancers were responsible
for 52% of all cancer deaths (> Table 48-3, > Figure 48-2).
For men, overall cancer mortality in Serbia was similar to that in Northern Europe
(> Table 48-4). Mortality in Europe varied by factor >2 between the lowest rate of
. Table 48-1
Number of cancer cases, and standardized incidence rates (1/100,000), by sex, Serbia, average for
the period 1999–2003
Men Women
Number Standardized Number Standardized
Cancer site of cases incidence ratea of cases incidence ratea
Mouth and pharynx (C00-C10) 332 7.90 167 3.96
Oesophagus (C15) 134 3.04 38 0.74
Stomach (C16) 637 14.00 344 6.24
Colon and rectum (C18-C21) 1,439 33.42 990 18.40
Liver (C22) 269 5.88 200 3.64
Pancreas (C25) 288 6.36 215 3.82
Larynx (C32) 528 12.40 57 1.20
Lung (C33-C34) 2,730 62.08 800 15.98
Melanoma (C43) 168 4.22 171 3.84
Breast (C50) 2,739 60.62
Cervix uteri (C53) 1,032 25.82
Corpus uteri (C54) 592 12.36
Ovary (C56) 456 10.24
Prostate (C61) 886 17.20
Testis (C62) 137 4.92
Kidney (C64) 238 5.64 152 3.10
Bladder (C67) 739 15.88 249 4.40
Brain (C71) 346 9.70 248 6.68
Hodgkin (C81) 103 3.28 85 2.38
Non-Hodgkin (C82-C85, C96) 232 5.34 170 4.04
Leukaemias (C91-C95) 261 8.54 188 4.80
All sites but non-melanoma skin 10,446 241.9 9,943 215.4
(C00-C96, but C44)
a
Incidence rate standardized according to world population (Jensen et al., 1991)
130.3/100,000 in Finland and the highest rate of 271.4/100,000 in Hungary (Ferlay

et al., 2004). For women, the mortality rate in Serbia resembled that of Western Europe
(> Table 48-4), and the range of variation between countries was smaller, from 81.8/100,000
and 81.9/100,000 in Spain and Greece respectively, to 148.1/100,000 in Denmark (Farlay et al.,
2004). Variations in incidence, early diagnosis and treatment procedures are the most probable
explanations of variations in cancer mortality between countries.
2.4 Disability Adjusted Life Years (DALY)
The burden of cancers (DALY) in the population of Serbia (Central Serbia and Vojvodina)
was estimated for the year 2000 (Atanasković-Markovic et al., 2003) using methods largely
. Figure 48-1
Leading cancers as a percentage of all cancer cases, (all sites but melanoma skin cancer) by sex,
Serbia, average for the period 1999–2003
. Table 48-2
Standardizeda incidence rates (1/100,000) of selected cancers for men (M) and women (W) in
Europe and Serbia
Standardized incidence 1/100,000 by cancer site

Region All sitesb Stomach Colorectal Lung Prostate Breast Cervix
c
Europe : M W M W M W M W M W W
Northern 283.1 252.3 12.4 6.0 37.5 26.4 44.3 21.3 57.5 82.5 9.0
Central & Eastern 257.7 175.1 29.6 12.8 30.1 20.1 65.7 8.7 17.4 42.6 14.5
Western 326.4 244.6 12.8 6.6 42.9 29.8 50.9 12.0 61.6 84.6 10.0
Southern 299.4 208.1 18.0 8.7 35.9 23.5 56.9 9.2 35.5 62.4 10.7
Serbiad 241.9 215.4 14.0 6.2 33.4 18.4 62.1 16.0 17.2 60.6 25.8
a
Standardized according to world population (Jensen et al., 1991)
b
All sites but non-melanoma skin
c
Data according to Ferlay et al. (2004)
d
Average for 1999–2003
based on those developed for the Global Burden of Disease Study (Murray and Lopez, 1996;
Murray et al., 2002).
DALY in Serbia was estimated only for the most frequent cancers: stomach, colorectal,
lung, breast and cervical cancer (Vlajinac et al., 2006).
Observed cancers were responsible for 73,197 DALYs in men and for 60,482 DALYs in
women. The burden of cancer was dominated by premature mortality, the participation of
YLL in DALY being 95.2% in men and 93.2% in women. The greatest part of the cancer burden
was caused by lung cancer in men and by breast cancer in women (> Table 48-5).
DALY per 1,000 population in Serbia was higher than in the European region for all
observed cancers, except for stomach cancer and this cannot be attributed only to the higher
incidence of these cancers in Serbia. The incidence of stomach and colorectal cancers was even
lower in Serbia. The difference in the YLD/DALY ratio between Serbia and the European
region (> Table 48-6) pointed to the importance of premature death from some of these
cancers in Serbia.
2.5 Temporal Trends
Since reliable incidence data were not available for a longer period, mortality data were used to
analyze the trend.
According to data from Serbia, during an 18-year period (1985–2002) a rising trend in
total cancer mortality was seen both in men (y = 118.54 þ 2.27x, p < 0.001) and in women
(y = 83.32 þ 1.02x, p < 0.001). The mean percentage of annual change was 1.62% in men and
1.05% in women (Markovic-Denic et al., 2006). Out of the most frequent cancers, lung cancer
and colorectal cancer mortality significantly increased in both sexes. This significant increasing
trend was also observed in breast and cervical cancer. Mortality rates for stomach cancer in
men gradually decreased after the 1990s, while prostate cancer mortality remained relatively
stable (> Figures 48-3 and > 48-4).
. Table 48-3
The number of cancer deaths, and standardized mortality rates (1/100,000), by sex, Serbia,
average for the period 1999–2003
Men Women
Number Standardized Number Standardized
Cancer site of cases mortality ratea of cases mortality ratea
Mouth and pharynx (C00-C10) 126 2.88 37 0.60
Oesophagus (C15) 125 2.78 34 0.60
Stomach (C16) 565 12.04 303 5.44
Colon and rectum (C18-C21) 823 17.22 597 10.38
Liver (C22) 325 6.96 222 3.92
Pancreas (C25) 332 7.18 256 4.54
Larynx (C32) 298 6.72 28 0.50
Lung (C33-C34) 2133 47.72 608 11.90
Melanoma (C43) 73 1.76 60 1.30
Breast (C50) 1017 20.96
Cervix uteri (C53) 348 7.46
Corpus uteri (C54) 80 1.40
Ovary (C56) 235 4.86
Prostate (C61) 482 9.06
Testis (C62) 19 0.60
Kidney (C64) 133 2.98 86 1.44
Bladder (C67) 284 5.70 92 1.44
Brain (C71) 243 6.30 183 4.20
Hodgkin (C81) 32 0.90 16 0.42
Non-Hodgkin (C82-C85, C96) 93 2.10 74 1.50
Leukaemias (C91-C95) 182 4.46 145 3.10
All sites but non-melanoma skin 7251 159.5 5502 106.4
(C00-C96, but C44)
a
The observed increase in overall cancer mortality in Serbia was most probably caused by
increasing incidence and to some extent by unfavorable changes in case fatality during the
1990s. The civil strife which led to the war and the break-up of the former Yugoslavia in the
year 1991, the economic sanctions imposed on Serbia by the United Nations in 1992, which
lasted 3½ years, the influx of more than half a million refugees and the resulting economic
crisis all had an adverse effect on the health service and inevitably led to poorer treatment of
patients. The increasing trend at the beginning of the observed period could also be at least
partly explained by improvements in diagnosing cancer deaths. The percentage of symptoms
and insufficiently defined conditions in all causes of death was high in the past, as much as
19.3% in 1975, but the frequency of this group of death causes fell to 7% in 1991 (Jevremovic
et al., 1994) and leveled off after that (Markovic-Denic et al., 2006).
. Figure 48-2
Leading cancers as a percentage of all cancer deaths, (all sites but melanoma skin cancer) by sex,
Serbia, average for the period 1999–2003
. Table 48-4
Standardizeda mortality rates (1/100,000) of selected cancers for men (M) and women (W) in
Europe and Serbia
Standardized mortality 1/100,000 by cancer site

Region All sitesb Stomach Colorectal Lung Prostate Breast Cervix
c
Europe : M W M W M W M W M W W
Northern 161.0 118.1 9.2 4.6 17.6 12.7 40.8 18.2 19.7 22.6 3.6
Central & Eastern 197.2 101.9 25.2 10.8 19.7 12.9 59.7 7.8 9.7 17.9 7.1
Western 173.9 106.1 8.9 5.0 19.0 14.0 46.2 10.3 17.5 22.3 3.4
Southern 170.1 92.2 12.9 6.3 17.1 11.0 49.1 7.5 13.2 18.1 3.3
Serbiad 159.5 106.4 12.0 5.4 17.2 10.8 47.7 11.9 9.1 21.0 7.5
a
b
All sites but non-melanoma skin
c
Data according to Ferlay et al. (2004)
d
Average for 1999–2003
. Table 48-5
The burden of selected cancers by site and sex in Serbia, 2000. Data from Vlajinac et al. (2006)
Men (3,673,529 inhabitants)

Cancer site YLDa YLD per 1,000 YLLb YLL per 1,000 DALYc DALY per 1,000
Stomach cancer 386 0.10 10,416 2.84 10,416 2.94
Colorectal 983 0.27 14,542 3.96 15,525 4.23
cancer
Lung cancer 2,136 0.58 44,407 12.09 46,543 12.67
Breast cancer 56 0.02 271 0.07 327 0.09
Total 3,561 0.97 69,636 18.96 73,197 19.93
Women (3,877,326 inhabitants)
Cancer site YLDa YLD per 1,000 YLLb YLL per 1,000 DALYc DALY per 1,000
Stomach cancer 198 0.05 5,487 1.42 5,685 1.47
Colorectal 802 0.21 9,680 2.49 10,482 2.70
cancer
Lung cancer 518 0.13 12,027 3.10 12,545 3.24
Breast cancer 2,078 0.54 21,463 5.54 23,541 6.07
Cervical cancer 529 0.14 7,701 1.99 8,230 2.12
Total 4,125 1.06 56,358 14.54 60,483 15.60
a
YLD – years lived with disability estimated by using the Global Burden Disease weight (Murray and Lopez, 1996)
b
c
DALY – disability adjusted life years
. Table 48-6
Incidence, YLDa and DALYb per 1,000 population (all persons) and YLD/DALY ratio from
selected cancers in Serbia and the EURO regionc. Data from Vlajinac et al. (2006)
Region
Cancer site Serbia EURO EURO A EURO B EURO C
Stomach cancer
Incidence 0.16d 0.25 - - -
YLD 0.06d 0.06 0.06 0.04 0.09
DALY 1.84d 1.83 1.15 1.48 3.29
YLD/DALY (%) 3 3 5 3 3
Colorectal cancer
Incidence 0.39d 0.43 - - -
d
YLD 0.20 0.27 0.50 0.12 0.20
DALY 2.85d 2.14 2.63 1.30 2.49
YLD/DALY (%) 7 13 19 9 8
Lung cancer
Incidence 0.62d 0.46 - - -
d
YLD 0.29 0.12 0.14 0.08 0.11
DALY 6.66d 3.75 4.04 2.76 4.49
YLD/DALY (%) 4 3 3 3 2
Breast cancer
Incidence 0.45d 0.42 - - -
YLD 0.25d 0.36 0.50 0.18 0.27
DALY 2.76d 2.14 2.46 1.36 2.29
YLD/DALY (%) 9 17 20 13 12
Cervical cancer
Incidence 0.15d 0.06 - - -
YLD 0.06d 0.05 0.03 0.05 0.06
DALY 0.98d 0.46 0.26 0.67 0.69
YLD/DALY (%) 6 11 12 7 9
a
YLD years lived with disability estimated by using the Global Burden Disease weight (Murray and Lopez, 1996)
b
DALY disability adjusted life years
c
EURO region (Murray et al., 2001). EURO A (very low child, very low adult mortality) – Andorra, Austria, Belgium,
Croatia, the Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxemburg,
Malta, Monaco, the Netherlands, Norway, Portugal, San Marino, Slovenia, Spain, Sweden, Switzerland, the United
Kingdom. EURO B (low child, low adult mortality). B1 – Albania, Bosnia and Herzegovina, Bulgaria, Georgia, Poland,
Romania, Slovakia, the Former Yugoslav Republic of Macedonia, Turkey, Serbia and Montenegro. B2 – Armenia,
Azerbaijan, Kyrgyzstan, Tajikistan, Turkmenistan, Uzbekistan. EURO C (low child, high adult mortality) –
Belarus, Estonia, Hungary, Kazakhstan, Latvia, Lithuania, the Republic of Moldavia, the Russian Federation, Ukraine
d
Standardized according to European population (Ahmad et al., 2000)
. Figure 48-3
Age-adjusted mortality trends for the most frequent cancers in men, Serbia (1985–2002). Data
from Marković-Denic et al. (2006), rhombs – Lung: y ¼ 32.38 þ 0.86x; p < 0.001; squares –
Colorectum: y ¼ 10.87 þ 0.33x; p < 0.001; triangles – Stomach: y(1985–1990) = 11.59 þ 0.34x;
y(1990–2002) ¼ 13.67–0.20x; p < 0.01; x – Prostate: y ¼ 6.37 þ 0.13x; p > 0.05
An increase in overall cancer mortality of 2.43% per year was seen in Central and Eastern
Europe during the period 1980–2001. At the same time, in countries of the European Union,
the Nordic countries and Switzerland mortality decreased by 7.27% yearly (Antunes et al.,
2003). The unfavorable trends in Central and Eastern Europe were attributed to the high
prevalence of risk factors (tobacco, alcohol, dietary habits, pollution, and hepatitis B) and
inadequate screening and treatment (Antunes et al., 2003; Levi et al., 2004d).
2.6 Patterns of Cancer Types
2.6.1 Lung Cancer
Lung cancer is the main cause of cancer morbidity and mortality worldwide, although various
countries are at different stages in their lung cancer epidemic.
With an estimated 3,530 new cases per year (2,730 in men, and 800 in women), lung cancer
was the most frequent cancer in Serbia (> Table 48-1). It was responsible for 26.1% of all
cancer incidence cases in men, and for 8.0% in women (> Figure 48-1). The age-standardized
incidence rate of 62.1 per 100,000 in men was close to the incidence in Central and Eastern
Europe, but the incidence rate for women of 16.0/100,000 was somewhere between the
incidence of Western and Northern Europe (> Table 48-2). The incidence rates in Europe
. Figure 48-4
Age-adjusted mortality trends for the most frequent cancers in women, Serbia (1985–2002).
Data from Markovic-Denic et al. (2006), rhombs – Breast: y = 14.48 þ 0.35x; p = 0.0001;
squares – Colorectum: y = 8.51 þ 0.09x; p < 0.05; triangles – Lung: y = 6.25 þ 0.25x; p < 0.001;
x – Cervix: y = 5.14 þ 0.14x; p < 0.01
ranged from 21.1/100,000 (Sweden) to 94.6/100,000 (Hungary) in males, and from 4.5/
100,000 (Belarus) to 30.0/100,000 (Iceland) in females (Ferlay et al., 2004).
Lung cancer is still a highly lethal disease. As a cause of death it occupied first place among
the men of Serbia accounting for 29.4% of all cancer deaths (2,133 deaths per year). In women,
lung cancer took second place, with an average of 608 deaths annually (11.0% of all cancer
deaths) (> Table 48-3, > Figure 48-2). Mortality rates of 47.7/100,000 in men and 11.9/
100,000 in women were similar to corresponding rates in Western Europe (> Table 48-4).
The rates in Europe ranged from 22.6/100,000 (Sweden) to 83.9/100,000 (Hungary) in males,
and from 4.2/100,000 (Belarus) to 27.8/100,000 (Denmark) in females (Ferlay et al., 2004).
Lung cancer survival was estimated as the mortality-to incidence rate ratio (MR: IR). This
ratio of 0.76 was lower than both in Western and Eastern Europe (Parkin et al., 2005). The
> MR: IR ratio has been used for survival estimation. However, this ratio can be influenced by
changes in incidence without any change in survival. An increase in incidence can lower the
MR: IR ratio.
Lung cancer was responsible for 12.67 DALYs per 1,000 men and 3.24 DALYs per 1,000
women per year (> Table 48-5), the burden being much higher in comparison to European
regions (> Table 48-6). Since early diagnosis and early and appropriate therapy do not
significantly influence the prognosis of lung cancer, the YLD/DALY ratio in Serbia was similar
to that in the developed countries.
Lung cancer mortality in Serbia significantly increased in both sexes, but the increase was
more pronounced in women (> Figure 48-3 and > 48-4). During the period 1985–2002, the
mean percentage of annual change in rates was 2.44% in men and 3.63% in women. In the
European Union, taken as a whole, lung cancer mortality in men, after reaching a peak in 1988,
began to decline (Levi et al., 2004c). However, in women, especially in young women (<55
years old), lung cancer mortality showed an increase, particularly in Spain and France.
However, some stagnation and even a tendency to decrease in the younger generations were
observed in some countries (Levi et al., 2007).
Although many risk factors for lung cancer development were identified (Alberg and
Samet, 2003), smoking is its predominant cause. Levels and changes in the prevalence of
smoking may explain both differences in lung cancer morbidity and mortality between
countries and between men and women and the decreasing/increasing tendency in lung cancer
rates. In Serbia, the prevalence of smoking is high, until recently among the highest in Europe,
and it had been increasing over time. According to data for the Belgrade population, there
were 49% male and 25% female smokers in the years 1976–1977, and 51% male and 37%
female smokers in the years 1988–1989 (Vlajinac et al., 1990). In Serbia, the cancer burden
(DALY) attributable to smoking was 82.8% of the total lung cancer burden for men and 90.2%
for women (Atanasković-Markovic et al., 2003).
The most important and effective approach aimed at reduction of the lung cancer burden
is tobacco control through behavioral interventions and public health policy (Roemer et al.,
2005). Thanks to preventive programs which have intensified in Serbia since 2000, the
smoking prevalence in the adult population dropped from 40.5% in 2000 to 33.6% in 2006,
and in the young population (aged 15–19), from 22.9 to 15.5% (Ministry of Health, Republic
of Serbia, 2007). Serbia also is among the countries which joined the World Health Organiza-
tion convention on tobacco control. The World Health Organization convention was ratified
in Serbia in 2005, and became effective in June 2006. Tobacco control was designated as a
priority by the government and the Ministry of Health developed a tobacco control strategy,
the positive effects of which can be expected in the future.
2.6.2 Breast Cancer
As in other countries, breast cancer was the most frequent cancer among the women of Serbia.
With 2,739 new cases per year, it was responsible for 27.6% of all incidence cancer cases
(> Table 48-1, > Figure 48-1). The average age standardized incidence rate of 60.6/100,000 was
similar to the incidence in Southern Europe, but lower than in Northern and Western Europe
(> Table 48-2). The highest incidence rates in Europe were in Belgium (92.0/100,000) and
France (91.9/100,000) and the lowest rate was in Belarus (36.0/100,000) (Ferlay et al., 2004).
International differences have been attributed to differences in the prevalence of risk factors
that determine lifetime exposure to estrogen, and to a lesser extent to differences in height,
diet, alcohol consumption, and exogenous estrogen use (Althuis et al., 2005), but also to
differences in the use of screening. The high incidence in the more affluent world areas is at
least partly the result of screening programs. Implementation of regular screening also partly
explains why breast cancer incidence has been increasing in most countries and especially in
those where rates were low (Parkin et al., 2001). During the period 1973–1997 breast cancer
incidence rose 30% in westernized nations where breast screening programs were implemen-
ted in the late 1980s and early 1990s (Shapiro et al., 1998). It was difficult to distinguish
. Figure 48-5
Age-specific incidence and mortality rates for breast cancer in women, Serbia, average for the
period 1999–2003, rhombs – Incidence; squares – Mortality
between that artefactual increase and a real rise resulting from changes in breast cancer risk
factors (Wun et al., 1995).
Age-specific breast cancer incidence rates in Serbia showed a sharp increase up to 55 years
of age, but after that, rates leveled off and even declined (> Figure 48-5). This pattern is similar
to the pattern present in less developed countries (Kamangar et al.,2006). In high-risk
countries (developed countries), breast cancer rates in post-menopausal women continue to
rise although more slowly in comparison with rates in pre-menopausal women. These
differences between countries in the breast cancer rate pattern among older women are
supposed to be the result of the different frequency of two main breast cancer types according
to the estrogen receptor: estrogen receptor – positive, late onset and indolent type, and
estrogen receptor – negative, early onset and more aggressive type (Kamangar et al., 2006).
Breast cancer in Serbia was responsible for 1,017 deaths per year and it was the leading cause of
cancer death in females (18.5% of all cancer deaths) (> Table 48-3, > Figure 48-2). The average
standardized mortality rate of 21.0/100,000 was similar to that in Northern and Western
Europe (> Table 48-4). The highest mortality rates in Europe were in Malta (29.6/100,000),
and the lowest in Belarus, Greece and Poland (15.3–15.5/100,000) (Ferlay et al., 2004). The
MR: IR ratio was 0.30. The survival of 70% was similar to that in Western Europe (74%)
(Parkin et al., 2005).
In Serbia, breast cancer was responsible for 6.07 DALYs per 1,000 women annually
(> Table 48-5), the total breast cancer burden being higher than in the European regions.
The YLD/DALY ratio was much higher than in Europe (> Table 48-6) and other developed
countries (Vlajinac et al., 2006), suggesting that premature death is still an important
component of the total breast cancer burden. The discrepancy between the MR: IR and
YLD/DALY ratios could most probably be explained by differences between countries
in the proportion of young females who died from breast cancer. The YLL is higher for
those who died younger because they lost more expected years of life. The burden of
breast cancer in Serbia was the highest in women aged 45–65 (Atanasković-Markovic
et al., 2003).
During the period 1985–2002 breast cancer mortality increased significantly (> Figure 48-4),
the annual percentage of changes being 2.23%. This increase can be attributed to an increase in
incidence and, to some extent, to shorter survival as a consequence of the unfavorable
conditions in the health care system during the 1990s. In addition, the proportion of
advanced-stage breast cancer cases at diagnosis is high in Serbia. Many women came to
their doctor too late as a result of poor health education. In the European Union, breast
cancer mortality peaked in 1989 and thereafter showed a tendency to level off and decline
moderately (Levi et al., 2004c).
It is expected that implementation of screening programs in Serbia, planned to begin in
the near future, will lead to an increase in breast cancer incidence, but at the same time, thanks
to earlier diagnosis, will lead to a decrease in breast cancer mortality.
2.6.3 Colorectal Cancer
With an average of 1,439 cancer cases per year (> Table 48-1) colorectal cancer in Serbia
was the second most common cancer in men accounting for 13.8% of all cancer cases
(> Figure 48-1). The standardized incidence rate of 33.4/100,000 was similar to the incidence
in Central and Eastern, and Southern Europe (> Table 48-2). In women colorectal cancer was
in third place with an average of 990 cases per year (10.0% of all cancer cases) (> Table 48-1,
> Figure 48-1). The standardized incidence rate of 18.4/100,000 was the closest to that
of Central and Eastern Europe (> Table 48-2). The incidence rates in Europe ranged from
19.4/100,000 (Greece) to 58.5/100,000 (the Czech Republic) in men, and from 14.4/100,000
(Romania) to 37.1/100,000 (Norway) in women (Ferlay et al., 2004).
Colorectal cancer incidence rates increased rapidly in countries where overall risk earlier
was low. In high-risk countries incidence rates increased more gradually or stabilized and even
began to decline as in the United States, and Northern and Western Europe (Chu et al., 1994;
Parkin et al., 2005). Differences between countries in the level and trend of incidence can be
attributed to differences in environmental risk factors, but also to differences in screening
practice. There is evidence that screening is effective in reducing of both incidence and mortality
(Kamangar et al., 2006).
In Serbia colorectal cancer occupied second place as a cause of death in men and third
place in women (11.3% and 10.8% respectively of all cancer deaths) (> Table 48-3,
> Figure 48-2). The standardized mortality rates of 17.2/100,000 in men and 10.4/100,000
in women were similar to mortality rates in Europe taken as a whole (> Table 48-4), although
rates ranged from 9.7/100,000 (Greece) to 35.6/100,000 (Hungary) in men and from
8.0/100,000 (Greece) to 21.2/100,000 (Hungary) in women (Ferlay et al., 2004). Colorectal
cancer survival in Serbia (the MR: IR ratio was 0.54) was lower than in Northern Europe and
Western Europe (Parkin et al., 2005).
In Europe, mortality trends tended to decline in the European Union from 1980 to
2000, but tended to increase in the Central and Eastern European countries that joined the
European Union in 2004 (Levi et al., 2004c, d). The levels and trends of colorectal cancer
mortality depend on the level of incidence and on early detection and therapy. Meta-
analysis of a controlled trial of colorectal cancer screening by fecal occult blood test
showed a reduction in colorectal cancer mortality of 14% over a 10-year period (Heresbach
et al., 2006).
The marked increase in colorectal mortality in Serbia from 1985 to 2002, with a mean
percentage of annual change of 2.78% in men and 0.99% in women, was most probably the
result of the increasing incidence and partly of the late detection and inadequate treatment
facilities during the 1990s.
Colorectal cancer in Serbia was responsible for 4.23 DALYs per 1,000 men yearly and for
2.70 DALYs per 1,000 women (> Table 48-5). The total colorectal cancer burden was higher
than in Europe. The YLD/DALY ratio in Serbia also was higher in comparison with all
European regions (> Table 48-6) indicating the importance of premature death in the total
burden. Diet (rich in meat and fat with low intake of fibers and vegetables), physical inactivity
and excessive body weight were related to the occurrence of colorectal cancer (Kamangar et al.,
2006). In Serbia 20.6% of the total colorectal cancer burden in men and 31.0% in women was
attributable to physical inactivity. As much as 13.1% of the total colorectal cancer burden in
men and 16.3% in women were attributable to obesity (Atanasković-Markovic et al., 2003).
The successful implementation of screening would result in a decrease both in incidence
and mortality. Changes in dietary pattern and lifestyle are no doubt more difficult to achieve.
2.6.4 Cervical Cancer
Cancer of the cervix was the fourth most common cancer in the population of Serbia, and the
second most common cancer among women. With 1,032 new cases per year it was responsible
for 10.4% of all cancers in females (> Table 48-1, > Figure 48-1). The standardized annual
incidence rate of 25.8/100,000 was the highest in Europe (> Table 48-2). High incidence rates
(>20.0/100,000) were also registered in Romania, Albania, and Bosnia and Herzegovina, and
the lowest rates in Europe (<5.0/100,000) were reported in Finland and Malta (Ferlay et al.,
2004). In women below 45 years of age, the standardized incidence rate in Serbia was 13.9/
100,000. Age-specific incidence rates increased up to 44 years of age, leveled off afterwards and
then began to decline (> Figure 48-6). The cumulative incidence rate in women under 45 was
0.83%, which is high in comparison with Finland (0.38%), but lower than in Lithuania
(1.64%) (Arbyn et al., 2007).
Cervical cancer in Serbia was responsible for an average of 348 deaths per year. It occupied
fourth place as a cause of cancer deaths among women (6.3% of all cancer deaths)
(> Table 48-3, > Figure 48-1). The average standardized mortality rate of 7.5/100,000 was
similar to that in Central and Eastern Europe (> Table 48-4). The highest mortality rate in
Europe was in Romania (13.0/100,000) and the lowest (<2.0/100,000) in Malta, Switzerland
and Finland (Ferlay et al., 2004). In women under 45 the standardized mortality rate in Serbia
was 1.9/100,000, and the cumulative mortality rate 0.12%, the same as in Finland (Arbyn et al.,
2007). Since survival in Europe was estimated to be 60% in Western Europe, and 51% in
. Figure 48-6
Age-specific incidence and mortality rates for cervix uteri cancer in women, Serbia, average for
the period 1999–2003, rhombs – Incidence; squares – Mortality
Eastern Europe (Parkin et al., 2005), the MR: IR ratio of 0.29 in Serbia was most probably the
result of increasing incidence.
In Serbia, cervical cancer was responsible for 2.12 DALYs per 1,000 women yearly
(> Table 48-5), the cervical cancer burden being higher than in European regions
(> Table 48-6). The YLD/DALY ratio was higher even in comparison with European B and
European C regions, suggesting that premature death was of great importance in the cervical
cancer burden. The YLL values were high because the disease affects younger women, and the
YLL is always higher for those who died young because they lost more expected years of life.
Cervical cancer is a preventable disease. The low incidence and mortality rates and their
substantial decreasing trend in the developed countries have been attributed to well-organized
screening programs (Bulk et al., 2005; Kamangar et al., 2006; Parkin et al., 2005). Before
introduction of screening programs, in the 1960s and 1970s, cervical cancer incidence in
developed countries was similar to that in developing countries today (Gustafsson et al., 1997).
In countries where cervical cancer subtypes were specified, decreasing incidence was seen for
squamous cervical cancer, but at the same time a rapid increase in cervical adenocarcinoma
was observed throughout Europe, especially in the younger generations (Bray et al., 2005a).
The inability to detect cervical adenocarcinoma within a screening program and the changing
distribution and prevalence of oncogenic human papilloma virus types were given as a
possible explanation of this trend. In several countries, at least part of the observed trend
could also be attributed to an increasing ability to diagnose the disease (Bray et al., 2005a; Bulk
et al., 2005). In Southern Europe an escalating risk of squamous cell carcinoma in successive
generations born after 1930 was observed, which was of obvious concern, particularly in
countries where no screening programs are in place (Bray et al., 2005b).
According to mortality data, cervical cancer is on the increase in Serbia. During the period 1985–
2002 mortality significantly increased, the mean percentage of annual change being 2.50%.
The very high incidence and increasing trend of cervical cancer mortality in Serbia make
implementation of a screening program a priority and this was planned to start in 2008. HPV
vaccines which have shown to be effective in reducing HPV infection (Parkin et al., 2005) are
already available, although expensive and not compulsory in the vaccination schedule.
2.6.5 Prostate Cancer
Prostate cancer was the third most common cancer among men in Serbia. With an average
number of 886 cases per year it accounted for 8.5% of all cancers (> Table 48-1,
> Figure 48-1). The standardized incidence rate of 17.2/100,000 was almost the same as in
Central and Eastern Europe (> Table 48-2). In Europe the lowest incidence rate was present in
Moldavia (10.6/100,000) and the highest in Sweden (90.9/100,000) (Ferlay et al., 2004). Al-
though differences in prostate incidence rates between countries may in part be due to variations
in diet and other risk factors, they are almost certainly mainly the result of variations in the
availability and use of screening with a prostate-specific antigen test. In most countries where the
practice of PSA testing is common, incidence is high (Kamangar et al., 2006; Parkin et al., 2005).
It is considered that the increased detection of prostate cancer which followed the increased use
of transurethral resection of the prostate and the use of prostate-specific antigen testing was also
the major factor in the increase of prostate cancer incidence seen in many countries and on most
continents (Parkin et al., 2005; Quinn and Babb, 2002).
With an average of 482 deaths per year, prostate cancer was in fourth place as a cause
of cancer deaths in men (6.6% of all cancer deaths) (> Table 48-3, > Figure 48-2). The
standardized mortality rate of 9.1/100,000 and the MR: IR ratio of 0.53 was like those in
Central and Eastern Europe (> Table 48-6). The lowest mortality rate in Europe was in
Moldavia (4.7/100,000) and the highest in Norway (28.4/100,000) (Ferlay et al., 2004). The
much higher survival in high-risk countries (72% in Western Europe) can be mainly attrib-
uted to the detection of more latent cancers.
Mortality from prostate cancer increased throughout Europe up to the early 1990s. Rates
peaked in 1993 in the European Union, and in 1996 in Central and Eastern Europe, leveled off
thereafter (Levi et al., 2004b), and began to decline in some countries (Cookson, 2001;
Kwiatkowski et al., 2004). During the period 1985–2002 prostate cancer mortality rates in
Serbia increased slightly, but not significantly.
While the increase of prostate cancer mortality could be explained by the increasing
risk of a fatal form of the disease (Post et al., 1999), it is difficult to tell whether the
present decline in mortality is a consequence of decline in the incidence of the advanced
stage of disease (Chu et al., 2003), improvement in treatment, changes in cancer regis-
tration coding or incorrect attribution of prostate cancer as the underlying cause of death
(Quinn and Babb, 2002).
2.6.6 Stomach Cancer
With an average number of 637 cases per year, stomach cancer in Serbia was the fifth most
common cancer in men (6.1% of all cancers). In women it was less frequent and with 344 cases
per year was responsible for 3.5% of all cancers (> Table 48-1, > Figure 48-1). The standar-
dized incidence rates in men (14.0/100,000) and women (6.2/100,000) were close to those in
Northern and Western Europe (> Table 48-2). In Europe stomach cancer incidence rates
ranged from 7.9/100,000 (Denmark) to 41.9/100,000 (Belarus) in males, and from 3.9/100,000
(Denmark) to 16.9/100,000 (Belarus) in females (Ferlay et al., 2004).
On average, 565 men in Serbia died from stomach cancer per year (7.8% of all cancer
deaths) (> Table 48-3, > Figure 48-2). The standardized mortality rate of 12.0/100,000 was
higher than mortality rates in Northern and Western Europe, but it was half the mortality rate
in Eastern Europe (> Table 48-4). In Europe stomach cancer mortality rates in men ranged
from 5.5/100,000 (Denmark) to 33.0/100,000 (Belarus). (Ferlay et al., 2004). Among women in
Serbia stomach cancer was responsible for 5.5% of all cancer deaths (an average of 303 deaths
per year) (> Table 48-3, > Figure 48-2), and the standardized mortality rate of 5.4/100,000 was
similar to that in Western Europe (> Table 48-4). In Europe, mortality rates in women ranged
from 3.1/100,000 in France to >13.0/100,000 in the Russian Federation and Belarus (Ferlay
et al., 2004).
Overall 5-year survival in stomach cancer is poor, about 20% in most areas of the world
with the exception of Japan where it is approximately 60% (Parkin et al., 2005). In Serbia,
survival was similar to that in Eastern Europe (Parkin et al., 2005), the MR: IR ratio being 0.86.
In Serbia stomach cancer was responsible for 2.94 DALYs per 1,000 men in a year, and for
1.47 DALYs per 1,000 women (> Table 48-5). The total burden was higher in comparison to
European A and B regions and lower than that in the European C region. As the survival does
not vary considerably across Europe, the YLD/DALY ratio in Serbia was lower only in
comparison with the European A region (> Table 48-6).
Throughout the world stomach cancer mortality has been decreasing, although not at
the same time. In the European Union as a whole, stomach cancer mortality steadily
declined between 1980 and 1999 from 18.6 to 9.8/100,000 in men and from 8.9 to 4.6/
100,000 in women (Levi et al., 2004a). Mortality rates in Serbia have been gradually
decreasing since the 1990s (> Figure 48-3), the mean percentage of annual change being
1.37%. This decline can be related to the widespread use of refrigeration and the decreasing
use of the salt- and smoke-based food preservation method (Tsugane and Sasazuki, 2007). It
may also reflect a diminishing prevalence of H. pylori infection thanks to improved sanitation
and personal hygiene (Kamangar et al., 2006; Parkin et al., 2005).
Summary Points
Standardized overall cancer incidence and mortality rates for men in Serbia were some-
what lower than average rates for Europe as a whole, and for women they were almost the
same as European average rates.
In men, the most frequent cancers were lung cancer, followed by colorectal, prostate,
bladder and stomach cancers. In women, incidence was highest for breast cancer, followed
by cervical, colorectal, lung and corpus uteri cancers.
In men, the highest mortality rates were for lung cancer and then for colorectal, stomach
and prostate cancers. In women, breast cancer occupied first place as a cause of death
followed by lung cancer, colorectal, cervical and stomach cancers.
The cervical cancer incidence rate in Serbia was the highest in Europe.
DALYs (the years of healthy life lost) per 1,000 population in Serbia were higher than in the
European region for lung, breast, colorectal and cervical cancers.
For breast, colorectal and cervical cancers the participation of premature death in the total
burden was higher in Serbia than in Europe.
During the period 1985–2002 in Serbia, there was a significant increase in mortality from
all cancers, lung, breast and cervical cancers. The increase in lung cancer mortality rates
was more pronounced in women.
Increasing cancer mortality trends underline the importance of implementing preventive
measures that have proved effective in other countries.
Serbia joined the WHO convention on tobacco control, the positive effects of which can be
expected in the future. A screening program for cervical cancer will start in 2008, and
implementation of screening programs for breast and colorectal cancers are planned for
the near future.
References
Adanja B, Gledovic Z, Pekmezovic T, Vlajinac H, Chu KC, Tarone RE, Chow WH, Hankey BF, Ries LA.
Jarebinski M, Zivaljevic V, Pavlovic M. (2000). Dig (1994). J Natl Cancer Inst. 86: 997–1006.
Liver Dis. 32: 386–391. Chu KC, Tarone RE, Freeman HP. (2003). Cancer. 97:
Ahmad OB, Boschi-Pinto C, Lopez A, Murray CJ, Lozano 1507–1516.
R, Inoue M. (2000). Age Standardization of Rates. Cookson M. (2001). JMCC. 8:133–140.
A New WHO Standard. GPE Discussion Paper Ferlay J, Bray F, Pisani P, Parkin DM. (2004). Globocan
Series No. 31. World Health Organization, Geneva. 2002: Cancer Incidence, Mortality and Prevalence
Alberg AJ, Samet JM. (2003). Chest. 123: 21S–49S. Worldwide, Version 2.0: IARC Cancer Base no. 5.
Althuis MD, Dozier JM, Anderson WF, Devesa SS, IARC Press, Lyon.
Brinton LA. (2005). Int J Epidemiol. 34: 405–412. Gustafsson L, Pontén J, Bergström R, Adami HO. (1997).
Antunes JL, Toporcov TN, de Andrade FP. (2003). Eur J Int J Cancer. 71: 159–165.
Cancer Prev. 12: 367–372. Heresbach D, Manfredi S, D ‘halluin PN, Bretagne JF,
Arbyn M, Raifu AO, Autier P, Ferlay J. (2007). Ann Branger B. (2006). Eur J Gastroenterol Hepatol. 18:
Oncol. 18: 1708–1715. 427–433.
Atanasković-Markovic Z, Bjegović V, Janković S, Kocev N, Institute of Public Health of Serbia. (2001–2005). Cancer
Laaser U, Marinković J, Marković-Denić L, Pejin- Registry of Central Serbia. Incidence and Mortality
Stokić Lj, Penev G, Stanisavljević D, Šantrić-Milićević in Central Serbia, Report no. 1–5. Institute of Public
M, Šaulić A, Šipetić-Grujičić S, Terzić-Šupićz, Vlajinac Health of Serbia, Belgrade.
H. (2003). The burden of disease and injury in Jensen OM, Parkin DM, Lennan R, Muir CS, Skeet RG.
Serbia (Ministry of Health of the Republic of (1991). Cancer Registration: Principles and Meth-
Serbia, Belgrade) Available online at: www.sbds.sr. ods. IARC, Lyon.
gov.yu. Jevremovic I, Jankovic S, Markovic-Denic L, Radosavljevic
Boyle P, Ferlay J. (2005). Ann Oncol. 16: 481–488. V, Radovanovic Z. (1994). Vojnosanit Pregl. 51:
Bray F, Carstensen B, Møller H, Zappa M, Zakelj MP, 114–117.
Lawrence G, Hakama M, Weiderpass E. (2005a). Kamangar F, Dores GM, Anderson WF. (2006). J Clin
Cancer Epidemiol Biomarkers Prev. 14: 2191–2199. Oncol. 24: 2137–2150.
Bray F, Loos AH, McCarron P, Weiderpass E, Arbyn M, Kwiatkowski M, Huber A, Moschopulos M, Lehmann K,
Møller H, Hakama M, Parkin DM. (2005b). Cancer Wemli M, Häfeli A, Recker F. (2004). Swiss Med
Epidemiol Biomarkers Prev. 14: 677–686. Wkly. 134: 580–585.
Bulk S, Visser O, Rozendaal L, Verheijen RH, Meijer CJ. Levi F, Bosetti C, Fernandez E, Hill C, Lucchini F, Negri E,
(2005). Int J Cancer. 113:1005–1009. La Vecchia C. (2007). Int J Cancer. 121:462–465.
Levi F, Lucchini F, Gonzalez JR, Fernandez E, Negri E, La Parkin DM, Bray F, Devesa SS. (2001). Eur J Cancer. 37:
Vecchia C. (2004a). Ann Oncol. 15: 338–345. S4–S66.
Levi F, Lucchini F, Negri E, Boyle P, La Vecchia C. Parkin DM, Bray F, Ferlay J, Pisani P. (2005).CA Cancer J
(2004b). Prostate. 60: 46–52. Clin. 55:74–108.
Levi F, Lucchini F, Negri E, La Vecchia C. (2004c). Can- Post PN, Straatman H, Kiemeney LA, Coebergh JW.
cer. 101: 2843–2850. (1999). Int J Epidemiol. 28: 403–408.
Levi F, Lucchini F, Negri E, Zatonski W, Boyle P, La Vecchia Quinn M, Babb P. (2002). BJU Int. 90: 162–173.
C. (2004d). Ann Oncology. 15: 1425–1431. Roemer R, Taylor A, Lariviere J. (2005). Am J Public
Markovic-Denic L, Zivkovic S, Sipetic S, Vlajinac H, Health. 95: 936–938.
Kocev N, Marinkovic J. (2006). Soz Praventiv Med. Shapiro S, Coleman EA, Broeders M, Codd M, de Koning
51: 117–122. H, Fracheboud J, Moss S, Paci E, Stachenko S,
Ministry of Health, Republic of Serbia. (2007). National Ballard-Barbash R. (1998). Int J Epidemiol. 27:
Health survey, Serbia 2006. Ministry of Health, 735–742.
Republic of Serbia, Belgrade. Shibuya K, Mathers CD, Boschi-Pinto C, Lopez AD,
Murray CJ, Lopez AD (ed.). (1996). The global burden of Murray CJL. (2002). BMC Cancer. 2: 37–63.
disease: a comprehensive assessment of mortality Tsugane S, Sasazuki S. (2007). Gastric Cancer. 10: 75–83.
and disability from diseases, injuries and risk factors Vlajinac H, Adanja B, Jarebinski M. (1990). Medicinska
in 1990 and projected to 2020. Global Burden of istrazivanja 23: 73–76.
Diseases and Injury Series, Vol. 1. , Harvard Univer- Vlajinac H, Marinkovic J, Kocev N, Adanja B, Sipetic S,
sity Press, Cambridge. Pekmezovic T, Zivaljevic V. (2000). Srp Arh Celok
Murray CJL, Lopez AD, Mathers CD, Stein C. (2001). Lek. 128: 309–315.
The Global Burden of Disease 2000 Project: Aims, Vlajinac H, Sipetic-Grujicic S, Jankovic S, Marinkovic J,
Methods and Data Sources. World Health Organi- Kocev N, Markovic-Denic L, Bjegovic V. (2006).
zation, Geneva. Croat Med J. 47: 134–141.
Murray CJL, Salomon JA, Mathers CD, Lopez AD (ed.). Wun LM, Feuer EJ, Miller BA. (1995). Cancer Causes
(2002). Summary Measures of Population Health: Control. 6: 135–144.
Concepts, Ethics, Measurement and Applications.
World Health Organization, Geneva.
49 The Disease Burden of
Mastectomy: Turkish
Perspective and Impact on
the Patient and Family
S. Özkan . M. Özkan . V. Özmen . Z. Armay
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
2 Incidence and Mortality Rates of Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
3 Risk Factors for Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
4 The Positive Effect of Early Diagnosis on the Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870
5 Healthcare Coverage Systems in Turkey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871
6 Financial Burden of Breast Cancer and its Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871
7 The Burden of Mastectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872
8 Psychological and Psychosocial Burden of Mastectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
9 The Effect of Mastectomy on Body Image, Sexuality and Marital

Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877
10 Burden Created on the Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
11 Breast Reconstruction after Mastectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
12 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881

866 49 The Disease Burden of Mastectomy
Abstract: Carcinoma of the breast is the most common site-specific cancer and is the leading
cause of death from cancer in women with an estimated 1.15 million cases diagnosed in 2002.
Breast cancer incidence and prevalence rates in Western Turkey in 1992 were 24.4/1000,000
and 0.3% respectively. Breast cancer incidence has increased in Turkey, and more than 15,000
new breast cancer cases were diagnosed in 2007. Breast cancer incidence and mortality show
differences in different regions of Turkey depending on breast health awareness, diagnostic and
therapeutic facilities, and other social, cultural and economic factors. The most common
surgical treatment of breast cancer in Turkey is > modified radical mastectomy, which involves
removal of the breast, pectoral muscles, and maxillary > lymph nodes. With its increasing
prevalence and advanced stage at diagnosis, breast cancer treatment results in significant
financial, social, psychological and psychosocial burden on the patients, families and the
society. Burden of treatment of especially advanced breast cancer are tremendous, these are,
morbidity, mortality, treatment expenses (hospitalization, outpatient care, and physician
services, loss of productivity, surgical-systemic-radiation therapies, and psychological disor-
ders of patients and their families). Intangible or psychosocial costs are pain and suffering
from disease and its treatment that affect health and well being not reflected in the categories
of direct or productivity costs. It is not possible to understand the breast cancer and
> mastectomy experience independent from the specific culture. The Turkish history, culture,
related values and traditions shape the experience of Turkish breast cancer patients. The
burden of mastectomy duplicates when a thorough analysis is conducted with its various
components that also greatly affect psychologically such as the reality of cancer, experiencing a
surgery, and organ loss. This chapter aims to review the current Turkish literature on the
various aspects of burden of breast cancer and mastectomy in comparison to the Western
literature. The review clearly documents that an interdisciplinary approach that combines
oncologic and psychiatric treatments is required for decreasing the burden of mastectomy.
List of Abbreviations: ASR, age standardized rates; BCS, breast conservation surgery; BHA,
breast health awareness; BMI, body mass index; CBE, clinical breast examination; DALY,
disability adjusted life years; MRM, modified > radical mastectomy; SLNB, sentinel lymph
node biopsy; TRAM, trans-rectus abdominis muscle
1 Introduction
Cancer is a chronic and life-threatening disease that greatly affects both developed and low-
middle income countries. According to a recent report on cancer statistics, every year more
than 11 million people in the world and 150,000 people in Turkey are newly diagnosed with
cancer, and this rate will approximately increase by 50% in year 2020 (National Disease Burden
and Cost-Effectiveness Project, 2004).
2 Incidence and Mortality Rates of Breast Cancer
Carcinoma of the breast is the most common site-specific cancer and is the leading cause
of death from cancer in women with an estimated 1.15 million cases diagnosed in 2002
(Parkin et al., 2005). There is a marked geographical variation in the incidence rates, being
highest in the developed world and lowest in the developing countries in Asia, Middle East,
The Disease Burden of Mastectomy 49 867
and Africa. The age-standardized incidence in North America is the highest, at 99.4
per 100,000, while the lowest is in central Africa where it is 16.5 per 100,000 (Parkin et al.,
2005). Although developed countries report higher rates of breast cancer incidence and
mortality, changes in the incidence of breast cancer are most dramatic in low-middle income
countries including Turkey. Forty-five percent of more than 1 million new cases of breast
cancer diagnosed each year, and more than 55% of breast-cancer–related deaths, occur in low-
and middle-income countries (Curado et al., 2007).
However, in most low and middle-income countries, incidence rates are increasing
more rapidly than in areas where incidence rates are already high. Global breast cancer
incidence rates have increased by about 0.5% annually since 1990 (Parkin et al., 2005)
(> Box 49-1). More than 15,000 new breast cancer cases are diagnosed in Turkey. Breast
cancer incidence and prevalence rates in Western Turkey in 1992 are 24.4/1000,000 and 0.3%
respectively (Fidaner et al., 2001). The incidence is heterogeneous in different regions of Turkey
due to geographic, economic, social, cultural factors. Breast cancer incidence in western part of
Turkey (50/100,000) is more than two times in Eastern part of Turkey (20/100,000) due to
‘‘Westernizing life’’ (early menarche, late menopause, first birth >30 years, less breast feeding,
etc.) (Ozmen, 2007; 2008a,b). Low and middle-income countries including Turkey now face the
challenge of effectively detecting and treating a disease that previously was considered too
uncommon to merit the allocation of precious health care expenses.
Box 49-1 Important characteristics of breast cancer*
Breast cancer is the most common cancer of women, comprising 23% of all female
cancers around the globe, with an estimated 1.15 million cases diagnosed in 2002.
There is marked geographical variation in incidence rates, being highest in the devel-
oped world and lowest in the developing countries in Asia and Africa.
In most low and middle income countries (LMCs), incidence rates are increasing at a
more rapid rate than in areas where incidence rates are already high. Global breast
cancer incidence rates have increased by about 0.5% annually since 1990, but cancer
registries in China are recording annual increases in incidence of 3–4%.
Prognosis from breast cancer is rather good, although globally it still ranks as the
leading cause of cancer mortality among women. Very favorable breast cancer survival
rates in the United States and other developed countries have been attributed to early
detection by screening mammography, and by timely and effective treatment.
The clinical features of breast cancer include palpable mass in the breast, skin and/or
nipple retraction, bloody or serous discharge from the nipple, and these are not early
signs of the disease. Non-palpable breast cancer can be detected by screening mam-
mography, and it increases survival and breast conserving surgery rate, and reduces
social, economic and psychological burden of breast cancer.
The treatment of breast cancer requires multidisciplinary approach and therapeutic
facilities (surgery, systemic therapy, radiation therapy, liaison psychiatry etc.). Mastec-
tomy is the treatment of choice in LMC due to late diagnosis at presentation and lack
therapeutic facilities.
*The content of this box describes the key facts of breast cancer, including epidemiology, clinical features, outcomes and
treatment
Poorer survival in LMCs is largely due to late presentation of the disease, which when
coupled with limited resources for diagnosis and treatment, leads to particularly poor
outcome. Five year overall survival rate is 88% in developed, 60% in LMCs respectively.
Compounding the problem of late diagnosis, breast cancer case fatality rates are high,
because LMCs typically lack major components of health care infrastructure and
resources necessary to implement improved methods for early detection, diagnosis
and treatment of breast cancer.
Prognosis from breast cancer is rather good, although globally it still ranks as the leading
cause of cancer mortality among women. Very favorable breast cancer survival rates in the
United States and other developed countries have been attributed to early detection by
screening, and by timely and effective treatment (Weir et al., 2003). For example, as reported
in the population-based case series from the Surveillance, Epidemiogy, and End Results
(SEER) program women diagnosed with breast cancer between 1990 and 1992, the 5-year
survival rate of 13,172 was 89% (Sant et al., 2004). By contrast, age-adjusted survival rates for
breast cancer in developing regions average 57% and are as low as 46% in India and 32% in
sub-Saharan Africa (Parkin et al., 2005).
In addition to the mentioned heterogeneity in incidence of breast cancer in Turkey, breast
cancer mortality also shows differences in different regions of Turkey depending on breast health
awareness, diagnostic and therapeutic facilities. In a study evaluating 1841 breast cancer patients
from Istanbul Medical Faculty, the 5 years breast cancer mortality rate was similar to rates for
developed countries (86% and 85% for patients with breast conserving surgery, and mastectomy
respectively, median follow up 76 months). This rate was low in Diyarbakir and other cities in
East Anatolia (around 60%) due to advanced stage at diagnosis lack of breast cancer awareness,
and other social, educational, cultural and economic barriers to early diagnosis and effective
treatment. Surgical procedure was modified radical mastectomy (MRM) in 66%, and breast
conserving surgery in 34% of patients (Karanlik et al., 2006).
A population-based cancer registry, covering the province of Izmir (population 2.7 million,
1993–1994) in Western Turkey was established in 1992 (Fidaner et al., 2001). Overall cancer
incidence was higher in males than in females (age-standardized rates 157.5 and 94.0 per
100,000, respectively), as in previous non-population-based series. The principal cancers
in males were tobacco-related - lung (age-standardized incidence rate (ASR) 61.6), bladder
(ASR 11.0) and larynx (ASR 10.6), consistent with the high prevalence of smoking, and use of
traditional high-tar tobaccos. In women, breast cancer was by far the most common malig-
nancy (ASR 24.4); cervical cancer was relatively rare (ASR 5.4). The estimations (Tuncer, 2008)
regarding the total female population which have the probability of being diagnosed to have
breast cancer, when the same conditions and environment conditions continue to exist in the
period 2007–2012 in Turkey are presented in > Table 49-1.
3 Risk Factors for Breast Cancer
In a prospective survey conducted by Ozmen et al. breast cancer risk factors in Turkish women
were studied (Ozmen et al., 2007). The participants were women admitted to clinics of
Istanbul Faculty of Medicine for examination and/or treatment. The control group was
selected from the waiting area of different clinics without breast cancer by convenience
. Table 49-1
Estimated number of breast cancers (females)
Years Number of breast cancer cases

2007 44,253
2008 45,696
2009 47,205
2010 48,809
2011 50,399
2012 51,99
sampling (n = 2,167) whereas patients with breast cancer were either selected from patients
visiting our Breast Clinic for follow-up, or from our breast cancer database (n = 1,492). The
results suggested that, being greater than or equal to age 35 years old, having induced
abortion, multiparity (1), late age at first birth (35 years old), late age at menopause
(50 years old), body mass index (BMI) 25 and having first-degree family history of breast
cancer were risk factors for breast cancer in Turkish women. Higher educational level (high
school), having induced abortion, cigarette smoking, oral contraceptive usage, breast-feeding
more than one child (unrelated to total period of breast feeding) reduced breast cancer risk.
Factors including use of hormone replacement therapy for 5 years or more and alcohol
consumption are not found to be associated with breast cancer risk (> Tables 49-2 and
> 49-3).
. Table 49-2
Factors increasing breast cancer risk in Turkish women (Ozmen, 2008a,b)
Breast cancer
Factors Control (n = 2,167) (n = 1,492) OR (95% CI) P value
Age (>35 years) 75% 94.5% 5.75(4.51–7.35) <0.001
Induced abortion 42.9 49.7 1.31 (1.13–1.53) <0.001
Menopause(>50 years) 28.3 34.9 1.36 (1.11–1.68) 0.002
BMI (>25) 44.8 64.2 1.46 (1.27–1.68) <0.001
Family history 5.0 7.2 1.46 (1.11–1.92) 0.002
. Table 49-3
Factors decreasing breast cancer risk in Turkish women (Ozmen, 2008a,b)
Breast cancer
Factors Control (n = 2,167) (n = 1,492) OR (95% CI) P value
Education (>12 years) 48.8% 40.3% 0.71 (0.62–0.81) <0.001
Spontaneous abortion 28.9% 22.5% 0.71(0.60–0.85) <0.001
Smoking 30.0% 23.5% 0.72 (0.61–0.85) <0.001
Lactation (>12 months) 55.7% 45.9% 0.67 (0.58–0.78) <0.001
National Federation of Breast Societies of Turkey funded in 2001 and has a breast cancer
registry program since 2005 (http://www.mdkk.org/memekanseri). In this registry program,
11,208-breast cancer patients were recorded till February 2008, 20.2% of them were 40 years
old (Ozmen, 2008a,b). Breast cancer in women under 35 years of age has been reported in the
West to account for 2–4% of all breast cancer cases (Shaw de Paredes et al., 1990), and only
6.5% of all breast cancers are detected in women under the age of 40 (Hankey et al., 1994). Our
young women breast cancer incidence is similar to other Middle Eastern and Asian countries
(Agarwal et al., 2007). Although this finding may be partially due to the age structure of the
population in Turkey, age-adjusted incidence still found that a higher proportion of young
women who present with breast cancer in this locality. There is also documentation that,
although the Asian population has a lower incidence of breast cancer, they have an earlier age
at maximal risk and less increase after menopause (Liede and Narod, 2002). The full reason for
the peak of onset of breast cancer at the age of 40 is still unclear. This may be attributed in part
to a more Westernized lifestyle, reflected by a significant difference in the mean age at first live
birth and mean age of menarche in our cohort. Further studies on the predisposition and
gene-environmental interaction in this age group (Juon et al., 2000; Robson, 2004) may
increase this understanding.
4 The Positive Effect of Early Diagnosis on the Burden
There is solid evidence supporting the value of early diagnosis of breast cancer and guidelines
on early detection are available. The only screening method that has been demonstrated to
reduce mortality from breast cancer is mammographic screening (Nystrom et al., 1993; Smith
et al., 2004). However, mammography is expensive and requires manpower and technical
expertise that is not affordable in most low-middle income countries. As a result, it was
recommend that breast health awareness (BHA) should be promoted to all women at the basic
level. In addition to this basic facility, further development will require training of relevant
staff to perform clinical evaluation, including taking a history and performing a clinical breast
examination (CBE) for both symptomatic and asymptomatic women.
There are socio-cultural, educational, economic barriers to breast cancer detection that
need to be overcome among women in Turkey. In some cultures, men who may be unaware of
breast screening as an effective, life-saving modality control the woman’s decision and actions.
According to Turkish Breast Cancer Registry Program, breast cancer stages at diagnosis were
27% (Stage I), 53% (Stage II), 9% (Stage III), and 6% (Stage IV), respectively (Ozmen,
2008a,b). Ninety percent of the patients admitted to the clinics with a complaint of a painless
mass in the breast, only 4.28% of patients had an opportunistic screening mammogram and
non-palpable breast cancer (Ozmen, 2008a,b).
In a study conducted by Yücel et al. (2005), the knowledge about breast cancer and
mammography on breast cancer screening among 298 women (between 29 and 79 years old)
awaiting for mammographic examination was investigated with a through interview. The
perception of susceptibility to breast cancer, severity of the disease, barriers to breast cancer
screening, and perceived benefits of mammography were determined. The patients’ knowledge
about the risk factors of breast cancer and self-examination were also assessed. The most
striking points in this study was that 95.3% of respondents knew that women should have
had periodic mammographic evaluations and 87.6% of them were aware of the fact that
mammography could find early occult breast cancer. However, 47% had never had a mam-
mography-screening test. Authors concluded that, despite expectations, knowledge about
breast cancer and mammography screening was not low in the study population, although
participation in mammography screening tests was less than optimal (Yucel et al., 2004).
As stated by Nahcivan and Seckingil (2007), women in Turkey are at great risk for
advanced and metastasic breast cancer because of their lack of knowledge. In their studies
Nahcivan and Seckingil (2007) found that women with knowledge about breast cancer had
more confidence in their abilities to perform breast self examination and were more likely to
practice breast self examination.
5 Healthcare Coverage Systems in Turkey
To better understand the impact of breast cancer and its treatment on the Turkish patients and
the nation, healthcare coverage systems in Turkey should be considered. The current health-
care coverage systems in Turkey are classified into 5 groups:
1. Civil Servants Medical Benefit Scheme (CSMBS).
2. Social Security Scheme (SSS) and Workmen’s Compensation Scheme.
3. Universal Coverage Scheme.
4. Self Employment Scheme.
5. Private Insurance Scheme.
The CSMBS provides full healthcare coverage to government officers, state enterprise employ-
ees and their family members in public hospitals and government medical schools for both
ambulatory and in-patient care. Partial coverage for in-patient healthcare services in private
hospitals is also provided. The CSMBS covers a total number of 4 million people – approxi-
mately 6% of the population in Turkey – with expenditures increasing dramatically every year.
The SSS provides the biggest healthcare coverage to formal private-sector employees and
some public-sector employees in Turkey. All employees covered in this scheme as well as their
employers contribute 5% of their gross wage for healthcare insurance in the Social Security
Fund. Healthcare services have to be delivered by pre-specified providers. Healthcare services
in other hospitals are not reimbursed except for emergency cases or formal referral. The SSS
covers the expenses of drugs listed in the NLED only; otherwise patients have to pay by
themselves. This scheme covers approximately 35 million people (50%) in Turkey.
The UC scheme was introduced in 1987 to replace the Healthcare Green Card Scheme and
Health Welfare for the low income and underprivileged groups. This scheme provides basic
coverage for 5.4% of the Turkish population, about 13 million people. Similar to the SSS,
people covered by the UC scheme are required to attend a pre-specified primary care unit
(PCU) or hospital. Drugs listed in the NLED are available without any co-payment but those
not listed in the NLED are not covered.
Private Insurance Scheme provides health care coverage for private hospitals and medical
schools, and its broadness depends on the payment of insurance owner. About 1.5% of the
Turkish population has private insurance.
6 Financial Burden of Breast Cancer and its Treatment
Breast cancer screening programs and breast health awareness in developed countries
increased non-palpable breast cancer and breast conserving treatment rate up to 75%. Breast
cancer mortality rate also reduced 50% in last 25 years. Low-resource countries have not
identified cancer as a priority health-care issue because infectious diseases and malnutrition
are a predominant public health problem. Compounding the problem of late diagnosis, breast
cancer case fatality rates are high because low and middle income countries typically lack
major components of health-care infrastructure and resources necessary to implement
improved methods for early detection, diagnosis, and treatment of breast cancer. Advanced
stage breast cancer (Stage III and IV) rate is 15–20% in western part, and 75% in eastern part
of Turkey (Ozmen, 2008a,b).
Early diagnosis of breast cancer decreases treatment costs, which increase in correlation
with stage. Indeed, in the calculations conducted by Yazihan et al. (2006) treatment costs at the
end of a 6 years period evidently dropped following screenings. Authors concluded that this
would surely affect the life span and life quality of the patient and that this is also supported by
DALY calculations (Yazihan et al., 2006).
Early diagnosis and effective treatment of cancer requires high medical technology,
diagnostic and therapeutic facilities, educated health care professionals, specialists which in
turn leads to an increase in health expenditures and the pressure on social resources. More-
over, not only diagnosis and treatment, but also the programs developed for prevention and
early diagnosis, and cancer registry require significant amounts of financial resources. But it is
well known that early diagnosis and effective treatment of breast cancer are more cost effective
than treatment of advanced disease.
7 The Burden of Mastectomy

After the initial diagnosis of breast cancer, patients are assessed for dissemination of disease, local
and systemic treatments. Complete history, clinical breast examination, and review of imaging
studies, and interactive discussion with the patient for treatment options and possible breast
reconstruction are crucial elements of the management. In patients with stage II and I
breast cancer, surgery is the treatment of choice. In patients with locally advanced breast cancer
(stage III), systemic therapy is first choice (neo-adjuvant chemotherapy). Distant metastatic
breast cancer mostly requires systemic therapy. There are two surgical treatment options for
patient with stage I and II breast cancer. Breast conserving surgery can be applied for patients with
small tumors localized at the one quadrant of the breast. Tumor/breast ratio should be convenient
for good cosmetics. This treatment also requires radiation therapy to all breast and additional
boost radiation, and additional cost for radiation therapy. Breast conserving surgery consists of
70–80% of surgical procedures in patients with early breast cancer (Stage I, II) in developed
countries by the way of screening mammogram. The other alternative is modified radical
mastectomy (MRM). In patients with multicentric and large tumors, MRM is performed.
MRM is the treatment of choice in low and middle income countries due to advanced stage at
diagnosis and lack radiation therapy facilities. Breast conserving surgery can be provided as a
limited resource, but requires proper breast conserving radiation therapy planning. If it is
unavailable, patients should be transferred to a higher-level facility for radiation. Breast conserv-
ing surgery rate is around 35–50% in central and western part of Turkey. But more than 90% of
breast cancer patients in Eastern part of Turkey have MRM (Ozmen, 2008a,b).
Surgical procedures for breast cancer and their definitions have explained in > Table 49-4
and > Figure 49-1.
Despite of advances and changing paradigms, surgery still preserves its important place in
the management of breast cancer treatment. Surgery for breast cancer has evolved over the
. Table 49-4
Outline of breast cancer surgeries and corresponding procedures
Type of surgery Procedure

Breast conserving surgery: Lumpectomy (wide Includes only the removal of tumor with at least
tumor excision with clear surgical margins) 1 cm normal breast tissue. In patients cN1 or cN0
Sentinel lymph node biopsy(SLNB) + axillary but SLNB+, axillary lymph node dissection is
lymph node dissection if SLNB(+) performed
Modified radical mastectomy En block removal of the breast and axillary lymph
nodes
Skin sparing or subcutaneous mastectomy Conserving breast skin with or without nipple-
Sentinel lymph node biopsy +axillary lymph areola complex and reconstruction with
node dissection (if SLNB(+) and breast prosthesis or latissimus dorsi/TRAM muscle flaps
immediate reconstruction In patients cN1 or cN0 with SLNB+, axillary lymph
node dissection are necessary
Radical mastectomy (It is a historical surgery Block removal of entire breast, pectoral muscles,
performed from 1890s to 1980s) and all axillary lymph nodes
. Figure 49-1
Surgical procedures for patients with breast cancer. BCS breast conservation surgery; MRM
modified radical mastectomy
past century from Halsted’s radical mastectomy to breast conservation surgery (BCS) with a
period of extended radical mastectomy common during the 1960s. Currently, MRM or BCS is
the standard-of-care for surgical treatment of breast cancer Mastectomy rate is over 90% in
east, and 35–40% in west part of Turkey. This type of surgery consists of removal of the breast
and all level axillary lymph nodes.
Breast cancer is mostly in advanced stage (70–80%) in low-middle income countries and
mastectomy is the only alternative as surgical procedure. In Turkey, stage III breast cancer rate
is 15% in Middle West Anatolia, and 75% in east Anatolia (Ozmen, 2008a,b). Breast conserv-
ing surgery rate is 35.9% and 3% in these two different geographical regions.
MRM essentially has two components, excision of the breast together with the axilla. But,
its high morbidity rate reaches over 50%, and lymphedema and loss of body image are most
important complications. Breast cancer treatment including MRM has also a significant
financial, socio-economic (such as; late return to work and daily activities, loss of productivity,
care and treatment expenses, longer hospitalization and limitation of shoulder and arm
movements in operated site), psychological and psychosocial burden on the patients, families
and the society.
The experience of any type of surgery is widely regarded as a stressor or a stressful life event,
which has great impact on patients’ financial, physiological, psychological and psychosocial
statuses According to Noyan et al. (2006); many women in Turkey see mastectomy as the
mandatory option. The National Cancer Data Base for 1999 lists 3,193 patients, with 9.24%
incidence, treated for breast cancer; most women underwent mastectomies (Noyan et al., 2006).
Government payment for mastectomy expenses is two times more than breast conserving
surgery (400 USD vs. 800 USD), and patients who require mastectomy have more advanced
stage at diagnosis. And, life expectancy is low, therapeutic costs are high (longer hospitalization
and systemic chemotherapy, loss of work and productivity, breast reconstructions if available).
Cost effectiveness calculation for hospital based diagnosis and treatment for breast cancers
based on the findings of National Burden of Disease Project are provided in > Table 49-5.
8 Psychological and Psychosocial Burden of Mastectomy

In addition to other known costs of breast cancer and its treatment, one key element in
increased burden of mastectomy is the psychological health of the patients. When psychologi-
cal health is negatively affected this in turn causes other disease related consequences in the
economic, familial and personal life of the patient. Related literature shows that the highest
percentage of psychiatric disorders is seen after the cancer surgery. (Reither and Stoudemire,
1987). Undergoing any surgical procedure following a diagnosis of breast cancer is a disturb-
ing and a distressing experience, that give rise to certain fears and anxieties related with the
surgery itself and other underlying psychological problems in the patients.
The psychological implications of mastectomy are doubled as these women face the
distress and disfigurement caused by the loss of the breast in addition to the fear of a
potentially life-threatening disease. Around 50% of women undergoing mastectomy or lump-
ectomy suffer clinically high levels of anxiety or depression prior to surgery and almost one-
third still report psychological problems 1 year later (Goldberg et al., 1992). Another study
reported that one in four women had significant psychological symptoms 12 months after
mastectomy, depression, anxiety, and > sexual dysfunction being the most prevalent disorders
(Dean, 1987).
. Table 49-5
Cost effectiveness calculation for hospital based diagnosis and treatment for breast cancers
Cases to be treated 16.883

Incidence cases 16.883
No. of deaths 4.043
YLL 49.063
YLD 17.062
Deaths without treatment (%) 0.55
Deaths without treatment 9.286
YLL without treatment 112.685
YLD without treatment 7.678
DALYs without treatment 120.363
DALYs saved 64.996
Cost/case (TL) 50.092.030.629.82
Cost/case (USD) 4.292.0
Total cost in TL 676.570.128.510.731.00
Total cost USD 57.970.079.37
Cost per DALY in TL 10.409.392.396.31
Cost per DALY in US dollars 891.90
(100% cases treated at hospital; Incidence rate (breast cancer): 24.9/100,000; Prevalence rate: 0.1/1,000). DALY
disability adjusted life years; YLD years of life lost due to disability; YLL years of life lost; Number of deaths (year
2000), YLL (2000), YLD (2000) are obtained from the Burden of disease calculations, cost of treatment / per case
were gathered from costing of health facilities and expert panels
In mastectomy patients’ specific fears, anxieties and difficulties that change due to
biological-psychological and cultural illness dynamics arise related with cancer and surgery.
Together with a serious experience of loss, mastectomy affects the daily functions, body image,
self-esteem, perception of ones body, psychological condition and relationships with the
environment. In addition, mastectomy may result in various other fears and anxieties; separa-
tion anxiety from the loved ones, fears loosing love, support, attention and approval due to
aesthetic anxieties and loosing basic functions and control of the body. Fears of
death, uncertainty related with the future, fears of recurrence feelings of guilt and fears of
punishment due to life style (smoking and alcohol usage, sexual life) are also common (Cooper
et al., 1989; Geer et al., 1990). In a patient with such anxieties various behavioral and emotional
reactions develop such as; shock, anxiety, denial, hostility, projection, pathologic dependency,
resistance and regression. In addition, the secondary problems such as pain, loss of sensation
and arm swelling is common among mastectomy patients resulting in further disability in daily
life. The side- effects and certain limitations brought by of adjuvant radiotherapy, chemother-
apy and hormone therapy adds on to the challenges that these women have to face. Most
prevalent psychiatric disorders in mastectomy patients are presented in > Table 49-6.
One important assumption derived from earlier studies is that major contributor to
psychopathology is the fact of cancer diagnosis (Özkan, 1993).
. Table 49-6
The most prevalent psychiatric disorders in mastectomy patients
Adjustment disorders
Depression and anxiety disorders
Sexual problems
Phobic reactions
Delirium
In a comprehensive, longitudinal study Özkan and Turgay (1992) investigated the psychi-
atric morbidity and psychosocial adjustment in mastectomy patients. The type, nature, and
prevalence of psychiatric morbidity associated with mastectomy and the factors relevant in
psychosocial adjustment were included in to the study. The results indicated that psychologi-
cal distress (mainly anxiety and depression) is most severe at early post-op and at 1 month
after the operation. Thirty-two percent of the patients in the pre-op period, 52% of the
patients in the post-op first month and 11% of the patients in the post-op first year were found
to be clinically depressed. The level of depression was higher in patients aged between 20
and 40, unmarried, with low education, patients who are not aware of the diagnosis and with
no spouse/partner support.
In addition, in Özkan and Turgay (1992) study anxiety disorders were found in 28% of the
patients in the pre-op period and 64% of the patients in the early post op period (1 week after
the surgery). Anxiety and depression decreased (gradually) at 1 year after the operation but
still did not decrease to premorbid level. Psychiatric morbidity was higher in those who were
not informed of their clinical conditions and of treatment alternatives, those who lack spouse’s
support, and in those with lower educational level. These patients demonstrated more severe
difficulties in psychosocial adjustment. The potential cause of psychiatric morbidity happened
to be the very diagnosis of cancer (and its implications) rather than the meaning of the loss of
the breast. Feeling under threat and fear of death and the associated anxiety is prominent,
rather than loss reaction associated with breast.
In all cases the first line distress focus was the fear of recurrence. Fear of recurrence was
high in the first year following total mastectomy (> simple (total) mastectomy) and decreased
with time. Differing from the Turkish literature, in western literature the first line distress
focus is reported to be related with femininity and sexuality. In the Turkish sample the second
distress focus was fears of loosing ones independency. Distress related with femininity and
sexuality was the third distress focus. Among the cases, 33% reported anxiety related with
body image and sexuality. This percentage is higher in western studies and in Eastern and far
eastern studies the percentage was reported between 10 and 11% (Özkan, 1993; Özkan and
Turgay, 1992). According to Noyan et al. (2006) although the breasts are a prominent symbol
of femininity, the emphasis placed on femininity is not highly valued in traditional groups
living in both rural and suburban areas in Turkey. According to the authors, Turkish cultural
belief has negative attitudes toward ‘‘preoccupation with femininity’’ and especially if a woman
is married, a mother, menopausal, or has had a mastectomy, society expects her to withdraw
her femininity. Although the loss of a breast is important to their sense of femininity and
attractiveness, only a small percentage of Turkish breast cancer patients have undergone breast
reconstruction. (Noyan et al., 2006).
Özkan and Turgay (1992) concluded that communication and medical psychotherapy
must focus mainly with the diagnosis of malignancy and the actual or perceived psychosocial
consequences. Important factors that increase the psychosocial adjustment and thus decrease
the psychosocial burden are summarized in > Table 49-7.
. Table 49-7
Factors that decrease the psychosocial burden
Communication
Providing information about the illness and treatment modalities
Encouraging emotional interaction
Support of the spouse
9 The Effect of Mastectomy on Body Image, Sexuality and

Marital Relationships
One of the other costs of mastectomy is its specific effect on intimate relationships and self-
esteem. In mastectomy applications body image is one of the important components of the
experienced distress and further adjustment. It is clear that women who consider body image
to be a major part of their sense of self-worth, attractiveness or wholeness are at an increased
risk of poor psychosocial adjustment following breast cancer surgery and this in turn increases
the burden of mastectomy.
As stated earlier, beyond being an organ that provides milk, breasts are strongly tied with
femininity and associated with the role of motherhood. Related with the value systems
attributed by the society breasts are symbols of femininity that have an important role in
sexuality. Sizable proportion of women described mastectomy as a mutilating and disfiguring
experience. Approximately a quarter of these women described negative effects on sexual
adjustment, including decreased frequency of intercourse, decreased sexual satisfaction, and
more difficulty in achieving orgasm (Burcham, 1997; Ganz et al., 1992).
The psychological squeal of surgical treatment for breast cancer on body image and
sexuality includes: embarrassment in exposing one’s body; discomfort showing scars, overall
body change; lack of sexual interest; problems with sexual relations and resumption of sexual
activity; general sexual dysfunction; sexual satisfaction and concern about frequency; and
difficulties with becoming sexually aroused (Burcham, 1997; Ganz et al., 1992).
Related literature involves studies that compare the effects of radical mastectomy and
partial mastectomy on body image, psychosocial adjustment, sexual life and recurrence
anxiety. The findings point out that the body image of women who had partial mastectomies
were more positive and fear of nudity is less prevalent. The effects of different surgical
approaches on psychological adjustment and quality of life have been also extensively
examined. A recent meta-analysis of 40 investigations examined post-surgical adjustment in

women who underwent partial or radical mastectomy. After controlling for unpublished
negative findings, body/self-image was the only factor that significantly differed between the
treatment groups, with women who underwent partial mastectomy reporting better body/self-
image (Cohen et al., 2000).
Yilmazer et al. (1994) conducted a study in order to compare the body image, social
support and self-esteem in total mastectomy and partial mastectomy patients in Turkey. These
two groups were compared in terms of body image, self-esteem and social support. The
women in the partial mastectomy group had more positive body images. The two groups
showed a negligible difference with respect to self-esteem and social support. Furthermore,
a negative correlation was found between body image and social support.
In another study, which aimed to examine the effects of surgery type on body image,
sexuality, self-esteem and marital adjustment, and to determine the most frequent sexual
dysfunction seen among breast cancer survivors, Sertöz et al. (2004) found that surgery type
had no effect on sexual satisfaction or on marital adjustment. Total mastectomy had a negative
impact on breast perception and self-esteem. Avoidance and non-communication areas of
sexual relations were the most frequent sexual dysfunctions seen among breast cancer survi-
vors. Furthermore, young patients preferred breast reconstruction more widely.
10 Burden Created on the Family
It is not possible to separate the experience of the breast cancer patient from the family of the
patient. The diagnosis of cancer is a traumatic experience for the entire family. Supportive
family relationships are particularly important to cancer patients due to the fear and uncer-
tainty associated with cancer. Related studies suggest that adjustment to cancer is better in
a family environment characterized by cohesiveness, open expression of feelings, and absence
of family conflict. Nevertheless, the fear of cancer, which leads cancer patients to need more
support from their families, also may interfere with how much support family members are
likely to provide (Friedman et al., 1988).
There is a reciprocal relationship between the partners’ adjustment and reactions with the
patients’ reactions and adjustment. As Baider et al. (2004) stated, the severity of depressive
symptoms experienced by a woman with breast cancer may be influenced by her appraisal of
the adequacy of support available from her partner. In their studies Hann et al. (2002)
reported that increased social support, larger network size, and higher perceived adequacy
of support from partners are associated with less depression in breast cancer patients.
A woman’s relationship with her partner may also suffer because a breast cancer diagnosis
can be highly distressing for a loved one. Quite often a spouse or significant other is confused
about the prospective effects of the illness and thus hide the feelings from the patient. This type
of behavior is more prevalent after mastectomy where the woman experiences a loss. Literature
on the area clearly presents that the partner relationship is unique and that additional social
support cannot overcome the negative effect of a distant husband on the female patient’s
emotional well being (Baider et al., 2004).
In addition, Northouse et al. (1998) found a high degree of correspondence between the
levels of adjustment reported by women with breast cancer and their husbands over time. Authors
discussed the importance of assisting couples, not just patients, to manage the adjustment
difficulties associated with breast cancer. Wellish et al. (1989) examined the reactions of
husbands of women who had a total mastectomy and breast reconstruction and reported
that husbands who had an active role in the decision making process had better psycholog-
ical adjustment. In addition, husbands displayed similar psychological reactions and distress
with their spouses throughout the course showing that the experience of breast cancer is a
shared experience for the couples. In a recent case study in Turkey, it was stated that
husbands of young women with cancer, especially gynecological and breast cancer perceive
the situation as highly traumatic and thus the marital relationship is negatively affected
(Hocaoğlu et al., 2007).
11 Breast Reconstruction after Mastectomy
Breast reconstruction is a common option for women undergoing mastectomy. It helps to

preserve body image and prevent organ loss. Breast reconstruction may be performed at the
time of mastectomy (immediate) or after all treatments for breast cancer completed (delayed
reconstruction). Reconstruction is cited to be the most commonly performed because women
have ‘‘the psychological desire to feel ‘whole’ again’’ and surgeons want to ‘‘restore self-image,
self-confidence and improve quality of life’’ (Clugston & Warren, 2001).
As presented above, breast cancer and mastectomy experience is perceived as a threat to life
and to the wholeness of the body and femininity. Although there is a slight increase in the
number of women preferring breast reconstruction in Turkey the number is still low when
compared with other countries. In a study performed in Istanbul Medical Faculty The Breast
Unit showed that breast reconstruction (immediate or delayed type) rate in patients with
mastectomy was 17% (Karanlik et al., 2006). The main reasons for this are; patients’ and their
families’ wishes, length of surgical time, extensive work load of operating rooms in medical
school and government hospitals, lack of breast and plastic reconstructive surgeons, fear of
recurrence and difficulty in diagnosis after recurrence, breast reconstruction surgery is not an
integral part of the management of mastectomy patients in some Turkish Health Care Systems,
the high costs of reconstruction and the operation is not covered by some private or National
Insurance Scheme (Noyan et al., 2006).
There are various studies proving the positive effects of breast reconstruction on the
psychological health of women with breast cancer. This intervention is very important in
overcoming the feeling of loss that accompanies mastectomy and in increasing the psycholog-
ical, social and sexual functionality of the patient. The effects of plastic and reconstructive
surgery on the body image, self-esteem and quality of life are also known. Reconstructive
options provide improved cosmetic outcomes for women with breast cancer. Earlier research
has suggested that conservation of the breast might alleviate the negative effects of breast
cancer on women’s sexual well being. The positive effects of this application, which contribute
to decrease the psychological burden, are summarized in > Table 49-8.
However, it is hard to suggest that only prosthesis application is sufficient in increasing
self-esteem, sexual desire, perception of attractiveness and sexual satisfaction. The overall
psychological state, characteristics of premorbid sexual life, the type of surgery and post
surgery sexual harmony are equally important. Some authors suggested that chemotherapy
and radiotherapy have more negative impact on the self-esteem and sexual life of women
(Rowland and Holland, 1990).
. Table 49-8
The positive effects of breast reconstruction
Increases and expands the relationships and social interactions

Positively affects body image
Supports psychological health
Increases self-esteem
Improves mood and body satisfaction
Improves social functioning
With the aim of establishing the demographical, medical, and psychological factors asso-
ciated with the breast cancer patient’s decision-making process, and assess their satisfaction with
the type of surgery received, Noyan et al. (2006) assessed patients with breast cancer who had
only mastectomy and women who had mastectomy and breast reconstruction surgery. Authors
reported that in both groups, women with a low income and less education were more likely to
experience decision regret or low satisfaction. Moreover, total mastectomy-alone patients had
lower self-esteem compared to reconstructive surgery patients and healthy women. According to
Noyan et al. (2006), Turkish breast cancer patients may be more concerned with surviving the
dreadful diagnosis of cancer than the presentation of their feminine form and, therefore, less
likely to be interested in breast reconstruction. In addition, according to the authors, Turkish
society’s attitude towards breast reconstruction is ‘‘not encouraging.’’ This common belief has
two outcomes: first, most our health insurance systems does not cover the breast implants or
breast reconstruction after mastectomy; second, women undergoing mastectomy are reluctant
to ask for breast reconstruction (Noyan et al., 2006).
12 Conclusion
When all the presented data covered in this chapter is taken in to account, it is clear that a
culturally sensitive approach is crucial in order to decrease the burden in breast cancer
patients. Within the cultural base, two important aspects stand aside. The first is the patients’
needs for more education and training regarding their illnesses. The other important conclu-
sion is the need for a more integrated treatment adapting the biopsychosocial approach for
cancer patients. Biopsychosocial approach to medicine views medical treatment and psycho-
logical treatment as a whole. This perspective involves an appreciation that disease and illness
do not manifest themselves only in terms of pathophysiology, but also may simultaneously
affect many different levels of functioning, from cellular to organ system to person to family to
society. The patients need psychological treatment and care besides medical treatment and
care before and after the surgery and throughout the treatment.
Within this understanding of providing psychological help to cancer patients and their
families psycho oncology is becoming widespread in Turkey in latest years. In the world,
psycho-oncology now has a recognized role within the oncology community through clinical
care, research, and training as it relates to prevention of cancer through lifestyle changes,
evaluation of quality of life, symptom control, palliative care and survivorship. Increasing
the knowledge regarding psycho-oncology in Turkey and expanding the application of

psycho-oncology in general hospitals is mandatory in order to decrease the psychological
and psychosocial burden of breast cancer and mastectomy in Turkey.
Summary Points
Carcinoma of the breast is the most common site-specific cancer and is the leading
cause of death from cancer in women with an estimated 1.15 million cases diagnosed in
2002.
Breast cancer incidence and prevalence rates in Turkey in 1992 are 24.4/1000,000 and 0.3%
respectively. More than 15,000 new breast cancer cases were diagnosed in Turkey in 2007.
Breast cancer incidence and mortality show changes in different regions of Turkey depend-
ing on breast health awareness, diagnostic and therapeutic facilities, social, economic and
educational factors.
Being greater than or equal to age 35 years old, having induced abortion, multi-
parity (1), late age at first birth (35 years old), late age at menopause (50 years
old), body mass index (BMI) 25 and having first-degree family history of breast cancer
were risk factors for breast cancer in Turkish women.
The only screening method that has been demonstrated to reduce mortality from breast
cancer is mammographic screening, but it is expensive and difficult to integrate in low and
middle income countries.
There are sociocultural, educational, economic barriers to early detection and effective
treatment of breast cancer in Turkey.
Breast cancer screening programs and breast health awareness in developed countries
increased non-palpable breast cancer and breast conserving treatment rate up to 75%.
Breast cancer mortality rate also reduced 50% in last 25 years.
MRM is the main surgery in patients with breast cancer, mean breast conserving surgery
rate changes from 35% (central and western of Turkey) to 5% (eastern part of Turkey).
The experience of any type of surgery is widely regarded as a stressor or a stressful life event
that requires coping and adaptation for a successful outcome.
Mastectomy patients’ specific fears, anxieties and difficulties that change due to biological-
psychological and cultural illness dynamics arise related with cancer and surgery.
In Turkey primary factors leading to psychopathology in mastectomy patients the are
related with the fears and perceptions related with the underlying illness (cancer) and less
related with organ loss.
The diagnosis of cancer is a traumatic experience for the entire family.
There is a reciprocal relationship between the partner’s adjustment and reactions with the
patients’ reactions and adjustment.
Although there is a slight increase in the number of women preferring breast reconstruc-
tion in Turkey the number is still low when compared with other countries.
A culturally sensitive approach is crucial in understanding the specific reactions and
experiences of Turkish breast cancer patients.
There is a need for a more integrated treatment adapting the biopsychosocial approach for
cancer patients.
Increasing the knowledge regarding psycho-oncology in Turkey and expand the applica-
tion of psycho-oncology in general hospitals is mandatory.
References
Agarwal G, Pradeep PV, Aggarwal V, Yip CH, Cheung PS. Nystrom L, Rutqvist LE, Wall S, et al. (1993). Lancet.
(2007). World J Surg. 31(5): 1031–1040. 341(8851): 973–978.
Baider L, Andritsch E, Goldzweig G. (2004). Psychoso- Özkan S. (1993). ‘‘İstanbul Tıp Fakültesi kliniklerinde
matics. 45: 58–68. psikiyatrik tıp hizmetlerinin gelişimi ve liyezon
Burcham J. (1997). ‘‘Breast Reconstruction: A Review of psikiyatrisi modelinin uygulanması’’, İ.Ü. İ.T.F. Psi-
the Research and Patient Professional Resources.’’ kiyatri ABD Profesörlük taktim tezi, İstanbul.
National Breast Cancer Center, Sydney. Özkan S, Turgay M. (1992). Nöro Psikiyatri Arşivi. 29(4):
Clugston P, Warren R. (2001). In: Glegg C (ed.) Intelli- 207–215.
gent Patient Guide to Breast Cancer: All you need to Ozmen V. (2007). J Breast Health. 3: 48–50.
know to take an active part in your treatment, 3 ed. Ozmen V. (2008a). J Breast Health (Meme Sağlığı
Gordon Soules Book Publishers Ltd., Vancouver, Dergisi). 4: 6–12. (www.memesagligi.org)
pp. 232–243. Ozmen V. (2008b). ‘‘Breast cancer screening and regis-
Cohen L, Thomas F, Hack J, et al. (2000). Ann Surg tration programms in Turkey’’. In: Tuncer M (ed.)
Oncol. 7(6): 427–434. Cancer Control in Turkey. Health Ministry Publica-
Cooper C, et al. (1989). Psychol Med. 19: 421–422. tion Number 740, Onur Press, Ankara, pp. 335–343.
Curado MP, Edwards B, Shin HR, et al. (ed.) (2007). Ozmen V, Cabioglu N, Gulluoglu B, Özcinar B. (2007).
‘‘Cancer Incidence in Five Continents’’, vol. IX. Survey on a pilot mammographic screening in Bah-
International Agency for Research on Cancer, cesehir, Istanbul, Turkey. Paper Presented at The
Lyon, France. IARC scientific publications no. 160. Breast Health Global Initiative Consensus Confer-
http://www-dep.iarc.fr/. Accessed 27 Dec 2007. ence,1–4 Oct 2007, Budapest, Hungary. http://www.
Dean C. (1987). J. Psychosom Res. 31: 385–392. fhcrc.org/science/phs/bhgi/
Fidaner C, Eser SY, Parkin DM. (2001). Eur J Cancer. Parkin DM, Bray F, Ferlay J, et al. (2005). CA Cancer J
37: 83–92. Clin. 55(2): 74–108.
Friedman PE, Baer DV, Nelson M, Lane FE, Smith D, Reither AM, Stoudemire A. (1987). In: Hackett TP,
Dworkin RJ. (1988). Psychosom Med. 50: 529–540. Cassen NH (ed.) Handbook of General Hospital
Ganz PA, et al. (1992). Cancer. 69: 1729–1738. Psychiatry. Year Book Medical publishers Inc.,
Geer S, et al. (1990). Lancet. 1: 49–50. Chicago, pp. 423–451.
Goldberg J, Scott R, Davidson P, et al. (1992). Eur J Surg Robson M. (2004). Clin Breast Cancer. 5: 260–268; dis-
Oncol.18: 327–331. cussion 269–271.
Hankey BF, Miller B, Curtis R, et al. (1994). J Natl Cancer Rowland JH, Holland JC. (1990). In: Holland JC,
Inst Monogr. 16: 7–14. Rowland JH (ed.) Handbook of Psychooncology.
Hann D, Baker F, Denniston M, Gesme D, Reding D, Psychological Care of The Patient With Cancer.
Flynn T, Kennedy J, Kieltyka RL. (2002). J Psycho- Oxford University Press, New York, pp. 188–207.
som Res. 52: 279–283. Sant M, Allemani C, Berrino F, et al. (2004). Cancer.
Hocaoğlu Ç, Kandemir G, Civil F. (2007). Meme Sağliği 100(4): 715–722.
Dergsi. 3(3): 163–166. Sertöz O, Elbi HM, Noyan A, Alper M, Kapkac M.
Juon HS, Choi Y, Kim MT. (2000). Cancer Detect Prev. (2004). Türk Psikiyatri Dergisi. 15(4): pp. 264–275.
24: 589–601. Shaw de Paredes E, Marsteller LP, Eden BV. (1990).
Karanlik H, Özmen V, et al. (2006). J Breast Health Radiology. 177: 117–119.
(Meme Sağliği Dergisi). 2: 89–95. (www.memesa- Smith RA, Duffy SW, Gabe R, et al. (2004). Radiol Clin
gligi.org) North Am. 42(5): 793–806.
Liede A, Narod SA. (2002). Hum Mutat. 20: 413–424. Tuncer M. (2008). ‘‘Significance of cancer in Turkey, the
Nahcivan NO, Seckingil S. (2007). Oncol Nurs Forum. burden of disease, and cancer control policies’’. In:
34(2): 425–432. Tuncer M (ed.) Cancer Control in Turkey. Health
National Disease Burden and Cost-Effectiveness Project. Ministry Publication No. 740, Onur Press, Ankara,
(2004). ‘‘T.C. Sağlık Bakanlığı Refik Saydam Hıfzıs- pp. 5–9.
sıhha Merkezi Başkanlığı Hıfzıssıhha Mektebi Weir HK, Thun MJ, Hankey BF, et al. (2003). J Natl
Müdürlüğü, Başkent Üniversitesi, Ulusal Hastalık Cancer Inst. 95(17): 1276–1299.
Yükü Ve Maliyet-Etkililik Projesi.’’ Wellisch D, et al. (1989). Psychosomatics. 30(4):
Northouse L, Teplin T, Mood D, Oberst M. (1998). 365–373.
Psychooncology. 7(1): 37–48. Yazihan N, Hakan H. (2006). Breast cancer in Turkey:
Noyan A, Sertöz OO, Elbi H, Kayar R, Yýlmaz R. (2006). Economic Efficiency and Cost Effectiveness, Cancer
Int J Psychiatry Med. 36(3): 299–313. Control in Turkey, Cancer Control in Turkey. Health
Ministry Publication, Number 740, Onur Press, and Mammography in Breast Cancer Screening
Ankara. among Women Awaiting Mammography. Turk.
Yİlmazer N, Aydİner A, Özkan S, Aslay I, Bilge N. (1994). J. Med Sci., 35: 35–42.
Support care cancer. 2(4): 238–241. Yücel A, Değirmenci B, Acar M, Ellidozkuz H,
Yucel A, Değirmenci B, Acar H, Ellidokuz H, Albayrak R, Albayrak R. (2005). Turk J Med Sci. 35: 35–42.
Haktanir A. (2004). Knowledge about Breast Cancer
50 The Burden of Chemotherapy
Induced Nausea and
Vomiting on Patients’ Daily
Lives: Italian Perspectives
E. Ballatori . F. Roila . B. Ruggeri . A. A. Bruno . S. Tiberti . F. di Orio
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 886
2 Current Therapies for Chemotherapy-Induced Nausea and Vomiting . . . . . . . . . . . . . 887
3 Antiemetic Prescriptions in Italy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 888
4 The Impact of CINV on Health-Related Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889
5 The Italian Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890
6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895
7 Features of Chemotherapy-Induced Nausea and Vomiting (CINV) . . . . . . . . . . . . . . . . 896
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897

886 50 The Burden of Chemotherapy Induced Nausea and Vomiting on Patients’ Daily Lives
Abstract: The Italian Group for Antiemetic Research evaluated the appropriateness of antie-
metic prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in two large
observational studies carried out in Italy in 1996 (antiemetic guidelines not yet published)
and 1999 (MASCC guidelines published in 1998). The pattern of prescription had improved,
but less than expected, given the published guidelines. A further study performed on cisplatin
treated patients showed that almost all patients received the recommended prophylaxis of
acute emesis, but only about half of them were treated according to the current guidelines.
The impact of CINV on patients’ daily lives was investigated using the Functional Living
Index or Emesis /> FLIE) questionnaire. Both acute and > delayed CINV were responsible for
the impact of CINV on patients’ daily lives, but their interaction was not significant: their
impact on patients’ daily lives is a simple sum of effects. About 50% of patients who
experienced either acute or delayed CINV had an impact on their daily life. This percentage
increased to up to 90% in patients who suffered from both acute and delayed CINV.
At a unifactorial analysis both intensity and > duration of CINV were found significant in
determining the impact of CINV on patients’ daily lives, but at a multifactorial analysis
adjusting for the effect of each variable on the other, only duration remained significant.
This finding suggests that the duration of CINV should be assessed with an accuracy much
greater than that currently used.
Despite the improved antiemetic prophylaxis, CINV is still prevalent and often impacts the
patients’ daily lives, especially in the delayed phase. A further effort should be made to reduce
the incidence of CINV not only by strengthening antiemetic research, but also by utilizing the
best antiemetic treatments in daily clinical practice.
List of Abbreviations: ASCO, American Society of Clinical Oncology; CINV, chemotherapy
induced nausea and vomiting; EORTC, European Organization for Research and Treatment of
Cancer; ESMO, European Society of Medical Oncology; FLIE, Functional Living Index for
Emesis; > HRQL, health-related quality of life; IGAR, Italian Group for Antiemetic Research;
LP, > Linear Predictor; MASCC, Multinational Association of Supportive Care in Cancer; NK1,
Neuro-kinine 1; NIDL, no (or minimal) impact on daily life; 30 items r.a., receptor antagonists;
QLQ-C30, EORTC Quality of Life Questionnaire-Core 30 items; r.a., receptor antagonists
1 Introduction
As long as 25 years ago vomiting and nausea ranked as the most distressing side effect of cancer
chemotherapy from the patients’ point of view (Coates et al., 1983).
Unfortunately, despite the progress achieved with the 5-HT3 receptor antagonists (r.a.),
chemotherapy-induced nausea and vomiting (CINV) remains a distressing adverse event. In
fact, in two studies carried out after their introduction in clinical practice, nausea still ranks as
the number one adverse event of chemotherapy of most concern to patients, with vomiting
ranking as the third and fifth most distressing symptom (de Boer-Dennert et al., 1997;
de Haes et al., 1990).
Therefore, in spite of the fact that the 5-HT3 r.a. were considered a real major advance in
the prevention and treatment of CINV, it seems that these agents have not had a major impact
on the incidence of chemotherapy-induced nausea.
CINV may manifest itself as either an acute (developing within 24 h of receiving chemo-
therapy), delayed (starting after 24 h after chemotherapy and persisting for several days),
The Burden of Chemotherapy Induced Nausea and Vomiting on Patients’ Daily Lives 50 887
or anticipatory (developing prior to start of a chemotherapeutical regimen) condition

(Beeckwith et al., 2001; Gralla et al., 1999).
Risk factors for acute nausea and vomiting include patient characteristics as well as the
type of chemotherapy. Patients who are young, female, non-drinkers, or who have experienced
prior episodes of CINV are most at risk for developing CINV. Certain chemotherapy com-
pounds, such as cisplatin and dacarbazine, almost always induce nausea and vomiting if the
antiemetic prophylaxis is not administered (highly emetogenic chemotherapy), while others,
such as cyclophosphamide and anthracyclines, induce a lesser incidence and severity of emesis
(moderately emetogenic chemotherapy). Finally, drugs such as 5-Fluorouracile, methotrexate,
vincristine and etoposide rarely cause emesis (chemotherapy with a low emetogenic potential)
Risk factors for delayed CINV include > acute CINV, and to a lesser extent chemotherapy
dose, and female gender. Characteristics such as a history of motion sickness, acute and
delayed CINV and young patients are associated with developing anticipatory CINV
Clinical consequences of CINV include esophageal tears, fracture, malnutrition, and acid-
base and electrolyte changes (Lindley et al., 1992b).
Patients who experience CINV may refuse subsequent chemotherapy cycles, thereby
compromising treatment efficacy. These clinical impacts of CINV may hamper patients’ ability
to perform their usual activities, thereby decreasing > health-related quality of life (HRQL).
They may also necessitate additional patient care such as nursing and physician time,
additional drug therapy or even hospitalization (Lindley et al., 1992a).
Aims of this article are to show the conditions of Italian cancer patients with respect to
their antiemetic prophylaxis as well as to evaluate the impact of CINV on their daily activities.
A brief overview of current practice patterns in managing CINV is necessary for a precise
evaluation of the results.
2 Current Therapies for Chemotherapy-Induced Nausea

and Vomiting
In the last 10 years some international oncological organizations, such as ASCO (American
Society of Clinical Oncology), ESMO (European Society of Medical Oncology) and MASCC
(Multinational Association of Supportive Care in Cancer), published recommendations about
the antiemetics to be used in preventing acute, delayed, and anticipatory emesis induced by
different chemotherapeutical regimens (Gralla et al., 1999; The Antiemetic Subcommittee of
the MASCC, 2006).
Before the antiemetic guidelines produced by the 2004 Perugia Consensus Conference
(The Antiemetic Subcommittee of the MASC, 2006), the regimen of choice for the prevention
of acute nausea and vomiting induced by both highly and moderately emetogenic chemother-
apy was represented by a combination of a 5-HT3 r.a. plus a corticosteroid (generally
dexamethasone) administered immediately prior to chemotherapy. This regimen was recom-
mended in both adults and children. No prophylaxis was recommended with regimens having
a low emetogenic potential (ESMO, 2001; Gralla et al., 1999).
The above-mentioned antiemetic guidelines also recommended a prophylaxis for delayed
emesis in patients submitted to both highly emetogenic chemotherapy (dexamethasone
plus either a 5-HT3 r.a. and metoclopramide) and moderately emetogenic chemotherapy
(dexamethasone).
Subsequently, two large studies on the effectiveness of aprepitant (a NK1 r.a.) added to
the standard prophylaxis showed that the most effective prophylaxis for acute CINV was
aprepitant + a 5-HT3 r.a. + dexamethasone, in both highly and moderately emetogenic
chemotherapy (The Antiemetic Subcommittee of the MASCC, 2006). Unfortunately, due to
two mistakes in the study design, the role of aprepitant in preventing delayed emesis still
remains unclear.
All the results of the studies were obtained before the introduction of aprepitant, and
therefore they should be evaluated according to the 1997 Perugia Consensus Conference
recommendations (MASCC, 1998).
3 Antiemetic Prescriptions in Italy

It is evident that the results of antiemetic trials can be reproduced in daily clinical practice only
if the prescription is made according to the antiemetic guidelines, or, when these are lacking,
to the published results of clinical trials.
The Italian Group for Antiemetic Research (IGAR) performed in 1996 a large prospective
observational study in 33 oncological centers aimed at evaluating the pattern of antiemetic
prescriptions in comparison with the published results of several antiemetic trials (IGAR, 1998).
More precisely, the results of antiemetic research had shown that the best antiemetic
prophylaxis for acute emesis was a 5-HT3 r.a. + dexamethasone for both cisplatin (IGAR,
1992) and moderately emetogenic chemotherapy (IGAR, 1995). Moreover, the prophylaxis
for delayed emesis should be prescribed in both cases.
The main results of the first study (IGAR, 1998) are summarized in > Table 50‐1.
From these results, the most critical points are:
a) About ¼ of patients submitted to cisplatin-containing chemotherapy did not receive the
best prophylaxis for acute emesis; moreover, prophylaxis for delayed emesis was not
prescribed for about half of them.
b) Less than half of the patients submitted to moderately emetogenic chemotherapy received
the best prophylaxis for acute emesis (1.5% were not treated), and to 2/3 of them no
prophylaxis for delayed emesis was prescribed.
In addition, over treatment was observed in about half the patients receiving low emetogenic
chemotherapy (data not shown).
Three years later, a new audit of clinical practice was performed by the IGAR (Roila and IGAR,
2004). In the meantime, the first Perugia Consensus Conference on antiemetics (1997)
recommended, for both highly and moderately emetogenic chemotherapies, a 5-HT3
r.a. + steroid to control acute emesis, and, as prophylaxis for delayed emesis, in cisplatin
treated patients a steroid + either a 5-HT3 r.a. or a benzamide. Instead, for patients who
underwent a moderately emetogenic chemotherapy the recommendation was either a 5-HT3
r.a. or a steroid, but only in patients who suffered from acute CINV (MASCC, 1998).
From 16 to 29 March 1999, all consecutive patients admitted to 103 Italian oncological
centers were enrolled. Overall, 3,024 of 4,477 observed patients received 1-day chemotherapy,
and among those 2,169 patients were considered: 270 were submitted to cisplatin-containing
chemotherapy, 1,566 to high-moderate emetogenic chemotherapy, and 333 to a low
. Table 50‐1
Percentage of antiemetics used for prophylaxis for both acute and delayed emesis with respect
to emetogenic potential of cancer chemotherapy (1996)
High (cisplatin) Moderate

Acute Delayed Acute Delayed
No. of patients 140 74 731 249
5-HT3 + steroid 76.4 5.0 42.3 1.6
5-HT3 alone 22.9 23.6 46.0 23.1
Benzamides alone 7.9 4.3 5.1
Benzamides + steroids – 15.7 2.7 0.8
Steroids alone – 0.7 2.8 2.7
Other 0.7 – 0.4 0.1
No antiemetics – 47.1 1.5 66.4
MASCC antiemetic guidelines (MASCC, 1998) had not yet been published. The results of antiemetic research
suggested, however, that all patients submitted to both high and moderate emetogenic chemotherapy should be
treated for preventing both acute and delayed emesis. More precisely, a 5-HT3 r.a. + corticosteroid should be used
to prevent acute CINV, in both cases. Moreover, for the prevention of delayed CINV, patients submitted to highly
emetogenic chemotherapy should receive a corticosteroid+ either a 5-HT3 r.a. or a benzamide (metoclopramide).
In 1996, the optimal prophylaxis for delayed emesis for patients submitted to moderately emetogenic chemo-
therapy was less clear. In > Table 50-1, about ¾ of patients submitted to cisplatin-containing chemotherapy and
less than ½ of patients submitted to moderately emetogenic chemotherapy received the optimal antiemetic
prophylaxis for acute CINV. For about 2/3 (½) of patients submitted to moderately (highly) emetogenic
chemotherapy, respectively, a prophylaxis of delayed CINV was not prescribed
emetogenic potential chemotherapy. The other 855 patients were excluded mainly because
they were treated with chemotherapeutical regimens different from those considered in the
MASCC classification. The results of the study (Roila and IGAR, 2004) are extremely rich, but
in this chapter only the totals have been extracted (see > Table 50‐2), in order to compare
them with the results shown in > Table 50‐1.
As can easily be seen, the pattern of prescription has improved, but less than what could be
thought given that the guidelines were published 1 year before:
a) prophylaxis for acute emesis: for cisplatin treated patients the percentage of standard
prophylaxis increased from 76.4% to 80.1%; moreover, all patients submitted to moderate
emetogenic chemotherapy received antiemetic prophylaxis for acute CINV;
b) the percentages of no treatment against delayed emesis decreased from 47.1 to 37.5% in
cisplatin-treated patients, and from 66.4 to 53.3% in patients submitted to moderately
emetogenic chemotherapy.
In conclusion, although the prophylaxis for CINV in Italy has improved, many patients still
do not receive the antiemetic treatment recommended by the MASCC guidelines.
4 The Impact of CINV on Health-Related Quality of Life
There are several means to measure the impact of CINV on a patient’s ability to perform
his/her activities of daily life. Because of the importance of CINV symptoms in terms of
incidence and severity, many valid quality of life questionnaires incorporate two or more items
. Table 50‐2
Percentage of antiemetics used for prophylaxis for both acute and delayed emesis with respect
to emetogenic potential of cancer chemotherapy (1999)
High (cisplatin) Highly-moderately

Acute Delayed Acute Delayed
No. of patients 272 272 1566 1566
a b a
Total standard prophylaxis 80.1 26.8 61.0 34.8c, d
No antiemetics – 37.5 – 53.3
About ½ of patients submitted to moderately emetogenic chemotherapy, and about ⅓ of patients submitted to
highly emetogenic chemotherapy prophylaxis for delayed CINV was not prescribed. With respect to 1996,
antiemetic prescription had improved but it is still far from the recommendations of antiemetic guidelines
a
5-HT3 r.a. + steroids
b
Steroids+ either benzamides or 5-HT3 r.a
c
Either 5-HT3 r.a. or steroids
d
Standard prophylaxis for delayed emesis in patients submitted to moderately emetogenic chemotherapy was
considered either a 5-HT3 r.a. or steroids, because a treatment should always be prescribed
to assess the burden of CINV on a patient’s Health-Related Quality of Life (HRQL).

For instance, the most used questionnaire in Europe, the EORTC (European Organization
for Research and Treatment of Cancer) Quality of Life Questionnaire (QLQ-C30) has two
items aimed at evaluating the importance of CINV on the patient’s daily life. Therefore, the
extraction of the response to these items could be used to reach the above-mentioned goal, and
this information can be useful when planning a study to evaluate a patient’s HRQL.
There is only one validated specific questionnaire able to measure the impact of CINV on a
patient’s HRQL: the Functional Living Index for Emesis (FLIE) (Lindley et al., 1992a,b; Martin
et al., 2003).
The FLIE questionnaire includes 9 items concerning vomiting plus nine items concerning
nausea. The content of the items is shown in > Table 50‐3. Responses for each item are marked
on a 100-mm visual analogue scale graduated from 1 to 7 points. Each domain score (i.e.,
nausea and vomiting) ranges from 9 (maximum impact) to 63 (no impact) with high scores
reflecting less impact on daily life. To calculate a FLIE domain score, the patient must answer
at least five of each of the nine FLIE domain items. If there are some missing responses, the
mean score calculated on the given responses is assigned to each of them. The FLIE question-
naire must be completed two times: FLIE1 before chemotherapy administration, and FLIE2 at
the sixth day after chemotherapy administration, in both cases with a 5-day recall.
The importance of evaluating the burden of CINV on a patient’s daily life is derived from
the fact that CINV does not have an impact on the HRQL of all patients who experience it.
Therefore, the analysis of this impact should be carried out only in patients who suffered from
CINV. This could seem obvious, but there are some clinical studies where this impact was
assessed on all the enrolled patients.
5 The Italian Experience
Several studies have been carried out to evaluate the impact of CINV on a patient’s daily life
(Lindley et al., 1992b; Osoba et al., 1997; Uyl-de Groot et al., 2000), but this issue has received
little attention in Italy. This prompted us to perform a study on this topic (Ballatori et al., 2007).
. Table 50-3
Content of the items of FLIE questionnaire
Nausea domain Vomiting domain

Quantity of nausea Quantity of vomiting
Ability to maintain usual recreation or leisure Ability to maintain usual recreation or leisure
activities activities
Ability to make a meal or do minor household Ability to make a meal or do minor household
repairs tasks
Ability to enjoy a meal Ability to enjoy a meal
Ability to enjoy liquid refreshment Ability to enjoy liquid refreshment
Willingness to spend time with family/friends Willingness to spend time with family/friends
Affected daily functioning Affected daily functioning
Imposed personal hardship Imposed personal hardship
Imposed hardship on others Imposed hardship on others
This prospective observational study was carried out in 2003 in seven Italian oncological
centers: three in northern, 2 in central, and 2 in southern Italy and the islands. We used wide
inclusion criteria to evaluate study outcomes under conditions of daily clinical practice.
Consecutive patients aged at least 18 years, affected by any cancer at any stage, and who had
to be undergoing a first cycle of cisplatin-containing chemotherapy (at a dose >50 mg/m2)
were eligible for enrollment.
Other than from the case record form, data were obtained from a diary card where the
patients recorded information about their CINV and any drug received. Finally, they were
asked to fill out both FLIE1 and FLIE2. Only FLIE2 was analyzed considering separately the
impact for nausea and vomiting. “No (or minimal) impact of nausea (or vomiting) on daily
life (NIDL)” was defined as a domain score 54 whereas an impact of nausea (or vomiting)
was defined as a domain score < 54.
Multifactorial logistic models were performed separately for nausea and vomiting, assum-
ing as dependent variable the impact of CINV on the patient’s daily life (1 – NIDL). The
presence of acute and delayed nausea and vomiting was considered as two explanatory
variables so as to assess their importance in affecting the patient’s daily life. To evaluate the
importance of both duration and severity in determining the impact of CINV on a patient’s
ability to perform daily activities, they were examined separately for nausea and vomiting.
Duration was defined according to the number of days during the 5-day period
when patients experienced either nausea or vomiting: 3 of 5 days was considered a long
time, 2 days was considered a not so long time. It is a rough indicator of duration, but the
information collected using the adopted diary card did not allow us a more precise evaluation.
The > intensity of vomiting was considered to be severe or less severe if the number
of emetic episodes was 3 or 2, respectively, during the 5-day period. The maximum
> intensity of nausea was evaluated using a Likert scale (“No nausea”; “Mild nausea,” which
allows the patient to do his daily activities; “Moderate nausea” which does not allow the
patient to do his daily activities; “Severe nausea” when the patient is bedridden due to nausea).
The intensity of nausea was defined as the patient’s peak intensity rating during days 1 to 5,
and was dichotomized in moderate-to-severe and mild.
The ratio between the contrast estimation and the correspondent estimation of the
standard error is asymptotically normally distributed. Therefore, the z-test was used to
evaluate the significance of the differences between the two levels of each factor, and the
second order interactions.
At the seven participating centers, 172 patients were enrolled, but 20 were excluded from
the analysis: 3 of them did not complete the diary card, 13 the FLIE2, and 4 because of a high
number of missing responses. Therefore, a total of 152 patients were evaluated; their main
characteristics are shown in > Table 50-4.
By comparing the data of the last two lines with those reported in > Table 50-2, the
improvement of the antiemetic prophylaxis with respect to the audit of 1999 is evident.
The incidence, duration and intensity of CINV, broken down according to nausea and
vomiting, are shown in > Table 50-5. The effects of acute on delayed CINV are shown in
> Table 50-6.
. Table 50-4
Patients’ characteristics
Number of patients (%)

Sex
Male 94 (61.8)
Female 58 (38.2)
Age (years)
60 70 (46.1)
>60 82 (53.9)
Dose of cisplatin
<70 mg/m2 77 (50.7)
70 mg/m2 75 (49.3)
Setting of chemotherapy administration
Inpatient 49 (32.2)
Outpatient 103 (67.8)
Prophylaxis of acute emesis appropriatea 146 (95.9)
Prophylaxis of delayed emesis appropriatea 71 (46.7)
a
According to MASCC guidelines (MASCC, 1998)
As can easily be seen, the incidence of delayed nausea is still an unsolved problem.
On days 1 to 5 after chemotherapy administration, 67% of patients who vomited and 77%
of those who suffered from nausea experienced an impact on their HRQL (see > Table 50-7).
Considering the 5-day period, it seems that patients who suffered from nausea more
frequently than those who had vomiting reported an impact on their daily life. Furthermore,
acute and delayed vomiting had a similar impact on daily life, but more patients with delayed
nausea reported an impact on daily life than did those with acute nausea. Worthy of note,
more than 90% of patients who had both acute and delayed CINV reported an impact on
their HRQL.
. Table 50-5
Incidence, duration, and intensity of CINV
Vomiting n/N (%) Nausea n/N (%)

Patients who had CINV (days 1–5) 52/152 (34.2) 94/152 (61.8)
Patients who had acute CINV (day 1) 23/152 (15.1) 58/152 (38.2)
Patients who had delayed CINV (days 2–5) 45/152 (29.6) 88/152 (57.9)
Duration of CINV (over 5-day period)
2 days 35/52 (67.3) 20/94 (21.3)
3 days 17/52 (32.7) 74/94 (78.7)
Intensity of CINV (5-day period)
Less severe 19/52 (36.5)a 36/94 (38.3)b
Severe 33/52 (63.5)c 58/94 (61.7)d
Patients suffering from acute CINV often have delayed CINV. Presence of delayed CINV strongly depends on the
presence of acute CINV
a
Overall number of emetic episodes 2
b
Mild nausea
c
Overall number of emetic episodes 3
d
Moderate-to-severe nausea
. Table 50-6
Effects of acute CINV on delayed CINV
Vomiting n/N (%) Nausea n/N (%)

Patients who had acute but not delayed CINV 7/152 (4.6) 6/152 (3.9)
Patients who had delayed but not acute CINV 29/152 (19.1) 36/152 (23.7)
Patients who had both acute and delayed CINV 16/152 (10.5) 52/152 (34.2)
Risk of delayed CINV among patients who did not have 29/129 (22.5) 36/94 (38.3)
acute CINV
Risk of delayed CINV among patients who suffered from 16/23 (69.6) 52/58 (89.7)
acute CINV
Presence of acute CINV is the main risk factor for suffering from delayed CINV. Relative risk to have delayed
vomiting for patients who had acute vomiting with respect to those who did not have it is equal to 3.09
(0.696/0.225): the probability to suffer from delayed vomiting for patients who had acute vomiting is more than
3 times higher than that calculated in patients who did not have acute vomiting. Relative risk for delayed nausea
with respect to the presence/absence of acute nausea is equal to 2.34 (0.897/0.383)
In the multifactorial logistic models, both acute and delayed CINV were significant factors
in explaining the variability of dependent variable, but their interaction was not statistically
significant. The highest incidence of impact observed among patients who suffered from both
acute and delayed CINV seems to be a simple sum of effects (see > Table 50-8).
The impact of both duration and intensity of CINV on a patients’ daily life are shown in
> Table 50-9. When the duration of nausea was 3 days (out of 5), regardless of intensity, the
incidence of its impact on daily life was greater than twice that observed when the duration
was 2 days. Considering the vomiting, the correspondent incidence of impact increased by
. Table 50-7
Incidence of impact on health-related quality of life among patients suffering from acute or
delayed CINV, or both
Impact on HRQL, n/N (%)

Patients who suffered from Vomiting Nausea
CINV during days 1–5 (total) 35/52 (67.3) 72/94 (76.6)
Acute but not delayed CINV 4/7 (57.1) 2/6 (33.3)
Delayed but not acute CINV 16/29 (55.2) 22/36 (61.1)
Both acute and delayed CINV 15/16 (93.7) 48/52 (92.3)
Not all patients who suffer from CINV record an impact on their daily life. Data shown in > Table 50-7 try to give an
answer to the question of whether acute or delayed CINV is more important in affecting a patient’s HRQL. From
these raw data, it seems that acute and delayed CINV are almost equally important, but almost all patients who
suffer from both acute and delayed CINV record an impact on their daily life
. Table 50-8
Multifactorial logistic models for the probability of the impact of CINV on patient’s daily life with
respect to the presence of acute and delayed CINV: Parameter estimations (z-test, significance
level)
Vomiting Nausea
General mean 4.761 4.052
Presence versus absence of acute CINV 4.561 (3.86, P < 0.001) 2.453 (3.95, P < 0.001)
Presence versus absence of delayed CINV 4.851 (4.60, P < 0.001) 4.389 (5.43, P < 0.001)
The interaction between the two factors was not significant. This means that the effects of the two factors should
be considered as additive: the increased risk of impact in patients who had both acute and delayed CINV can be
seen as the sum of effects of acute plus delayed CINV. Parameter estimations could be used to calculate the
probability of impact of CINV (Y) on patient’s daily life with respect to the presence/absence of acute and delayed
CINV. First, linear predictor (LP) should be calculated; then, its value should be replaced in the logistic model:
P(Y/.) = eLP/(1+eLP). Examples:
a) Probability of impact of acute vomiting on patients’ daily lives, P(Y/acute vomiting): LP = 4.761 (general mean)
+ 4.561 (presence of acute vomiting)+ 0 (no delayed CINV) = 0.2; P(Y/acute vomiting) = e 0.2/(1+e 0.2) = 0.450
b) Probability of impact of both acute and delayed vomiting on patients’ daily lives, P(Y/acute and
delayed vomiting): LP = 4.761+ 4.561+ 4.851 = 4.651; P(Y/acute and delayed vomiting) = e4.651/(1+e4.651) = 0.991
c) Probability of impact of delayed nausea, P(Y/delayed nausea) on patients’ daily lives, P(Y/delayed
nausea): LP = 4.052+ 0 (no acute nausea)+ 4.389 (presence of delayed nausea) = 0.337; P(Y/delayed nausea)
= e0.337/(1+e0.337) = 0.583
about 50%. Also the intensity of CINV was an important determinant: patients who suffered
from severe CINV had an incidence of impact about 50% superior than those who had less
severe CINV.
The duration and intensity of CINV are correlated phenomena. When the logistic models
are performed separately for duration and intensity, they are both significant, but when
adjusting each for the effect of the other factor, only duration remains significant (see
> Table 50-10). This is an important finding because, in antiemetic research, attention is
typically focused more on intensity and less on duration of CINV.

. Table 50-9
Effects of duration and intensity of CINV on patients’ daily lives: number of patients (%) of those
who had CINV who experienced an impact on HRQL
Impact on HRQL, n/N (%)

Vomiting Nausea
Duration of CINV (over 5-day period)
2days 19/35 (67.3) 8/20 (40.0)
3 days 16/17 (94.1) 64/74 (86.5)
Intensity of CINV (5-day period)
Less severe 9/19 (47.4)a 22/36 (61.1)b
c
Severe 26/33 (78.8) 50/58 (86.2)d
a
Number of emetic episodes 2
b
Mild nausea
c
Number of emetic episodes 3
d
Moderate-to-severe nausea
. Table 50-10
Multifactorial logistic models for the probability of the impact of CINV on patient’s daily life with
respect to the duration and the intensity of CINV in days 1–5: Parameter estimations (z-test,
significance level)
Vomiting Nausea
General mean 0.11 0.77
Duration: 3 days versus 2 days 2.262 (1.96, P < 0.05) 2.023 (3.43, P < 0.001)
Intensity: severe versus less severe 0.616 (0.89, n.s.)a 0.992 (1.76, n.s.)b
Worthy of note, at unifactorial analysis both duration and intensity of nausea and vomiting are significant (data not
shown), but, when adjusting the effect of each factor for the effect of the other, intensity looses its significance
(see > Table 50-10). In conclusion, in our study, duration is more important than intensity of CINV in producing an
impact on patients’ daily lives. If this result is confirmed by other studies, future antiemetic studies should assess
duration with the greatest precision. The results shown in the second column of > Table 50-10 refer only to
patients who suffered from vomiting in days 1–5, and in the third column to the patients who had nausea in days
1–5. n.s. not significant
a
A number of emetic episodes 3 was considered as “severe vomiting”; a number of emetic episodes 2 was
considered as “less severe vomiting”
b
Moderate-to-severe nausea was considered as “severe nausea”; mild nausea was considered as “less severe
nausea”
6 Conclusions
Today, the best antiemetic prophylaxis for acute emesis includes aprepitant, for both highly
(Kriss et al., 2005) and moderately (Herrstedt et al., 2005) emetogenic chemotherapy. There-
fore, we do not know if the daily clinical practice in Italy is actually administering according to
the MASCC recommendations. Probably it is not, because it has been shown that in Italy
about 5 or 6 years are necessary to implement guidelines in a massive way in daily clinical
practice. At any rate, the prophylaxis for delayed emesis is surely far from that recommended
by current guidelines. It is thus probable that an inferior rate of inappropriate prescriptions,

leading to an improvement in the control of delayed CINV, could reduce the impact of CINV
on patients’ daily lives.
We think that the most relevant result of an observational clinical study is to detect
relationships between variables, because they can often be generalized to other contexts.
Therefore, the importance of both intensity and duration of CINV on patients’ daily lives
can be considered as the most relevant finding of this study. In particular, the burden of the
duration of CINV (especially the nausea) on patients’ HRQL, greater than that produced by an
increased intensity, should be further investigated. In fact, if this result is confirmed by other
studies, the duration of CINV should be assessed with an accuracy much greater than that
currently used.
Despite the importance of duration and intensity of CINV, the incidence of the impact of
CINV on daily life was also high in patients who had a shorter and less intense CINV: 19/35
(67%)/9/19 (47%) patients with a lesser duration/intensity of vomiting, and 8/20 (40%)/22/36
(61%) patients who had a shorter/less severe nausea recorded impairment in performing their
daily activities.
In conclusion, notwithstanding substantially improved antiemetic prophylaxis, CINV is
still prevalent and often impacts the daily lives of patients, especially in the delayed phase. An
effort should be made to reduce the incidence of CINV by utilizing the best antiemetic
treatment in daily clinical practice.
7 Features of Chemotherapy-Induced Nausea and

Vomiting (CINV)
Despite of the improvement of antiemetic prophylaxis, CINV continues to be considered

by the patients as one of the most distressing side effects of chemotherapy.
CINV can be classified as either acute, delayed, or anticipatory. Acute CINV occurs within
the 24 h following chemotherapy administration, delayed CINV after 24 h, and anticipa-
tory nausea and vomiting occurs before the chemotherapy administration and likely is
conditioned by previous episodes of poorly controlled CINV.
Certain factors are known to increase the risk of CINV. The most important are both the
previous experience of CINV and the emetogenicity of specific chemotherapeutic agents.
Gender, age and setting of chemotherapy administration are, albeit less important, also
risk factors.
Chemotherapies can be classified with respect to their emetogenic potential in highly
emetogenic (cisplatin at dose 50 mg/m2, dacarbazine, etc.), moderately emetogenic
(carboplatin, cyclophosphamide, etc.), and chemotherapies with a low emetogenic poten-
tial (capecitabine, gefitinib, etoposide, etc.).
Since 1997 several consensus conferences have provided antiemetic guidelines. Moreover,
in the 1997 Perugia consensus conference specific recommendations for antiemetic re-
search were also given.
For chemotherapies with a low emetogenic potential, no prophylaxis was recommended:
antiemetic drugs should be used as rescue treatment. The prophylaxis for acute CINV for
both highly and moderately emetogenic chemotherapies was a 5-HT3 r.a. + a corticoste-
roid; today the addition of aprepitant (an NK1 r.a.) is recommended. The recommended
prophylaxis for delayed emesis for highly emetogenic chemotherapies is a corticosteroid
plus either a 5-HT3 r.a. or a benzamide (metoclopramide). For the prophylaxis of delayed
CINV in patients submitted to moderately emetogenic chemotherapy a corticosteroid
alone should be used. The role of a NK1 r.a. in the prevention of delayed emesis is today
debatable.
Not all patients who experienced CINV have an impact on their daily lives. In the most
used quality of life questionnaires there are two items aimed to explore this domain, but
the only validated, specific tool for evaluating the impact of CINV on a patient’s daily life is
the Functional Living Index for Emesis (FLIE).
Summary Points
An audit on the appropriateness of antiemetic prescription in daily clinical practice was

performed by IGAR in Italy in 1996, when antiemetic guidelines had not yet been published,
but the results of antiemetic studies had clearly detected the best prophylaxis of CINV.
A second large observational study on antiemetic prescription was carried out in 1999,
1 year after the publication of MASCC antiemetic guidelines. The pattern of prescription
was found improved, but less than expected.
A further study performed in 2003 on cisplatin-treated patients showed that almost all
received the recommended prophylaxis for acute emesis, but the prophylaxis for delayed
CINV had been prescribed to only about half of them.
The HRQL of patients who suffer from CINV is not always impacted. To evaluate the
incidence of the impact of CINV on patients’ daily lives the FLIE questionnaire was used.
Both acute and delayed CINV were responsible for the impact of CINV on patients’ daily
lives: about 50% of patients who had either acute or delayed CINV reported an impact on
their daily activities, but this percentage increased to more than 90% in patients who
suffered from both acute and delayed CINV.
Both intensity and duration of CINV are important determinants of its impact on a
patient’s daily life. When separately analyzed, they are both significant, but at a multifac-
torial analysis, only duration (adjusted for intensity) remains significant.
The duration of CINV was found more important than its intensity in determining an
impact on a patient’s daily life. This finding suggests that the duration of CINV should be
assessed with much greater accuracy than that currently used.
Despite the improved antiemetic prophylaxis, CINV is still prevalent and often impacts on
a patient’s daily life, especially in the delayed phase. Further efforts should be made to
reduce the incidence of CINV not only by strengthening antiemetic research, but also by
utilizing the best antiemetic treatments in daily clinical practice.
Acknowledgments
> Tables50-4, 50-6, 50-7 and 50-9 were reproduced with kind permission of Springer Science
and Business Media.
We thank Mrs. Katherine Brandt for her helpful assistance in reviewing the text.
References
Ballatori E, Roila F, Ruggeri B, Betti M, Sarti S, Soru G, IGAR. (1998). Ann Oncol. 9: 759–765.
Cruciani G, Di Maio M, Biffi A, Deuson RR. (2007). IGAR. (1992). Lancet. 340: 96–99.
Support Care Cancer. 15: 179–185. IGAR. (1995). N Engl J Med. 332: 1–5.
Beeckwith MC, Mullin S. (2001). Hosp Pharm. 36: Kris M, Hesketh PJ, Herrrstedt J, Rittenberg C, Einhorn
67–82. LH, Grunberg S, Koeller J, Olver J, Borjeson S,
Coates A, Abraham S, Kaye SB, Sowerbutts T, Frewin C, Ballatori E. (2005). Support Care Cancer. 13: 85–96.
Fox RM, Tattersall MH. (1983). Eur J Cancer Clin Lindley CM, Hirsch JD. (1992a). Br J Cancer. 66(suppl
Oncol. 19: 203–208. XIX): S26–S29.
De Boer-Dennert M, de Wit R, Schmitz PIM, Djontono J, Lindley CM, Hirsch JD, O’Neil CV, Transan MG, Gilbert
Beurden V, Stoter G, Verweij I. (1997). Br J Cancer. CS, Osterhaus JT. (1992b). Qual Life Res. 1:
76: 1055–1061. 331–340.
De Haes JCJM, Van Knippenberg FCE, Nejit JP. (1990). Martin AR, Pearson GD, Cai B, Elmer M, Horgan K,
Br J Cancer. 62: 1034–1038. Lindley C. (2003). Support Care Cancer. 11:
ESMO guidelines task force. (2001). Ann Oncol. 12: 522–527.
1059–1060. MASCC. (1998). Ann Oncol 15: 2966–2973.
Gralla RJ, Osoba D, Kris MG, Kirkbribe P, Heskett P, Osoba D, Zee B, Warr D, Latreille J, Kaizer L, Pater J.
Chinnery LW, Clark-Snow R, Gill DP, Groshen S, (1997). Support Care Cancer. 5: 307–313.
Grunberg S, Koeller JM, Morrow GR, Perez EA, Roila F, IGAR. (2004). Supp Care Cancer. 12: 446–453.
Silber JH, Pfister DG. (1999). J Clin Oncol. 17: The Antiemetic Subcommittee of the MASCC. (2006).
2971–2994. Ann Oncol. 17: 20–28.
Herrstedt J, Koeller JM, Roila F, Hesketh PJ, Warr D, Uyl de Groot CA, Wait S, Buijt I. (2000). Eur J Cancer. 36:
Rittenberg C, Dicato M. (2005). Support Care 1522–1535.
Cancer. 13: 97–103.
Impacts
2.4 Cardiac, Vascular, Pulmonary
and Dietary
51 Atherosclerotic Burden and
Mortality
J. Roquer . Angel Ois
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
2 How to Measure Atherosclerotic Burden? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
3 Atherosclerotic Burden and Mortality in Patients with Cardiovascular

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
3.1 Mortality and Arterial Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 908
3.2 Mortality and Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
3.3 Mortality and Dyslipemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
3.4 Mortality and Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
3.5 Mortality and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
3.6 Mortality and Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
3.7 Mortality and Multiple Cardiovascular Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
4 Atherosclerotic Burden and Mortality in Patients with

Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 911
4.1 CHD Mortality and ATB Impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
4.2 Stroke Mortality and ATB Impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915
4.3 PAD Mortality and ATB Impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916

902 51 Atherosclerotic Burden and Mortality
Abstract: Cardiovascular diseases are the main cause of death in developed countries, in spite
of the fact that cardiovascular disease rates and case-fatality rates have fallen considerably over
the last two decades in these countries. Atherosclerosis is the leading cause of cardiovascular
diseases, and can remain asymptomatic for many years, with sudden death often being its first
clinical manifestation. Atherosclerosis represents a grave health problem, it increases mortali-
ty, is associated with a poor prognosis, and significantly reduces life expectancy. > Athero-
sclerotic burden is a concept that has gained considerable interest due to the fact that it is a
powerful predictor of new cardiovascular events and is related to poor outcome after cardio-
vascular events. There are several well documented methods to evaluate and quantify
the atherosclerotic burden, > resting ankle-brachial index, > carotid intima-media thickness,
ultrasound-based endothelial function, and high-sensitivity testing for C – Reactive Protein
being the most widely used. Other current methods used to identify high-risk people are
assessment using some scores such as > Framingham risk scoring. The impact of some
cardiovascular risk factors on global and cardiovascular mortality is evident, mainly for
arterial hypertension and diabetes. The addition of cardiovascular risk factors is associated
with an increased risk of cardiovascular events, as well as early mortality after cardiovascular
events. Moreover, multiple disease locations increased the risk of cardiovascular events as well
as mortality compared with patients having multiple risk factors only, peripheral arterial
disease patients being those with the highest cardiovascular mortality rate. Atherosclerosis
should be considered as a global disease and, as a consequence, studied globally. Identification
and quantification of global atherosclerotic burden is a useful tool to identify those patients at
high risk of cardiovascular events or cardiovascular death.
List of Abbreviations: ABI, resting ankle-brachial index; ATB, atherosclerotic burden; BMI,
> body mass index; CEC, > circulating endothelial cells; CEPC, > circulating endothelial
progenitor cells; CHD, coronary heart disease; CRP, high-sensitivity C-reactive protein;
FDG-PET, 18- fluorodeoxyglucose positron emission tomography imaging; FMD, brachial
flow-mediated dilation; IMT, carotid intima-media thickness; IS, ischemic stroke; IVUS,
intravascular ultrasound; NHANES, National Health and Nutrition Examination Survey;
PAD, peripheral arterial disease; REACH, reduction of atherothrombosis for continued health
study; REGICOR, Registre Gironı́ del Cor; SCORE, systematic coronary risk evaluation
1 Introduction
Atherosclerosis is a generalized disease that affects the coronary, cerebral, and peripheral
vasculature, with clinical manifestations that include coronary heart disease (CHD), ischemic
stroke (IS), and peripheral arterial disease (PAD). Atherosclerosis represents a grave health
problem, annually accounting for at least 30% of all deaths globally (> Figure 51-1). It is
associated with a poor prognosis and significantly reduces life expectancy in the 60-year-old
patient by 8–12 years depending on the vascular event. Moreover, life expectancy is substan-
tially reduced in patients with more than one atherothrombotic event. The prevalence of
atherosclerotic disease is increasing as a result of increased longevity which leads to a larger
cohort of older individuals. The number of deaths from atherosclerotic diseases continues to
increase and is projected to be the leading cause of death worldwide by 2020. Stroke in
particular is a major burden, is the primary cause of adult disability, the second most
important cause of dementia, and the third leading cause of death in industrialized countries.
Atherosclerosis development is clearly associated with several vascular risk factors that,
Atherosclerotic Burden and Mortality 51 903
. Figure 51-1
Causes of death globally. Cardiovascular disease is the number one cause of death globally.
Source: World Heatlh Organization. http://www.who.int/cardiovascular_diseases/en/
according to the Reduction of Atherothrombosis for Continued Health study (REACH) data,
are similar in patients throughout the world (Bhatt et al., 2006), a high proportion of whom
suffer from hypertension (81.8%), hypercholesterolemia (72.4%), and diabetes (44.3%). The
prevalence of overweight (39.8%), obesity (26.6%), and morbid obesity (3.6%) is highest in
North America (overweight: 37.1%, obese: 36.5%, and morbidly obese: 5.8%; P < 0.001)
versus other regions.
In recent years the term > atherosclerotic burden (ATB) has been used to describe the
global extension of atherosclerosis. ATB has gained considerable interest due to two reasons:
first, it is a powerful predictor of new cardiovascular events (Bhatt et al., 2006) and; second, its
relationship to poor outcome after cardiovascular events in patients with CHD (Cotter et al.,
2003; Steg et al., 2007), PAD (Steg et al., 2007), or IS (Roquer et al., 2007a) has been well
documented. Knowledge of an individual’s overall ATB is extremely important as it enables
risk factors to be treated more aggressively. However, whilst the measurement of ATB in a
single arterial bed (cerebral, extracranial, coronary, aortic, renal, or peripheral) is, in general,
easy to obtain, there is no consensus as to which method is better at identifying the global
burden of atherosclerosis in an individual patient. In fact, most of the information available on
cardiovasacular risk has been derived from studies which were often confined to a single
subtype of patient, or to patients in clinical trials.
2 How to Measure Atherosclerotic Burden?
There are many invasive and non-invasive techniques providing and quantifying ATB
(> Table 51-1) a number of which evaluate a segment or a single vascular bed. Atherosclerosis
. Table 51-1
Techniques to quantify atherosclerotic burden
Imaging
▪ Carotid artery imaging
▪ Coronary artery imaging
▪ Aorta artery imaging
▪ Carotid intimal-medial thickness
▪ Two-dimensional echocardiography
▪ Coronary artery calcium imaging (by electron beam tomography or multidetector computed
tomography)
▪ Cardiac magnetic resonance imaging
▪ Left ventricular echocardiography imaging
▪ Magnetic resonance imaging
▪ 18-fluorodeoxyglucose (FDG)-positron emission tomography
▪ Intravascular ultrasound
Functional
▪ Ankle-brachial indices
▪ Brachial artery reactivity testing
▪ Endothelial function: brachial flow-mediated dilation.
▪ Epicardial coronary flow reserve measurements
▪ Arterial compliance
Laboratory test
▪ Microalbuminuria
▪ High sensitivity C-reactive protein
▪ IL-6
▪ IL-8
▪ MMP-9
▪ PAI-1
▪ VEGF
▪ Fibrinogen
▪ sP-selectin
▪ Leukocyte and neutrophil count
▪ Circulating endothelial progenitor cells
▪ Circulating endothelial cells
Techniques to quantify atherosclerotic burden. IL interleukin; MMP matrix metalloproteinase; PAI-1 plasminogen
activator inhibitor; VEGF vascular endothelial growth factor; sP-selectin soluble plasmatic selectin
is, however, a diffuse process, and it is not clear whether the extent of atheroma within the
studied segment reflects the disease contained in the remainder artery or in the general arterial
tree. Despite this limitation, the impact of some of these measures on clinical outcome
after cardiovascular events or in asymptomatic patients with cardiovascular risk factors has
been demonstrated. > Resting ankle-brachial index (ABI), > carotid intima-media thickness,
determination of coronary calcium scores, ultrasound-based > endothelial function, and

intravascular ultrasound (IVUS) studies offer the potential to directly or indirectly measure
and monitor atherosclerosis in symptomatic and asymptomatic people. High-sensitivity
testing for C-reactive protein and other biomarkers may also represent a measure of ATB
and may be considered as potential markers of atherosclerosis disease risk.
The ABI is a non-invasive method to assess the potency of the lower extremity arterial
system and to screen for the presence of PAD. Follow-up studies have shown that an abnormal
ABI supplies greater incremental coronary and cardiovascular risk assessment information
than that provided by traditional risk factors. It is agreed nowadays that the ABI is an indicator
of generalized atherosclerosis. Some studies (Newman et al., 1993) have reported a combined
incidence of cardiovascular disease morbidity and mortality in people with PAD detected by
ABI. The ABI is also associated with an increased risk of CHD, IS, and death. A recent study
revealed an increase of the risk for myocardial infarction and cardiovascular and total mortality
of 22, 35, 32%, respectively, per 0.1 unit decrease in ABI (Lamina et al., 2006). The specificity
of a low ABI to predict future cardiovascular outcomes is high although its sensitivity is low.
The ABI might be an useful addition for the assessment of cardiovascular disease risk in
selected populations, especially in people 50 years old or in those who appear to be at
intermediate or higher risk on the basis of traditional risk factor assessment, such as smokers
or people with diabetes, who have a particularly high risk of PAD (Greenland et al., 2000).
Carotid intima-media thickness (IMT) is being increasingly used as a surrogate end point of
vascular outcomes (> Figure 51-2). IMT has been validated as a marker of generalized athero-
sclerotic disease and correlates linearly with the number of atherosclerotic risk factors. Increased
carotid IMT reflects atherosclerosis in the abdominal aorta, in the arteries of the lower limbs, and
in the coronary arteries. Increased carotid IMT values are associated with a higher risk of
atherosclerosis in the peripheral arteries, long-term stroke recurrence, and progression
of CHD. It was observed in lipid-lowering treatments trials that a decrease in IMT was associated
with a reduction in the incidence of cardiovascular events. Many epidemiological and clinical
studies have documented that the average annual IMT progression rates in common carotid
artery are 0.03 mm, (Greenland et al., 2000) and that this progression is accelerated in people with
diabetes, reaching 33.9 mm/year in those persons with undiagnosed diabetes (Wagenknecht et al.,
2003). IMT is an operational measure of atherosclerosis and its severity is an independent
predictor of transient cerebral ischemia, stroke, and coronary events such as myocardial infact.
Elevated coronary calcium scores are predictive of cardiovascular events. Patients with
increased coronary calcium scores are approximately 10-fold more likely to suffer a cardiac
event over the next 3–5 years. Both electron beam tomography and multidetector computed
tomography can accurately detect and quantify coronary calcium scores. Coronary calcium
detection significantly improves the accuracy of global cardiovascular risk prevention, ATB
tracking, and the prediction of cardiovascular events.
More recently, the ATB of coronary arteries has been assessed by IVUS a technique that
provides significantly better plaque characterization than angiography. IVUS has been applied
to study the effects of lipid-lowering therapy on atherosclerosis progression in patients with
CHD and hyperlipidemia. Unfortunately, it is time consuming, slightly invasive, and not
widely available.
High-resolution ultrasound techniques can study endothelial function non-invasively.
Brachial flow-mediated dilation (FMD) is a validated physiological measure of endothelial
dysfunction, and has emerged as the most common assessment tool of endothelial function.
FMD response is nitric oxide dependent, abnormal early in the course of the atherosclerotic
. Figure 51-2
Carotid intima-media thickness. Carotid intima-media thickness (IMT) assessed by B-mode
ultrasound is marked in red color
process, and dysfunctional in response to various cardiovascular risk factors. FMD has been
associated with traditional cardiovascular risk factors, and its dysfunction is considered to be a
preclinical marker of cardiovascular disease (Rundek et al., 2006). Decreased FMD is an
independent predictor of events in subjects with established atherosclerosis, and is associated
with carotid plaque (Rundek et al., 2006). The Cardiovascular Health Study (Yeboah et al.,
2007) has recently concluded that whilst brachial FMD is a predictor of future clinical
cardiovascular events in older adults, including those who are asymptomatic and without
cardiovascular risk factors, it adds little to the prognostic accuracy of traditional cardiovascu-
lar risk scores/factors.
18- Fluorodeoxyglucose positron emission tomography imaging (FDG-PET) can image
inflammation in atherosclerosis, and serial imaging might be used to measure drug effective-
ness. FDG-PET imaging could image metabolic activity within carotid atherosclerosis as a
marker of plaque inflammation. A significant correlation between the positron emission
tomography signal from the carotid plaques and the macrophage staining from the
corresponding histologic sections and macrophage content has been demonstrated (Tawakol
et al., 2006), and can be used to assess the severity of inflammation in carotid plaques. FDG-
PET allows detection of small metabolic changes within plaques that occur before structural
alterations can be detected by other modalities. FDG-PET reproducibility measurements
compare well with other atherosclerosis imaging techniques such as MRI, IVUS, and CT.
High-Sensitivity C-Reactive Protein (CRP) is an independent predictor of future cardio-
vascular risk and a potent proatherogenic agent. Among all the markers of inflammation
studied to date, CRP appears to be the most suitable for use in clinical practice. CRP has been
shown to predict future coronary events in several prospective studies and may add to the
predictive value of lipid testing alone. In stable CHD, an elevated CRP level, even >1 mg/L, is a
significant predictor of adverse cardiovascular events independent of baseline characteristics
and treatments (Sabatine et al., 2007). Patients with both CRP and HbA1c in the upper
quartiles are at a particularly high risk for poor cardiovascular outcome. Patients with elevated
levels of CRP exhibit an increased risk for adverse cardiovascular outcomes including IS
attributable to clinical adverse events of progressive atherosclerotic disease.
Circulating Endothelial Cells (CEC) count measured in peripheral blood is related with
endothelial dysfunction, as well as with atherosclerosis. CEC quantification at 48 h after acute
myocardial infarction has been shown to be an accurate predictor of major adverse coronary
events and death at both 1 month and 1 year (Boos et al., 2006). In patients with PAD and
ischemic rest pain, CEC count is elevated compared with normal levels in patients with
intermittent claudication and in healthy controls, and in patients with acute ischemic stroke.
Circulating endothelial progenitor cells (CEPC) are also related wih atherosclerotic dis-
ease. The number of CEPC has been reported to be lower in patients with cardiovascular risk
factors such as smoking, hypercholesterolemia, diabetes, and hypertension. The CEPC count
also correlates negatively with carotid IMT, and is an independent risk factor for increased
carotid IMT and the presence of carotid plaque (Lau et al., 2007). Low CEPC levels predict
outcome in patients with atherosclerotic vascular disease, and are an independent predictor of
all-cause mortality among patients with congestive heart failure (Michowitz et al., 2007). A
higher increase in circulating EPC during the first week is independently associated with a
better clinical outcome in acute IS patients (Sobrino et al., 2007). The reduction of CEPC may
contribute to the progression of carotid atherosclerosis, and provide a marker for the burden
of carotid atherosclerosis (Lau et al., 2007).

Cardiovascular Risk Factors
Many people without clinical atherosclerotic disease or diabetes are at risk from cardiovascular
disease death due to advanced atherosclerosis. Factors that increase short-term risk for
cardiovascular diseases are well known, and their impact on global and cardiovascular
mortality has been widely reported. The most reliable method currently available to identify
these high-risk people is the assessment of absolute risk with the > Framingham risk scoring
(Wilson et al., 1998). Other algorithms such as SCORE (Systematic COronary Risk Evalua-
tion) (de Backer et al., 2003), or REGICOR (REgistre GIronı́ del COR) have been adapted
from the original Framinghan risk scoring in order to improve the prediction of cardiovascu-
lar events in low-risk countries (Comı́n et al., 2007). When an asymptomatic person has an
absolute 10-year risk as high as that of one with established CHD he can be classified as having
a CHD risk equivalent. It is, therefore, appropriate to employ risk-reduction therapy, similar
to that used with established CHD. Moreover, in recent years, a number of studies have
defined the beneficial effects of healthy lifestyle factors and lower cardiovascular risk factor
burden on cardiovascular disease outcomes and longevity. The Multiple Risk Factor Interven-
tion Trial defined low risk status as follows: serum cholesterol level <200 mg/dL, untreated
blood pressure <120/80 mm Hg, absence of current smoking, absence of diabetes, and
absence of major electrocardiographic abnormalities (Stamler et al., 1986). The NHANES II
Mortality Follow-Up Study indicate that the risk for fatal CHD was 51% lower for men and
71% lower for women with none of 3 major risk factors (hypertension, current smoking, and
elevated total cholesterol) compared with those with 1 or more risk factors. Had all 3 major
risk factors not occurred, it is estimated that 64% of all CHD deaths among women and 45%
of CHD deaths in men could have been avoided (Mensah et al., 2005). These studies suggest
that prevention of risk factor development at younger ages may be the key to ‘‘successful
aging’’ and highlight the need for intensive prevention efforts at young and middle ages, once
risk factors develop, in order to improve healthy longevity. The absence of established risk
factors at 50 years of age is associated with a very low lifetime risk for cardiovascular diseases
and markedly longer survival. People with optimal risk factor levels at 50 years of age
(representing only 3.2% of men and 4.5% of women in the Framingham cohort) have very
low remaining lifetime risk for cardiovascular diseases and markedly longer survival, whereas
people with 2 major risk factors (20.2% of men and 17.1% of women) have very high lifetime
risk (Lloyd-Jones et al., 2006). Diabetes at 50 years of age confers the highest lifetime risk of
any single risk factor for cardiovascular diseases.
Data from the REACH registry, an international, prospective cohort of 68,236 patients with
either established atherosclerotic arterial disease (cerebrovascular disease, PAD, CHD;
n = 55,814) or at least 3 risk factors for atherothrombosis (n = 12,422), showed the 1-year
outcomes: cardiovascular death, myocardial infarction, or stroke rates were 4.24%, ranging from
4.69% for those with established atherosclerotic arterial disease to 2.15% for patients with
multiple risk factors only. Among patients with established disease, major cardiovascular event
rates were 4.52% for patients with CHD, 6.47% for patients with cerebrovascular disease, and
5.35% for patients with PAD. The incidences of the end point of cardiovascular death,
myocardial infarction, stroke, or hospitalization for atherothrombotic events were 12.8% in
the total patient population, and 14.41% in the population with established arterial disease
(15.20% for CHD, 14.53% for cerebrovascular disease, and 21.14% for PAD patients) whereas
the incidence was 5.31% in the population with multiple risk factors only. It is noteworthy that
these event rates increased with the number of symptomatic arterial disease locations, ranging
from 5.31% for patients with risk factors only to 12.58% for patients with 1, 21.14% for patients
with 2, and 26.27% for patients with 3 symptomatic arterial disease locations (P < 0.001). The
study confirmed that multiple disease locations increased the 1-year risk of cardiovascular events
(Steg et al., 2007). Mortality at 1 year was higher in patients who had established arterial disease
compared with patients who had multiple risk factors only (2.81% vs. 1.51%). The highest
cardiovascular mortality rate was observed in patients with PAD, whereas CHD patients had the
highest non-fatal myocardial infarction rate, and the highest non-fatal stroke rate was seen
among patients with cerebrovascular disease. In the overall stable population with established
arterial disease, approximately 1 in 7 patients had a major event or were hospitalized for a
cardiovascular event or revascularization procedure within a year of enrollment. The 1-year hard
event rates increased with the number of symptomatic arterial disease locations, ranging from
2.2% in patients with risk factors only to 9.2% in patients with disease in all three locations.
3.1 Mortality and Arterial Hypertension
People with arterial hypertension have an increased risk of CHD and a risk of stroke about
4-fold greater than that of those with normotensive blood pressure. In the Asia-Pacific region
the fraction of CHD attributable to hypertension ranged from 4 to 28% in men and from
8 to 39% in women whilst the corresponding ranges for hemorrhagic stroke were 18–66% and
15–49%, and 8–44% and 12–45% for IS. Up to 66% of some subtypes of cardiovascular
diseases can be attributed to hypertension (Martiniuk et al., 2007). Hypertension is associated

not only with shorter life expectancy, but also with a shorter life expectancy free from cardio-
vascular diseases. Life expectancy at age 50 is 5.1 years longer for normotensive men and
4.9 years longer for nonhypertensive women compared with hypertensives (Rosamond et al.,
2008). Approximately 25% of all deaths in Spain were attributable to hypertension in a middle-
aged population, and a quarter of these deaths were cardiovascular (Banegas et al., 2003a).
3.2 Mortality and Diabetes
Diabetes mellitus raises the risk of cardiovascular diseases and all-cause mortality. Cardiovas-
cular mortality risk increases continuously with blood glucose. CHD death rates among adults
with diabetes are 2–4 times higher than the rates for adults without diabetes (Rosamond et al.,
2008), and 65% of people with diabetes mellitus die of some form of heart disease and stroke
(Centers for Disease Control and Prevention, 1999). People with type 2 diabetes should be
managed as if they have a CHD risk equivalent. People with diabetes who develop CHD have a
relatively poor prognosis for recurrent CHD events and coronary death. The AusDiab study
showed that, compared with those with normal glucose tolerance, the adjusted all-cause
mortality hazard ratios for known diabetes mellitus and newly diagnosed diabetes mellitus
were 2.3 and 1.3, respectively. The risk of death also increased in those people with impaired
fasting glucose (HR 1.6) and impaired glucose tolerance (HR 1.5). Sixty-five percent of all
those who died of cardiovascular diseases had known diabetes mellitus, newly diagnosed
diabetes mellitus, impaired fasting glucose, or impaired glucose tolerance at baseline.
Known diabetes mellitus (HR 2.6) and impaired fasting glucose (HR 2.5) were independent
predictors for cardiovascular disease mortality (van den Hoogen et al., 2000). In addition to
the deaths directly assigned to diabetes, 21% of CHD deaths and 13% of stroke deaths may be
attributable to high blood glucose (Danaei et al., 2006). Approximately 6% of all cardiovascu-
lar deaths in Spain were attributable to diabetes in adults >/ = 35 (Banegas et al., 2003a).
3.3 Mortality and Dyslipemia
There is a direct relationship between LDL cholesterol and total cholesterol and the rate of
new-onset CHD in men and women who were initially free of CHD, (Stamler et al., 1986;
Wilson et al., 1998) as well as for recurrent coronary events in people with established CHD.
According to a study in New Zealand, high blood cholesterol (> dyslipemia) contributed to
17% of all deaths from CHD and IS (Turley et al., 2006). The impact of cholesterol after stroke
is different according subtypes: high cholesterol blood values are protective for death after IS
(Vauthey et al., 2000) and low cholesterol and triglyceride blood values are deleterious for
intracerebral hemorrhage patients (Roquer et al., 2005).
3.4 Mortality and Smoking
Cigarette smoking is associated with an elevated risk of mortality from all causes, several
cardiovascular diseases, cancer, and chronic obstructive pulmonary disease. More than 1/3 of
all smoking-related deaths are due to cardiovascular diseases. On average, men smokers
die 13.2 years earlier than non-smokers and women smokers die 14.5 years earlier than
non-smokers (Centers for Disease Control and Prevention, 1999). Cigarette smoking increases
2- to 3-fold the risk of dying from CHD, and is an independent predictor of sudden cardiac
death in patients with CHD. Quitting cigarette smoking was associated with a 41% lower risk of
death than continuing smoking, but with a 23% higher risk than constant non-smoking
(Paffenbarger et al., 1993). Current smoking is also an independent factor related with
increased mortality after suffering an IS. In 1998 in Spain, 55,613 deaths were attributable to
smoking; this meant that one out of 4 deaths in males and one out of 40 deaths in females were
attributable to tobacco (Banegas et al., 2001). Globally, about 16% of all deaths were attribut-
able to tobacco use in adults >/ = 35: lung cancer (26.5%), chronic obstructive pulmonary
disease (20.9%), coronary heart disease (12.8%), and stroke (9.2%) (Banegas et al., 2003a).
3.5 Mortality and Obesity
Abundant evidence links overweight and obesity with impaired health. Among adults obesity
(> Body Mass Index (BMI) greater than 30), as well as underweight, was associated with
excess deaths relative to normal weight (Flegal, et al., 2005). Overweight (BMI 25–30) was not
associated with excess mortality. For individuals with either no cardiovascular risk factors or
those with 1 or more risk factors, those who are obese in middle age have a higher risk of
hospitalization and mortality from CHD, cardiovascular disease, and diabetes in older age
than those who are normal weight (Yan et al., 2006). Beginning moderately vigorous sports
activity, quitting cigarette smoking, maintaining normal blood pressure, and avoiding obesity
were separately associated with lower rates of death from all causes and from CHD among
middle-aged and older men (Paffenbarger et al., 1993). In 1997, in the European Union, a
minimum of 7.7% of all deaths were attributable to excess weight, varying from 5.8% for
France to 8.7% for the United Kingdom. More attributable deaths occurred among the obese
than among the overweight, and around 70% were cardiovascular disease deaths and 20%
cancer deaths. At least one in 13 annual deaths in the European Union are likely to be related to
excess weight (Banegas et al., 2003b).
3.6 Mortality and Metabolic Syndrome
The > metabolic syndrome is defined as a clustering of cardiovascular risk factors character-
ized by insulin resistance. It is associated with adverse cardiovascular outcome independent of
its associations with diabetes and obesity. In people with metabolic syndrome, but without
diabetes, risks of CHD and cardiovascular disease mortality remained elevated. People with
even 1–2 metabolic syndrome factors were at increased risk for mortality from CHD and
cardiovascular diseases. Metabolic syndrome predicts more strongly CHD, cardiovascular
disease, and total mortality than its individual components. The adverse impact of metabolic
syndrome or diabetes mellitus on cardiovascular events is greater among men, and the
presence of both conditions increases the risk substantially among women.
3.7 Mortality and Multiple Cardiovascular Risk Factors
The addition of cardiovascular risk factors is associated with an increased risk of cardiovascu-
lar events. The percentage of patients in Spain with 0, 1, 2, 3 and 4–6 cardiovascular risk factors
(smoking, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, diabetes and

obesity) was 39.1, 32.8, 17.5, 6.9 and 3.7, respectively, and the odds ratio for experiencing a
cardiovascular event associated with 1, 2, 3 and 4–6 cardiovascular risk factors was 1.6, 2.8, 3.6
and 5.6, respectively (Baena Dı́ez et al., 2002). The accumulative deleterious impact of
cardiovascular risk factors on mortality has also been reported: The REACH register (Steg
et al., 2007), focused on the impact of the number of symptomatic arterial disease locations,
showed that the 1-year event rates, including cardiovascular death, myocardial infarct, or
stroke, increased markedly with the number of symptomatic arterial disease locations, ranging
from 2.2% in patients with risk factors only, to 9.2% in patients with symptomatic disease in
all 3 locations. The Chicago Heart Association Detection Project in Industry showed that a
greater risk factor burden is associated with a higher incidence of cardiovascular disease and
non-cardiovascular death: compared with participants with > or = 3 risk factors, those with
favorable profiles had substantially lower lifetime risks for cardiovascular death (20.5% vs.
35.2% in men, 6.7% vs. 31.9% in women) and markedly longer median Kaplan-Meier survival
(>35 vs. 26 years in men, >35 vs. 28 years in women) (Roquer et al., 2007a). The impact of
clustering of cardiovascular risk factors on early mortality and stroke severity after first-ever IS
has also been reported (Roquer et al., 2007b).

Cardiovascular Diseases
Whilst cardiovascular disease rates and case-fatality rates in the United States, and in most
other developed countries (> Table 51-2), have fallen considerably over the last two decades,
cardiovascular diseases remain the leading cause of death. In the United States cardiovascular
diseases accounted for 36.3% of all deaths, or 1 of every 2.8 deaths in 2004 (Rosamond et al.,
2008). Cardiovascular diseases claim more lives each year than cancer, chronic lower respira-
tory diseases, accidents, and diabetes mellitus combined. The 2004 cardiovascular disease
death rates were 341.8 for men and 246.3 for women. In 2004, 32% of deaths from cardiovas-
cular diseases occurred prematurely. If all forms of cardiovascular diseases were eliminated, life
expectancy would rise by almost 7 years, whereas if all forms of cancer were eliminated, the
gain would be only 3 years (National Center for Health Statistics, 1999). The probability at
birth of eventually dying from major cardiovascular diseases is 47%, and the chance of dying
from cancer is 22%. Additional probabilities are 3% for accidents, 2% for diabetes, and 0.7%
for HIV (National Center for Health Statistics, 1999). The lifetime risk for cardiovascular
diseases and median survival are highly associated with risk factor burden at age 50
(Michowitz et al., 2007). Remaining lifetime risks for atherosclerotic cardiovascular disease
events were only 5.2% in men and 8.2% in women with optimal risk factors at age 50,
compared with 68.9% in men and 50.2% in women with 2 or more major risk factors at
age 50. Men and women with optimal risk factors had a median life expectancy at least 10 years
longer than those with 2 or more major risk factors at age 50 (Lloyd-Jones et al., 2006). The impact
of cardiovascular risk factors on survival is also very clear: factors associated with survival to age
85 included female sex, lower systolic blood pressure, lower total cholesterol, better glucose
tolerance, absence of current smoking, and higher attained level of education. A recent study,
using the validated statistical model IMPACT, concluded that approximately half the decline
in U.S. deaths from CHD from 1980 to 2000 may be attributable to reductions in major risk
factors and approximately half to evidence-based medical therapies. This study analyzed the
. Table 51-2
International death rates
CVD deaths CHD deaths Stroke deaths Total deaths

Men, Ages 35–74 year
Russian Federation (2002) 1,555 835 453 3,187
Bulgaria (2004)* 916 273 227 1,610
Romania (2004) 770 314 251 1,652
Hungary (2003) 714 358 181 1,860
Poland (2003) 557 228 118 1,484
Czech Republic (2004) 481 231 94 1,248
China Rural (1999)* 413 64 243 1,260
Argentina (2001) 406 120 103 1,262
China Urban (1999)* 389 106 217 1,003
Scotland (2002) 373 247 61 1,084
Ireland (2002) 337 217 41 875
Finland (2004) 334 211 54 921
Colombia (1999) 331 168 95 1,021
Northern Ireland (2002) 322 217 53 876
Greece (2003)* 311 166 68 784
England/Wales (2002) 301 196 49 811
Belgium (1997)* 289 143 50 991
United States (2004) 289 174 35 907
Denmark (2001) 286 142 52 956
New Zealand (2000) 279 190 40 779
Germany (2004) 271 142 39 846
Portugal (2003) 253 97 96 967
Sweden (2002) 247 151 44 686
Republic of Korea (2002) 236 57 143 1,085
Mexico (2001) 235 130 58 1,056
Austria (2004) 226 131 34 818
The Netherlands (2004) 222 96 37 759
Italy (2002) * 218 101 41 744
Norway (2003) 217 125 36 720
Canada (2002) 212 142 28 741
Spain (2003) 205 101 43 822
Australia (2002) 196 127 30 659
France (2002) 183 73 35 896
Switzerland (2002) 181 97 23 674
Israel (2003) 180 95 38 717
Japan (2003) 170 53 66 694
Women Ages 35–74 year
CVD deaths CHD deaths Stroke deaths Total deaths

Russian Federation (2002) 659 288 257 1,192
Bulgaria (2004)* 435 100 133 746
Romania (2004) 403 134 166 787
Hungary (2003) 303 133 91 807
China Rural (1999)* 279 41 152 799
China Urban (1999)* 273 71 147 663
Colombia (1999) 230 95 71 640
Poland (2003) 222 68 63 617
Czech Republic (2004) 213 82 52 594
Scotland (2002) 183 98 48 649
Argentina (2001) 174 35 55 617
Mexico (2001) 166 69 47 713
Northern Ireland (2002) 150 79 41 534
United States (2004) 150 73 27 575
England/Wales (2002) 138 68 36 509
New Zealand (2000) 136 71 33 498
Greece (2003)* 134 46 44 364
Republic of Korea (2002) 133 24 87 452
Ireland (2002) 130 66 27 502
Denmark (2001) 127 51 37 642
*
Belgium (1997) 126 44 35 494
Portugal (2003) 123 35 55 449
Germany (2004) 111 45 23 426
Sweden (2002) 107 51 30 422
Finland (2004) 104 48 32 412
The Netherlands (2004) 102 34 26 466
Canada (2002) 92 48 20 452
Italy (2002)* 92 29 25 372
Austria (2004) 90 42 19 405
Norway (2003) 88 38 25 430
Australia (2002) 85 43 20 390
Israel (2003) 83 31 22 431
Spain (2003) 79 26 23 343
Switzerland (2002) 71 27 15 362
Japan (2003) 69 16 31 302
France (2002) 66 16 18 389
International death rates (revised 2007): death rates (per 100,000 population) for total cardiovascular disease,
coronary heart disease, stroke, and total deaths in selected countries (most recent year available). Sources: The
World Health Organization Web page, NCHS, and NHLBI (Rosamond et al., 2008)
use and effectiveness of specific cardiac treatments and changes in risk factors between 1980
and 2000. In this period of time, the age-adjusted death rate for CHD fell from 542.9 to
266.8 deaths per 100,000 populations among men and from 263.3 to 134.4 deaths per
100,000 populations among women, resulting in 341,745 fewer deaths from CHD in 2000.
Approximately 47% of this decrease was attributed to treatments, including secondary
preventive therapies after myocardial infarction or revascularization (11%), initial treat-
ments for acute myocardial infarction or unstable angina (10%), treatments for heart failure
(9%), revascularization for chronic angina (5%), and other therapies (12%). Approximately
44% was attributed to changes in risk factors, including reductions in total cholesterol
(24%), systolic blood pressure (20%), smoking prevalence (12%), and physical inactivity
(5%), although these reductions were partially offset by increases in the body-mass index
and the prevalence of diabetes, which accounted for an increased number of deaths (8% and
10%, respectively) (Ford et al., 2007).
4.1 CHD Mortality and ATB Impact
In spite of the fact that mortality caused by CHD has been reduced in the last decades,
CHD represents the major cause of mortality in North America and Western Europe
(> Figure 51-3). In the United States CHD caused 1 of every 5 deaths in 2004. In Spain, one
of the countries with the lowest incidence of CHD, this disease was also the first current cause
of mortality in 2005. In the United States, CHD is the single largest killer of American males
and females. Approximately every 26 s, an American will suffer a coronary event and every
minute someone will die from one. Approximately 38% of the people who experience a
coronary attack in a given year will die from it (Rosamond et al., 2008). Having coronary
disease increased future CHD event risk approximately 7-fold compared to healthy indivi-
duals, with an absolute risk of 50–60% per decade (Rossouw et al., 1990). People with
established CHD have a risk for recurrent myocardial infarction and CHD death that exceeds
20% per 10 years. In acute CHD patients previous history of stroke, including TIA or PAD,
increases clinical severity and worse outcome (Cotter et al., 2003). In patients with myocardial
. Figure 51-3
Percentage of deaths due to cardiovascular diseases. Percentage breakdown of deaths due to
cardiovascular diseases (United States: 2004). Source: NCHS and NHLBI (Rosamond et al., 2008)
infarction treated with angioplasty, the presence of PAD is an independent predictor of

intrahospitalary death as well as 1-year mortality (Cotter et al., 2003). Moreover, the relative
risk for CHD associated with the presence of 1, 2, 3, and 4 risk factors were 1.6, 2.2, 3.1, and
5.0, respectively (Yusuf et al., 1998) and the combination of high systolic blood pressure and
high serum cholesterol dramatically increased cardiovascular disease and CHD in subjects
under 55 years of age, especially in men.
4.2 Stroke Mortality and ATB Impact
Stroke accounted for approximately 1 of every 16 deaths in the United States in 2004, and
approximately 50% of these deaths occurred out of the hospital. After diseases of the heart and
cancer, stroke ranks third as a cause of death. In a study of people >65 years of age in 4 United
States’ communities, the 1-month case fatality was 12.6% for all strokes, 8.1% for IS, and
44.6% for hemorrhagic strokes (El-Saed et al., 2006). According to the American Heart
Association data (Rosamond et al., 2008) the percentages of death 1 year after a first stroke
were as follows: at 40–69 years of age: 14% of white men, 20% of white women, 19% of black
men, and 19% of black women. At >70 years of age: 24% of white men, 27% of white women,
25% of black men, and 22% of black women. The percentages of death within 5 years after a
first stroke were as follows: at 40–69 years of age: 32% of white men, 32% of white women,
34% of black men, and 42% of black women; at > = 70 years of age: 58% of white men, 58% of
white women, 49% of black men, and 54% of black women. The median survival times after a
first stroke are: at 60–69 years of age: 6.8 years for men and 7.4 years for women; at 70–79 years
of age: 5.4 years for men and 6.4 years for women; at > = 80 years of age: 1.8 years for men and
3.1 years for women. Patients with a history of stroke have a 10-fold increase in all-cause
mortality. Because women live longer than men, more women than men die of stroke each
year (Rosamond et al., 2008; Roquer et al., 2003). In Catalonia, during the year 2002, the
unadjusted stroke mortality rate per 100,000 population aged over 24 years was 92 in men and
119 in women. The age-adjusted rates were 58 and 43, respectively. The cumulative incidence
of stroke per 100,000 populations was 218 in men and 127 in women. The unadjusted 28-day
case fatality rate in the population was 36.2%: 30.3% in men and 42.0% in women. A total of
62.5% of patients (57.2% of men and 66.4% of women) died from cardiovascular diseases
outside hospital (Marrugat et al., 2007).
Pre-existing cardiovascular conditions such as atrial fibrillation (Roquer et al., 2003, 2006)
and left ventricular dysfunction (Ois et al., 2008) are associated with increased mortality. The
deleterious impact of ATB evaluated by the quantity of aortic atheroma in stroke has been
demonstrated in patients with stroke of undetermined etiology. In addition, ATB evaluated by a
clinical score (from 0 to 2 points) including the past history of PAD (one point) and/or CHD
(one point) has a deletereous impact on survival in patients with first-ever IS of atherothrom-
botic and lacunar origin. Comparing patients having no previous ATB to those with an ATB
score of 1 or 2, the risk for 30 days-mortality increased from 1.71 (95% CI 1.06–2.75) for
patients with an ATB score of 1–5.90 (95% CI 2.48–14.04) for those with an ATB of 2 (Roquer
et al., 2007a). Moreover, the presence of severe arterial atenosis/oclussion is the factor with the
highest relationship with 90-day mortality (adjusted OR: stenosis 2.13, occlusion 4.42, both
3.36) in patients with first ever IS (Ois et al., 2007), in addition to well-known factors related to
mortality (age, stroke severity, CHD, heart failure, and previous disability). Arterial stenosis/
occlusion was a higher predictor of 90-day mortality in patients with mild (adjusted OR: 5.38)
than severe stroke (adjusted OR: 3.05). Severe arterial stenosis/occlusion in the early arterial
study was highly related with 90-day mortality in an unselected series of patients with stroke.
4.3 PAD Mortality and ATB Impact
A diagnosis of PAD is critical evidence of more widespread atherothrombotic disease, with

substantial risks of subsequent cardiovascular events and death. PAD prevalence is very high,
affecting 12 to 20% of Americans aged 65 and older, but only 25% of PAD patients are
undergoing treatment (Yusuf et al., 1998). People with PAD, compared with those without,
have 4–5 times the risk of dying of a cardiovascular disease event, resulting in a 2-to 3-times
higher total mortality risk (Newman et al., 1993). People with documented PAD (without
CHD) had a total CHD mortality of 2% per year. The conclusion of most studies supports the
concept that PAD, whether diagnosed by ABI, lower limb blood flow studies, or clinical
symptoms, is a CHD risk equivalent. A low ABI (<0.9) is associated with an increased risk
of subsequent all cause mortality, cardiovascular mortality, CHD and stroke.
Summary Points
The number of deaths from atherosclerotic diseases is projected to be the leading cause of
death worldwide by 2020.
Stroke is the primary cause of adult disability, the second most important cause of
dementia, and the third leading cause of death in industrialized countries.
The probability at birth of eventually dying from major cardiovascular diseases is 47%, and
the chance of dying from cancer is 22%.
The most reliable method currently available to identify these high-risk people is the
assessment of absolute risk with the Framingham risk scoring.
The highest 1-year cardiovascular mortality rate is observed in patients with peripheral
arterial disease.
People with arterial hypertension have an increased risk of coronary heart disease and a
risk of stroke about 4-fold greater than that of those with normotensive blood pressure.
In addition to the deaths directly assigned to diabetes, 21% of coronary heart disease
deaths and 13% of stroke deaths may be attributable to high blood glucose.
More than 1/3 of all smoking-related deaths are due to cardiovascular diseases.
The addition of cardiovascular risk factors is associated with an increased risk of cardio-
vascular events.
Approximately 38% of the people who experience a coronary attack in a given year will die
from it.
References
Baena Dı́ez JM, Alvarez Pérez B, Piñol Forcadell P, Martı́n Banegas JR, Dı́ez Gañán L, Rodrı́guez-Artalejo F, González
Peñacoba R, Nicolau Sabaté M, Altès Boronat A. Enrı́quez J, Graciani Pérez-Regadera A, Villar
(2002). Rev Esp Salud Publica. 76: 7–15. Alvarez F. (2001). Med Clin (Barc). 117: 692–694.
Banegas JR, López-Garcı́a E, Gutiérrez-Fisac JL, Guallar- Marrugat J, Arboix A, Garcı́a-Eroles L, Salas T, Vila J,
Castillón P, Rodrı́guez-Artalejo F. (2003b). Eur J Castell C, Tresserras R, Elosua R. (2007). Rev Esp
Clin Nutr. 57: 201–208. Cardiol. 60: 573–580.
Banegas JR, Rodrı́guez-Artalejo F, Graciani A, Villar F, Martiniuk AL, Lee CM, Lawes CM, Ueshima H, Suh I,
Herruzo R. (2003a). Eur J Clin Nutr. 57(Suppl. 1): Lam TH, Gu D, Feigin V, Jamrozik K, Ohkubo T,
S18–21. Woodward M; Asia-Pacific Cohort Studies Collabo-
Bhatt DL, Steg PG, Ohman EM, Hirsch AT, Ikeda Y, ration. (2007). J Hypertens. 25: 73–79.
Mas JL, Goto S, Liau CS, Richard AJ, Röther J, Mensah GA, Brown DW, Croft JB, Greenlund KJ. (2005).
Wilson PW; REACH Registry Investigators. (2006). Am J Prev Med. 29 (Suppl. 1): 68–74.
JAMA. 295: 180–189. Michowitz Y, Goldstein E, Wexler D, Sheps D, Keren G,
Boos CJ, Lip GYH, Blann AD. (2006). J Am Coll Cardiol. George J. (2007). Heart. 93: 1046–1050.
48: 1538–1547. National Center for Health Statistics U.S. (1999). Decen-
Centers for Disease Control and Prevention. (1999). nial Life Tables for 1989–91, Vol. 1, No. 4. Eliminat-
Diabetes Surveillance Report, 1999. United States ing Certain Causes of Death, 1989–91. National
Department of Health and Human Services, Center for Health Statistics, Hyattsville, MD.
Atlanta, GA. Newman AB, Sutton-Tyrrell K, Vogt MT, Kuller LH.
Comı́n E, Solanas P, Cabezas C, Subirana I, Ramos R, (1993). JAMA. 270: 487–489.
Gené-Badı́a J, Cordón F, Grau M, Cabré-Vila JJ, Ois A, Cuadrado-Godia E, Jiménez-Conde J, Gomis M,
Marrugat J. (2007). Rev Esp Cardiol. 60: 693–702. Rodrı́guez-Campello A, Martı́nez-Rodrı́guez JE,
Cotter G, Cannon CP, McCabe CH, Michowitz Y, Munteis E, Roquer J. (2007). Stroke. 38: 2085–2089.
Kaluski E, Charlesworth A, Milo O, Bentley J, Ois A, Gomis M, Cuadrado-Godia E, Jiménez-Conde J,
Blatt A, Krakover R, Zimlichman R, Reisin L, Rodrı́guez-Campello A, Bruguera J, Molina Ll,
Marmor A, Lewis B, Vered Z, Caspi A, Braunwald E; Comin J, Roquer J. (2008). J Neurol. 255: 385–389.
OPUS-TIMI 16 Investigators. (2003). Am Heart J. Paffenbarger RS, Hyde RT, Wing AL, Lee IM, Jung DL,
145: 622–627. Kampert JB. (1993). N Engl J Med. 328: 538–545.
Danaei G, Lawes CM, Vander Hoorn S, Murray CJ, Roquer J, Martı́nez-Rodrı́guez JE, Rodrı́guez-Campello A,
Ezzati M. (2006). Lancet. 368: 1651–1659. Gomis M, Munteis E, Jiménez-Conde J, Cuadrado-
De Backer G, Ambrosioni E, Borch-Johnsen K, Godia E, Ois A. (2007a). Arch Neurol. 64: 699–704.
Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Roquer J, Ois A, Rodrı́guez-Campello A, Gomis M,
Faergeman O, Graham I, Mancia G, Manger Cats V, Munteis E, Jiménez-Conde J, Cuadrado-Godia E,
Orth-Gomér K, Perk J, Pyörälä K, Rodicio JL, Martı́nez-Rodrı́guez JE. (2007b). J Neurol. 254:
Sans S, Sansoy V, Sechtem U, Silber S, Thomsen T, 1636–1641.
Wood D. (2003). Eur Heart J. 24: 1601–1610. Roquer J, Rodrı́guez Campello A, Gomis M. (2003).
El-Saed A, Kuller LH, Newman AB, Lopez O, Stroke. 34: 1581–1585.
Costantino J, McTigue K, Cushman M, Kronmal Roquer J, Rodrı́guez Campello A, Gomis M, Ois A,
R. (2006). Stroke. 37: 1975–1979. Munteis E, Böhm P. (2005). Neurology. 65:
Flegal KM, Graubard BI, Williamson DF, Gail MH. 1198–202.
(2005). JAMA. 293: 1861–1867. Roquer J, Rodrı́guez Campello A, Ois A, Gomis M,
Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, Martinez-Rodriguez JE, Munteis E, Jiménenz
Kottke TE, Giles WH, Capewell S. (2007). N Engl J Conde J, Montaner J, Álvarez-Sabı́n J. (2006).
Med. 356: 2388–2398. J Neurol. 253: 1484–1489.
Greenland P, Abrams J, Aurigemma GP, Bond MG, Rosamond W, Flegal K, Furie K, Go A, Greenlund K,
Clark LT, Criqui MH, Crouse JR, Friedman L, Haase N, Hailpern SM, Ho M, Howard V, Kissela B,
Fuster V, Herrington DM, Kuller LH, Ridker PM, Kittner S, Lloyd-Jones D, McDermott M, Meigs J,
Roberts WC, Stanford W, Stone N, Swan J, Moy C, Nichol G, O’Donnell CJ, Roger V, Sorlie P,
Taubert KA, Wexler L. (2000). Circulation. 101: e16. Steinberger J, Thom T, Wilson M, Hong Y for the
Lamina C, Meisinger C, Heid IM, Lowel H, Rantner B, American Heart Association Statistics Committee
Koenig W, Kronenberg F. (2006). Eur Heart J. 27: and Stroke Statistics Subcommittee. (2008). Circu-
2580–2587. lation. 117: e25–e146.
Lau KK, Chan YH, Yiu KH, Li SW, Tam S, Lau CP, Rossouw JE, Lewis B, Rifkind BM. (1990). N Engl J Med.
Kwong YL, Tse HF. (2007). J Hum Hypertens. 21: 323: 1112–1119.
445–451. Rundek T, Hundle R, Ratchford E, Ramas R, Sciacca R,
Lloyd-Jones DM, Leip EP, Larson MG, D’Agostino RB, Di Tullio MR, Boden-Albala B, Miyake Y,
Beiser A, Wilson PW, Wolf PA, Lery D. (2006). Elkind MS, Sacco RL, Homma S. (2006). BMC
Circulation. 113: 791–798. Cardiovasc Disord. 6: 35.
Sabatine MS, Morrow DA, Jablonski KA, Rice MM, van den Hoogen PCW, Feskens EJM, Nagelkerke NJD,
Warnica JW, Domanski MJ, Hsia J, Gersh BJ, Menotti A, Nissinen A, Kromhout D; for the Seven-
Rifai N, Ridker PM, Pfeffer MA, Braunwald E; Countries Research Group. (2000). N Engl J Med.
PEACE Investigators. (2007). Circulation. 115: 342: 1–8.
1528–1536. Vauthey C, de Freitas, GR, van Melle, G, Devuyst G,
Sobrino T, Hurtado O, Moro MA, Rodrı́guez-Yáñez M, Bogousslavsky J. (2000). Neurology. 54: 1944–1949.
Castellanos M, Brea D, Moldes O, Blanco M, Wagenknecht LE, Zaccaro D, Espeland MA, Karter AJ,
Arenillas JF, Leira R, Dávalos A, Lizasoain I, O’Learly, Haffner SM. (2003). Arterioscler Thromb
Castillo J. (2007). Stroke. 38: 2759–2764. Vasc Biol. 23: 1035–1041.
Stamler J, Wentworth D, Neaton JD; for the MRFIT Wilson PWF, D’Agostino RB, Levy D, Belanger AM,
Research Group. (1986). JAMA. 256: 2823–2828. Silbershatz H, Kannel WB. (1998). Circulation. 97:
Steg PG, Bhatt DL, Wilson PW, D’Agostino R Sr, 1837–1847.
Ohman EM, Röther J, Liau CS, Hirsch AT, Mas JL, Yan LL, Daviglus ML, Liu K, Stamler J, Wang R,
Ikeda Y, Pencina MJ, Goto S; REACH Registry Inves- Pirzada A, Garside DB, Dyer AR, Van Horn L,
tigators. (2007). JAMA. 297: 1197–1206. Liao Y, Fries JF, Greenland P. (2006). JAMA. 295:
Tawakol A, Migrino RQ, Bashian GG, Bedri S, 190–198.
Vermylen D, Cury RC, Yates D, LaMuraglia GM, Yeboah J, Crouse JR, Hsu JC, Burke GL, Herrington DM.
Furie K, Houser S, Gewirtz H, Muller JE, Brady TJ, (2007). Circulation. 115: 2390–2397.
Fischman AJ. (2006). J Am Coll Cardiol. 48: Yusuf HR, Giles WH, Croft JB, Anda RF, Casper ML.
1818–1824. (1998). Prev Med. 27: 1–9.
Turley ML, Tobias M, Lawes CM, Stefanogiannis N,
Vander Hoorn S, Mhurchu CN, Rodgers A. (2006).
Aust N Z J Public Health. 30: 252–257.
52 Burden of Cardiovascular
Diseases Among Aboriginal
and Torres Strait Islander
Peoples: Mortality,
Hospitalization and Risk
Factors
A. G. Thrift . S. L. Gall . A. D. Brown
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920
2 Burden of Cardiovascular Diseases in Australia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923

2.1 Decline in Cardiovascular Disease Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924
2.2 Increase in Cardiovascular Disease Hospitalizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924
3 Cardiovascular Diseases in Aboriginal and Torres Strait Islander Peoples . . . . . . 924

3.1 Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924
3.2 Hospitalizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 926
3.3 Disability Adjusted Life Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927
3.4 Disparity in the Decline in Mortality Between Socioeconomic Groups . . . . . . . . . . . . 927
3.5 What is the Reason for the High Rates of Cardiovascular
Disease and Stroke? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 928
4 National Strategy for Improving Vascular Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929

920 52 Burden of Cardiovascular Diseases Among Aboriginal and Torres Strait Islander Peoples
Abstract: Aboriginal and Torres Strait Islander peoples (referred to as > Indigenous
Australians) comprise about 2.4% of the Australian population, yet they are overrepresented
in all markers of health and social disadvantage. This pattern is reflected in national data
that exists describing the burden and outcomes of > cardiovascular disease. Available infor-
mation, obtained from quasi-national statistics because of suboptimal accuracy of ethnic
status across several States and Territories, demonstrate that Indigenous Australians are
more likely to die from coronary heart disease, > stroke and other cardiovascular conditions;
are more likely to be hospitalized; and suffer greater adverse outcomes than their non-
Indigenous counterparts.
The reasons for these adverse patterns are likely to be multi-factorial, complex and inter-
related. When compared to the non-Indigenous population Indigenous Australians
more often live in rural and > remote regions (isolated from necessary services); have lower
> educational attainment and lower income; are more likely to be > unemployed; more
frequently experience adverse life events and illness throughout the life-course, particularly
in childhood; are more likely to exhibit all documented > risk factors for cardiovascular
conditions; and are less likely to receive evidence-based care.
As is the case among non-Indigenous Australians and throughout high income countries
across the world, CVDs are the most common causes of death in the Indigenous popu-
lation. However, the rate experienced by Indigenous Australians far exceeds that of non-
Indigenous Australians. > Age-standardized rates of death from CVDs are 2.8-fold that of
non-Indigenous males and 2.4-fold that of non-Indigenous females, and > hospitalizations
for CVDs are 1.4-fold greater than for non-Indigenous Australians. Most concerning, these
disparities are greatest among younger individuals.
CVDs are common among Indigenous Australians, and occur considerably more often and
at a younger age than in non-Indigenous Australians. They are also the main contributor to the
profound life-expectancy gap between Indigenous and non-Indigenous populations. Adopting
targeted national, state and local strategic action is urgently required to reduce the > incidence
of > vascular diseases in these groups and reduce the documented life expectancy gap.
List of Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease; DALY,
disability adjusted life year; NHMRC, National Health and Medical Research Council; SMR,
standardized > mortality ratios
1 Introduction
In 2001, the Aboriginal and Torres Strait Islander population was estimated to be 458,520;
approximately 2.4% of the entire Australian population (see > Table 52-1). By mid 2008,
this population is estimated to grow to between 519,459 and 580,486 (Australian Bureau of
Statistics and Australian Institute of Health and Welfare, 2005); representing the fastest
growing population sub-group within contemporary Australian society.
Despite having a collective ‘‘ethnic label’’ – Indigenous Australians – there is significant
heterogeneity that exists across this group, in terms of language, culture, governance, geo-
graphical location, population size, community structure and history. The majority (about
90%) of the Indigenous population identify themselves as being of Aboriginal origin, 6%
identify as being of Torres Strait Islander origin, and 4% as being of both Aboriginal and Torres
Burden of Cardiovascular Diseases Among Aboriginal and Torres Strait Islander Peoples 52 921
. Table 52-1
Population characteristics of Indigenous and non-Indigenous Australians
Indigenous Non-indigenous
Population (2001 census) 458,520 (2.4%) 18.5 million (97.6%)
Median age, years 21 36
Aged >55 yearsa 6.8% 22.4%
Living in remote areasa 26% 2%
Completed high schoola 18.5% 43.5%
Completed a Bachelor degree (aged 18 years)a 4.6% 20.6%
Unemployed (aged 18–64 years)a 20.3% 5.8%
Mean household income (before tax) $394 $665
a
Percentage of indigenous or non-indigenous group
. Table 52-2
Summary of the health of Aboriginal and Torres Strait Islander Peoples
Males Females
Life expectancy at birth (1996–2001), years 59.4 65.0
Deaths before age 65 yearsa 75% 65%
Infant deaths per 1,000 live births 15 12
Cardiovascular disease deaths (1999–2003)a 26.9% 27.9%
Coronary heart disease deaths (2000–2002)b 62.3% 50.5%
b
Stroke deaths (2000–2002) 14.7% 20.1%
a
As a proportion of all deaths
b
As a proportion of deaths from cardiovascular diseases
Strait Islander origin (Australian Bureau of Statistics and Australian Institute of Health and
Welfare, 2005). Within each of these groups, the population is culturally diverse.
Despite these differences, Indigenous Australians share profound markers of socio-economic
and health disadvantage (> Table 52-2). In 2001, the Indigenous population had a median
age of 21 years; considerably younger than the median age of the non-Indigenous population
(36 years) (Australian Bureau of Statistics and Australian Institute of Health and Welfare,
2005). Approximately 50% of the Indigenous population was less than 20 years of age,
compared with about 27% of the non-Indigenous population (> Figure 52-1). In addition, only
6.8% of the Indigenous population were aged 55 years and over compared with 22.4% of the
non-Indigenous population (> Table 52-1).
Other factors such as geographical location, educational attainment, unemployment, and
income vary considerably between Indigenous and non-Indigenous populations. In 2001,
a relatively large proportion of the Indigenous population (26%) lived in remote areas
(Australian Bureau of Statistics and Australian Institute of Health and Welfare, 2005),
. Figure 52-1
Age distribution of the Indigenous and non-Indigenous Australian population. Age and sex
distribution of the Indigenous (open bars) and non-Indigenous (grey bars) population of
Australia. (Data obtained from (Australian Bureau of Statistics and Australian Institute of Health
and Welfare, 2005; Appendix 1)
with greater than half living in remote areas in some regions (such as the Northern Territory).
This compares with only about 2% of the non-Indigenous population (> Table 52-1). Fewer
than one-third (30%) of Indigenous Australians live in major cities compared with approxi-
mately two-thirds of the non-Indigenous population.
In 2002, 18.5% of Aboriginal and Torres Strait Islander peoples had completed high school
and 4.6% of those aged 18 years and over had completed a bachelor degree or above
(Australian Bureau of Statistics and Australian Institute of Health and Welfare, 2005). This
is less than half the proportion of non-Indigenous Australians completing high school, and
less than a quarter of non-Indigenous Australians completing a bachelor degree or above.
These figures are mirrored in employment and income figures (> Table 52-1).
Of major concern is the life expectancy gap that exists between Indigenous and non-
Indigenous Australians. Life expectancy at birth is 59.4 years among Indigenous males and
65.0 years among Indigenous females (> Table 52-2). This compares with 76.6 years among
non-Indigenous males and 82.0 years among non-Indigenous females; a difference of approxi-
mately 17 years. Furthermore, data from the Northern Territory of Australia provide evidence
that although life expectancy among Indigenous Australians increased over the 20 years from
1981 to 2000 this increase was not as great as that observed among non-Indigenous Australians
(> Figure 52-2). Thus, in this region of Australia, there has been an increase in the disparity
between life expectancies over this period.
Limitations of health data for Indigenous Australians
There are a number of caveats with routinely collected hospital > morbidity and mortality data.
Firstly, there remain uncertainties about the number of people who identify themselves as being
of Aboriginal and Torres Strait Islander origin. Secondly, there is incomplete identification of
Indigenous Australians in hospital records and birth and death registrations, largely occurring at
the time of data capture. Despite a common and nationally accepted definition of ‘‘Indigenous
status,’’ there are different methods of data collection. The accuracy of identification of Indige-
nous status differs significantly across States and Territories, ranging from below 50% in the
south-eastern states of Australia [NSW, Victoria and Tasmania], to greater than 90% in
the Northern Territory. Combined national data-sets currently utilize data from Queensland,
Western Australia, South Australia and the Northern Territory, covering approximately 60% of
the Indigenous population. Despite better quality, they are still thought to underestimate the
rates of illness and death among Indigenous Australians (Australian Bureau of Statistics and
Australian Institute of Health and Welfare, 2005).
. Figure 52-2
Trends in the Life expectancy gap between Indigenous and non-Indigenous people in the
Northern Territory, 1981–2000, for males (left panel) and females (right panel). Shaded region
depicts the contribution of cardiovascular diseases to this life expectancy gap. (Figure adapted
from Zhao Y et al. Causes of inequality of life expectancy between Indigenous and
non-Indigenous people in the Northern Territory, 1981–2000: a decomposition analysis. MJA
2006; 184: 490–494. ßCopyright 2006. (Zhao and Dempsey, 2006, reproduced with permission))
2 Burden of Cardiovascular Diseases in Australia
Cardiovascular diseases (CVD) are the major cause of death in high-income countries and are
becoming a major cause of death across lower-income countries across the world (Heller et al.,
1999; Joshi et al., 2006). Cardiovascular conditions are now the leading cause of death and
burden of disease worldwide, being responsible for approximately 16.5 million deaths in 2002
(Murray and Lopez, 1997; World Health Organization, 2004). Similarly, deaths from CVD are
the most common cause of death in Australia, accounting for 37.6% of deaths in 2002
(Australian Institute of Health and Welfare, 2004), and 21.9% of all disability adjusted life
years (DALYs) (Mathers et al., 2000). They are also the most costly health conditions, conser-
vatively costing Australian society over $14 billion in direct and indirect health expenditure
(Access Economics, 2005).
2.1 Decline in Cardiovascular Disease Mortality
In many high-income countries there has been a decline in age-standardized mortality from
CVDs over the last 35 years (Higgins and Thom, 1989; Thom, 1989). This is also true of
Australia (Beaglehole et al., 1989). Over the 12-year period from 1991 to 2002 deaths from
CVD declined by 36.3% in men and 33.7% in women (Australian Institute of Health and
Welfare, 2004). Deaths from coronary heart disease declined by 41.1% among males and
40.1% among females, while deaths from stroke declined by 28.1% among males and 27.3%
among females (Australian Institute of Health and Welfare, 2004). Part of the decline has been
attributable to a declining incidence of these diseases and to improved survival. The decline in
smoking rates, improved treatment of hypertension and high cholesterol levels, changes to our
diets, and improved medical care are all thought to have contributed to these declines (Brown
et al., 2006).
2.2 Increase in Cardiovascular Disease Hospitalizations
Occurring in parallel to reductions in mortality, there have been increases in the rates of
hospitalization for CVD. Over the 8-year period from 1993–1994 to 2001–2002 there was a
19.8% increase in the age-standardized hospitalization rate for CVDs (Australian Institute of
Health and Welfare, 2004).
3 Cardiovascular Diseases in Aboriginal and Torres Strait

Islander Peoples
3.1 Mortality
Collectively, cardiovascular conditions are the most common cause of mortality in the
Aboriginal and Torres Strait Islander population (> Table 52-2), accounting for more than
one-quarter of all deaths (Australian Bureau of Statistics and Australian Institute of Health
and Welfare, 2005). Over half of these are due directly to coronary heart disease (CHD)
(Australian Institute of Health and Welfare, 2004). In addition, CVD is the leading contributor
to the gap in life-expectancy between Indigenous and non-Indigenous Australians, accounting
for 30% of excess deaths, and almost a third of the almost 20-year life expectancy gap (see
> Figure 52-2) (Zhao and Dempsey, 2006). In an analysis of national data from 2001 to 2003,
CHD accounted for 21 and 19 years of life lost among Indigenous Australian males and
. Figure 52-3
Ratio of the observed number of deaths among Indigenous Australians to the number of
expected deaths. These rates are standardized to the age and sex of the Australian population
(2001). Data for Indigenous deaths and hospitalizations are for usual residents of Queensland,
Western Australia, South Australia and the Northern Territory. The expected number of deaths is
that observed for non-Indigenous Australians. Data obtained from (Australian Institute of Health
and Welfare, 2004)
females (Australian Institute of Health and Welfare, 2006), compared to 12.1 and 8.6 years in
non-Indigenous males and females respectively.
> Figure 52-3 shows the standardized mortality ratios (SMR) from cardiovascular condi-
tions comparing Indigenous and non-Indigenous Australians (SMR = ratio of the observed
number of deaths among Indigenous Australians to the expected number of deaths; based on
the expected number of deaths observed among non-Indigenous Australians of the same age
and gender). Aboriginal and Torres Strait Islander peoples have a considerably greater rate of
death than that expected given the younger age structure of the population; being 2.8-fold that
of non-Indigenous males and 2.4-fold that of non-Indigenous females (Australian Institute of
Health and Welfare, 2004). The SMR is greater for all cardiovascular conditions in both males
and females (with the exception of > peripheral vascular disease). The greatest difference in
mortality is seen in > rheumatic fever and chronic > rheumatic heart disease, where death
rates were approximately 17-fold for Indigenous men and 21-fold for Indigenous women.
A considerable proportion of Indigenous Australians who died from CVDs, died before
the age of 65 years (62%) (Australian Institute of Health and Welfare, 2004). This compares to
only about 10% for other Australians. Mortality in Indigenous Australians was greater in all
age categories up to age 75, and the greatest disparity occurred in the 25–44 year age group.
Deaths rates among Indigenous Australians in this age group were 10 times those of other
Australians.
3.2 Hospitalizations
Aboriginal and Torres Strait Islander peoples have significantly greater hospitalization rates
than other Australians (> Figure 52-4), yet at levels less than one would expect given their
profoundly disparate disease burden. The overall age-standardized hospitalization rate for
CVDs is approximately 1.4 times as high as for other Australians. The greatest disparity
occurred for acute rheumatic fever and chronic rheumatic heart disease, 5.7-fold for males
and 8.1-fold for females.
. Figure 52-4
Ratio of the observed number of hospitalizations among Indigenous Australians to the number
of expected hospitalizations. These rates are standardized to the age and sex of the Australian
population (2001). Data for Indigenous deaths and hospitalizations are for usual residents of
Queensland, Western Australia, South Australia and the Northern Territory. The expected
number of hospitalizations is that observed in non-Indigenous Australians. Data obtained from
(Australian Institute of Health and Welfare, 2004)
These disparities in hospitalization rates are not as high as those for mortality, and are
likely to have several explanations. Firstly, hospital records do not always report the Indigen-
ous status of patients, with patients of unknown ethnicity automatically identified as non-
Indigenous. Many Indigenous Australians also live in remote areas, geographically isolated
from a range of services, and so may not have ready access to a hospital or other specialist care.
As a consequence, observed rates are likely to underestimate the true rates of hospitalization
of Indigenous people. Further, beyond geographical access to services, Indigenous people
experience many barriers to accessing necessary care (Cass et al., 2002; Cass et al., 2003). This
is particularly so for Indigenous males, whom despite greater burdens of disease are far less
likely to present for and receive care (Brown and Blashki, 2005).
Similar to the mortality figures, Indigenous Australians were hospitalized for CVDs at
younger ages than non-Indigenous Australians. A total of 59% of hospitalizations for CVDs
among Indigenous Australians occurred in those less than 65 years of age. This compares
with 23% for other Australians. The hospitalization rates were similar in those aged
75 years and over, but the greatest disparity occurred in those aged 35–54 years. In this
age group hospitalization rates for Indigenous Australians were three times that of other
Australians. Furthermore, length of hospital stay, excluding those discharged on the same day,
was 7.2 days for Indigenous Australians. This was 1.9 days longer than for non-Indigenous
Australians.
3.3 Disability Adjusted Life Years
The leading cause of disease burden among Aboriginal and Torres Strait Islander peoples is
CVD, being responsible for 17.5% of the total disease burden in these peoples in 2003 (Vos
et al., 2007). This is similar to the proportion of disease burden in other Australians (18%).
Among Indigenous Australians, coronary heart disease contributed the most (10.4%) to the
total disease burden while stroke contributed the second most (2.8%). The total cardiovascu-
lar burden was 4.6-fold greater among the Indigenous population than non-Indigenous
Australians (Vos et al., 2007).
3.4 Disparity in the Decline in Mortality Between Socioeconomic

Groups
In Australia, declines in mortality that have been observed have not been equal among all
groups of people. In particular the declines have been less in people with greater socioeco-
nomic disadvantage (Bennett, 1996). Mortality declines have also not been equal between
Indigenous and non-Indigenous Australians. Over the period 1991–1996, mortality from
CVD did not change for Indigenous males, but it declined by 3.1% per year among non-
Indigenous males (Mathur and Gayanayake, 1998). During the same period declines in
mortality from CVD were greater in Indigenous females (5.2% per year) than in non-
Indigenous females (2.6% per year) (Mathur and Gayanayake, 1998). This provides evidence
that the disparity in mortality from CVD deaths between Indigenous and non-Indigenous
males is widening, but the gap may be closing in women.
3.5 What is the Reason for the High Rates of Cardiovascular

Disease and Stroke?
The antecedents to high rates of CVD and stroke are likely attributable to a change in lifestyle
from a traditional one to one that encompasses more of the Western lifestyles (Gault et al.,
1996; O’Dea, 1992). It has been proposed that the excess risk of CVD among the Aboriginal
population is complex and originates from a number of factors (Brown et al., 2006). These
include factors ranging from their relative social, economic and educational disadvantage to
physiological and psychological factors. Other factors that contribute significantly include
their limited access to basic culturally-appropriate medical care and preventive treatment in
rural and remote areas and, indeed, urban regions.
It is likely that conventional risk factors play a major part in the increased occurrence of
vascular disease among the Indigenous population. Many of these risk factors are more
common in Aboriginal and Torres Strait Islander peoples. As can be seen in > Table 52-3, the
proportion of people smoking in the Indigenous population is more than double that in the non-
Indigenous population (Australian Bureau of Statistics and Australian Institute of Health and
. Table 52-3
Comparison of selected risk factors between indigenous and non-indigenous Australians
Risk Factor Indigenous Non-indigenous

a
Current smoker 43% 19%
Alcohol consumption
High risk consumptiona 9.3% 2.7%
Abstains from alcohol 30.6%b 18.5%a
Type 2 diabetes 11% 3%
Overweightc 64% 50%
Hypertensiond 15% 10%
a
People aged 14 years and over
b
c
d
Self-report
Welfare, 2005; Australian Institute of Health and Welfare, 2004). In addition, the > prevalence of
> type 2 diabetes is approximately four times greater in the Indigenous population than the non-
Indigenous population (Australian Bureau of Statistics and Australian Institute of Health and
Welfare, 2005), being more common in remote regions than in urban regions and occurring at
younger ages in the Indigenous population. > Overweight and obesity (> obese) is also more
common, and is present in approximately 64% of the Aboriginal population, compared with 50%
of the non-Indigenous population (Australian Institute of Health and Welfare, 2004). There are
no national data on blood pressure levels and cholesterol levels of the Indigenous population,
although self-reported data on high blood pressure and high cholesterol were collected in the
2001 National Health Survey (Australian Bureau of Statistics and Australian Institute of Health
and Welfare, 2005). Indigenous Australians reported having high blood pressure more often
(15%) than non-Indigenous Australians (10%), and also reported having high blood pressure at
younger ages. Similar proportions of Indigenous (6%) and non-Indigenous Australians (7%)
reported high cholesterol levels (Australian Bureau of Statistics and Australian Institute of Health
and Welfare, 2005), although self-reported rates tend to underestimate the proportion of those
with high cholesterol levels. Surveys of risk factors in a number of Indigenous Australian
communities have also found high levels of hypertension, hypercholesterolemia, hypertriglycer-
idemia, and the clustering of multiple risk factors amongst individuals in rural, remote and urban
settings (Gault et al., 1996; Rowley, 2003; Thompson et al., 2003).
These risk factors are all modifiable, and reducing their prevalence would reduce the
incidence of CVDs, including stroke and coronary heart disease.
Although these conventional risk factors play a part in the greater incidence of CVD in the
Indigenous population, other socio-economic, social, and psychosocial factors also contribute
significantly (Brown et al., 2005). For example, Indigenous Australians have greater unemploy-
ment, lower income, and lower levels of education than non-Indigenous Australians. Other
factors may also contribute either directly or indirectly. These include poor housing, over-
crowding, poor sanitation, high levels of stress, poor coordination across the health system, lack
of culturally appropriate health services, and reduced availability of transport to health services.
4 National Strategy for Improving Vascular Health
Urgent actions are required to improve the health of Aboriginal and Torres Strait Islander peoples.
The National Strategy for Heart, Stroke and Vascular Health Strategies Group has identified
some actions for reducing the impact of CVDs (National Heart Stroke and Vascular Health
Strategies Group, 2004). Important actions identified include providing a comprehensive prima-
ry health care program; improving identification and approaches to management of risk factors;
and increasing training and support for health care providers, including Aboriginal health
workers.
Additional requirements must be to address the imbalance in the provision of services to
Australia’s most vulnerable population; this group having a profoundly heightened level of
need. National and jurisdictional data point to marked disparities in access to, receipt of, and
outcomes from, necessary cardiovascular therapies for Aboriginal people with CHD (Mathur
et al., 2006). Disparities in care clearly contribute to adverse outcomes, and the lower access to
and receipt of evidence-based care for Indigenous people is a target for system wide reform.
If these strategies can be successfully implemented they should help in improving
the health of Aboriginal and Torres Strait Islander peoples (Thrift and Hayman, 2007).
Importantly they may help in reducing the imbalance in health status that currently exists,
particularly the profound and unacceptable gap in life expectancy between Indigenous and
non-Indigenous Australians.
Summary Points
The Aboriginal and Torres Strait Islander population comprises approximately 2.4% of the
Australian population.
The Aboriginal and Torres Strait Islander population are a culturally diverse group of
people living in Australia having many languages, and clan and tribal groups (Clan, Tribal
or Language Group).
The Indigenous population has a median age that is about 15 years younger than the rest of
the Australian population.
Approximately 26% of Indigenous Australians live in remote areas of Australia compared

with 2% of non-Indigenous Australians.
The quality of mortality and morbidity data on Aboriginal and Torres Strait Islander
populations is relatively poor.
Similar to other developed nations, CVDs are the most common cause of death in
Australia.
Deaths from CVDs are greater in Indigenous Australians than in non-Indigenous Aus-
tralians being 2.8-fold among males and 2.4-fold among females.
Sixty-two percent of Indigenous Australians who died from CVD were less than 65 years of
age. This compares with 10% for non-Indigenous Australians.
Hospitalization rates for CVD were 1.4 times greater among Indigenous than non-Indige-
nous Australians.
There have been declines in mortality from CVDs in non-Indigenous males, but not
among Indigenous males, and so the disparity in CVD deaths is increasing.
Indigenous Australians have greater prevalence of conventional risk factors for CVDs, as
well as social, economic and educational disadvantage.
There is a lack of culturally appropriate health services for Indigenous Australians,
including primary health care services.
Urgent action is required to reduce the disparity in health status between Indigenous and
non-Indigenous Australians.
Acknowledgments
A/Prof Thrift was supported by a senior research fellowship from the National Health and
Medical Research Council of Australia (NHMRC), and Dr. Gall was supported by a post-
doctoral public health fellowship from the NHMRC.
References
Access Economics. (2005). The Shifting Burden of Bennett S. (1996). Int J Epidemiol. 25: 266–275.
Cardiovascular Disease in Australia. Access Econom- Brown A, Blashki G. (2005). Aust Fam Physician. 34:
ics and The National Heart Foundation of Australia. 813–819.
Australian Bureau of Statistics and Australian Institute of Brown A, Walsh W, Lea T, Tonkin A. (2005). Heart Lung
Health and Welfare. (2005). The Health and Welfare Circ. 14: 158–162.
of Australia’s Aboriginal and Torres Strait Islander Brown AD, Morrissey MJ, Sherwood JM. (2006). Ethn
Peoples. Commonwealth of Australia, Canberra. Health. 11: 191–210.
Australian Institute of Health and Welfare. (2004). Heart, Cass A, Cunningham J, Arnold P, Snelling P, Wang Z,
Stroke and Vascular Diseases – Australian Facts Hoy W. (2002). MJA. 177: 135–138.
2004. AIHW and National Heart Foundation of Cass A, Cunningham J, Snelling P, Wang Z, Hoy W.
Australia (Cardiovascular Disease Series No. 22), (2003). Health Place. 9: 175–182.
Canberra. Gault A, O’Dea K, Rowley KG, McLeay T, Traianedes K.
Australian Institute of Health and Welfare. (2006). (1996). Diabetes Care. 19: 1269–1273.
Chronic Disease and Associated Risk Factors in Heller RF, O’Connell RL, Lim LL, Atallah A, Lanas F,
Australia, 2006. Cat. No. PHE 81. AIHW, Canberra. Joshi P, Tatsanavivat P. (1999). Int J Cardiol. 68:
Beaglehole R, Dobson A, Hobbs MS, Jackson R, 63–67.
Martin CA. (1989). Int J Epidemiol. 18: S145–148. Higgins M, Thom T. (1989). Int J Epidemiol. 18: S58–66.
Joshi R, Cardona M, Iyengar S, Sukumar A, Raju CR, and Vascular Health in Australia. Commonwealth of
Raju KR, Raju K, Reddy KS, Lopez A, Neal B. Australia, Canberra.
(2006). Int J Epidemiol. 35: 1522–1529. O’Dea K. (1992). J Intern Med. 232: 103–117.
Mathers CD, Vos ET, Stevenson CE, Begg SJ. (2000). Med Rowley K, Walker KZ, Cohen J, et al. (2003). Med J Aust
J Aust. 172: 592–596. (MJA). 178: 495–500.
Mathur S, Gayanayake I. (1998). Surveillance of Cardio- Thom TJ. (1989). Int J Epidemiol. 18: S20–28.
vascular Disease in Australia 1985–1996. (AIHW Thompson PL, Bradshaw PJ, Veroni M, Wilkes ET.
cat. no. CVD 3). Australian Institute of Health and (2003). Med J Aust. 179: 143–146.
Welfare, Canberra. Thrift AG, Hayman N. (2007). Int J Stroke. 2: 57–59.
Mathur S, Moon L, Leigh S. (2006). Aboriginal and Vos T, Barker B, Stanley L, Lopez A. (2007). The Burden
Torres Strait Islander people with Coronary Heart of Disease and Injury in Aboriginal and Torres Strait
Disease: Further Perpsectives on Health Status and Islander peoples 2003. School of Population Health,
Treatment. AIHW Cat. No. CVD 34. Australian In- The University of Queensland, Brisbane.
stitute of Health and Welfare, Canberra. World Health Organization. (2004). World Health Report
Murray CJ, Lopez AD. (1997). Lancet. 349: 1498–1504. 2004: Changing History, pp 112–125, Retrieved 18 May
National Heart Stroke and Vascular Health Strategies 2006, from http://who.int/whr/2004/en/index.html
Group. (2004). National Strategy for Heart, Stroke Zhao Y, Dempsey K. (2006). Med J Aust. 184: 490–494.
53 Burden of Ischemic Heart
Diseases in Serbia
S. Sipetic-Grujicic . H. Vlajinac . J. Marinkovic . V. Bjegovic . I. Ratkov .
J. Maksimovic
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
2 The Burden of IHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935

2.1 Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935
2.1.1 CVD as a Cause of Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935
2.1.2 The Mortality Trend for CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
2.1.3 IHD as a Cause of Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
2.1.4 The Mortality Trend for IHD in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
2.1.5 The IHD Mortality Trend in Serbia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937
2.1.6 Factors with the Greatest Impact on the IHD Mortality Trendy . . . . . . . . . . . . . . . . . . 938
2.1.7 Age Specific CVD and IHD Mortality Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 938
2.2 Disability Adjusted Life Years (DALY) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
2.3 Years of Life Lost (YLL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
2.3.1 Calculating Years of Life Lost in Serbia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
2.3.2 Total Years of Life Lost in Various Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
2.3.3 Years of Life Lost due to CVD in Various Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
2.3.4 Years of Life Lost Due to IHD in Various Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
2.4 Years of Life with Disability (YLD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
2.4.1 Calculation of Years of Life with Disability in Serbia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
2.4.2 Disability Adjusted Life Years Lost due to IHD in Various Countries . . . . . . . . . . . . 943
2.5 Risk Factors for IHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945
3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 946
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 946

934 53 Burden of Ischemic Heart Diseases in Serbia
Abstract: For decades now, cardiovascular disease (CVD) in Belgrade (Serbia) has occupied
first place as a cause of death. In the Belgrade population aged 30–69, CVD caused about 40%
of all deaths. During the period 1975–2000, mortality rates of all CVD increased significantly
by 17.1%. Yet mortality rates of IHD decreased by 8% in men and 22% in women.
In the Serbian population, as in the populations of developed countries, IHD is the leading
single cause of premature years of life lost (YLL) for both sexes, being responsible for 16.7% of
the total YLL. It is the leading single cause of premature death for males with 87,191 YLLs in
2000. In females, cerebrovascular disease is the leading cause of YLL followed by IHD (48,965
YLLs in 2000).
In Serbia in 2000, IHD was responsible for 8,833 years of life with disability (YLD) in men
and 5,902 YLD in women.
The total burden of > ischemic heart disease (IHD) in Serbia in 2000 was estimated at
96,023 disability adjusted life years (DALY) for men and 54,866 DALY for women. The total
burden of IHD was higher for males than females. For IHD, the DALY rates per 1,000
population increased with aging in both men and women, and peaked in the oldest, 75
years of age and over. The proportion of YLD in DALY (10%) for IHD in Serbia was higher
than in the EURO region (6%). The factors most responsible for this IHD burden were
smoking, physical inactivity, hypertension and overweight/obesity.
Despite obvious limitations, the DALYestimates can be used as a guide for preventing IHD
as well as for evaluating the scope of future health gains obtained by reducing population
exposure to various risk factors.
List of Abbreviations: AP, > angina pectoris; > CI, confidence interval; CVD, > cardiovascular
diseases; DALY, disability adjusted life lost; EMS, established market economics; EU, European
Union; FSE, formerly socialist economies; IHD, ischemic heart disease; SBDS, Serbian burden
disease study; WHO, World Health Organization; YLD, years of life with disability; YLL, years
of life lost
1 Introduction
The number of deaths worldwide from cardiovascular disease (CVD) increased from 14 million
in 1990 (Murray and Lopez, 1996a) to more than 16.7 million in 2002 (Mackey and
Mensah, 2004). In Europe, CVD is the main cause of death (4.35 million deaths – 49% of
all deaths) and the main cause of years of life lost (YLL) (about 30% of the total YLL)
(Allender et al., 2008). As a cause of disability adjusted life years (DALY) lost, cardiovascular
disease occupies second place in the Established Market Economies (EME)(18% of the total
DALY), and first place in the Former Socialist Economies (FSE) (23% of the total DALY
(Murray and Lopez, 1996a). CVD is responsible for 10% of DALY lost in low and middle
income countries, and 18% in high income countries (Mackey and Mensah, 2004).
The main forms of CVD are ischemic heart disease (IHD) and cerebrovascular disease. IHD
is the leading single cause of death in the world at large. It kills 7.2 million people each year
(Mackey and Mensah, 2004). Most of these deaths occurred in the developing countries. IHD
burden is expected to rise from around 47 million DALY in 1990 to 82 million DALY in 2020
(Murray and Lopez, 1996a). In Europe it is also the most common cause of death accounting for
1.92 million deaths and over 34 million DALY lost (10% of all DALY) (Allender et al., 2008).
The aim of this report is to present data on the IHD burden in Serbia.
Burden of Ischemic Heart Diseases in Serbia 53 935
2 The Burden of IHD
2.1 Mortality
The mortality rates presented in this report refer to Belgrade (the capital of Serbia). They were
restricted to the Belgrade population aged 30–69 years (about 800,630 inhabitants) and to the
period 1975–2000.
2.1.1 CVD as a Cause of Death
For decades CVD in Serbia and Belgrade has occupied first place as a cause of death (Sipetic
et al., 2001; Vlajinac et al., 1994, 2000). In the Belgrade population aged 30–69, CVD
accounted for around 2,359 deaths each year (> Table 53-1) and caused about 40% of all
. Table 53-1
The average age-standardized mortality rate (per 100,000) and the perceptual change in
temporal trends for all causes of death and for major causes of death in people aged 30–69 years
in Belgrade, 1975–2000
Average % change in the

Cause of death (ICD codes, number of Average mortality temporal trend
eighth, ninth, and tenth revision) deaths rate (95% CI) (95% CI)
Neoplasms (140–239, C00–D48) 1,742 224.2 (194.7–253.3) +63.3 (47.7–78.9)
Endocrinal, nutritional and 134 17.6 (9.4–25.8) +4.3 (0.3–8.4)
metabolic disease (240–279,
E00–E90)
Cardiovascular disease (390–458/ 2,359 302.0 (268.0–336.0) +17.1 (9.0–25.2)
459, I00–I99)
a
Diseases of the respiratory system 174 23.1 (13,7–32.5)
(460–519, J00–J99)
a
Diseases of the digestive system 260 34.0 (22.6–45.4)
(520–577/579, K00–K93)
Diseases of the genitourinary 121 16.2 (8.3–24.1) 36.0 (24.2–47.8)
system (580–629, N00–N99)
a
Injury and poisoning (800–999, 413 52.2 (45.0–59.4)
S00–T98)
All causes (000/001–999, A00–Z99) 5,923 758.2 (704.4–812.0) +53.7 (39.3–68.1)
The average age-standardized mortality rate is the average number mortalities observed in the average number of
the population at risk from mortality calculated for the same period of time, 1975–2000. Average mortality rates
are directly standardized based on the “European population” (Ahmad et al., 2000). Direct standardization used
weighted averages of specific rates in the study population based on distribution in the European standard
population. Regression analysis is a statistical procedure which was used to find the best fit between a dependent
(time) and independent variable (mortality rates). A linear regression equation was used to calculate the presence
of change in the temporal trend. CI confidence interval
a
An appropriate regression equation was not found
deaths. CVD causes almost half of all deaths in Europe (49%) and in the European Union
(EU) (42%) (Allender et al., 2008).
2.1.2 The Mortality Trend for CVD
In Belgrade during the period 1975–2000, mortality rates of all CVD increased significantly by
17.1% (95% confidence interval – CI: 9.0–25.2) (> Table 53-1). During the same period, an
increasing mortality trend was observed for endocrinal, nutritional and metabolic diseases
(4.3%; CI: 0.3–8.4), neoplasms (63.3%; CI: 47.7–78.9) and all causes of death (53.7%; CI:
39.3–68.1).
The proportion of deaths worldwide from CVD was expected to increase by 7% between
1990 and 2020, from 29 to 36% of all deaths (Murray and Lopez, 1996a). The anticipated rise
in CVD worldwide was related principally to two trends in the developing countries: (1) the
reduction of malnutrition and infectious diseases as a cause of death, which resulted in an
aging of the population, and (2) a marked increase in cigarette smoking. During the period
1972–2005, CVD mortality fell in most Northern, Southern and Western European countries but
neither dropped as fast nor rose in Central and Eastern European counties (Allender et al., 2008).
2.1.3 IHD as a Cause of Death
IHD is the most common single cause of death in Europe and accounts for nearly 2 million
deaths in Europe each year (Allender et al., 2008). More than one in five women (23%) and
more than one in five men (21%) died from IHD. In the Belgrade population, more than
one in three men (38.9%) and more than one in three women (40.9%) died from IHD
(> Table 53-2). IHD is also responsible for 36.0% and 25.1% of all CVD deaths in men and
women, respectively.
Death rates for IHD are generally higher in Central and Eastern Europe than in Northern,
Southern and Western Europe, showing a clear east-west gradient, the highest mortality rates
showing in Eastern Europe (Allender et al., 2008; European Society of Cardiology Force on
Cardiovascular Mortality and Morbidity Statistics in Europe, 1997). In 2000, in the male
population of Belgrade aged 35–74 the IHD death rate (157.7 per 100,000) was most similar to
the rates of Luxemburg (145 per 100,000), Albania (162 per 100,000) and Austria (194 per
100,000), and it was nearly six times less than that of Ukraine (839 per 100,000), Belarus (789
per 100,000) and the Russian Federation (771 per 100,000) (Peterson et al., 2005). In the
female population of Belgrade aged 35–74, the IHD death rate (60.2 per 100,000) was most
similar to rates in Austria (59 per 100,000 in 2000), Finland (68 per 100,000 in 2000) and the
United Kingdom (80 per 100,000 in 2000), and nearly six times less that in Ukraine (373 per
100,000 in 2000) and Belarus (307 per 100,000 in 2000) (Peterson et al., 2005).
2.1.4 The Mortality Trend for IHD in Europe
Between 1990 and 2020, the increase in IHD mortality (120% in women and 137% in men)
in the developing countries is expected to be much greater than in the developed countries
(29 and 48%, respectively) (Murray and Lopez, 1996a). In Europe, over the past 30 years,
. Table 53-2
The average age-standardized mortality ratea (per 100,000) from all causes of death and from
cardiovascular disease in men and women aged 30–69 years, Belgrade, 1975–2000
95%
Cause of death (ICD codes, eighth, ninth, Average number Average confidence
and tenth revision) of deaths mortality ratea interval
Men
All causes (000–999, A00–Z99) 3,593 984.9 923.9–1046.1
Cardiovascular disease (390–458/459, 1,398 391.0 352.3–429.7
I00–I99)
Ischemic heart disease (410–414, I20–I25) 503 142.0 118.7–165.3
Acute heart attack (410, I20–I25) 415 116.9 95.7–138.1
Women
All causes (000–999, A00–Z99) 2,271 558.9 512.7–605.1
Cardiovascular disease (390–458/459, 929 229.0 199.4–258.6
I00–I99)
Ischaemic heart disease (410–414, I20–I25) 233 57.5 42.7–72.4
Acute heart attack (410, I20–I25) 179 44.1 31.1–57.1
The average age-standardized mortality rate is the average number mortalities observed in the average number of
the population at risk from mortality calculated for the same period of time, 1975–2000. Average mortality rates
are directly standardized based on the “European population” (Ahmad et al., 2000). Direct standardization used
weighted averages of specific rates in the study population based on distribution in the European standard
population
a
Mortality rates are standardized by using the “European population” (Ahmad et al., 2000)
death rates from IHD have been falling rapidly in most Northern and Western European
countries but rising fast in most Central and Eastern European countries (Allender et al.,
2008). Very high rates and a spiraling increase in mortality from IHD since 1990 have been
observed in Russia. For example, IHD death rates in Finland and the United Kingdom in the
35–74 age group fell by 41 and 39% for men, and by 46 and 43% in women, respectively
between 1989 and 1999 (Allender et al., 2008). On the other hand, in Romania and the Russian
Federation, IHD mortality rates rose by 35 and 33% for men aged 35–74 and by 21 and 25%
for women, respectively between 1989 and 1999. The IHD rising trend in Central and Eastern
Europe was less pronounced in women than in men.
2.1.5 The IHD Mortality Trend in Serbia
In contrast to the increase in IHD mortality in Eastern European countries, a decreasing trend
in IHD mortality was observed in the Belgrade population in both sexes (about 8% in men and
22% in women) (> Table 53-3 and > Figure 53-1). Generally speaking, the decline in IHD
mortality could be due to declining incidence, declining severity of the disease, and/or
improved management of IHD. The fact that mortality from other heart diseases increased
suggests that some of the trends may have been influenced by changes in the method of
assessing the cause of death within the heart disease group. Therefore it is possible that many
. Table 53-3
Trends in cardiovascular disease: the percentage change in age-standardized mortality rates in
men and women aged 30–69 years in Belgrade, 1975–2000
Cause of death (ICD codes, Men % change in the Women % change in the
eighth, ninth and tenth temporal trend (95% temporal trend (95%
revision) confidence interval) confidence interval)
All causes (000–999, +69.1 (52.8–85.4) +37.2 (25.2–49.2)
A00–Z99)
Cardiovascular disease +30.8 (19.9–41.7) +10.3 (4.0–16.6)
(390–458/459, I00–I99)
Ischaemic heart disease 8.2 (2.6–13.8) 21.7 (12.6–30.8)
(410–414, I20–I25)
a a
Acute heart attack (410,
I20–I25)
Regression analysis is a statistical procedure used to find the best fit between a dependent (time) and independent
variable (mortality rates). A linear regression equation was used to calculate the presence of change in the
temporal trend
a
An appropriate regression equation was not found
deaths, previously attributed to IHD, were later attributed to some other form of heart disease
(Vlajinac et al., 1994). That change could account for a substantial part of the decline. For
myocardial infarction, the diagnosis of which should be more precise, a decrease in mortality
rates was also found in both sexes, but it was not significant.
2.1.6 Factors with the Greatest Impact on the IHD Mortality Trendy
The WHO MONICA project measured trends in IHD mortality between the early 1980s and
1990s in 37 populations worldwide. The results showed that 2/3 of the decline in IHD
mortality was due to a decline in IHD incidence and 1/3 was due to improvements in survival
because of better therapy (Tunstall-Pedoe et al., 1999). In England and Wales, it was found that
58% of the decline in IHD mortality was attributable to reductions in major risk factors such
as smoking (Unal et al., 2004), but in the majority of Eastern European countries, the increase
in IHD mortality was due to the socio-economic and political changes which took place in
1990, changes that had a significant effect on both risk factors for IHD and the quality of
medical care.
2.1.7 Age Specific CVD and IHD Mortality Rates
In Belgrade, the mortality rates for CVD, IHD and > acute heart attack increased with age in
both men and women and peaked in the oldest, 75 years of age and over (> Figure 53-2). In all
other countries in Europe the situation is the same. The mortality rates for IHD are
higher among women than men and increase with age (Allender et al., 2008; World Health
Organisation, 2004).
. Figure 53-1
Age standardized cardiovascular disease mortality (per 100,000) in men and women aged 30–69
years in Belgrade, 1975–2000 for all causes of death; all cardiovascular disease; ischemic heart
disease; and acute heart attack. Mortality rates are directly standardized using the “European
population” (Ahmad et al., 2000). Direct standardization used weighted averages of specific rates
in the study population based on distribution in the European standard population
2.2 Disability Adjusted Life Years (DALY)
DALY (the sum of YLL-years of life lost because of premature death, and YLD-years of life
lived with disability) was estimated for Serbia without Kosovo and Metohia (hereinafter:
Serbia). The reference year for calculating DALY was 2000. According to the population
census, the total population in Serbia was 7,551,000 (3,673,529 men and 3,877,326 women).
. Figure 53-2
Average age specific mortality rates (per 100,000) for all cardiovascular disease, ischemic
heart disease and acute heart attack in the male and female population in Belgrade,
1975–2000. The average age-specific rate means the average number mortalities observed in
the specific age group for the period 1975–2000. The numerator of the average age-specific
rate is the average number of mortalities observed in that age group and the denominator is
the average number of persons in that age group at risk from mortality calculated for the
same period, 1975–2000
2.3 Years of Life Lost (YLL)
2.3.1 Calculating Years of Life Lost in Serbia
In the Serbian Burden of Disease Study (Jankovic et al., 2006; SBD study group, 2003; Vlajinac
et al., 2006), all deaths of people resident in Serbia in 2000 were taken into consideration when
calculating YLL.
The Serbian Statistics Office mortality database for 2000 was found to be 98% complete.
Aside from the 2% of missing data, two other problems linked to the validity and reliability
of cause of death data emerged: (1) the failure to assign a specific code, using instead senility or
some other ill-defined code, and (2) assigning the wrong code due to manner of diagnosis,
negligence, etc. These problems were resolved in the way recommended in the NBD manual
The 8.67% of deaths assigned to ill-defined and senility codes (U161) were redistributed by
sex for age groups below 5 proportionally across a group of communicable, maternal, perinatal
and nutritional conditions, and for age groups over 5 proportionally across a group of non-
communicable diseases.
Cardiovascular garbage codes (U110), 10.72% of all deaths, were redistributed using the global
burden of disease regression formula (high ill-defined coding) to IHD (Lozano et al., 2001).
The 0.09% of deaths with missing ages was redistributed proportionally by sex and cause.
YLL was determined by the average life expectancy at time of death while discounting
future years by three percent. The life expectancy at birth was fixed at 82.5 years for females
(the life expectancy of women in Japan) and 80.0 years for males (Coale et al., 1983).
The Global Burden of Disease Study weighted a year of healthy life lived at young ages and
older ages lower than at other ages. This choice was based on a number of studies that have
indicated there is a broad social preference to value a year lived by a young adult more highly
than a year lived by a young child or at older ages (Murray and Lopez, 1996a). In the 2000
SBDS we decided to use this approach in order to compare our results with other studies. In
the exponential function Cxe bx which can express this age (x), recommended weighting
values of C = 0.1658 and b = 0.04 were applied.
2.3.2 Total Years of Life Lost in Various Countries
In 2000 in Serbia all causes of death were responsible for 814,022 YLL (> Table 53-4). Males
lost more YLL than females (462,050 compared to 351,972 retrospectively). It is typical that
males lose more life years than females, i.e., in the 1990 Global Burden Study in the EME,
males lost 60% of all YLL and in FSE 62.1% (Murray and Lopez, 1997). In the 2000 Global
Burden Study in the EURO region, males lost 61.5% of all YLL (Mathers et al., 2002), in the
Australia Burden Study about 55.8% (Mathers et al., 1999) and in the Victoria Burden Study
54.7% (Department of Human Services, 1999).
2.3.3 Years of Life Lost due to CVD in Various Countries
In 2000 in Serbia, CVD dominated the burden of premature mortality, being responsible for
48% of the total YLL. Males lose more YLL than females (52.4% compared to 47.6% of YLL
. Table 53-4
Years of life lost (YLL), by sex and disease groups, Serbia 2000
Causes by sex Number of YLL % of YLL YLL rate per 1,000

Men
All causes of death 462,050 56.8 125.8
Cardiovascular disease 206,400 52.4 56.2
Ischemic heart disease 87,191 64.0 21.9
Women
Ischemic heart disease 48,965 36.0 10.2
Total
Ischaemic heart disease 136,156 100.0 16.1
Years of life lost (YLL) were used as an indicator of the social burden of fatal health outcomes, calculated by
subtracting the age at death from the life expectancy remaining at that age. The life expectancy at birth was fixed
at 82.5 years for females and 80.0 years for males
respectively) (> Table 53-4). In 1996 in the Victoria Global Burden Study, CVD was responsi-
ble for over a fifth of the total disease burden or 7,375 DALY in men and 62,726 DALY in
women (Department of Human Services, 1999). Four-fifths of this burden was due to
mortality. In 1996 in the Australia Global Burden Study, males (237,844 YLL) lost more
years of life due to CVD than females (208,912) (Mathers et al., 1999).
2.3.4 Years of Life Lost Due to IHD in Various Countries
In the Serbian population, as in the populations of developed countries, IHD is the leading
single cause of YLL because of premature death for both sexes, being responsible for 16.7% of
the total YLL. It was the leading single cause of premature death for males with 87,191 YLL in
2000 (> Table 53-4), followed by cerebrovascular disease and lung cancer (2003 SBD Study
Group). In females, cerebrovascular disease was the leading cause of YLL followed by IHD
(48,965 YLL in 2000).
The WHO Global Burden of Disease Study found that in 1990, an average of 16% of YLL was
due to IHD in most Northern, Southern and Western countries and all the member states of the
European Union, and 18% in Central and Eastern European countries (Murray and Lopez,
1996b). In 1996, IHD was by the far the greatest cause of premature death in both males (9,141
or 22% of total YLL) and females (7,393 or 20% of total YLL) of the Southern Metropolitan
Region (Department of Human Services and Southern Health Care Network, 2000). In the 1996
Australia Burden Study, males had 34.9% more years of life lost due to premature deaths than
females (158,378 YLL and 117,399 YLL, respectively) (Mathers et al., 1999).
2.4 Years of Life with Disability (YLD)
2.4.1 Calculation of Years of Life with Disability in Serbia
In the SGBD (Jankovic et al., 2006; SBD study group, 2003; Vlajinac et al., 2006), out of CVD,
YLD was calculated only for IHD and cerebrovascular disease. YLD for IHD was calculated on
the basis of incidence data. The IHD (ICD10 codes I20–I25) model assumed that disease
might start as either angina pectoris (AP) or acute heart attack.
All data on acute heart attack were derived from the Register of Myocardial Infarction – the
Cindy and Monica Collaborative Centre, Novi Sad, for 1998 (Cindy and Monica Collaborative
Centre, 1998). Incidence included cases that in the course of the year experienced AMI for the
first time.
Lacking appropriate data on AP, AP incidence was estimated to be 1.8 times higher than
for acute heart attack. This estimate was based on data from hospitals in Belgrade (for the year
2000) showing that out of all hospitalized IHD cases, 64% were admitted with AP and 36%
with acute heart attack.
The disability duration for acute heart attack in 28-day non-survivors was assessed on the
basis of data from the Register. The disability duration for acute heart attack in 28-day
survivors was taken from the Global Burden Study – estimate for FSE (Murray and Lopez,
1996b). For AP disability duration was taken from the Victorian Burden of Disease Study
(Department of Human Services, 1999).
The disability weights used for IHD were slightly modified Global Burden Study weights
(Murray and Lopez, 1996a). It was assumed that each of the non-survivors suffered disability
of the severest category, similar to terminal cancer (Mathers and Boschi-Pinto, 2003). For the
rest, disability weights were calculated on the basis of Global Burden Study weights assuming
that, according to the Global Burden Study estimate for the FSE, 20% of IHD incidence cases
went untreated (Murray and Lopez, 1996a).
The standardization of IHD incidence and YLL, YLD and DALY rates was done using the
direct method and the European population as the standard (Ahmad et al., 2000).
2.4.2 Disability Adjusted Life Years Lost due to IHD in Various Countries
In 2000 in Serbia, years of life with disability (YLD) due to IHD yielded 8,833 YLD in men and
5,902 YLD in women (> Table 53-5). Males had 33.1% more years of life with disability than
females. The burden of IHD was dominated by mortality rather than a lengthy period of
disability (the total YLL and YLD contributions being 90.8% and 9.2% for men, and 89.2%
and 10.8% for women).
The proportion of YLD in DALY (10%) for IHD in Serbia was higher then in the EURO
region (6%) (Murray et al., 2001) and closer to that found in the Victoria study (11.8%)
(Department of Human Services, 1999). To calculate YLD due to IHD, the disability duration
of AP was taken from the Victoria study, since it was not available in the GDB study, which
probably explains this finding.
The total burden of IHD in Serbia in 2000 was estimated at 96,023 DALY for men and
54,866 for women or 26.1 of DALY lost per 1,000 population for men and 14.1 of DALY lost
per 1,000 for women (> Table 53-5) The burden of IHD was higher for males. For IHD, the
944 53
. Table 53-5
Burden of Ischemic Heart Diseases in Serbia
The Burden of ischemic heart disease in Serbia, 2000
Men
0–14 15–34 35–54 55–74 75+ Total
Population 632,181 1,012,725 1,100,538 792,886 135,199 3,673,529
Incidence
No 0 198 8,585 22,800 5,716 37,299
Rate/1,000 0 0.2 7.8 28.8 42.3 10.1
Standardized rate/1,000a 8.8
Death
No 0 91 2,312 6,631 1,850 10,884
Rate/1,000 0 0.1 2.1 8.4 13.7 3.0
YYL
No 0 1,680 23,564 51,995 9,951 87,190
Rate/1,000 0 1.7 21.4 65.6 73.6 23.7
YLD
No 0 68 2,621 5,304 840 8,833
Rate/1,000 0 0.1 2.4 6.7 6.2 2.4
DALY
No 0 1,748 26,185 57,299 10,791 96,023
Rate/1,000 0 1.7 23.8 72.3 79.8 26.1
Women
0–14 15–34 35–54 55–74 75+ Total
Population 599,759 994,831 1,120,051 939,446 223,239 3,877,326
Incidence
No 0 0 2,009 11,100 5063 18,172
Rate/1,000 0 0 1.8 9.9 22.7 4.7
Death
No 0 42 510 3,824 3,321 7,698
Rate/1,000 0 0.04 0.5 4.1 14.9 2.0
YYL
No 0 345 5,128 31,389 12,102 48,964
Rate/1,000 0 0.3 4.6 33.4 54.2 12.6
a
Standardized rate/1,000 9.1
YLD
No 0 0 1,273 3,882 747 5,902
Rate/1,000 0 0 1.1 4.1 3.3 1.5
DALY
No 0 345 6,401 35,271 12,849 54,866
Rate/1,000 0 0.3 5.7 37.5 57.6 14.1
a
Standardized rate/1,000 10.3
Disability adjusted life years (DALY) are the sum of YLL – years of life lost because of premature death, and YLD –
years of life lived with disability. Years of life lost (YLL) were used as an indicator of the social burden of fatal health
outcomes, calculated by subtracting the age at death from the life expectancy remaining at that age. YLD was
used to measure the burden of non-fatal health outcomes. It represents the equivalent of years of life lost to
severity-adjusted disability. YYL years of life lost; YLD years of life with disability; DALY disability adjusted life years
a
Standardized rate according to the European population (Ahmad et al., 2000)
DALY rates per 1,000 population increased with age in both men and women, and peaked in
the oldest age category, 75 and over.
In the Euro region 10% of all DALY lost are due to IHD and 8% in the EU (Allender
et al., 2008). The age-standardized DALY rate per 100,000 for IHD were highest in
Turkmenistan (2,860), Belarus (2,497), Kazakhstan (2,452), and Azerbaijan (2,316), and
lowest in Israel (370), Italy (409), Belgium (512), and Austria (579).
2.5 Risk Factors for IHD
Changes in the IHD burden should be analyzed in relation to changes in IHD risk factors in
the population. The decline in IHD mortality in the developed countries is partially attribut-
able to improved primary and secondary prevention as well as to changes in human behavior,
regarding smoking, diet, physical activity, etc. that accompany changes in the economy (Yusuf
et al., 2001).
In the SGBD study the population-attributable risks were applied to YLL, YLD and DALY
data, thus allowing an estimate to be made of the burden attributable to seven major risk
factors: cigarette smoking, alcohol consumption, physical inactivity, low vegetable and fruit
intake, high blood pressure and obesity (SGB study group, 2003). Attributable fractions were
calculated from the prevalence of risk factors in the population and the relative risk of dying if
exposed to a risk factor (English et al., 1995; Lilienfeld and Lilienfeld, 1980).
Risk factors for IHD which were more prevalent in men were smoking (47.5%), alcohol
consumption (62.7%), inadequate intake of fruit and vegetables (34.3), and overweight/
obesity (48.5) (Serbian Institute of Public Health, 2001). Physical inactivity (53.5%) and
hypertension (19.4%) were more prevalent in women. Out of the factors contributing to the
IHD burden in men, those most responsible were smoking (22.5%), physical inactivity
(22.2%), hypertension (19.2%) and overweight/obesity (14.7%). The same factors were
most responsible for IHD in women (about 89.3%), but their ranking, according to their
percentage of the IHD total burden, differed from that in men: physical inactivity (27.7%)
coming first, followed by hypertension (24.7), overweight/obesity (15.3%) and smoking
(1.3%). Alcohol consumption had a protective effect (attributable burden percentage of the
total IHD DALY-10.6% for men and 8.7% for women) in both sexes. The greatest sex
difference was found in the IHD burden attributable to smoking – the burden attributable
to tobacco was almost twice as high in males (22.5%) as that found in females (11.3%).
Despite obvious limitations, the attributable DALY estimates provide a useful tool to
measure the size of the health problem as presented by the observed risk factors (Mathers
et al., 1999). These estimates can be used as a guide for preventing IHD as well as for evaluating
the scope of future health gains by reducing population exposure to these hazards.
3 Conclusions
Taking into account experience in the developed countries, two complementary strategies for
primary prevention – the population approach and the high-risk approach – should be used in
order to prevent or reverse the rise of CVD morbidity and mortality. The population approach
comprises policy changes and community level programs in order to influence the distribution
of risk factors in the population, especially programs that control cigarette smoking, promote
a healthy diet, reduce obesity, and increase physical activity. Since a large number of people are
exposed to various CVD risk factors, it is expected that even modest changes in these factors
will have a significant impact on the cumulative population risk of CVD. The high-risk
approach focuses on identifying individuals who are at high risk of CVD because of marked
elevation of single or multiple risk factors. As Rose (1992) stated, the population approach aims
at reducing the CVD burden in the whole community, but provides small benefits to each
individual. On the other hand, the high-risk approach provides wide benefits, but to a limited
number of people who are most vulnerable. As the majority of CVD comes from large
segments of the population who are at modest risk, both strategies should be used as they
are complementary. Some improvement in mortality trends could also be achieved through
the prevention of recurrence and progression of the disease.
Summary Points
For decades, cardiovascular disease (CVD) in Belgrade (Serbia) has occupied first place as
a cause of death.
In Belgrade during the period 1975–2000, mortality rates of all CVD increased significantly
by 17.1%.
In contrast to the increase in IHD mortality in Eastern European countries, a decreasing
trend in IHD mortality was observed in the Belgrade population in both sexes (about 8%
in men and 22% in women).
In the Serbian population, as in the populations of the developed countries, IHD is the
leading single cause of premature death for both sexes being responsible for 16.7% of total
YLL.
In Serbia in 2000, IHD was responsible for 8,833 YLD in men and 5,902 YLD in women.
The total burden of IHD in Serbia in 2000 was estimated at 96,023 DALY (26.1 DALY lost
per 1,000 population) for men and 54,866 DALY for women (14.1 DALY lost per 1,000).
The burden of IHD was dominated by mortality rather than a lengthy period of disability
(participation by total YLL and YLD being 90.8 and 9.2% for men, and 89.2 and 10.8% for
women, respectively).
The proportion of YLD in DALY (10%) for IHD in Serbia was higher than in the EURO
region (6%).
The factors most responsible for the IHD burden were smoking, physical inactivity,
hypertension and overweight/obesity.
Taking into account the experience of the developed countries, two complementary
strategies for primary prevention, the population approach and the high-risk approach,
should be used in order to prevent or reverse the rise in CVD morbidity and mortality.
References
Ahmad OB, Boschi–Pinto C, Lopez A, Murray CJL, Force of the European Society of Cardiology on Cardio-
Lozano R, Inoue M. (2000). Age Standardization vascular Mortality and Morbidity Statistics in
of Rates. A New WHO Standard. GPE Discussion Europe. (1997). Eur Heart J. 18: 1231–1248.
Paper Series No. 31. WHO, Geneva, p. 3. Institute of Public Health of Serbia. (2001). 2000 Popu-
Allender S, Scarborough P, Peto V, Rayner M, Leal J, lation Health Survey in Serbia. Belgrade, Serbia.
Luengo-Fernandez, Gray A. (2008). European Car- Lozano R, Murray CJL, Lopez D, Satoh T. (2001).
diovascular Disease Statistics, BHF, London. Also Miscoding and Misclassification of Ischaemic
available at: http://www.dphpc.ox.ac.uk/bhfhprg. Heart Disease Mortality. GPE Discussion Paper
Cindy and Monica Collaborative Center (unpublished No. 12. WHO, Geneva. Also available at: http://
data). (1998). Register of Myocardial Infarction www.who.int./evidence.
and Stroke, Novi Sad. Lilienfeld MA, Lilienfeld ED. (1980). Foundation of
Coale AJ, Demeny P, Vaughan B. (1983). Models of Epidemiology, 2nd ed. Oxford University Press,
mortality and age composition. In: Coale et al. New York, pp. 217–218.
(eds.) Regional Model Life Tables and Stable Popu- Mackey J, Mensah G. (2004). The Atlas of Heart Disease
lations, 2nd ed. Academic Press, New York, pp. 1–8. and Stroke. WHO, CDC, Geneva.
Department of Humane Services. (1999). The Victorian Mathers C, Vos T, Stevenson C. (1999). The Burden of
Burden of Disease Study–Morbidity. DALY (YLD Disease and Injury in Australia. Australian Institute
and YLL). Public Health and Development Division, of Health and Welfare. AIHW, Canberra. Also avail-
Department of Human Services, Melbourne. Avail- able at: http://www.aihw.gov/au.
able at: www.dhs.vic.gov.au. Mathers C, Boschi-Pinto C. (2003). Global Burden of
Department of human service and Southern health care Cancer in the Year 2000: Version 1 Estimates. In
network. (2000). Southern Metropolitan Burden of Global Burden of Disease 2000. WHO, Geneva.
Disease Study: Mortality and Morbidity. Depart- Mathers C, Stein C, Ma Fat D, Rao C, Inoue M,
ment of Human Services, Victoria. Also available Tomijima N, Bernard C, Lopez A, Murray C.
at: http://www.dhs.vic.gov.au/phd/9909073/index. (2002). Global Burden of Disease 2000: Version
htm. 2 Methods and Results. GPE Discussion Paper No.
Jankovic S, Vlajinac H, Bjegovic V, Marinkovic J, 50. WHO, Geneva. Also available at: http://www.
Sipetic-Grujicic S, Markovic-Denic, Kocev N, who.int./evidence.
Santric-Milicevic M, Terzic-Supic Z, Maksimovic Murray CJL, Lopez AD. (1996a). The Global Burden of
N, Lasser U. (2006). Eur J Public Health. 122: Disease: A Comprehensive Assessment of Mortality
277–284. and Disability from Disease, Injuries and Risk
English DR, Holman CDJ, Milne E. (1995). The Quanti- Factors in 1990 and Projected to 2020. Harvard
fication of Drug Caused Morbidity and Mortality in University Press, Cambridge, MA.
Australia, 1995 edition. Commonwealth Depart- Murray CJL, Lopez AD (eds.). (1996b). Global Health
ment of Human Services and Health, Canberra. Statistics: A Compendium of Incidence, Prevalence
and Mortality Estimates for over 200 Conditions. Belgrade for the Period 1975–1999. I Yugoslav
(Global Burden of Disease and Injury Series, Congress of Aterosclerosis, Belgrade, 178 (abstract).
Vol. 2). Harvard School of Public Health, World Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, Tolenen
Health Organization and World Bank, Cambridge. H, Ruokokoski E, Amouyel P, for the WHO
Murray CJL, Lopez AD, Mathers CD. (2001). The Global MONICA Project. (1999). Lancet. 353: 1547–1557.
Burden of Disease 2000 Project: Aims, Methods and Unal B, Critchley J, Capewell S. (2004). Circulation. 109:
Data Sources. Global Programme on Evidence for 1101–1107.
Health Policy Discussion Paper No. 36. WHO, Vlajinac H, Adanja B, Jarebinski M, Sipetic S. (1994).
Geneva. Also available at: http://www.who.int./ J Epidemiol Community Health. 48: 254–257.
evidence. Vlajinac H, Marinkovic J, Kocev N, Adanja B, Sipetic S,
Peterson S, PetoV, Rayner M, Leal J, Luengo-Fernandey R, Pekmezovic T, Zivaljevic V. (2000). Serb Arch Med.
Gray A. (2005). European CVD Statistics. BHF, 128: 309–315.
London. Vlajinac H, Sipetic S, Saulic A, Atanackovic Z,
Rose G. (1992). The Strategy of Preventive Medicine. Marinkovic J, Bjegovic V. (2006). Eur J Cardiovasc
Oxford University Press, New York, NY. Prev Rehabil. 13: 753–759.
SBD Study group. (2003). The Burden of Disease and World health report. (2004). The World Health Report.
Injury in Serbia. Ministry of Health of the Republic WHO, Geneva.
of Serbia, Belgrade, pp 63–64. Also available at: Yusuf S, Reddy S, Ounpuu S, Anand S. (2001).
http://www.sbds.sr.gov.yu. Circulation. 104: 2746–2753.
Sipetic S, Vlajinac H, Kocev N, Stosic M, Sljivic M.
(2001). Cardiovascular Disease Mortality in
54 Burden of Cerebrovascular
Diseases (Stroke) in Serbia
T. Pekmezovic . H. Vlajinac . S. Sipetic-Grujicic . N. Kocev . D. K. Tepavcevic .
L. B. Bumbasirevic
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
2 The Burden of Stroke: Mortality Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951
3 Stroke Mortality in the Population of Belgrade (Serbia) . . . . . . . . . . . . . . . . . . . . . . . . . . 953
4 Cohort Analysis of Stroke Mortality Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954
5 Stroke Mortality Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954
6 The Burden of Stroke: Years of Life Lost (YLL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955
7 The Burden of Stroke: Incidence and Prevalence Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . 956
8 The Burden of Stroke: Years Lived with Disability (YLD) . . . . . . . . . . . . . . . . . . . . . . . . . 957
9 The Burden of Stroke: Disability-Adjusted Life Years (DALY) . . . . . . . . . . . . . . . . . . . . . 958
10 The Mortality Burden Attributable to Risk Factors in Serbia . . . . . . . . . . . . . . . . . . . . . 960
11 Tobacco Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
12 Alcohol Consumption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 961
13 Physical Inactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 961
14 Inadequate Intake of Fruit and Vegetables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
15 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
16 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963

950 54 Burden of Cerebrovascular Diseases (Stroke) in Serbia
Abstract: The purpose of the study was to provide a comprehensive review of the most
important features regarding burden of cerebrovascular disease (i.e., stroke) in > Serbia.
In Serbia, stroke is the leading cause of mortality in females (20.8% of all deaths) and
the second cause in males (15.5%). The crude mortality rate from stroke in Serbia in 2000
was 248.8/100,000, and age-adjusted rate 122.6/100,000 (using Segi’s world standard popula-
tion), while in the Belgrade population (period of observation: 1989–2003), the average
standardized mortality rates (using Segi’s world standard population) for all stroke subtypes
were 90.8/100,000 overall, 98.0/100,000 for men and 82.4/100,000 for women. The average
standardized stroke mortality rates in Belgrade changed in the period 1989–2003 for both
genders, the highest values being registered in the period 1994–1998 and the lowest in the
period 1989–1993.
The burden of cerebrovascular disease in Serbia without Kosovo and Metohia in 2000,
expressed in terms of as DALY was 65,795 in men and 70,295 in women (136,090 DALY for the
total population). Stroke is the second leading cause of DALY for males, after IHD, and the
leading cause for females. In Serbia 2000, YLL rates per 1,000 for stroke were lower in males
(15.6/1,000) than in females (16.7/1,000). Moreover, in males stroke was the second leading
single cause of premature YLL (13% of total YLL), while in females it ranked first (18% of total
YLL). Rates of YLD per 1,000 were 2.3 for males and 1.4 for females. Hypertension as one of
the most important risk factors for stroke was responsible for 13.3% of the total YLL in Serbia
2,000 in females and 9.7% in males. The proportion of total DALY calculated for stroke due to
hypertension was higher for females (48.65%) than for males (40.51%).
In conclusion, the important findings obtained in the SBDS should be used as a guide for
implementing preventive strategies, as well as for evaluating the scope of future gains obtained
by reducing exposure to known risk factors for cerebrovascular disease.
List of Abbreviations: CT, > computed tomography; CVD, cerebrovascular diseases; DALY,
disability adjusted life years; ICD, International Classification of Diseases; ICH, > intracere-
bral hemorrhage; IHD, ischemic heart disease; MONICA, Monitoring of Trends and Deter-
minants in Cardiovascular Disease; MRI, > magnetic resonance imaging; SAH,
> subarachnoid hemorrhage; SBDS, Serbian Burden of Disease Study; YLD, years lived with
disability; YLL, years of life lost; WHO, World Health Organization
1 Introduction
The group of cerebrovascular diseases (CVD) is a general term encompassing different clinical
entities, which are major clinical manifestations of vascularization in the brain. The vast
majority of deaths due to cerebrovascular diseases are however due to stroke. Thus, the
general term ‘‘stroke’’ is used synonymously with the group of CVD (codes 430–438, 9th
codes I60–I69, 10th, International Classification of Diseases-ICD).
By definition, stroke is a focal neurological deficit caused by a local disturbance in cerebral
circulation – predominantly either an obstruction of cerebral blood vessels (> ischemic
stroke) or a rupture to a vessel wall supplying blood to either the brain or the spinal cord
(intracerebral hemorrhage – ICH or subarachnoid hemorrhage – SAH, respectively). These
three distinct etiological groups – ischemic stroke, ICH and SAH – comprise 75–85%, 15–20%
and about 6%, respectively, of all stroke cases annually (American Heart Association, 2008).
A number of epidemiological studies have adopted a uniform definition of stroke as suggested
Burden of Cerebrovascular Diseases (Stroke) in Serbia 54 951
by the World Health Organisation (WHO), as a ‘‘neurological deficit lasting 24 h or longer, or

a defined lesion on imaging associated with presenting symptoms’’ (World Health Organisa-
tion, 1997).
For many years stroke has been recognized as one of leading causes of serious and long-
term disability and mortality in many developed countries. Furthermore, stroke can seriously
decrease the quality of life of patients and also place a burden on the family and society.
According to WHO estimates, 15 million people have strokes each year (World Health
Organisation, 2004). A stroke is more disabling than fatal: the estimated annual cost of
stroke-related health care is more than 60 billion dollars, measured in both health-care dollars
and lost productivity (American Heart Association, 2008).
Improvements in technology have increased the precision and generalization of data on
stroke. The universal application of computed tomography (CT) brain imaging to confirm the
presence of a lesion has been critical for early recognition and diagnosis of stroke. However,
despite recognition of and treatment modalities for modifiable stroke risk factors such as
hypertension and cardiac disease, stroke incidence appears to be rising. Overall stroke mortal-
ity may be declining, especially in the developed countries, but differentials in stroke mortality
continue to be reported between different racial/ethnic groups. In addition, the aging of the
population could lead to an increased absolute number of stroke cases per year, resulting in
greater incidence, mortality, and cost. However, unlike developed countries, such as Japan,
the USA, and the countries of Western Europe, where stroke mortality rates have decreased
during the past few decades, in developing countries, including the former Yugoslavia, death
rates associated with stroke have increased (Feigin et al., 2003; Sarti et al., 2000). Additionally,
these geographic areas are undergoing a demographic transition, the unfavorable effect of
which is expected to become manifest in the coming years (Murray and Lopez, 1997a).
Today, the burden of stroke remains significant in the world. For the Serbian population,
stroke is a particular problem. According to the results obtained in the Serbian Burden of
Disease Study (SBDS), stroke has been highlighted as one of the dominant causes of the
burden of premature death. Thus, the main aim of this chapter was to describe burden of
stroke in Serbia without Kosovo and Metohia (hereinafter: Serbia) with special emphasis on
the population of Belgrade (the capitol of Serbia). Kosovo and Metohia were not included
since data for this region were either unreliable or unavailable.
2 The Burden of Stroke: Mortality Data
Stroke mortality rates differ by country and geographic region (> Table 54-1). International
differences in stroke mortality are significant: there is a wide range of variations in mortality
rates from 23/100,000 for men and 15/100,000 for women in Switzerland rising to 361/100,000
for men and 229/100,000 for women in Russia (the population aged between 35 and 74 years)
(Rosamond et al., 2007). If the frequency of stroke deaths is considered on a global level, the
countries of Eastern Europe, especially Bulgaria and Romania, as well as the Russian Federa-
tion, occupy the lead positions, while Switzerland, Australia and the USA are countries with
the lowest stroke mortality rates, resulting in almost 15-fold difference between these regions.
One of the most reliable resources of information used to monitor the distribution and
frequency of stroke is the system of stroke registries, including the multicentric studies in
18 countries organized as part of the MONICA (Monitoring of Trends and Determinants
in Cardiovascular Disease) project and supported by WHO (World Health Organisation)
. Table 54-1
Death rates (/100,000) for stroke in selected countries, ages 35–74
Country Year Death rate Percentage of total death rate
Males
Russian Federation 1998 361 14.4
Bulgaria 2004 227 14.1
Romania 2004 251 15.2
Hungary 2003 181 9.7
Poland 2003 118 7.8
Argentina 1996 116 7.5
China-rural 1999 243 19.3
China-urban 1999 217 21.6
Finland 2004 54 5.9
Greece 2003 68 8.7
USA 2004 35 3.9
Denmark 2001 52 5.4
Mexico 1995 61 5.2
Republic of Korea 2002 143 13.2
Canada 2002 43 3.8
Australia 2002 30 4.6
Israel 2003 38 6.9
Japan 2003 66 9.5
Switzerland 2002 23 3.4
Females
Russian Federation 1998 229 22.9
Bulgaria 2004 133 17.8
Romania 2004 166 21.1
Hungary 2003 91 11.3
Poland 2003 63 10.2
Argentina 1996 63 9.8
China-rural 1999 152 19.0
China-urban 1999 147 22.2
Finland 2004 32 7.8
Greece 2003 44 12.1
USA 2004 27 4.7
Denmark 2001 37 5.8
Mexico 1995 52 6.7
Republic of Korea 2002 87 19.2
Canada 2002 20 4.4
Australia 2002 19 5.1
Israel 2003 22 5.1
Japan 2003 31 10.3
Switzerland 2002 15 4.1
Death rates adjusted according to the European standard population
(Thorvaldsen et al., 1997). Reports from MONICA project studies also pointed out the
differences between Eastern and Western Europe in the distribution of stroke mortality,
which is partly explained by huge social and economic differences (Stegmayr et al., 2000).
According to data obtained in the Serbian Burden of Disease Study (SBDS), CVD (I60-I69,
10th ICD) were registered among top twenty causes of death in Serbia in 2000. This group of
diseases was the leading cause of death in females (20.8% of all deaths) and the second cause in
males (15.5%) (Atanackovic Markovic et al., 2003).
The comparison between the ten leading causes of death for Serbia (total population) and
selected subregions in the World 2000 pointed up similarities with the developed countries as
far as causes of death are concerned. Among leading causes of global mortality in 1990, stroke
was the second most common cause of death (4.38 million deaths, almost 3 million in
the developing countries) (Murray and Lopez, 1997b). In Serbia CVD (mainly stroke) together
with IHD were responsible for the biggest share in the mortality rate (18.1% in Serbia –
first position, 9.6% in the World – third position, 13.4% in developed countries – second
position, 8.4% in developing countries – second position) (Mathers et al., 2002). The crude
mortality rate from CVD in Serbia in 2000 was 248.8/100,000, and age-adjusted rates were:
201.3/100,000 (using the European standard population), 150.8/100,000 (using the WHO’s
world standard population), and 122.6/100,000 (using Segi’s world standard population)
(Atanackovic Markovic et al., 2003). Ischemic heart disease and CVD (stroke) were the leading
causes of death in both low- and middle-income and high-income countries, jointly responsi-
ble for more than a fifth of all deaths worldwide. Almost 5.4 million individuals died of stroke,
of whom 4.6 million lived in low-and-middle-income countries (9.5%) and about 0.8 million
(9.9%) lived in high-income countries (Lopez et al., 2006).
3 Stroke Mortality in the Population of Belgrade (Serbia)
In recent analyses of the Belgrade population (period of observation: 1989–2003), the average
standardized mortality rates (based on Segi’s world standard population) for all stroke
subtypes were 90.8/100,000 overall, 98.0/100,000 for men and 82.4/100,000 for women
(Pekmezovic et al., 2007). Belgrade is the capital of Serbia, with a 2002 census population of
1.6 million in 16 municipalities. The Belgrade population was chosen because the determina-
tion of causes of death is more accurate in Belgrade than in the country as a whole (the average
proportion of symptoms and ill-defined conditions from all causes of death in Belgrade
between 1975 and 1997 was 6.9%) (Adanja et al., 2000).
The average standardized stroke mortality rates in Belgrade changed during the period
1989–2003 in both genders, the highest values being recorded in the period 1994–1998 and the
lowest in the period 1989–1993. The birth cohort analysis, performed in the same study, also
revealed that the major part of this upward trend in 1994–1998 was attributed to increasing
stroke mortality in the older age groups (Pekmezovic et al., 2007). For Serbia, the decade of
the 1990s was a period of economic uncertainty and political instability, including the
economic sanctions imposed by the United Nations, the war in the neighboring countries
and the break-up of the former Yugoslavia, which resulted in a dramatic increase in poverty
and deteriorated performance of the health care system. In this situation, the lack of medical
equipment and drugs, and a shortage of other medical supplies, as well as lack of funding,
re-focusing medical services on urgent and priority cases only (Tosic, 1992; Vlajinac et al.,
1997, 2000). The rapid increase in stroke mortality in the period 1994–1998 could be a
manifestation of these unfavorable living and health conditions, when prevention, diagnosis,
and treatment of stroke were very limited. The negative influence of socio-economic factors on
stroke mortality has been widely reported (Avendano et al., 2005; Jakovljevic et al., 2001).
4 Cohort Analysis of Stroke Mortality Data

It is well known that mortality time trends by year of death, frequently used in epidemiological
studies, fail to offer an adequate explanation for differences in mortality rates between
generations. The age-period analysis of mortality time trends measures the component
attributed to the birth cohort and the risk of dying in circumstances prevailing at the time
of death, i.e., the period effect. These factors include the short-term effects of primary and
secondary prevention, changes in diagnostic procedures and modifications in cause-of-death
coding practices. Conversely, the cohort effect relates to lifelong exposure to risk factors
shared by the whole generation (Pekmezovic et al., 2007). In the Belgrade stroke mortality
study, age- and gender-specific mortality rates were calculated for the cohorts of individuals
born between 1904–1908 and 1964–1968. The majority of successive generations had an
increasing risk of death from stroke in more recent cohorts, especially among females. The
most impressive cohort effect was demonstrated in the male and female generations born
between 1914 and 1918, where the lowest age-specific rates of stroke-related mortality
occurred during the entire period studied (Pekmezovic et al., 2007). This indicated that the
mortality pattern for stroke in a given birth cohort was influenced by a specific profile of
stroke risk factors typical for this generation, independent of the time of observation and the
age of the individuals. An inverse cohort effect existed for several other populations in
previous studies (Cayuela et al., 2002; Peltonen and Asplund, 1996) and can be interpreted
as a reduction in exposure to risk factors for stroke.
5 Stroke Mortality Trends

The average cause-specific stroke mortality rates in Belgrade in the same period observed were
higher for ischemic stroke (45.3/100,000, 95% CI 39.6–50.9) than for > hemorrhagic stroke
(18.9/100,000, 95% CI 16.4–21.4). Also, considering the subtypes of hemorrhagic stroke, the
mortality rate for ICH was 14.3/100,000 (95% CI 12.2–16.3) and for SAH 4.6/100,000 (95% CI
4.1–5.1) (Pekmezovic et al., 2008). The well-known differences in frequency of occurrence,
case fatality ratio and etiology between subtypes of stroke are possible explanations for
variations in the mortality rates (Sturgeon and Folsom, 2006). In the Belgrade study, mortality
rate from stroke of undetermined type was 26.1/100,000 (95% CI 23.0–31.1). Precise and
accurate classification of stroke subtypes, based on the type of lesion, depends on access to and
use of neuroimaging diagnostic procedures (CT and MRI). The rate of undetermined stroke in
Belgrade was high and could be related to a lack of complete examination and subsequent
registration of the cause of death in these cases. The time trends of stroke mortality rates in the
Belgrade population during the period 1989–2003, showed that the most excessive statistically
significant increase in death rates was related to ICH in both sexes. The death rates from SAH
also tended to increase in both sexes, statistically significantly in women (p = 0.017). Upward
trends were also observed for ischemic stroke mortality rates, with statistical significance for
men (p = 0.048). The trends of standardized mortality rates of all stroke subtypes showed an
increasing tendency by linear model, although statistical significance occurred only for the
male population (p = 0.022). A decrease in stroke mortality in the second half of twentieth
century was observed in almost all the developed countries (World Health Organisation,
2006). Recent analysis of mortality rates from different stroke subtypes in Minneapolis,
USA, showed that total stroke mortality declined by almost 50% over the study period
(1980–2002). The death rates from ischemic stroke and SAH also declined. However, mortality
rates from ICH were stable (Sturgeon and Folsom, 2006). Similar results were observed in
a study from Finland (1991–2002), where despite a decrease in mortality for all stroke
subtypes in both sexes in all age groups, ICH death rates remained stable among men aged
75þ years and even increased among women over the age of 85 (Pajunen et al., 2005). It is
generally accepted that the decrease in mortality from stroke seen in developed countries can
be explained in large part by reductions in incidence, widespread control of hypertension and
higher survival rates (Feigin et al., 2003). Sarti et al. (2000) pointed out that the distinction
between East and West in the matter of mortality due to CVD was not a consequence of
inadequate hypertension control only, but could also be related to differences in other risk
factor trends such as smoking, alcohol consumption and dietary habits.
6 The Burden of Stroke: Years of Life Lost (YLL)

Years of life lost (YLL) is the number of years of life lost because of premature death. In other
words, YLL is the number of years by which a disease shortens normal life expectancy. In
numerous investigations it has been emphasized that YLL rates provide a more complex
measure of the impact of premature mortality than traditional death rates (Mariotti et al.,
2003). The ranking of some diseases by YLL differs from their ranking based on number of
deaths (Vlajinac et al., 2008). Age-weighting and discounting, two discretionary modifications
for calculating YLL, can also influence the significance attached to a given health condition.
In comparison to standard mortality measures, YLL is therefore a more exacting tool for
‘‘quantifying’’ the burden of mortality, providing a much more in-depth look at the con-
sequences of lethal disease and the interventions used to extend life (Mariotti et al., 2003).
According to findings obtained in the SBDS, stroke was one of the leading specific diseases
contributing to YLL, causing 57,478 years of life lost in males and 64,691 in females (122,169,
15% of total YLL). Therefore, in males stroke was the second leading single cause of premature
years of life lost (13% of total YLL), while in females it ranked as the first cause (18% of total
YLL) (Atanackovic et al., 2003).
In Serbia 2000, IHD and CVD were the main causes of YLL for the total population, and
for both sexes. According to the data presented in > Table 54-2, CVD was one of the leading
causes of the mortality burden in males aged 45–64 (3rd position) and 65 þ years (2nd
position). In females CVD was the leading cause of the death burden in these age groups, too.
In the population of Belgrade, 2000, CVD was the leading cause of YLL (11,622 YLL, 16.7% of
total YLL) for females and the second leading single cause of premature years of life lost
(11,432 YLL, 12.4% of total YLL) for males. In Serbia 2000, YLL rates per 1,000 for stroke were
lower in males (15.6/1,000) than in females (16.7/1,000). A similar situation was recorded in
the population of Belgrade (15.2/1,000 for males and 14.0/1,000 for females). Both first and
second causes of YLL are identical for males and females in Belgrade and Serbia. Vlajinac et al.
(2006) underlined that the great percentage of YLL in the total stroke burden calls for efforts to
. Table 54-2
YLL for cerebrovascular diseases according to age and sex in Serbia, 2000
Age groups YLLs per 1,000 person-years Percentage of total YLL Rank
Males
15–24 444 2.46 8
25–44 4,261 7.27 4
45–64 21,423 11.57 3
65+ 31,096 17.62 2
Females
15–24 0 0 0
25–44 2,252 7.98 4
45–64 16,982 16.10 1
65+ 45,044 23.12 1
YLL years of life lost. Ranked in order of % of total YLL
be made to improve stroke therapy. The final results of the SBDS showed that stroke is one of
the most important national health priorities.
In analyzing the burden of CVD in Serbia 2000, YLL was calculated using country
mortality statistics. Vlajinac et al. pointed out that the precision of YLL estimates was almost
entirely dependent on the quality of data on the underlying cause of death. Besides the fact that
cause-of-death registration was reasonably accurate in Serbia, there were several ICD-10
categories (‘‘garbage’’ codes and ill-defined or unknown categories) for which deaths were
reallocated to disease and injury causes. These reallocations involved a considerable number
of deaths and certainly had some effect on the precision of the YLL estimates (Vlajinac
et al., 2006).
For the world population in 2000, CVD ranked eighth among 20 causes of YLL for
both sexes combined, while in the EURO region 2000 it was ranked high (2nd position), as
well as in Serbia in 2000 (Murray et al., 2001). According to the findings of the Burden of
Disease Calculations for the Netherlands, 1994, CVD was the underlying cause of death in
12,595 cases and resulted in 110,400 years of life lost (Melse et al., 2000). In the Australian
Burden of Disease Study, the single largest cause of YLL for both males and females was IHD,
followed by stroke and breast cancer in females, and by lung cancer, suicide and stroke in
males (Mathers et al., 2001). Stroke caused 8.3% of total YLL due to mortality (ranked 2nd),
5.6% in males (ranked 4th) and 9.5% in females (ranked 2nd) (Mathers et al., 2000). In
the Italian Burden of Disease Study, analysis of YLL showed lower rates than in the SBDS:
for females 493.7/100,000, for males 452.5/100,000, and 473.7/100,000 for both genders
(Francescutti et al., 2005).
7 The Burden of Stroke: Incidence and Prevalence Data
Reliable data on stroke incidence and prevalence are essential for calculating the burden
of stroke and the planning of prevention and treatment of stroke patients. Up till now,
there has been strong evidence indicating differences in stroke mortality between different
European countries with several Eastern European countries having high and increasing
stroke mortality rates while low and decreasing rates are reported from most West European
countries. According to WHO estimates the number of stroke events in the selected countries
is likely to increase from 1.1 million per year in 2000 to more than 1.5 million per year in 2025
solely because of demographic changes (Truelsen et al., 2006). Projections for the European
region suggest that the proportion of the population aged 65þ, in which most stroke events
occur, will increase from 20% in 2000 to 35% in 2050 (Truelsen et al., 2006).
In the late 1980s, the WHO MONICA stroke project showed relatively large geographical
differences in stroke incidence, with the rates in less developed countries were among the
highest in the world (confined to patients 35–64 years old). The corresponding population of
Novi Sad (province of Vojvodina, Serbia) participated in MONICA at that time. According
to data from that period, the incidence of stroke in the male population of Novi Sad was
235/100,000 and in the female population 110/100,000 (Thorvaldsen et al., 1995). The high
incidence of stroke in Eastern European countries can be attributed to the well-known
social and economic changes that have occurred over the past decade, including changes
in medical care and exposure to risk factors. The marked difference in stroke incidence between
genetically similar areas (Eastern and Western Europe) suggests that potentially modifiable
environmental factors are more important than genetic differences in determining stroke sus-
ceptibility (World Health Organisation, 2006). According to a recent analysis, in the European
male population, the lowest stroke incidence rates were estimated for France and Switzerland.
The highest rates were estimated for Latvia where age-specific stroke incidence rates were more
than twice those for France and Switzerland. In the European female population, low incidence
rates are estimated for France, Switzerland and Slovakia, whereas high incidence rates are
estimated for Greece and Latvia. Rates in the latter two were up to three times higher than in
countries with the lowest estimated stroke incidence rates (Truelsen et al., 2006).
The best measure of the total burden of stroke in any population is prevalence, which
provides information about the number of people at any one time in that population who have
survived a stroke. However, exact estimates of stroke prevalence are difficult to obtain. The
prevalence of stroke among white populations ranges from 500 to 600 per 100,000. Reported
rates per 100,000 in New Zealand are 793 crude, 991 men and 700 women; in Finland
1,030 men and 580 women; and in France 1,445 crude rate in the older population. Rates
per 100,000 in the developing countries are also variable and range from 58 in India and 76 in
the United Republic of Tanzania to 620 in China and 690 in Thailand (World Health
Organisation, 2006).
Since population-based stroke registries have not yet been established in Serbia, inci-
dence and prevalence data are not available. For the purposes of the SBDS, all data on
stroke were derived from the Registry of Myocardial Infarction and Stroke – CINDY
and MONICA Collaborative Centre, Novi Sad, 1998 (unpublished data). Incidence com-
prised cases where, in the course of the year, stroke was experienced for the first time
(Atanackovic et al., 2003).
8 The Burden of Stroke: Years Lived with Disability (YLD)
Years lived with disability (YLD) is a measure of the burden of non-fatal outcome and
represents the equivalent of years of life lost to severity-adjusted disability.
Since calculation of YLD needs incidence data, in the SBDS the Stroke Registry in the
MONICA Collaborative Centre in Novi Sad for 1998 was used as a main source. The disability
duration in stroke cases was assessed in the manner applied in the South and West DALY
project (Bevan et al., 1998). An average of three-week disability was assumed for incidence
cases who died within the first 28 days. Those who survived the first 28 days were expected to
live out their full life expectancy if under 65, live another 5 years if aged 65–74, and live
another 3 years if over 74 years. The disability weights used for stroke were slightly modified
GBD weights (Murray and Lopez, 1996). It was assumed that each one of the non-survivors
(stroke) suffered disability of the severest category, similar to terminal cancer (Bevan et al.,
1998). For the rest, disability weights were calculated from GBD weights assuming that,
according to the GBD estimate for the former socialist economies of Europe (FSE), 20% of
stroke incidence cases went untreated (Murray and Lopez, 1996).
In the SBDS 2000, CVD caused 8,316 YLD in males and 5,604 YLD in females, i.e., rates of
YLD per 1,000 were 2.3 for males and 1.4 for females. The corresponding values in the
population of Belgrade were almost equal (Atanackovic et al., 2003).
In Italy, about 153,000 YLD due to first-ever stroke was estimated in 1998, YLD rates per
100,000 people were 228 for males and 308 for females (Francescutti et al., 2005). In the
Australian Burden of Disease Study, stroke caused 3.3% of the total YLD (3.9% in males, and
2.7% in females) (Mathers et al., 2001). In a similar study in the Netherlands stroke caused
59,200 YLD (Melse et al., 2000). The authors underlined that within the YLD ranking, it is
clear that some diseases rank high on the basis of their disability weight (e.g., CVD) and others
on the basis of their high prevalence (e.g., hearing impairments).
9 The Burden of Stroke: Disability-Adjusted Life Years (DALY)
Disability-adjusted life years (DALY) is the sum of YLL and YLD. One DALY can be thought of
as one lost year of healthy life and the burden of disease as a measure of the gap between
current health status and an ideal situation where everyone lives into old age free from disease
and disability (World Health Organisation, 2006).
The burden of CVD in Serbia without Kosovo and Metohia in 2000, expressed in terms of
DALY were 65,795 in men and 70,295 in women (136,090 DALY for the total population).
Stroke was the second leading cause of DALY for males, after IHD, and the leading cause for
females. The total burden of CVD in Belgrade in 2000 was estimated at 25,000 DALY, 23,000
YLL and 2,000 YLD, with similar values in both genders (Atanackovic et al., 2003).
In Serbia without Kosovo and Metohia, the burden of stroke was slightly higher for females
than for males. The rates of DALY per 1,000 population were 17.9 in males and 18.1 in females
(> Table 54-3). For stroke, the DALY rates per 1,000 population increased with aging in both
men and women, and peaked in the oldest, 75 years and over. The burden of stroke in
Belgrade, by gender and age, and demonstrated a similar pattern to that seen in the population
of Serbia (> Table 54-3).
According to the data presented in > Table 54-4, the proportion of YLD in DALY for stroke
in Serbia was 12.6% in men and 8.0% in women. It is half of that in EURO B. It is lower even
when compared with EURO C. This could be probably explained by the fact that in Serbia a
high percentage of stroke cases die within the first 28 days. In addition to the obvious need for
improvement of CVD primary prevention, such results call for efforts to improve stroke
therapy (Jankovic et al., 2007).
. Table 54-3
YLD, YLL and DALY per 1,000 population for cerebrovascular diseases, by gender in populations
of Serbia and Belgrade
Serbia
Gender YLD per 1,000 YLL per 1,000 DALY per 1,000
Males 2.05 13.71 15.76
Females 1.26 11.97 13.23
Belgrade
Gender YLD per 1,000 YLL per 1,000 DALY per 1,000
Males 2.29 15.18 17.46
Females 1.45 13.97 15.42
YLD years of life with disability; YLL years of life lost; DALY disability-adjusted life years. All parameters standardized
according to the European standard population
. Table 54-4
YLD and DALY per 1,000 population and YLD/DALY ratio (%) for stroke in Serbia, Belgrade and
the EURO regions
Region YLD per 1,000 DALY per 1,000 YLD/DALY (%)

Serbia 1.84 18.02 10
Belgrade 1.85 16.39 11
EURO 2.55 11.94 21
EURO A 2.03 6.63 31
EURO B 2.48 11.05 22
EURO C 3.49 21.73 16
YLD years of life with disability; DALY disability-adjusted life years; EURO European region. EURO A includes
following countries: Andorra, Austria, Belgium, Croatia, the Czech Republic, Denmark, Finland, France, Germany,
Greece, Iceland, Ireland, Israel, Italy, Luxemburg, Malta, Monaco, the Netherlands, Norway, Portugal, San Marino,
Slovenia, Spain, Sweden, Switzerland, and the United Kingdom. EURO B includes following countries: Albania,
Bosnia and Herzegovina, Bulgaria, Georgia, Poland, Romania, Slovakia, the Former Yugoslav Republic of
Macedonia, Turkey, Serbia and Montenegro, Armenia, Azerbaijan, Kyrgyzstan, Tajikistan, Turkmenistan, and
Uzbekistan. EURO C includes following countries: Belarus, Estonia, Hungary, Kazakhstan, Latvia, Lithuania, the
Republic of Moldavia, the Russian Federation, and Ukraine
The results of the Global Burden of Disease Study showed that CVD caused about
38.5 106 DALY and occupies sixth position among 30 leading causes of worldwide DALY
for both sexes in 1990 (Murray and Lopez, 1997c). CVD was the fifth leading cause of the
global burden of disease in 2001 (4.5% of total DALY) in low- and middle-income countries
and the second leading cause in high-income countries (6.3% of total DALY) (Lopez et al.,
2006). According to the burden of disease calculation in the Netherlands, CVD caused
169,600 DALY, i.e., 6.6% of total DALY (Melse et al., 2000). Among the 15 leading causes of
the disease burden in Australia 1996, CVD ranked second, before IHD, and contributed 5.4%
of the total disease burden (4.8% in males and 6.1% in females) (Mathers et al., 2000, 2001).
According to the results obtained in the SBDS, the proportion of YLD in DALY for stroke
for Serbia is 10%. In the Italian Burden of Disease Study they found that the estimated
proportion of YLD in the total DALY (27%) is comparable with that obtained in the EURO
A group (the European area including Italy) of the GBD 2000 Study (31%), and the Australian
BD Study (35%) (Francescutti et al., 2005).
10 The Mortality Burden Attributable to Risk Factors in Serbia
The mortality burden attributable to tobacco, alcohol, physical inactivity, insufficient intake to
fruit and vegetables, high blood pressure, high blood cholesterol, and obesity in Serbia in 2000
was also estimated in the SBDS. The estimated attributable fractions were interpreted as a
proportion of the current burden attributable to exposure to the risk factors selected. The
model used in the study produced relatively simplistic estimates, because each of these risk
factors was associated with disease or injury independently of other risk factors. The preva-
lence data from most selected factors were derived from the 2000 Population Health Survey in
Serbia (Institute of Public Health of Serbia, 2001).
11 Tobacco Smoking
The prevalence of current smokers in Serbia was 47.5% in males and 33.1% in females
(Serbian Institute of Public Health, 2001) being among the highest recorded in Europe
(> Table 54-5). Out of the total stroke burden in Serbia, 23% in males and 13% in females
was attributable to smoking. The corresponding percentages for Belgrade were 24% and 14%
(> Table 54-6). The CVD burden attributable to smoking was greatest in the age groups from
45 to 65 years, while in the Australian study (Mathers et al., 2000) the greatest burden was in
the oldest age groups. Tobacco control measures have been implemented in Serbia, but their
impact on the occurrence on smoking-related diseases will only become apparent in the
coming years or decades.
. Table 54-5
The prevalence of risk factors and the proportion of total DALY due to stroke by gender in the
population of Serbia, 2000
Percentage of the
total stroke DALY
Prevalence of risk attributable to risk
Risk factor factor (%) factor
Males Females Males Females
Tobacco smoking 47.5 33.1 23.2 13.0
Alcohol consumption 62.7 42.7 10.9 19.4
Physical inactivity 41.9 53.5 24.7 30.9
Inadequate intake of fruit and vegetables 34.3 30.9 4.3 3.3
Hypertension 15.5 19.4 40.5 48.6
Obesity 48.5 43.2 11.6 12.4
DALY disability-adjusted life years
. Table 54-6
The stroke burden attributable to tobacco and hypertension by gender in populations of Serbia
and Belgrade, 2000
Tobacco smoking
Serbia
Gender YLL YLD DALY Percentage of total DALY
Males 12,348 2,915 15,263 23.19
Females 7,543 1,617 9,160 13.03
Belgrade
Males 2,542 2,915 3,146 23.91
Females 1,441 1,617 1,796 14.00
Hypertension
Serbia
Males 23,244 3,412 26,656 40.51
Females 31,700 2,504 34,204 48.65
Belgrade
Males 4,752 706 5,459 41.50
Females 5,716 533 6,249 48.71
YLD years of life with disability; YLL years of life lost; DALY disability-adjusted life years
12 Alcohol Consumption
At the time when the SBDS was conducted, there were no separate mortality data for
hemorrhagic and ischemic stroke. These two types of stroke were regarded as one condition.
For the purposes of calculation in the SBDS, the proportion of these two conditions by age
group and gender was taken from the Victoria Burden of Disease Study (Department of
Human Services, 1999). The prevalence of alcohol consumption in Serbia was 62.7% for males
and 42.7% for females (Serbian Institute of Public Health, 2001) (> Table 54-5). Alcohol
intake had a harmful effect on stroke in males (10.9% of the total DALY in Serbia and 11.4% in
Belgrade) and beneficial effect in females (19.4% of the total DALY in Serbia and 20% in
Belgrade) (Atanackovic et al., 2003). For ischemic stroke in Serbia, as well as in Belgrade,
alcohol use was beneficial at middle and older ages, while excessive use of alcohol was harmful
at all ages (Atanackovic Markovic et al., 2003).
13 Physical Inactivity
There is evidence that physical inactivity often occurs together with other risk factors
for cardiovascular disease, such as obesity, high blood pressure and high blood cholesterol,
and that physical activity plays an important protective role in stroke. In 2000, the prevalence
of physical inactivity in Serbia was very high, 41.9% for males and 53.5% for females (Serbian
Institute of Public Health, 2001) (> Table 54-5). In males, 24.7% of the total stroke burden
and in females 31.0% of the total stroke burden was attributable to physical inactivity.
The greatest burden was in the older age groups in which both the prevalence of stroke and
the prevalence of physical inactivity were the highest (Atanackovic Markovic et al., 2003).
14 Inadequate Intake of Fruit and Vegetables
The inadequate intake of fruit and vegetables has been recognized as a risk factor in cardio-
vascular disease and cancer. The prevalence of inadequate intake of fruit and vegetables
in Serbia was 34.3% for males and 30.9% for females (Institute of Public Health of Serbia,
2001) (> Table 54-5). In younger age groups women consume more fruit and vegetables than
men, but in older ages, the differences between the genders were very small. Out of the total
stroke DALY in Serbia, 4.3% in males, and 3.3% in females were attributable to an inadequate
intake of fruit and vegetables (Atanackovic Markovic et al., 2003). The number of attributable
deaths in Belgrade in 2000 was 90, while attributable YLL was 884 (Atanackovic Markovic
et al., 2003).
15 Hypertension
In the SBDS hypertension is used as a term to refer to those people with high blood pressure
and/or receiving treatment for high blood pressure, while high blood pressure was defined as
systolic blood pressure higher or equal to 160 mmHg and/or diastolic blood pressure higher or
equal to 95 mmHg. This is the most important risk factor for all types of stroke. The
prevalence of hypertension was 15.5% in males and 19.4% in females, based on findings
obtained from 2,000 population Health Survey Study in Serbia (Serbian Institute of Public
Health, 2001) (> Table 54-5). The prevalence data for hypertension in Serbia confirmed results
from other similar studies that prevalence is higher for males in younger age groups (35–44)
and for females in older age groups. Since hypertension-related illnesses are most common in
old age, the attributable deaths are higher for females. According to the results obtained in the
SBDS, the proportion of total DALY for stroke attributable to hypertension in Serbia was
higher for females (48.6%) than for males (40.5%) (> Table 54-6). Similar values (48.7% and
41.5%) were registered for the population of Belgrade. The burden attributable to hyperten-
sion grew with age.
16 Obesity
Obesity is a risk factor for many diseases, among them for stroke. It is also associated with
hypertension and high blood cholesterol. The proportion of overweight in Serbia was 36.3%
for males and 26.5% for females, and for obesity 12.2% for males and 16.7% for females
(a total of 48.5% for men and 43.2% for females) (Serbian Institute of Public Health, 2001).
According to the results of the SBDS, the proportion of the total stroke burden in Serbia
attributable to obesity was 11.6% in males and 12.3% in females (corresponding percentages
for Belgrade were 12.2% and 13.1%).
The association of stroke with the risk factors observed is well known. The results obtained
in the SBDS are close to those found in the Global Burden of Disease Study (Murray and
Lopez, 1996) and Australian study (Mathers et al., 2000). The main differences were found
for sex and age distribution of the attributable burden related to age differences in disease
morbidity and mortality, and age differences in the prevalence of exposure to risk factors
(Vlajinac et al., 2006).
In conclusion, the important findings obtained in the SBDS should be used as a guide for
implementing preventive strategies, as well as for evaluating the scope of future gains obtained
by reducing exposure to known risk factors for CVD.
Summary Points
Cerebrovascular disease has been recognized as one of leading causes of serious and long-
term disability and mortality in many developed countries.
Important findings obtained in the Serbian Burden of Disease Study should be used as a
guide for implementing preventive strategies for cerebrovascular diseases.
According to the findings obtained in the Serbian Burden of Disease Study, cerebrovascu-
lar diseases are among the leading specific diseases contributing to years of life lost (YLL).
Cerebrovascular diseases are the second leading cause of disability-adjusted life years
(DALY) for males, after ischemic heart disease, and the leading cause for females.
The proportion of total disability-adjusted life years (DALY) calculated for stroke due to
hypertension was higher for females (48.65%) than for males (40.51%).
References
Adanja B, Gledovic Z, Pekmezovic T, Vlajinac H, Feigin VL, Lawes CMM, Bennett DA, Anderson CS.
Jarebinski M, Zivaljevic V, Pavlovic M. (2000). Dig (2003). Lancet Neurol. 2: 43–53.
Liver Dis. 32: 386–391. Francescutti C, Mariotti S, Simon G, D’errigo P,
American Hear Association. (2008). Heart Disease and Di bidino R. (2005). Disabil Rehabil. 27: (5)
Stroke Statistics. 2008 Update At-a-Glance. 229–240.
Atanackovic Markovic Z, Bjegovic V, Jankovic S, Institute of Public Health of Serbia. (2001). 2000 Popu-
Kocev N, Laaser U, Marinkovic J, Markovic Denic lation Health Survey in Serbia. Ministry of Health,
Lj, Pejin Stokic Lj, Penev G, Stanisavljevic D, Santric Republic of Serbia, Belgrade.
Milicevic M, Saulic A, Sipetic Grujicic S, Terzic Jakovljevic D, Sarti C, Silvenius J, Torppa J, Mahonen M,
Supic Z, Vlajinac H. (2003). The Burden of Disease Immonen-Raiha P, Kaarsalo E, Alhainen H,
and Injury in Serbia. Ministry of Health of Republic Kuulasmaa K, Tuomilehto J, Puska P, Salomaa V.
of Serbia, Belgrade. (2001). Stroke. 32: 1492–1498.
Avendano M, Kunst AE, van Lenthe F, Bos V, Costa G, Jankovic S, Vlajinac H, Bjegovic V, Marinkovic J,
Valkonen T, Cardano M, Harding S, Borgan JK, Sipetic-Grujicic S, Markovic-Denic LJ, Kocev N,
Glickman M, Reid A, Mackenbach JP. (2005). Am J Santric-Milicevic M, Terzic-Supic Z, Maksimovic N,
Epidemiol. 161: 52–61. Laaser U. (2007). Eur J Publ Health. 17: 80–85.
Bevan G, Hollinghurst S, Raftery J, Gold L, Stevens A, Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray
Smithies A, Spurgeon R, Bowie C. (1998). The CJL. (2006). Lancet. 367: 1747–1757.
South and West DALYs Project: Developing a pow- Mariotti S, D’Errigo P, Mastroeni S, Freeman K. (2003).
erful tool for health care planning. Somerset Health Eur J Epidemiol. 18: 513–521.
Authority, Wellsprings Road, Taunton, Somerset. Mathers C, Stein C, Ma Fat D, Rao C, Inoue M, Tomijima
Cayuela A, Rodriguez S, Iglesias P, Lapetra J, Gil-Pelralta A. N, Bernard C, Lopez A, Murray C. (2002). Global
(2002). Neuroepidemiology. 21: 142–147. Burden of Disease 2000: Version 2 Methods and
Department of Human Services. (1999). The Victorian Results. GPE Discussion Paper No. 50. World Health
Burden of Disease Study: Mortality. Public Health Organization, Geneva.
and Development Division, Department of Human Mathers CD, Theo Vos E, Stevenson CE, Begg SJ. (2000).
Services, Melbourne. Med J Aust. 172: 592–596.
Mathers CD, Theo Vos E, Stevenson CE, Begg SJ. (2001). Sarti C, Rastenyte D, Cepatis Z, Tuomilehto J. (2000).
Bull World Health Organ. 79: 1076–1084. Stroke. 31: 1588–1601.
Melse JM, Essink-Bot ML, Kramers PGN, Hoeymans N, Stegmayr B, Vinogradova T, Malyutina S, Peltonen M,
on behalf of the Dutch Burden of Disease Group. Nikitin Y, Asplund K. (2000). Stroke. 31: 2–8.
(2000). Am J Publ Health. 90: 1241–1247. Sturgeon JD, Folsom AR. (2006). Neuroepidemiology.
Murray CJL, Lopez AD, (eds.) (1996). The global burden 28: 39–45.
of disease: a comprehensive assessment of mortality Thorvaldsen P, Asplund K, Kuulasmaa K, Rajakangas
and disability from diseases, injures and risk factors AM, Schroll M. (1995). Stroke. 26: 361–367.
in 1990 and projected to 2020. In: Global Burden of Thorvaldsen P, Kuulasmaa K, Rajakangas AM, Rastenyte
Disease and Injury Series. Harvard University Press, D, Sarti C, Wilhelmsen L. (1997). Stroke. 28:
Cambridge. 500–506.
Murray CJL, Lopez AD. (1997a). Lancet. 349: 1498–1504. Tosic O. (1992). Lancet. 340: 295–296.
Murray CJL, Lopez AD. (1997b). Lancet. 349: 1269–1276. Truelsen T, Piechowski-Jozwiak B, Bonita R, Mathers C,
Murray CJL, Lopez AD. (1997c). Lancet. 349: 1436–1442. Bogousslavsky J, Boysen G. (2006). Eur J Neurol. 13:
Murray CJL, Lopez AD, Mathers CD, Stein C. (2001). 581–598.
The Global Burden of Disease 2000 project: aims, Vlajinac H, Marinkovic J, Kocev N, Adanja B, Pekmezo-
methods and data sources. World Health Organiza- vic T, Sipetic S, Jovanovic D. (1997). J Epidemiol
tion, Geneva. Available on the worldwide web at Commun Health. 51: 172–174.
www.who.int/evidence Vlajinac H, Marinkovic J, Kocev N, Adanja B, Sipetic S,
Pajunen P, Paakkonen R, Hamalainen H, Keskimäki I, Pekmezovic T, Zivaljevic V. (2000). Srp Arh Celok
Laatikainen T, Niemi M, Rintanen H, Salomaa V. Lek. 128(9–10): 309–315.
(2005). Stroke. 36: 244–248. Vlajinac H, Marinkovic J, Kocev N, Sipetic S, Bjegovic V,
Pekmezovic T, Kisic Tepavcevic D, Jarebinski M, Kostic Jankovic S, Stanisavljevic D, Markovic-Denic Lj,
M, Bumbasirevic Lj. (2007). Cerebrovasc Dis. 24: Maksimovic J. (2008). Public Health. 122: 277–284.
191–195. Vlajinac H, Sipetc S, Saulic A, Atanackovic Z, Marinkovic J,
Pekmezovic T, Kisic Tepavcevic D, Jarebinski M, Kostic Bjegovic V. (2006). Eur J Cadiovasc Prev Rehabil. 13:
M, Bumbasirevic Lj. (2008). Clin Neurol Neurosurg. 753–759.
110: 51–57. World Health Organization. (1997). World Health Re-
Peltonen M, Asplund K. (1996). Stroke. 27: 1981–1985. port 1997. Conquering Suffering, Enriching Hu-
Rosamond W, Flegal K, Friday G, Furie K, Go A, Green- manity. World Health Organization, Geneva.
lund K, Haase N, Ho M, Howard V, Kissela B, World Health Organization. (2004). Global burden of
Kittner S, Lloyd-Jones D, McDermott M, Meigs J, stroke. In: Atlas of Heart Disease and Stroke.
Moy C, Nichol G, O’Donnell CJ, Roger V, Rumsfeld J, World Health Organization, Geneva, pp. 50.
Sorlie P, Steinberger J, Thom T, Wasserthiel-Smoller World Health Organization. (2006). Neurological
S, Hong Y. for the American Heart Association Disorders: Public Health Challenges. World Health
Statistics Committee and Stroke Statistics Subcom- Organization, Geneva.
mittee. (2007). Circulation. 115: e69–e171.
55 DALYs and Public Health
Programs for Stroke:
Australian Perspectives
D. A. Cadilhac . M. L. Moodie . E. E. Lalor
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966
2 The Burden of Disease Attributable to Stroke in Australia . . . . . . . . . . . . . . . . . . . . . . . 968
3 Comparisons of the Disease Burden from Stroke

in Australia to Other Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972
4 Differences in Methodology Used to Calculate DALYs

for Stroke in Australia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974
4.1 Stroke Incidence Determining the Size of the Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 975
4.2 Case Fatality Determining the Years of Life Lost
from Premature Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976
4.3 Disability Weights Determining the Extent of Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . 977
5 Overview of Public Health Programs for Stroke in Australia . . . . . . . . . . . . . . . . . . . . 979
6 Programs to Improve the Diagnosis of Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 980
7 Program to Improve Delivery of Evidence Based Care . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
8 Programs to Facilitate Long Term Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
9 Potential for Public Health Programs to Reduce

the Burden of Disease in Australia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
9.1 Calculating Predicted Health Gain from Reduced Death and Disability . . . . . . . . . . . 982
9.2 Determining the Eligible Cases That Would Benefit
from Public Health Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
9.3 Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
9.4 Results of Simulation Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
10 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987

966 55 DALYs and Public Health Programs for Stroke: Australian Perspectives
Abstract: > Stroke is a major cause of death and disability in many countries. In Australia, as
in many other parts of the world, the incidence of stroke will increase because of the aging
population. The purpose of this chapter was to describe the disease burden attributable to
stroke expressed as Disability Adjusted Life Years (DALYs) in Australia; and to provide an
overview of public health programs that exist to reduce this disease burden.
Methods of > DALY estimation for stroke in Australia are outlined and compared. Despite
some differences in methodologies and data sources, results were consistent.
Public health programs to reduce the stroke burden include generic programs aimed at
reducing common risk factors across a number of chronic diseases; and stroke specific programs
to address unique aspects of stroke. Examples of these programs are provided.
A simulation analysis is presented to demonstrate the potential impact of public health
programs. This analysis is based on the concept of improving access to interventions that we
already know are effective in preventing stroke and/or improving stroke outcomes in a
representative year (2015) using local epidemiological data. DALYs saved were calculated for
the additional cases that would benefit if > current practice were improved to more closely
reflect ‘‘> best-practice.’’ Interventions included: blood pressure lowering; > warfarin for
atrial fibrillation; access to > stroke care units; increased use of > intravenous thrombolysis,
cholesterol lowering and aspirin for ischemic events; and > carotid endarterectomy. In
present-value (2006) terms, this would result potentially in the recovery of more than
92,000 DALYs. Thus, improving access to effective prevention and treatment interventions
should produce important health gains.
List of Abbreviations: ABHI, Australian Better Health Initiative; AF, atrial fibrillation; ARR,
> absolute risk reduction; ASAP, Avoid Stroke as soon As Possible general practice stroke
audit; AUD, Australian dollars; BoD, burden of disease; BP, blood pressure; CHD, coronary
heart disease; COPD, chronic obstructive pulmonary disease; DALY, disability adjusted life
year; GP, general practitioner; ICD, International Classification of Diseases; IHD, ischemic
heart disease; MONICA, monitoring trends and determinants in cardiovascular disease;
MORUCOS, Model Of Resource Utilization, Costs and Outcomes for Stroke; NEMESIS,
North East Melbourne Stroke Incidence study; NHMRC, National Health and Medical
Research Council; NSF, National Stroke Foundation (Australia); PCSS, Perth Community
Stroke study; QALY, quality adjusted life year; QOL, quality of life; SCU, stroke care unit;
Southern MR, southern metropolitan region; SPARCL, Stroke Prevention by Aggressive Re-
duction in Cholesterol Levels; TIA, transient ischemic attack; WHO, World Health Organiza-
tion; YLD, years lived with disability; YLL, years of life lost
1 Introduction
Stroke is a heterogeneous condition and can result in a variety of symptoms. These can include
sensory or motor deficits to the face, hands, limbs, or problems with vision and/or speech. The
World Health Organization (WHO) defines stroke as a ‘‘vascular lesion of the brain resulting
in a neurological deficit persisting for at least 24 h or resulting in the death of the individual’’
(World Health Organization, 1989). About one third of people who experience a first-ever
stroke will die, and a further third are left with significant levels of disability (Bonita, 1993).
Stroke is caused by a number of modifiable and non-modifiable risk factors, many of
which are common to other conditions. About 11.7 million or 90% of adult Australians have
DALYs and Public Health Programs for Stroke: Australian Perspectives 55 967
at least one of the major modifiable risk factors for heart, stroke and vascular disease
(Australian Institute of Health and Welfare, 2004). The most important risk factors for stroke
are age, elevated blood pressure (BP), atrial fibrillation (AF), carotid artery disease, coronary
heart disease (CHD), smoking and male gender. Transient ischemic attack (TIA), or a mini
stroke, is often cited as a stroke risk factor because symptoms resolve, but the subsequent risk
of permanent stroke is large (Hankey, 2001). In > Table 55-1, we provide a summary of the
main facts about stroke including issues pertinent to Australia.
The purpose of this chapter is to describe the disease burden attributable to stroke
expressed as Disability Adjusted Life Years (DALYs). In addition, we provide a summary of
how DALYs for stroke have been measured in Australia and how the methods have been
. Table 55-1
Main facts about stroke and stroke in Australia
What is a stroke?
Stroke occurs when the supply of blood to the brain is suddenly disrupted. Blood may stop moving
through an artery to the brain because the artery is blocked by a blood clot or plaque, or because
the artery breaks or bursts
What are the signs of stroke?
The signs of stroke may be any one or a combination of the following:
Weakness or numbness or paralysis of the face, arm or leg on either or both sides of the body
Difficulty speaking or understanding
Dizziness, loss of balance or an unexplained fall
Loss of vision, sudden blurred or decreased vision in one or both eyes
Headache, usually severe and of abrupt onset or unexplained change in the pattern of
headaches
Difficulty swallowing
What are the major risk factors for stroke?
Age
High blood pressure
Atrial fibrillation (having an abnormal heart rhythm)
Carotid artery disease
Coronary heart disease
Smoking
Male gender
Interesting facts about stroke
Stroke is Australia’s second single greatest killer and a leading cause of disability
Every 10 min, an Australian suffers a stroke
Almost one in five people who experience a stroke are under the age of 55
Strokes kill more women than breast cancer
Men are more likely to suffer a stroke and at an earlier age
A stroke occurs when the brain is deprived of oxygen – it is not a heart attack
This summary of facts was compiled from material published on the National Stroke Foundation (Australia)
website www.strokefoundation.com.au
adapted through time. This is followed by an outline of current public health programs in
Australia designed to reduce the burden of stroke; and the results of scenario modeling which
illustrate the potential impact of such programs.
2 The Burden of Disease Attributable to Stroke in Australia

Worldwide, stroke is a significant contributor to the burden of disease (BoD). In Australia, it is
estimated that more than 50,000 strokes occur each year, and in 2003, it was estimated that
there were about 346,700 Australians (1.7% of the population) who had had a stroke during
their lifetime (Senes, 2006). Each year, strokes contribute to 7% of all deaths in Australia
(Senes, 2006). About half of those that survive to 12 months are dependent on others for
assistance with personal everyday living (Sturm et al., 2002b). The > lifetime costs of stroke to
the Australian community have been estimated as more than AUD2 billion per annum in 2004
dollar terms (unpublished, Cadilhac et al., 2007).
Since stroke causes premature mortality and increased morbidity, both outcomes should
be considered when describing the effects of stroke on society. The DALY is a summary
measure of population health and is divided into two components: the years of life lost
(YLL) due to premature mortality from stroke (number of deaths multiplied by standard life
expectancy at age of deaths in years); and the years of life lived with disability (YLD) as a
consequence of having had a stroke (number of incident cases multiplied by disability weights by
average duration of disability until remission or death in years). The most current national
estimates of disease burden from stroke using DALYs were reported in the latest Australian
BoD study. The total DALYs from stroke were reported to be 118,462 or 4.5% of the total
DALY burden in 2003 (Begg et al., 2007).
> Table 55-2 lists DALY estimates compiled for a range of > Australian jurisdictions, and
despite some differences in methodology, the ranking of stroke is consistent. Studies under-
taken during the 1990s ranked stroke as the second leading cause of DALY burden after
ischemic heart disease (IHD), amongst males and females (Magnus and Bensberg, 2000;
Mathers et al., 1999; Victorian Government Department of Human Services, 1999b). Stroke
accounted for a larger share of the female disease burden (6.0–6.6% of total DALYs), than the
male burden (4.6–4.8%).
More recent studies and future projections (Begg et al., 2007; Victorian Government
Department of Human Services, 2005) suggest that the DALY burden from stroke is reducing.
Two Australian studies indicate a 13.9% decline in stroke DALYs between 1996 and 2003 (Begg
et al., 2007; Mathers et al., 1999). In addition, there was a commensurate fall in stroke’s
proportionate share of the total burden (from 4.8 to 3.9% for males, and 6.1 to 5.1%
for females) and ranking as a leading cause (from second to fifth for males and third for
females). This trend is reinforced by the projections made in the 1999 Victoria study
where a 37% decline in DALY burden was predicted over the 20 year period between 1996
and 2016. This may partly be explained by improvements in stroke prevention, treatment
and management.
Overall, most of the stroke burden is attributable to premature mortality, with YLLs
accounting for approximately two thirds of the DALYs arising from stroke. For females, the
YLLs from stroke are only exceeded by those from IHD, whilst amongst males, IHD, lung
cancer, suicide and self-inflicted injuries are more major causes of premature mortality
than stroke.
. Table 55-2
Ranking of stroke in mortality and morbidity burden by sex
Males Females
% %
Jurisdiction Year Stroke total Ranking Stroke total Ranking
DALYs
Australiaa 1996 64,330 4.8% 2nd after IHD 72,248 6.1% 2nd after IHD
b
Victoria 1996 15,384 4.7% 2nd after IHD 18,031 6.0% 2nd after IHD
Southern 1996 3,549 4.8% 2nd after IHD 4,551 6.6% 2nd after IHD
MRc
Queenslandd 1996–1998 11,160 4.6% 4th after IHD, lung 11,943 5.7% 2nd after IHD
cancer, suicide
and self-inflicted
injuries
South 1999–2001a 5,556 5.0% 2nd after IHD 6,174 6.1% 2nd after IHD
Australiae
Victoriaf 2001 14,713 4.3% 2nd after IHD 19,096 6.3% 2nd after IHD
Australiag 2003 53,296 3.9% 5th after IHD, type 65,166 5.1% 3rd after anxiety
2 diabetes, anxiety and depression,
and depression, IHD
lung cancer
Victoria 2016 10,329 3.0% 10th after IHD, 10,828 3.2% 9th after
diabetes mellitus, dementia, IHD,
prostate cancer, breast cancer,
cancer of trachea/ depression, cancer
bronchi/lung, of trachea,
dementia, heroin bronchi/lung,
dependency and osteoarthritis,
poly drug use, COPD, diabetes
hearing loss,
cancer of colon
and rectum,
depression
Mortality (Years of life lost)
Australiaa 1996 41,863 5.5% 4th after IHD, lung 56,660 9.5% 2nd after IHD
cancer, suicide
and self-inflicted
injuries
Victoriab 1996 10,430 5.8% 3rd after IHD and 13,684 9.2% 2nd after IHD
lung cancer
Southern 1996 2,401 5.7% 3rd after IHD and 3,496 9.5% 2nd after IHD
MRc lung cancer
Queenslandd 1996–1998 7,062 5.1% 4th after IHD, lung 9,214 9.0% 2nd after IHD
cancer, suicide
and self-inflicted
injuries
Males Females
% %
a
South 1999–2001 3,143 5.1% 4th after IHD, lung 4,562 9.1% 2nd after IHD
Australiae cancer, suicide
and self-inflicted
injuries
Western 2000 2,875 5th after IHD, 4,175 2nd after IHD
Australiah suicide and self-
inflicted injuries,
lung cancer, road
traffic accidents
Victoriaf 2001 9,036 5.3% 4th after IHD, lung 11,582 8.2% 2nd after IHD
cancer, self-
inflicted injuries
Australiag 2003 36,152 5.1% 4th after IHD, lung 48,548 8.5% 2nd after IHD
cancer, suicide
and self-inflicted
injuries
Morbidity (Years lived with disability)
Australiaa 1996 22,467 3.8% 7th after 15,588 2.6% 8th after
depression, adult depression,
onset hearing loss, dementia,
alcohol osteoarthritis,
dependence/ asthma,
harmful use, generalized
dementia, asthma, anxiety disorders,
COPD type 2 diabetes,
age related vision
disorders
Victoriab 1996 4,954 3.5% 10th after 4,347 2.9% 9th after
depression, depression,
hearing loss, dementia,
alcoholic abuse/ osteoarthritis,
dependence, asthma, diabetes
dementia, asthma, mellitus,
COPD, diabetes generalized
mellitus, anxiety disorder,
osteoarthritis, IHD breast cancer,
other vision
disorders
DALYs and Public Health Programs for Stroke: Australian Perspectives

55 971
Males Females
% %
Southern 1996 1,147 3.6% 10th after 1,055 3.2% 8th after
MRc depression, depression,
hearing loss, dementia, asthma,
dementia, alcohol generalized
abuse/ anxiety disorders,
dependence, breast cancer
COPD, asthma,
diabetes mellitus,
osteoarthritis, IHD
Queenslandd 1996–1998 4,097 3.9% 9th after 2,729 2.6% 8th after
depression, adult depression,
onset hearing loss, dementia, asthma,
asthma, COPD, osteoarthritis,
alcohol generalized
dependence/ anxiety disorders,
harmful use, IHD, type 2 diabetes,
dementia, age-related vision
osteoarthritis disorders
South 1999–2001i 2,413 5.3% 4th after adult- 1,613 3.2% 8th after
Australiae onset hearing loss, depression,
depression, dementia and
dementia and Alzheimer’s
Alzheimer’s disease,
disease osteoarthritis,
asthma, age-
related vision
disorders,
generalized
anxiety disorder,
type 2 diabetes
Victoriaf 2001 5,677 3.3% 7th after 7,514 4.3% 6th after
depression, Type depression,
2 diabetes, Alzheimers and
hearing loss, other dementias,
Alzheimers and type 2 diabetes,
other dementias, asthma,
asthma, prostate generalized
cancer anxiety disorders
Males Females
% %
g
Australia 2003 17,144 2.6% 8th after anxiety 16,619 2.4% 9th after anxiety
and depression, and depression,
type 2 diabetes, type 2 diabetes,
adult-onset dementia, asthma,
hearing loss, IHD, adult-onset
asthma, dementia, hearing loss,
COPD, IHD breast cancer,
osteoarthritis
These data presented highlight the various estimates of disease burden obtained from a range of studies for stroke
conducted in Australia
DALY disability adjusted life years; IHD ischemic heart disease; COPD chronic obstructive pulmonary disease;
Southern MR Southern Metropolitan Region of Melbourne
a
Mathers et al, 1999
b
Victorian Government Department of Human Services, 1999a, b
c
Magnus and Bensberg, 2000
d
Pike et al, 2002
e
Department of Health (South Australia), 2005
f
Victorian Government Department of Human Services, 2005
g
Begg et al, 2007
h
Katzenellenbogen et al, 2003
i
3 year annual average
Although the disability resulting from stroke is enormous, it is typically ranked somewhere
between sixth and tenth place in terms of YLD, and is exceeded by other diseases such as
depression, dementia, hearing loss, asthma, and osteoarthritis. Being a disease which predomi-
nantly affects the aged population, the majority of the DALY burden from stroke occurs amongst
persons aged 75 years and over, especially amongst females. Whilst the overall disease burden is
much higher amongst the female population, their total YLDs from stroke are generally lower
compared to other conditions because of shorter life expectancies at stroke onset.
3 Comparisons of the Disease Burden from Stroke in Australia

to Other Countries
> Table 55-3 includes global and regional estimates of DALYs arising from stroke for the years
1990, 2000, 2010 and 2020 obtained from the Global BoD study (Murray and Lopez, 1996). At
a world level, the total DALYs arising from stroke were predicted to increase from 38.5 million
in 1990 to 61.4 million in 2020. Consequently, the world’s total disease burden attributable to
stroke was anticipated to rise from 2.8 to 4.4% during the 30 year period. Authors of the
Global BoD study report that stroke death rates are likely to be over-estimated, given evidence
from stroke incidence studies suggesting that vital registration systems tend to over code
cerebrovascular mortality (Bonita, 1996). Therefore, these predictions of stroke-related DALY
burden may be overestimated.
. Table 55-3
Projections of DALYs from stroke by world regions for 1990, 2000, 2010 and 2020a
1990 2000 2010 2020

Stroke Stroke Stroke Stroke
Country/ Total as % Total as % Total as % Total as %
regional stroke total stroke total stroke total stroke total
grouping DALYs DALYs DALYs DALYs DALYs DALYs DALYs DALYs
Established 4,977,000 5.04% 5,166,000 5.14% 5,070,000 5.14% 4,988,000 5.14%
market
economiesb
Formerly 4,447,000 7.15% 5,050,000 7.74% 5,007,000 7.72% 4,886,000 7.69%
socialist
economies
of Europe
India 4,235,000 1.47% 5,223,000 2.09% 6,398,000 2.67% 7,971,000 3.37%
China 10,821,000 5.19% 13,388,000 6.67% 15,279,000 7.57% 18,170,000 8.23%
Other Asia 4,478,000 2.52% 5,237,000 3.19% 6,230,000 3.83% 7,457,000 4.49%
and islands
Sub- 4,595,000 1.56% 5,487,000 1.72% 6,752,000 2.11% 8,542,000 2.59%
Saharan
Africa
Latin 2,489,000 2.53% 3,160,000 3.09% 3,899,000 3.74% 4,640,000 4.31%
America
and the
Caribbean
Middle 2,481,000 1.64% 3,059,000 1.97% 3,769,000 2.39% 4,737,000 2.82%
Eastern
Crescent
World 38,523,000 2.79% 45,770,000 3.37% 52,405,000 3.88% 61,392,000 4.42%
These data presented highlight the various estimates of stroke disease burden for various regions in the world
a
Compiled from The global burden of disease book, World Health Organization, 1996
b
Established market economies includes Australia;
DALY: disability adjusted life years
Australia falls into the ‘‘Established Market Economies’’ grouping, where the proportion of
DALYs attributable to stroke was expected to stabilize at 5.1% during the period 2000 and
2020 (World Health Organization, 1996). In many regions of the world, stroke accounts for a
smaller share of the total disease burden. Nevertheless, these data show that in most regions of
the world, with the exception of the ‘‘Established Market Economies’’ and the ‘‘Formerly
Socialist Economies of Europe,’’ DALYs attributable to stroke are forecasted to increase in each
10-year period.
> Table 55-4 compares DALYs arising from stroke for Australia against selected western
countries based on WHO data for 2002 (World Health Organization, 2004). Australia com-
pares favorably to other western nations in terms of the proportion of its ‘‘all causes’’ disease
burden which is attributable to stroke (3.5%). Of the 192 WHO member states, only 26
countries were reported to have a lower rate of stroke DALYs per 100,000 population than
. Table 55-4
Total stroke DALYs and DALYs per 100,000 population, 2002a
Total stroke Stroke as % total Stroke DALYs per 100,000

Country DALYs DALYs population
Australia 76,000 3.5% 391
Canada 120,000 3.2% 382
Denmark 35,000 4.7% 660
Finland 36,000 5.4% 689
France 259,000 3.5% 433
Germany 514,000 4.9% 623
Greece 131,000 9.4% 1,190
Ireland 20,000 4.1% 510
Italy 386,000 5.7% 671
Netherlands 86,000 4.6% 536
New Zealand 19,000 4.2% 491
Norway 25,000 4.8% 561
Sweden 53,000 5.4% 592
Switzerland 26,000 3.3% 365
United Kingdom 366,000 4.8% 619
United States of 1,467,000 3.5% 504
America
These data presented highlight the various estimates of stroke disease burden for various western countries
a
Complied from World Health Report: 2004 (World Health Organization, 2004); DALYs disability adjusted life years
Australia. With the exception of Canada and Switzerland, the lower stroke rates were in
countries of lower socio-economic status, such as in South American countries, where people
more often die from other causes at younger ages.
4 Differences in Methodology Used to Calculate DALYs for

Stroke in Australia
This section outlines the differences in methodologies used to calculate DALYs for stroke in
Australia. Methods used in the BoD studies, as well as research studies evaluating the potential
effectiveness of interventions to reduce the DALY burden were included. In each instance, the
methodology employed in the Global BoD Study (Murray and Lopez, 1996) was the basis for
calculating the DALYs. However, there were differences which mostly include the data sources
for stroke incidence rates; > case fatality rates; the prevalence and duration of disability; and the
use of stroke disability weights which reflect the severity of the disease on a scale of 0 (good
health) to 1 (dead).
Overall, to estimate DALYs, stroke was generally modeled in terms of the following health
states: a short period of disability for those who die in the first 28 days following a stroke;
survival beyond 28 days with no permanent impairment at 1 year after onset; and survival
beyond 28 days with permanent impairment (Mathers et al., 1999; Victorian Government
Department of Human Services, 2005). The Australian BoD studies (Begg et al., 2007; Mathers
et al., 1999) applied the same level of discounting (3%) as the Global BoD Study (Murray and
Lopez, 1996), but did not follow suit in age weighting DALYs to capture greater social
responsibility in young and mid adult life, as this remains controversial.
4.1 Stroke Incidence Determining the Size of the Problem
Fundamental to the calculation of DALYs is determining the baseline numbers of cases

affected by the disease in the reference year of interest. Stroke incidence rates are usually
reported for both first-ever and recurrent events since the probability of survival and outcome
are often different. Sources of underestimation are associated with hospital admissions data, as
not all strokes are admitted to hospitals. Furthermore, the coding of stroke using international
disease classification systems do not differentiate between first-ever and recurrent events. The
conduct of well-designed, > community-based stroke incidence studies in Australia has
improved the reliability of stroke incidence rates since these differentiate between hospitalized
and non-hospitalized cases, as well as first-ever and recurrent stroke events (Anderson et al.,
1993; Thrift et al., 2000).
In terms of stroke incidence rates used in the BoD studies, different data were used and
reflect the best sources available at the time. The 1999 Victorian BoD Study was confined to
hospital admissions of first-ever non-fatal stroke (Victorian Government Department of
Human Services, 1999a). Recognizing a possible underestimation, the authors made an
adjustment upwards by 44% for over 75 year olds (to cover cases residing in nursing
homes); and 17% for males and 9% for females of younger ages to account for non-
hospitalized non-fatal strokes. Then, overall incidence was adjusted downwards to 69%.
This was undertaken to account for the proportion of first-ever strokes amongst all strokes
and was based on findings from the Perth Monitoring Trends and Determinants in Cardio-
vascular Disease (MONICA) study, (Bonita et al., 1994). This was to ensure only incident cases
in the reference year were counted. Interestingly, this methodology produced similar figures to
the initial incidence rates published from the North East Melbourne Stroke Incidence Study
(NEMESIS) in Victoria, which included both hospitalized and non-hospitalized stroke (Thrift
et al., 2000). In NEMESIS, only 85% of persons experiencing first-ever stroke were admitted to
hospital, and first-ever cases comprised 72% of cases identified in the 1997 reference year.
In the later 2001 report of the Victorian BoD study (Victorian Government Department of
Human Services, 2005), the source of stroke incidence data was changed to first-ever non-fatal
stroke rates obtained from NEMESIS (Thrift et al., 2000). The authors of this study decided to
adjust the NEMESIS 1997 incidence rates downwards, based on the assumption that half of the
decline in annual Victorian stroke mortality rates between 1997 and 2000 was associated with
a decline in incidence rates.
In another example, a stroke model (Model of Resource Utilization, Costs and Outcomes
for Stroke [MORUCOS]) commissioned by the National Stroke Foundation (NSF) (Australia)
(Mihalopoulos et al., 2005) was used to estimate DALYs for Australia (Moodie, 2003). These
DALYs were then used in economic evaluations of stroke interventions. Both first-ever and
recurrent stroke incidence rates were included in the model and were based on published rates
from the Perth Community Stroke Study (PCSS) (Anderson et al., 1993) and NEMESIS (Thrift
et al., 2000). Although, it is preferable to use actual patient-level data drawn from such
community-based studies, it was noted that the application of incidence rates from specific
geographical locations to the wider Australian population could have potential limitations. The
incidence rates may not be generalizable to a national population. These examples highlight
some issues arising in the estimation of base numbers for DALY calculations.
4.2 Case Fatality Determining the Years of Life Lost from Premature
Mortality
Similar to the issues raised about use of stroke incidence data, sources of case fatality rates and
assumptions have varied over time. In general, case fatality rates have been based on Australian
Bureau of Statistics data on causes of deaths by age and gender. These data are compiled from
the Registry of Births, Deaths and Marriages death certificate records, and are classified using
the International Classification of Diseases (ICD-9). Despite such a system possibly over-
estimating stroke death rates (Bonita, 1996), no adjustment was made for potential over
coding by the Global BoD investigators (Murray and Lopez, 1996). This was because of
inadequate information on which to base any reassignment of stroke deaths.
In the most recent Australian BoD study, annual case fatality rates were based on Western
Australian hospital admissions collected over a 5 year period for 28 day survivors and adjusted
for background mortality (Begg et al., 2007). In this study, case fatality was determined as the
excess mortality in prevalent cases, defined by the authors as anyone still alive at the beginning
of the follow-up period (mid 1998–mid 2004) with a mention of stroke during any admission
between 1989 and 1998, as well as any new cases of admitted stroke during follow-up (Begg
et al., 2007). This appears a more fine-grained method to those reliant on vital statistics
registrations data alone, but is only applicable for hospitalized cases.
In the earlier Victorian study, the number of deaths within 28 days was derived using case
fatality rates from the PCSS (Anderson et al., 1994) of 24 and 29% for over 75 year old males
and females, and 14 and 17% for younger males and females (Victorian Government Depart-
ment of Human Services, 1999b). The rates were adjusted to reflect declining stroke rates since
1990 of about 2.5 and 5% per annum for the two age groups respectively, half of which was
attributed to declining incidence. For stroke patients who survived beyond 28 days, mortality
was extrapolated based on death registrations for which stroke was the recorded cause of death
on the assumption that this represented only 58% of all stroke deaths (Anderson et al., 1994).
Although Perth data comes from Western Australia and may not be representative for Victoria,
the regular follow-up of patients in community-based stroke incidence studies provides
greater confidence in the classification of deaths attributable to stroke. Therefore, use of the
Perth data, given a lack of available data at the time from NEMESIS, would have been
considered more reliable than other available sources. Interestingly, for the 2001 Victorian
study (Victorian Government Department of Human Services, 2005) the authors based
mortality rates following first-ever stroke on the Danish MONICA study (Bronnum-Hansen
et al., 2001). Standardized mortality ratios were calculated for the period 1982–1997 specified
by two age groups (25–69 years and 70 years and over) at the time of first-ever stroke, and in
each of the age groups by 1–5, 5–10 and 10–15 years after stroke. These contrasting methods
emphasize the problems in attempting to ensure accurate case fatality within regions with
limited data.
Lastly, the estimation of DALYs by Moodie, who applied NEMESIS survival data in the
MORUCOS model, provides an example of an even more detailed estimation of case fatality,
. Table 55-5
Mortality in first-ever stroke cases derived from the North East Melbourne Stroke Incidence Study
Mortality at Mortality at 3 months Mortality at 12 months

Treatment pathway 12 days % (cumulative %) (cumulative %)
Patients admitted to hospital 15 25 35
Patients not admitted to hospital 25 69 88
and in a nursing home
Patients not admitted to hospital 25 31 31
and at home
These data presented highlight the proportion of cases that died at various time points in the North East
Melbourne Stroke Incidence Study. Treatment pathway refers to where patients were managed following stroke
onset. Source: (Moodie, 2003)
although more labor intensive. In this study, first-ever stroke mortality was disaggregated by
age and gender; treatment pathways (hospitalized, non-hospitalized and in a nursing home,
non-hospitalized and at home); and by deaths at seven different time points following stroke
(1 day, 3 days, at discharge [12 days], 28 days, 3 months, 6 months, and 12 months post stroke)
(Moodie, 2003). Overall mortality for each pathway at discharge, 3 months and 6 months are
shown in > Table 55-5. These data highlight the variation in case fatality amongst different
groups of stroke patients, in particular those that do not access the health system and whom
are therefore potentially left out of administrative data collections.
The case fatality rates are essential in the estimation of the YLL component of the DALY.
Therefore, reliability of these estimates is very important and it is concerning that disparate
methods have been used. Nonetheless, much of this is an artifact of having reliable data at the
time such studies were conducted, and no method is flawless. In the calculation of YLL from
stroke, the Australian studies all employ an Australian cohort life expectancy table, rather than
the standard table used in the Global BoD Study. This is because of the longer life expectancy
in Australia.
4.3 Disability Weights Determining the Extent of Morbidity
The estimation of YLD attributable to stroke is more complex than that of YLL. At each time
point, the number of persons still alive is multiplied by a disability weight which reflects their
level of impairment attributable to stroke for a given duration. Again different approaches
have been undertaken in Australia. For example, YLDs were estimated by Moodie separately
for 3 time points within the first 12 months for patients who died within 3 months of first-ever
stroke. Moodie’s selection of 3 months as the first cut-off point, rather than 28 days as used in
the Australian BoD study (Mathers et al., 1999), was based on the consideration that most of
the recovery from stroke occurs within the first 3 months (Moodie, 2003). Consistent with the
Australian BoD study (Mathers et al., 1999), Moodie made assumptions about the functional
outcomes of those patients surviving 1 year after stroke based on the results reported from
New Zealand (Bonita et al., 1997), as local evidence was unavailable. In contrast, authors of
state-based BoD studies in Western Australia and Queensland, decided to use synthetic
estimates derived by applying the Australian ratio of YLD to YLL, estimated in the 1996
Australian BoD study (Mathers et al., 1999). This method assumed that the disability burden
of conditions changed in the same proportion to the mortality of the same disease in different
regions; and required some statistical adjustments to account for local differences (Pike et al.,
2002; Somerford and Katzenellenbogen, 2004).
With the exception of the most recent BoD study, the Dutch disability weights for stroke
(Stouthard et al., 1997) have been used in Australia for YLD estimation. These weights are
based on the views of a panel of health experts and > person trade-off methods which entails
individuals assessing how many outcomes of one kind are equivalent to the social value of a
different number of outcomes of another kind (Drummond and McGuire, 2001).
There were several advantages to using the Dutch weights in Australia. Firstly, the Dutch
weights provide more detail than the Global BoD weights for estimating YLDs, as they are
differentiated by disease severity. Secondly, these weights also represent more of the common
diseases found in low mortality countries such as Australia. Lastly, the Dutch weights facilitate
comparisons across diseases and between countries as they were calculated in a systematic way
for all diseases at the one time. The Dutch weights for stroke are provided in > Table 55-6.
The alternative to application of the Dutch weights would be the development of Austra-
lian specific weights. In the case of stroke, these could be elicited through the same method
using a local panel of experts. Alternatively, a method more typical of quality adjusted life year
(QALY) calculations, which incorporates individual health-state preferences of quality of life
(QOL) derived from samples of either the general population or a group of stroke patients
(Sassi, 2006), could be used. It is noted that in the literature such ‘‘preference’’ weights are
referred to in a variety of ways. This includes terms such as ‘‘disability weights,’’ ‘‘QALY
weights,’’ ‘‘> Quality of Life (QOL) weights,’’ ‘‘health state preferences,’’ or ‘‘health state
utilities’’ (Mathers et al., 1999; Post et al., 2001; Tengs et al., 2001). It is also often assumed
that 1-quality of life = disability (Sassi, 2006).
In the studies reporting QOL weights for stroke, many have shown wide variability, even
for strokes of the same level of severity. In a recent review, ‘‘QOL weights’’ for major stroke
ranged from 0.02 to 0.71, moderate stroke from 0.12 to 0.81, and minor stroke from 0.45 to
0.92 (Tengs et al., 2001). Such large variation in weights makes consistent comparisons
unlikely between studies using patient data. It has also been demonstrated that the bounds
of the scale of 0–1 used in the measurement of QOL may influence QOL weighting (Tengs and
Lin, 2003). > Table 55-7 illustrates the variation in weights when the upper and lower bounds
of the QOL scale are defined differently.
. Table 55-6
The ‘‘Dutch’’ disability weights for strokea
Sequelae Definition Weight

First-ever stroke with First-ever stroke, no long-term disability after 6 months 0.000
full recovery
Mild permanent No mobility or self-care problems, some problems usual 0.360
impairments activities, pain, anxiety/depression
Moderate permanent Some mobility or self-care problems, some problems usual 0.630
Severe permanent Some problems walking about, severe problems self-care, usual 0.920
a
Complied from a report on disability weights for diseases in the Netherlands (Stouthard et al., 1997)
. Table 55-7
Impact of scale bounds on quality of life weights
Major stroke Moderate stroke Minor stroke

Death to perfect health 0.52 0.68 0.87
Death to excellent health 0.28 0.45 0.64
Death to normal health 0.28 0.45 0.64
Worst possible to perfect health 0.38 0.54 0.73
These data presented highlight the differences in quality of life weights when the upper and lower bounds are
defined differently, for example perfect health is equal to 1. Data were derived from a meta-analysis published by
Tengs and Lin, 2003
In the most recent Australian BoD study there has been a shift to the use of disability
weights directly derived from patients. In this study, disability weights were estimated using
1-year follow-up data of stroke survivors in the PCSS (Begg et al., 2007). Health status
information before, and at 4 months and 1 year after stroke were compared. This method is
essentially a ‘‘hybrid’’ technique, which combines elements of both QALY and DALY method-
ology. In 28 day stroke survivors, various outcome measures from the PCSS participants were
mapped retrospectively to functional dimensions of the > EuroQOL5+, the QOL instrument
used in the original Australian BoD study to derive disability weights (Mathers et al., 1999).
Adjustments were made for pre-stroke morbidity and the Australian study multiple regression
equation (Mathers et al., 1999) was used to calculate the disability weights (Begg et al., 2007).
Because this method enabled all severity levels of stroke to be accounted for in the one estimate,
disability weights were only defined for different ages and by gender.
This overview of the methods used to calculate DALYs for stroke in Australia has high-
lighted many issues in relation to the input variables required to make accurate estimations of
both the YLL and YLD components of the DALY. At every level there was shown to be potential
sources of under- and overestimation. The most recent studies have moved to using more
direct patient-level sources of data (Begg et al., 2007; Moodie, 2003), but again these had
limitations. Nonetheless, opportunities to build on existing methodologies may improve
DALY estimation for stroke. However, this may be at the expense of comparability of DALYs
between diseases (and countries), if similar methods with the same level of rigor are not
applied.
In the next sections public health programs being conducted in Australia are outlined; and
a simulation exercise is presented to show the potential impact of such programs in reducing
the DALY burden attributable to stroke.
5 Overview of Public Health Programs for Stroke in Australia

Public health programs have been designed to reduce the impact of stroke on the Australian
community through prevention, improved treatment and enhanced long term support. Some
prevention strategies are generic and target risk factors common to many chronic diseases such as
physical activity and smoking. Therefore, outcomes for stroke may benefit from programs
taking a population approach to common risk factors. Strategies exist in Australia to reduce
the burden of stroke. However, their implementation is complicated by a range of factors, for
example, health system financing methods and availability of health services outside metro-
politan areas.
In Australia, different levels of governments have different responsibilities in terms of
purchasing and funding health and community services. Broadly speaking, the federal govern-
ment is responsible for primary and aged care, whereas state governments maintain responsi-
bility for the provision of acute and post acute hospital services. Overlap in the delivery of
programs is coordinated to some extent by the Australian Health Ministers Council. Although
many Australians have private health insurance, the majority of health care is funded by a
public Medicare system.
At a national level, the Council of Australian Governments has recently announced
the Australian Better Health Initiative (ABHI) (http://www.health.gov.au/internet/wcms/
Publishing.nsf/Content/8F84093D1E4FA53FCA25711100261015/$File/factsheet3.pdf). ABHI
promotes a preventative approach to chronic disease with further investment in campaigns to
increase physical activity and promote healthy eating. Furthermore, the Federal government
has created new Medicare reimbursement items to permit more comprehensive assessments of
people potentially ‘‘at risk’’ of chronic disease. In this way, it is envisaged that early detection
and prevention management can be commenced. In addition, there have been other long
term successful strategies, such as the QUIT campaign (http://www.quitnow.info.au/), which
is credited with reducing smoking prevalence from 23.5% in 1997 to 17.4% in 2004 (http://www.
health.gov.au/internet/wcms/publishing.nsf/Content/health-pubhlth-strateg-drugs-tobacco-
education.htm). Separate approaches are also undertaken in the various Australian state
and territory jurisdictions for example, the ‘‘Go for Your Life’’ program in Victoria
which encourages physical activity and healthy eating amongst people of all ages (http://
www.goforyourlife.vic.gov.au).
Other programs are stroke specific and focus on improving awareness of the signs of stroke
in order to promote better responsiveness to effective time-dependent interventions; enhanc-
ing and facilitating access to evidence based clinical practice; and delivering appropriate long
term support after stroke. This is because caring for stroke patients is a complex process and
since the proportion of disability is large and the risk of a recurrent stroke common, survivors
and their families often require long term support.
In 2007, the NSF targeted a high risk approach to stroke prevention with the development
of a program to reduce the rate of high blood pressure amongst the 3.7 million Australians
over the age of 25 years with inadequately treated or undetected hypertension (Australian
Institute of Health and Welfare, 2004). This was determined to be a ‘‘priority objective’’ as high
blood pressure is the most important modifiable risk factor for stroke. The ‘‘Know Your
Numbers’’ campaign, based on a program run by the Blood Pressure Association in the
United Kingdom, was piloted in one Victorian region (http://www.strokefoundation.com.
au/stroke-prevention-blood-pressure-program). It used social marketing and community
based ‘‘pressure’’ stations to allow people to have their blood pressure tested before being
given information about what action to take. The program linked in with other Australian
initiatives for management of risk factors, such as ‘‘Go for Your Life.’’
6 Programs to Improve the Diagnosis of Stroke
Stroke is a condition that benefits from prompt diagnosis and assessment. Early recognition
and intervention after stroke will therefore lead to improved outcomes and reduce the risk
of another event. In 2003, the NSF launched the strokesafe™ campaign to improve the
recognition of the signs of stroke amongst Australians aged 50 years and over. The 6 week
campaign used television, radio and print advertising and was supported by publications,
direct mail, a public relations campaign, community-based seminars, the NSF website and a
free telephone help line. Following 2 years of the strokesafe™ campaign, a 10% improvement
in people aged 40 years and over naming at least one sign of stroke was found.
7 Program to Improve Delivery of Evidence Based Care
Results of well designed clinical trials have shown that stroke outcomes can be improved
through the use of intravenous thrombolysis within 3 h of ischemic stroke onset (Wardlaw
et al., 2000), aspirin within 48 h (Chen et al., 2000), and organized specialist, multidisciplinary
care in a dedicated Stroke Care Unit (SCU) (Stroke Unit Trialists’ Collaboration, 2003).
However, we also know that delivery of evidence-based care is inadequate. In a national
survey, conducted in 2007, only about 19% of Australian public hospitals were found to
have a dedicated SCU (Cadilhac et al., 2006).
Clinical guidelines for stroke that outline recommendations for evidence-based care in
Australia were developed by the NSF and endorsed by the National Health and Medical
Research Council (NHMRC) in 2005 and 2007. The NSF has developed programs to facilitate
implementation of these guidelines including a national stroke audit of acute care (National
Stroke Foundation, 2007b,c) linked to an educational program (strokelink) that will encour-
age local clinicians to identify care gaps informed by the audit results; and to develop and
implement plans to improve adherence to recommendations.
8 Programs to Facilitate Long Term Recovery

Mechanisms by which stroke survivors may be supported to recover QOL in the community
are varied. Consumers report that the most valuable services include peer support, self-
management programs, home help, counseling and education (National Stroke Foundation,
2007d). Whilst the diversity of available services in Australia ensures that heterogeneous needs
are met, it also contributes to fragmentation of the system. In 2006, less than 3,000 stroke
survivors were accessing peer support through about 160 stroke support groups nationally.
Generic self-management programs are available across Australia and are provided as part of
the ABHI. However, these programs typically exclude people with severe disability and
cognitive impairment. To address this, the NSF is testing a self-management program designed
for stroke survivors.
In summary, both government and non-government agencies in Australia are implement-
ing or planning to implement a range of programs to prevent and better manage stroke. It was
highlighted, that access to evidence-based treatments are limited. The final section of this
chapter provides an analysis of the potential reductions in disease burden if there was better
access to effective interventions.
9 Potential for Public Health Programs to Reduce the Burden

of Disease in Australia
The potential health benefits which could be achieved from public health programs that result
in improved access to effective interventions as recommended in current clinical guidelines
(National Stroke Foundation, 2007a) was estimated. A pragmatic approach was adopted based
on improving access to the interventions if both full implementation and > feasible effective-
ness potential (that is, ‘‘steady-state’’ operation) could be achieved. This work provides an
updated sub-analysis to that published by Cadilhac et al. (2007). The representative year
selected was 2015, as this was deemed as the first year that ‘‘steady-state’’ operation was likely
to be achieved given the recent implementation of many programs. Any benefits achieved before
2015 were excluded. Only first-ever stroke cases were considered in the representative year.
Interventions included in the analysis were: SCUs and blood pressure lowering; as well as
warfarin for atrial fibrillation, intravenous thrombolysis, aspirin, cholesterol lowering, and carotid
endarterectomy for eligible patients (> Table 55-8). It is acknowledged that there are other
potential interventions that could have been included in this evaluation. However, this analysis
was limited to the interventions known to have the most influence on stroke incidence and
outcome.
9.1 Calculating Predicted Health Gain from Reduced Death and

Disability
To convert the numbers of strokes prevented into DALYs saved, the average DALYs per stroke
estimated by Moodie (Moodie, 2003) were applied. These DALYs are age-sex adjusted
‘‘lifetime estimates.’’ The average DALYs lost per case for a first-ever event was 3.99 and for a
recurrent stroke, 4.91. The average incremental DALYs per case gained over a lifetime for SCU
treatment over general management was estimated as 0.46; and 0.61 for intravenous thrombol-
ysis (Mihalopoulos et al., 2005).
9.2 Determining the Eligible Cases That Would Benefit from Public
Health Programs
The ‘‘outcomes’’ in this analysis were calculated for those additional cases that would benefit if
current practice were improved to a defined ‘‘achievable’’ level. This involved estimating, from
the best sources of local data: (1) the number of persons currently receiving evidence-based
care; (2) the number eligible but not currently receiving evidence-based care; and (3) the
number who could realistically be receiving evidence-based care (given that 100% coverage is
not possible for all interventions). The ‘‘achievable’’ level therefore varied depending on the
intervention, current practice and the realities of service provision (> Table 55-8). For
example, the blood pressure lowering intervention was estimated to reach an achievable
level at 70% coverage, whilst use of SCUs was set at 80%.
9.3 Analysis
A conceptual framework model was developed in Excel (Microsoft Excel 2000). This model
incorporated population projections for 2015 (http://www.abs.gov.au/AUSSTATS/abs@.nsf/
PrimaryMainFeatures/3222.0?OpenDocument), best estimates of the prevalence of relevant
risk factors in Australia (Australian Institute of Health and Welfare, 2004; Briganti et al., 2003),
current age and sex-specific stroke incidence rates (Thrift et al., 2000) and an interventions
. Table 55-8
Interventions, current practice assumptions, treatment potential and expected outcomes
Eligible Health
Current population 2015 Benefit
with risk factor or target Cases (DALYs
Intervention eligible for treatment Current practice assumptions Criteria for eligibility group* ARR prevented saved)
Primary Prevention N % N
a a b
Blood pressure 29% 25 years 15.2% untreated 25 years 3,626,160 1.04 26,398 105,330
(BP) reduction 8% uncontrolled treateda Control in 70% of eligible cases
Warfarin for 5% 65 years 85% visit GPc 65 years 3,450 3 104 413
atrial fibrillation 3.4% (untreated) All eligible get treated
35% contraindicationsd
Acute Treatment
Stroke Care 83% hospitalized 89% hospitalizede 80% access 18,289 5.6 8,374
Units (SCU) strokes 25% treated in SCU
Intravenous 10% ischemic cases 2% treated Arrive in 2 h 1,543 11 934
thrombolysis Treated in SCU (80% access)
<3 h
Secondary Prevention j
BP reduction 55% (hospitalized 37% untreated or uncontrolled at Adequate control in 70% of 14,824 2.2 326 1,603
cases) 5 yearsf eligible hospitalized cases
Warfarin for 23.6% have AF 16% hospitalized AF cases on Ischemic strokes 3,743 8 300 1,471
atrial fibrillation warfarin f

(AF) 89% hospitalizede
35% contraindicationd
Aspirin 0.2% TIAg 72.5% first- 17% untreated TIA ischemic stroke 8,023 1 80 394
ever ischemic strokes
55
983
Eligible Health 984

Current population 2015 Benefit
with risk factor or target Cases (DALYs
Intervention eligible for treatment Current practice assumptions Criteria for eligibility group* ARR prevented saved)
55
Carotid 8% > 70% carotid 25% currently treated within TIA/ischemic strokes 1,436 3.8 55 268
Endarterectomy stenosisg 2 weeks Treatment in SCU within
2 weeks of stroke (80% access)h
Cholesterol 72.5% first-ever 85% visit GPc Ischemic strokes discharged 17,335 2.2 381 1,873
lowering ischemic strokes from hospital and managed by
a general practitioner
89% hospitalizede 70% receive treatment
10.8% currently treated by GPs
with no history CHD lipids
between 2.6 and 4.9 mmolsi
Total (range for worst case/best case scenario) 27,664 120,660
(23,497; (102,552;
30,408) 132,747)
3% discounting 92,474
5% discounting 77,777
a
Australian (AusDiab study) data (Briganti et al., 2003)
b
Based on meta analysis of randomized controlled trials of BP reduction in persons with high blood pressure and no history of cardiovascular disease (Law et al., 2003)
c
Australian data (Senes and Britt, 2001)
d
Extrapolated from UK prevalence study (Sudlow et al., 1998)
e
Proportion of strokes hospitalized in community-based incidence study NEMESIS (Thrift et al., 2000)
f
NEMESIS data (Paul and Thrift, 2006) (Nicol, unpublished data, 2005)
g
Reasonable estimate of population prevalence (Hankey, 2001)
h
Best-practice management is surgery within 2 weeks to avoid a recurrent event and this is assumed possible only in centers with stroke units (Rothwell et al., 2004)
i
Accords with criteria for the SPARCL study (Amarenco et al., 2006); AF: atrial fibrillation; ARR: absolute risk reduction; Avoid Stroke as Soon as Possible (ASAP) general practice
stroke audit; BP: blood pressure; CHD: coronary heart disease; DALY: disability adjusted life year; GP: general practitioner;. NEMESIS: north east Melbourne stroke incidence study;
SCU: stroke care unit; SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels; TIA: transient ischemic attack; Current practice assumptions: refers to estimates of
the national population that are currently treated and/or known to not be receiving treatment so that a realistic estimate of increased exposure to effective treatments can be made
j
Numbers adjusted for reductions in stroke numbers with primary prevention
spreadsheet to define the eligible populations for treatment (preventive and/or curative).
Current incidence rates and clinical practice were assumed to remain constant over time.
The number of additional ‘‘incident’’ strokes to be prevented and additional DALYs
recovered through better treatment were calculated. To avoid double counting benefits of
> secondary prevention of stroke and treatment, the effects of improved > primary preven-
tion of stroke were incorporated. That is, first-ever stroke cases prevented were removed from
the eligible population for treatment and secondary prevention. The health benefit was
determined by multiplying the absolute risk reduction expected for each intervention by the
additional cases that would receive that intervention.
A sensitivity analysis was conducted taking a ‘‘best case/worst case’’ scenario approach by
varying the size of eligible groups to assess the robustness of estimates. This was varied because
‘‘size of eligible group’’ was deemed the most useful in capturing a range of possible areas of
uncertainty (for example, treatment coverage and absolute risk rates). The DALY estimates
were not varied directly, as these were derived from the same economic model and were
therefore internally consistent. The calculated point estimates were discounted by 3% to
accord with BoD studies, as well as 5% to be consistent with prior work by Moodie (2003).
9.4 Results of Simulation Analysis
In the indicative year of 2015, approximately 71,500 strokes were expected to occur if clinical
practice and incidence rates remain the same. Given age-sex adjusted stroke incidence
predictions for 2015, about 27,000 strokes (38%) could be prevented with better manage-
ment through increasing the use of current evidence-based interventions. In present-value
(2006) terms, this would result potentially in the recovery of more than 92,000 DALYs
(> Table 55-8).
Blood pressure interventions as primary prevention would produce 88% of the health
gains (> Figure 55-1). SCUs comprised 7% of the total health gains. The results were sensitive
to variations in size of eligible group.
Overall, this analysis provides evidence that improved stroke prevention and better access
to effective stroke treatment could potentially result in substantial health gains to society.
10 Conclusions
In this chapter a number of important issues were raised and discussed in relation to the
estimation of DALYs for stroke in Australia. Overall, stroke contributes to 4.5% of the disease
burden in Australia and is ranked fifth for men and third for women compared with the other
diseases examined in the current BoD study (Begg et al., 2007). Important issues were
identified concerning the methods to calculate DALYs. In particular, the limitations of data
on incidence, case fatality, and prevalence of disability following stroke. Nonetheless, the
detailed natural history of stroke obtained from Australian community-based incidence
studies provides a richness of data unavailable for many conditions. Furthermore, there has
been no study undertaken to determine local disability weights for stroke or other health states
relevant to Australia, although it is understood that this is proposed component of a research
project recently funded by the NHMRC in Australia. Whilst the development of a set of
. Figure 55-1
Proportion of potential Disability Adjusted Life Years saved from improved access to selected,
effective interventions
Australian weights would be more appropriate to the formulation of Australian health policy,
it requires an extensive and costly exercise (if done for all diseases), and may produce weights
which are less amenable to international comparisons. The choice is between achieving
precision across a range of diseases versus precision within a specific disease.
A description of public health programs that exist or are planned to reduce the burden of
disease associated with stroke was provided. The WHO has set a goal to reduce global chronic
disease death rates by an additional 2% annually by 2015 (Strong et al., 2005). It is recognized
that this can only be achieved by levering all partners from all sectors of society. Investment in
public health programs requires commitment by government and non-government sectors, as
well as clinicians to reduce the stroke burden. As has been outlined, there is good evidence that
such programs are starting or have recently been put in place in Australia to meet this
challenge. Improving the awareness and knowledge of stroke risk factors and signs, increasing
the uptake of evidence-based management strategies and ensuring appropriate community
support are components of the multifaceted approach being adopted. As was demonstrated in
the simulation analysis presented, improved stroke prevention and better access to effective
stroke treatment could potentially result in substantial health gains for Australia. It is
acknowledged that there are limitations to this analysis including assumptions based on the
likely effectiveness of public health programs; estimates of the feasible coverage of interventions;
and the absolute risk reductions anticipated. To compensate for any potential ‘‘overestima-
tion’’ of results, benefits that may have accrued to prevalent cases or potential reductions in
coronary heart disease were not included. The results are indicative of what could potentially
be achieved if current practice was improved to reflect best practice.
Summary Points
Stroke is an important contributor to the burden of disease globally.

In Australia, about 5% of the DALY burden is attributable to stroke.
The disease burden from stroke is lower in countries where people are more likely to die of
other causes at a younger age.
Methods for estimating stroke DALYs vary in terms of the data sources, but most are based
on the original Global BoD methods.
The most current Australia BoD study for stroke has used local disability weights derived
from patient data, rather than those developed with a panel of health experts overseas.
The ideal source of incidence and case-fatality data for DALY estimates are those derived
from well-designed community-based incidence studies.
Public health programs to reduce the stroke burden include generic programs aimed at
reducing common risk factors across a number of chronic diseases; and stroke specific
programs to address unique aspects of stroke.
Despite high levels of evidence for effective interventions to prevent and treat stroke,
adherence to recommendations in clinical practice is limited.
Improved stroke prevention and better access to effective stroke treatment could poten-
tially result in substantial health gains for Australia.
References
Amarenco P, Bogousslavsky J, Callahan A, Goldstein LB, in Australia 2003. PHE 82. Australian Institute of
Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Health and Welfare, Canberra.
Szarek M, Welch KM, Zivin JA. (2006). N Engl J Bonita R. (1993). Ann Epidemiol. 3: 529–533.
Med. 355: 549–559. Bonita R. (1996). In: Murray CJ, Lopez AD (ed.) Global
Anderson CS, Jamrozik KD, Broadhurst RJ, Stewart- Perspectives on Non-Communicable Disease:
Wynne EG. (1994). Stroke. 25: 1935–1944. The Epidemiology of Cancers, Cardiovascular Dis-
Anderson CS, Jamrozik KD, Burvil PV, Chakera MH, eases, Diabetes Mellitus, Respiratory Disorders and
Johnson GA, Stewart-Wynne EG. (1993). Med J Other Major Conditions. Harvard University,
Aust. 158: 80–84. Cambridge.
Australian Institute of Health and Welfare. Heart, Stroke Bonita R, Anderson CS, Broad JB, Jamrozik KD,
and Vascular Diseases: Australian facts 2004. (2004). Stewart-Wynne EG, Anderson NE. (1994). Stroke.
AIHW, Canberra, pp. 140. 25: 552–557.
Begg SJ, Vos ET, Barker B, Stevenson CE, Stanley L, Bonita R, Solomon N, Broad JB. (1997). Stroke. 28:
Lopez AD. (2007). The Burden of Disease and Injury 1898–1902.
Briganti EM, Shaw JE, Chadban SJ, Zimmet PZ, Welborn Support After Stroke. National Stroke Foundation,
TA, McNeil JJ, Atkins RC. (2003). Med J Aust. 179: Melbourne.
135–139. Paul SL, Thrift AG. (2006). Hypertension. 48: 260–265.
Bronnum-Hansen H, Davidsen M, Thorvaldsen P. Pike A, Baade P, Harper C, Muller S, Kennedy B. (2002).
(2001). Stroke. 32: 2131–2136. Quantifying the Burden of Disease and Injury
Cadilhac DA, Carter RC, Thrift AG, Dewey HM. (2007). in Queensland 1996–1998. Queensland Health,
Health Policy. 83: 287–294. Brisbane.
Cadilhac DA, Lalor EE, Pearce DC, Levi CR, Donnan GA. Post PN, Stiggelbout AM, Wakker PP. (2001). Stroke. 32:
(2006). Intern Med J. 36: 700–704. 1425–1429.
Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP,
Liu LS, Xie JX, Warlow C, Peto R. (2000). Stroke. 31: Barnett HJ. (2004). Lancet. 363: 915–924.
1240–1249. Sassi F. (2006). Health Policy Plan. 21: 402–408.
Department of Health (South Australia). (2005). Popu- Senes S. (2006). How we manage stroke in Australia.
lation Health in South Australia: Burden of Disease AIHW cat no CVD 31. Australian Institute of Health
and Injury Estimates, 1999–2001. Government of and Welfare, Canberra.
South Australia, Adelaide. Senes S, Britt H. (2001). A General Practice View of
Drummond M, McGuire A (eds.). (2001). Economic Cardiovascular Disease and Diabetes in Australia.
Evaluation in Health Care: Merging Theory with Australian Institute of Health and Welfare,
Practice Oxford University Press, New York. Canberra.
Hankey GJ. (2001). In: Norris JW, Hachinski V (ed.) Somerford P, Katzenellenbogen J. (2004). Western Aus-
Stroke Prevention. Oxford University Press, tralia Burden of Disease: Disability-Adjusted Life
London, pp. 313–332. Years: Technical Overview. Epidemiology Branch,
Katzenellenbogen J, Somerford P, Serafino S. (2003). Health Information Centre, Department of Health,
Western Australian Burden of Disease Study: Western Australia, Perth.
Mortality 2000. Department of Health (Western Stouthard ME, Essink-Bot M, Bonsel GJ, Barendregt
Australia), Perth. JJ, Kramer P, van der Water H, Gunning-Schepers
Law M, Wald N, Morris J. (2003). Health Technol Assess. LJ, van der Maas PJ. (1997). Disability weights for
7: 1–94. diseases in the Nether lands. Eramus University
Magnus A, Bensberg M. (2000). Southern Metropolitan (Department of Public Health), Rotterdam.
Burden of Disease Study: Mortality and Morbidity. Stroke Unit Trialists’ Collaboration. (2003). Cochrane
Victorian Department of Human Services-Southern Database Syst Rev. CD000197.
Health Care Network., Melbourne. Strong K, Mathers C, Leeder S, Beaglehole R. (2005).
Mathers C, Vos ET, Stevenson CE. (1999). The Burden of Lancet. DOI:10.1016/S0140–6736(05)657341–2: 5.
Disease and Injury in Australia. Australian Institute Sturm JW, Davis SM, O’Sullivan JG, Vedadhaghi ME,
of Health and Welfare, Canberra. Donnan GA. (2002a). Med J Aust. 176: 312–316.
Mihalopoulos C, Cadilhac DA, Moodie ML, Dewey HM, Sturm JW, Dewey HM, Donnan GA, Macdonell RA,
Thrift AG, Donnan GA, Carter RC. (2005). Int J McNeil JJ, Thrift AG. (2002b). Stroke. 33: 762–768.
Technol Assess Health Care. 21: 499–505. Sudlow M, Thomson R, Thwaites B, Rodgers H,
Moodie ML. (2003). Trial application of a Model of Kenny RA. (1998). Lancet. 352: 1167–1171.
Resource Utilisation, Costs and Outcomes for Tengs TO, Lin TH. (2003). Pharmacoeconomics. 21:
Stroke (MORUCOS) to Assist Priority Setting in 191–200.
Stroke (Thesis). School Public Health, The Univer- Tengs TO, Yu M, Luistro E. (2001). Stroke. 32: 964–972.
sity of Melbourne, Melbourne. Thrift AG, Dewey HM, Macdonell RA, McNeil JJ,
Murray CJ, Lopez AD. (1996). The Global Burden of Donnan GA. (2000). Stroke. 31: 2087–2092.
Disease. Harvard University Press, Cambridge, MA. Victorian Government Department of Human Services.
National Stroke Foundation. (2007a). Clinical Guidelines (1999a). Victorian Burden of Disease Study:
for Acute Stroke Management. National Stroke Morbidity. Public Health and Development Divi-
Foundation, Melbourne. sion, Victoria Government Department of Human
National Stroke Foundation. (2007b). National Stroke Services, Melbourne.
Audit Clinical Report: Acute Services. National Victorian Government Department of Human Services.
Stroke Foundation, Melbourne. (1999b). Victorian Burden of Disease Study:
National Stroke Foundation. (2007c). National Stroke Mortality. Public Health and Development Division,
Audit Organisational Report: Acute Services. Victoria Government Department of Human
National Stroke Foundation, Melbourne. Services, Melbourne.
National Stroke Foundation. (2007d). Walk in our Victorian Government Department of Human Services.
Shoes. Stroke Survivors and Carers Report on (2005). Victorian Burden of Disease Study.
Mortality and morbidity in 2001. Rural and World Health Organization. (1996). The global Burden
Regional Health and Aged Care Services Division, of Disease: A Comprehensive Assessment of Mortal-
Victorian Government Department of Human Ser- ity and Disability from Diseases, Injuries, and Risk
vices, Melbourne. Factors in 1990 and Projected to 2020. Harvard
Wardlaw JM, del Zoppo G, Yamaguchi T. (2000). University, Cambridge.
Cochrane Database Syst Rev. CD000213. World Health Organization. (2004). The World
World Health Organization. (1989). Stroke. 20: Health Report 2004: Changing History. World
1407–1431. Health Organisation, Geneva.
56 Burden of Stroke: Indian
Perspective
P. M. Dalal . M. Bhattacharjee
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 992
1.1 India: Demographic and Epidemiologic Transitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993
1.2 The Stroke (CVD) Epidemic – India and Developing Countries . . . . . . . . . . . . . . . . . . . 995
2 Stroke Epidemiology in India . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998

2.1 Stroke Prevalence Studies in India . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998
2.2 Incidence of Stroke and Clinical Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998
2.3 Clinical Profile in Mumbai Stroke Registry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999
2.4 Stroke Risk Factors (RF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999
2.5 Mortality Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001
2.6 India: Quality of Life (QOL) After Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1002
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004

992 56 Burden of Stroke: Indian Perspective
Abstract: In recent years economic and demographic transitions in India have resulted in shift
to lifestyle-related chronic diseases like > stroke, ischemic heart disease (IHD), diabetes
and cancer. In the year 2005, India accounted for more than 53% of all deaths and 44% of
> disability adjusted life years (> DALYs) lost from chronic diseases including stroke; without
successful intervention, this is estimated to increase by 18% in the next 10 years. Furthermore,
by 2016 an estimated US$ 84 billion of national income will be lost, in middle and low income
countries, from chronic diseases alone. To reduce burden of disease in general, World Health
Organization (WHO) has proposed a global goal, to reduce chronic disease mortality by 2%
per year, over and above what will be achieved by routine intervention; and this is likely to avert
6.4 million deaths from stroke by 2015. However, there is paucity of standardized comparable
data on stroke epidemiology to design sustainable primary or secondary prevention strategies.
On account of scarce resources and high costs, modern stroke-care for timely treatment of
acute stroke is beyond the reach of patients in India. Nonetheless, risk factors for stroke are
mainly conventional and intervention to reduce exposure to raised blood pressure, diabetes
mellitus, smoking, high cholesterol, and physical inactivity, and multidrug strategy will be cost-
effective. Health education, low-salt intake, stopping tobacco use, and lifestyle changes may
prove effective. Surveillance of cerebrovascular disease (CVD) risk factors and their determi-
nants for intervention and prevention strategies need emphasis. Indian Council of Medical
Research has initiated ‘‘risk factors surveillance’’ in populations. In addition, the Government
of India has now launched National Rural Health Mission (NRHM) in support of the above
objectives. To reduce the burden of disease in developing nations, an integrated approach for
prevention (primary and secondary) of chronic diseases and stroke should receive high priority.
List of Abbreviations: DALYs lost, disability adjusted life years lost; IHD, ischemic heart
disease; HIV/AIDS, human immunodeficiency virus/acquired immunodeficiency syndrome;
NCD, noncommunicable diseases; MOHFW, Ministry of Health and Family welfare, Govern-
ment of India; OxHA, Oxford Health Alliance; CVD, cerebrovascular disease/stroke; GBD,
global burden of disease; FES, > first ever stroke; TIA, transient ischemic attack; CT, compu-
terized tomography; GSI, global stroke initiative; SD, standard deviation; CI, confidence
interval; WHO, World Health Organization; BP, blood pressure; OR, odds ratio; RF, risk
factors; ICASS, Indian Collaborative Acute Stroke Study; QOL, quality of life; HT, hyperten-
sion; DM, diabetes mellitus; NIHSS, > National Institute of Health Stroke Scale; t-PA, tissue
plasminogen activator; MRS, > modified Rankin Scale; INR, Indian rupees
1 Introduction
There is an epidemic of stroke in developing countries as a leading cause of disability adjusted

life years (DALYs) lost (Editorial, 2007; Feigin, 2007). Global burden of disease study, for the
year 2005, projected 16 million first ever stroke, 62 million stroke survivors, 51 million DALYs
lost, and 5.7 million deaths (Strong et al., 2007). This burden predominantly affects low and
middle income countries. In the year 2005, India accounted for more than 53% of all deaths
from and 44% of DALYs lost from chronic diseases (including stroke) (Reddy et al., 2005);
without successful intervention this is estimated to increase by 18% in the next ten years
(World Health Organization Global Report, 2005). In this paper, we review the available
information in stroke epidemiology and the key challenges to be addressed to reduce the
burden of disease in developing countries including India.
Burden of Stroke: Indian Perspective 56 993
1.1 India: Demographic and Epidemiologic Transitions
India is going through a period of epidemiologic and demographic transition (> Table 56-1,
> Figure 56-1, and > 56-2) resulting from decline in infant mortality and increase in life
expectancy of ageing population (Population projections for India and states 2001–2026,
revised December 2006, 2007). Infectious diseases (e.g., tuberculosis, malaria, human immu-
nodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), etc.) still prevail
as major health problem and emergence of newer drug resistant strains is an extra burden
(> Table 56-2).
. Table 56-1
India: Demographic changes from 2006 to 2026
Indicators 2006 2011 2016 2026

Population (in millions) 1112 1192 1268 1399
Life expectancy at birth (Years)
Males 65.8 67.3 68.8 69.8
Females 68.1 69.6 71.1 72.3
Crude birth rate per 1000 population 21.3 19.6 18 16
Infant mortality rate per 1000 live-births 54.3 49.2 44 40.2
Crude death rate per 1000 population 7.3 7.2 7.1 7.2
Source: Population projections for India and states 2001–2026, revised December 2006, Office of the Registrar
General and Census Commissioner India
The data show that by year 2026, the Indian population will be 1,399 million people as a result of decline in crude
birth rate and infant mortality rate. The mean age of survival will be in the range of 69.8 years for males and 72.3
years for females
. Figure 56-1
India – 2001: Population pyramid
. Figure 56-2
India – 2026: Projected population pyramid. By the year 2026, the shape of the population
pyramid will change on account of decline in infant mortality and survival of subjects in younger
age groups. Increase in life expectancy of the elderly people will be an additional factor (Source:
Population projections for India and states 2001–2026, revised December 2006, 2007.)
. Table 56-2
India (2005) prevalence and mortality estimates of noncommunicable and communicable
diseases
Diseases Total number of cases (million) Total number of deaths

Noncommunicable diseases
IHDa 29.8 2,989,000
Stroke 0.93
Diabetes 37.8 674,000
Cancer 2.4 826,000
Communicable diseases
Tuberculosis 8.5 370,000
HIV/AIDSb 5.2 Not available
Malaria 0.8 819
This table shows the prevalence and mortality estimates, for noncommunicable and communicable diseases, for
the year 2005, as burden of disease.
a
IHD: Ischemic heart disease (Source: Annual Report of the Ministry of Health and Family Welfare, Government of
India (2006–2007), 2007)
b
HIV/AIDS: Human immunodeficiency virus/Acquired immunodeficiency syndrome
India is an emerging economy. With rapid urbanization and industrialization the population
is now exposed to modifiable stroke risk factors like, high blood pressure, diabetes mellitus,
obesity, etc. Consumption of high energy foods with poor dietary fiber and micronutrients will
predispose to nutritional and infectious diseases. In addition, rising tobacco consumption has
aggravated the situation (> Table 56-2) (Anand et al., 2007; Ministry of Health and Family
Welfare, Government of India. Annual Report, 2007; Reddy et al., 2006). These three transi-
tions – demographic, lifestyle, and socioeconomic – have been implicated in the emergence of
chronic noncommunicable and lifestyle-related diseases (Anand et al., 2007; Indian economy
overview, 2008).
The notion that stroke and chronic diseases are primary problems of wealthy nations is not
true (> Table 56-3) (Lopez et al., 2006). For the year 2005, 87% of deaths from stroke at all
ages were in low and middle income countries, and this rose to 94% for deaths under the age
of 70 years; and in contrast, the high income countries contributed only 13% of stroke deaths
for all ages (Strong et al., 2007). Updated projections of global mortality and burden of disease
(DALYs lost), for 2002–2030 indicate rising trend for chronic diseases like ischemic heart
disease (IHD), stroke, cancer, and HIV (Mathers and Loncar, 2006). To address these ‘‘grand
challenges,’’ the international agencies like World Health Organization (WHO), Oxford
Health Alliance (OxHA) have defined goals and suggested interventions (Berndtson et al.,
2007; Darr et al., 2007).
1.2 The Stroke (CVD) Epidemic – India and Developing Countries
The Global Burden of Disease (GBD) Study reported 9.4 million deaths in India, of which 619,
000 were from ‘‘Stroke,’’ and the DALYs almost accounted to 28.5 million; nearly six times
higher than that due to Malaria (Murray and Lopez, 1997). For India, the World Health
Organization projects DALYs lost from stroke as a part of global burden at 2.67% for the year
2010, and 3.37% for the year 2020 (World Health Organization, 1996). Thus stroke (CVD)
epidemic is emerging in most developing nations including India (Editorial, 2007; Feigin,
2005; Feigin et al., 2003). The available information on stroke epidemiology from selected
developed and developing nations is summarized in > Table 56-4. It shows that annual
> incidence of ‘‘first ever stroke’’ (FES) and its subtypes and > case fatality rates are broadly
similar between nations. Furthermore, WHO has stressed the rising ‘‘burden and cost of
chronic diseases in low and middle income countries’’ and emphasized the importance of
intervention and prevention of chronic and lifestyle-related diseases (Abegunde et al., 2007;
Strong et al., 2007).
. Table 56-3
Regional differences in burden of cardiovascular diseases in low/middle and high income
countries (2001)
Disease Low and middle income countries High income countries

Deaths (millions) DALYs (millions of years) Deaths (millions) DALYs (millions of years)
IHD 5.70 71.88 1.36 12.39
Stroke 4.61 62.67 0.78 9.35
Source: Lopez et al. (2006)
The table illustrates that burden of disease (IHD and Stroke) is significantly high in low and middle income
countries as compared to its occurrence in high income countries
996
56
. Table 56-4
Stroke incidence in population-based studies (1986–2006) in selected developed and developing nations
Types of stroke by age-

Incidence for CT/MRI sex groups, as
Data Age Total strokes per Hospital or determined by
collection Duration Population range FES 100,000 (95% admission autopsy CT/MRI autopsy findings
Burden of Stroke: Indian Perspective
Study area (years) (years) (Tn) (years) (Tn) CI) rate (%) rate and other findings Source
Asia Pacific Countries
Oyabe, 1987–1991 4 32,859 25 701 410 (380–440) 41 – 28-day case fatality rates Morikawa Y
Japan for men 14.2% and et al., Stroke
women 19.1% 2000; 31
(7):1583–7
China Jiang 1991–2000 10 15, 05,176a 35 – 135 (126–144) – 81.7 ICVD (43.7–78.9%), ICH Ming L et al,
(18.8–47.6%) SAH (0– Lancet Neurol
1.4%) Unsp (1.4–7.8%) 2007; 6:456–464
Auckland, 1991–1992 1 9, 45,369 15 1305 140 (130–150) 73 41 28-day case fatality for Feigin (2003)
New men-21.9% and women
Zealand 25.8%
Melbourne, 1996–1997 1 1, 33,816 All 276 210 (180–230)b – 91 ICVD (72.5%), ICH (14.5%) Feigin (2003)
Australia SAH (4.3%), Unsp (8.7%)
Asia: India
Mumbai 2005–2006 2 1, 56,861 25 456 152 (132–172)b 67.2 89.2 ICVD (80.2%), ICH (14.6%) Current report
SAH (3%), Unsp (1.9%)
Kolkata 2003–2005 2 52,377 All 247 145 (120–174) – 51.4 30-day case fatality was Das SK et al.
41.08% Stroke 2007;
38:906–910
Other developing countries
Martinique, 1998–1999 1 3, 60,000 All 580 160 (150–180)b 94 93 ICVD (79.8%), ICH (14.3%) ERMANCIA,
French SAH (3.4%), Unsp (2.4%) Smadja (2001)
West Indies —
Chile 2000–2002 2 3, 96,712 All 292 140 (124–156)c 71 91 28-day case fatality was Lavados (2005)
(PISCIS 23.3%
Study)
Brazil 2003–2004 1 75,053 All 81 137 (112–166) – – ICVD (85.2%), ICH (13.6%) Minelli (2007)
SAH (1.2%), 30-day case
fatality was 18.5%
a
Person years
b
Age standardized incidence rates by direct method with Segi (1996 World population). Source: Feign V, Lawes CMM, Bennett DA et al. (2003). Lancet Neurol.; 2:43–53
c
Age standardized Segi rate (European population)
56
997
2 Stroke Epidemiology in India
2.1 Stroke Prevalence Studies in India
Magnitude of the Problem: In published literature there are reports on prospective and
retrospective surveys for ‘‘hemiplegia’’ presumed to be CVD. The > prevalence rates (or
estimates) for ‘‘completed strokes’’ for North India (Kashmir) being 143/100,000 persons;
for West India (Mumbai) at 245/100,000; for South India (Vellore) it has been 64/100,000, and
for East India (Assam) it was 270/100,000. The average range being 90–220/100,000 persons
(Dalal, 1997). Above reports do not take into account Transient ischemic attacks (TIAs) and
sudden deaths nor confirmation of diagnosis by computerized tomography (CT) imaging
tests. Because of methodological limitations and nonuniform definitions as well as regional
variations it is difficult to compare the above studies (Dalal et al., 2007; Editorial, 2007).
Recent prospective neuroepidemiological surveys in Bangalore (rural and urban) report a
point prevalence rate at 136–165/100,000 (Gourie-Devi et al., 2004) and similar prospective study
from rural West Bengal reported point prevalence rate of 168/100,000 with age specific rate for
41–60 years in the range of 540–850/100,000 persons (Saha et al., 2003). Thus, the prevalence of
hemiplegia presumed to be stroke is rising with advancing age. To get the real estimate of
prevalence rate for recent strokes (CVD) in India, one will have to initiate multicentric prospec-
tive surveys using uniform definitions and methodologies with validation of diagnosis. This will
give valid information on interregional differences, and in planning intervention strategies.
As ‘‘Global Stroke Initiative (GSI),’’ WHO recommends use of STEPwise Stroke Surveil-
lance Instrument on representative samples of regional populations (Bonita et al., 2004;
Truelsen et al., 2007). The purpose of surveillance is to (1) assess the magnitude of stroke,
(2) describe population at risk, (3) identify associated risk factors, (4) monitor trends over
time, (5) implement intervention strategies, and (6) evaluate the outcome of intervention. It
will also give estimates of mortality and disability expressed as DALYs lost. For complete
registration of stroke events in the community, one will have to register hospitalized and
nonhospitalized events both fatal and nonfatal. The basic aim will be to develop an ‘‘ideal’’
stroke registry to provide health workers and policy makers with reliable baseline information
to plan cost-effective health-care and prevention strategies.
2.2 Incidence of Stroke and Clinical Profile
At present uniform and comparable data on stroke incidence from India and other developing
nations are meager. For example, population-based Vellore (India) stroke study (1969–1971)
quotes an annual incidence of 13/100,000 persons and the WHO Rohtak (India) study
(1971–1974) quotes an annual incidence of 33/100,000 population for all ages and 356/
100,000 population for those above the age of 70 years (Abraham et al., 1970; Aho et al.,
1980). To plan intervention and prevention strategies, well-designed prospective population-
based stroke surveys using standardized terminologies and methodologies (e.g., STEPS stroke)
(Truelsen et al., 2007) for interregional comparisons are essential. Objectives of such studies
would be to estimate annual incidence of ‘‘first ever stroke,’’ assess clinical profile, risk
factors, and 28 days morbidity and mortality status as shown in > Table 56-4. Prospective
population-based Mumbai stroke registry using STEPS stroke protocol is an example (Dalal
et al., 2007; Editorial, 2007).
2.3 Clinical Profile in Mumbai Stroke Registry
During the 2-year study period (Jan, 2005–Dec, 2006), 521 cases with new stroke cases were
identified: here, 456 patients had ‘‘first ever stroke’’ (males-238 and females-218) and 65 had
history of previous stroke. As shown in > Figure 56-3 and > Table 56-5, the annual incidence
rate for ‘‘first ever stroke’’ (FES) being 145 per 100,000 persons, CI 95%: 120–170 (Segi rate
152/100,000/year CI 95% 132–172) (Ahmad et al., 2000). The mean age was 66 years,
SD13.60; women were older (68.9 years) compared to men (63.4 years). 306 of 456
(67.2%) FES cases were seen at health care (‘‘inhospital’’) facility(Step I) and remaining 150
(32.8%) of 456 FES were treated at home or nursing homes (Step II and Step III). Clinical
diagnosis on new stroke event was supported by CT (Computed Tomography) data in 407
(89.2%) of 456 cases. By diagnostic tests, 366(81%) had ischemic CVD, 81(17%) had hemor-
rhagic CVD and 9(2%) were of unspecified type. There was no significant gender difference
with regard to neurological deficit on admission, timing of first scan, stroke subtype, alive, or
dead status by day 28.
In Mumbai registry, the age standardized annual incidence rate for FES has been
152/100,000; (95% CI 132–172 Segi method) (Ahmad et al., 2000) and this is not significantly
different from that reported from China (Liu et al., 2007), Martinique (ERMANCIA
study) (Smadja et al., 2001) and Chile (PISCIS study) (Lavados et al., 2005) and Brazil (Minelli
et al., 2007). On analysis of proportional frequency of stroke types in selected population
(10 studies) around the world, Feigin et al. (2003) reported that ischemic strokes were
present to the tune of 67.3–80.5%, whereas primary intracerebral hemorrhage was respon-
sible for 6.5–19.6% of cases, subarachnoid hemorrhage accounted for 0.8–7.0% and
2.0–14.5% were undefined type. In the Mumbai Stroke Registry (2005–2006), 81% had
ischemic strokes, 17% had hemorrhagic strokes, and 2% were unspecified type (Dalal et al.,
2007). These findings are not significantly different from those reported from the
above studies.
2.4 Stroke Risk Factors (RF)
Hospital based case-control studies using standardized methodologies have shown that (1)
hypertension (>160/90 mmHg), (2) high blood sugar, (3) tobacco use, and (4) low normal
hemoglobin were significant RF for stroke (Dalal, 2004; Dalal et al., 1989; Sridharan, 1992).
Another hospital-based prospective multicentric ICASS study (Indian Collaborative Acute
Stroke Study), using standardized WHO STEPS stroke protocol on unselected 2,162 cases of
acute stroke (less than 72 h) identified hypertension alone in 40%, hypertension with diabetes
in 25%, and hypertension with other risk factors (raised cholesterol, ischemic heart disease)
accounted for another 20% as shown in > Figure 56-4. (Dalal, 2006) Recent population-based
Mumbai stroke survey also identified hypertension alone or associated with diabetes, ischemic
heart disease as major risk factor (RF). Complete data for risk factor analysis were available in
427 (93.6%) cases: hypertension alone (Blood pressure (BP) more than 140/90 mm Hg) and in
various combinations was present in 378 (88.5%) cases. Thus community screening surveys to
identify subjects having hypertension and stroke prone symptoms and their management may
prove rewarding but, mass screening surveys may not be feasible, practical, or cost-effective
(Editorial, 2007).
1000
. Figure 56-3
56
Annual Incidence of ‘‘First ever stroke’’/100,000 and Population distribution (%) by age groups. This figure illustrates rising annual incidence of ‘‘first ever
stroke’’ with advancing age, with reference to surveyed population
. Table 56-5
Annual incidence of ‘‘first ever stroke’’ per 100,000 by age groups and sex in survey population.
Overall age standardized annual incidence rate is 152/100,000 persons (by Segi method) (Ahmad
et al., 2000)
Age groups 25–34 35–44 45–54 55–64 65–74 75–84 85–94+ Total
Total Population 47,298 38,245 29,806 20,232 14,401 5,593 1,286 1,56,861
Total FES cases 6 26 55 96 140 92 41 456
Cases/100,000/yr 6.3 33.9 92.2 237.2 486 822.4 1594 145
a
95% CI 2–13 23–47 72–110 210–270 440–530 770–880 1520–1670 120–170
a
CI: confidence interval Annual incidence rate (Segi) (Ahmad et al., 2000): 152/100,000 persons; CI 95% 132–172
. Figure 56-4
Indian Collaborative Acute Stroke Study (ICASS): Associated ‘‘risk factors’’ in 1559 acute
stroke cases (Dalal, 2006). The figure illustrates distribution of risk factors by
percentage, in 1559 acute stroke cases. HT, hypertension, DM, Diabetes mellitus, IHD, ischemic
heart disease; n = number of cases (Reproduced by kind permission of Blackwell Publishers.)
2.5 Mortality Estimates
The 28-day case-fatality rate in 13 selected studies has ranged from 17 to 33%, average being
22.9% (Feigin et al., 2003). In the Mumbai Stroke Registry (2005–2006), the overall case-fatality
rate for FES was 29.8% (136 cases) but the stroke-related case-fatality rate was 17.9% (82 cases),
and deaths unrelated to stroke were 11.8% (54 cases). The latter were related to concurrent
comorbid conditions like congestive cardiac failure, respiratory infections, septicemia, etc.
For the year 2005, age standardized death rates (age 30–69 years) from stroke varied from
180(Russia) to 20(UK) per 100,000 persons; whereas it was in the range of 100 per 100,000
persons for developing countries like India, China, and Brazil (Strong et al., 2007). However,
for comparing burden of disease among developing nations, case-specific and cause-specific
morbidity and mortality data based on uniform terminologies and methodologies are not
available (Feigin et al., 2003). This is not always possible because of (1) incomplete death
certification, (2) incorrect death classification, (3) etiology of sudden deaths, and (4) estimates
based on ‘‘verbal autopsy’’ which are difficult to interpret (Anand et al., 2001; Reddy and
Yusuf, 1998). To collect comparable, standardized information among regions on stroke
epidemiology, WHO recommends establishing surveillance systems through use of standar-
dized tool (STEPS Stroke method) (Truelsen et al., 2007) Such surveillance should be
implemented in phased manner- core, expanded, or optional depending upon available
resources and community support (Bonita and Beaglehole, 2007).
2.6 India: Quality of Life (QOL) After Stroke
In the population based Mumbai stroke registry there is reliable information on degree of
neurological deficit at onset (hospital or community) and outcome status by > Barthel Index
(handicap status) at 28 days (Sulter et al., 1999). It shows that patients with mild neurological
deficit National Institute of Health Stroke Scale (NIHSS score less than 5) (Goldstein and
Samsa, 1997) survived with slight disability, whereas in subjects with moderate to severe
neurological deficit (NIHSS score 6–15 and >15) the disability required assistance in activities
of daily life. > Table 56-6 illustrates above findings.
Similar observations have been made in hospital-based ICASS (Indian Collaborative Acute
Stroke Study) (Dalal, 2006) at tertiary university medical centers having organized ‘‘stroke
units.’’ In this study uniform methodology (STEPS stroke protocol) was used for data
. Table 56-6
Mumbai stroke registry (2005–2006): Severity of neurological deficit on admission (NIHSS score)
and disability status at 28 days (Barthel Index) (Goldstein and Samsa, 1997; Sulter et al., 1999)
NIHSS score Barthel Index at 28 days (number of cases) Total cases

On admission Death <50 51–75 76–100 Missing
0–5 3 7 29 89 3 131
6–15 15 50 53 29 2 149
16–42 48 17 3 0 2 70
No data 67 8 11 13 4 103
Death 3 0 0 0 0 3
Total cases 136(29.8%) 82(18%) 96(21%) 131(28.8%) 11(2.4%) 456
Table illustrates severity of neurological deficit on admission by NIHSS score and outcome status by Barthel Index
at 28 days, in 456 ‘‘first ever stroke’’ cases. Barthel index is a scoring technique that measures patient’s perfor-
mance in 10 activities of daily life and it is considered a reliable disability scale for stroke patients. For clinical
evaluation: 76–100 points denote ‘‘good function’’; 51–75 points denote ‘‘moderate disability,’’ and score under 50
denotes ‘‘severe disability.’’ 0 score represents totally dependant bedridden state
collection, evaluation, management, and analysis. Here again, subjects with mild neurological
deficit had better outcome (82%), whereas those with moderate to severe neurological deficit
on admission had poor outcome (63%).
From the above findings it is evident that timely medical evaluation and treatment is of
prime importance. However, in implementation of these objectives there are difficulties: (1)
lack of public awareness, (2) poor telecommunication facilities, (3) lack of organized ambu-
lance services, (4) poor transportation facilities and traffic snarls, (5) nonavailability of acute
care beds, (6) nonfunctioning diagnostic facilities (e.g., CT scanning), (7) prohibitive cost of
medications (thrombolytics like Tissue plasminogen activator(t-PA)), and (8) lack of medical
insurance coverage or free medical care facilities for the poor. For example, diagnostic CT
evaluation, specific treatment (e.g., anticoagulant drugs, etc.), and 7-day intensive care will
cost to the tune of Indian Rupees (INR) Rs. 10,000 (US$ 250), excluding the cost of t-PA. It is
worth noting that there are hardly 1,000 trained neurologists predominantly practicing in
metropolitan areas, in a country with more than 1 billion people; emergency stroke treatment
in semi-urban areas is usually given by general medical practitioners. Specialized evaluation
and medical care (stroke unit neuroimaging, and t-PA therapy) as available at tertiary
hospitals is beyond the reach of acute stroke patient in rural and semi-urban areas thereby
increasing the burden of disease from poststroke disability (Dalal, 2006).
Thus, community awareness and early reference for speedy diagnosis and treatment of
stroke and concurrent comorbid conditions are of vital importance to reduce the burden of
disease and DALYs lost (Bhattacharjee and Hastak, 2007) In stroke prevention, the importance
of health education, awareness on warning symptoms, physical exercise, and dietary habits,
modification of lifestyle and early detection and control of modifiable RF like hypertension,
diabetes, tobacco use, etc. need emphasis to improve quality of life.
Summary Points
It is advisable that stroke prevention strategies (primary and secondary) should get
priority in National Health Programes (Editorial, 2007).
‘‘WHO pocket guidelines for assessment and management of cardiovascular risk’’ outlines
some of the measures on primary and secondary prevention (Prevention of cardiovascular
disease pocket guidelines for assessment and management of cardiovascular risk, 2007)
The ‘‘action plan’’ as proposed by WHO on an integrated programe for prevention
and control of diabetes mellitus, cardiovascular disease, and stroke needs to be implemen-
ted. The value of ‘‘> poly-pill’’ in stroke prevention requires evaluation (Bonita and
Beaglehole, 2007). Whether this can be successfully implemented in developing countries
like India needs to be assessed in National Rural Health Mission (NRHM) (Editorial, 2008;
National Rural Health Mission, 2008).
The role of health education by community social worker, comprehensive stroke care training
programs for medical practitioners, and reference to secondary and tertiary medical centers
for specialized care, and vocational rehabilitation at home and in community will have to be
collectively addressed to reduce the burden of stroke.
Appendix
National Institute of Health Stroke Scale (NIHSS) (Goldstein and Samsa, 1997)
No. Category Response (Score)

1A Consciousness Alert (0)/Arousable (1)/Obtunded (2)/Unresponsive (3)
1B Answers to questions Answers correctly: Both (0)/One (1)/Neither (2)
1C Commands Both correctly (0)/One correctly (1)/Neither (2)
2. Gaze Normal (0)/Partial palsy (1)/Total palsy (2)
3. Visual fields No loss (0)/Partial hemianopsia (1)/Complete (2)/Bilateral (3)
4. Facial palsy None (0)/Minor (1)/Partial (2)/Complete (3)
5. Motor arm No drift (0)/Drift <10 s (1)/Falls <10 s (2)
a. left, b. right No effort against gravity (3)/No movement (4)
6. Motor leg No drift (0)/Drift <10 s (1)/Falls <10 s (2)
a. left, b. right No effort against gravity (3)/No movement (4)
7. Ataxia None (0)/One limb (1)/Two limbs (2)
8. Sensory Normal (0)/Mild loss (1)/Severe loss (2)
9. Language Normal (0)/Mild (1)/Severe (2)/Mute or global aphasia (3)
10. Dysarthria None (0)/Mild (1)/Severe (2)
11. Extinction None (0)/Mild (1)/Severe (2)
Total NIHSS Score – (0–42)
Source: Goldstein LB, Samsa GP. Stroke.1997; 28(2):307–310
NIHSS is a scoring technique defines degree of neurological deficit ranging from none (0), mild (1) or severe (2–4)
for eleven categories of neurologic functions. For practical purpose score of 0–5 indicates mild deficit, 6–15
denotes moderate deficit and score of more than 15 is suggestive of severe neurologic deficit
Barthel Index (Sulter et al., 1999)
No. Category Response/Score

1. Feeding Independent-10/Needs help-5/Inferior-0
2. Bathing Independent-5/Inferior-0
3. Personal toilet Washes face, combs hair, brushes teeth, shaves-5/Inferior-0
4. Dressing Independent-10/Needs help-5/Inferior-0
5. Bowel control Able to use enema, no help-10/needs help-5/Inferior-0
6. Bladder control (Use No accidents-10/Occasional accidents-5/Inferior-0
of device)
7. Toilet transfers Independent-10/Needs help-5/Inferior-0
8. Chair/Bed Transfers Independent-15/Minimum assistance-10/Able to sit, needs
maximum assistance-5/Inferior-0
9. Ambulation Independent for 50 yards-15/With help 50 yards-10/Independent

with wheelchair-5/Inferior-0
10. Stair climbing Independent-10/Needs help-5/Inferior-0
Source: Sulter G, Steen C, Keyser JD (1999). Stroke. 30: 1538–1541
Barthel Index is a scoring technique that measures patient’s performance in ten activities of daily life and it is
considered a reliable disability scale for stroke patients. For clinical evaluation: 76–100 points denote ‘‘good
function’’; 51–75 points denote ‘‘moderate disability’’ and score under 50 denotes ‘‘severe disability.’’ 0 score
represents totally dependant bedridden state
Modified Rankin Scale (Sulter et al., 1999)
Category Score
No symptoms at all 0
No significant disability despite symptoms 1
Slight disability 2
Moderate disability, but able to walk without assistance 3
Moderate disability, but unable to walk without assistance 4
Severe disability 5
Source: Sulter G, Steen C, Keyser JD (1999). Stroke. 30:1538–1541
Modified Rankin Scale measures independence rather than performance of specific tasks. Scale consists of six
grades from 0 to 5; 0 denotes no symptoms and 5 indicates severe disability. For clinical purpose, mild disability
range is from 0 to 2; moderate disability ranges from 3 to 4 and 5 indicates severe disability
References
Abegunde DO, Mathers CD, Adam T, Ortegon M, Dalal PM. (1997). J. Assoc. Physician India. 45: 125–131.
Strong K. (2007). Lancet. 370: 1929–1938. Dalal PM. (2004). J. Assoc. Physicians India. 52: 695–696.
Abraham J, Rao PSS, Imbraj SG, Shetty G. (1970). Stroke. Dalal PM. (2006). Int. J. Stroke. 1: 164–166.
1: 477–481. Dalal P, Bhattacharjee M, Vairale J, Bhat P. (2007). Ann.
Ahmad OB, Pinto CB, Lopez AD, Murray CJL, Lozano R, Indian Acad. Neurol. 10: 130–136.
Inoue M. (2000). GPE Discussion Paper Series(31). Dalal P, Bhattacharjee M, Vairale J, Bhat P. (2007).
EIP/GPE/EBD World Health Organization. Neuroepidemiology. 28: 121–134.
Aho K, Harmsen P, Hatano S, Marquardsen J, Dalal PM, Dalal KP, Rao SV, Parikh BR. (1989). Strokesin
Smirnov VE, Strasser T. (1980). Bull. World Health West-Central India: A Prospective Case-Control Study
Organ. 58: 113–130. of ‘Risk Factors’ (a problem of developing countries).
Anand K, Chowdhury D, Singh KB, Pandav CS, Kapoor In: Bartko D, Gerstenbrand F, Turcani P (ed.)
SK. (2001). Neuroepidemiology. 20: 208–211. Neurology in Europe. Publishers John Libbey &
Anand K, Shah B, Yadav K, Singh R, Mathur P, Eldho P, Co. Ltd., London, pp. 16–20.
Kapoor SK. (2007). NMJI. 20: 115–120. Darr AS, Singer PA, Persad DL, Pramming SK, Matthews
Berndtson K, Daid T, Shawn TC, Bhan A, Cohen ERM, DR, Beaglehole R, Bernstein A, Borysiewicz LK,
Upshur REG, Singh JA, Darr AS, Lavery JV, Singer Colagiuri S, Ganguly N, Glass RL, Finegood DT,
PA. (2007). PLoS Medicine. 4: 1445–1450. Koplan J, Nabel EG, Sarna G, Sarrafzadegan N,
Bhattacharjee M, Hastak SM. (2007). J. Assoc. Physicians Smith R, Yach D, Bell J. (2007). Nature. 450:
India. 55: 874–875. 494–496.
Bonita R, Beaglehole R. (2007). Stroke. 38: 2871–2872. Editorial. (2007). J. Assoc. Physicians India. 55: 689–691.
Bonita R, Mendis S, Truelsen T, Bogousslavsky J, Toole J, Editorial. (2007). Lancet. 369: 247.
Yatsu F. (2004). Lancet Neurol. 3: 391–393. Editorial. (2008). Lancet. 7: 1.
Feigin VL. (2005). Lancet. 365: 2160–2161. able at: http://www.who.int/cardiovascular_di-

Feigin VL. (2007). Lancet Neurol. 6: 94–97. seases/resources/publications/en/index.html.
Feigin VL, Lawes CMM, Bennett DA, Andersen CS. Reddy KS, Prabhakaran D, Chaturvedi V, Jeemon P,
(2003). Lancet Neurol. 2: 43–53. Thankappan KR, Ramakrishnan L, Mohan BVM,
Goldstein LB, Samsa GP. (1997). Stroke. 28: 307–310. Pandav CS, Ahmed FU, Joshi PP, Meera R, Amin
Gourie-Devi M, Gururaj G, Satishchandra P, Subbak- RB, Ahuja RC, Das MS, Jaison TM. (2006). Bull.
rishna DK. (2004). Neuroepidemiolgy. 23: 261–268. World Health Organ. 84: 461–469.
Indian Economy Overview. Available at: www.economy- Reddy KS, Shah B, Varghese C, Ramadoss A. (2005).
watch.com/indianeconomy/indian-economy-over- Lancet. 366: 1744–1749.
view.html. Accessed 10th March, 2008. Reddy KS, Yusuf S. (1998). Circulation. 97: 596–601.
Lavados PM, Sacks C, Prina L, Escobar A, Tossi C, Saha SP, Bhattacharya S, Das SK, Maity B, Roy T, Raut
Araya F, Feuerhake W, Galvez M, Salinas R, DK. (2003). J Assoc Physicians India. 101: 299–304.
Alvarez G. (2005). Lancet. 365: 2206–2215. Smadja D, Cabre P, May F, Fanon JL, Rene-Corail P,
Liu M, Wu B, Wang W, Lee LM, Zhang SH, Kong LZ. Riocreux C, Charpentier JC, Fournerie P, Saint-Vil
(2007). Lancet Neurol. 6: 456–464. M, Ketterle J ERMANCIA Study Group. (2001).
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray Stroke. 32: 2741–2747.
CJL. (2006) Lancet. 367: 1747–1757. Sridharan R (1992). Neuroepidemiology. 11: 24–30.
Mathers CD, Loncar DP. (2006). PLoS Medicine. Strong K, Mathers C, Bonita R. (2007). Lancet Neurol.
3: 2011–2030. 6: 182–187.
Minelli C, Fen LF, Denise P, Minelli C. (2007). Stroke. Sulter G, Steen C, Keyser JD. (1999). Stroke. 30:
38: 2906–2911. 1538–1541.
Ministry of Health and Family Welfare, Government Truelsen T, Heuschman PU, Bonita R, Arjundas G,
of India. Annual Report. (2006–2007). Chapter 12, Dalal P, Damasceno A, Nagraja D, Ogunniyi A,
22–27. Available at: http://mohfw.nic.in/annualrep/ Oveisgharan S, Radhakrishnan K, Skvortsoya VI,
contents.pdf. Accessed 24th Nov, 2007. Stakhovskaya V. (2007). Lancet Neurol. 2: 134–139.
Murray CJL, Lopez AD. (1997). Lancet. 349: 1269–1276. World Health Organization. (1996). The Global Burden
National Rural Health Mission. Available at: www. of Disease: A Comprehensive Assessment of Mortal-
mohfw.nic.in/NRHM.html. Accessed 4th April, 2008. ity and Disability from Diseases, Injuries, and Risk
Population Projections for India and States 2001–2026, Factors in 1990 and Projected to 2020. Harvard
Revised December 2006, Office of the Registrar Gen- University, Cambridge, MA.
eral and Census Commissioner India. Available at: World Health Organization Global Report. (2005).
http://www.censusindia.net. Accessed 18th Nov, 2007. Geneva. Available at: http://www.who.int/chp/
Prevention of Cardiovascular Disease Pocket Guidelines chronic_disease_report/en/. Accessed 6th Mar,
for Assessment and Management of Cardiovascular 2008.
Risk. (2007). Accessed 25th September, 2007. Avail-
57 Disability-Adjusted Life
Years, Years of Life Lived with
Disability, and Years of Life
Lost in Stroke: Italian
Perspectives
S. Mariotti
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
1.1 Impact of Stroke on Mortality and Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
1.2 Definition of Stroke and Types of Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
2 Mortality Due to Cerebrovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009

2.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
2.2 Problems in Estimating Stroke Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
2.3 YLLs Due to Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
3 Methods for Calculating the Burden of Stroke and Data Sources . . . . . . . . . . . . . . . 1011
3.1 Population Studies of Stroke Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
3.2 National BOD Stroke Models: Australian BOD, US BOD . . . . . . . . . . . . . . . . . . . . . . . . . 1011
3.3 The Italian Model for the Burden of Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
3.4 Data Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014
4 Estimates of the Quantities Needed for Obtaining the YLD . . . . . . . . . . . . . . . . . . . . . 1015

4.1 Incidence Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
4.2 28-day Case Fatality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017
4.3 Relative Risk of Mortality of Stroke Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017
4.4 Health Status Post-Stroke and Disability Weights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019
4.5 Disability Duration and Age at Onset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1020
5 Estimates of YLD for Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
6 YLD, DALYs and YLD/DALY Ratios: International Comparisons . . . . . . . . . . . . . . . 1021
7 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1024
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026

1008 57 Disability-Adjusted Life Years, Years of Life Lived with Disability, and Years of Life Lost in Stroke
Abstract: This chapter evaluates the impact of > stroke in Italy in 1999, expressed in terms of
disability adjusted life years (> DALYs) using mostly the methods developed by WHO in the
Global Burden of Disease (GBD) Study. For mortality, the official mortality data for Italy from
ISTAT (Italian National Statistical Institute) was used. For disability, the data on first-ever
stroke incidence (FES), remission rate and case fatality derived from the health information
system and a research on post-FES disability of the Friuli Venezia-Giulia (FVG) region and
similar data from the Tuscany region and from the province of Verona in the Veneto region
were used and pooled.
Both the mortality and disability aspects of the impact of stroke are taken into account and
> YLLs (years of life lost) and > YLDs (years of life lived with disability) respectively are
calculated and then summed to obtain the DALYs. To calculate the YLDs, several epidemio-
logical quantities are estimated by sex and age class and for each of the three areas considered
in the study. A mean of the pooled data was used to extrapolate the results to the whole Italy.
About 258,000 YLLs and 153,000 YLDs due to FES were estimated in 1999 for Italy. The
results in terms of YLLs, YLDs and DALYs were compared with other studies for which
detailed results were available, relative to populations with similar characteristics of develop-
ment: YLD rates per 100,000 people were similar in Italy to the values obtained in the US BOD
study both for men (228 vs. 244) and women (308 vs. 301), but values considerably lower were
obtained in the Australian BOD study (175 for men and 118 for women). In terms of DALYs
rates per 100,000 people, Italy (723) is more similar to the EURO-A group (the European area
including Italy) of the GBD study (671) than to the US (569) or Australia (435), because YLLs
in Italy are higher than in those other areas.
List of Abbreviations: BOD, Burden of Disease; DALY(s), Disability Adjusted Life Years;
GBD, Global Burden of Disease; EURO-A, (a group of 26 economically developed European
countries); FES, First-Ever Stroke; MONICA, MONItoring of trends and determinants
in CArdiovascular disease; ICD, International Classification of Diseases; ISTAT, Italian
National Statistical Institute; TIA, Transient Ischemic Attack; WHO, World Health Organiza-
tion; FVG, Friuli Venezia-Giulia; YLD(s), Years of life Lived with Disability; YLL(s), Years of
Life Lost
1 Introduction
1.1 Impact of Stroke on Mortality and Disability
The importance of cerebrovascular disease as a cause of mortality and disability is well defined
by the following facts:
According to an unpublished paper available on the WHO web site, yielding an updated
estimate of the global burden of cerebrovascular disease (Truelsen et al., 2003): ‘‘In 2001 it
was estimated that cerebrovascular diseases (stroke) accounted for 5.5 million deaths world-
wide, equivalent to 9.6% of all deaths. Two-thirds of these deaths occurred in people living in
developing countries and 40% of the subjects were aged less than 70 years. Additionally,
cerebrovascular disease is the leading cause of disability in adults and each year millions of
stroke survivors has to adapt to a life with restrictions in activities of daily living as a
consequence of cerebrovascular disease. . .’’
Disability-Adjusted Life Years, Years of Life Lived with Disability, and Years of Life Lost in Stroke 57 1009
Cerebrovascular disease, as reported in the most recent update of the GBD study (Lopez
et al., 2006), is the second single cause of healthy life lost as a result of a specific disease or
injury (6.3% of the total DALYs), and also the second cause of death (9.9% of all deaths) in
the high-income countries.
In the EURO-A region (a group of 26 European countries), as defined in the 2000 update of the
GBD Study (Murray et al., 2001), in which Italy is included along with most other European
Union (extended) countries, cerebrovascular disease is the second leading cause of mortality
and contributes with 5.17% to the total burden of disease (BOD) computed in terms of
DALYs. Considering the disability component (YLDs-years of life lived with disability) of
DALYs by itself, stroke takes the sixth position with 3.14% of the total YLDs component.
In Italy, stroke is the second leading cause of mortality, both in terms of number of deaths,
and in terms of YLLs (years of life lost) (Francescutti et al., 2005).
1.2 Definition of Stroke and Types of Stroke
According to the World Health Organization (WHO), the definition of stroke is: ‘‘rapidly
developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms
lasting 24 h or longer or leading to death, with no apparent cause other than of vascular origin’’.
The pathological origin for stroke may either be ischemic or hemorrhagic disturbances of
the cerebral blood circulation. A review of several studies in western white populations found
that approximately 80% of all strokes are ischemic, 10-15% intracerebral hemorrhage, 5%
subarachnoid hemorrhage, and the rest is due to other causes (Sudlow and Warlow, 1997).
2 Mortality Due to Cerebrovascular Disease
2.1 Definition
Cerebrovascular disease is a general term encompassing different disturbances of the vascu-

larisation of the brain. In the International Classification of Diseases (ICD) 9th and 10th
revision, cerebrovascular diseases are referred to with the codes 430–438 and I60–I69.
By applying the definition, only a subgroup of cerebrovascular diseases is stroke: transient
ischemic attack (TIA), which is defined to last less than 24 h, and stroke symptoms caused
by tumors, poisoning or trauma are excluded. The vast majority of deaths attributed to
cerebrovascular diseases are due to stroke.
2.2 Problems in Estimating Stroke Mortality
There are several problems in estimating the quantities needed to calculate the impact of
stroke even in European high-income countries like Italy, both for what concerns mortality
and for disability, although these problems are less severe than those encountered in the
estimates relative to the developing world.
For what concerns the estimate of deaths due to stroke from routinely collected mortality
data, a brief review of several validation studies is presented in the previously mentioned
WHO Report on Burden of Cerebrovascular Diseases (Truelsen et al., 2003). The main
conclusion of this review is that ad hoc studies for the validation of routine mortality data
on stroke showed that this source of information is of varying quality.
According to a study from the Northern Sweden MONICA population (Stegmayr and
Asplund, 1992), official mortality statistics based on death certificates with cerebrovascular
disease (ICD codes 430–438) give a reasonably good estimate of fatal stroke cases in Sweden,
but the study included only stroke patients aged 25–74 years, and therefore the age groups
with the highest rate of stroke events were not included. The authors estimated that 91.7% of
980 true stroke deaths were correctly coded.
In the POL-MONICA Warsaw Project only 206 (63%) out of 326 registered stroke deaths
were registered as stroke in the Central Statistical Office (CSO) (Szczesniewska et al., 1990),
and use of routine statistics alone would have provided a total of 213 stroke deaths. The
completeness of the MONICA registers with respect to the CSO data was 78%, and
the completeness of the CSO data with respect to the MONICA registers was 88%.
In another study belonging to the MONICA Project and relative to 16 European and
2 Asian populations (Thorvaldsen et al., 1995) it is remarked that in several of the examined
populations the stroke mortality rate calculated from official routine statistics was higher than
that measured by the stroke registers. This was attributed in part to more deaths being
attributed to cerebrovascular disease (stroke or late sequela of stroke) after the 28th day of
stroke onset or to an excess number of cases that for other reasons did not fulfill MONICA
criteria for stroke. Among most MONICA populations, however, there was very good agree-
ment between mortality rates by official statistics versus the stroke registers. The conclusion
was that official mortality statistics may be used in most cases for comparisons of international
populations in which validation has been undertaken.
However, in almost all studies here mentioned the proportion of false negative diagnoses
increases significantly with increasing age, both for men and women. In general, the quality of
routine mortality data is likely to vary between and within populations and it seems likely that
the validity decreases with increasing age.
2.3 YLLs Due to Stroke
Using official mortality data from ISTAT (Italian National Statistical Institute) the mortality
component was measured by the years of life lost (YLLs) defined by the formula: S dx ex*, where
dx is the number of deaths at age x and ex* is the expectation of life at age x based on some ideal
standards. The mathematically-derived model life-table referred to as ‘‘Coale and Demeny
West level 26’’ was used as a standard for the GBD Study (Murray and Lopez, 1996) and was
also adopted for this study. In this table, life expectancy at birth is 82.5 years for females and
80 years for males. The GBD study used the YLL formula, with the additional possibility of
adding age-weighting and discounting. Age-weighting is a computational method that can be
conceptualised as the differential degree of importance placed by society on saving lives at
different ages, whereas the use of discounting (in our study, the discount rate was set equal to
3%, as in the GBD Study) is necessary to compare and combine events that occurs in different
moments (now and in the future).
YLLs estimates in Italy in 1998 for more than one hundreds conditions evaluated in the
first phase of the Italian Burden of Disease project, have been reported previously (Mariotti
et al., 2003). The estimates for stroke reported here use the same methods, referring to official
mortality data for 1999.
Special attention has been paid to problems of misattribution or miscoding of causes of
death in cardiovascular diseases, and general ill-defined categories. A correction algorithm for
reclassifying ill-defined cardiovascular codes has been developed and applied.
Overall 258,425 years of life were lost in 1999 to stroke mortality (120,386 in men and
138,039 in women), using a discount of 0.03 and using for the results age-weighting. These
values are similar to those previously reported for 1998 (126,523 for males and 146,273 for
females). If age-weighting is discarded but still the same discount rate is used the numbers
obtained are 209,548 for males and 274,952 for females for a total of 484,500 years. If
discounting is also not used in the calculations, YLL turns out as 254,978 for men and
325,650 for women, for a total of 580,628 YLLs.
3 Methods for Calculating the Burden of Stroke and Data

Sources
3.1 Population Studies of Stroke Epidemiology
The estimation of the burden of stroke should ideally be based on data from real study
populations providing data on stroke incidence, prevalence, mortality, morbidity, and disabil-
ity. In 1987, Malmgren et al. published an important paper in stroke epidemiology defining
the criteria for designing and analyzing stroke incidence studies (Malmgren et al., 1987). A key
issue was to include both hospitalized and non-hospitalized events, as well as fatal and non-
fatal events. Stroke registries meeting all the ‘‘ideal’’ criteria are expensive and require a well-
defined population where it is possible to identify and follow-up all stroke patients. The most
important effort in establishing such registries was the already mentioned WHO MONICA
Project (MONItoring trends and determinants in CArdiovascular disease) initiated in the
early 1980s, but unfortunately in this project there is complete registration only for subjects
aged 35–64 years thereby excluding the age groups where the majority of strokes occur. A list of
studies providing ‘‘good’’ stroke data is provided in > Table 57-2 of a previously mentioned
reference (Truelsen et al., 2003).
3.2 National BOD Stroke Models: Australian BOD, US BOD
The Australian Burden of Disease study for 1996 (Mathers et al., 1999) used a model to
estimate the burden of stroke, based on incident cases of first-ever stroke (FES). After a FES,
people can die within 28 days, or they can recover completely or they can survive this period
with a permanent disability. Incidence of first ever stroke is derived from public and private
hospital data for Australia in 1996 on hospitalized cases of stroke (ICD-9 codes 430–434,
436–437 in principal diagnosis field). Admission data are based on counting people rather
than admission episodes and exclude people who died during the hospital episode. Incidence
and duration estimates were derived from the numbers of hospitalized stroke patients using
the > DISMOD II program (a modeling software developed by WHO and made freely available
on the WHO international site: http://www.who.int/whosis/database/burden/burden_dismod/

dismod2_setup.zip), and modeling assumptions drawn from a community stroke study in
Perth and a study of Perth and Auckland population-based stroke registers. Based on
national hospital inpatient data for Australia in 1996, admissions for stroke were adjusted
to account for stroke managed outside hospitals.
The US Burden of Disease study, recently completed (Michaud et al., 2006), has used a
very similar model of stroke. For estimating hospitalized stroke in the US, they adopted the
approach described by Williams (Williams, 1999) in which first-ever and recurrent stroke
hospitalizations are identified by ICD-9 codes 430–438 in any diagnosis field. Williams argues
against stroke ascertainment from hospital discharge data using other strategies (i.e., restrict-
ing to codes 430–436 only in the primary position) because improvements in the rate of false
positives achieved using these strategies come at the expense of complete ascertainment.
Adjustments were also made to account for multiple admissions for the same event. There is
conflicting evidence in the USA on the proportion of total stroke events that fail to present to
hospital (Sacco et al., 1998; McGovern et al., 1993). The Northern Manhattan Stroke Study
(Sacco et al., 1998) suggests about 5% and the Rochester study (Brown et al., 1996) suggests a
figure of about 15%. In the absence of further information, in the US BOD Study a flat 10%
for non-fatal strokes below 75 years and 15% above 75 years were assumed, and for fatal
strokes, an exponential increase with age.
Since the GBD 1990 was completed, more stroke studies have become available and they
have contributed to the development of a more sophisticated model for estimating the global
burden of stroke. This mathematical model is reported in the already mentioned WHO paper
on Burden of stroke (Truelsen et al., 2003).
3.3 The Italian Model for the Burden of Stroke
The model chosen to estimate the burden of stroke, based on incident cases of first-ever stroke
(FES), is analogous to the one used in the Australian BOD study (Mathers et al., 1999) and its
schematic diagram is shown in > Figure 57-1, while the definitions of the different stages are
given in > Table 57-1. FES cases are identified by the codes ICD-IX 430, 431, 432, 434, 436 in
the first diagnosis field. To isolate FES from recurring episodes, all subjects previously
admitted to hospital (in the period 1991–1999) with the same diagnostic codes but in any
of all four diagnosis fields were excluded.
> Table 57-1 shows the disability weights to be applied to the different post-FES stages, one
for full recovery and three others associated with different levels of daily activity limitations, as
defined by the Australian BOD study. The Australian BOD adopted for stroke the Dutch
disability weights (Melse et al., 2000; Stouthard et al., 1997).
The schematic diagram for estimating the epidemiology of stroke is shown in
> Figure 57-1. The assumptions of the model are explained hereafter. After a FES episode,
an individual can die within 28 days, and in this case he will experience a disability for the
corresponding period. After that he will not contribute anymore to the calculation of YLDs,
but his death will contribute to the calculation of YLLs. Alternatively, he can survive longer
and will almost always go through a rehabilitation procedure whose duration will depend
upon the judgment of the clinical team. At the end of this period, the patient can experience a
full recovery, or remain permanently disabled, in a state of mild, moderate, or severe disability.
. Figure 57-1
Schematic diagram for estimating the epidemiology of stroke
. Table 57-1
Stroke stages and disability weights – derived from the Australian BOD
Disability
Sequela/stage/severity level Health state description weights
First ever stroke with full After 1 year, no impairments or limitations in activities 0.000
recovery
First ever stroke with long- Permanent impairments and disability after 1 year. 0.360
term disability – mild Motor impairment resulting in some problems with
usual activities, some pain and discomfort, some
depression or anxiety. No problems in self-care or
cognition
First ever stroke with long- Permanent impairments and disability after 1 year. 0.630
term disability – moderate Cognitive or cognitive plus motor impairment
resulting in some problems with mobility, usual
activities, some pain and discomfort, some depression
or anxiety, and some problems in self-care
First ever stroke with long- Severe permanent impairments and disability after 0.920
term disability – severe 1 year. Severe cognitive problems, unable to perform
usual activities or self-care., Severe pain or discomfort.
Some problems in mobility and some depression or
anxiety
3.4 Data Sources
To derive stroke mortality, the ISTAT (Italian National Statistical Institute) 1999 mortality data
were used selecting the ICD-IX 430–438 codes.
To estimate the FES incidence rates, data from the highly reliable population-based health
information system (PBHIS) of Friuli Venezia-Giulia (FVG) a region located in North-East
Italy were used, and complemented with data from two other Italian regions: the whole
‘‘Toscana’’ (Tuscany), where a regional health information system is also present, and the
province of Verona in the Veneto region, although in these regions the PBHIS is not as complete
as the one in FVG. The PBHIS of FVG is a system intended to organize all data coming from
the health services daily activities and to design an individual profile regarding each access
to the health services by linking the various sources with a unique identification ‘‘key’’. The
information collection covers all the residents of the region. The information content therefore:
(a) is individually profiled; (b) involves various health institutions that generate the data;
(c) is longitudinal: i.e., each person’s health events are cumulated progressively.
The basis of a PBHIS is data collected routinely by health services, coming from hospitals,
nursing homes, ambulatory care and so on, and linked together to form a population register,
which covers all residents and all people using regional health services. Data pertinent to
hospital admissions, laboratory analyses, birth records, pharmaceutical prescriptions, outpa-
tient services, general mortality and child mortality, have been progressively added to the
population register.
Hospitals in Italy code diagnosis using the International Classification of Disease 9 (ICD-9)
and they code procedures using ICD-9 Clinical Modifications. The ICD-IX 430–434, 436–437
codes were selected from the 1999 hospital admissions database in the first diagnostic position.
Transient cerebral ischemia (ICD-IX 435) and later effects of cerebrovascular diseases (ICD-IX
438) were excluded from the analysis. Non hospitalized cases were also excluded from the
analysis. However, a detailed screening of regional databases ascertained that the cases of FES
treated outside hospitals were a negligible number, mainly consisting of a few fatal events
registered in hospital emergency departments. When the same person was admitted in 1999
more than once with ICD-IX stroke related codes, that person was computed only once. The
1999 cases selected according to this model were followed up for a year since the admission, to
ascertain their disability status, and then for another 4 years to monitor their vital status.
The 28-day case-fatality is commonly used to account for the short-time survival in stroke
patients. In the first weeks after stroke symptoms onset, death directly related to stroke is the
main cause of death. It was assumed that all deaths occurring within 28 days were due to
stroke. By means of available follow-up data, stroke ‘‘case-fatality’’ was estimated.
Our disease model required to evaluate the disability level of 28-day FES survivals. Because
of the lack of national data on the disability experience of 28-day FES survival, a longitudinal
study performed in FVG in the year 2000 was adopted as reference (Tesio, 2002). The study
aimed to evaluate post-stroke disability. All patients with FES admitted to regional hospitals
were monitored at every stage of care till the end of the rehabilitation process. At each stage,
from acute care to outpatient facilities, pre and post measures of disability were collected. For
this purpose, the functional independence measure (FIM) scale was used. The FIM scale was
developed in 1984 by the UB Department of Rehabilitation Medicine, copyrighted by Uniform
Data for Medical Rehabilitation UB Foundation Activities, and since then has been largely
adopted as a measure to characterize the level of adult disability (Keith et al., 1987; Linacre
et al., 1994).
4 Estimates of the Quantities Needed for Obtaining the YLD
To calculate the YLDs it is necessary to estimate a certain number of quantities for each stage of
the sequela that characterizes the condition in study, by sex and age class. Usually at least an
estimate of the incidence or prevalence of the condition is necessary. In the case of the incidence,
which is the method that we used, it is necessary to estimate along with incidence, some other
quantities: (1) Case fatality; (2) Relative Risk of mortality of stroke survivors; (3) Health status
post-stroke and Disability Weights; (4) Disability duration and mean age at onset of the disease.
4.1 Incidence Estimates
The incidence rates per thousand as a function of age, separately for males and females in the
two regions and one province where the study was conducted are shown in > Figure 57-2. The
graph shows that incidence trends are very similar, almost coincident both for males and
females in Toscana and FVG, except for the last age class.
An earlier review of available scientific literature (Marini et al., 2001) examined the
differences in incidence rates among comparable registries maintained in industrialized
. Figure 57-2
Incidence rates per 100,000 of first ever stroke by age in three Italian studies on stroke,
separately for males (M) and females (F)
countries. To extend the comparison to a deeper level, we compared age and sex specific
incidence rates standardised according to the European Standard Population in all studies in
the literature for which we could find FES cases distribution by age classes. > Figure 57-3
shows the result of this comparison. As shown in the graph, FES incidence rates found in the
literature range from 100 incidence cases per 100,000 inhabitants in Dijon (Giroud et al.,
. Figure 57-3
Age-standardized FES incidence rates in several stroke incidence studies as reported in the
literature. Columns with a diagonal pattern are relative to previous Italian studies, and columns
in dark (red for on-line version) report estimated FES incidences in the three regions of our study.
All others columns are non-Italian studies
1989) to a maximum of 192 cases in Valle D’Aosta region (D’Alessandro et al., 1992) and in the
Oxfordshire (Dennis et al., 1993). FVG and Toscana results (118 and 121 per 100,000
respectively) are similar and are lower than previous Italian studies (columns with a diagonal
pattern in the graph), and the data of the province of Verona are even slightly lower (107 per
100,000).
Although the differences in FES incidence rates found are by no means negligible, a deeper
examination of the available literature reveals differences in the methodology used for
collecting data, which could partially account for this difference. A review of several interna-
tional studies of stroke incidence underlined the intrinsic sensitivity of the results to the data
collection method, and found that out of 65 studies only 9 met a set of standard criteria
sufficiently well to be considered comparable (Malmgren et al., 1987). The method used in the
FVG region seems superior to all others. The PBHIS was searched back 10 years to be sure that
each reported case of stroke was actually a FES, and this sort of cleaning procedure was
rarely used in other studies. Every possible effort to insure completeness of data was also
implemented in Toscana and Verona. Extrapolation of FVG, Toscana and Verona data to the
rest of Italy is based on the assumption that observed differences in incidence are mostly due to
the data collection method.
We took a weighted mean of the incidence rates per 100,000 estimates for the three regions
as representative estimate for the rate of the whole Italy.
The data on stroke incidence in relation to age are confirmed by the results of the ILSA
Study (Italian Longitudinal Study on Aging), a follow-up study on several local population
samples aged 65–84 extracted from anagraphic lists (Di Carlo et al., 2003a). When we
complemented the ILSA study with other studies covering younger age classes, and extra-
polated these data to the whole population living in the areas covered by the ILSA study,
comparable results for the incidence rates of FES were obtained.
In > Figure 57-4, the estimated FES incidence rates per 100,000 for Italy for males and
females are compared to those reported in the Australian BOD Study (1999 – data refer to
1996) and in the US BOD Study, which refers to data of the year 1996, although it was
completed in 2006. For the US BOD we chose to show data relative to white male and females
rather than to the whole US population, to eliminate possible racial effects on FES incidence.
4.2 28-day Case Fatality
The 28-day case-fatality is a common parameter for the short-time survival in stroke patients.
In the first weeks after stroke symptoms onset, death directly related to the stroke is the main
cause of death. Total case fatality in the three areas of the study is reported in > Table 57-2.
In > Figure 57-5 28-day case fatality as a function of age in the age classes with a significant
number of cases is reported.
The 28-day case fatality in the FVG region (22%), in Tuscany (16.3%) and in Verona (20.8%)
all lie in the middle of the range reported in previous studies, which showed values between 13%
(Dijon) and 33% (Belluno, (Lauria et al., 1995)); 28-day case fatality in the other Italian
studies was 25.6, 23.7, 21, and 20% respectively for L’Aquila (Carolei et al., 1997), Vibo Valentia
(Di Carlo et al., 2003b), Umbria (Ricci et al., 1991) and Valle d’Aosta (D’Alessandro et al., 2000).
Due to the small variability shown by the three regions, the mean of the three values was
assumed to be representative of the case fatality for Italy.
The 28-day case fatality is needed to evaluate the YLDs associated with 28-day FES
survivors and the YLDs of FES patients who died in the first 28 days, according to the disease
model previously described. For those who died in the first 28 days, the disability duration was
set equal to age- and sex-specific average hospital length of stay, and a disability weight of
0.920 (severe) was used.
4.3 Relative Risk of Mortality of Stroke Survivors
The relative risk of death in stroke survivors and case fatality in stroke survivors are two
measures that are closely related and depend on the number of stroke survivors that die each
year. In the Australian Burden of Disease the long-term mortality in 28-day stroke survivors
was estimated on the basis of the Perth Community study (Anderson et al., 1994). This study
found that only 58% of deaths in stroke patients were attributed to stroke. In the US BOD
study, duration in stroke survivors was calculated using the program DISMOD II (WHO site),
. Figure 57-4
Estimated FES incidence rates per 100,000, as a function of age class, for Italy, for the Australian
BOD Study (1996) and the US BOD Study, separately for males (M) and females (F)
. Table 57-2
28-day case fatality rates (%) in three Italian areas, separately for males (M) and females (F),
together with total (T)
Case fatality comparison Verona (Veneto) Friuli VG Toscana

F M T F M T F M T
Total 19.8 21.9 20.8 24.5 19.0 22.0 17.4 15.1 16.3
based on data on incidence, prevalence (extracted from the National Health Interview Survey)
and an assumption of zero remission. The overall proportion of estimated stroke-attributable
deaths to coded stroke deaths was lower than the estimates assumed by the Australian BOD.
. Figure 57-5
Case fatality rates (%) as function of age (only in the age classes with a significant number of
cases) in three Italian areas, separately for males (M) and females (F)
In addition to the case-fatality in stroke survivors the DISMOD calculations also provided
estimates on the relative risk of death in stroke survivors.
In our study, we were able to follow all stroke registered patients as admitted to local
hospital for a four-year period, registering all deaths (whether they were stroke-related or not),
and by means of a classic mortality table we were therefore able to derive directly the relative
risks of stroke patients in relation to the healthy population.
The relative risks of the stroke patients in a four-year follow-up are reported in > Table 57-3.
There is considerable uncertainty on the estimates in the younger age groups since few events
are occurring in these groups, and therefore the values were not shown in the Table.
The relative risks decrease by increasing age, which reflects the fact that the difference in
risk of death between stroke survivors and the general population decreases when the
underlying death intensity increases. We used the mean values of these relative risks as
long-term relative risks for stroke patients compared to the Italian population, although
there might be an overestimate, since in the long run the mortality for surviving stroke
patients might be more and more similar to the one of the general population, and in the
end run all people must die whether they had or not a stroke.
4.4 Health Status Post-Stroke and Disability Weights
There are serious problems in evaluating precisely the health status of people after a stroke, as
pointed out in a study on disability: ‘‘.. the vast literature on impairment, disability and
handicap indicates the problems of developing a simple, easy, reliable and valid measure for
. Table 57-3
Relative risks of stroke patients in comparison with the general population (risk = 1) in a
four-year follow-up as a function of age, separately for males (M) and females (F), together
with total (T)
ASL Verona Friuli VG Toscana

M F T M F T M F T
<55 14.3 51.4 24.5 15.1 7.8 15.2 15.5 15.9 17.0
55–64 1.5 1.7 1.7 3.4 3.7 4.0 3.5 5.3 4.3
65–74 1.9 4.7 2.8 2.5 3.2 2.8 1.8 3.2 2.3
75–84 1.7 2.3 1.9 2.0 2.2 2.0 1.4 1.8 1.5
measuring the outcome of a disease like stroke which can have a wide spectrum of residual
disability not covered in a simple measure of dependence on another person for daily
activities..’’ (Orgogozo, 1994).
The FVG FIM study, a longitudinal study performed in FVG in the year 2000 aimed at
evaluating post-stroke disability estimated that 45% of 28-day FES survivors experienced a full
recovery in a variable period. A clinician judgement of complete recovery or no more expected
benefits in disability reduction (i.e., permanent disability) defined the ending point of the
rehabilitation process. The duration of the rehabilitation period varied accordingly with the
severity of post-stroke disability, ranging from two weeks to several months. The median
rehabilitation duration for patients with mild or severe disability was three months.
A higher percentage of women (28%) than males (14%) experienced a severe long-term
disability. Males were also more likely to recover completely from a stroke than females (56%
against 37%). These figures are strikingly similar to those found by Bonita et al. in the
Auckland Stroke study (Bonita et al., 1997) and that were used by the Australian BOD study
as best guess for the unknown rate of recovery in their study. Similar percentages were found
in males and females for mild (19% vs. 22%) and moderate disability (11% vs. 13%).
To choose the values of the disability weights corresponding to measures which are
difficult to undertake is not an easy task and while aware that an expanded knowledge on
measurement of disability is needed, we decided to use the weights of the Netherlands Study
(Stouthard et al., 1997).
It is known that recovery from stroke depends strongly on sex and age. For this reason we
decided to follow the Australian approach, in which a sex- and age-weighted average of the
Dutch weights was calculated in the case of long-term disability (mild, moderate or severe)
using the information on the distribution of disability classes. These weights were used for the
28-day survivors experiencing any form of long-term disability. As a consequence of this
approach, in the presence of some form of permanent disability, the disability weights were
differentiated by age and sex, in such a way that the worst (highest) disability weight (0.680)
was applied to women older than 75 years with any form of long-term disability, while the
lowest weight (0.428) was the one for women younger than 54 years.
4.5 Disability Duration and Age at Onset
In addition to the estimates of incidence, case fatality and distribution of long-term disability,
other relevant parameters for the final YLDs calculations are the average age of FES cases at FES
onset and the disability duration. > Table 57-4 shows the age at FES onset and the post-FES
disability duration, by age class and sex. The average age at FES onset for each age class shown in
the Table was obtained as an average, weighted by the number of expected events in each 1-year
group. When there was not enough number of cases, the central value of the age interval was
assumed to avoid data instability. To estimate the disability duration, we evaluated a stroke-specific
survival function. The disability duration was considered as a life expectancy conditioned by the
event of FES. Relative risks (RRs) measure the increased risk of dying in the 5-years post-FES
compared to the overall population. In the life table, we used the total relative risks shown in
> Table 57-3 for both males and females rather than separately, for reasons of stability of the
estimates.
The age at onset is usually near to the mid-point of the interval, but tends to be greater
than this value for old age, when the distribution of deaths in the class tends to be skewed as
the oldest people die significantly more often.
5 Estimates of YLD for Stroke
The formula adopted for the estimation of YLDs (not considering age weighting and time
preferences) was the following:
YLD ¼ I DW L
where: I is the number of incidence cases, DW is the disability weight (ranging from 0(=full
health) to1(=death)), and L is the disability duration (in years).
When age-weighting is used, as in our case, the calculated value depends also on the age at
the onset of the disease. For the full calculation formula, including age-weighting and dis-
counting refer to the National Burden of Disease Studies Practical Guide (Mathers et al., 2001).
The total YLDs value is obtained by the sum of the YLDs associated with 28-day deaths,
with full recovery and long-term disability in mild, moderate or severe state. Partial and total
values both with discounting and age-weighting and without are reported in > Table 57-5.
About 153 thousands YLDs (0.03, 1) (using discounting and age-weighting) due to FES were
estimated in 1999 for Italy. Without these methodological modifications, the number of YLDs
(0,0) is about 294 thousands, which points out the non negligible effect of these methodological
issues. The corresponding numbers of DALYs are 412 thousands and 874 thousands.
The total YLD for females is considerably bigger than for males both with (90,589 vs.
62,928) and without (186,989 vs. 106,635) discounting and age-weighting. Again comparing
men and women, the ratio F/M of the female burden of disability to the male burden is greater
than one in all rows except the second, since women tend to live longer but also due to the fact
that women tend to have worst disability conditions after a stroke, and this can be observed
from the smaller numbers in the category of survivors who recover completely, and bigger
numbers in the category of those that have permanent disability, since there are more women
than men in this category and there are more women in severe conditions.
6 YLD, DALYs and YLD/DALY Ratios: International

Comparisons
We compared our results with the figures obtained in the most important BOD studies
conducted in countries not dissimilar from Italy. > Table 57-6 shows the YLD rates per
1022
57
. Table 57-4
Mean age at FES onset and post-FES disability duration, by age class and sex, in three Italian areas
Friuli VG Toscana Verona

Males Females Males Females Males Females
Age at Age at Age at Age at Age at Age at
Age onset Duration onset Duration onset Duration onset Duration onset Duration onset Duration
0–4 2.5 46.2 2.5 59.3 2.5 44.8 2.5 58.8 2.5 39.1 2.5 53.4
5–14 10.0 40.3 10.0 53.5 10.0 39.0 10.0 53.1 10.0 33.8 10.0 48.2
15–24 20.0 32.2 20.0 44.6 20.0 31.1 20.0 44.3 20.0 26.4 20.0 39.9
25–34 30.0 26.2 30.0 36.3 30.0 25.3 30.0 36.3 30.0 21.6 30.0 32.4
35–44 40.0 20.2 40.0 28.7 40.0 19.6 40.0 29.0 40.0 16.9 40.0 25.8
45–54 50.2 16.0 50.0 23.3 50.3 16.1 50.0 24.2 50.9 15.2 48.5 22.8
55–64 60.1 13.3 60.1 18.9 60.0 14.4 59.9 20.7 59.9 15.0 60.3 20.2
65–74 69.9 8.6 70.4 12.5 69.7 10.2 70.1 14.6 69.9 8.8 70.3 12.7
75+ 80.5 4.8 81.7 6.8 80.5 6.1 81.5 8.7 80.3 5.0 81.2 7.1
Disability-Adjusted Life Years, Years of Life Lived with Disability, and Years of Life Lost in Stroke
. Table 57-5
Years of life lived with disability and rates per 100,000 persons, both with and without
discounting and age-weighting, separately for those who die within 28 days, for those that
survive and recover completely, and for those who survive with permanent disability, and total
YLD, separately for males(M) and females(F)
YLD (0,0)-without discount & AgeWt YLD (0.03,1)-with discount& AgeWt

Absolute Absolute
numbers Rates *100,000 numbers Rates *100,000
Ratio Ratio
M F M F F/M M F M F F/M
YLD for those 165 214 0.6 0.7 1.2 105 124 0.4 0.4 1.1
who die within
28 days
YLD for survivors 4,496 2,980 16.3 10.1 0.6 3,180 1,837 11.5 6.2 0.5
who recover
completely
YLD for those 101,974 183,795 370 625 1.7 59,643 88,628 216 301 1.4
who survive
28 days with
permanent
disability
Total YLD 106,635 186,989 387 636 1.6 62,928 90,589 228 308 1.4
. Table 57-6
Years of life lived with disability (rates per 100,000) for cerebrovascular diseases in Italy (1999),
Australia (1996), US (1996), and the Euro-A group of the Global Burden of Disease Study,
separately for males and females
YLD[3,1] *100,000 Males Females

Australia 1996 174.7 118.1
United States 1996 244.2 301.2
EURO-A 2000 197.4 209.2
Italy 1999 228.1 308.1
EURO-A (an area including Italy, covering Western Europe and some countries of the
East side) of the GBD study (2000). Those three were the studies for which more detailed
results were available and with populations of similar characteristics of development:
YLD rates per 100,000 people were similar in Italy to the values obtained in the US
BOD study both for men (228 vs. 244) and women (308 vs. 301), but values considerably
lower were obtained in the Australian BOD study (175 for men and 118 for women).
In > Table 57-7 the DALYs rates per 100,000 people and the YLD/DALY ratio estimated in
Italy are compared with the estimates of the Australian study, the US BOD Study and the
EURO-A group of the GBD Study for the year 2000.
The value of DALYs rates per 100,000 people in Italy (723) is more similar to the EURO-A
group (the European area including Italy) of the GBD study (671) than to the US (569) or
Australia (435), because YLLs in Italy are higher than in those other areas.
. Table 57-7
Disability adjusted life years (DALYs) estimates for cerebrovascular diseases and ratio YLD/DALY
in Italy (1999), Australia (1996), US (1996), and the Euro-A group of the Global Burden of Disease
Study (2000)
DALYs/Population (*100,000) YLD/DALY (%)

Australia 1996 435 34
United States 1996 569 48
EURO-A 2000 671 31
Italy 1999 723 37
The estimated proportion of the YLDs on total DALYs (37%) is comparable with that
obtained in the EURO-A group of the GBD 2000 Study (31%), and the Australian BOD Study
(34%), with the highest ratio being in the US.
7 Discussion
Considerable international effort led by WHO has been concentrated in the last few years into
the development of summary measures of population health that combine information on
mortality and non-fatal health outcomes. This study combines measures of mortality and
morbidity to calculate the impact of stroke in Italy in terms of DALYs.
Several limitations of the available data however must be taken into account before an
absolute value can be assigned to the estimates obtained.
For mortality data, there is some concern in the literature about a possible misclassification
of stroke death codes. While it is very likely that such a misclassification is unavoidable at old
age, and it is possible that not all stroke death are classified as such, the false negative and false
positive were found in some studies to counterbalance each other. Since no specific studies on
agreement between official statistics mortality data and more refined coding coming from
registries exists for Italian regions that could be representative of the whole country, and some
data from the Italian Monica Study show that these differences are negligible, we decided to
avoid applying specific corrections besides the reassignment of ill-defined codes.
In comparing different studies due account must be given to the year in which the study
was conducted or the year to which the data are referred to. Indeed a non negligible trend has
been observed for stroke incidence, with a general tendency for age-specific rates to decrease,
which is partly counterbalanced sometimes by the aging of the population.
The trend concerns not only incidence rates, but also mortality: it is known from stroke
mortality studies, based on routine mortality statistics, that there are constant changes in
stroke rates with decreasing stroke mortality rates in many Established Market Economies
countries (Sarti et al., 2000). There is conflicting evidence on whether changes in stroke
mortality rates are due to changes in incidence or case fatality. Results from the WHO
MONICA Project suggest that one-third is explained by changes in incidence while two-thirds
are due to changes in case fatality (Sarti et al., 2002).
WHO developed a mathematical model to be able to estimate some of the necessary
quantities, which are sometimes difficult to evaluate, from other quantities that can be
evaluated more easily, and made full use of the DISMOD model in the report on global
burden of cerebrovascular disease (Truelsen et al., 2003). While we also used DISMOD for
evaluation purposes, we found non necessary in the Italian context to use such instruments,
that although sometimes very useful are nonetheless limited because of their inherent statio-
narity hypothesis, and we felt that we could trust enough the data that we were able to derive
from our population registries.
Even in the most developed countries, it is very rare that all information necessary to
reliably assess the burden of morbidity is readily available for most conditions. In Italy a few
regions or provinces and notably the region of Friuli Venezia Giulia since many years built a
PBHIS to connect in principle all information relative to the health of its citizens. With
reference to stroke information, we could obtain reliable information also from the region
Tuscany and from the province of Verona, belonging to the Veneto region.
Using these databases, we obtained and compared estimates of several key quantities
necessary to estimate the years lived with disability, according to the methods developed for
the GBD study: incidence, case fatality, relative risk of mortality of stroke survivors, health
status post-stroke, and disability duration.
Extrapolation of FVG, Toscana and Verona data to the rest of Italy is based on the
assumption that observed differences in incidence are mostly due to the data collection
method.
The results of these extended comparisons allowed us to validate our stroke incidence
estimates, and we took a weighted mean of the incidence rates per 100,000 estimates for the
three regions as representative estimate for the rate of the whole Italy. Although the three areas
considered in our study were not including areas from the south of Italy, the results shown in
> Figure 57-3 for Vibo Valentia (Di Carlo et al., 2003b), the only study in the South of Italy,
makes us confident that the chosen incidence of FES stroke for Italy can be representative also
for the south regions.
The Italian ratio DALYs/population was pretty close to the value obtained for EURO-A,
whereas the Australian ratio was lower. The value for US was intermediate. However, attention
should be paid to the age structure of the four populations given that the Australian popula-
tion is younger than the Italian, US and European ones.
Although Italy has the highest DALY rates among the four studies presented in > Table 57-7,
this is mainly due to a highest YLL component (453 per 100,000 vs. 296 in the US and 289 in
Australia). We know that in the last years stroke mortality in Italy has declined considerably
and therefore in an updated estimate we would obtain values of YLLs more similar to the
other two countries, but we were obliged to use the disability data of 1999 (and conse-
quently corresponding mortality data) to be able to follow-up the stroke survivors al least
for four years.
The estimates seem generally coherent with those of previous national and international
studies. However, since the available disability data are not uniformly spread geographically
across Italy, it is possible that they do not depict exactly the overall Italian situation for stroke.
Summary Points
Stroke is one of the major killers in developed regions and one of the major causes of
disability. Hence the importance of studying in details this disease to understand whether
to concentrate on primary prevention or rehabilitation or both.
Data on disability are very difficult to obtain with completeness and reliability: only where
some sort of register is present we can hope to be able to get the data that we need.
Three regions of Italy: FVG, Tuscany and part of Veneto (Verona province) participated
actively to the data collection relative to all episodes of first-ever stroke in 1999 in their area.
Statistical methods similar to those used in the GBD study allowed us to obtain several
epidemiological quantities needed for the final estimate of the Years of life lived with
disability, such as stroke incidence and others.
In Italy women tend to recover less well from stroke than men, and tend to have a higher
amount of disability, also because they live longer.
The total YLD for females is considerably bigger than for males (90,589 vs. 62,928). The
YLD rates per 100,000 persons are much bigger for females than for males (308 vs. 228).
The previous point is confirmed also in the US BOD study and in the EURO-A group of
the GBD study, but not in Australia.
More than 258 thousands of years were estimated to be lost in Italy in 1999 for premature
mortality due to stroke, and 153,000 years of ‘‘good health’’ were lost due to mild,
moderate or severe disability.
The disability burden in Italy represents 37% of the total burden of disease for stroke.
Both previous results are coherent with other major studies of BOD.
Acknowledgements
This study was made possible by two grants from the Italian Ministry of Health. The author
acknowledges also the important contributions of ideas and work by Dr. Antonella Franzo,
Dr. Carlo Francescutti, Dr. Giorgio Simon and Dr. Rossella Di Bidino, co-authors together
with Dr. Sergio Mariotti of other papers treating similar subjects.
References
Anderson C, Jamrozik KF, Broadhurst RF, Stewart- Dennis MS, Burn JPS, Sandercock PAG, Bamford
Wynne EG. (1994). Stroke. 25(10): 1935–1944. JM, Wade DT, Warlow CP. (1993). Stroke. 24:
Bonita R, Solomon N, Broad JB. (1997). Stroke. 796–800.
28: 1898–1902. Di Carlo A, Baldereschi M, Gandolfo C, et al. (2003a).
Brown RD, Whisnant JP, Sicks JD, O’Fallon WM, Cerebrovasc Dis. 16: 141–150.
Wiebers DO. (1996). Stroke. 27: 373–380. Di Carlo A, Inzitari D, Galati F, et al. (2003b). Cerebro-
Carolei A, Marini C, Di Napoli M. (1997). Stroke. 28: vasc Dis. 16: 410–417.
2500–2505. Francescutti C, Mariotti S, Simon G, D’Errigo P, Di
D’Alessandro G, Di Giovanni M. (1992). Stroke. 23: Bidino R. (2005). Disability and Rehabilitation, 27
1712–1715. (5): 229–240.
D’Alessandro G, Bottacchi E, Di Giovanni M, Giroud M, Beuriat P, Vion P, D’Athis PH,
Martinazzo C, Sironi L, Lia C, et al. (2000). Neurol. Dusserre L, Dumas R. (1989). Neuroepidemiology.
Sci. 21: 13–18. 8: 97–104.
Keith RA, Granger C, Hamilton BB, Sherwin FS. (1987). Mortality and Disability from Diseases, Injuries,
Adv Clin Rehabil. 1: 6–18. and Risk Factors in 1990 and Projected to 2020.
Lauria G, Gentile M, Fassetta G, Casetta I, Agnoli F, Global Burden of Disease and Injury series vol. 1.
Andreotta G, et al. (1995). Stroke. 26: 1787–1793. Harvard University Press, Harvard.
Linacre JM, Heinemann AW, Wright BD, Granger CV, Orgogozo JM. (1994). Cerebrovasc Dis. (suppl 2)4: 2–6.
Hamilton BB. (1994). Arch Phys Med Rehabil 75: Ricci S, Celani MG, La Rosa F, et al. (1991). J Neurol
127–132. Neurosurg Psychiatry. 54: 695–698.
Lopez AD, Mathers CD, Majid Ezzati, Dean T, Jamison, Sacco RL, Boden-Albala B, Gan R, Chen X, Kargman DE,
Christopher J. Murray L. (eds.) (2006). Global Bur- Shea S, et al. (1998). Am J Epidemiol. (JID–
den of Disease and Risk Factors. Oxford University 7910653) 147: 259–268.
Press, New York. Sarti C, Rastenyte D, Cepaitis Z, Tuomilehto J. (2000).
Malmgren R, Warlow C, Bamford J, and Sandercock P. Stroke. 31: 1588–1601.
(1987). Lancet 2(8569): 1196–1200. Sarti C, Stegmayr B, Tolonen H, Mahonen M, Tuomi-
Marini C, Triggiani L, Cimini N, Ciancarelli I, lehto J, and for the WHO MONICA Project. (2002).
De Santis F, Russo T, Baldassarre M, di Orio F, Are Changes in Stroke Mortality Due to Changes in
Carolei A. (2001). Neuroepidemiology 20: 91–95. Stroke Attack Rates or Changes in Case Fatality?
Mariotti S, D’Errigo P, Mastroeni S, Freeman K. (2003). American Heart Association, TX.
Eur J Epidemiol. 18: 513–521. Stegmayr B, Asplund K. (1992). Neuroepidemiology 11:
Mathers C, Vos T, Stevenson C. (1999). The Burden of 204–213.
Disease and Injury in Australia. Australian Institute Stouthard M, Essink-Bot M, Bonsel G, Barendregt J,
of Health and Welfare (AIHW), Canberra. Also Kramers P. (1997). Disability weights for diseases
available on the worldwide web at www.aihw.gov.au in the Netherlands. Erasmus University. The
Mathers CD, Vos T, Lopez AD, et al. (ed.). (2001). Netherlands, Rotterdam.
National Burden of Disease Studies: a Practical Sudlow CLM, Warlow CP. (1997). Stroke 28: 491–499.
Guide. edn 2.0. Global Program on Evidence for Szczesniewska D, Kurjata P, Broda G, Polakowska M,
Health Policy. World Health Organization, Geneva. Kupsc W. (1990). Rev.Epidemiol.Sante Publique
McGovern PG, Pankow JS, Burke GL, Shahar E, Sprafka 38: 435–439.
JM, Folsom AR, Blackburn H. (1993). Stroke. 24: Tesio L. (2002). Progetto di sperimentazione gestionale
1640–1648. rete informativa sul percorso riabilitativo del
Melse JM, Essink-Bot ML, Kramers PG, Hoeymans N. paziente con ictus nella Regione Autonoma Friuli
(2000). Am J Public Health. 90: 1241–1247. Venezia Giulia, So. Ge. Com., Editrice Ricerca in
Michaud CM, McKenna MT, Begg S, et al. (2006). Popul Riabilitazione, Milano.
Health Metr. 4: 11. Thorvaldsen P, Asplund K, Kuulasmaa K, Rajakangas
Murray CJ, Lopez AD, Mathers CD, Stein C. (2001). AM, Schroll M. (1995). Stroke. 26(3): 361–367.
The Global Burden of Disease 2000 Project: Aims, Truelsen T, Begg S, Mathers C. (2003). The Global Bur-
Methods and Data Sources. WHO, Geneva (Global den of Cerebrovascular Disease. WHO.
Program on Evidence for Health Policy, Discussion Williams A. (1999). Practitioner. 243: 222–225.
Paper). WHO site-http://www.who.int/whosis/database/burden/
Murray CJ, Lopez AD (eds.). (1996). The Global Burden burden_dismod/dismod2_setup.zip.
of Disease: a Comprehensive Assessment of
58 Burden of Ischemic Stroke
and Benefits of Stroke Unit
Care and Thrombolytic
Therapy
A. Meretoja . M. Kaste . T. Tatlisumak
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1030
2 Burden of Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031

2.1 Epidemiology of Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031
2.2 Incidence of Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032
2.3 Prevalence of Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033
2.4 Survival after Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038
2.5 Stroke Recurrence after Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1041
2.6 Quality of Life after Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1042
2.7 Cost of Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1043
3 Thrombolytic Therapy for Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045

3.1 Effectiveness of Thrombolytic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045
3.2 Cost of Thrombolytic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1050
3.3 Cost-Effectiveness of Thrombolytic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1050
4 Stroke Unit Care for Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053

4.1 Effectiveness of Stroke Unit Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
4.2 Cost of Stroke Unit Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
4.3 Cost-Effectiveness of Stroke Unit Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1056
5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1056
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1057

1030 58 Burden of Ischemic Stroke and Benefits of Stroke Unit Care and Thrombolytic Therapy
Abstract: > Ischemic stroke is among the leading causes of mortality and disability responsi-
ble for over 5.5 million deaths worldwide. Many survivors must give up productive life and
require institutional care. Ischemic stroke is, therefore, an expensive disease, with a lifetime
direct cost of around 75,000 US dollars (50,000 euros, 40,000 UK pounds) per patient. Stroke
accounts for around 3% of all health care expenditure, that is, 0.3% of gross domestic
production, in an industrialized country.
Thrombolysis, when given to well-selected acute ischemic stroke patients within 3 hours of
symptom onset, and > stroke unit care for all stroke patients significantly improve outcome
and reduce burden of the disease. Widespread utilization of > thrombolytic therapy and
admission to stroke units could notably impact even national economies, and improve quality
of life of stroke victims and their careers. Thrombolytic therapy and stroke unit care are
currently underused and should be adopted in large scale for the benefit of all nations.
List of Abbreviations: ADL, activities of daily living; DRG, diagnosis related group; ER,
emergency room; ICU, intensive care unit; LACI, lacunar anterior circulation infarction;
mRS, modified rankin scale; NEMESIS, North East Melbourne stroke incidence study; NNT,
number needed to treat; NOMASS, Northern Manhattan stroke study; OCSP, Oxford com-
munity stroke project; OXVasc, Oxford vascular study; PACI, partial anterior circulation
infarction; POCI, posterior circulation infarction; QALY, quality adjusted life year; QOL,
quality of life; rt-PA, recombinant tissue-type plasminogen activator (alteplase); SU, stroke
unit; TACI, total anterior circulation infarction; TIA, > transient ischemic attack; TOAST, trial
of org 10172 in acute stroke treatment; WHO, World Health Organization
1 Introduction
Stroke is defined by the WHO as a clinical syndrome of rapid onset of focal cerebral deficit,
lasting more than 24 h or leading to death before that, with no apparent cause other than a
vascular one. It can be divided into ischemic, which represents 80% of all strokes, and
hemorrhagic, which can further be divided in to intra-cerebral (15%) and subarachnoid
(5%) hemorrhages. (Warlow et al., 2003).
Studying the economic dimensions and humane aspects of stroke is important. Stroke
incidence, prevalence, morbidity, and mortality are high, and it is a major cause of health care
costs with alarmingly increasing trends.
To assess the burden of stroke from a broad perspective, several parameters on how the
disease affects an individual, family, and society should be studied:
Incidence of stroke, time trends in the incidence, and issues affecting future expectations in
incidence, such as population aging and stroke risk factors
Stroke survival, which determines, together with incidence, the overall stroke prevalence
Disability due to prevalent stroke, which could be measured in a number of ways, quality of
life being the most universal
Direct costs due to stroke
Stroke-related loss of production for both patient and caregiver (indirect costs)
This article first presents the available data on these issues, namely incidence, survival,
quality of life, and costs due to ischemic stroke.
Burden of Ischemic Stroke and Benefits of Stroke Unit Care and Thrombolytic Therapy 58 1031
To reduce the burden of a disease one has to reduce either loss of lives, disability or loss of
quality of life, or the economic burden the disease causes, and preferably succeed in all of these
issues. Cost-effectiveness analysis takes each of these components into account. To assess cost-
effectiveness of a treatment in stroke one needs the following information:
Patient all cause mortality over time with and without treatment
Patient quality of life over time with and without treatment
Costs over time with and without treatment
Mortality, disability, quality of life, and cost of stroke vary strongly according to patient
age, sex, and stroke subtype. For primary prevention cost-effectiveness analysis, one also
needs information on the same variables in the population without stroke. Relevant cost-
effectiveness data on a condition that affects the total remaining life-time has to be calculated
over a long period of time, say 15–30 years. Long-term age, sex, and stroke subtype-specific
follow-up information on survival, disability, quality of life, and costs are scarce for stroke
patients in general and even less available for new treatments. Therefore, estimates and
modeling have to be used until > population-based exact figures become available.
The latter part of this article will present available cost-effectiveness information on
thrombolytic therapy and stroke unit care for acute ischemic stroke.
2 Burden of Stroke
2.1 Epidemiology of Stroke
A plethora of scattered data exists on stroke epidemiology, but the studies vary in methodolo-
gy and quality, which makes international and longitudinal comparisons difficult. To address
the problem, a set of so called ‘‘ideal’’ criteria for stroke epidemiological studies have been
suggested as presented in > Table 58-1 (Sudlow and Warlow, 1996). According to the criteria,
> hospital-based populations never represent the whole community, as a significant propor-
tion of patients are not admitted to a hospital. Stroke subtype- and risk factor profiles differ
between hospitalized and non-hospitalized patients (Schulz and Rothwell, 2003). A person
might not be hospitalized for several reasons: death before admission; no perceived advantage
due to old age; previous disability; too severe or too mild stroke; too remote or expensive
hospital; or no beds available for admitting. Recent population-based epidemiological stroke
studies report hospitalization rates ranging between 41% in Oyabe, Japan; and 95% in
Erlangen, Germany (Feigin et al., 2003).
Thus in order to evaluate the total burden of stroke to a society, one must include all
patients treated both in and outside hospitals. Hospital-based data is much easier and cheaper
to acquire, and often of higher quality. Population-based studies are necessary for constructing
the big picture on stroke in countries, such as the UK, where almost half of stroke patients are
still managed as outpatients (Rothwell et al., 2004), but less so for countries, such as Germany,
Italy, Finland, Scandinavia, and most regions of USA, where about 95% of all stroke patients
are admitted to hospitals.
Case ascertainment is another key issue in epidemiological studies, especially when
considering > stroke subtypes. Proportion of patients with imaging or autopsy has ranged
between 41% and 96% even in high-quality studies done in the 90s (Feigin et al., 2003).
. Table 58-1
Core criteria for a comparable study of stroke incidence (Sudlow and Warlow1996)
1. Standard definitions
2. World Health Organization definition
3. First-ever-in-a-lifetime stroke
4. Standard methods
5. Complete, community-based case ascertainment, based on multiple overlapping sources
6. Prospective study design, ideally with ‘‘hot pursuit’’ of cases
7. Large, well-defined, stable population
8. Reliable method for estimating denominator
9. Standard data presentation
10. Whole years of data
11. Not >5 years of data averaged together
12. Men and women presented separately
13. Include ages up to 85 years if possible
14. Standard mid-decade age bands (eg., 55 to 64 years) used in publications
15. Unpublished 5-year age bands available for comparison with other studies
16. Presentation of 95% confidence intervals around incidence rates
Epidemiological studies on stroke have previously been variable in methods, but are now more comparable with
common criteria.Reproduced with permission from: Sudlow CL, Warlow CP. Comparing stroke incidence world-
wide: what makes studies comparable? Stroke;27(3):550–8
The third key issue in epidemiology of stroke is in population demographics. Whereas

there is little difference in the outcome and costs of the two sexes, age does play a much larger
role. Survival of 45 and 85 year-old patients are very different, as is the incidence rate in these
two age groups. As there are large differences in the mean age of different populations around
the world, studies can only be generalized if age and sex are adjusted for. Stroke studies with an
upper age limit are therefore excluded from this paper.
2.2 Incidence of Ischemic Stroke
It has been estimated that there were 16 million > first-ever strokes in the year 2005 globally
and that this global annual incidence will rise to 23 million by the year 2030, the rise mainly
due to longer life expectancy and thus aging populations (Strong et al., 2007). Each year there
are more than 500,000 new ischemic stroke patients in the USA (Rosamond et al., 2008), and
slightly less than 1 million in Europe (Truelsen et al., 2006).
Average age of onset for stroke is 70 years for men and 75 years for women, with large
geographical variation due to age structures, but also risk factor profiles. Well-conducted
epidemiological studies report age-standardized annual total stroke incidence rates for people
aged over 55 years to be in the range of 0.4–1.2%, and for people over 85 years in the range of
1–4%. Age-matched men have in general a higher stroke incidence rate compared to women.
Population-based age-standardized stroke incidence rates have been declining, with a few
exceptions in the eastern European countries (Feigin et al., 2003; Thorvaldsen et al., 1997).
There are only few well-conducted large population-based studies in stroke incidence,
which fulfill the ‘‘ideal’’ criteria, all of which were conducted in developed countries. Among
the most referred to cohorts are the Framingham study and the WHO MONICA Studies
(which have an upper age limit of 65–75 and will not be discussed further in this article); the
Rochester study, and the Northern Manhattan Stroke Study (NOMASS) in the USA;
the Oxfordshire Community Stroke Project (OCSP), the South London Stroke Register,
and the Oxford Vascular Study (OXVasc) in the UK; and the Perth and North East Melbourne
(NEMESIS) Stroke Studies in Australia. Most stroke epidemiological studies report total
stroke, and do not give separate data on the ischemic subtype and hemorrhagic subtypes.
The proportion of patients with ischemic and hemorrhagic stroke varies in different popula-
tions and these subtypes have varying impacts on survival and morbidity, hemorrhagic stroke
being associated with poorer outcome.
Population-based studies, which report ischemic stroke incidence, are summarized in
> Table 58-2. Only few studies report incidence adjusted to an external population, which
makes them less comparable. The crude annual incidence rate for total population ranged
between 65 (Finland in the 70’s), and 232 (Norway in the 90’s) per 100,000 population. It must
be stated, though, that older studies conducted in the pre-CT era are less likely to be successful
in classifying stroke into correct subtypes.
2.3 Prevalence of Ischemic Stroke
Prevalence of stroke and particularly of ischemic stroke is not well-known. Just as with
incidence, in general, men have a higher age-adjusted total stroke prevalence rate (Truelsen
et al., 2006). Prevalence in the developing countries is much lower, likely due to lower
incidence in a younger population, and worse survival. Crude prevalence reports of
0.2–1.0% for South American countries (Saposnik and Del Brutto, 2003), 0.3% for rural
South Africa (Connor et al., 2004), 0.1% for urban Nigeria (Danesi et al., 2007), and 0.1%
for Calcutta, India (Banerjee et al., 2001) are available. Of European countries, only 7 have
recent scientific reports on prevalence of stroke, none differentiating between ischemic and
hemorrhagic subtypes. Most prevalence studies have only included the oldest fraction of
the population; usually those over 65 years of age; and thus international comparisons are
practical only in this group. Total stroke prevalence is about 5% (range 2–20%) in 65–69 year
old Europeans, and about 10% (range 7–16%) in those over 80 years of age (Truelsen et al.,
2006). For USA the total prevalence of stroke in the adult population is about 2.6%, affecting
5.8 million individuals (Rosamond et al., 2008). In the 55-year old USA population one in
seven men and one in six women will have an ischemic stroke during their lifetime (Seshadri
et al., 2006).
The percentage of stroke survivors in a population can be estimated in three ways:
Ask the population (surveying)
Ask the population, but check their answers against health care records
Estimate the prevalence from incidence and survival
Self-reported stroke is usually based on asking a person whether they have ever had a
stroke diagnosed by a physician. Self-reporting has been estimated 80% sensitive and 99%
specific for stroke and seems to overestimate true prevalence of stroke slightly (Engstad et al.,
2000). Self-reported stroke prevalence of 1.9% in over 35 year old Taiwanese (Lin et al., 2007);
1034
. Table 58-2
58
Population-based studies on ischemic stroke incidence
Reports
age- and
sex
specific
Age Crude Incidence 1 month 1 year CT, MRI incidence
range Incident incidence adjusted case case or rates for
(mean ischemic per to external fatality fatality Hospitalization autopsy ischemic
Study Years Population age) strokes 100,000 population rate (%) rate (%) rate (%) rate (%) stroke
Rochester, USA 1945– 42,000 All ( ) 1,691 115 – – 36 – CT 67% in No
(Garraway et al., 1983; 1979 1975–
Meissner et al., 1988) 1979,
autopsy
in 67%
Rochester, USA (Petty 1975– – All (75) 1,111 – – 24 27 82 80 No
et al., 1998) 1989 (22–26) (25–30)
Rochester, USA (Petty 1985– – All (75) 444 (454) – 147 (133– 17 29 80 92 (all No
et al., 1999; Vernino 1989 161) US stroke)
et al., 2003) population
Espoo-Kauniainen, 1972– 113,100 >15 (64 148 65 – 22 31 89 (all stroke) CT not No
Finland (Numminen 1973 for all available,
et al., 1996) incident autopsy
stroke) in 48% of
those
who died
Burden of Ischemic Stroke and Benefits of Stroke Unit Care and Thrombolytic Therapy
Espoo-Kauniainen, 1978– 136,850 >15 (65 188 69 – 25 35 95 (all stroke) CT 11%, No
Finland (Numminen 1980 for all autopsy
et al., 1996) incident in 51% of
stroke) those
who died
Shibata, Japan (Tanaka 1976– 75,168 >20 (–) 240 151 – – – – 42% Yes
et al., 1981) 1978
Oxfordshire, UK 1981– 105,000 545 130 10 (7–13) 23 41 93 No
(Bamford et al., 1990; 1986 (19–27)
Dennis et al., 1993)
4 rural districts, 1989– 134,804 >15 (71 469 174 – 19 31 86 (all stroke) CT 60%, No
Finland (Numminen 1991 for all autopsy
et al., 1996) incident in 11% of
stroke) those
who died
Perth, Australia 1989– 138,708 All (73 173 125 72 (World 12 26 80 (all stroke) 86 (all Yes
(Anderson et al., 1990 for all population) (21–31) stroke)
1993a; Jamrozik et al., incident
1999; Hardie et al., stroke)
2005; Anderson et al.,
1994; Anderson et al.,
1993b)
Perth, Australia 1995– 136,095 All (75 166 122 58 (World 15 – 88 (all stroke) 78 (all No
(Jamrozik et al., 1999; 1996 (Feigin for all population) stroke
Hardie et al., 2005) et al., 2003) incident

stroke)
Belluno, Italy (Lauria 1992– 211,389 All ( ) 319 150 (133– 110 26 – 93 (all incident 90 (all Yes
et al., 1995) 1993 168) (European stroke) incident
population) stroke)
58
1035
1036
58
Reports
age- and
sex
specific
Age Crude Incidence 1 month 1 year CT, MRI incidence
range Incident incidence adjusted case case or rates for
(mean ischemic per to external fatality fatality Hospitalization autopsy ischemic
Study Years Population age) strokes 100,000 population rate (%) rate (%) rate (%) rate (%) stroke
Cincinnati, USA (white 1993– 1,114,092 All ( ) 1,325 119 – 13 27 91 (all stroke) – Yes
population) (Kissela 1994
et al., 2004)
L’Aquila, Italy (Carolei 1994 297,838 All (75 657 221 – 21 32 92 (all incident 89 (all Yes
et al., 1997) for all (204–238) (18–24) (29–36) stroke) incident
incident stroke)
stroke)
Innherred, Norway 1994– 69,295 >15 (76, 322 232 – 11 – 86 (all stroke) 88 (all No
(Ellekjaer et al., 1997) 1996 77 for all (207–260) incident
incident stroke)
stroke)
Erlangen, Germany 1994– 101,450 All (73 278 137 – 12 (9–15) 30 95 (all incident 96 (all Yes
(Kolominsky-Rabas 1996 for all (124–151) (24–35) stroke) stroke)
et al., 1998) incident
stroke)
Melbourne, Australia 1996– 133,816 All ( ) 200 149 71 (55–88) 12 (7–16) 31 – 91 (all Yes
(Thrift et al., 2001; 1997 (129–170) (World (24–37) stroke)
Dewey et al., 2003a) population)
Martinique, French 1998– 360,000 All (71 463 129 – 16 – 94 (all incident 93 (all No
West Indies (Smadja 1999 for all stroke) incident
et al., 2001) incident stroke)
stroke)
Northern Manhattan, 1993 142,925 >20 (68 511 119 – – – 95 (all incident 99 (all No
USA (Sacco et al., 1998; – all stroke) incident
Hartmann et al., 2001; 1996 incident stroke)
Dhamoon et al., 2006) stroke)
South London, UK 1995– 234,533 All (71) 419 89 87 (76–96) – – 84 (all incident 88 (all No
(Stewart et al., 1999; 1996 (European stroke) incident
Hillen et al., 2003) population) stroke)
Oxfordshire, UK 2002– 91,106 All (74 385 141 – – – 56 (all incident 97 (all Yes
(Rothwell et al., 2005) 2005 for all (127–156) stroke) stroke)
incident
stroke)
Ischemic stroke incidence rate is highly dependent on population age, with the highest rates in the oldest populations. All values are mean with 95% confidence intervals where
available.
58
1037
and 2.6%–4.0% in non-institutionalized adult U.S. residents (Towfighi et al., 2007; Neyer
et al., 2007) have been published. Eighteen percent of U.S. population reported having had at
least once a symptom suitable with stroke or TIA (sudden painless weakness on one side of the
body, sudden numbness on one side of the body, sudden painless loss of vision in one or both
eyes, sudden hemifield visual loss, sudden inability to understand speech, or sudden inability
of linguistic expression) (Howard et al., 2006).
Some of the verified stroke prevalence studies have published prevalence rates of 0.8% in
Finland aged >20 with also some information on subtypes (Aho et al., 1986); 1.6% in Japan
when defined as stroke causing disability (Iso et al., 1998); 3.7% in Singapore residents over
50 years of age (Venketasubramanian et al., 2005); and 3–5% in >55 year olds in Rotterdam,
the Netherlands (Bots et al., 1996). The last study also compared self-reported and ascertained
stroke, and found about 25% overestimation if only self-reported numbers were used.
Estimated prevalence of 1.0% has been published for Auckland, New Zealand, with 0.2%
needing help in activities of daily living (ADL) (Bonita et al., 1997). Lacking sound studies for
most countries, the WHO gives country-, age-, and sex-specific estimates on stroke prevalence
based on multiple sources and models in the World Heath Report (Truelsen et al., 2006). It has
been estimated that there are 62 million stroke survivors in the world (Strong et al., 2007).
2.4 Survival after Ischemic Stroke
Stroke is the second leading cause of death globally, after ischemic heart disease, and accounts for
10% of all deaths in both industrialized and developing countries (Lopez et al., 2006). Stroke is
estimated to have caused a total of 5.7 million deaths in 2005 and the figure will rise to 7.8 million
by 2030. Practically all of the increase will be in low and middle income countries, mainly due to
ageing population (Strong et al., 2007). Age-adjusted stroke mortality rates are declining inter-
nationally, with the eastern European countries being the sad exception (Sarti et al., 2000).
Mortality is mainly monitored through official statistics of death certificates. Case fatality
due to stroke refers usually to death-rate from any cause within one month (usually 28 days,
but sometimes 30 days) of the stroke onset, and cannot be monitored through death
certificates, as the recorded underlying cause of death can be other than stroke. Case fatality
information is available for most incidence studies, and is 3–7 times higher for hemorrhagic
stroke than for ischemic stroke (Jamrozik et al., 1999; Kiyohara et al., 2003). Case fatality
varies also according to patient’s age, race, co-morbidities, and treatment (Wolfe et al., 2005).
Population-based ischemic stroke case-fatality, summarized in > Table 58-2, has been in the
range of 10–20% since 1980, with a couple of outliers.
Few community-based studies on 5 or more years survival after an ischemic stroke exist,
namely the Rochester and NOMASS studies in the USA, the Hisayama study in Japan, the
OCSP in the UK, and the Perth study in Australia. Only the Rochester, Hisayama, and Perth
studies report 10-year survival after an ischemic stroke. The studies report 1-year crude
survival in the range of 64–82%, 5-year survival in the range of 40–58%, and 10-year survival
in the range of 22–31%. Older studies and older patients showed lower survival, as can be
expected. The results of these studies are summarized in > Table 58-3.
For practical reasons it is useful to have a model for stroke patient survival beyond
collected data, that is beyond 10 years. For example, the OCSP report for ischemic stroke a
22% first year death rate and an average annual 9% death rate thereafter.
. Table 58-3
Population-based studies on long-term survival and recurrence after first-ever ischemic stroke
1 month
case
Mean fatality 1 year 2 year 5 year 10 year 1 year 2 year 5 year 10 year
Study Years Patients age rate mortality mortality mortality mortality recurrence recurrence recurrence recurrence
Rochester, US 1950– 1,546 – – 36 – 59 78 5.7 – 19.3 29
(Meissner et al., 1979
1988)
Rochester, US 1975– 1,111 75 13.9 27.2 35.6 52.9 73.6 12.0 17.9 29.2 39.3
(Petty et al., 1998) 1989 (11.8– (24.6– (32.7– (50.0– (70.4– (9.9–14.1) (15.4–20.5) (25.9–32.4) (34.9–43.8)
15.9) 29.8) 38.4) 55.9) 76.8)
Hisayama, Japan 1961– 298 74 (all 9.0 (5.4– ~30b ~40 b >60b ~75b 10.0 – 34.1 49.7
(Hata et al., 2005; 1993 stroke) 12.6) (6.3–13.8) (27.3–40.9) (41.4–57.9)
Kiyohara et al.,
2003)
Oxfordshire, UK 1981– 545 72 (all 10 22.1 30.6a 52.0a – – – 29.7 (19– –
(Dennis et al., 1993; 1985 stroke) (18.9– 40)
Burn et al., 1994) 26.9)
New York, US 1990– 980 70 5 18 30 42 – 7.7 15.0 18.3 –
(Hartmann et al., 1997 (3 years) (5.5–9.8) (12.0–18.0) (14.8–21.7)
2001; Dhamoon (3 years)

et al., 2006)
58
1039
1040
58
1 month
case
Mean fatality 1 year 2 year 5 year 10 year 1 year 2 year 5 year 10 year
Study Years Patients age rate mortality mortality mortality mortality recurrence recurrence recurrence recurrence
Perth, Australia 18 247 73 (all 12 26 (21– – – – ~10b ~12b ~20b –
(Anderson et al., months stroke) (8–16) 31)
1994; Hankey et al., in
1998) 1989–
1990
Perth, Australia 12 173 73 (all 9 (5–13) >20b ~30b >50b 69 – – – 28.0
(Hardie et al., 2003; months stroke) (55–83)
Hardie et al., 2004) in
1989–
1990
South London, UK 1995– 1,166 71 (all – – – – – 7.8 10.9 18.9 –
(Hillen et al., 2003) 2000 stroke) (6.2–9.9)
5 years from a first ischemic stroke up to a third of the patients have had a second stroke, and only half of all patients survive that long. All Survival and recurrence data are mean(%)
with 95% confidence intervals where available.
a
Calculated from reported 8.5% (6.1–10.5%) average annual risk for years 2–5
b
Estimated from Kaplan-Meier curve
When evaluating the impact of stroke on a person’s life-span, it is often desired to compare
the survival of stroke patients with survival of a matched population without a stroke, for
which so called life tables can be used. In the late 1980’s in Perth having any stroke attributed a
9-times increase in the relative risk of death during the first year after a stroke, and 2-times
thereafter, as compared to the general population of the same age and sex. The increase in
excess mortality was highest in the youngest age groups, up to 80-fold over ten years in
patients younger than 45 years of age (Hardie et al., 2003). In the Hisayama study the excess
relative risk of death after any stroke was 12 for the first year, 3 for years 2–5, and 1.6 for years
6–10 (Kiyohara et al., 2003). Neither the Perth nor the Hisayama study report excess mortality
due to ischemic stroke separately.
The Rochester study reports excess mortality due to an incident ischemic stroke, but only
as a Kaplan-Meier curve, which makes it hard to quantify this effect (Petty et al., 1998). In the
OCSP the excess mortality after any stroke as compared to age- and sex-matched general
population was 4-fold over the mean 4 years follow-up, and 40-fold in the patients younger
than 45 years of age. For ischemic stroke and all age groups combined, this excess mortality as
relative risk was 4.8 (95% CI, 4.2–5.7) in the first year, and 2.1 (95% CI, 1.8–2.5) over the next
5 years (Dennis et al., 1993).
Ischemic stroke can be classified in several ways, the most often used are the OCSP
classification for stroke size and location (TACI, PACI, LACI, POCI) (Bamford et al., 1991),
and the TOAST classification for stroke etiology (large-artery atherosclerosis, cardioembolism,
small-vessel occlusion, stroke of other determined etiology, and stroke of undetermined
etiology) (Adams et al., 1993). Risk of death and stroke recurrence is lower in patients with
lacunar ischemic stroke as compared to non-lacunar stroke in the first month after the stroke,
but the risks are similar thereafter (Jackson and Sudlow, 2005). Death rate after lacunar stroke
is 2.5% at 30 days, 2.8% at 1 year, and 27.4% at 5 years. In the long run also lacunar
stroke patients have a poor outcome, just like other stroke patients, and at 14 years after the
lacunar stroke, only 25% of patients survive (Norrving, 2003). The prognosis is much worse in
cardioembolic stroke (Vernino et al., 2003; de Jong et al., 2003).
For any incident stroke patient, the most likely cause of death is the incident or recurrent
stroke for the first year and cardiovascular causes thereafter. For incident ischemic stroke
patient, the most likely cause of death over 10 years is nonvascular, followed by cardiovascular,
and followed by stroke (Dennis et al., 1993; Hardie et al., 2003).
2.5 Stroke Recurrence after Ischemic Stroke
In population-based studies on first-ever ischemic stroke, the risk of stroke recurrence was
6–12% for first year, 18–34% for 5 years, and 28–50% for 10 years (> Table 58-3). Recurrence
rates for ischemic and hemorrhagic strokes seem to be similar (Hata et al., 2005; Burn et al.,
1994). Large-artery atherosclerotic disease and cardio-embolic stroke have higher recurrence
rates than small-vessel disease or stroke of undetermined etiology (Lovett et al., 2004).
Case fatality for recurrent ischemic stroke is higher than for first-ever ischemic stroke
(Jamrozik et al., 1999), possibly up to twice as high (Hardie et al., 2004). Just as stroke
incidence, so does stroke recurrence increase with age (Hata et al., 2005).
After presenting to the ER with a TIA, the 90-day risk of stroke is about 10%, half of which
happened over the first two days after the TIA (Johnston et al., 2000). In another study, stroke
recurrence rate after TIA or minor stroke has been 5.7% for the first year, 12.0% for 5 years,
and 18.4% for 10 years (van Wijk et al., 2005). Stroke recurrence after a lacunar stroke is 7.7%
during the first year, about 5% yearly during the next five years, and about 1% yearly
thereafter. There is no evidence that a lacunar infarction would differ from other stroke
subtypes in risk of recurrence. When there is a recurrence after a lacunar stroke it is of lacunar
type in 50% cases only. After lacunar infarct, just as after stroke in general, the recurrence is of
hemorrhagic subtype in 10% of cases (Norrving, 2003).
Few community-based studies exist on long-term prognosis of stroke. In the 1950’s- 1970’s
in Rochester, USA, 1 546 first-ever ischemic stroke patients were followed-up for 10 years
(Meissner et al., 1988). Recurrence was 6% for the first year, and 29% for 10 years. In the
1960’s-1980’s in Hisayama, Japan, 410 stroke patients were followed for 10 years (Hata et al.,
2005). Recurrence was 13% at 1 year and 51% at 10 years. For ischemic stroke only, the figures
were 10% and 50%. For stroke subtypes lacunar infarction recurrence rates were 7% and 47%,
atherothrombotic infarction recurrence rates were 15% and 47%, and cardioembolic infarction
recurrence rates were 20% and 75% for 1 and 10 years, respectively. Recurrence rates in
ischemic strokes increased with age, with the exception of cardioembolic infarction, which
recurred at the same rate irrespective of age. In the late 1980’s in Perth, Australia, 251 first-ever
ischemic and hemorrhagic (17%) stroke patients were followed-up for 10 years (Hardie et al.,
2004). Risk of stroke recurrence was 16% in the first year and about 4% annually thereafter with
a cumulative risk of recurrence at 10 years of 43%. Having had a stroke increased the patient’s
risk for a new stroke 6-fold as compared to the age- and sex-matched general population.
Thirty day case-fatality for a recurrent stroke was 41%, which was significantly higher than the
22% for a first-ever stroke in the same population. The type of the recurrent stroke is usually the
same as the first stroke. In the 1990’s in New York, USA, a first-ever ischemic stroke patient had
a 1-year stroke recurrence rate of 7.7%, and 5-year recurrence rate of 18.3% (Dhamoon et al.,
2006). Stroke was 3 times more likely to occur than a cardiac event, but the patient was twice
more likely to die due to cardiac causes rather than the recurrent stroke.
2.6 Quality of Life after Ischemic Stroke
It is obvious that having a stroke reduces one’s quality of life (QOL), and that the severity of
post-stroke disability is the main factor determining the loss in QOL. The research on patients’
perceived QOL after stroke has been reviewed for the years 1985–2000 (Tengs et al., 2001).
Their review gave median utility values, based on 67 studies, for major (0.36), moderate
(0.39), minor (0.76), and general stroke (0.74). They concluded that there is enormous
variation in QOL data between these studies, that many authors use previous data not suitable
for their own patient group in their cost-effectiveness reports, and that disability as measured
by the modified Rankin scale (mRS) only explains half of QOL variation in stroke patients.
Another review (Post et al., 2001) based on extensive literature analysis concluded that utility
values of 0.0–0.3 for major stroke and 0.6–0.7 for minor stroke should be reasonable.
One study (Samsa et al., 1998) used the time trade-off method to interview people with a
history of minor stroke or TIA (n = 294) or at an increased risk of stroke (n = 319). The
interviewees had a current mean utility state of 0.81, and estimated a utility value of 0.3 for a
major stroke. 45% of respondents considered having a major stroke worse than death. Another
study (Solomon et al., 1994) used a similar method to interview chronically ill patients
without a prior stroke (n = 117). This group of patients assigned a utility of 0.46 for mild,
0.33 for moderate, and 0.02 for severe stroke, when 0 was death and 1 was perfect health.
Xie and co-workers (Xie et al., 2006) compared QOL in a US survey of non-institutionalized
adults with a self-reported history of stroke (n = 1 040) and those without (n = 38 640). They
report utility values of 0.69 for stroke survivors, compared to 0.84 to stroke-free population, but
the age groups were not similar. When adjustment was made for age-, sex-, race- and geographic
region the stroke survivors scored lower on the 12-item Short-Form Health Survey (SF-12) ( 4.4
points on the mental score and 9.6 on the physical score), on the EUROQOL Group index
( 0.14 points), and visual analogue scales ( 14.6 points). All of these differences remained
significant when confounders were controlled for. Clinical data and verification of stroke was not
available, as stroke was self-reported. More severely affected patients with cognitive problems, or
need for institutional care, were not represented in this study, which unquestionably leads to
overestimation of the QOL if generalized to all stroke patients.
Measuring quality of life in stroke patients with generic QOL instruments can be prob-
lematic due to cognitive and communication problems associated with the disease. Therefore
proxy ratings and proxy measures have been evaluated. QOL reports by patient caregivers have
been considered valid (Sneeuw et al., 1997; Pickard et al., 2004), although the proxy, just as
matched controls, generally tends to underestimate the QOL of the patients (Murphy et al.,
2001). The relationship between the Barthel Index, a commonly used generic measure of
disability, and the QOL-measures EUROQOL (van Exel et al., 2004) and Assessment of
Quality of Life (AQOL) (Sturm et al., 2002) instrument have been established, suggesting
that Barthel Index can be used as a proxy measure if real QOL-measures are not available.
Of 1 662 ischemic stroke patients who were disabled at 2 weeks after their stroke as
measured by mRS 3–5, 53% gained independence (mRS 0–2) later. This took on average
12 months. The likelihood of independence was 63% for mRS score of 3, 41% for mRS 4, and
18% for mRS of 5. This means that even those patients who are in the poorest condition, but
still alive at 2 weeks after their stroke, have a 1 in 5 chance of gaining independence (Hankey
et al., 2007).
2.7 Cost of Ischemic Stroke
To evaluate costs incurred by a stroke, we must first define these costs. Stroke patients are old,
and elderly people use health care resources even without a stroke. For example, when a similar
population with and without stroke was followed up, the long-term use of nursing home days
was similar, as stroke patient’s increased mortality compensated for their increased need for
nursing home services (Leibson et al., 1998).
Many models that calculate cost of stroke actually include all healthcare costs after the
stroke, irrespective of whether they are related to the stroke or not, which leads to overestima-
tion of costs truly caused by the stroke.
Ways to estimate costs that are attributable to the stroke are:
a) Attribute costs of immediate hospital care and rehabilitation only
b) Attribute all stroke patient’s costs and deduct average health care costs of age- and sex-
matched population
c) Attribute all stroke patient’s costs and deduct the same patient’s healthcare cost one year
prior to the stroke
A Swedish population-based study has reported total direct health care costs during the
first and second year after a first-ever stroke to be 22,248 USD and 19,582 USD respectively,
and the total direct health costs during one year before the incident stroke to be 11 735 USD in
1991 values (Terent et al., 1994). This would imply that less than half of a stroke patient’s
health care costs are direct add-on costs caused by the stroke.
Which costs to count? This depends on the perspective of the study, which could be that of the
patient, treating hospital, third party payer, or preferably that of the society as a whole. The
perspective chosen for a given country may depend on the social security system of that country.
Direct health care costs are usually always counted, although it might be difficult to give a true
monetary value for a complicated many-faceted process such as inpatient care. The costs can be
broken down to components, such as radiological and laboratory diagnostics, intensive care unit
and stroke unit care, standard ward care, inpatient medication etc. but this information is difficult
to account for each patient. More often the costs are evaluated on an average principle, such as the
diagnosis-related group (DRG) method, which is likely to lead to bias if the method does not take
into account differences in different stroke subtypes. Cost of outpatient visits and medication are
more straightforward. Home modifications, nursing home, and outpatient social services, are not
always included in the total costs incurred by stroke, as they should be.
Indirect costs, such as lost productivity, as a standard should not be counted together with
direct costs, as indirect costs are highly variable depending on the model used, and in any case
should be given separately. The same applies for lost time and productivity of caregivers. Lately
it has become standard practice to use the so-called ‘‘friction method’’ for assessing lost
productivity, which assumes that as long as there is unemployment in the society, the costs
of losing one person from the workforce are those of hiring and training a new one, although
this approach has built-in underestimating tendency. In the case of stroke, where average age
at onset is above 70, lost production may not be viewed as a large issue. However, stroke-
related early retirement has already become a major issue in industrialized countries, being
much higher than that for coronary heart disease.
If indirect costs are imprecise, even more so are intangible costs, which are the monetary
value of suffering due to a disease. With cost-effectiveness evaluations, the need to evaluate
intangible costs becomes insignificant, as the suffering is reflected in the QALY-part of the
calculation.
Cost of stroke can be measured by either summing up the costs of individual patients,
called the ‘‘bottom-up method’’, or breaking down the total medical costs to different disease
and conditions, the so-called ‘‘top-down method’’. Prevalence-based cost studies are better
suited for estimation of economic burden of disease today, and incidence based studies for
making future projections. Check-list for cost of illness studies in stroke has been presented
(Evers et al., 2004), as shown in > Table 58-4.
The costs of inpatient care in stroke are mainly driven by length of stay, not so much by
workup procedures or salaries (Warlow et al., 2001). The modified Rankin Scale (mRS) is the
most commonly used, robust measure for disability after stroke, where score from 0 to 6 is
given, with 0 signifying no symptoms, 5 total dependency, and 6 death. Both length of stay
(LOS) and costs of stroke patients are strongly correlated with 90 day mRS, with each category
being significantly different from the other, mRS 0 (LOS 17, cost £ 2 953), mRS 1 (LOS 25, cost
£ 3 924), mRS 2 (LOS 44, cost £ 6 396), mRS 3 (LOS 58, cost £ 7 906), mRS 4 (LOS 79,
cost £ 10 618), mRS 5 (LOS 81, cost £ 12 666). The patients who died (mRS 6) are the cheapest
ones. Their mean LOS is 17 and cost £ 2 972) (Dawson et al., 2007). Mean length of stay
in Germany for ischemic stroke is 35 days (Weimar et al., 2003). Early supported discharge
from hospital reduces length of stay and total costs without compromising clinical outcome
(Anderson et al., 2002; Fjaertoft et al., 2005).
. Table 58-4
Checklist for cost of illness (COI) studies on stroke (Evers et al., 2004)
Design part
Year of publication
Sponsor
Country
Year of COI
Currency used and price year
Perspective of analysis
COI study type (disease specific/general)
COI study design (incidence/prevalence)
COI estimation procedure (top-down/bottom-up)
Unit of measurement (year, 1st year, and lifetime costs)
Data source population
Population size
Inclusion and exclusion criteria
Patient recruitment (inpatient, outpatient, open population)
Cost part
Costs included (direct, indirect, comorbidity)
Costs measurement (questionnaire, diary, etc)
Costs valuation (market prices, tariffs)
Costs reported (total direct costs, costs per health care sector)
Cost of illness studies in stroke can be performed in several ways and must rigorously report their methodology to
be comparable. Reproduced with permission from Evers SM, Struijs JN, Ament AJ, van Genugten ML, Jager JH,
van den Bos GA. International comparison of stroke cost studies. Stroke;35(5):1209–15
Cost of illness studies in ischemic stroke are summarized in > Table 58-5. These can be
divided to short term hospital cost studies, with initial hospitalization costs mainly in the
range of USD 3 500-8 000; one or two year studies, with first year cost of stroke in the range of
USD 18 000–40 000; and long term studies, with direct healthcare lifetime cost of stroke at
USD 40 000–110 000 (all costs discounted with consumer price index to 2008 currency).
Top down estimates for total cost of stroke to a society have been published, but not for
ischemic stroke alone. These have estimated that currently about 2–4% of total health care
expenditure in developed countries is due to stroke, which account for about 0.3% of gross
domestic product (Evers et al., 2004). In Finland 6.1% of all health care expenditure is directly
due to stroke (Fogelholm et al., 2001).
3 Thrombolytic Therapy for Ischemic Stroke
3.1 Effectiveness of Thrombolytic Therapy
Thrombolytic therapy with intravenous recombinant tissue-type plasminogen activator alte-

plase (rt-PA) 0.9 mg/kg, max 90 mg, started within 3 hours of stroke onset, has been approved
1046
. Table 58-5
58
Studies on cost of ischemic stroke
Future
Year Initial cost
Mean and hospitalization First year discount
Study Population age Stroke type Cost type currency costs costs Lifetime costs rate
Short term hospital cost studies
(Mamoli Single hospital in 71 Ischemic stroke Direct hospital 1996 3,289 – – –
et al., 1999) Bergamo, Italy costs USD
1996
(Diringer Single hospital in 70 Ischemic stroke Direct hospital 1996 4,408 – – –
et al., 1999) St Louis, USA costs USD
1996
(Reed et al., 150 US Hospitals, 73 Ischemic stroke in Direct hospital 1998 5,837 – – –
2001) 1998 hospital discharge costs USD
diagnosis
(Epifanov Single hospital in 70 Ischemic stroke patients Direct hospital 2002 3,070 – – –
et al., 2007) Marburg, treated in a regular costs, with EUR
Germany 1998 neurological ward breakup to
components
(Dodel et al., Single hospital in 69 Ischemic stroke patients Direct hospital 2002 3,480 – – –
2004) Marburg, treated in a stroke unit costs, with EUR
Germany 2000 breakup to
components
(Yoneda Single hospital in 70 Ischemic stroke patients Direct hospital 2001 6,887 – – –
et al., 2003) Himeji, Japan costs USD
2000–2001
(Qureshi 1,919 US 73 Ischemic stroke in Hospital charges 2001 16,200 (time – – –
et al., 2007) Hospitals, hospital discharge without USD period not
Nationwide diagnosis professional fees stated)
Inpatient Sample
2000–2001
Long term cost estimates
STEM (Caro Lubeluzole trial 71 First-ever ischemic stroke Direct health 1996 13,649 – 82,000 6%
and patients in 13 care costs USD (3 months)
Huybrechts industrialized
1999) countries
(Fagan et al., NINDS rt-PA trial 67 Ischemic stroke Direct hospital, 1996 14,923 29,810 62,716 5%
1998) placebo rehabilitation, USD (30 years)
patients, USA and nursing
home care costs
(Spieler Multiple centers 65 First-ever ischemic stroke Direct heath 1997 7,480 (initial 19,725 – –
et al., 2003) in France in 18–85 year old care costs EUR acute care) (1.5 years)
patients, who survived
initial hospitalization
(Spieler Multiple centers 68 Recurrent ischemic Direct heath 1997 7,639 (initial 18,560 – –
et al., 2003) in France stroke in 18–85 year old care costs EUR acute care) (1.5 years)
patients, who survived
initial hospitalization
(Lee et al., USA Medicare - Ischemic stroke in over Medicare 2001 6,190 – 39,396 (4 year –
2007) Beneficiaries 65 year old patients, with reimbursements USD costs)
1997 no stroke in 1996

(Samsa et al., USA Medicare 79 Ischemic stroke in over Direct health 1991 7,091 22,353 – –
1999a) Beneficiaries 65 year old patients, with care costs USD (14,016 for
1991 no stroke in 1987–1990 second
year)
58
1047
1048
58
Future
Year Initial cost
Mean and hospitalization First year discount
Study Population age Stroke type Cost type currency costs costs Lifetime costs rate
(Samsa et al., USA Medicare 79 Ischemic stroke in over Direct health 1991 6,939 25,245 – –
1999a) Beneficiaries 65 year old patients, with care costs USD (18,960 for
1991 prior stroke in 1987–1990 second
year)
(Levy et al., Expert panel – Ischemic stroke Direct health 1996 4,404–14,047 35,699 – – 5%
2003) estimations for care costs EUR (acute care) 56,370
8 European (2 year
countries costs)
(Taylor et al., Model estimate – Ischemic stroke patients Direct and 1990 – Direct costs 90,981 (about 5%
1996) for USA 1990 with insurance or indirect costs USD in range of 50% of which
Medicare claims 15,102 to are direct)
20,574
(Bergman Model estimate – First-ever ischemic stroke Direct heath 1991 – – 152,830 0%
et al., 1995) for Netherlands care costs USD (15 years)
1991
Population based studies
(Persson Lund-Orup, 73 Population based first- Direct heath 1993 SEK 29,618 96,567 283,000 (72 5%
et al., 1990) Sweden 1983 ever ischemic stroke care costs year old men),
(7/125 patients had ICH) 561,000
(72 year old
women)
(Dewey NEMESIS, 73 Population based first- All direct and 1997 4,827 (acute 15,177 31,902 5%
et al., 2001; Australia 1997 ever ischemic stroke indirect (friction USD hospitalization (direct
Dewey et al., model) costs only) health care
2003b) costs are 13
705)
(Kolominsky- Erlangen, 74 Population based first- Direct health 2004 – 15,140 43,129 3%
Rabas et al., Germany 2004 ever ischemic stroke care costs EUR
2006)
While the cost of initial hospital treatment in stroke is significant, it only amounts to a fraction of the lifetime costs of the disease
58
1049
for carefully selected ischemic stroke patients more than ten years ago. The evidence for the
treatment comes from four major trials done in the 1990’s, namely the NINDS, ECASS I and
II, and ATLANTIS –trials (Hacke et al., 2004). Thrombolytic therapy reduces the risk of
3-month death or dependency by 36%, number needed to treat (NNT) to prevent one such
adverse event being 10 (Wardlaw et al., 2003). The number needed to harm for thrombolytic
therapy has been estimated at 100, harm being due to increased risk of hemorrhage (Saver,
2007). Thrombolytic therapy as a part of clinical practice has produced better outcomes
(54.8% of patients independent at 90 days) and less adverse events (7.3% symptomatic
intra-cerebral hemorrhage rate) than was observed in the above mentioned major trials
(Wahlgren et al., 2007).
For thrombolytic therapy all evidence of long-term effectiveness is limited to the
12 months follow-up of the NINDS trial (Kwiatkowski et al., 1999). Favorable outcome
(mRS 0–1) was more likely in rt-PA (41%) patients than placebo patients (28%), OR
1.8 (1.3–2.5), NNT being 8.
3.2 Cost of Thrombolytic Therapy
Thrombolytic therapy incurs extra costs compared to conservative treatment. The drug itself,
alteplase, has a cost of around 2 000 USD per patient. The patients should be transferred by the
emergency medical service (EMS) directly to the emergency room (ER) of a hospital providing
this treatment, usually a fully equipped stroke center. Sometimes extra brain imaging is
required to confirm the diagnosis and the eligibility of the patient for thrombolytic therapy.
Thrombolysed patients should be followed up in the ICU or SU which requires more
monitoring and nursing staff. More thorough workup and more severe stroke in rt-PA treated
patients have also been suggested (Bambauer et al., 2006).
When patient-level data is used from administrative databases, initial hospital charges in
1999 were almost double, that is 18 000 USD higher, for rt-PA treated patients compared to age-
and sex-matched regular stroke patients (Bambauer et al., 2006). Doubling of acute hospital
costs for rt-PA patients has been reported in another bottom-up costing study (Ehlers et al.,
2007). Currently costing systems, such as DRG-based costing, do not sufficiently take throm-
bolytic therapy into account. Reimbursement and legal disincentives seem to be obstacles in the
USA (Bambauer et al., 2006), where rt-PA is currently used in only about 1% of ischemic stroke
patients (Schumacher et al., 2007) in spite of the recommendations from the American Heart
Association (Adams et al., 2007) and National Institutes of Health (NIH Task Force, 2003).
3.3 Cost-Effectiveness of Thrombolytic Therapy
Thrombolytic therapy for acute ischemic stroke has been evaluated in several well-conducted
cost-effectiveness studies. All of these showed thrombolysis to be a dominant therapy in the
long run when compared to standard care. The studies are summarized in > Table 58-6.
Thrombolytic therapy has been shown to be a dominantly cost-effective treatment com-
pared to routine treatment even if only the first year costs and benefits are accounted for. For
lifetime, an average of 0.75 QALYs are gained, and when only direct health care costs,
discounted at 5%, are considered, one treated patient saves more than USD 4 000 (Fagan
et al., 1998).
. Table 58-6
Studies on cost-effectiveness of thrombolytic therapy for stroke
Incremental QALYs
Cost per Cost per cost per gained per Incremental cost
Cost QALY rt-PA patient not rt-PA rt-PA per QALY for
Year and Discount Discount Time treated treated treated treated patient treated
Study Population currency Costs Perspective rate rate horizon patient with rt-PA patient patient with rt-PA
(Fagan et al., 67 year old 1996 USD Direct Health care 5% – 30 years 58,461 62,716 4,255 0.75 Dominance
1998) stroke health care system
patients costs
(Chambers UK 1996 1996 GBP Direct Health and 6% 6% 5 years 23,080 25,410 2,333 0.16 Dominance
et al., 2002) health care social care
costs system
(Sinclair et al., Canada 1999 Direct Health care 5% 3% 30 years 103,100 106,800 3,700 3.46 Dominance
2001) 1999 Canadian health care system
Dollar costs due
to stroke
(Mar et al., Spain 2000 2001 EUR Direct Societal 3% 3% Lifetime 82,508 90,382 7,874 0.53 Dominance
2005) societal (men)
costs
Lifetime 100,206 110,702 10,496 0.66 Dominance

(women)
58
1051
1052
58
Incremental QALYs
Cost per Cost per cost per gained per Incremental cost
Cost QALY rt-PA patient not rt-PA rt-PA per QALY for
Year and Discount Discount Time treated treated treated treated patient treated
Study Population currency Costs Perspective rate rate horizon patient with rt-PA patient patient with rt-PA
(Sandercock UK 2003 2003 GBP Direct Societal 6% 6% 1 year 6,260 6,150 110 0.01 13,581 ( 44,065
et al., 2004) societal to 47,095)
costs
Lifetime 26,209 29,714 3,504 0.04 Dominance
(Ehlers et al., Denmark 2004 USD Direct Societal 5% 5% 1 year 26,934 23,599 3,335 0.06 55,591
2007) 2004 societal
costs
2 years 35,480 35,047 433 0.12 3,615
3 years 43,229 45,322 2,100 0.16 Dominance
30 years 95,776 112,337 16,561 0.43 Dominance
(Yip and Canada 2005 Direct Health care – – 1 year – – 678 –
Demaerschalk, 2005 Canadian health care system
2007) Dollar costs due
to stroke
Thrombolytic therapy dominates in all studies with a longer time horizon. Dominance means that it both saves money and increases quality adjusted life years (QALYs)
While thrombolytic therapy is dominant, there are some other proven treatments in
stroke. The incremental cost of a QALY for treating a patient in a stroke unit has been
estimated at £ 900, and incremental cost of QALY for treating with ASA + DP vs ASA has
been estimated at £ 5 800 in 1997 currency (Chambers et al., 2002).
A theoretical ceiling of 20% of ischemic stroke patient treated with rt-PA has been
estimated, which could rise to 25–35% under optimal public and emergency transport service
education. If thrombolytic therapy was administered to 20% of ischemic stroke patients in the
USA, 74 million USD would be saved each year in comparison to the current treatment rate of
1% (Demaerschalk and Yip, 2005).
4 Stroke Unit Care for Ischemic Stroke
4.1 Effectiveness of Stroke Unit Care
Stroke unit, or organized inpatient stroke care, reduces short-term relative risk of death and
dependency by 18% when compared to general medical ward care. It does not significantly
affect the hospital length of stay. (Stroke Unit Trialists’ Collaboration, 2007).
Two studies on long-term effect of stroke unit care are available, neither which report
ischemic stroke separately. The first one carried out in Norway (Indredavik et al., 1999) reported
10-year outcome. 220 patients were randomized of whom 80% had ischemic stroke, 13%
hemorrhagic stroke, and 7% disease other than stroke. Average age was 73 years, and 23% of
the patients had had a previous stroke. Death rate at 10 years was 76% for acute and rehabilitation
stroke unit and 87% for general ward treatment. Relative risk reduction for death was 33%. Risk
of death or institutional care was reduced by 12% with a NNT of 9. Quality of life was better in
stroke unit treated patients. The second study in UK (Drummond et al., 2005) reported 10-year
outcome for 315 patients, with mean age of 69 years, randomized to stroke unit or conventional
ward treatment. Death rate was 69% for the rehabilitation stroke unit care and 80% for
conventional care. Relative risk reduction for death was 13%. Risk of death or institutional care
was reduced by 9% through stroke unit care, which was non-significant.
It is not clearly known which components of stroke unit care contribute to its positive
effects, as there is a plethora of ways to organize stroke inpatient care. Many of the randomized
studies actually compared conventional care with a rehabilitation stroke unit or a step-down
unit, although some studied a combined acute and rehabilitation unit. While thrombolytic
therapy can be given for ischemic stroke patients, and even at its best for a fraction of them
only, stroke unit care can benefit all stroke patients.
Stroke unit care can be augmented by early supported discharge (ESD) in selected patient
groups to further reduce risk of institutional care, while reducing initial hospital LOS by
8 days. (Norrving and Adams, 2006). ESD also improves patient QOL (Fjaertoft et al., 2004),
but its cost-effectiveness is uncertain (Brady et al., 2005). Mobile stroke teams as an alternative
to stroke unit care are inferior both in outcomes and cost (Norrving and Adams, 2006).
4.2 Cost of Stroke Unit Care
Cost of stroke unit care has been compared to conventional care in relatively few studies
(> Table 58-7), none of which give separate figures for ischemic and hemorrhagic stroke
1054
58
. Table 58-7
Studies on cost and cost-effectiveness of stroke unit care
QALYs
gained Incremental
Cost per Incremental per cost per
Cost per patient cost per patient QALY for
Cost QALY patient treated in patient treated in patient
Currency Discount Discount Time treated in conventional treated in stroke treated in
Study Population and year Costs Perspective rate rate horizon stroke unit care stroke unit unit stroke unit
Cost of stroke unit care

(Major and Model from 1997 GBP Direct Health care – – 1 year – – 256 – –
Walker multiple in-pa- system
1998) sources of tient
data, UK care
costs
(Claesson 70 + years 1996 USD Direct Societal – – 1 year 25,474 28,578 3,104 – –
et al., 2000) old stroke medical
patients, costs
Sweden and in-
1993–1994 direct
costs
(Moodie Any 1998 AUD Direct Health care – – 28 weeks 15,383 12,251 3,132 – –
et al., 2006) ischemic or medical system
ICH stroke costs
patient,
Australia
1998–1999
(Epifanov Any stroke 2002 EUR Direct Hospital – – Initial acute 3,500 (acute) 3,270 (acute) 411 – –
et al., 2007) in one medical and third and post- 9,880 (rehabil- 10,530 (reha-
hospital, costs party payer acute in-pa- itation) bilitation)
Germany tient care
1998 and (mean 7
2000 weeks)
Cost-effectiveness of stroke unit care
(Chambers Model from 1996 GBP Direct Societal 6% 6% 5 years 20,590 20,390 200 0.22 900
et al., 2002) multiple medical
sources of costs
data, UK
1996
(Patel et al., Moderately 1997 GBP Direct Societal – – 1 year 11,450 6,840 4,610 0.08 60,658
2004) severe medical
stroke costs
patients, UK and in-
1995–1999 direct
costs
(Launois Model from 1997 EUR Direct Health care 3% – 5 years 34,638 30,983 3,655 (0.90 4,078 per year
et al., 2004) multiple medical system years without dis-
sources of costs without ability
data, France disability)
1997
(van Exel All stroke, 2000 EUR Direct Health care – – 6 months 16,703 13,810 2,893 0.01 Conventional
et al., The medical system care domi-
2005)a Netherlands costs nates
1999–2000
The literature on stroke unit care cost-effectiveness includes large variability, and the results are difficult to summarize, likely due to different treatment schemes, cost structures, and
study methodology
a
In the study by van Exel and co-workers, the data for three presented stroke unit’s areas are aggregated
58
1055
patients. Of the randomized trials, one showed stroke unit care to be less expensive (Claesson
et al., 2000), and three more expensive (Moodie et al., 2006; Patel et al., 2004; van Exel et al.,
2005) than conventional care. There is large heterogeneity between the studies and the
maximum follow-up was one year. Overall there is little evidence to say whether stroke unit
care on general is more or less expensive than conventional care in the long run.
4.3 Cost-Effectiveness of Stroke Unit Care
Cost-effectiveness studies on stroke unit care are summarized in > Table 58-7. Again the
results are conflicting. One randomized study (Patel et al., 2004) showed the incremental cost
per QALY gained for a patient treated in a stroke unit as compared to home care to be 60 658
GBP in 1997, which is about 140 000 USD in 2008. This is more than what is usually
considered cost-effective. Another non-randomized study (van Exel et al., 2005) showed the
average outcome of patients treated in three Dutch geographical areas with stroke units to be
on average poorer than that of patients treated in conventional care, with extra cost associated
with stroke unit care. These two studies applied a relatively short 6–12 month perspective. Two
cost-effectiveness models, using data from multiple sources and a longer time horizon of
5 years, demonstrated cost-effectiveness of stroke unit care with incremental cost per QALY
at 2000 USD in the UK (Chambers et al., 2002), and incremental cost per year without
disability at 7000 USD in France (Launois et al., 2004). Some reports of stroke unit care
dominance, that is, reduced costs of 2600–5500 USD per patient combined with reduced
disability, are available (Asplund and Indredavik, 1997; Jorgensen et al., 1995). Theoretically
even small short-term positive effects on disability, as shown in most stroke unit trials, should
translate to significant long-term cost-effectiveness in stroke (Samsa et al., 1999b).
5 Conclusions
The global burden of stroke is huge and growing. Stroke is the second most common cause of
death and disability worldwide. Treating stroke consumes 3% of an average industrialized
country’s health care budget. As the negative impact of ischemic stroke is increasing, signifi-
cant additional resourcing for therapeutic breakthroughs is mandatory for fighting stroke.
Thrombolytic therapy is a fine example of how suffering and costs can be simultaneously
reduced by implementing effective treatments.
Thrombolytic therapy is cost-effective and should be made available to all ischemic stroke
patients. More widespread use of thrombolytic therapy for acute ischemic stroke could make a
significant difference for patients, relatives, and the society, and at the same time lead to
significant savings.
Stroke unit care improves patient outcome, but the evidence on its costs and thus cost-
effectiveness is heterogeneous. All stroke patients can benefit from stroke unit care, which
makes it an even more important intervention than thrombolytic therapy.
While disseminating best available treatment globally, new therapeutic approaches must
be developed simultaneously. On the other hand, development and utilization of precise tools
for measuring disease burden will help nations in correctly allocating research and patient-care
resources and better determine areas of priority.
Summary Points
A new ischemic stroke strikes more than 10 million individuals each year
One out of six people will have an ischemic stroke in their lifetime
Quality of life is reduced after stroke and this correlates with stroke severity
Treating stroke patients consumes 3% of an industrialized country’s health care spending
Thrombolytic therapy reduces both the disability and costs caused by an ischemic stroke
Stroke unit care reduces death and disability of all stroke patients
Thrombolytic therapy and stroke unit care are underused and should be adopted to a
larger extent
Developing precise health economic measures will help countries in allocating their
resources
Acknowledgments
This work is supported in part by the Helsinki University Central Hospital, the Finnish
Neurological Foundation, the Aarne Koskelo Foundation, the Orion-Farmos Research Foun-
dation, the Maire Taponen Foundation, the Paavo Ahvenainen Foundation, and the Instru-
mentarium Science Foundation.
References
Adams HP Jr., Bendixen BH, Kappelle LJ, Biller J, Bamford J, Sandercock P, Dennis M, Burn J, Warlow C.
Love BB, Gordon DL, Marsh EE III. (1993). Stroke. (1990). J Neurol Neurosurg Psychiatry. 53: 16–22.
24: 35–41. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C.
Adams HP Jr., del Zoppo G, Alberts MJ, Bhatt DL, (1991). Lancet. 337: 1521–1526.
Brass L, Furlan A, Grubb RL, Higashida RT, Banerjee TK, Mukherjee CS, Sarkhel A. (2001). Neuroe-
Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, pidemiology. 20: 201–207.
Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF. Bergman L, van der Meulen JH, Limburg M, Habbema
(2007). Stroke. 38: 1655–1711. JD. (1995). Stroke. 26: 1830–1836.
Aho K, Reunanen A, Aromaa A, Knekt P, Maatela J. Bonita R, Solomon N, Broad JB. (1997). Stroke.
(1986). Stroke. 17: 681–686. 28: 1898–1902.
Anderson C, Ni Mhurchu C, Brown PM, Carter K. Bots ML, Looman SJ, Koudstaal PJ, Hofman A, Hoes AW,
(2002). Pharmacoeconomics. 20: 537–552. Grobbee DE. (1996). Stroke. 27: 1499–1501.
Anderson CS, Jamrozik KD, Broadhurst RJ, Brady BK, McGahan L, Skidmore B. (2005). Int J Technol
Stewart-Wynne EG. (1994). Stroke. 25: 1935–1944. Assess Health Care. 21: 15–21.
Anderson CS, Jamrozik KD, Burvill PW, Chakera TM, Burn J, Dennis M, Bamford J, Sandercock P, Wade D,
Johnson GA, Stewart-Wynne EG. (1993a). Med J Warlow C. (1994). Stroke. 25: 333–337.
Aust. 158: 80–84. Caro JJ, Huybrechts KF. (1999). Stroke. 30: 2574–2579.
Anderson CS, Jamrozik KD, Burvill PW, Chakera TM, Carolei A, Marini C, Di Napoli M, Di Gianfilippo G,
Johnson GA, Stewart-Wynne EG. (1993b). Med J Santalucia P, Baldassarre M, De Matteis G, di
Aust. 158: 85–89. Orio F. (1997). Stroke. 28: 2500–2506.
Asplund K, Indredavik B. (1997). In: Castillo J, Dávalos Chambers MG, Koch P, Hutton J. (2002). Value Health.
A, Toni D. (eds.) Management of Acute Ischemic 5: 82–97.
Stroke. Springer-Verlag Ibérica, Barcelona, pp. 3–15. Claesson L, Gosman-Hedstrom G, Johannesson M,
Bambauer KZ, Johnston SC, Bambauer DE, Zivin JA. Fagerberg B, Blomstrand C. (2000). Stroke.
(2006). Arch Neurol. 63: 661–664. 31: 2569–2577.
Connor MD, Thorogood M, Casserly B, Dobson C, Garraway WM, Whisnant JP, Drury I. (1983). Mayo Clin
Warlow CP. (2004). Stroke. 35: 627–632. Proc. 58: 520–523.
Danesi M, Okubadejo N, Ojini F. (2007). Neuroepide- Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer
miology. 28: 216–223. R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley
Dawson J, Lees JS, Chang TP, Walters MR, Ali M, EC, Jr., Kwiatkowski T, Levine SR, Lewandowski C,
Davis SM, Diener HC, Lees KR. (2007). Stroke. 38: Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers
1893–1898. G, Bluhmki E, Wilhelm M, Hamilton S. (2004).
de Jong G, van Raak L, Kessels F, Lodder J. (2003). J Clin Lancet. 363: 768–774.
Epidemiol. 56: 262–268. Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill
Demaerschalk BM, Yip TR. (2005). Stroke. 36: PW, Anderson CS, Stewart-Wynne EG. (1998).
2500–2503. Stroke. 29: 2491–2500.
Dennis MS, Burn JP, Sandercock PA, Bamford JM, Wade Hankey GJ, Spiesser J, Hakimi Z, Bego G, Carita P,
DT, Warlow CP. (1993). Stroke. 24: 796–800. Gabriel S. (2007). Neurology. 68: 1583–1587.
Dewey HM, Sturm J, Donnan GA, Macdonell RA, Hardie K, Hankey GJ, Jamrozik K, Broadhurst RJ,
McNeil JJ, Thrift AG. (2003a). Cerebrovasc Dis. 15: Anderson C. (2003). Stroke. 34: 1842–1846.
133–139. Hardie K, Hankey GJ, Jamrozik K, Broadhurst RJ,
Dewey HM, Thrift AG, Mihalopoulos C, Carter R, Anderson C. (2004). Stroke. 35: 731–735.
Macdonell RA, McNeil JJ, Donnan GA. (2001). Hardie K, Jamrozik K, Hankey GJ, Broadhurst RJ,
Stroke. 32: 2409–2416 Anderson C. (2005). Cerebrovasc Dis. 19: 179–185.
Dewey HM, Thrift AG, Mihalopoulos C, Carter R, Hartmann A, Rundek T, Mast H, Paik MC, Boden-Albala
Macdonell RA, McNeil JJ, Donnan GA. (2003b). B, Mohr JP, Sacco RL. (2001). Neurology. 57:
Stroke. 34: 2502–2507. 2000–2005.
Dhamoon MS, Sciacca RR, Rundek T, Sacco RL, Elkind Hata J, Tanizaki Y, Kiyohara Y, Kato I, Kubo M, Tanaka K,
MS. (2006). Neurology. 66: 641–646. Okubo K, Nakamura H, Oishi Y, Ibayashi S, Iida M.
Diringer MN, Edwards DF, Mattson DT, Akins PT, (2005). J Neurol Neurosurg Psychiatry. 76: 368–372.
Sheedy CW, Hsu CY, Dromerick AW. (1999). Stroke. Hillen T, Coshall C, Tilling K, Rudd AG, McGovern R,
30: 724–728. Wolfe CD. (2003). Stroke. 34: 1457–1463.
Dodel RC, Haacke C, Zamzow K, Paweilik S, Spottke A, Howard VJ, McClure LA, Meschia JF, Pulley L, Orr SC,
Rethfeldt M, Siebert U, Oertel WH, Schoffski O, Friday GH. (2006). Arch Intern Med. 166:
Back T. (2004). Value Health. 7: 144–152. 1952–1958.
Drummond AE, Pearson B, Lincoln NB, Berman P. Indredavik B, Bakke F, Slordahl SA, Rokseth R, Haheim
(2005). Bmj. 331: 491–492. LL. (1999). Stroke. 30: 1524–1527.
Ehlers L, Andersen G, Clausen LB, Bech M, Kjolby M. Iso H, Shimamoto T, Naito Y, Sato S, Kitamura A,
(2007). Stroke. 38: 85–89. Iida M, Konishi M, Jacobs DR Jr., Komachi Y.
Ellekjaer H, Holmen J, Indredavik B, Terent A. (1997). (1998). Stroke. 29: 1510–1518.
Stroke. 28: 2180–2184. Jackson C, Sudlow C. (2005). Brain. 128: 2507–2517.
Engstad T, Bonaa KH, Viitanen M. (2000). Stroke. 31: Jamrozik K, Broadhurst RJ, Lai N, Hankey GJ, Burvill
1602–1607. PW, Anderson CS. (1999). Stroke. 30: 2105–2111.
Epifanov Y, Dodel R, Haacke C, Schaeg M, Schoffski O, Johnston SC, Gress DR Browner WS, Sidney S. (2000).
Hennerici M, Back T. (2007). Health Policy. 81: Jama. 284: 2901–2906.
339–349. Jorgensen HS, Nakayama H, Raaschou HO, Larsen K,
Evers SM, Struijs JN, Ament AJ, van Genugten ML, Jager Hubbe P, Olsen TS. (1995). Stroke. 26: 1178–1182.
JH, van den Bos GA. (2004). Stroke. 35: 1209–1215. Kissela B, Schneider A, Kleindorfer D, Khoury J, Miller R,
Fagan SC, Morgenstern LB, Petitta A, Ward RE, Tilley Alwell K, Woo D, Szaflarski J, Gebel J, Moomaw C,
BC, Marler JR, Levine SR, Broderick JP, Kwiatkowski Pancioli A, Jauch E, Shukla R, Broderick J. (2004).
TG, Frankel M, Brott TG, Walker MD. (1998). Neu- Stroke. 35: 426–431.
rology. 50: 883–890. Kiyohara Y, Kubo M, Kato I, Tanizaki Y, Tanaka K,
Feigin VL, Lawes CM, Bennett DA, Anderson CS. (2003). Okubo K, Nakamura H, Iida M. (2003). Stroke. 34:
Lancet Neurol. 2: 43–53. 2343–2347.
Fjaertoft H, Indredavik B, Johnsen R, Lydersen S. (2004). Kolominsky-Rabas PL, Heuschmann PU, Marschall D,
Clin Rehabil. 18: 580–586. Emmert M, Baltzer N, Neundorfer B, Schoffski O,
Fjaertoft H, Indredavik B, Magnussen J, Johnsen R. Krobot KJ. (2006). Stroke. 37: 1179–1183.
(2005). Cerebrovasc Dis. 19: 376–383. Kolominsky-Rabas PL, Sarti C, Heuschmann PU, Graf C,
Fogelholm R, Rissanen A, Nenonen M. (2001). Suomen Siemonsen S, Neundoerfer B, Katalinic A, Lang E,
Lääkärilehti (Finnish Medical Journal). 56: Gassmann KG, von Stockert TR. (1998). Stroke. 29:
3563–3567. 2501–2506.
Kwiatkowski TG, Libman RB, Frankel M, Tilley BC, Post PN, Stiggelbout AM, Wakker PP. (2001). Stroke. 32:
Morgenstern LB, Lu M, Broderick JP, Lewandowski 1425–1429.
CA, Marler JR, Levine SR, Brott T. (1999). N Engl J Qureshi AI, Suri MF, Nasar A, Kirmani JF, Ezzeddine MA,
Med. 340: 1781–1787. Divani AA, Giles WH. (2007). Stroke. 38: 2180–2184.
Launois R, Giroud M, Megnigbeto AC, Le Lay K, Reed SD, Blough DK, Meyer K, Jarvik JG. (2001). Neu-
Presente G, Mahagne MH, Durand I, Gaudin AF. rology. 57: 305–314.
(2004). Stroke. 35: 770–775. Rosamond W, Flegal K, Furie K, Go A, Greenlund K,
Lauria G, Gentile M, Fassetta G, Casetta I, Agnoli F, Haase N, Hailpern SM, Ho M, Howard V, Kissela B,
Andreotta G, Barp C, Caneve G, Cavallaro A, Cielo Kittner S, Lloyd-Jones D, McDermott M, Meigs J,
R, et al. (1995). Stroke. 26: 1787–1793. Moy C, Nichol G, O’Donnell C, Roger V, Sorlie P,
Lee WC, Christensen MC, Joshi AV, Pashos CL. (2007). Steinberger J, Thom T, Wilson M, Hong Y. (2008).
Cerebrovasc Dis. 23: 57–65. Circulation. 117: e25–146.
Leibson CL, Ransom JE, Brown RD, O’Fallon WM, Hass Rothwell PM, Coull AJ, Giles MF, Howard SC, Silver LE,
SL, Whisnant JP. (1998). Neurology. 51: 163–168. Bull LM, Gutnikov SA, Edwards P, Mant D, Sackley
Levy E, Gabriel S, Dinet J. (2003). Pharmacoeconomics. CM, Farmer A, Sandercock PA, Dennis MS, Warlow
21: 651–659. CP, Bamford JM, Anslow P. (2004). Lancet. 363:
Lin HC, Lin YJ, Liu TC, Chen CS, Chiu WT. (2007). 1925–1933.
J Urban Health. 84: 604–614. Rothwell PM, Coull AJ, Silver LE, Fairhead JF, Giles MF,
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray Lovelock CE, Redgrave JN, Bull LM, Welch SJ,
CJ. (2006). Lancet. 367: 1747–1757. Cuthbertson FC, Binney LE, Gutnikov SA,
Lovett JK, Coull AJ, Rothwell PM. (2004). Neurology. 62: Anslow P, Banning AP, Mant D, Mehta Z. (2005).
569–573. Lancet. 366: 1773–1783.
Major K, Walker A. (1998). In: Langhorne P, Dennis M Sacco RL, Boden-Albala B, Gan R, Chen X, Kargman DE,
(eds.) Stroke Units: An Evidence Based Approach. Shea S, Paik MC, Hauser WA. (1998). Am J Epide-
BMJ Books, London, pp. 56–65. miol. 147: 259–268.
Mamoli A, Censori B, Casto L, Sileo C, Cesana B, Camer- Samsa GP, Bian J, Lipscomb J, Matchar DB. (1999a).
lingo M. (1999). Neurology. 53: 112–116. Stroke. 30: 338–349.
Mar J, Begiristain JM, Arrazola A. (2005). Cerebrovasc Samsa GP, Matchar DB, Goldstein L, Bonito A, Duncan
Dis. 20: 193–200. PW, Lipscomb J, Enarson C, Witter D, Venus P,
Meissner I, Whisnant JP, Garraway WM. (1988). Stroke. Paul JE, Weinberger M. (1998). Am Heart J. 136:
19: 459–463. 703–713.
Moodie M, Cadilhac D, Pearce D, Mihalopoulos C, Samsa GP, Reutter RA, Parmigiani G, Ancukiewicz M,
Carter R, Davis S, Donnan G. (2006). Stroke. 37: Abrahamse P, Lipscomb J, Matchar DB. (1999b).
2790–2795. J Clin Epidemiol. 52: 259–271.
Murphy R, Sackley CM, Miller P, Harwood RH. (2001). Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan
J Neurol Neurosurg Psychiatry. 70: 679–681. J, Lewis S, Lindley R, Neilson A, Wardlaw J. (2004).
Neyer JR, Greenlund KJ, Denny CH, Keenan NL, Stroke. 35: 1490–1497.
Casper M, Labarthe DR, Croft JB. (2007). MMWR Saposnik G, Del Brutto OH. (2003). Stroke. 34:
Morb Mortal Wkly Rep. 56: 469–474. 2103–2107.
NIH Task Force. (2003). NIH Publication No. 03–5348. Sarti C, Rastenyte D, Cepaitis Z, Tuomilehto J. (2000).
Norrving B. (2003). Lancet Neurol. 2: 238–245. Stroke. 31: 1588–1601.
Norrving B, Adams RJ. (2006). Stroke. 37: 326–328. Saver JL. (2007). Stroke. 38: 2279–2283.
Numminen H, Kotila M, Waltimo O, Aho K, Kaste M. Schulz UG, Rothwell PM. (2003). Stroke. 34: 2050–2059.
(1996). Stroke. 27: 1487–1491. Schumacher HC, Bateman BT, Boden-Albala B, Berman
Patel A, Knapp M, Perez I, Evans A, Kalra L. (2004). MF, Mohr JP, Sacco RL, Pile-Spellman J. (2007).
Stroke. 35: 196–203. Ann Emerg Med. 50: 99–107.
Persson U, Silverberg R, Lindgren B, Norrving B, Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R,
Jadback G, Johansson B, Puranen BI. (1990). Int J Kannel WB, Wolf PA. (2006). Stroke. 37: 345–350.
Technol Assess Health Care. 6: 125–137. Sinclair SE, Frighetto L, Loewen PS, Sunderji R, Teal P,
Petty GW, Brown RD, Jr., Whisnant JP, Sicks JD, Fagan SC, Marra CA. (2001). Pharmacoeconomics.
O’Fallon WM, Wiebers DO. (1998). Neurology. 50: 19: 927–936.
208–216. Smadja D, Cabre P, May F, Fanon JL, Rene-Corail P,
Petty GW, Brown RD Jr., Whisnant JP, Sicks JD, O’Fallon Riocreux C, Charpentier JC, Fournerie P, Saint-Vil
WM, Wiebers DO. (1999). Stroke. 30: 2513–2516. M, Ketterle J. (2001). Stroke. 32: 2741–2747.
Pickard AS, Johnson JA, Feeny DH, Shuaib A, Carriere Sneeuw KC, Aaronson NK, de Haan RJ, Limburg M.
KC, Nasser AM. (2004). Stroke. 35: 607–612. (1997). Stroke. 28: 1541–1549.
Solomon NA, Glick HA, Russo CJ, Lee J, Schulman KA. Larrue V, Lees KR, Roine RO, Soinne L, Toni D,
(1994). Stroke. 25: 1721–1725. Vanhooren G. (2007). Lancet. 369: 275–282.
Spieler JF, De Pouvourville G, Amarenco P. (2003). Eur J van Exel NJ, Koopmanschap MA, Scholte op Reimer W,
Neurol. 10: 621–624. Niessen LW, Huijsman R. (2005). Qjm. 98: 415–425.
Stewart JA, Dundas R, Howard RS, Rudd AG, Wolfe CD. van Exel NJ, Scholte op Reimer WJ, Koopmanschap MA.
(1999). Bmj. 318: 967–971. (2004). Qual Life Res. 13: 427–433.
Stroke Unit Trialists’ Collaboration. (2007). Cochrane van Wijk I, Kappelle LJ, van Gijn J, Koudstaal PJ, Franke
Database Syst Rev. CD000197. CL, Vermeulen M, Gorter JW, Algra A. (2005). Lan-
Strong K, Mathers C, Bonita R. (2007). Lancet Neurol. cet. 365: 2098–2104.
6: 182–187. Venketasubramanian N, Tan LC, Sahadevan S, Chin JJ,
Sturm JW, Osborne RH, Dewey HM, Donnan GA, Krishnamoorthy ES, Hong CY, Saw SM. (2005).
Macdonell RA, Thrift AG. (2002). Stroke. 33: Stroke. 36: 551–556.
2888–2894. Vernino S, Brown RD, Jr., Sejvar JJ, Sicks JD, Petty GW,
Sudlow CL, Warlow CP. (1996). Stroke. 27: 550–558. O’Fallon WM. (2003). Stroke. 34: 1828–1832.
Tanaka H, Ueda Y, Date C, Baba T, Yamashita H, Hayashi Wardlaw JM, Zoppo G, Yamaguchi T, Berge E. (2003).
M, Shoji H, Owada K, Baba KI, Shibuya M, Kon T, Cochrane Database Syst Rev. CD000213.
Detels R. (1981). Stroke. 12: 460–466. Warlow C, Dennis M, van Gijn J, Hankey GJ, Sandercock
Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, PAG, Bamford JM, Wardlaw JM. (2001). Stroke – A
Jacobson MF. (1996). Stroke. 27: 1459–1466. Practical Guide to Management. Blackwell Science,
Tengs TO, Yu M, Luistro E. (2001). Stroke. 32: 964–972. Oxford, pp. 755–757.
Terent A, Marke LA, Asplund K, Norrving B, Jonsson E, Warlow C, Sudlow C, Dennis M, Wardlaw J, Sandercock
Wester PO. (1994). Stroke. 25: 2363–2369. P. (2003). Lancet. 362: 1211–1224.
Thorvaldsen P, Kuulasmaa K, Rajakangas AM, Rastenyte Weimar C, Weber C, Wagner M, Busse O, Haberl RL,
D, Sarti C, Wilhelmsen L. (1997). Stroke. 28: Lauterbach KW, Diener HC. (2003). Cerebrovasc
500–506. Dis. 15: 29–36.
Thrift AG, Dewey HM, Macdonell RA, McNeil JJ, Wolfe CD, Smeeton NC, Coshall C, Tilling K, Rudd AG.
Donnan GA. (2001). Stroke. 32: 1732–1738. (2005). Bmj. 331: 431.
Towfighi A, Saver JL, Engelhardt R, Ovbiagele B. (2007). Xie J, Wu EQ, Zheng ZJ, Croft JB, Greenlund KJ,
Neurology. 69: 1898–1904. Mensah GA, Labarthe DR. (2006). Stroke. 37:
Truelsen T, Piechowski-Jozwiak B, Bonita R, Mathers C, 2567–2572.
Bogousslavsky J, Boysen G. (2006). Eur J Neurol. 13: Yip TR, Demaerschalk BM. (2007). Stroke. 38:
581–598. 1952–1955.
Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Yoneda Y, Uehara T, Yamasaki H, Kita Y, Tabuchi M,
Hacke W, Hennerici MG, Kaste M, Kuelkens S, Mori E. (2003). Stroke. 34: 718–724.
59 Economic Burden of
Complications During
Percutaneous Coronary
Intervention
M. Dewan . K. M. Jacobson . C. S. Rihal
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
2 Case: Uncomplicated PCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
3 Case: Vascular Complication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
4 Defining Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
5 Incidence of Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
6 Cost of Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064
7 The Source of the Problem – Why are There so Many Complications? . . . . . . . . . 1065
8 The Possible Solution – Ways to Target Improvement . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066

8.1 Identify At-Risk Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
8.2 Modify Techniques to Improve Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
8.3 Engage in Continuous Quality Improvement (CQI) Initiatives . . . . . . . . . . . . . . . . . . . . 1068
8.4 Utilization Management Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068
8.5 Gain-Sharing Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1069
8.6 Prioritize Value-Added Procedures and Treatment Modalities . . . . . . . . . . . . . . . . . . . . . 1069
8.7 Know Your Source of Reimbursements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1069
9 Getting Harder to Break-Even . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070
10 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1071
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1071

1062 59 Economic Burden of Complications During Percutaneous Coronary Intervention
Abstract: > Percutaneous Coronary Intervention (PCI) is a resource intensive and common-
ly performed procedure in the developed world today. Technological advances have enabled
PCI to be applied with expanding indications; however escalating costs are of concern. Recent
economic analyses have demonstrated the economic impact of complications following PCI.
Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) and bleeding complica-
tions occur at significant rates and contribute greatly to the cost of these procedures. In this
chapter we define the complications and examine their impact on healthcare economics. We
then highlight potential solutions that may aid providers and organizations in ways of
targeting and reducing the economic burden of complications following PCI.
List of Abbreviations: ACT, activated clotting times; CQI, continuous quality improvement;
LAD, left anterior descending artery; MACCE, major adverse cardiovascular and cerebrovas-
cular events; PCI, percutaneous coronary intervention; SGR, sustainable growth formula; UM,
utilization management
1 Introduction
Percutaneous coronary intervention (PCI) is a resource intensive and commonly performed
procedure in the developing world today. In the United States alone during 2003, over
1.2 million PCI procedures were performed. Rapid expansion of PCI has continued owing
to advancements in peri-procedural anti-thrombotic medications, new > stent technology,
and a rising target population. Technology advances will continue to enable PCI to be applied
with expanding indications, especially in areas where there is an aversion to more invasive
procedures such as > coronary artery bypass grafting or where medical therapy may fall short
such as refractory chronic stable > angina. Unfortunately with these advancements, escalating
costs are of significant concern. Efforts at reducing costs associated with PCI have previously
been limited to targeting earlier discharge or by reducing equipment costs through competi-
tive bidding practices (Eagle et al., 2002; Moscucci et al., 2003). More recently however,
economic analysis have demonstrated the financial impact of complications following PCI
suggesting that targeting these complications may enhance not only clinical but financial
performance (Jacobson et al., 2007). In this chapter we define the complications and examine
their impact on healthcare economics. We then highlight potential solutions that may aid
providers and organizations in ways of targeting and reducing the economic burden of
complications following PCI.
2 Case: Uncomplicated PCI

Mr. A, a 70 year-old male with new-onset angina and an abnormal stress test, was referred to a
Midwest hospital for a coronary > angiogram. His angiogram revealed a significant > stenosis
in the mid Left Anterior Descending Artery (LAD) consistent with the perfusion abnormality
on his stress test. A bare-metal stent was placed in the LAD without complications. Mr. A had
an uneventful 2-day stay in the hospital and was subsequently discharged. Estimated fully
loaded cost of care, taking into account fixed and variable costs, from the hospital’s micro cost
accounting system was $12,500, and the hospital billed Medicare $22,000. In the end, Medicare
reimbursed the hospital $15,000.
Economic Burden of Complications During Percutaneous Coronary Intervention 59 1063
3 Case: Vascular Complication
Ms. B, a 76 year-old female with a known history of hypertension, hyperlipidemia, and obesity
was admitted to the hospital for unstable angina. Ms. B underwent percutaneous coronary
intervention (PCI) with drug-eluting stent placement to the suspected culprit lesion in her
proximal right coronary artery. One day post-procedure, she developed a large > hematoma
at the right femoral artery access site. An ultrasound subsequently showed a 2 cm > pseu-
doaneurysm and she was taken to the operating room for repair. After surgery, Ms. B
developed a right groin infection. She was treated with intravenous antibiotics and required
hospitalization for 18 days. Estimated costs of treatment were over $40,000. The hospital billed
Medicare $70,000 and was reimbursed $23,000. Overall, the hospital lost $17,000 – primarily
due to the required treatment for complications.
The two examples mentioned above exhibit the dramatic impact that complications of
percutaneous coronary intervention (PCI) can have on cost of individual cases. Amplify this
problem by the rising utilization of PCI in the developed and developing world, and the
impact becomes monumental. To understand the scope of the issue, we must first know how
to recognize these complications and identify the frequency for which they occur.
4 Defining Complications
It is important to understand what is considered a procedural complication of PCI in order to

understand the source of the increased costs. The cardiovascular community has established
commonly accepted endpoints for following outcomes of cardiovascular trials to monitor
impact of a treatment or an intervention. Two major groups of complications have been
defined including major adverse cardiovascular and cerebral events (MACCE) and bleeding
complications. MACCE typically includes the following events: death, myocardial infarction,
emergent coronary artery bypass surgery, target vessel revascularization, and stroke. Bleeding
complications generally include: clinically overt blood loss resulting in a decrease in hemoglo-
bin, blood loss requiring transfusion, access-site complications such as soft-tissue hematoma
or > aneurysm, central nervous system bleeding, gastrointestinal bleeding, and > retroperi-
toneal bleeding. Other complications such as acute kidney injury, drug or contrast reactions,
and infections related to instrumentation do occur and warrant consideration but are typically
of low enough incidences that they are seldom reported by most major trials and observational
studies.
5 Incidence of Complications
The complications of PCI are an infrequent occurrence from the perspective of the individual
receiving the procedure. However, due to the steep utilization of PCI in the developed world,
even a low incidence of complications can have a staggering impact on cost when applied to a
population. At Mayo Clinic a review of over 8,109 PCI’s performed in a 5-year period revealed
1,071 procedures associated with at least one complication. > Table 59-1 shows the frequency
of adverse events observed. In this study MACCE complications occurred at an incidence of
7.1% whereas 7.9% of procedures were associated with bleeding complications. Multiple other
studies have demonstrated comparable event rates in both categories. For instance, Kinnaird’s
. Table 59-1
Observed in-hospital adverse events by complication category (Jacobson et al., 2007)
Complication N (%)
Any complication 1071 (13.2)
MACCE complications 577 (7.1)
Death 130 (1.6)
Myocardial infarction 419 (5.2)
Emergent CABG 35 (0.4)
Target vessel revascularization 33 (0.4)
Stroke 35 (0.4)
Bleeding complications 641 (7.9)
Blood loss requiring transfusion 484 (6.0)
Hematoma 203 (2.5)
Aneurysm 62 (0.8)
CNS bleed 0 (0)
GI bleed 76 (0.9)
Retroperitoneal bleed 23 (0.3)
Bleeding-only 494 (6.1)
MACCE-only 430 (5.3)
MACCE and bleeding 147 (1.8)
CABG coronary artery bypass graft; CNS central nervous system; GI gastrointestinal; MACCE major adverse
cardiovascular and cerebrovascular events
study (Kinnaird et al., 2003) demonstrated an incidence of major and minor bleeding
complications of 5.4 and 12.7% respectively in patients undergoing PCI. Ischemic event
rates were also similar in previous studies (Batchelor et al., 2000; Lincoff et al., 2003;
Moses et al., 2003).
6 Cost of Complications
While much clinical research to date has focused on the incidence of PCI-related complica-
tions, studies of the economic impact of the associated costs are just now emerging. At Mayo
Clinic, bleeding-only complications contributed an average of $13,092 in increased costs per
patient and MACCE-only complications had an additional $9,096 cost per patient (Jacobson
et al., 2007) (see > Table 59-2). Furthermore, patients with multiple complications had the
highest additional costs of $42,952 on average. Jacobson et al. showed that greater than 25% of
the costs associated with PCI were attributed to PCIs with complications, however of all PCIs
done only 13% actually had complications. Kugelmass et al. (2006) also noted significantly
higher resource use among Medicare beneficiaries associated with acute PCI complications.
The observed average cost of a PCI hospitalization for all patients in this study was approxi-
mately $15,089 $13,063. However, patients who developed no complications had signifi-
cantly lower observed average costs ($13,861 $9,635 vs. $26,807 $27,596) than did
. Table 59-2
Observed inpatient costs by selected complication following PCI (Jacobson et al., 2007)
Total costs ($)

Mean (median) SD Difference (95% CI)
All PCI episodes 14,337 (11,380) 16,524 –
Uncomplicated PCI 12,279 (10,776) 6,796 –
Any complication 27,865 (18,462) 39,424 15,586 (14,579; 16,593)
Bleeding only 25,371 (18,234) 21,193 13,092 (12,315; 13,869)
MACCE only 21,375 (16,366) 17,954 9,096 (9,096; 9,864)
MACCE and bleeding 55,230 (30,714) 89,598 42,952 (40,953; 45,310)
CI confidence interval; PCI percutaneous coronary intervention; MACCE major adverse cardiovascular and cerebro-
vascular events; SD standard deviation
patients with 1 complication. Estimated incremental costs associated with complications

ranged from a high of $33,030 for > septicemia patients to a low estimate of $4,278 for patients
developing vascular complications. The most important predictor of added cost for both
studies was hospital length of stay. This suggest that more costly complications resulted in
significantly longer stays in addition to the added services necessary to address the complica-
tion. These data clearly demonstrate that resource consumption and treatment costs are
dramatically increased when complications of PCI occur. For this reason, > percutaneous
coronary interventions are an obvious and appropriate target for cost reduction and quality
improvement initiatives.
7 The Source of the Problem – Why are There so Many

Complications?
Technological advances in cardiac care such as drug-eluting stents, combined with a growing
population of elderly patients with symptomatic coronary artery disease, are promoting a
steep rise in the utilization of percutaneous coronary interventions. It is estimated that in
2005, over 1,256,000 PCIs were performed in the United States, and of those 620,000 PCIs
included stent placement (AHA, 2008 Update). The American Heart Association (AHA) also
found that in 2005, over 50% of PCIs were performed on patients over the age of 65. With a
larger number of comorbidities and a long list of medications, patients over the age of 65 are at
a significantly higher risk of complications when receiving PCI. For instance, in one study,
approximately 17% of elderly patients needed at least one repeat revascularization within the
first year of PCI with an increase cost of care of over $19,000 (Clark et al., 2004). The overall
cost of treating multiple restenosis events was found to be six times higher than treating
patients without complications (Clark et al., 2005). Due to improved stent technology and
the use of antithrombotics during PCIs, ischemic complications have declined in numbers;
however, bleeding complications are becoming more common as a consequence of aggressive
antithrombotic use and riskier patient profiles. Kinnaird et al. discovered that age, along with
other factors further increases bleeding risks. The study showed that age greater than 80 years
and > chronic renal insufficiency were strongly associated with bleeding risks during PCIs.
The growing population of elderly combined with increased utilization of PCI in this higher
risk population is resulting in escalating complication rates and, thus, increasing cost of
treatments with less value added.
8 The Possible Solution – Ways to Target Improvement

8.1 Identify At-Risk Patients
First it seems reasonable to identify patients at greatest risk of procedural complications with
the intent of creating awareness and modifying care to minimize the possibility of adverse
outcomes. This is quality improvement in its simplest form. Simple integer risk scores have
been developed and validated in clinical cardiology for identifying patients at increased risk
for in-hospital complications after PCI (Singh et al., 2003). Below is the new Mayo Clinic Risk
Score demonstrating the prognostic value of clinical and laboratory variables for accurately
estimating the peri-procedural risk from PCI (> Figure 59-1).
. Figure 59-1
Estimated rates of procedural complications for the integer scoring system (Singh et al., 2002).
The integers are proportional to the estimated continuous coefficient from the logistic model.
Percentages at risk are shown for each of the five risk categories: 2% is very low risk for
complications with coronary angioplasty; >2–5% low risk; >5–10%, moderate risk; >10–25%,
high risk; and >25%, very high risk. NYHA = New York Heart Association classification
Nikolsky et al. using the REPLACE-1 and REPLACE-2 trial data developed and validated a
prognostic risk score for major bleeding in patients undergoing PCI using the femoral artery
approach (> Figure 59-2).
. Figure 59-2
Algorithm used to determine the risk score for major bleeding using clinical and procedural
variables (Nikolsky et al., 2007). eGFR estimated glomerular filtration rate; SCr serum creatinine;
PCI percutaneous coronary intervention
Identifying patients at higher risk of ischemic and/or bleeding complications is the first
step to preventing adverse events. Techniques theoretically could then be modified in order to
mitigate the risk of complications.
8.2 Modify Techniques to Improve Outcomes
Such technical changes could include the choice of access site, use of closure devices, or choice
of peri-procedural > anticoagulation and dosing modifications. The MORTAL study recently
demonstrated that the radial approach is associated with less risk of transfusion and subsequent
mortality compared to the femoral approach. Alternative antithrombotic regimens may be
useful in lowering events. Use of bivalirudin was associated with fewer bleeding events and was
found to be noninferior to heparin plus glycoprotein IIbIIIa inhibitor use in patients with acute
coronary syndrome presenting for PCI (Lincoff et al., 2003). The unit cost of bivalirudin is
higher than heparin however cost-analysis reveals it to be less expensive as a result of fewer
bleeding events with comparable ischemic outcomes (Cohen et al., 2004). Earlier sheath
removal and careful monitoring of > activated clotting times (ACT) prior to sheath removal
may also limit vascular access site complications (Mandak et al., 1998). For any of these
approaches to work, a system needs to be in place to streamline the process of decision-making

so that assessment of patient risk becomes standard and protocol driven. This helps to avoid
inconsistencies and promotes compliance by all members of the healthcare team.
8.3 Engage in Continuous Quality Improvement (CQI) Initiatives
The CQI process aims to identify and pursue opportunities for expense reduction while
improving evidence-based clinical practice. It is essentially a process designed for cost-
containment without sacrificing patient care. In 1996 at the Mayo Clinic (Rihal et al., 2006),
a multidisciplinary team of physicians, nurses, technicians, administrators, and quality im-
provement experts were charged with critically evaluating the PCI practice in an effort to
identify and pursue opportunities for expense reduction while improving current evidence-
based clinical practice. The group used the Plan-Do-Study-Act cycle model for improvement
which initially focuses on three important questions:
1. What are we trying to accomplish?
2. How will we know whether a change is an improvement?
3. What changes can we make?
The PDSA cycle helps develop, test, and implement change with an efficient trial and learning
process (Berwick, 1998; Langley et al., 1996). Cycles are initiated for tests of change on a small
scale, which eventually can lead to larger improvements. The Mayo group subsequently made
several large alterations in the management of cardiac supplies and developed a resource
protocol for appropriate tests and supplies, and hospital resources deemed necessary to
perform uncomplicated PCI procedures with an expense goal below the total Medicare
reimbursement. The group subsequently evaluated the impact of the CQI effort in the Cardiac
Catheterization Laboratory on economic and clinical outcomes using its own PCI registry and
administrative data sources. Encouragingly, CQI favorably impacted costs despite higher
clinical risk-factors (i.e., riskier patients) and greater utilization of new high-cost technologies.
Observed costs were not only contained but were 12% lower for patients undergoing PCI post-
CQI compared with the patients undergoing PCI pre-CQI. After adjusting for confounding
factors, estimated costs were ~28% lower for PCI patients treated post-CQI. This approach
can be applied to developing resource protocols for potentially riskier procedures in identified
‘‘high-risk’’ patients, thereby creating awareness and potentially lowering adverse event rates.
The lower adverse event rates should then translate to a lower cost burden.
8.4 Utilization Management Systems
In the past, options such as utilization management (UM) have been used to control costs
within a hospital. Managed care systems pioneered utilization management which is described
as a set of techniques used by or on-behalf of purchasers of health benefits to manage health
care costs by influencing patient care decision-making through case-by-case assessment of the
appropriateness of care. The idea being that unnecessary care can be controlled, saving
substantial amounts of money and improving the quality of care. Of course, that is assuming
the cost of operating a UM system is small compared to the savings. At the system level, UM
has been associated with a significant reduction in the rate of increase in hospital costs during
the 1980s (Schwartz and Mendelson, 1991). Clinical practice guidelines established by physi-
cian focus groups to guide UM has the potential of reducing unnecessary or non-indicated
procedures thereby reducing patient exposure to costly procedures and potential complica-
tions. Unfortunately, UM has been viewed by many, including physicians, as being restrictive
of care for those in need and continues to face much opposition.
8.5 Gain-Sharing Systems
A gain-sharing system works by giving physicians financial incentives to practice more cost-
effective evidence-based care. It works best when performance levels can be easily evaluated
and quantified which in this case would require careful monitoring of PCI outcomes for each
practicing interventional cardiologist. This is accomplished at many academic institutions
who maintain PCI registries that record extensive data on each patient encounter but the
expenses of running a database may be too costly for smaller, lower volume centers. Gain-
sharing also requires regular episodes of open discussion on ways to further create perfor-
mance improvement which can be difficult given time restraints on many clinicians. Potential
advantages to this approach include physician ‘‘buy-in’’ to organizational goals of reducing
complications, sustainable change, and an open line of communication further fostering
cooperation and potentially opening the door for future ideas of how to improve outcomes.
However, as history has proven, such mechanisms of cost reduction have led to an underutili-
zation of potentially value-adding procedures and in the end have not controlled overall costs
of complications. Furthermore, patients have been short-changed appropriate quality-care.
How this method could be utilized to reduce complications and impact quality of care would
need further careful review.
8.6 Prioritize Value-Added Procedures and Treatment Modalities
This is a very promising area for cost management. The theory is to invest in procedures that
may initially cost more, but overall control costs by reducing the complications associated with
procedures. Cost savings associated with advances in technology may encourage hospitals to
adopt them and for insurers to reimburse these new developments. For instance, when drug-
eluting stents were first brought to market, they were $2,000 more per stent compared with
bare-metal stents. However, drug-eluting stents decrease restenosis rates by 60–80% compared
with bare-metal stents (Clark et al., 2004). This equated to approximately $25,000 in cost
reduction per procedure (Clark et al., 2004). Bivalirudin as a unit is more expensive than
heparin alone; however, with fewer bleeding complications than heparin plus glycoprotein
IIb/IIIa inhibitor and with comparable ischemic events, cost-effectiveness analysis has actually
found it to be overall less expensive (Cohen et al., 2004). Further investigation into identifying
value-adding procedures or treatment modalities is certainly warranted and can clearly have
an impact on overall cost of providing PCI.
8.7 Know Your Source of Reimbursements
Medicare is the nation’s largest single payer with over 44 million beneficiaries. The healthcare
insurer has been planning cuts in its reimbursements for some time and when these cutbacks
are implemented it is plausible that physicians will be unable to break-even when treating
patients. According to the American Medical Association, Medicare was planning a 10% cut to
take place in January 2008 (David, 2007). In response to the cut, over one-third of physicians
were planning to stop accepting new Medicare patients and thereby leaving many elderly
patients without access to healthcare (David, 2007). These detrimental outcomes require
addressing the flaws in our current healthcare system. There must be adequate coverage of
costs for physicians to continue treating patients. Trogdon, et al. recommend making changes
in reimbursements by incorporating trends in healthcare and demand for certain procedures.
For instance, including patient demands for cardiovascular procedures into Medicare’s reim-
bursement schedule and paying more for procedures that have lower complication rates,
rather than simply paying for lower cost procedures, may help motivate physicians to provide
quality care. The O’Shea article (O’Shea, 2008) suggests a similar Medicare reform to better
align incentives for everyone involved in the healthcare process. O’Shea recommends a twofold
reform: First, make spending patient-centric, by allowing beneficiaries to take control of their
own spending budgets. Similar to a healthcare spending account, allow patients to create a
spending account in which they can contribute their coverage dollars. Beneficiaries will
be allowed to spend their resources in a variety of healthcare plans and products. This
will provide incentives for patients to evaluate the value of discretionary services and create
a dialogue with physicians, thus reducing costs. The second part of O’Shea’s recommendation
is to create a balance billing system, whereby physicians can, within limits, bill certain
patients more than normal charges. This system would incorporate market forces such that
physicians would be driven to provide quality-care to compete for higher-paying patients.
Although these solutions provide some reprieve from the declining margins in the current
market and the struggle to break-even, they do not address the major issue at hand – the
high costs of complications. Identifying additional solutions available to providers to reduce
costs associated with complications should be the emphasis of future research and quality
initiatives.
9 Getting Harder to Break-Even
With tightening reimbursements and increased costs from advancing technology and com-
plications of treatment, hospitals are struggling to break-even with each PCI procedure.
Approximately 17% of medical expenditures and 30% of Medicare expenditures are attribut-
able to heart disease. Medicare’s fee schedule is determined by an expenditure target that is
calculated using the sustainable growth formula (SGR) (O’Shea, 2008). The SGR method is
based on growth in inflation-adjusted gross domestic product, changes in practice cost
inflation, increases in Medicare enrollment, and healthcare spending changes secondary to
changes in laws. SGR works by adjusting the fee schedule based on estimated spending targets.
If spending deviates from target, then adjustments are made to the fee schedule so that over
several years cumulative spending is brought back to target. Since 2002, SGR has called for
negative updates to the fee schedule, but Congress has not allowed these changes to occur.
Thus spending has remained above target for years. However, in time these adjustments will
have to be made, and it is estimated that payment rates will decrease by 5% per year for at least
9 years. By 2015 reductions of at least 40% are expected (O’Shea, 2008). The most likely
candidates for decreases in reimbursements are procedural-based practices. Currently,
cardiac catheterization labs are a huge source of income for hospitals. However, with these
reimbursement cutbacks in the near future and rising costs of technology, cardiac catheteriza-
tion labs may become a financial burden.
10 Conclusion
Percutaneous coronary interventions are a resource intensive and commonly performed

procedure in the developed world today. The growing population of elderly and new innova-
tions in PCI technology assures that demand for this procedure will remain high and so
complications, and therefore cost, will remain a paramount issue. It is hopeful, that through
patient risk stratification, continuous quality improvement, and other cost-containment
efforts we can produce a safer practice with enhanced clinical outcomes at a lower total
economic burden.
Summary Points
PCI is a resource intensive procedure commonly performed today.
Escalating costs owing to technological advancements, expanding indications, and rising
target population are of significant concern.
Procedural complications such as MACCE and bleeding events dramatically impact the
financial as well as clinical outcomes of our PCI practices.
Identifying riskier patients, modifying procedural techniques and therapies, in addition to
CQI and other cost-containment methods can create a safer practice and impact favorably
on clinical as well as financial outcomes.
Efforts designed to change practice patterns will need to be protocol driven to ensure
acceptance by all members of the healthcare team and should come about by direct input
by physicians, nurses, technicians, and administrators.
References
American Heart Association. (2008). Heart Disease and David RM. Help Stop the Medicare Cuts. American
Stroke Statistics – 2008 Update. American Heart Medical Association – eVoice. 2007 Nov.
Association, Dallas, TX. Available at: http://www. Eagle KA, Knight BP, Moscucci M, Strickberger SA,
americanheart.org/presenter.jhtml?identifier= Duvernoy CS, Pelosi F, Werns SW, Eitzman DT,
3000090 (accessed on 27 January 2008). Morady F, Bates ER. (2002). Am J Manag Care. 8:
Batchelor WB, Anstrom KJ, Muhlbaier LH, Grosswald R, 384–388.
Weintraub WS, O’Neill WW, Peterson ED. (2000). Jacobson KM, Long KH, McMurtry EK, Naessens EK,
J Am Coll Cardiol. 36: 723–730. Rihal CS. (2007). Quality Safety Healthcare. 16:
Berwick DM. (1998). Ann Intern Med. 128: 651–656. 154–159.
Clark MA, Bhakai A, Pelletier EM, Cohen DJ. (2005). Kinnaird DT, Stabile E, Mintz GS, Lee CW, Canos DA,
Managed Care. 14(4): 42–51. Pinnow EE, Kornowski R, Suddath WO, Satler LF,
Clark MA, Bhakai A, Lacey MJ, Pelletier EM, Cohen DJ. Pichard AD, Kent KM, Weissman NJ. (2003). Am J
(2004). Circulation. 110: 259–264. Cardiol. 92: 930–935.
Cohen DJ, Lincoff AM, Lavelle TA, Chen HL, Bakhai A, Kugelmass AD, Cohen DJ, Brown PP, Simon AW, Simon
Berezin RH, Jackman D, Sarembock IJ, Topol EJ. AW, Becker ER, Culler SD. (2006). Am J Cardiol. 97:
(2004). J Am Coll Cardiol. 44: 1792–1800. 322–327.
Langley G, Nolan K, Nolan T, Norman C, Provost L. Williams DO, Teirstein PS, Jaeger JL, Kuntz RE,
(1996). The Improvement Book. Jossey-Bass, San SIRIUS Investigators. (2003). N Engl J Med. 349:
Francisco, California. 1315–1323.
Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Nikolsky E, Mehran R, Dangas G, Fahy M, Na Y, Pocock
Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, SJ, Lincoff AM, Stone GW. (2007). Eur Hear J. 28:
Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, 1936–1945.
Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de O’Shea JS. (2008). J Am Coll Surg. 206(1): 165–170.
Feyter PJ, Vahanian A, Topol EJ, REPLACE-2 Inves- Rihal CS, Kamath CC, Holmes DR, Reller MK, Anderson
tigators. (2003). JAMA. 289: 853–862. SS, McMurtry EK, Long KH. (2006). Am J Managed
Mandak JS, Blankenship JC, Gardner LH, Berkowitz SD, Care. 12(8): 445–452.
Aguirre FV, Sigmon KN, Timmis GC, Gilchrist IC, Schwartz WB, Mendelson DN. (1991). N Engl J Med. 324
McIvor M, Resar J, Weiner BH, George BS, Talley JD, (15): 1037–1042.
Lincoff AM, Tcheng JE, Califf RM, Topol EJ. (1998). Singh M, Lennon RJ, Holmes DR. Jr, Bell MR, Rihal CS.
J Am Coll Cardiol. 31(7): 1518–1524. (2002). J Am Coll Cardiol. 40(3): 387–393.
Moscucci M, Muller DW, Watts CM, Bahl V, Bates ER, Singh M, Rihal CS, Seilzer F, Kip KE, Detre K, Holmes
Werns SW, Klein-Rogers E, Karavite D, Eagle KA. DR. (2003). J Am Coll Cardiol. 42(10): 1722–1728.
(2003). Am J Manag Care. 9: 365–372.
Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes
DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ,
60 Features of Mediterranean
Diet and Burden of
Cardiovascular Disease
D. B. Panagiotakos . C. Pitsavos . D. P. Mikhailidis
1 Introduction, the Global Burden of CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074
2 A Healthy Diet: The Mediterranean Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1075
3 Mediterranean Diet and CVD, the Epidemiologic and Clinical Evidence . . . . . . . . . 1076
4 Potential Pathophysiological Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078
5 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083

1074 60 Features of Mediterranean Diet and Burden of Cardiovascular Disease
Abstract: The burden of chronic diseases is rapidly increasing worldwide. Based on accurate
calculations, chronic diseases contributed approximately 60% of the 56.5 million total
reported deaths in the world, in 2001, and roughly 46% of the global burden of disease.
Moreover, most of the Western countries face high and increasing rates one of the most
common chronic diseases, > cardiovascular disease (CVD). Fortunately, CVD is preventable.
Currently available research provides sufficiently strong evidences for the risks attributed to
lifestyle and behavioral factors (e.g., smoking, and unhealthy diets and physical inactivity) as
well as various social factors that include a complex mixture of interacting socioeconomic,
cultural and other environmental parameters. Among the aforementioned risk factors, un-
healthy dietary choices are known to increase the risk for various chronic diseases, especially
CVD and some types of cancer. In contrast, traditional, largely plant-based diets (> traditional
diet), like the Mediterranean diet, have been associated with lower risk of CVD and some types
of cancer.
List of Abbreviations: AHA, American Heart Association; CVD, cardiovascular disease;
EPIC, European Prospective Investigation into Cancer and Nutrition; HALE, healthy ageing
a longitudinal study in Europe; HDL, high density lipoprotein; LDL, low density lipoprotein;
TNF, tumor necrosis factor; WHO, World Health Organization
1 Introduction, the Global Burden of CVD
It is now accepted that the burden of chronic diseases is rapidly increasing worldwide. Based
on accurate calculations, chronic diseases contributed approximately 60% of the 56.5 million
total reported deaths in the world, in 2001, and roughly 46% of the global burden of disease
(World Heart Organization Study Group, 2002). Furthermore, the proportion of the burden
of chronic diseases is expected to increase to 57% by 2020. According to current epidemiologic
evidence, most Western countries face high and increasing rates one of the most common
chronic diseases, cardiovascular disease (CVD). It has been reported that about the half of the
total chronic disease deaths in the Westernized world are attributable to CVD, while diabetes
and obesity are also showing increasing trends, even from young ages. Based on previous
WHO fact sheets, CVD alone caused 30% of all deaths worldwide, with other diseases of the
cardiovascular system responsible for substantial further death and disability (World Heart
Organization Study Group, 1990). Further reports from the World Health Organization
(WHO) suggest that until the 2005, CVD was the first cause of death and disability in the
United States and several European countries. Although it was believed that CVD was a disease
of middle aged adults, mainly males, recent studies showed that vascular injury accumulates
from adolescence, making primary prevention efforts necessary from childhood. Furthermore,
the standardized CVD mortality rates vary considerably from country to country around the
developed world (World Heart Organization Study Group, 1990). Results from the 25-year
follow-up (1960–1985) of the Seven Countries Study (Keys et al., 1986) suggest that the
prevalence of CVD varied from 2 to 10% in southern European countries and from 10 to
18% in northern European countries.
Fortunately, CVD is preventable Executive Summary of the Third Report of the National
Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treat-
ment of High Blood cholesterol in Adults (Adult Treatment Panel III) (2001); Ford et al.
(2002); Grundy (2004); Grundy et al. (2005); Haffner (2006); Kim and Reaven (2004);
Features of Mediterranean Diet and Burden of Cardiovascular Disease 60 1075
Phillips (1978); Reaven (1988); Roberts and Barnard (2005); Stone and Saxon (2005); Pana-
giotakos et al. (2002). Although more basic research may be needed to further explore the
mechanisms associated with the initiation and progression CVD, currently available research
provides sufficiently strong evidence for the risks attributed to several lifestyle and behavioral
factors (e.g., smoking, unhealthy diets and physical inactivity) as Alberti Zimmet (1998) well as
various social factors that include a complex mixture of interacting socioeconomic, cultural and
other environmental parameters. Among the aforementioned risk factors, unhealthy dietary
choices, high in total fat, with substantial content of animal-based foods, have been known for
decades to increase the risk for various chronic diseases, especially CVD and some types of
cancer. On the other hand, traditional, largely plant-based diets, like the Mediterranean diet,
have long been associated with lower risk of chronic diseases, mainly coronary heart disease and
nutrition-related types of cancer. In this chapter, we present scientific evidence regarding the
benefits on cardiovascular health attributed to the Mediterranean diet.
2 A Healthy Diet: The Mediterranean Diet
As mentioned in the Introduction, the prevalence and incidence of CVD varies from country to
country and culture to culture. This variation in CVD mortality has been attributed, at least in
part, to different nutritional habits. For example, the investigators of the, multi-cultural, Seven
Countries Study observed that the > dietary habits of people living in the northern European
regions of the study had an increased intake of saturated fat, while people living in the
Mediterranean region consumed fruits, vegetables more frequently and they used monoun-
saturated fat, as the main added lipid (Keys et al., 1986). Moreover, one of the Greek cohorts of
the Mediterranean region (i.e., the island of Crete) showed the lowest all cause and CVD
mortality rates during the first 10 years of the Seven Countries Study (Keys et al., 1986). This
observation led Ancel Keys and his colleagues to define a healthy dietary pattern that was
observed in these cohorts of the study, the Mediterranean diet. The aforementioned dietary
pattern observed, particularly in Crete in the middle 1950s, was rich in fruits, vegetables,
cereals and whole grain products, moderate in fish, potatoes, alcoholic beverages and dairy
products, and with rare (i.e., monthly) intake of meat and its products. Based on the inherent
characteristics of the Mediterranean diet, it can be observed that this dietary pattern is high in
monounsaturated fat, mainly due to the increased intake of olive oil, low in saturated fat, high
in complex carbohydrates, mainly from legumes, and high in fiber, mostly from vegetables and
fruits. Total fat is considered high, since it has been suggested that it is approximately 40% of
total energy intake, however, the monounsaturated-to-saturated fat ratio is around 2 (Matalas
et al., 2001). The high content of vegetables, fresh fruits, cereals, and olive oil guarantees a high
intake of beta-carotene, vitamins C and E, polyphenols, as well as various important minerals.
The Mediterranean diet is usually presented in a form of a diet pyramid, the Mediterranean
Diet Pyramid (> Figure 60‐1).
As we can see in > Figure 60‐1, this dietary pattern consists of:
Daily consumption: non-refined cereals and products (whole grain bread, pasta, brown
rice, etc), vegetables (2–3 servings/day), fruits (6 servings/day), olive oil (as the main added
lipid) and dairy products (1–2 servings/day).
Weekly consumption: fish (4–5 servings/week), poultry (3–4 servings/week), olives, pulses,
and nuts (3 servings/week), potatoes, eggs, and sweets (3–4 servings/week).
Monthly consumption: red meat and meat products (4–5 servings/month).
. Figure 60‐1
The Mediterranean Diet Pyramid. The figure represents recommendations for a healthy diet
(permission to copy from www.oldwayspt.org)
The Mediterranean diet is also characterized by moderate consumption of red or white wine
(i.e., more than 100–200 mL/day) and almost always during meals. All the key elements
included in the Mediterranean dietary pattern have been suggested to be responsible for the
beneficial effect on human health and especially on CVD.
3 Mediterranean Diet and CVD, the Epidemiologic and

Clinical Evidence
From the late 1960s, the Mediterranean diet received much attention, since it was associated
with a lower incidence of CVD and all cause mortality. Data from the Seven Countries Study
of 12,763 middle-aged men from 16 cohorts around the world, first suggested that people in
the Mediterranean cohorts of the Study live longer and die less frequent from CVD, compared
to the participants from northern regions of Europe and the US. This was mainly attributed
to their healthy dietary choices. As Ancel Keys wrote many years later, his concerns
about unhealthy diet as a public health problem began in the early 1950s in Naples, where
very low incidences of CVD were observed associated with what later came to call Das (2004)
the ‘‘good Mediterranean diet’’ (Keys, 1995). As Keys added ‘‘the main component of this diet
is mainly vegetarian, and differs from American and northern European diets in that it is
much lower in meat and dairy products and uses fruit for dessert’’.
More recently, investigators from a randomized clinical trial, the Lyon Heart Study
(de Lorgeril M et al., 1999), evaluating middle-aged patients with previous myocardial
infarction found that the benefits of a Mediterranean type of diet extended to the secondary
prevention of CVD. Those who followed the Mediterranean diet had 50–70% lower risk of
recurrent heart disease compared with those who followed a diet similar to the American
Heart Association diet (> Figure 60‐2).
. Figure 60‐2
Survival after myocardial infarction in the Lyon Heart Study patients. End points of the Lyon
Heart Study. One group was the experimental (i.e., adopted the Mediterranean diet) and the
other group was the control (i.e., adopted the Step I AHA diet) (de Lorgeril, 1999)
In addition, the CARDIO2000 investigators (Panagiotakos et al., 2001) studying a large

sample of middle-aged patients with acute coronary syndromes and age-sex matched controls
from several Greek regions, observed that adopting a Mediterranean diet was associated with
an adjusted 16% rate reduction in the likelihood of having a first event, irrespective of various
socio-demographic, lifestyle and clinical characteristics of the participants (> Figure 60‐3).
Another large prospective study involving 22,043 adults from Greece (the EPIC-Greek),
(Trichopoulou et al., 2003) observed a strong, inverse association between adherence to the
Mediterranean diet and death from coronary heart disease. In particular, approximately a 20%
increment in the Mediterranean diet score was associated with a 33% reduction in coronary
heart disease mortality, irrespective of sex, smoking status, level of education, body mass index
and physical activity. Furthermore, the benefits from the Mediterranean diet seems to hold
even in the elderly, since the investigators from the Health and Aging longitudinal study in
Europe (HALE) observed that adherence to a Mediterranean diet was associated with 23%
lower risk of death among older adults from various European countries (Knoops et al., 2004).
This evidence makes the Mediterranean diet a useful tool for the prevention of CVD.
. Figure 60‐3
Mediterranean diet and the likelihood of having acute coronary syndromes, by type of Greek
region. Adjusted effect of the adoption of Mediterranean type of diet on the likelihood of having
acute coronary syndromes, by type of Greek region. Results are presented as odds ratios and
95% confidence intervals and are from the CARDIO2000 epidemiological study (Panagiotakos
et al., 2002)
4 Potential Pathophysiological Mechanisms
Adopting a Mediterranean diet has been associated with favorable effects on arterial blood
pressure, lipoprotein levels, endothelial function, inflammation and oxidation process, as well
as insulin resistance (Chrysohoou et al., 2004; Matalas et al., 2001; Pitsavos et al., 2005; Ruit-
Gutierrez et al., 1996; Serra-Majem et al., 2006). The beneficial effects on surrogate markers of
CVD risk add biological plausibility to the aforementioned epidemiologic and clinical evi-
dence that supports a protective effect of the Mediterranean diet. Olive oil, a rich source of
monounsaturated fatty acids, is the main lipid component of the Mediterranean diet. Virgin
olive oil retains all the lipophilic components of the fruit, a-tocopherol, and phenolic
compounds with strong antioxidant and anti-inflammatory properties. In addition, tree
nuts, which are typical of the Mediterranean diet, have a favorable fatty acid profile and are
a rich source of nutrients and other bioactive compounds, which may beneficially influence
the risk for CVD, such as fiber, phytosterols, folic acid, and antioxidants. Frequent nut intake
has been associated with decreased CVD incidence rates. Walnuts differ from all other nuts
through their higher content of polyunsaturated fatty acids, particularly a-linolenic acid, a
plant n-3 fatty acid (Kouris-Blazos et al., 1999), which may confer antiatherogenic properties.
The ATTICA study investigators also reported the influence of Mediterranean diet on
various inflammatory markers (Chrysohoou et al., 2004). This finding, although novel, was
not surprising since some earlier studies documented the effect of w-3 fatty acids on various
anti-inflammatory markers, including inhibition of tumor necrosis factor and interleukin
production (de Lorgeril et al., 1994; Endres et al., 1989). In particular, the analysis of the
ATTICA study that was held in Athens greater area in 2001–2002, showed that participants
who were closer to the Mediterranean diet had lower C-reactive protein, interleukin-6,
homocysteine, and fibrinogen levels, as well as white blood cell counts, compared with those
who were away of this dietary pattern. A borderline decrease was also observed as regards
tumor necrosis factor-a, and amyloid-A levels. > Table 60‐1 illustrates the influence of
. Table 60‐1
Mediterranean diet and inflammation markers levels
Hyper-
Hypertensive Diabetic cholesterolemic
All subjects subjects subjects subjects Smokers
(n = 3,042) (n = 860) (n = 194) (n = 1,142) (n = 1,704)
Amyloid A 0.09 0.24 0.14 0.75 0.14 0.32 0.08 0.5 0.1 0.11
(per 1 mg/dL)
C-reactive 0.21 0.12* 0.20 0.31* 0.15 0.15* 0.17 0.17* 0.18 0.24*
protein
(per 1 mg/L)
Fibrinogen 12.7 1.15* 11.5 1.53* 10.6 1.0* 11.6 1.21* 12.2 1.23*
(per 1 mg/dL)
Homocysteine 0.83 0.25* 0.84 0.26* 0.77 0.83 0.67 0.35* 0.75 0.24*
(per 1 mmol/L)
Interleukin-6 0.25 0.34* 0.15 0.55* 0.17 0.31* 0.18 0.81 0.17 0.26*
(per 1 pg/mL)
TNF-a 0.25 1.23 0.17 1.68 0.21 1.32 0.17 0.90 0.17 0.3
(per 1 pg/mL)
White blood 0.26 0.11* 0.21 0.10* 0.16 0.17* 0.17 0.19* 0.16 0.18*
cell (1,000
counts)
The data are from the ATTICA Study (Chrysohoou et al., 2004). The results are from multi-adjusted regression
analysis and represented as b-coefficient standard error. The influence of the Mediterranean diet on inflammation
markers levels was tested using a special diet score (per 10/55-unit increase). *p < 0.05. TNF tumor necrosis-a factor
long-term adherence to the Mediterranean diet on inflammation and coagulation markers

among 3,042 apparently healthy adults, after taking into account socio-demographic, clinical,
lifestyle and behavioral characteristics. It is of interest that among the various food groups
evaluated in this study, fruits, vegetables and moderate alcohol intake (negative), as well as
meat and increased alcohol (positive) showed the highest degree of association with the
investigated inflammatory and coagulation markers (Chrysohoou et al., 2004).
Regarding the exact mechanisms that may explain the aforementioned relationship is hard
to conclude from this study. However, based on some experimental and clinical reports it
could be suggested that the high content of vegetables, fresh fruits, cereals and olive oil
guarantee a high intake of b-carotene, vitamins B6, B12, C and E, polyphenols and various
minerals, may explain these findings (Kromhout et al., 2002).
Alcohol consumption has received considerable attention as a factor with properties that
tend to reduce the risk of developing CVD events (Imhof et al., 2001). Its protective effect has
been illustrated in low quantity intake (like the Mediterranean dietary pattern) and has
been mainly attributed to a mild vasodilator effect, an increase in high density lipoprotein
cholesterol levels, and on the anti-inflammatory characteristics of flavonoids (mainly
contained in wine) and other anti-oxidative nutrients. The ATTICA Study investigators
observed a J-shaped association between alcohol consumption and arterial blood pressure
levels (> Figure 60‐4).
. Figure 60‐4
Arterial blood pressure levels and alcohol consumption. Systolic and diastolic blood pressures
(mean value ± 1 standard error) by alcohol consumption in the ATTICA Study participants
(Panagiotakos et al., 2003)
Regarding CVD risk factors, the Seven Countries Study (Kromhout D et al., 2002) first
reported that the protective role of the Mediterranean diet against atherosclerosis can be
partially attributed to the reduction in blood pressure levels. In a more recent epidemiological
study, the ATTICA study (Panagiotakos et al., 2003), the investigators observed that consum-
ing a Mediterranean diet was associated with 26% lower odds of being hypertensive, after
adjusting for demographic, clinical, and lifestyle variables. Moreover, the consumption of the
Mediterranean diet was associated with a 27% lower relative risk of being uncontrolled after
adjusting for these confounders.
With regards to obesity, the effect of Mediterranean diet is controversial. Some investigators
suggest that this inversely associated with body mass index (McManus et al., 2001; Mendez
et al., 2006; Panagiotakos et al., 2006; Schroder et al., 2004), whereas others did not find any
association (Goulet et al., 2003; Sanchez-Villegas et al., 2006; Trichopoulou et al., 2005). In
particular, McManus et al. studying 100 overweight adults in a randomized clinical trial
concluded that a Mediterranean-style diet, offers an alternative to a low-fat diet, with superior
long-term participation and with consequent improvements in weight loss (McManus et al.,
2001). Schroder and colleagues, studying about 3,000 men and women from a general popula-
tion found that people in the highest tertile of the Mediterranean diet score were 39% less likely
to be obese, after adjusting for several potential confounders (Schroder et al., 2004). Similarly,
the ATTICA study investigators found that greater adherence to the Mediterranean diet was
associated with a 51% lower odds of being obese and a 59% lower odds of having central obesity
compared with a non-Mediterranean diet, after controlling for age, sex, physical activity status,
metabolism, and other variables (Panagiotakos et al., 2006). Furthermore, high levels of
adherence to Mediterranean diet were associated with reduced incidence of obesity in the
Spanish cohort of about 28,000 not obese men and women of the European Prospective
Investigation into Cancer and Nutrition group (EPIC-Spain) (Mendez et al., 2006). In contrast,
the dose-response relationship between weight gain and adherence to the Mediterranean diet
observed in the SUN study, also from a Spanish population, became non-significant after
adjusting for potential confounders (Sanchez-Villegas et al., 2006). In accord to the latter
report, Trichopoulou et al., from the Greek-EPIC cohort reported that adherence to a Medi-
terranean diet was unrelated to body mass, with small differences depending on model choice
but having no practical consequences (Trichopoulou et al., 2005). Other observational studies
also failed to provide significant associations between dietary factors, either at a nutrient or a
dietary pattern level, and body mass or obesity status (Jorgensen et al., 1995; Togo et al., 2004).
During the last years, several researchers associated the Mediterranean diet with improve-
ments in the blood lipid profile (in particular HDL cholesterol and oxidized LDL)
(Kris-Etherton et al., 2001), while the ATTICA Study investigators showed that adherence to
the Mediterranean diet was associated with 20% lower odds of having the metabolic syn-
drome, irrespective of age, sex, physical activity status, lipids and blood pressure levels
(Panagiotakos et al., 2004).
At this point, it should be noted that adherence to Mediterranean diet in all the aforemen-
tioned studies is evaluated using dietary indices. However, several methodological issues have
arisen with regards to the use of these Mediterranean diet scores. Failure to include of lipid
intake in the index or accurately scoring of dairy products consumption, may be some of the
methodological concerns regarding the association between adherence to Mediterranean diet
and obesity.
5 Concluding Remarks
It is common knowledge that more or less all nutrient components are necessary for human
health. However, diets should consider a balanced intake of nutrient elements (World Health
Organization Study Group, 2003). During the past decades considerable evidence linked
balanced dietary patterns, like the Mediterranean, to lower rates of mortality, a decreased
prevalence of some metabolic disorders (e.g., hypertension, obesity), as well as a lower
incidence of CVD and some types of cancer. The Mediterranean diet is characterized by the
use of olive oil, which is important not only because it has several beneficial properties, but also
because it allows the consumption of large quantities of vegetables in the form of salads and
equally large quantities of legumes as cooked food. Other essential components of the Medi-
terranean diet are wheat, olives and grapes, and their various derivative products. Total lipid
intake may be high, but, the ratio of monounsaturated to saturated fats is much higher in the
Mediterranean regions than in other places of the world (Trichopoulou and Lagiou, 1997). A
potential explanation for the beneficial effect of this dietary pattern on human health is because
it is low in saturated fat, high in monounsaturated fat, mainly from olive oil, high in complex
carbohydrates, from legumes, and high in fiber, mostly from vegetables and fruits. The high
content of vegetables, fresh fruits, cereals and olive oil, guarantees a high intake of b-carotene,
vitamins C and E, polyphenols and various important minerals. These key elements have been
suggested to be responsible for the beneficial effect of this diet. Interestingly, during the last
years, several researchers associated the Mediterranean diet with improvements in the lipid
profile (in particular HDL cholesterol and oxidized LDL), decreased risk of thrombosis (i.e.,
fibrinogen levels), improved endothelial function and insulin sensitivity, reduced plasma
homocysteine concentrations and decreased body fat (Chrysohoou et al., 2004; Kris-Etherton
et al., 2001; Martinez-Gonzalez et al., 2002; Panagiotakos et al., 2002; Schroder et al., 2004;
Trichopoulou et al., 2003; World Health Organization Study Group 2003). Furthermore,
antioxidants represent a common element in the Mediterranean diet and antioxidant action
provides a plausible explanation for the apparent benefits. It is known that wild edible greens
frequently eaten in the form of salads and pies contain very high quantities of flavonoids.
Although there is no direct evidence that these antioxidants are central to the benefits of the
Mediterranean diet, indirect evidence from epidemiological data and the increasing under-
standing of their mechanisms of action suggest that antioxidants may play a role.
In 2001 the National Cholesterol Education Program suggested therapeutic lifestyle
changes in order to reduce the prevalence of CVD (National Cholesterol Education Program
Adult Treatment Panel III, 2001). Small changes can lead to great improvements, not for
achieving a perfect but for working towards a better and healthier lifestyle (> Figure 60‐5).
. Figure 60‐5
A conceptual model for lifestyle changes and better health. Conceptual model for reduced risk of
CVD, increased quality of life and life expectancy
However, it should be noted that although lifestyle changes can provide many benefits for
human health, and especially for the management of metabolic disorders, sometimes these
changes are difficult to implement and maintain. Among several factors related to lifestyle
habits the beneficial effect of diet has been highlighted in many clinical and epidemiological
studies (Kannel et al., 1976; Keys et al., 1986; Knapp, 1997; Kris-Etherton et al., 2001;
Martinez-Gonzalez et al., 2002; Panagiotakos et al., 2002; Trichopoulou et al., 2003; Tricho-
poulou et al., 1995; Trichopoulou and Lagiou, 1997).
Undoubtedly the Mediterranean diet, a healthy dietary pattern, is strongly associated with
better health status, including lower risk of CVD, and other metabolic disorders. Today, the
healthy Mediterranean diet is changing (Kafatos et al., 2000). Our challenge is to persuade
people to persist with the traditional Mediterranean diet.
Summary Points
An unhealthy diet is one of the main causes of death and disability in the world.
The Mediterranean diet is a healthy dietary pattern.
Clinical and epidemiological research has shown that the Mediterranean diet is strongly
associated with lower risk of CVD, cancer and other metabolic disorders.
The high intake of fruits, vegetables, olive oil, guarantees a high intake of vitamins B, C and
E, polyphenols and other various important minerals.
The Mediterranean diet can be implemented into other cultures, and therefore, it could be
a part of any country’s health policy.
References
Alberti KG, Zimmet P. (1998). Diabet Med. 15: 539–553. Keys A, Menotti A, Karvonen MJ, Aravanis C,
Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Blackburn H, Buzina R, Djordjevic BS, Dontas AS,
Stefanadis C. (2004). J Am Col Cardiol. 44: 152–158. Fidanza F, Keys MH. (1986). Am J Epidemiol. 124:
Das UN. (2004). Curr Hypertens Rep. 6: 66–73. 903–915.
de Lorgeril M, Renaud S, Mamelle N. (1994). Lancet. Keys A. (1995). Am J Clin Nutr. 61: 1321S–1323S.
343: 1454–1459. Kim SH, Reaven GM. (2004). Diab Vasc Dis Res.1: 68–75.
de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Knapp HW. (1997). Am J Clin Nutr. 65: 1687S–1698S.
Mamelle N. (1999). Circulation. 99: 779–785. Knoops KT, de Groot LC, Kromhout D, Perrin AE,
Endres S, Ghorbani R, Kelley VE. (1989). N Engl J Med. Moreiras-Varela O, Menotti A, van Staveren WA.
320: 265–271. (2004). JAMA. 292: 1433–1439.
Executive Summary of the Third Report of the National Kouris-Blazos A, Gnardellis C, Wahlqvist ML, Tricho-
Cholesterol Education Program (NCEP) Expert poulos D, Lukito W, Trichopoulou A. Br J Nutr.
Panel on Detection, Evaluation, and Treatment of 1999 Jul; 82(1): 57–61.
High Blood Cholesterol in Adults (Adult Treatment Kris-Etherton P, Eckel R, Howard B, Jeor S, Bazzare T.
Panel III). (2001). JAMA. 285: 2486–2497. (2001). Circulation. 103: 1823–1825.
Ford ES, Giles WH, Dietz WH. (2002). JAMA. 287: Kromhout D, Menotti A, Kesteloot H, Sans S. (2002).
356–359. Circulation 105: 893–898.
Goulet J, Lamarche B, Nadeau G, Lemieux S. (2003). Martinez-Gonzalez MA, Fernandez-Jarne E, Serrano-
Atherosclerosis. 170: 115–124. Martinez M. (2002). Eur J Nutr. 41: 153–160.
Grundy SM. (2004). J Clin Endocrinol Metab. 89: Matalas AL, Zampelas A, Stavrinos V (eds.). (2001). The
2595–2600. Mediterranean diet. The CRC Press, Boca Raton, FL.
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel McManus K, Antinoro L, Sacks F. (2001). Int J Obes
RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Relat Metab Disord. 25: 1503–1511.
Smith SC Jr, Spertus JA, Costa F. (2005). Circula- Mendez MA, Popkin BM, Jakszyn P, Berenguer A, Tormo
tion. 112: 2735–2752. MJ, Sanchez MJ, Quiros JR, Pera G, Navarro C,
Haffner S. (2006). Diabetes and the metabolic syndrome. Martinez C, Larranaga N, Dorronsoro M, Chirlaque
Atherosclerosis 7: S3–S10. MD, Barricarte A, Ardanaz E, Amiano P, Agudo A,
Haffner SM. (2006). Am J Cardiol. 97: 3A–11A. Gonzalez CA. (2006). J Nutr. 136: 2934–2938.
Imhof A, Froehlich M, Brenner H, Boeing H, Pepys M, Panagiotakos DB, Pitsavos C, Chrysohoou C, Stefanadis
Koenig W. (2001). Lancet . 357: 763–767. C, Toutouzas P. (2001). J Cardiovasc Risk. 8:
Jorgensen LM, Sorensen TI, Schroll M, Larsen S. (1995). 329–335.
Int J Obes Relat Metab Disord. 19: 909–915. Panagiotakos DB, Pitsavos C, Chrysohoou C, Stefanadis
Kafatos A, Verhagen H, Moschandreas J, Apostolaki I, C, Toutouzas P. (2002). East Mediterr Health J. 8:
Van Westerop JJ. (2000). J Am Diet Assoc. 100: 593–602.
1487–1493. Panagiotakos DB, Pitsavos C, Chrysohoou C, Tzioumis K,
Kannel WB, McGee DL, Gordon T. (1976). Am J Cardiol. Papaioannou I, Stefanadis C, Toutouzas PK. (2002).
38: 46–51. Int J Cardiol. 19: 141–147.
Panagiotakos DB, Pitsavos CH, Chrysohoou C, Skoumas J, Stone N, Saxon D. (2005). Am J Cardiol. 22: 15E–21E.
Papadimitriou L, Stefanadis C, Toutouzas PK. Togo P, Osler M, Sorensen TI, Heitmann BL. (2004). Int J
(2003). J Hypertens. 21: 1483–1489. Obes Relat Metab Disord. 28: 583–593.
Panagiotakos DB, Pitsavos CH, Chrysohoou C, Trichopoulou A, Kouris-Blazos A, Wahlqvist M,
Skoumas J, Tousoulis D, Toutouza M, Toutouzas Trichopoulos D. (1995). Br Med J. 311: 1457–1460.
PK, Stefanadis C. (2004). Am Heart J. 147: 106–112. Trichopoulou A, Lagiou P. (1997). Nutr Rev. 55:
Panagiotakos DB, Chrysohoou C, Pitsavos C, Stefanadis C. 383–389.
(2006). Nutrition 22: 449–456. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D.
Phillips GB. (1978). Am J Med. 65: 7–11. (2003). N Engl J Med. 348: 2599–2608.
Pitsavos C, Panagiotakos DB, Tzima N, Chrysohoou C, Trichopoulou A, Naska A, Orfanos P, Trichopoulos D.
Economou M, Zampelas A, Stefanadis C. Am J Clin (2005). Am J Clin Nutr. 82: 935–940.
Nutr. 2005; 82: 694–699. World Heart Organization Study Group. (1990). Geneva,
Reaven GM. (1988). Diabetes. 37: 1595–1607. Switzerland: World Heart Organization; Technical
Roberts CK, Barnard RJ. (2005). J Appl Physiol. 98: 3–30. Report Series, 797.
Ruit-Gutierrez V, Muriana FJ, Guerrero A, Cert AM, World Heart Organization Study Group. (2002). Geneva,
Villar J. (1996). J Hypertens. 14: 1483–1490. Switzerland: World Health Organization, Technical
Sanchez-Villegas A, Bes-Rastrollo M, Martinez-Gonzalez Report Series, 800.
MA, Serra-Majem L. (2006). Int J Obes (Lond). 30: World Health Organization Study Group. (2003).
350–358. Geneva, Switzerland: World Health Organization;
Schroder H, Marruqat J, Vila J, Covas MI, Elosua R. Technical Report Series, 916.
(2004). J Nutr. 134: 3355–3361.
Serra-Majem L, Roman B, Estruch R. (2006). Nutr Rev.
64: S27–S47.
61 Obesity’s Final Toll: Influence
on Mortality Rate,
Attributable Deaths, Years of
Life Lost and Population Life
Expectancy
K. R. Fontaine . S. W. Keith . J. A. Greenberg . S. J. Olshansky . D. B. Allison
1 World Wide Prevalence of Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
2 What is Obesity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
3 Effects of Obesity (via BMI) on Life and Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087

3.1 Historical Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087
3.2 Obesity and Mortality Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1088
3.3 Obesity and Attributable Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1088
3.4 Obesity and Years of Life Lost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089
3.5 Obesity and Population Life Expectancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
4 Effects of Obesity Operationalized via Other Indices . . . . . . . . . . . . . . . . . . . . . . . . . . 1092
5 Methodological Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1092

5.1 Reverse Causation, Confounding, Confounding by Indication . . . . . . . . . . . . . . . . . . 1092
5.2 Methods of Correcting Reverse Causation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
5.3 Correcting Reverse Causation and the Relation Between
Relative Risk and BMI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
5.4 Correcting Reverse Causation and the Health Hazards of Obesity . . . . . . . . . . . . . . 1093
5.5 Alternative Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
5.6 Regression Dilution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095
5.6.1 Description of Regression Dilution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095
5.6.2 Measurement-Error Methods of Correction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097
5.6.3 Secular Changes of True Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097
5.6.4 Modeling the Functional Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
5.6.5 Accounting for Uncertainty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101
5.6.6 Choosing Reference Categories and Cut Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102
6 Summary and Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103

1086 61 Obesity’s Final Toll
Abstract: > Obesity is recognized as a contributor to health maladies and premature death for
millennia and, given the worldwide increase in the prevalence of obesity, is currently one of the
greatest public health challenges of the twenty-first century. Apart from obesity’s association
with diseases in virtually every major organ system, it also adversely affects quality of life, and
appears to have a marked effect on duration of life. That is obesity, herein defined as ‘‘excess’’ of
body fat, probabilistically threatens future health and longevity. In this chapter we review the
association of obesity to indices of mortality, including: (1) mortality rate (MR), (2) attribut-
able deaths, (3) > years of life lost (YLL) and (4) population life expectancy. Overall, there
appears to be a J- or U-shaped association between body weight and mortality rate. The extent
to which the elevated mortality rate with low BMIs represents causation or merely association
remains the subject of debate and inquiry. The (presumed causal) association of obesity with
elevated mortality rate translates into a substantial number of > obesity-attributable deaths
and reduced life expectancy. There are several methodological and statistical issues involved in
estimating the effect of obesity on indices of longevity. Among these issues are > reverse
causation, > confounding, confounding by indication, > regression dilution, secular changes
in the true effects of obesity on mortality, accounting for uncertainty, and choosing reference
categories and cut-points. We review these issues and offer suggestions for future research.
List of Abbreviations: BIA, bioelectric impedance analysis; BMI, > body mass index; CVD,
cardiovascular disease; FFM, fat-free mass; FM, fat mass; HRs, > hazard ratios; IOM, Institute
of Medicine; MR, mortality rate; NHANES I, First National Health and Nutrition Examination
Survey; NHANES II, Second National Health and Nutrition Examination Survey; NHANES
III, Third National Health and Nutrition Examination Survey; NH2MS, NHANES II mortality
study; NHEFS, NHANES I epidemiological follow-up study; US, United States; WC, waist
circumference; WHR, waist-to-hip ratio; YLL, years of life lost
1 World Wide Prevalence of Obesity
Obesity is a great public health challenge. Its prevalence has tripled in many countries since the
1980s, and even developing countries such as Nigeria and Uganda are experiencing increased
obesity rates. Reasons for the increased prevalence of obesity are not fully understood and
almost certainly manifold (Keith et al., 2006).
Obesity is a concern because it appears to contribute to serious medical conditions such as
hypertension, arthritis, high cholesterol, sleep apnea, asthma, type-2 diabetes, heart disease,
stroke, and many forms of cancer. A salient consequence of obesity is its effect on duration of
life. Herein, we review the association of obesity and human duration of life. Specifically,
we examine the association of obesity with: (1) mortality rate (MR), (2) attributable deaths,
(3) years of life lost (YLL) and (4) population life expectancy. We discuss selected methodo-
logical issues in estimating the association of obesity with indices of longevity and finally
provide recommendations for future research.
2 What is Obesity?
Obesity is an excess of body fat. The excess of body fat can be one of total body lipid (fat) or
any anatomical depot of fat or adipose tissue. The ‘‘excess’’ could even relate to the morphol-
ogy and function of body fat. Hence, particularly enlarged adipocytes, independent of total fat
Obesity’s Final Toll 61 1087
mass or fat mass distribution, might be considered excessive. It is well documented that
enlarged depots of visceral (intra-abdominal) adipose tissue is strongly associated with adverse
health consequences above and beyond that of total body fat. It is possible that this is due to
enlarged visceral adipocytes that secrete certain inflammatory ‘‘adipokines’’ at higher levels
and other apparently beneficial substances at lower levels. The ‘‘excess’’ in the conceptual
definition of obesity, denotes an amount of body fat that is capable of impairing health or
reducing longevity (herein, unless otherwise noted, we use ‘‘longevity’’ to refer to duration of
life for individuals, rather than for populations). The impairment in health will not necessarily
be manifest immediately for all obese persons. Rather, for many, obesity ‘‘probalistically
threatens’’ future health and longevity.
Note that we have not defined obesity as a body mass index (BMI) (kg/m2) 30. That is
the standard and a useful operational definition of obesity today. However, it should not be
conflated with the conceptual definition. Some authors (e.g., Kragelund and Omland, 2005)
are beginning to question whether BMI greater than 30 is even useful as an operational
definition and whether the obesity research and treatment communities should move to
alternative and, presumably, more useful operational definitions. However, others disagree,
feeling that BMI 30 remains a useful definition of obesity (Bouchard, 2007). Moreover, the
deleterious effects of varying masses and morphologies of adipose tissue depots may differ as a
function of demographic factors such as age, ethnicity, and sex. Therefore, any operational
definition of obesity may work best if cutpoints or even the exact indicator used (e.g., waist
circumference or BMI) is allowed to vary as a function of these demographic factors. Whether
different definitions of obesity should be used as a function of demographic factors remains an
area of active inquiry.
3 Effects of Obesity (via BMI) on Life and Death
3.1 Historical Overview
That obesity decreases lifespan has been believed for millennia. For example, more than
500 years BC, Hippocrates observed that obesity predisposed to sudden death (Allison et al.,
submitted). A review of commentaries dating from the 1600s shows that many prominent
physicians and scientists considered obesity to be a disease, at least when it reached sever
proportions (Allison et al., 2008). Shakespeare’s Henry the IV remarked to the obese Falstaff
‘‘Make less thy body hence and more thy grace; Leave gormandizing; know the grave doth gape
for thee thrice wider than for other men.’’ Even the particularly deleterious effects of visceral
adipose tissue were presaged long ago. In 1875, Gardner wrote, ‘‘When fat is increased beyond
a certain limit, it may be regarded as a disease. . .When it accumulates locally, about or within
the vital organs – the heart, liver, – it shortens life.’’ Perhaps not surprisingly, around that same
time, ‘‘Thirty-four insurance companies pooled their data on males issued life policies
between 1870 and 1899. Special classes of risk were defined by . . .the observation that
abdominal girth exceeded the girth of the expanded chest (abdominal obesity). . . .Among
moderately overweight men, those with abdominal obesity experienced 133% of the expected
MR compared to 112% of the expected mortality for those who were not abdominally
obese. . ..These early actuarial findings, taken with more recent reports, establish that abdom-
inal enlargement. . .constitutes a major health hazard’’ (Kahn and Williamson, 1994). The idea
that visceral or abdominal obesity was especially harmful was then formalized by Vague (1947)
and a clear demonstration of its adverse impact on the risk of death at the individual level has
now been offered in modern times (Kuk et al., 2006).
It has also long been observed that the adverse impact of obesity may vary as a function of
demographic factors. In 1893, Adolf von Strümpell wrote ‘‘We have thus seen that corpulence
may sometimes be associated with grave and dangerous lesions; but, on the other hand, it
should be stated that this unfortunate condition by no means invariably exists. Not infre-
quently the corpulence remains moderate, in which case it is not really dangerous, however
inconvenient. . . .that seen in many elderly persons and in women is often comparatively free
from peril. These latter individuals are, to be sure, discommoded by their great weight, can
accomplish less than they used to, are easily put out of breath, and have a certain tendency to
catarrhal inflammations and rheumatic difficulties; but they escape the severer lesions above
enumerated. Even these apparently harmless conditions should not be disregarded by the
physician, as he can never be absolutely certain that grave complications may not be developed
eventually.’’ In many respects this statement rings as true today as it did over 100 years ago.
3.2 Obesity and Mortality Rate
Population studies of the effect of variations in BMI on mortality remain somewhat contro-
versial (Fontaine and Allison, 2003). A few studies (e.g., Manson et al., 1995) suggest that that
the relationship between BMI and MR is monotonically increasing meaning, essentially, that
one can never be too thin. Alternatively, some studies suggest that BMI has little influence on
longevity (e.g., Menotti et al., 1993). Most studies, however, lay between these extremes
suggesting that the association between BMI and mortality is U-shaped or J-shaped indicating
higher MRs at the low and high ends of the BMI distribution. That is, MR tends to increase not
only above a BMI value in the mid-to-high 20s (the nadir of the curve) but also as BMI
decreases from values in the mid-to-high 20s (e.g., Durazo-Arvizu et al., 1997). Although the
preponderance of BMI-mortality studies indicate that the association is U- or J-shaped, the
association can vary as a function of demographic characteristics such as age, sex, race and
other unidentified factors.
3.3 Obesity and Attributable Deaths
Another way to investigate and express obesity’s toll on duration of life is to estimate the
number of deaths attributable to obesity. Allison and colleagues (1999) used US data to answer
the question, ‘‘Of all the people who were alive at the beginning of 1991, how many fewer
would have died by the end of that year if all of the obese people alive at the beginning of the
year had not been obese and if those people had the hazard of those with a BMI just below the
cutoff for obesity (i.e., BMI 23–24.9)?’’ Estimating this quantity requires data on number of
deaths in the time period of interest, the distribution of BMI in the time period of interest, and
the hazard ratios (HRs) of mortality associated with various BMIs in the U.S. population.
When all subjects were included the estimate of obesity-attributable deaths was about 280,000.
The estimate based on HRs only on never smokers, to account for the possible confounding
effects of smoking on the BMI-MR association, was about 325,000.
Other investigators built on this work to estimate obesity-attributable deaths in the United
States (e.g., Flegal et al., 2005; Mokdad et al., 2004, 2005), Europe (Banegas et al., 2003), and
Canada (Katzmarzyk and Ardern, 2004; Luo et al., 2007) (see > Table 61-1). > Table 61-1 also
shows PAF-derived estimates of obesity-attributable deaths in several countries.
. Table 61-1
Obesity-attributable deaths estimated from selected countries
Author Country Approximate annual estimated deaths

Allison et al. (1999c) United States 285,000 all subjects
325,000 non-smokers in 1999
Mokdad et al. (2004) United States 400,000 in 2000
Mokdad et al. (2005) United States 365,000 in 2000
Flegal et al. (2005) United States 112,000 in 2000
Katzmarzyk and Ardern (2004) Canada 57,000 between 1985 and 2000
Luo et al. (2007) Canada 8,500 in 2004
Ni Mhurchu et al. (2005) New Zealand 3,100 in 1997
Allender and Rayner (2007) United Kingdom 67,000 in 2003/2004
Banegas et al. (2003) Spain 28,000 in 2002
Banegas et al. (2003) European Union 279,000 all subjects
304,000 non-smokers in 1997
3.4 Obesity and Years of Life Lost
Public health organizations and health care providers are interested in finding ways to convey
the effect of obesity at the level of the individual. One way to quantify individual effects is to
estimate the expected number of YLL as a function of obesity. YLL refers to the difference
between the number of years a person would be expected to live if she or he was not obese
(based on period life tables for populations within which the obese reside) and the number of
years expected to live if the person were obese (Fontaine et al., 2003).
We estimated YLLs for each integer defined BMI category at each integer defined year of
age by integrating information from three data sources: (1) US Life Tables of the conditional
probability of death during each year of life; (2) the NHANES III BMI distribution; and (3) the
NHANES I Epidemiological Follow-up Study (NHEFS) and NHANES II Mortality Study
(NH2MS) to derive HR’s for each BMI level in each year of adult life. We then estimated the
conditional probability of death within each age interval for each BMI category. The YLL for a
person of a given age in a given BMI category was then calculated as the difference of median
age relative to being in the reference category (i.e., a BMI of 24). > Figure 61-1 shows the YLL
results for white men and women. Consistent with BMI-MR analyses, YLL begins to be
apparent at BMI levels in the mid-to-high 20s. Moreover, the expected YLL was greatest at
younger ages. For example, a 20 year-old white male with a BMI of 45 or greater is estimated to
lose about 13 years of life due to obesity. Peeters and colleagues (2003), using data from the
well-known Framingham Heart Study, found similar results for whites. In our study, among
blacks (data not shown) the results suggested that obesity may not decrease life expectancy
until BMI reaches the low 30s among men, and the high 30s among women.
. Figure 61-1
Years of life lost among white men and women (Adapted from: Fontaine et al., 2003). YYL years of
life lost; BMI body mass index
3.5 Obesity and Population Life Expectancy
Although the life-shortening effect of obesity has been well-documented, its negative effect on
current and future life expectancy of national populations and survival prospects of existing
younger cohorts has rarely been studied. This issue is of interest to the insurance industry and
policy makers involved in evaluating the future solvency of age-entitlement programs because
of the speed with which adult and childhood-onset obesity are spreading across the globe.
Olshansky et al. (2005) estimated the effect of adult obesity on the life expectancy of the U.S.
population by calculating how life expectancy would change if adult obesity was hypothetically
eliminated.
Data for this analysis included age-race-sex-specific prevalence of obesity in the U.S. from
NHANES III, estimates of race-sex-specific death rates for people aged 20–85 with levels of
BMI that ranged from 17 to 45 and complete life tables for the U.S. by race and sex for year
2000. With empirical data linking BMI levels with age-specific conditional probabilities of
death, and with estimates of the proportion of the population at every adult age that is
currently obese, the effect of obesity on life expectancy was estimated by assuming that
everyone who is obese acquires the MR of those with the optimum BMI. The resulting
death rates were then used to generate a hypothetical life table for the U.S. population
under the assumption that obesity has been eliminated.
The results of this research suggest that life expectancy at birth in the U.S. would be higher
by 0.33–0.93 years for white males, 0.30–0.81 years for white females, 0.30–1.08 years for black
males, and 0.21–0.73 years for black females if obesity did not exist (> Figure 61-2). Assuming
current death rates associated with obesity remain constant in this century, the overall negative
impact of obesity on life expectancy in the U.S. is to reduce it by approximately one-half to
three-fourths of a year. This reduction in life expectancy is roughly equivalent to the negative
effect of all accidental deaths combined which include accidents, homicide and suicide.
Several facts suggest that the negative effect of obesity on the life expectancy of future
generations will not stay constant, but instead rise in the coming decades: (1) current estimates
of the impact of eliminating obesity are based on past trends when the prevalence was much
lower; (2) obesity prevalence, especially among children has continued to rise since these
estimates were published; (3) with obesity occurring at younger ages, the children and young
adults of today will carry and express obesity-related risks for more of their lifespan than
previous generations; (4) BMIs are shifting toward higher ranges throughout the age structure;
(5) death rates from diabetes have risen steadily in the last 20 years and are expected to rise
further as younger cohorts age; and (6) the medical treatment of obesity has been minimally
. Figure 61-2
Observed and projected negative effect of obesity on life expectancy at birth by race and sex for
the United States, 2000 (Adapted from: Olshansky et al., 2005)
successful. It has been estimated that the life-shortening effect of obesity could rise from its
current level of about two-thirds of a year to as much as 2–5 years or more in the coming
decades as the obese who are now at younger ages carry their elevated risk of death into middle
and older ages. Unless the adult and childhood obesity epidemic is held in check or amelio-
rated, these data suggest that this could be the first generation of children to live a shorter and
less healthy life than their parents.
4 Effects of Obesity Operationalized via Other Indices
The majority of obesity-longevity studies have used BMI as a proxy for obesity. This is because
BMI correlates well (0.70–0.80) with the percent of body weight as fat (e.g., Bouchard, 2007)
and is easy to collect. Yet, BMI is composed of two components, fat mass (FM) and fat-free
mass (FFM). Thus, using BMI as a proxy for obesity may mask any differential health
consequences associated with both FM and FFM.
> Bioelectrical impedance analysis (BIA) has been used as an inexpensive method to assess
FM and FFM. BIA equations have been devised to predict FM and FFM by using a measure-
ment of the body’s resistance to electrical current, gender, and age. BIA has been criticized for
being an imprecise predictor of adiposity and, possibly as a result, was not found to be useful
in predicting all-cause mortality independent of other adiposity measures (e.g., waist and hip
circumferences) (Simpson et al., 2007).
Because precise measurement of FM and FFM would require expensive radiological
imaging techniques such as MRI’s, waist circumference (WC), waist-to-hip ratio (WHR),
and skinfold measures are the most common proxies of > body composition in epidemiologic
studies (Simpson et al., 2007).
A growing number of cohort studies have compared BMI to WC, WHR, and skinfolds as
predictors of mortality (e.g., Simpson et al., 2007). On the whole, findings have been mixed.
Some studies have found that WHR and/or WC are better predictors of mortality than is BMI
(e.g., Bigaard et al., 2005), while others (e.g., Manson et al., 1995) have found BMI superior.
Still other studies (e.g., Bigaard et al., 2004) question the usefulness of WHR because waist and
hip circumference measures can have opposite associations with mortality. Few studies have
actually investigated the association of direct measures of FM and FFM or percent body fat to
all-cause mortality. Allison and associates (1997) generated hypothetical mortality models
(using real body composition data from 1,136 healthy subjects) in which MR increased
monotonically with FM and decreased monotonically with FFM. Using this model they
showed that a U-shaped association between BMI and mortality could occur even when: (1)
MR increased monotonically with FM; (2) MR decreased monotonically with FFM; and (3)
percent body fat increased monotonically, nearly linearly, with BMI. Thus, BMI may not
capture adequately the effect of adiposity on MR despite its high correlation with adiposity.
5 Methodological Issues
5.1 Reverse Causation, Confounding, Confounding by Indication
Factors that simultaneously increase MR and decrease body weight have also been hypothe-
sized to artifactually increase MR at low BMI. Such factors include smoking and serious
illnesses, including cardiovascular disease and cancer, and advanced aging. The reputed
artifactual increase in MR at low BMI due to such factors is commonly referred to as reverse
causation in the obesity research literature.
5.2 Methods of Correcting Reverse Causation
One commonly-used method involves excluding from the analysis participants who exhibit a
reverse-causation factor, such as smoking or serious illness. The justification is that the
included participants will be free of reverse causation because the excluded group will contain
all participants who could cause the bias. Another widely-used method involves excluding
early deaths during the follow up period. This method is based on the empirical finding that in
survival analyses excess mortality among underweight participants tends to occur early in
follow up while excess mortality among overweight participants tends to occur late in follow
up. A third method involves excluding participants with weight loss or weight change prior to
start of follow up. This method is based on evidence showing that at low BMI excess mortality
is largely confined to participants with prior weight loss (e.g. Rhoads and Kagan, 1983).
5.3 Correcting Reverse Causation and the Relation Between Relative

Risk and BMI
There are conflicting findings with regard to the effectiveness of methods for correcting reverse
causation. Among the researchers who have found these methods to be effective in decreasing
relative risk at low BMI is Garfinkel (1986) who, in the American Cancer Society Study,
concluded that the mortality of smokers in the lowest weight category was nearly double that
of nonsmokers in the same category. Lee et al. (1993) found that excluding participants with
illness and simultaneously excluding smokers and/or early deaths was effective in the Physicians
Health Study. Manson et al. (1995), and Hu et al. (2004) and others have found similar results.
Most investigations of the relation between MR and obesity have found that these methods
of correcting reverse causation do not remove the elevated risk of death at low BMI. The same
conclusion was arrived at by Seidel et al. (1996) in a prospective analysis of a Dutch cohort with
48,827 women and men, and by Sempos et al. (1998) analyzing the Framingham Heart Study
data. Allison et al. (1997a) found that excluding participants with prior ill health did not change
the relation between risk of death and BMI noticeably in older adults. Adams et al. (2006) found
that excluding smokers and early deaths only attenuated MR slightly for underweight partici-
pants even though it increased MR for overweight and obese participants in a cohort of 527,265
men and women in the National Institutes of Health-American Association of Retired Persons
cohort. Allison et al. showed by means of mathematical-statistical modeling (1997b), Monte-
Carlo simulation (1999a) and a meta-analysis involving data from 29 studies and 1,954,345
participants (1999b), that excluding early deaths is not a reliable method of reducing bias due to
occult disease, and could actually exacerbate the confounding (1997b).
5.4 Correcting Reverse Causation and the Health Hazards of Obesity
There have also been some conflicting reports on the effects of methods correcting for reverse
causation on estimates of the health hazards of obesity. Flegal et al. (2005), for instance, found
that excluding smokers, and early deaths made little difference to estimates of mortality
attributable to obesity in the NHANES I, II and III data. Also, Flegal et al. (2007) found
that excluding smokers, participants with serious illness, and early deaths, made little differ-
ence to estimates of attributable fractions of mortality associated with obesity in the NHANES
I, II and III data. On the other hand, Greenberg (2006) found that excluding smokers and
participants with serious illness increased estimates of mortality attributable to obesity by over
150% and 250%, respectively, in the NHANES I data. Based on a survival analysis in the
prospective Atherosclerosis Risk in Communities Studies database, Greenberg et al. (2007)
calculated that excluding smokers and participants with illness could increases estimates of
mortality attributable to obesity in the U.S. population by about 50%. It may also be
important to consider the type of BMI information available (i.e., measured or self-reported
height and weight). We (Keith et al., 2007) analyzed NHANES II data and found that, as
compared to measured BMI, self-reported BMI showed an upward bias in mortality hazard
among the overweight and obese in an apparently healthy never-smoker subcohort which was
not observed in the complete cohort.
5.5 Alternative Perspectives
Allison et al. (1997c), using body composition data from 1,137 health individuals have shown
that the elevated MR at low BMI may not be due to reverse causation. Instead, it might be the
result of an increasing relation between MR and fat mass and a decreasing relation between
MR and lean mass.
There are many reasons why existing techniques might not be effective, including:
1. Allison et al. (1997c) might be correct in that the elevated MR at low BMI might be a
natural consequence of the relative hazards of different body compartments, rather than
due to reverse causation.
2. Existing techniques involve excluding some participants with reverse-causation factors
who actually do not cause reverse causation. For instance, participants with evidence of
serious illness in a survival analysis may not have lost weight prior to the start of follow up,
and/or may not die during follow up. It is possible that exclusion of participants with
serious illness who do not contribute to reverse causation may actually cause other biases
in estimates of risk associated with obesity.
3. Participants who are not smokers and do not exhibit serious illness constitute small
portions of some cohorts, and could be different from most participants. Such differences
could lead to biases in estimates of MR associated with obesity.
4. Excluding smokers and participants with serious illness does not account for reverse
causation due to aging. Participants at older ages tend to lose weight and experience
increased mortality risk as a function of age and hence induce reverse causation, indepen-
dent of smoking and illness. Correcting for reverse causation due to smoking and illness
would not correct for reverse causation due to healthy non-smoker participants of
advanced age.
5. There is evidence that a wide variety of serious illnesses are more prevalent at low BMI.
Hence the effectiveness of excluding participants with serious illness may depend on the
definition used for serious illness. For instance, the definition used by Greenberg (2006)
was cardiovascular disease, cancer, emphysema or limitations in Activities of Daily Living,
whereas the definition used by Flegal et al. (2007) was cardiovascular disease and cancer.
Greenberg found that excluding serious illness yielded a 264% increase in mortality
attributable to obesity, whereas Flegal et al. found no noticeable effect.
6. Similarly, the effectiveness of excluding early deaths might depend on how many years of
early follow up are used in defining ‘‘early’’ (Allison et al., 1997b).
7. The effectiveness of a method for correcting reverse causation might depend on the length
of follow up which has varied widely in different studies involving corrections for reverse
causation. Underweight participants tend to die during the early years of follow up and
overweight participants tend to die during the later years of follow up, so that longer
follow up should decrease the relative risk at low BMI and increase relative risk for
overweight and obesity.
8. Differences between different cohorts in factors such as distributions of age, smoking and
serious illness could influence the effectiveness of particular methods for correcting reverse
causation.
5.6 Regression Dilution
5.6.1 Description of Regression Dilution
Within-person variation in a single-point observation of the independent or dependent

variable has long been known to weaken the association between these two variables in
regression analyses, including linear regression, non-linear regression, logistic regression,
and regression-model survival analyses. In one of the earliest reports of this phenomenon,
Spearman (1904) referred to it as ‘‘attenuation by errors.’’ It is associated with regression to
the mean, which Sir Francis Galton labeled ‘‘regression towards mediocrity’’ upon observing
that children of tall parents were on average shorter than their parents and children of short
parents were on average taller than their parents (Galton, 1885–1886). The attenuation of the
regression association between risk factor and risk was first referred to as regression-dilution
by MacMahon et al. (1976), because it attenuates or ‘‘dilutes’’ the strength of the association.
In human studies, within-person variation, also called intra-individual variation, is caused
by random within-person measurement error, and by other short- or long-term variations.
For body weight data such short- or long-term variations can be caused by factors such as
smoking, illness, and changes in diet or exercise.
Within-person variations that cause regression dilution also cause regression to the mean
patterns. Regression to the mean occurs in measurements of a number of different variables,
including blood pressure and cholesterol, alcohol intake, and body weight. > Figure 61-3.
A shows these patterns in body weight data in the First National Health & Nutrition Exami-
nation (NHANES I) Survey Epidemiologic Follow Up Study (Greenberg, 2006). Persons with
high body weight in a baseline survey tend to have lower weight before and after the survey;
and the opposite for persons with low weight in the survey. The average weight during the
months or years before or after the survey can be referred to as the ‘‘usual’’ weight. The within-
person variation can be thought of as the difference between the usual weight and the weight
measured in the survey. In a regression-model survival analysis, risk associated with a high
usual BMI will be attributed to a higher baseline BMI, and vice-versa for low usual BMI. This
may artifactually decrease the risk at high levels of baseline BMI (Clarke et al., 1999), and
suggest that the risk for obesity is lower than its true value. > Figure 61-3. B shows that in the
1096
61
. Figure 61-3
Weight change between the 1971–1975 and 1982–1984 surveys in the NHANES I Epidemiologic Follow Up Study vs. baseline Body Mass Index (BMI)
in 1982–1984 (a) and vs. average BMI in 1971-1975 and 1982--1984 (b), by age level in 1982--1984. Adapted by permission from Macmillan Publishers Ltd:
Int J Obes, Putative bases in estimating mortality attributable to obesity in the US population, copyright 2007. BMI body mass index
Obesity’s Final Toll
NHANES I Epidemiologic Follow Up Study there is almost no regression to the mean in a

measure of average BMI assessed over a 10-year period, a surrogate for usual BMI.
5.6.2 Measurement-Error Methods of Correction
Most methods for correcting regression dilution between one independent and the dependent
variable, referred to as univariate methods, are based on the classic measurement error model,
in which the error is additive, normally distributed with mean zero and constant variance
(Carroll et al., 2006, p. 3). Univariate measurement-error methods have been used to make
corrections in a wide variety of predictors in survival analyses. Methods have been developed
for correcting regression dilution in multivariate regression models, in which the relations
between more than two variables can be effected by regression dilution (e.g., Carroll et al.,
2006). Multivariate methods are generally based on assumptions similar to those described
above for univariate methods. They have been found to be useful in a number of circum-
stances. Further research is needed to apply these methods to understanding the relation
between adiposity and MR. Greenberg (2006) used one such method in a survival analysis in
the NHANES I Epidemiologic Follow Up Study to correct the hazard ratio (HR) for obesity
for regression dilution in BMI data. This method uses the average of several sequential
observations of BMI rather than a single-point observation as predictor, which yields a
predictor corrected for regression-dilution. The hazard ratio for obesity was then used to
make estimates of mortality attributable to obesity. With 18.5–25 Kg/m2 as the BMI referent,
the correction increased the hazard ratio for stage-1 obesity from 1.25 to 1.41, and mortality
attributable to obesity by 127%. Similarly, Greenberg (2006) found that the correction
increased the hazard ratio for obesity from 1.26 to 1.46, based on a 21–25 Kg/m2 BMI referent
in the prospective Atherosclerosis Risk in Communities database. They projected that such
an increase in hazard ratio could increase estimates of mortality attributable to obesity for the
U.S. population by about 90%. These findings suggest that estimates of the health hazards of
obesity derived from hazard ratios for obesity could be greatly underestimated if not corrected
for regression dilution in BMI.
5.6.3 Secular Changes of True Effects
It has been suggested that the strength of the BMI-mortality association has decreased over
calendar time because of improvements in treating obesity-associated medical co-morbidities
such as high cholesterol and hypertension. In this regard, Flegal et al. (2005) reported a decline
in the BMI-attributable deaths in NHANES II & III relative to NHANES I. Specifically, they
noted ‘‘. . .the largest difference is due to inclusion of mortality data from NHANES II and
NHANES III, which decreased estimates by 63% or more relative to NHANES I mortality data
alone (p. 1865).’’ They speculate that improvements in medical care, particularly for CVD,
might explain the decreased association between BMI and total MR. This speculation is
supported by additional analyses of NHANES data (Gregg et al., 2005) indicating that risk
factors for cardiovascular disease have declined markedly over the past 40 years in lean,
overweight, and obese BMI-defined categories. Specifically, compared with obese persons in
the early 1960s, obese persons in 1999–2000 had a significantly lower prevalence of high total
cholesterol, lower prevalence of hypertension, and lower smoking prevalence (32 vs. 20%).
In contrast, a recent analysis by Calle et al. (2005) of the Cancer Prevention Study II data
found no indication that the relative risks associated with overweight or obesity have decreased
in recent years. Indeed, the relative risks for overweight and obesity during the earliest survey
period (1982–1991) were slightly lower than those found in the latest period (1998–2002), even
when eliminating the potential confounding due to smoking and preexisting illness.
This conflicting evidence is subject to multiple interpretations, such as: (1) Either the
results of Flegal et al. (2005) or Calle et al. (2005) could be a statistical fluke (i.e., a type 1 or type
2 error, respectively), which is unlikely given the sample sizes used and the p-values obtained,
(2) The finding from Flegal et al. may reflect the true situation and result from improvements in
treatments for the negative sequelae of obesity, whereas Calle et al.’s results may stem from some
artifact that is not fully understood. For example, either the less representative sampling relative
to that used in NHANES or the use BMIs based on self-reported heights and weights may create
some yet-to-be specified bias, (3) The finding from Calle et al. may reflect the true situation
whereas Flegal et al.’s results may stem from some incompletely understood artifact of the
NHANES series. For example, the three NHANES studies used by Flegal et al. were inconsistent
in their criteria for subject inclusion and in the lengths of follow-up. Moreover, several
investigators have criticized Flegal et al. for not effectively controlling for or taking into account
‘‘reverse causation’’ whereby pre-existing disease causes weight loss and, thereby, confounds the
observed BMI mortality relation (e.g., Greenberg, 2005, 2007). Flegal et al. state that they
applied exclusions in supplementary analyses that account for these factors. However, others
contend that their approach was still not adequate.
Willett et al. (2005) points out that ‘‘lean persons are a mix of smokers, healthy active
persons, and those with chronic illness’’ and then contend that the analyses in Flegal et al. do
not successfully account for this diversity, partly because ‘‘the study apparently did not exclude
persons with known chronic disease at baseline.’’ While Willett et al. acknowledge that Flegal
and colleagues made efforts to address this potential confounding they opine that the efforts
were flawed or inadequate, particularly when dealing with elderly persons who exhibit a higher
prevalence of chronic disease and loss of lean mass. They conclude that ‘‘analyses that simply
use current BMI may be particularly misleading in this group.’’
We agree with Willett et al. about the possibility (indeed likelihood) of bias. This putative
reverse causation bias may contribute to: (1) the relatively low HRs among the overweight, (2)
the elevation in MR at the left end of the BMI curve, and (3) the association of age with a
decrease in the HR due to obesity. It may also contribute to the apparent reduction in the effect
of obesity on MR over calendar time. If one accepted the following premises: (1) Among
‘‘healthy’’ people, the environment promoted higher BMIs on average in the period of
NHANES-III’s collection than in the period of NHANES-I’s collection (almost a certainty,
given the markedly greater prevalence of obesity in NHANES-III vs. NHANESI); (2) Certain
forms of ill-health that lead to weight reduction or less weight gain over calendar time have not
lessened in their ability to affect individuals’ body weights and have not radically reduced in
frequency; then, the BMI distribution of healthy people would have been shifted to the right
and the distribution of people with some types of ill health would not have been shifted to the
right. This would result in greater overrepresentation of ill people at lower BMI levels in recent
times than in earlier times and consequently, greater confounding by preexisting disease and
greater underestimation of the ill effects of obesity on MR over calendar time.
At least three investigations offer evidence suggesting that the effect of BMI on MR has not
changed over time. First, Peeters et al. (2003) analyzed the Framingham data, tested for
proportionality and came to the conclusion (see below). Unlike Calle et al.’s study, Peeters
et al.’s cannot be criticized for using self-reported heights and weights or for insufficient follow-
up. Similarly, when analyzing the NHANESI and NHANES-II datasets combined, we (Fontaine
et al., 2003) came to the conclusion (see below). Finally, Greenberg (2006) investigated whether
the association between obesity and MR decreased with time, as found by Flegal et al. Generally,
he used the procedures described by Flegal et al. and the NHANES I and its follow-up, but there
are two important differences: (1) he adjusted for age in 5-year intervals, whereas Flegal et al.
stratified by age; and (2) he excluded participants with serious illness and death during the first
10 years of follow up. His conclusions (see text box) are consistent with our conjecture.
Thorough and well-designed analyses of multiple datasets including but not limited to those
mentioned above may help to resolve these important questions.
" ‘‘The proportional hazards assumption seemed appropriate for BMI, both by analysis of the
Schoenfeld residuals and by comparison of the Cox-derived hazard ratios for two distinct follow-
up periods with approximately equal numbers of events (follow-up years 4–28 [725 deaths]; and
follow-up years 29–40 [919 deaths]). For all nonsmokers, sex-adjusted hazard ratios for BMI group
II were 1.47 in period 1 . . .versus 1.53 in period 2. . ., and . . .for BMI group III were 2.05 . . .versus
2.27. . .’’ (Peeters et al., 2003).
" ‘‘To test the proportionality assumption, Schoenfeld residuals were computed . . .When the
proportionality assumption is met, Schoenfeld residuals should be independent of survival
time. Therefore, we plotted these residuals against survival time for each independent variable
involving BMI (i.e., BMI; BMI2; BMI*age; BMI2*age) and also computed the Spearman nonpara-
metric correlation between these residuals and survival time. This was performed separately for
each of the 4 sex and race groups. . . .plots gave no indication of a nonrandom pattern of
association. Moreover, across all 4 variables in all 4 groups, the largest Spearman r2 for the
correlation with survival time was less than 0.5% of the variance. Thus, there is substantial
evidence for the validity of the proportionality assumption’’ (Fontaine et al., 2003).
" ‘‘. . .after correction was made for reverse causation. . .the association between obesity and
mortality was no longer stronger for 1971–5 than for 1982–4. The HR for overweight, grade 1
obesity and grade 2–4 obesity for the 1971–5 analysis. . . were all within the 95% confidence
intervals of the equivalent HR for the 1982–4 analysis. . .. This finding did not appear to be affected
by the method used to correct for reverse causation. The HRs in the 1971–5 analysis were
essentially the same when two different methods were used to correct for reverse causation:
(1) only excluding participants with serious illness; and (2) only excluding deaths during the first
ten years of follow up. . . Flegal et al.’s finding that the association between obesity and mortality
decreased over time . . . [may be] an artifact of higher levels of uncorrected reverse causation in
their NHANES II and NHANES III analyses than in their NHANES I analysis’’ (Greenberg, 2006).
5.6.4 Modeling the Functional Form
A key assumption in fitting statistical models for estimating YLL is that there is an underlying
quantitative relationship between BMI and mortality risk. Furthermore, we assume that
mortality risk can be represented well by some estimable function of BMI (i.e., a functional
form). There are basically three different ways of treating BMI as a predictor in fitting models
to characterize the functional form of the relation between BMI and mortality risk: categori-
zation or continuously by either polynomials or piecewise polynomial splines.
Many investigators have applied (e.g., Manson et al., 1995) contiguous categories of BMI
set a priori by common standards (e.g. underweight: BMI < 18; normal: 18BMI < 25;
overweight: 25BMI < 30; and obese: 30≥BMI), quintiles, or some other arbitrary classifica-
tion rules. The reasons for this treatment of BMI are most likely borne out of convenience or
convention. Theoretically, categorization permits an examination of differences in risk among
categories and does not assume linearity or smoothness in the relationship. However, catego-
rization of BMI has significant disadvantages and limitations, including: (1) ignoring within-
category BMI information resulting in decreased statistical power; (2) insensitivity of trend
tests to non-monotonic relationships; (3) trend tests may indicate a trend, but cannot describe
it; (4) similar individuals within a BMI category are treated as though they have a uniformly
constant MR regardless of their actual BMI level; (5) the results can depend heavily upon how
the categories are chosen and (6) unfortunately, a priori classification boundaries of BMI are
not likely to represent ‘‘true’’ partitions that would group individuals according to the
underlying pattern of MR within a BMI category.
Using categorical analysis is a useful exploratory technique allowing one to evaluate the
extent to which any smooth function one has fit to the data adequately captures the true
pattern in the data and suggest alternative functions when appropriate and necessary. Follow-
ing this exploration, in the overwhelming majority (though perhaps not all) cases, we believe it
appropriate to return to a continuous metric and model any nonlinearity with appropriate
functions.
Treating BMI continuously with polynomial predictor variables does not degrade data,
tends to preserve power, and does not impose arbitrary cut-points. Curvilinear relationships
(U- or J-shaped) have commonly been detected between BMI and mortality risk when
modeled using polynomials of BMI. Modeling substantially nonlinear relationships via poly-
nomials will also have disadvantages and limitations, including: (1) lack of flexibility possibly
leading to biased estimation, particularly in the tails of the BMI distribution; (2) poorly
parameterized models; and (3) the model will smooth over any cutpoints between BMI groups
with different mortality risk relationships.
Piecewise polynomial spline modeling can offer some of the best features of continuous
and categorical modeling of BMI. Perhaps the most useful class of splines are known as free-
knot splines. They are models that incorporate ‘‘local’’ polynomials over contiguous regions of
BMI that are joined at so-called knots. In these models, the number and locations of the knots
are estimated simultaneously with the coefficients of the polynomials and other model
parameters. The knots may estimate the boundaries or thresholds of BMI groups experiencing
differing, non-uniform risk relationship. The localized estimation properties of these models
may help pick out the relationships in the tails of the BMI distribution where polynomial
models tend to lack flexibility. A disadvantage of using free-knot splines is that they can be
challenging to estimate and apply as most statistical software packages do not fit them
automatically.
Molinari et al. (2001) give an excellent discussion of how to utilize and interpret free-knot
splines with knots in the log hazard function where the risk, expressed as a hazard ratio, may
vary greatly. In a similar fashion, Keith et al. (2008) used free-knot splines to show how
increased BMI is associated with a steady decrease in risk of severe or frequent headache in
women with BMI below a threshold of 20 (an estimated risk threshold parameter in the
population) and a steady increase in risk above 20 (see > Figure 61-4). A similar analysis
stemming from categorized BMI would only describe an average risk of headache within each
. Figure 61-4
Results on Body Mass Index and risk of headache United States women surveyed in NHIS 2003
(Keith et al., 2008), BMI stands for boy mass index
arbitrary classification (say above vs. below the detected threshold of BMI = 20), thus giving
little information regarding the patterns of risk over the complete range of BMI.
5.6.5 Accounting for Uncertainty
We have described how complex summary statistics, such as YLL, have been computed to
estimate the effects of obesity on duration of life and risk of death. Here we will discuss how to
account for uncertainty in these estimates. First, recall that the estimates require input from
various data sources in terms of statistics that have their own uncertainty (i.e., standard errors)
that affects the overall level of uncertainty about the estimate output. Therefore, it is impor-
tant to begin analyses by carefully ascertaining correct estimates and standard errors for input.
In cases where the input statistics (e.g., hazard ratios that estimate relative risks) are estimated
from complex samples (e.g., the NHANES series), specialized software such as SUDAAN
(Research Triangle Institute, Research Triangle Park, NC) is required to account for the
nonrandom sampling design, apply sampling weights, and provide adjusted parameter esti-
mates and standard errors (Korn and Graubard, 1999). Once input estimates have been
computed, one approach to accounting for uncertainty in complex output estimates (e.g.,
YLL) is by either nonparametric resampling (i.e., bootstrap or jackknife procedures) within
the original data or by parametric resampling (i.e., Monte Carlo simulations) (Korn and
Graubard, 1999) to generate hypothetical distributions of input statistics that may be used to
generate a hypothetical distribution of output estimates from which standard errors and
confidence intervals may be obtained. Another more direct and comprehensive approach
has been developed by Parmigiani (2002). He describes how to build complex decision models
for explicitly differentiating and modeling all sources of uncertainty whether they stem from
individual-to-individual variability within a given population or limitations in the level of
knowledge of information input applied to the model.
5.6.6 Choosing Reference Categories and Cut Points
Whenever one calculates a statistic like YLL for people at a particular body size or degree of
fatness, there is an implicit ‘‘counterfactual.’’ The counterfactual is the alternative condition
that could, hypothetically, have existed. In the case of the YLL calculations and attributable
death calculations with respect to obesity, the counterfactual is some body size or BMI level
that a person could hypothetically have had that is different than the one they do have. For
example, if we say that a person with a BMI of 40 is estimated to and X YLL, we mean that their
life expectancy with a BMI of 40 is X years less than it would be if they had had some other
BMI, R. We use R to denote ‘‘reference’’ BMI or BMI category. This invites the question, to
which value should we set R? The answer is important because the choice of R can have major
effects on the estimated YLL.
In our work (Allison et al., 1999c; Fontaine et al., 2003) we have typically used values of R
for BMI between 23 and 25. Our rationale has been several-fold. First, such values are relatively
near the center of the distribution of BMI suggesting that they are attainable by many people
and, therefore, perhaps not too unreasonable goals to aim for. Second, such values are just
below the BMI cutoff for overweight (i.e., 25) indicating a value suggested as ‘‘healthy’’ by
leading authoritative bodies and yet also not extreme. Third, these are values that are roughly
associated with the lowest MR’s across many studies.
In similar research projects, others have sometimes used different values of R. One popular
choice has been to use a reference category that includes BMIs between 18.5 and 25. We think this is
misguided. Our reasoning involves the frequent observation that there is a U or J-shaped relation
between BMI and MR. Specifically, at BMI values below 23, MRs tend to increase. Therefore, when
obese oroverweight BMIs will appear less deleterious if compared to a reference category of 18.5–25
than,forexample23–25.Now,letusassumethattheelevationinMRatBMIvaluesbelow23are‘‘real,’’
i.e., that low BMIs truly cause increases in MR. Then surely we would not want to implicitly
orexplicitly advocate that people strive for have such low BMIs. In that case we would be comparing
one unhealthy range of BMI (overweight and obesity) to another unhealthy range (low BMIs).
This makes little sense. Alternatively, instead of assuming that the elevation in MR at BMI values
below23is‘‘real,’’i.e., thatlowBMIs trulycauseincreases inMR,wemightassumethat thiselevation
is simply due to confounding by occult disease. If that is the case, one is assuming that the elevated
values are not valid. If one assumes they are not valid, why would one include them in one’s
analysis?Forthesereasons,wethinkthatuseofthebroadreferencerangeofBMI18.5–25ismisguided
and reference ranges around 23–25 are far more reasonable.
6 Summary and Recommendations
Although obesity associates with myriad health problems and appears to reduce lifespan,
there are a host of methodological and statistical issues that preclude the exact calculation
of the toll obesity takes, yet reasonable estimates are available. In this chapter we have highlighted
the most salient issues, including confounding, reverse causation, secular changes, and the choice
of reference categories. However, because there are reasonable arguments that can be made to
underlie a variety of decisions concerning these issues, there is little consensus of ‘‘best practices’’
on how to analyze data to estimate the association of obesity to mortality indices. Nonetheless, we
believe the following recommendations will move us closer toward developing the best possible
estimates of the mortality consequences imposed by obesity.
Develop methods for correcting reverse causation, other than excluding smokers and
participants with obvious serious illness.
Search for factors other than smoking and serious illness that could cause confounding.
Explore the possibility that advanced aging causes reverse-causation.
Investigate the effects on the relation between adiposity and MR of correcting for
measurement-error in the adiposity predictor and covariates measured with error.
Model the functional relationship between adiposity and MR as accurately as possible.
This may call for new statistical methods of calculating YLL based on models of continu-
ous (not categorized) BMI.
Summary Points
The prevalence of obesity has tripled in many countries since the 1980s, and developing
countries such as Nigeria are also experiencing increased obesity rates.
Obesity is an excess of body fat that can be one of total body lipid (fat) or any anatomical
depot of fat or adipose tissue.
Obesity appears to contribute to serious medical conditions such as type-2 diabetes, heart
disease, stroke, and many forms of cancer.
That obesity decreases lifespan has been hypothesized, if not fully documented, for millennia.
With few exceptions, BMI-mortality studies indicate that the association is U- or J-shaped,
though the association can vary as a function of factors such as age, sex, and race.
The extent to which the elevated mortality rate with low BMIs represents causation or
merely association remains the subject of debate and inquiry.
Estimates of obesity-attributable deaths have been published for the United States and
several other countries.
Obesity appears to reduce life expectancy at the individual and population level.
The association of obesity, measured by indices such as circumference measures, skinfolds,
and bio-impedance, to indices of mortality has recently become an area of inquiry.
BMI may not capture adequately the effect of adiposity on MR despite its high correlation
with adiposity.
Reverse causation, confounding, regression dilution, accounting for uncertainty, and
choosing reference categories and cut-points are among the statistical issues that make it
challenging to generate definitive estimates of the association of obesity to indices of
mortality.
References
Adams KF, Schatzkin A, Harris RB, Kiphis V, Mouw T, Allison DB, Faith MS, Heo M, Kotler DP. (1997c). Am J
Ballard-Barash R, Hollenbeck A, Leitzmann M. Epidemiol. 146: 339–349.
(2006). N Engl J Med. 355: 763–778. Allison DB, Faith MS, Heo M, Townsend-
Allender S, Rayner M. (2007). Obes Rev. 8: 467–473. Butterworth D, Williamson DF. (1999b). Obes Res.
Allison DB, Downey M, Atkinson RL, Billington CJ, 4: 342–354.
Bray GA, Eckel RH, Finkelstein EA, Jensen MD, Allison DB, Fontaine KR, Manson JE, Stevens J,
Tremblay A (2008). Obesity. 16: 1161–1177. VanItallie TB. (1999c). JAMA 282: 1530–1538.
Allison DB, Gallagher D, Heo M, Pi-Sunyer FX, Gregg EW, Cheng YJ, Cadwell BL, Imperatore G,
Heymsfield SB. (1997a). Int J Obes Relat Metab Williams DE, Flegal KM, Venkat Narayan KM,
Disord. 21: 424–431. Williamson DF. (2005). JAMA. 293: 1868–1874.
Allison DB, Heo M, Flanders DW, Faith MS, Carpenter Hu FB, Willett WC, Li T, Stampfer MJ, Colditz GA,
KM, Williamson DF. (1999a). Ann Epidemiol. 9: Manson JE. (2004). N Engl J Med. 352: 2694–2703.
132–142. Kahn HS, Williamson DF. (1994). Int J Obes Relat Metab
Allison DB, Heo M, Flanders DW, Faith MS, Williamson Disord. 10: 686–691.
DF. (1997b). Am J Epidemiol. 146: 672–680. Katzmarzyk PT, Ardern CI. (2004). Can J Public Health.
Banegas JR, Rodriquez-Artalejo F, Graciani A, Villar F, 95: 16–20.
Herruzo R. (2003). Eur J Clin Nutr. 51(Suppl): Keith SW, Fontaine KR, Greenberg JA, Allison DB.
S18–S21. (2007). Obesity. 15(Suppl): A111.
Banegas JR, Lopez-Garcia E, Guiterrez-Fisac JL, Guallar- Keith SW, Redden DT, Katzmarzyk P, Boggiano MM,
Castillon P, Rodriquez-Artalejo F. (2003). Eur J Clin Hanlon EC, Benca RM, Ruden D, Pietrobelli AMD,
Nutr. 57: 201–208. Barger J, Fontaine KR, Wang C, Aronne LJ,
Bigaard J, Frederiksen K, Tjonneland A, Thomsen BL, Wright S, Baskin M, Dhurandhar N, Lijoi MC,
Overvad K, Heitmann BL, Sorensen TI. (2005). Int J Grilo CM, DeLuca M, Westfall AO, Allison DB.
Obes (Lond). 29: 778–784. (2006). Int J Obes. 30: 1585–1594.
Bigaard J, Frederiksen K, Tjonneland A, Thomsen BL, Keith SW, Wang C, Fontaine KR, Cowan CD, Allison DB.
Overvad K, Heitmann BL, Overvad K, Heitmann BL, (2008). Obesity 16: 377–383.
Sorensen TI. (2004). Obes Res. 12: 1042–1049. Korn EL, Graubard BI. (1999). Analysis of Health
Bouchard C. (2007). Int J Obes. 31: 1552–1553. Surveys. Wiley & Sons, New York.
Butler RN, Allison DB, Ludwig DS. (2005). N Engl J Kragelund C, Omland T. (2005). Lancet. 366: 1589–1591.
Med. 352: 1138–1145. Kuk JL, Katzmarzyk PT, Nichaman MZ, Church TS, Blair
Calle EE, Teras LR, Thun MJ. (2005). N Engl J Med. 353: SN, Ross R. (2006). Obesity (Silver Spring). 14:
2197–2199. 336–341.
Carmelli D, Halpern J, Swan GE. (1991). J Clin Epide- Landi F, Onder G, Gambassi G, Pedone C, Carbonin P,
miol. 44: 1341–1351. Bernabei R. (2000). Ann Intern Med. 160:
Carroll RJ, Ruppert D, Stefanski LA, Crainiceanu CM. 2641–2644.
(2006). Measurement Error in Nonlinear Models: A Lee IM, Manson JE, Hennekens CH, Paffenbarger RS.
Modern Perspective, 2nd ed. Chapman & Hall/CRC, (1993). JAMA. 270: 2823–2828.
Boca Raton, FL. Luo W, Morrison H, de Groth M, Waters C,
Clarke R, Shipley M, Lewington S, Youngman L, Desmeules M, Jone-Mclean E, Ugnat A-M, Dejar-
Collins R, Marmot M. (1999). Am J Epidemiol. dins S, Lin M, Mao Y. (2007). Chronic Dis Can. 27:
150: 341–353. 135–144.
Dhurandhar N, Lijoi MC, Grilo CM, DeLuca M, Westfall MacMahon S, Peto R, Cutler J, Collins R, Sorlie P,
AO, Allison DB. (2006). Int J Obes. 30: 1585–1594. Neaton J, Abbott R, Godwin J, Peto R. (1976). In:
Durazo-Arvizu R, McGee D, Li Z, Cooper R. (1997). J Fletcher CM, Peto R, Tinker CM, Speizer FE (eds.)
Am Stat Assoc. 92: 1312–1319. The Natural History of Chronic Bronchitis and
Dyer A, Stamler J. (1990). Lancet. 335: 765–774. Emphysema. Oxford University Press, Oxford, pp.
Flegal KM, Graubard BI, Williamson DF, Gail MH. 218–223.
(2005). JAMA. 293: 1861–1867. Manson JE, Willett WC, Stampfer MJ, Colditz GA,
Flegal KM, Graubard BI, Williamson DF, Gail MH. Hunter DJ, Hankinson SE, Hennekens CH, Speizer
(2007). Am J Epidemiol. 166: 975–982. FE. (1995). N Engl J Med. 333: 677–685.
Fontaine KR, Allison DB. (2003). In: Bray G, Bouchard C Menotti A, Descovich GC, Lanti M. (1993). Prev Med.
(eds.) Handbook of Obesity, 2nd ed. Dekker and 22: 293–303.
Co., New York, pp. 767–785. Molinari N, Daures JP, Durand JF. (2001). Stat Med. 20:
Fontaine KR, Redden D, Wang C, Westfall A, Allison DB. 237–247.
(2003). JAMA. 289: 187–193. Mokdad AH, Marks JS, Stroup DF, Geberding JL. (2005).
Galton F. (1885). J Antropol Inst 15: 246–263. JAMA. 293: 293–294.
Gardner J. (1875). Longevity: The means of prolonging Mokdad AH, Marks JS, Stroup JL, Gerberding JL. (2004).
life after middle age. Boston, W.F. Gill and Company. JAMA. 291: 1238–1245.
Garfinkel L. (1986). Cancer. 58: 1826–1829. Ni Mhurchu C, Turley M, Stefanogiannis N, Lawes CM,
Greenberg J. (2005). JAMA. 294: 552. Rodgers A, Vander Hoorn S, Tobias M. Public
Greenberg JA. (2006). Obesity. 14: 2071–2079. Health Nutr. (2005). 8: 402–408.
Greenberg JA. (2007). Int J Obes. 25: 1071–1078. Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al
Greenberg JA, Fontaine K, Allison DB. (2007). Int J Obes Mamun A, Bonneux L. (2003). Ann Intern Med 138:
(Lond). 31: 1449–1455. 24–32.
Olshansky SJ, Passaro D, Hershow R, Layden J, Carnes Simpson JA, MacInnis RJ, Peeters A, Hopper JL, Giles
BA, Brody J, Hayflick L, Butler RN, Allison DB, GG, English DR. (2007). Obesity 15: 994–1003.
Ludwig DS. (2005). N Engl J Med. 352: 1138–1145. Spearman C. (1904). Am J Psychol. 15: 72–101.
Parmigiani G. (2002). Stat Methods Med Res. 11: Vague J. (1947). Presse Med. 30: 339–340.
513–537. von Strümpell A (Published 1893). A Text-book of medi-
Rhoads GG, Kagan A. (1983). Lancet. 8323: 492–495. cine for students and practitioners. (Translated by
Seidel JC, Verschuren WMM, van Leer EM, Kromhout D. Herman Frank Vickery and Philip Coombs Knapp).
(1996). Arch Intern Med. 156: 958–963. D. Appleton and Co.
Sempos CR, Durazo-Arvizu R, McGee DL, Cooper RS, Willett WC, Hu FB, Colditz GA, Manson. (2005). JAMA.
Prewitt TE. (1998). Ann Epidemiol. 8: 289–300. 294: 551.
62 Financial Impact of Obesity
L. Barrios . D. B. Jones
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
2 Main Text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108

2.1 The Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
2.2 Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
2.3 Impact of Lifestyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
2.4 Social Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111
2.5 Economics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111
2.6 Weight Loss Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1117

1108 62 Financial Impact of Obesity
Abstract: > Obesity is associated with serious medical conditions, psychosocial problems,
and major health costs. Medical illnesses associated with obesity include diabetes mellitus,
hypertension, coronary artery disease, stroke, cancer, hyperlipidemia, gastroesophageal reflux
disease, obstructive sleep apnea, degenerative joint disease, and back pain. Socially, obese
individuals may suffer from discrimination at work, lower wages, inability to find a love
companion, and overall poor quality of life.
As the prevalence of obesity soars, the number of bariatric operations performed in the
United States has increased dramatically over the last decade. Weight loss surgeries such as the
laparoscopic Roux-en-Y gastric bypass, laparoscopic adjustable > gastric band placement, and
> sleeve gastrectomy are being performed more frequently in adults, and are now also being
performed in children and adolescents. This article summarizes findings from recent studies
discussing the financial implications of these trends. Specifically, we address the high medical
costs associated with weight related co-morbid illnesses, and we discuss the indirect costs to
employers of the obese workforce.
List of Abbreviations: > BMI, Body Mass Index; BPD, Biliopancreatic Diversion; > CEA,
Cost-Effectiveness Analyses; CMS, Centers for Medicare and Medicaid Services; LAGB,
Laparoscopic Adjustable Gastric Band; > NHANES, National Health and Nutrition Examination
Survey; > QALY, Quality Adjusted Life Year; > RYGBP, Roux-en Y Gastric Bypass; SG, Sleeve
Gastrectomy
1 Introduction
Obesity is a multifactorial disease of global proportions, and is associated with serious medical
conditions, psychosocial problems, and major health costs (Obesity by Numbers).
Currently, approximately one-third of Americans and an estimated 1.7 billion individuals
worldwide are obese. (Buchwald et al., 2004) Due in large part to this increase in obesity
prevalence, the number of bariatric operations performed in the United States has risen
dramatically over the last several years. The purpose of this article is to summarize findings
from recent studies which elucidate the financial implications of these dual trends. Specifically,
this article reviews the high medical costs associated with weight-related co-morbid illnesses
and discusses the indirect costs to society of obese employees.
2 Main Text
2.1 The Problem
In adults, obesity is defined by a BMI (Body Mass Index) of 30 kg m 2 or greater. BMIs greater
than or equal to 40 kg m 2 or, when accompanied by significant comorbidities (e.g., obstruc-
tive sleep apnea, diabetes mellitus, and hypertension) as 35 kg m 2 are considered morbid
obesity (> Table 62‐1).
Obesity is directly related to a number of serious medical conditions including gastro-
esophageal reflux disease, weight related arthropathies, depression, and cancer. Morbid obesity
has been further associated with early mortality – for example, a 25 year old morbidly obese
man will live approximately 12 years fewer than his normal weight counterpart (Buchwald
et al., 2004).
Financial Impact of Obesity 62 1109
Over the last 20 years, obesity has steadily increased in the United States; overall obesity is
estimated to have doubled from 1986 to 2000, while extreme obesity increased 400% from
1983 to 2000 (Sturm, 2002). According to Buchwald, 65% of the US adult population is
overweight or obese, 30.6% are obese, and 5.1% are extremely obese (Buchwald et al., 2004).
Results from the 2003–2004 National Health and Nutrition Examination Survey (NHANES),
using measured heights and weights, indicate that an estimated 66% of U.S. adults are either
overweight or obese, as shown in the graph on > Figure 62‐1 (from CDC. gov-National Health
and Nutrition Examination Survey (NHANES)).
. Table 62‐1
Comorbid conditions
Diabetes Mellitus
Hypertension
Coronary Artery Disease
Stroke
Cancer
Hyperlipidemia
Gastroesophageal Reflux Disease
Obstructive Sleep Apnea
Degenerative Joint Disease
Back Pain
Medical illnesses associated with obesity
. Figure 62‐1
Prevalence of adult overweight and obese has been increasing over the last 20 years
2.2 Children and Adolescents
Alarmingly, the prevalence of obese children and adolescents in the US has also increased
significantly, rising by as much as 50–60% in a single generation (Ogden et al., 2006).
Currently, approximately 2 million children suffer from extreme obesity (Collins et al.,
2007). Data from NHANES in > Table 62‐2 depicts the national increase in overweight
. Table 62‐2
Increasing prevalence of obesity in children and adolescents
There has been an increase in the prevalence of obesity in children and adolescents of all age groups over the last
30 years
children and adolescents from 1971 to 2004, where overweight is defined as those children
whose BMI > 95 percentile for age. All age groups demonstrate clearly significant increases in
percentage of overweight children; overweight adolescents (ages 12–19) in particular rose
from 6.1% in 1974 to 17.4% overweight in 2004. Although all ethnicities showed increases in
adolescent/child overweight and obesity, non-Hispanic white males, and non-Hispanic black
females show the greatest prevalence in overweight in 2004, at 19.1 and 25.4% respectively.
2.3 Impact of Lifestyle
Environmental changes have contributed greatly to the current obesity problem. For example,
over the last 30 years, the price of food has dropped by 12–14%, and more people than
ever have access to fast food establishments, and lifestyles have become more sedentary
(Lakdawalla, 2006). The cost of unhealthy food has decreased the most, while healthy meals
have become relatively more expensive. The bottom line is that sweets and fats both dropped
in price, 45 and 35% respectively, while fish, fruit, vegetables and dairy products have
increased in price by more than 50% (Herper, 2006; Lakdawalla, 2006).
Undoubtedly, today’s sedentary lifestyle has also contributed to the development of an
obese nation. The level of physical activity has diminished; more people drive longer distances
to work, and fewer people are exercising. A significant portion of the population sits in front
of a computer all day, and comes home to relax and watch television. The media, with
increasing advertisements for unhealthy foods, promotes the consumption of such products.
In the UK, approximately £522 million was spent in 2003 for food, soft drinks, and restaurant
advertisement on television (Boyce, 2007). Children spend more time playing video games as
opposed to playing sports, and their food selection is influenced by what is observed on
television (Boyce, 2007). Several studies have shown that children who spend more than 1 h
per week watching TV, are at increased risk of becoming obese, with an increased prevalence by
up to 2% for every additional hour viewed (Kaiser, 2004).
2.4 Social Issues
The socioeconomic consequences of morbid obesity are difficult to assess. Several studies have
shown that obese adolescents tend to have higher high school drop out rates, less marriage,
and higher rates of household poverty compared to their non-overweight peers. These
social issues not only permeate the lives of obese children and adolescents, but also
will burden them throughout their entire lives. Some of these issues include discrimination
at work, which may explain lower wages, inability to find a love companion, and overall
poor quality of life. The Medical Outcomes Study Short-Form Health Survey evaluated aspects
such as physical functioning, social functioning, mental health, and pain, and found obese
adults to score poorly in all these areas (Martin et al., 1998). Several studies have also shown
a causal relationship between poverty and obesity. In the ‘‘food choice constraint model,’’
the ability to purchase healthy foods is limited to those who are impoverished because
healthier choices are generally more expensive. Their budget will only allow them to purchase
the generally cheaper high-calorie foods (Martin, 2005). Therefore, treating obesity has
become not only a major health care priority, but also an important social concern.
2.5 Economics
Medical costs alone are significantly higher for obese individuals, especially those with asso-
ciated chronic medical conditions, such as type 2 diabetes, cardiovascular disease, fatty liver, or
other metabolic disorders. Indeed, obese and morbidly obese patients are reported to have
14–38% more physician visits, 48% more inpatient days and 1.8 times the number of annual
pharmacy dispenses – particularly for diabetic and cardiovascular medications (Finkelstein
et al., 2005b; Thompson et al., 1998). A Healthcare for Communities survey reports that
financially, this translates into higher annual medical (36%) and medication (77%) costs for
obese patients compared to normal weight controls (Sturm, 2002). Similarly, Finkelstein et al.’s
study used data from the 1998 Medical Expenditure Panel Survey (MEPS) and Behavioral Risk
Factor Surveillance System (BRFSS) survey and found an increase in annual medical costs in the
order of 37% ($1,486) for Medicare patients and 39% ($864) for Medicaid patients (Finkelstein
et al., 2004). In sum, these figures represent roughly 5–7% of the total US annual health care
expenditures – or $75–93 billion per year, $17 billion of which is financed by Medicare and $21
billion by Medicaid (Finkelstein et al., 2004; Gates et al., 2006; Herper, 2006).
Intriguingly, obese individuals also experience significantly more non-medical expenditures
compared to normal weight controls, which is most apparent in the form of workplace absentee-
ism. Obese employees are reported to be 1.7 times more likely to have seven or more absences due
to illness during a 6-month period than their leaner counterparts (Finkelstein et al., 2005b;
Thompson et al., 1998; Tucker and Friedman, 1998). Finkelstein found that an obese male
employee costs approximately $670 more annually, and an obese female cost an average of
$1,200 more annually than normal weight workers (Finkelstein et al., 2005a, b). On a grander
scale, Thomson et al. report that such obesity-attributable absenteeism cost employers roughly
$2.4 billion in 1998; others estimate this figure to be up to $4 billion annual dollars (Finkelstein
et al., 2005b; Herper, 2006; Thompson et al., 1998). At this point in time, obesity-related health
care costs exceed spending for smoking and problem drinking (Sturm, 2002).
Unforeseen weight-related costs have been identified in fuel requirements for transport:
airplanes are now required to use an extra 350 million gallons of fuel each year for the added
weight of obese and overweight flyers, costing approximately $275 million, according research-
ers at Cornell University (Herper, 2006). By the same token, an obese person will spend an extra
5 cents on gasoline per year compared to a normal weight individual (Herper, 2006).
Part and parcel, perhaps, of weight-related comorbidities, a large portion of disability
claims now are secondary to obesity related conditions. One of the largest US disability
carriers, Unum Provident, reported a ten-fold increase in the incidence of obesity-related
disability claims; according their databases, the average annual health care cost for a disabled,
obese individual is $51,023 ($30,567 medical + $8,720 disability payments + $11, 736 morbid
medical costs) (> Bariatric Surgery Policy Guidance). Other studies have shown similar
results: Arena and colleagues evaluated the association between BMI and short-term disability
amongst 19,061 employees of a large financial services corporation. Their group found that
BMI is an independent predictor for short term disability events, resulting in loss of produc-
tivity and increased costs to the companies (Arena et al., 2006). The overall message is that
with enhancement of employee health, there should be fewer disability claims and a decrease
in the costs incurred by employers.
It is no surprise that obese individuals also have more injuries at work and increased claims
to workers’ compensation. In evaluating the relationship between BMI and the number and
type of workers’ compensation claims in 11,728 Duke University employees, Ostbye et al.
reported a link between higher BMI and greater number of claims, mostly related to lower
extremity, wrist, hand, and back injuries from falls or slips, lifting, and exertion. This study
also identified a linear relationship with BMI and lost workdays, medical claims costs ($51,091
vs. $7,503), and indemnity claims costs ($59,178 vs. $5,396) (Ostbye et al., 2007). A similar
investigation in a US aluminum manufacturing company noted that, of 7,690 employees, at
least 85% of injured workers were considered overweight or obese. Occupational injuries to
the leg or knee were the most common among workers with higher BMI’s (Pollack et al.,
2007). Given the strong association between worker’s injuries and BMI, employers should
consider it a priority to provide alternatives for employees to attain a healthy weight.
Several studies have examined the impact of obesity on occupational choice and wages and
observed that a higher incidence of obese individuals, particularly white obese women, have
relatively low paying occupations, are less likely to obtain managerial or professional positions,
and have higher rates of poverty when compared to same age normal weight females (Averett
and Korenman, 1999; Cawley, 2000; Finkelstein et al., 2005b; Pagan JA, 1997). Cawley et al.
noted that an increase in weight of two standard deviations (roughly 65 pounds) is associated
with a 7% decrease in wages of white women (Cawley, 2000). Clearly, the economic ramifica-
tions of obesity are numerous, and have permeated all layers of society.
2.6 Weight Loss Surgery
According to the 1991 National Institute of Health Consensus Statement, indications for
bariatric surgery include those patients who have a BMI greater than 40, or greater than 35
with serious comorbid conditions (NIH, 1991). For such morbidly obese individuals, bariatric
surgery is a very valuable treatment option, providing not only an effective weight loss therapy,
but frequently leading to an amelioration of many comorbid conditions, reducing mortality,
and ultimately decreasing health care costs. In a 2004 meta-analyses of 136 studies, totaling
22,094 patients, Buchwald et al. showed that weight loss surgery resulted in the resolution of
diabetes in 76% of subjects; hypertension was eliminated in 61.7%; obstructive sleep apnea in
85.7%; and high cholesterol levels decreased in more than 70% of patients who underwent
bariatric surgery (Buchwald et al., 2004). Similarly, Christou et al. reported an absolute
mortality reduction of 5.49% (P < .001) when comparing 1,035 patients who underwent
weight loss surgery with 5,746 controls in a 5 year follow-up (Christou et al., 2004). Oster et al.
found that a sustained weight loss of around 10% initial body weight reduced hypertension,
hypercholesterolemia, and type 2 diabetes, decreased the expected lifetime incidence of heart
disease and stroke, increased life expectancy by 2–7 months, and reduced expected lifetime
medical care costs by $2,200–5,300 (Oster et al., 1999).
Paralleling adult trends, bariatric procedures performed in obese children and adolescents
have become increasingly frequent in an effort to decrease associated health problems and
. Figure 62-2
Roux-en-Y Gastric Bypass (RYGB) involves the creation of a small (<30 ml) gastric pouch and a
Roux limb (typically 75–105 cm) that reroutes a portion of the alimentary tract to bypass the
distal stomach and proximal small bowel. Illustrations reprinted with permission from Atlas of
Metabolic and Weight Loss Surgery, Jones et al., Cine-Med, 2008
decrease the incidence of premature mortality. These patients must meet the same criteria for
BMI, and must further have achieved complete psychological maturity, obtained 95% of their
estimated adult stature, participated in the decision making, and have a general understanding
of the bariatric procedure and associated lifestyle change (Tsai et al., 2007).
Inge et al. found a threefold increase in bariatric case volumes for adolescents from 2000 to
2003, and Tsai et al. reported 2,744 bariatric procedures performed on adolescents between
1996 and 2003, encompassing approximately 0.7% of total bariatric procedures performed
that year (Inge et al., 2007; Tsai et al., 2007). Further, in 2003, 69.9% of adolescents undergoing
bariatric surgery were female, 87.1% of the cases were Roux-en-Y Gastric Bypass (RYGB), and
81.4% had a private payer source (Tsai et al.). A 20-year follow up of 33 adolescent bariatric
surgeries (subjects were aged 12–18 at the time of surgery, and 85% of the surgeries performed
were RYGB) showed that most subjects maintained weight loss after 14 years, and nearly all
comorbid conditions resolved after the first year (Sugarman, 2003). Retrospective studies
further demonstrate the success of bariatric surgery in young populations; from 1999 to 2005,
11 patients under 18 years of age who underwent laparoscopic RYGB again showed a 70%
. Figure 62-3
Adjustable Gastric Band (LAGB) involves the placement of a band around the upper stomach,
thereby creating a small gastric pouch. The degree of stomach constriction can be adjusted by
modifying the amount of saline injected into a subcutaneous port, which is linked to a balloon
within the band. Illustrations reprinted with permission from Atlas of Metabolic and Weight Loss
Surgery, Jones et al., Cine-Med, 2008
resolution and/or improvement of preoperative comorbidities, as well as improved self-

esteem, social functioning and academic/employment productivity (Collins et al., 2007).
Financial Impact of Bariatric Surgery.
Approximately 102,794 bariatric operations were performed in 2003, and it is estimated
that by 2010, over 200,000 operations will be performed (Santry et al., 2005). Although the
length of stay, mortality, and complication rates for bariatric surgery have all decreased, the
cost of bariatric surgery is steadily rising. The Betsy Lehman Center for Patient Safety and
Medical Error Reduction Expert Panel on Weight Loss Surgery reported that national coverage
for Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, and biliopancreatic
diversion with l > duodenal switch (BPD) are permitted by Centers for Medicare and
Medicaid Services (CMS). > Figure 62‐2–62‐4 However, the mean cost per operation for all
payers has increased 21% from $12,872 in 1998 to $15,533 in 2003 (HCUP). It is interesting to
note that 80–90% of all bariatric cases performed are the gastric bypass, and that, while this
procedure can be performed either open and laparoscopically, the laparoscopic approach
. Figure 62-4
Biliopancreatic Diversion with Duodenal Switch (BPD) creates malabsorption by maintaining a
flow of bile and pancreatic juice through the biliopancreatic limb. The common-channel length
of small intestine in the duodenal switch severely limits caloric absorption. The extent of
malabsorption is thought to be a function of the length of the common channel. Illustrations
reprinted with permission from Atlas of Metabolic and Weight Loss Surgery, Jones et al.,
Cine-Med, 2008
seems to be more cost effective – the average total cost of laparoscopic RYGB falls in the range
of $17,660, in comparison to the higher cost of the open gastric bypass, which averages $20,443
(Paxton and Matthews, 2005). > Figure 62‐2 Other studies report similar results, where the
laparoscopic adjustable gastric band appears to be the more expensive ($25,355), and the
laparoscopic gastric bypass the most economical ($19,794) – even when compared to the open
approach ($22,313) (Livingston, 2005). A relatively newer procedure, the sleeve gastrectomy,
fairs between the laparoscopic adjustable gastric band and the laparoscopic gastric bypass in
terms of cost. This procedure is performed by removing a large portion of the greater curve of
the stomach. > Figure 62‐5 Clinical pathway development has also been shown to decrease
costs to providers involved in weight loss surgery.
. Figure 62-5
Sleeve gastrectomy (SG) SG consists of the restrictive component of the duodenal switch (DS), a
vertical resection of the greater curvature of the stomach creating a long tubular stomach along
the lesser curvature. The pylorus and part of the antrum are preserved. Illustrations reprinted
with permission from Atlas of Metabolic and Weight Loss Surgery, Jones et al., Cine-Med, 2008
Several researchers have studied the cost-effectiveness of weight loss surgery in the Unites
States and other countries. In the US, Cost-Effectiveness Analyses (CEA) have shown that
gastric bypass has provided net savings in the order of $35,000 per QALY (Quality Adjusted
Life Year), and appears to be more cost effective for women than for men, for individuals with
a BMI greater than 40, and for younger individuals (Craig and Tseng, 2002). Similarly, Clegg
et al.’s study out of the United Kingdom reported that in comparison with nonsurgical
management of obesity, weight loss operations were indeed more cost effective at £11,000 per
QALY (Clegg et al., 2003). Snow and colleagues reported a savings of approximately
$240,566.04 dollars per year on medications by patients undergoing gastric bypass (Snow
et al., 2004). Improvement or elimination of comorbid conditions, decreased requirement for
medications of chronic disease, such as diabetes and hypertension, and increase in productiv-
ity, are all considered in the cost-effectiveness analysis of weight loss surgery.
In summary, obesity is a major health, social, and financial issue permeating all layers of
society in the US and abroad. This disease is not exclusive to adults, and has similar, if not
worse implications for children and adolescents. Weight loss surgery is a viable and effective
alternative, and has been shown to improve quality of life, decrease morbidity and mortality,
and decrease overall health costs to individuals and their employers. As a nation, we must
increase awareness of this major health and socio-economic problem, and promulgate the
extensive benefits of weight loss surgery.
Summary Points
Prevalence of obesity is increasing in adults and children.

Weight loss surgery is a viable alternative for obese individuals.
Medical and non-medical costs in the obese population are growing.
Weight loss surgery is associated with a decrease or eradication of medical problems,
increased life expectancy, and improved morale.
Weight loss will ultimately result in decreased costs to the individual and society.
Acknowledgments
We would like to thank Ms. Shannon Fischer for her editorial assistance with this manuscript.
References
Arena VC, Padiyar KR, Burton WN, Schwerha JJ. (2006). Christou NV, Sampalis JS, Liberman M, Look D, Auger S,
J Occup Environ Med. 48: 1118–1124. Mclean AP, Maclean LD. (2004). Ann Surg. 240:
Averett S, Korenman S. (1999). Int J Obes Relat Metab 416–423; discussion 423–424.
Disord. 23: 166–173. Clegg A, Colquitt J, Sidhu M, Royle P, Walker A.
Bariatric Surgery Policy Guidance. (2003). Int J Obes Relat Metab Disord. 27:
Betsy Lehman Center for Patient Safety and Medical 1167–1177.
Error Reduction. Commonwealth of Massachusetts, Collins J, Mattar S, Qureshi F, Warman J, Ramanathan R,
Expert Panel on Weight Loss Surgery. Schauer P, Eid G. (2007). Surg Obes Relat Dis. 3:
Boyce T. (2007). Obes Rev. 8(Suppl 1): 201–205. 147–152.
Buchwald H, Avidor Y, Braunwald E, Jensen MD, Commonwealth of Massachusetts Betsy Lehman
Pories W, Fahrbach K, Schoelles K. (2004). JAMA. Center for Patient Safety and Medical Error Reduc-
292: 1724–1737. tion Expert Panel on Weight Loss Surgery: executive
Cawley J. (2000). Body Weight and Women’s Labor report. Conference on 12/12/07.
Market Outcomes. NBER Working Paper Paper no. Craig BM, Tseng DS. (2002). Am J Med. 113: 491–498.
7841. National Bureau of Economic Research, Finkelstein E, Fiebelkorn C, Wang G. (2005a). Am J
Cambridge, U.S. Health Promot. 20: 45–51.
Finkelstein EA, Fiebelkorn IC, Wang G. (2004). Obes Res. Obesity by Numbers. Obesity in America. http://www.
12: 18–24. obesityinamerica.org/
Finkelstein EA, Ruhm CJ, Kosa KM. (2005b). Annu Rev Ogden CL, Carroll MD, Curtin LR, Mcdowell MA, Tabak
Public Health. 26: 239–257. CJ, Flegal KM. (2006). JAMA. 295: 1549–1555.
Gates D, Brehm B, Hutton S, Singler M, Poeppelman A. Ostbye T, Dement JM, Krause KM. (2007). Arch Intern
(2006). Aaohn J. 54: 515–520. Med. 167: 766–773.
HCUP Cost and utilization project (HCUP). Agency Oster G, Thompson D, Edelsberg J, Bird AP, Colditz GA.
for Healthcare Research and Quality. Rockville, (1999). Am J Public Health. 89: 1536–1542.
MD. http://www.ahrq.gov/data/hcup/ Pagan JA, Davila A. (1997). Social Science Quarterly. 78:
Herper M. (2006). The Hidden Cost of Obesity. Available 756–770.
at: Forbes.Com. Paxton JH, Matthews JB. (2005). Obes Surg. 15: 24–34.
Inge TH, Xanthakos SA, Zeller MH. (2007). Int J Obes Pollack KM, Sorock GS, Slade MD, Cantley L, Sircar K,
(Lond). 31: 1–14. Taiwo O, Cullen MR. (2007). Am J Epidemiol. 166:
Kaiser. (2004). The Role of Media in Childhood 204–211.
Obesity. The Henry J. Kaiser Family Foundation, Santry HP, Gillen DL, Lauderdale DS. (2005). JAMA.
Washington, D.C. 294: 1909–1917.
Lakdawalla D. (2006). Cheap Food, Societal Norms And Snow LL, Weinstein LS, Hannon JK, Lane DR, Ringold
the Economics of Obesity. Wall St J. http://online. FG, Hansen PA, Pointer MD. (2004). Obes Surg. 14:
wsj.com/public/article/SB115634907472843442- 1031–1035.
_xrNV2M1Pwf8pAcQYUWEBITP1LQ_20060901. Sturm R. (2002). Health Aff (Millwood). 21: 245–253.
html Sugerman HJ, Sugerman EL, De Maria EJ, Kellum JM,
Livingston EH. (2005). Am J Surg. 190: 816–820. Kennedy C, Mowery Y, Wolfe LG. J Gastrointest
Martin LF, White S, Lindstrom W Jr. (1998). World J Surg. 2003 Jan; 7(1): 102–107; discussion 107–108.
Surg. 22: 1008–1017. Thompson D, Edelsberg J, Kinsey KL, Oster G. (1998).
Martin SS. (2005). From Poverty to Obesity: Exploration Am J Health Promot. 13: 120–127.
of the Food Choice Constraint Model and the Tsai WS, Inge TH, Burd RS. (2007). Arch Pediatr Adolesc
Impact of an Energy-Dense Food Tax. http://www. Med. 161: 217–221.
allbusiness.com/accounting/1086324-1.html Tucker LA, Friedman GM. (1998). Am J Health Promot.
National Health and Nutrition Examination Survey 12: 202–207.
(NHANES). NHANES can be accessed at: www.
cdc.gov
NIH. (1991). Gastrointestinal surgery for severe obesity.
Proceedings of a National Institutes of Health Con-
sensus Development Conference. Bethesda, MD.
63 Burden of Disease
Attributable to Obesity and
Overweight: Korean Focus
Seok-Jun Yoon . Jae-Hyun Park
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
2 Measuring Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123

2.1 Disease Selection Related to Overweight and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123
3 Relative Risk (RR) Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123

3.1 The Burden of Disease Attributable to Overweight and Obesity . . . . . . . . . . . . . . . . . . 1126
3.2 Disease Burdens Attributable to Overweight and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . 1127
4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133

1120 63 Burden of Disease Attributable to Obesity and Overweight: Korean Focus
Abstract: This chapter estimates the burden of disease attributable to > overweight and
> obesity in Korea using disability adjusted life-years (DALYs). First, overweight- and obesi-
ty-related diseases and their > relative risks (RRs) were selected by systematic review. Second,
population-attributable fractions (PAFs) were computed by using a formula that included RR
and the prevalence of exposure (Pe) of overweight and obesity. Third, the DALYs of over-
weight and obesity-related diseases in Korea were estimated. Finally, the attributable burden
(AB) of disease due to overweight and obesity was calculated as the sum of the products
resulting from the multiplication of the DALYs of overweight and obesity-related diseases by
their PAFs.
In 2002, the disease burden attributable to overweight was 827.1 PYs overall: 732.6 for men
and 922.9 for women per 100,000 persons. The disease burden attributable to obesity was
260.0 PYs overall: 144.2 for men and 377.3 for women. The burden of diabetes attributable to
overweight and obesity was higher than that of any other disease in both genders. The disease
burden attributable to overweight was 3.2 times higher than that attributable to obesity. In
conclusion, the greatest disease burden attributable to a high BMI occurred among those with
only moderately elevated BMI scores, such as overweight, and not those with extremely
elevated BMI scores, such as obesity. This suggests that population-based, public health
intervention is more effective than high-risk group-focused strategies at reducing the burden
of disease attributable to overweight and obesity in Korea.
List of Abbreviations: AB, attributable burden; AICR, American Institute For Cancer Re-
search; BMI, > body mass index; DALY, disability adjusted life-year; GBD, > global burden of
disease; PAFs, population attributable fractions; Pe, prevalence of exposure; PYs, person-years;
RR, relative risk; WHO, World Health Organization; YLL, years of life lost due to premature
death; YLD, > years lived with disability
1 Introduction
Overweight and obesity are major > risk factors for > cardiovascular diseases, > stroke,
diabetes, hypertension, hyperlipidemia, musculoskeletal diseases and cancer, and they are
serious public health threats (British Nutrition Foundation Task Force, 1999; National Task
Force on the Prevention and Treatment of Obesity, 2000). The increased prevalence of
overweight adds a socioeconomic burden to the public health system. In Korea, obesity-
related medical expenses accounted for 0.91% to 1.88% of the total national health expendi-
ture in 1998, and this socioeconomic burden is likely to increase in the future (Jeong et al.,
2002). The socioeconomic burden associated with overweight and obesity is higher globally
and the 25% ($1.7 billion) of global population has been suffered from obesity and overweight
(WHO, 2000). In Korea, the socioeconomic burden related to obesity and overweight also
increases from 11.7 billion won in 1998 to 11.8 billion won in 2005.
In a 1997 report reflecting the opinions of health care experts from 25 countries, WHO
predicted that obesity would emerge as a great health risk, as was the case with smoking, in the
twenty-first century, even though it has been largely ignored as a public health concern, despite
its effect on a number of health care problems. In Korea, the prevalence of overweight
increased from 25.0% in 1998 to 32.2% in 2001 and to 35.1% in 2005 in the male population
and from 27.0% in 1998 to 27.9% in 2001 and to 28.0% in 2005 in the female population
during the same period (> Figure 63-1). The prevalence of obesity also increased from 1.7% in
1998 to 3.96% in 2001 in the male population and to 3.4% from 3.0% in the female
Burden of Disease Attributable to Obesity and Overweight: Korean Focus 63 1121
. Figure 63-1
Age-standardized prevalence of overweight in Korea (1998–2005). Source: Ministry of Health and
Welfare (2007). National Health and Nutrition Survey, Korea
population during the same period (Ministry of Health and Welfare, 2001, 2007). Notably, the
prevalence of overweight in the male population increased in all age groups over a 7-year
period. In the female population, the prevalence of overweight only increased in the age group
older than 60 during the same period (> Figure 63-2). The burden of disease attributable to
overweight and obesity is expected to be a significant public health concern in coming years.
The burden of disease attributable to obesity can be prevented through public health
policy. For this reason, in its 2002 report, WHO introduced the use of the Disability-Adjusted
Life Year (DALY) as the unit of measurement for the Global Burden of Disease (GBD)
attributable to 26 risk factors, including obesity (Murray and Lopez, 1996; Murray et al.,
2002). However, the WHO report only presented the burden of disease attributable to obesity
for six sub-regions, and not for specific countries, such as Korea. Furthermore, the report
discussed uncertainties in estimation of disease incidence, duration, and disability weighting.
Uncertainty in this risk assessment is by far dominated by the absence or limitations of direct
studies on exposure, hazard, and background disease burden. The extrapolation of hazard
from the limited number of studies in other populations, which was the case in the WHO
report, is another source of potential error (Rodgers et al., 2004). Therefore, as the public
health impact of obesity increases, accurate assessment of the burden of disease attributable to
overweight and obesity is an essential step in establishing public health interventions designed
to prevent obesity-induced diseases in Korea. With the above background, this study aimed to
estimate the burden of disease attributable to overweight and obesity by gender and age using
the DALY in Korea and to provide a basis for developing the public health strategies needed for
the prevention of overweight and obesity.
Investigators usually use the Disability Adjusted Life-Year (DALY) developed by World
Health Organization (WHO) researchers to quantify the burden of disease. The DALY is the
sum of the life years lost due to disability and premature death. DALY-based estimation of
disease burden is useful for measuring the general state of health in a population, comparing
the state of health and public health systems between countries, setting national priorities in
the allocation of limited medical care resources and evaluating the cost-effectiveness of public
health interventions (Murray and Lopez, 1996).
1122
. Figure 63-2
63
Age-standardized prevalence of overweight by sex and age group in Korea (1998–2005). Source: Ministry of Health and Welfare (2007). National Health
and Nutrition Survey, Korea
Burden of Disease Attributable to Obesity and Overweight: Korean Focus
2 Measuring Methods
2.1 Disease Selection Related to Overweight and Obesity
According to the WHO criteria for overweight and obesity, overweight was defined as a BMI
between 25 and 29.9 kg/m2 and obesity was defined as a BMI of 30 kg/m2 or above in the
present study (National Institutes of Health Clinical, 1998).
Overweight- and obesity-related diseases were selected through a systematic review using
MEDLINE, the Korean National Assembly Library, and the Research Information Center for
Health to screen for studies with the following key words: obesity, body weight, overweight, fat,
adiposity and body mass index (BMI). In addition, a manual search was conducted by referring
to the citations identified through the recent reviews of obesity-induced diseases (Bray, 2003a, b;
National Institute of Health, 2000; Reilly et al., 2003; Visscher and Seidell 2001).
The criteria used for the selection of research evidence were as follows: it had to have
(1) been published between 1970 and 2004 (2) suggested obesity-induced diseases, (3) sug-
gested relative risk (RR) values of obesity-induced diseases, (4) used BMI to define obesity,
and (5) met the 2b level of evidence in the Oxford Center for Evidence Based Medicine Levels
of Evidence (CEBM, 2003) (a cohort study and a systematic review using cohort). We used
the research results of the American Institute for Cancer Research (AICR) (1997) to identify
obesity-induced cancers (American Institute for Cancer Research, 1997). The AICR study
classified the association between the incidence of cancer and overweight or obesity into the
following four categories based on systematic reviews and the opinions of investigators:
convincing, probable, possible and insufficient. The study further stressed that the impact of
overweight and obesity on those captured under the latter two categories was not clear due
to a lack of evidence or divided opinions among investigators. The study included research
evidence related to endometrial, breast and renal cancers, as these cancers are included
under the ‘‘convincing’’ and ‘‘probable’’ categories. Finally, recent studies have shown that
Asian populations have a higher risk of metabolic syndromes, such as type 2 diabetes and
cardiovascular disease (CVD), than Caucasians (Deurenberg et al., 2000, 2001, 2002, 2003;
Dudeja et al., 2001; Norgan, 1994; Tai et al., 1999). Therefore, for diabetes, > ischemic heart
disease (IHD), and stroke, we selected studies performed in Asian populations (Jee et al.,
2005; Oh et al., 2004; Zhou, 2002). More specifically, studies performed in a Korean
population were selected for diabetes and ischemic heart disease (Jee et al., 2005; Oh et al.,
2004). For stroke, we selected studies performed in a Chinese population (Zhou, 2002)
because we could not find a study that suggested the relative risk values of obesity-induced
stroke for a Korean population.
A total of 63 studies met the selection criteria, and 14 diseases related to overweight and
obesity were identified (> Table 63-1) (Cedergren, 2004; Felson et al., 1997; Furberg and
Thune, 2003; He et al., 2001; Jee et al., 2005; Kato et al., 1992; Layde et al., 1982; Marshall,
2002; O’Brien et al., 2003; Oh et al., 2004; Van den Brndt et al., 2000; Weintraub et al., 2002;
Zhou, 2002).
3 Relative Risk (RR) Assessment
The study used the RR ratio suggested in previous studies with the highest possible degree of
internal and external validity for each of the 14 diseases related to overweight and obesity.
. Table 63-1
Overweight- and obesity-related diseases and their relative risks (RRs)
Disease [NO scalea] ICD-10 Males Females

Ischemic heart disease (Jee et al., I20–I25 2.39 (BMI 25–25.9) 2.39 (BMI 25–25.9)
2005) 2.61 (BMI 26–26.9) 2.61 (BMI 26–26.9)
3.26 (BMI 27–27.9) 3.26 (BMI 27–27.9)
3.29 (BMI 28–28.9) 3.29 (BMI 28–28.9)
3.54 (BMI 29–29.9) 3.54 (BMI 29–29.9)
4.37 (BMI 30) 4.37 (BMI 30)
Stroke (Zhou et al., 2002)b I60–I69 1.061 (BMI per 1.061 (BMI per 2-unit
2-unit difference) difference)
Congestive heart failure (He et al., I50.0 1.23 (BMI 27.8) 1.34 (BMI 27.8)
2001)
Diabetes mellitus (Oh et al., 2004) E10–E14 2.74 (BMI 25–<27) 5.08 (BMI 25–<27)
3.65 (BMI 27–<29) 10.77 (BMI 27–<29)
4.31 (BMI 29–<30) 11.19 (BMI 29–<30)
4.79 (BMI 30–<32) 13.15 (BMI 30)
6.75 (BMI 32–<34)
7.98 (BMI 34)
Osteoarthritis (Felson et al., 1997) M15–M19 1.0 (BMI per 5-unit 1.8 (BMI per 5-unit
difference) difference)
Endometrial cancer (Furberg and C54–55 Age < 50 years
Thune, 2003) 1.90 (BMI 25–30)
2.59 (BMI 30)
Age 50 years
2.28 (BMI 30)
Breast cancer (Van den Brandt C50 Postmenopausal
et al., 2000) (age < 50 years)
1.14 (BMI 21–<23)
1.15 (BMI 23–<25)
1.26 (BMI 25–<27)
1.43 (BMI 27–<29)
1.21 (BMI 29–<31)
1.29 (BMI 31–<33)
1.27 (BMI 33)
b
Renal cancer (Marshall, 2002) C64 1.35 (BMI 25–<30) 1.35 (BMI 25–<30)
1.70 (BMI 30–<35) 1.70 (BMI 30–<35)
2.05 (35–<40) 2.05 (35–<40)
2.40 (BMI 40) 2.40 (BMI 40)

63 1125
Disease [NO scalea] ICD-10 Males Females

Preeclampsia (O’Brien et al., O10–O14 Reproductive age (age
2003)b 15–50 years)
1.54 (BMI 25–<30)
1.81 (BMI 30–<35)
2.08 (35–<40), 2.35
(BMI 40)
Maternal hemorrhage O44–O46, O67, Reproductive age (age
(Cedergren, 2004) O72 15–50 years)
1.19 (BMI 30–<35)
1.35 (35–<40)
1.70 (BMI 40)
Obstructed labor (Cedergren, O64–O66 Reproductive age (age
2004) 15–50 years)
2.14 (BMI 30–<35)
2.82 (35–<40)
3.14 (BMI 40)
Birth asphyxia and birth trauma P03, P10–P15, Reproductive age (age
(Cedergren, 2004) P20–P29 15–50 years)
1.61 (BMI 30–<35)
2.13 (35–<40)
2.52 (BMI 40)
Cholecystitis (Kato et al., 1992) K80–K81 1.4 (BMI 23.8–25.8) 1.36 (BMI 22.5–<25)
(Layde et al., 1982) 1.4 (BMI 23.8–25.8) 1.74 (BMI 25.0–<27.5)
3.26 (27.5–<30)
5.54 (BMI 30)
Cataract (Weintraub et al., 2002) H25–H26 1.07 (BMI 25–27.7) 1.07 (BMI 25–<27.8)
1.20 (BMI 27.8) 1.20 (BMI 27.8)
Source: Park et al. (2006)
a
NO scale: Newcastle-Ottawa quality assessment scale
b
This study was a meta-analysis of cohort studies. Therefore, we did not measure Newcastle-Ottawa Quality
Assessment scales
Two of the authors separately assessed the internal validity of the cohort studies that met the
selection criteria using the Newcastle-Ottawa Quality Assessment scales for cohort and case-
control studies (Kashyap et al., 2004). This assessment instrument is designed to determine the
internal and external validity of cohort studies by assessing the representative of the study
population, control group, accuracy in measuring exposure to risk factors, explanation for
predicted study results, control of major conflicting variables, accuracy in analyzing results,
appropriateness of follow-up period, and number of subjects who withdrew from the study.
Each item was rated on a scale from 0 to 9. The validity of this assessment instrument was proven
in previous studies (Kashyap et al., 2004). The study first selected research evidence that had the
highest score, and if two research evidences had the same score, the one that included research
subjects of both genders and had the broader range of age groups was selected. The RR ratio
and Newcastle-Ottawa Quality Assessment scales of the selected studies are presented in
> Table 63-1. The RR ratio suggested in the selected literature was used to calculate the
burden of disease.
3.1 The Burden of Disease Attributable to Overweight and Obesity
The following processes were performed to estimate the burden of disease attributable to
overweight and obesity:
First, the population attributable fraction (PAF) was calculated using the prevalence of
overweight and obesity in the population (pe), and the RR described in the previous
paragraph were calculated using formulas 1 and 2. Pe was calculated using data from the
2001 National Health and Nutrition Survey of Korea. Formula 1 was used to estimate the
attributable burden (AB) of a risk factor, while formula 2 was used to estimate the PAF (all) of
the incidence or mortality attributable to joint effects of multiple risk factors (Walter, 1976;
Weintraub et al., 2002). For instance, if there are three RR ratios at a given exposure level, k is 3
in formula 2. The values of Pe1 and RR1 can be applied at the first exposure level (i = 1).
PeðRR 1Þ
PAF ¼ ðFormula 1Þ
PeðRR 1Þ þ 1
1
PAF ðallÞ ¼ 1 ðFormula 2Þ
P
k
Pei RRi
i¼1
Second, DALY was calculated for each disease by adding the > years of life lost (YLL) due to
premature mortality and the years lived with disability (YLD). The data used to calculate DALY
were derived using the 2001 life table from the National Statistical Office (NSO) for calculating
life expectancy at birth and the NSO’s 2001 statistics of the cause of death and age at the time of
death. The incidence of diseases needed for the YLD calculation was ascertained from insurance
claim data submitted to the National Health Insurance Corporation during the period from
1998 through 2001. The average age at disease onset and the morbidity period were calculated
using the DISMOD II model. This study also used the same assumptions adopted by Global
Burden of Disease researchers (Murray and Lopez, 1996). However, in 2003, we newly developed
the Korean disability weights for 123 diseases using the person trade-off method and used it to
reflect the actual condition of Korean patients (Lee et al., 2003).
Third, WHO has suggested three methods for measuring the burden of disease attributable
to a risk factor, such as overweight and obesity, which include the burden of disease and injury
attributable to the risk factor (AB), the overall burden of disease (burden: B) and PAF, a
contribution of a risk factor to the proportion of disease, and injury attributable to the risk
factor in a population (formula 3).
AB ¼ B PAF ðFormula 3Þ
AB was calculated for each disease and injury category by multiplying the disease burden by
the PAF value. The burden of disease attributable to the risk factor equals the sum of all
attributable disease burdens. The AB of overweight and obesity was calculated for each disease
category by multiplying its DALY by PAF, and the disease burden attributable to overweight
and obesity was calculated by summing all ABs.
3.2 Disease Burdens Attributable to Overweight and Obesity
The disease burdens attributable to overweight and obesity are presented by gender in
> Table 63-2. The burden of disease attributable to overweight was 827.1 person years (PYs)
per 100,000 persons. In terms of the size of overweight-attributable burden (AB), diabetes had
the most significant overweight-attributable disease burden overall (535.8 PYs, 64.8%), as well
as for men (435.2 PYs, 59.4%) and women (637.8 PYs, 69.1%), followed by ischemic heart
disease (205.1 PYs, 24.8%), stroke (50.6 PYs, 6.1%), cholecystitis (20.9 PYs, 2.5%), osteoar-
thritis (6.8 PYs, 0.8%) and breast cancer (4.0 PYs, 0.5%).
The burden of disease attributable to obesity was 260.0 PYs per 100,000 persons. Diabetes
had the most significant obesity-attributable disease burden overall at 193.7 PYs (74.5%), as
well as for men (91.3 PYs, 63.3%) and women (297.6 PYs, 78.9%), followed by ischemic heart
disease (46.9 PYs, 18.0%), stroke (9.0 PYs, 3.5%), cholecystitis (8.3 PYs, 3.2%), endometrial
cancer (0.5 PYs, 0.2%) and osteoarthritis (0.5, 0.2%).
The burden of overweight-related disease is presented by gender and age in > Table 63-3.
. Table 63-2
Burden of diseases attributable to overweight and obesity in Korea (unit: person years/100,000
persons)
Overweight Obesity
Disease Person Male Female Person Male Female
Diabetes mellitus 535.8 435.2 637.8 193.7 91.3 297.6
Ischemic heart disease 205.1 224.2 185.7 46.9 40.0 53.9
Stroke 50.6 47.0 54.3 9.0 6.0 12.0
Cholecystitis 20.9 17.9 24.0 8.3 5.7 10.9
Osteoarthritis 6.8 5.5 8.2 0.5 0.8 0.2
Breast cancer 4.0 0.0 8.0 0.4 0.0 0.8
Renal cancer 1.8 2.4 1.2 0.3 0.4 0.3
Endometrial cancer 1.3 0.0 2.5 0.5 0.0 1.1
Cataracts 0.5 0.3 0.8 0.2 0.1 0.3
Congestive heart failure 0.2 0.1 0.2 0.05 0.02 0.1
Preeclampsia 0.1 0.0 0.1 0.01 0.0 0.02
Maternal hemorrhage 0.02 0.0 0.03 0.02 0.0 0.03
Obstructed labor 0.01 0.0 0.02 0.01 0.0 0.02
Birth asphyxia and birth trauma 0.00 0.0 0.0 0.0 0.0 0.0
Total 827.1 732.6 922.9 260.0 144.2 337.3
Overweight: BMI 25–29.9 kg/m2; Obesity: BMI 30 kg/m2
1128
63
. Table 63-3
Burden of diseases attributable to overweight by gender and age group (unit: person years/100,000 persons)
Male Female
Disease 20–29 30–39 40–49 50–59 60–69 70+ 20–29 30–39 40–49 50–59 60–69 70+
Diabetes mellitus 60.8 318.1 958.54 1321.4 1063.5 537.7 111.1 263.2 978.9 1952.5 1979.2 1223.9
Ischemic heart disease 46.5 152.8 387.4 641.5 725.0 535.6 6.5 40.3 191.5 505.4 774.9 617.0
CVA 6.9 21.0 68.5 137.6 179.6 185.1 2.6 7.9 42.7 128.5 234.2 244.4
Symptomatic gall bladder 7.3 15.8 28.9 45.3 54.6 38.2 9.4 20.9 34.5 59.2 66.2 38.4
Osteoarthritis 1.6 2.7 8.3 20.2 18.4 8.2 0.2 0.7 10.6 35.7 32.8 6.1
Breast cancer 0.0 0.0 0.0 0.0 0.0 0.0 1.3 11.5 36.1 0.0 0.0 0.0
Renal cancer 0.5 1.8 4.5 5.0 8.5 5.4 0.0 0.5 1.0 3.5 5.1 3.4
Endometrial cancer 0.0 0.0 0.0 0.0 0.0 0.0 0.3 2.2 9.0 2.8 4.0 1.8
Cataracts 0.1 0.2 0.6 0.8 1.0 1.0 0.0 0.1 0.4 2.3 4.6 1.7
Congestive heart failure 0.0 0.1 0.1 0.3 0.1 0.2 0.0 0.0 0.1 0.4 1.3 1.3
Preeclampsia 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.3 0.0 0.0 0.0 0.0
Maternal hemorrhage 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.0
Obstructed labor 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.0
Birth asphyxia and birth trauma 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Total 123.7 512.5 1456.7 2172.0 2050.8 1311.4 131.8 347.8 1304.9 2690.1 3102.1 2138.0
In both males and females, the overweight-attributable burden (AB) was highest in the 60s
age group. The burden of diabetes attributable to overweight was higher than that for any
other disease in both genders and in all age groups. The burdens of diabetes, ischemic heart
disease, stroke, cholecystitis, renal cancer and cataracts attributable to overweight were
correlated with age in both men and women. The burdens of osteoarthritis and congestive
heart failure attributable to overweight were also correlated with age in both men and women,
showing the highest level in the 50s age group and decreasing in the over-60 age group.
The burden of breast cancer was highest for women in their 40s. The burden of preeclampsia
and post-delivery hemorrhage was highest for women in their 20s, and the burden of post-
delivery hemorrhage, obstructed labor, birth asphyxia and birth trauma was highest for women
in their 30s.
The burden of disease attributable to obesity is presented by gender and age in
> Table 63-4. In both males and females, the obesity-AB reached its highest level in the
60s age group but decreased in the over-70 age group. The burden of diabetes attributable
to obesity was higher than that of any other disease in men of all ages, except for those in their
70s. For men in their 70s, the burden of ischemic heart disease was higher than that of any
other disease. For women, the burden of diabetes was higher than that of any other disease
in all age groups.
In both males and females, the obesity-AB was correlated with age for diabetes, stroke, and
cholecystitis, showing its highest level in the 60s age group and decreasing in the over-70 age
group. For women, ischemic heart disease-AB reached its highest level in the 60s age group but
decreased in the over-70 age group. Unlike women, men had a greater burden of ischemic
heart disease attributable to obesity in their 40s. The burden of breast cancer was highest for
women in their 40s. The burden of preeclampsia and post-delivery hemorrhage was highest
for women in their 20s, and the burden of obstructed labor, birth asphyxia and birth trauma
was highest for women in their 30s.
4 Discussion
This study used a variety of research methods to estimate the burden of overweight- and
obesity-related diseases with the following considerations.
First, according to the WHO criteria for overweight and obesity, overweight was defined as
a BMI between 25 and 29.9 kg/m2 and obesity was defined as a BMI of 30 kg/m2 or above in
the present study (National Institutes of Health, 1998). The international criteria for BMI were
used to make the results of this study comparable to those reported from similar studies in
other countries. WHO also recommends using the same cutoff points for BMI to compare
BMI between groups and among individuals within the group (WHO, 2000). Thus, the results
of this study are comparable with those of other studies using the BMI classification system
developed by WHO, thus making a comparison between countries possible.
However, recent studies have shown that Asian populations have a higher risk of metabolic
syndromes, such as type 2 diabetes and cardiovascular disease, than Caucasians (Deurenberg
et al., 2000, 2001, 2002, 2003; Dudeja et al., 2001; Norgan, 1994; Tai et al., 1999). Therefore, for
diabetes, ischemic heart disease, and stroke, we selected studies performed in Asian population
(Jee et al., 2005; Oh et al., 2004; Zhou, 2002). More specifically, studies performed in a Korean
populations were selected for diabetes and ischemic heart disease (Jee et al., 2005; Oh et al.,
2004). For stroke, we selected a study performed in a Chinese population (He et al., 2001)
1130
63
. Table 63-4
Burden of diseases attributable to obesity by gender and age group (unit: person years/100,000 persons)
Male Female
Disease 20–29 30–39 40–49 50–59 60–69 70+ 20–29 30–39 40–49 50–59 60–69 70+
Diabetes mellitus 24.3 77.3 267.6 163.9 175.2 91.1 40.6 104.9 410.0 969.4 1098.8 456.9
Ischemic heart disease 15.5 33.6 100.1 61.0 95.8 91.3 4.3 15.5 52.1 150.4 252.9 128.9
CVA 20. 3.3 12.9 10.2 18.8 24.4 0.7 1.9 8.7 30.1 60.5 40.7
Symptomatic gall bladder 3.8 5.8 12.4 7.9 13.6 11.1 4.3 9.2 14.3 27.9 35.4 14.4
Osteoarthritis 0.5 0.5 1.7 1.5 2.0 1.2 0.0 0.0 0.2 1.0 1.0 0.1
Breast cancer 0.0 0.0 0.0 0.0 0.0 0.0 0.2 1.3 3.4 0.0 0.0 0.0
Renal cancer 0.1 0.3 0.9 0.4 1.0 0.8 0.0 0.1 0.2 0.9 1.4 0.7
Endometrial cancer 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.5 1.9 2.8 4.0 1.8
Cataracts 0.1 0.1 0.2 0.1 0.3 0.3 0.0 0.0 0.1 0.8 2.1 0.5
Congestive heart failure 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.1 0.1 0.6 0.4
Preeclampsia 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.0
Maternal hemorrhage 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.0
Obstructed labor 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.0
Birth asphyxia and birth trauma 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Total 46.2 120.8 395.8 245.1 306.7 220.3 50.4 133.7 491.1 1183.2 1456.7 644.3
because no study investigating the relative risk values of obesity-induced stroke in a Korean
population has been conducted thus far. For other overweight- and obesity-related diseases,
we could not use the RRs suggested by studies performed in Asian populations because we
could not find studies that met this study’s inclusion criteria. However, for further evaluation,
cohort studies of obese Asians are critically needed to measure the disease burden attributable
to obesity in Korea.
Second, diseases attributable to overweight and obesity were selected by conducting a
systematic review. Although there are some review articles of obesity-induced diseases,
no systematic review has been conducted in the same area. Therefore, the findings from this
study can be used as references in other studies, especially those conducted in Asian popula-
tions. In addition to a systematic review, this study also used the research results of the AICR
(1997) to identify obesity-induced cancers. The need for the AICR study results stemmed from
the fact that although there are numerous studies of diseases associated with obesity, the
results of these studies are inconsistent or contradictory, so it is difficult to determine a cause-
effect relationship. In the process of conducting a systematic review of diseases associated with
obesity, diseases and physical disabilities, including sleep apnea, were omitted because respec-
tive studies did not have the level of validity of evidence required in this study (Level 2b or
better of the Oxford Center for Evidence Based Medicine Levels of Evidence) (CEBM, 2003).
The validity of evidence is critical when assessing the burden of disease because low levels of
evidence do not provide accurate RRs, and therefore the cause-effect relationship cannot be
proven. Although this study failed to investigate all of the diseases related to overweight and
obesity, there could be more diseases associated with obesity. For instance, Strauss suggested an
association between low self-esteem and obesity (Strauss, 2000), but failed to quantify the cause-
effect relationship. This study was also limited by the failure to include diseases for which the
incidence or prevalence is not easily estimated and diseases for which the burden cannot be
quantified. This study used national disease-related statistics, such as the 2001 statistics of the
cause of death and insurance claim data submitted to the National Health Insurance Corpora-
tion, which only contained an ICD-10 coded disease database. Therefore, disorders and other
problems related to overweight and obesity, such as low self-esteem and physical disabilities,
could not be included in this study because they do not have ICD-10 codes.
Third, RRs can be divided into two categories based on whether the study suggested RRs of
incidence or RRs of mortality for the health condition resulting from obesity. The Australian
Burden of Disease Study used RRs of mortality to assess the disease burden attributable to
obesity (Victorian Burden of Disease Study, 1999). However, it is assumed that obesity is more
closely related to the incidence of disease and injury than to mortality, so the use of RRs of
death might lead to the underestimation of the burden of disease. This study used RRs
of disease incidence resulting from obesity to estimate the disease burden, thereby raising
the reliability of the results.
The burden of disease attributable to overweight was 732.6 and 922.9 PYs per 100,000
persons in men and women, respectively. The top four categories of diseases, diabetes,
ischemic heart disease, stroke, and cholecystitis, accounted for 98.2% of the total disease
burden. Thus, the impact of overweight was strong in these four diseases, while the contribu-
tion of overweight to the remaining diseases was meager. Men had a greater disease burden
attributable to ischemic heart disease than women (30.6% for men, 20.1% for women),
whereas women had a greater disease burden attributable to diabetes than men (69.1% for
men, 59.4% for women). This difference between men and women was explained by the RRs
of disease incidence that resulted from obesity. There was no gender difference in the RRs for
ischemic heart disease, but the DALYs of ischemic heart disease were higher for men (345 PYs)
than for women (302 PYs). However, the RRs for diabetes were almost two times higher in
women than in men, but the DALYs of diabetes showed little difference between men (801 PYs)
and women (740 PYs).
The disease burden attributable to obesity was 144.2 PYs and 337.3 PYs per 100,000
persons in men and women, respectively. The top four categories of diseases, diabetes, ischemic
heart disease, stroke, and cholecystitis, accounted for 99.2% of the total disease burden,
whereas the contribution of obesity to the remaining diseases was very small. Consistent
with overweight, men had a greater disease burden attributable to ischemic heart disease
than women, and women had a greater disease burden attributable to diabetes than men.
Women have a greater burden of disease attributable to overweight and obesity than men.
This is primarily because diabetes accounts for the highest burden of disease in both men and
women, and diabetes attributable to overweight and obesity is more common in women than
in men. This finding was inconsistent with the 2002 WHO report in which the disease burden
attributable to overweight was higher in women.
According to the WHO’s World Health Report in 2002, diabetes was responsible for 58%
of the global disease burden attributable to a BMI above 21 kg/m2, and ischemic heart disease
and cancer contributed to 21% and 8 to 42% of the global disease burden, respectively (WHO,
2002). This study also demonstrated the highest obesity-AB for diabetes in comparison to a
limited range of diseases for which the contribution of obesity was significant, which is
consistent with the WHO report. However, the contribution of obesity to diabetes was higher
in this study than in the WHO report. This discrepancy can be explained by the differences in
the RRs of disease incidence, especially in diabetes. WHO reports used RRs of diabetes
incidence derived from studies performed in Western countries, primarily in Caucasian
subjects, and reported lower RRs than those reported in this study. The same discrepancy
was observed when the results of this study were compared with those from The Australian
Burden of Disease Study. The reason for the discrepancy is the same as that for the discrepancy
between our study findings and those of the 2002 WHO report: The Australian Burden of
Disease Study used RRs of diabetes incidence derived from studies performed in Caucasian
subjects (Carey et al., 1997; Colditz et al., 1990, 1995; Njolstad, 1998) in which the RRs of
diabetes incidence due to overweight and obesity were 1.8 and 3.2, respectively, which are
lower than the RRs reported in this study.
In terms of age, the proportion of burden of disease associated with overweight and
obesity increased with age for diabetes, ischemic heart disease, stroke, cholecystitis, osteoar-
thritis, endometrial cancer, cataracts and congestive heart failure. This positive correlation
between the disease burden and age was also suggested in the 2002 WHO report (World
Health Organization, 2002).
The disease burden attributable to overweight was 827.1 PYs, which was 3.2 times higher
than that attributable to obesity at 260.0 PYs. This difference was explained by the higher
prevalence of overweight, even though the RRs of overweight are insignificant when compared
to those of obesity. The prevalence of overweight was 29.6% in men and 25.9% in women,
which was 7.5 times higher than the prevalence of obesity of 4.0% in men and 3.4% in
women (Ministry of Health and Welfare, 2001). The impact of a higher prevalence of
overweight is consistent with the proposition suggested by Rose et al. (1992). Rose stated
that risk typically increases across the spectrum of a risk factor. Rose’s work led to one of the
most fundamental axioms in disease prevention across risk factors: ‘‘A large number of people
exposed to a small risk may generate many more cases than a small number exposed to high
risk’’ (Rodgers et al., 2004). Other studies have proven that the incidence of complications was
higher in the population with moderate hypertension than in that with high-level hyperten-
sion (Cook et al., 1995; Rodgers et al., 2000). These findings demonstrate that health inter-
ventions aimed at influencing the entire population and shifting the entire distribution of a
risk factor would be more effective at reducing the impact of the risk factor than high-risk
group-focused strategies (Murray et al., 2003). For instance, WHO recommended the imple-
mentation of a policy for controlling the prices of high calorie foods and distribution costs to
reduce the disease burden attributable to obesity (WHO, 2002).
This study was limited because it failed to quantify the burden of disease attributable to
overweight and obesity in terms of demographic characteristics, such as region and income
level. Kim et al. (2001) reported a negative correlation between the prevalence of overweight
and obesity and education level. The result of the present study may also show the same
negative correlation between the disease burden attributable to obesity and education level.
However, the association of the disease burden with demographic factors was not proven in
this study, but the importance of disease burden estimation based on sociodemographic
variables in establishing public health strategies was suggested.
Summary Points
The increased prevalence of overweight adds a socioeconomic burden to the public health
system.
This chapter estimates the burden of disease attributable to overweight and obesity in
Korea using disability adjusted life-years (DALYs).
The burden of diabetes attributable to overweight and obesity is higher than that of any
other disease in both genders.
The disease burden attributable to overweight was 3.2 times higher than that attributable
to obesity.
The greatest proportion of disease burden attributable to high BMI occurred among those
with only moderately elevated BMI levels, such as overweight, and not those with
extremely elevated levels, such as obesity. This suggests that population-based, public
health intervention rather than high-risk group-focused strategies would be more effective
in reducing the burden of disease attributable to overweight and obesity in Korea.
References
American Institute for Cancer Research. (1997). Food, Carey VJ, Walters EE, Colditz GA, Solomon CG, Willett
Nutrition and the Prevention of Cancer: A Global WC, Rosner BA, Speizer FE, Manson JE. (1997). Am
Perspective. American Institute for Cancer Research, J Epidemiol. 145(7): 614–619.
Washington DC. Center for Evidence Based Medicine (CEBM). (2003).
Bray GA. (2003a). Endocrinol Metab Clin North Am. 32 Levels of Evidence and Grades of Recommendation.
(4): 787–804. Available http://www.cebm.net/levels of evidence.
Bray GA. (2003b). Risks of obesity. Prim Care. 30(2): asp (2003.11).
281–299. Cedergren MI. (2004). Obstet Gynecol. 103(2): 219–224.
British Nutrition Foundation Task Force. (1999). Colditz GA, Willett WC, Rotnitzky A, Manson JE.
Obesity. UK Blackwell, Oxford. (1995). Ann Intern Med. 122(7): 481–486.
Colditz GA, Willett WC, Stampfer MJ, Manson JE, Hen- Murray CJL, Lopez AD. (1996). The Global Burden of
nekens CH, Arky RA, Speizer FE. (1990). Am J Disease: A Comprehensive Assessment of Mortality
Epidemiol. 132(3): 501–513. and Disability from Disease. Injuries and Risk Fac-
Cook NR, Cohen J, Hebert P, Taylor JO, Hennekens CH. tors in 1990 and Projected to 2020. Harvard School
(1995). Arch Intern Med. 155: 701–709. of Public Health, WHO and World Bank, Boston.
Deurenberg P, Deurenberg-Yap M, Foo LF, Schmidt G, National Institute of Health. (2000). Clinical Guidelines on
Wang J. (2003). Eur J Clin Nutr. 57: 405–409. the Identification, Evaluation, and Treatment of Over-
Deurenberg-Yap M, Schmidt G, van Staveren WA, Deur- weight and Obesity in Adults. Available at http://www.
enberg P. (2000). Int J Obes Relat Metab Disord. 24: nhlbi.nih.gov/guidelines/obesity/ob_home.htm.
1011–1017. National Institutes of Health. (1998). Obes Res. 6: 51S–209S.
Deurenberg-Yap M, Chew SK, Deurenberg P. (2002). National Task Force on the Prevention and Treatment of
Obes Rev. 3: 209–215. Obesity. (2000). Arch Int Med. 160: 898–904.
Deurenberg-Yap M, Chew SK, Lin VF, Tan BY, van Sta- Njolstad I, Arnesen E, Lund-Larsen PG. (1998). Am J
veren WA, Deurenberg P. (2001). Int J Obes Relat Epidemiol. 147(1): 49–58.
Metab Disord. 25: 1554–1562. Norgan NG. (1994). Eur J Clin Nutr. 48(Suppl. 3): 10–25;
Dudeja V, Misra A, Pandey RM, Devina G, Kumar G, discussion 26-27.
Vikram NK. (2001). Br J Nutr. 86: 105–112. O’Brien TE, Ray JG, Chan WS. (2003). Epidemiology. 14
Felson DT, Zhang Y, Hannan MT, Naimark A, Weissman (3): 368–374.
B, Aliabadi P, Levy D. (1997). Arthritis Rheum. 40 Oh SW, Shin SA, Yun YH, Yoo T, Huh BY. (2004). Obes
(4): 728–733. Res. 12(12): 2031–2040.
Furberg AS, Thune I. (2003). Int J Cancer. 104(6): Park JH, Yoon SJ, Lee H, Jo HS, Kim Y, Kim YI and
669–676. Shin Y. (2006). Int J Obes. 30: 1661–1669.
He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Reilly JJ, Methven E, McDowell ZC, Hacking B,
Whelton PK. (2001). Arch Intern Med. 161(7): Alexander D, Stewart L, Kelnar CJ. (2003 Sep).
996–1002. Arch Dis Child. 88(9): 748–752.
Jee SH, Pastor-Barriuso R, Appel LJ, Suh I, Miller ER 3rd, Rodgers A, Ezzati M, Vander Hoorn S, Lopez AD, Lin RB,
Guallar E. (2005). Am J Epidemiol. 162(1): 42–48. Murray CJ. (2004). PLoS Med. 1(1): e27.
Jeong BG, Moon OR, Kim NS, Kang JH, Yoon TH, Lee Rodgers A, Lawes C, MacMahon S. (2000). J Hypertens.
SY, Lee SJ. (2002). Kor J Prev Med. 35(1): 1–12 18: S3–S5.
(Korean). Rose G. (1992). The Strategy of Preventive Medicine.
Kashyap S, Moher D, Fung MF, Rosenwaks Z. (2004). Oxford University Press, Oxford, 138 P.
Obstet Gynecol. 103(4): 785–794. Strauss RS. (2000). Pediatrics. 105: e15.
Kato I, Nomura A, Stemmermann GN, Chyou PH. Tai ES, Ho SC, Fok AC, Tan CE. (1999). Ann Acad Med
(1992). Dig Dis Sci. 37(5): 784–790. Singapore. 28: 445–450.
Kim NS, Moon OR, Kang JH, Lee SY, Jeong BG, Lee SJ, Van den Brandt PA, Spiegelman D, Yaun SS, Adami HO,
Yoon TH, Hwang KH. (2001). Kor J Prev Med. 34 Beeson L, Folsom AR, et al. (2000). Am J Epide-
(4): 309–315 (Korean). miol. 152(6): 514–527.
Layde PM, Vessey MP, Yeates D. (1982). J Epidemiol Victorian Burden of Disease Study. (1999). Morbidity.
Community Health. 36(4): 274–278. Victorian Government, Department of Human Ser-
Lee HK, Yoon SJ, Do YK, Kwon YH, Kim CY, Park K, vices, Public Health and Development Division,
Kim YI, Shin YS. (2003). Kor J Prev Med. 36(2): Melbourne, Victoria.
1–26 (Korean). Visscher TL, Seidell JC. (2001). Annu Rev Public Health.
Marshall FF. (2002). J Urol. 168(2): 877. 22: 355–375.
Ministry of Health and Welfare. (2001). National Health Walter SD. (1976). Biometrics. 32: 829–849.
and Nutrition Survey 1998. Korea. Weintraub JM, Willett WC, Rosner B, Colditz GA,
Ministry of Health and Welfare. (2007). National Health Seddon JM, Hankinson SE. (2002). Int J Obes
and Nutrition Survey 2001. Korea. Relat Metab Disord. 26(12): 1588–1595.
Murray CJ, Salomon JA, Mathers CD, Lopez AD. (2002). WHO. (2000). Obesity-Preventing and Managing the Glob-
Summary Measures of Population Health: Concepts, al Epidemic. World Health Organization, Geneva.
Ethics, Measurement and Applications. WHO, Geneva. World Health Organization. (2002). The World Health
Murray CJL, Lauer JA, Hutubessy RCW, Niessen L, Report 2002: Reducing Risks, Promoting Healthy
Tomijima N, Rodgers A, Laroes CM, Evans DB. Life. World Health Organization, Geneva, p. 250.
(2003). Lancet. 361: 717–725. Zhou BF. (2002). Biomed Environ Sci. 15(3): 245–252.
64 Economic Burden of the
Components of the
Metabolic Syndrome
P. J. Marangos . L. J. Okamoto . J. J. Caro
1 Disease Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1136

1.1 Defining the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1136
1.2 The Metabolic Syndrome Controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1138
1.3 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1138
1.4 Clinical Consequences and Burden of Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1140
2 Economic Burden of the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1142

2.1 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1143
2.2 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1145
2.3 Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146
2.4 Hyperglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147

1136 64 Economic Burden of the Components of the Metabolic Syndrome
Abstract: The components of the > metabolic syndrome have been extensively defined,
studied, and debated. The prevalence has risen recently and affected patients use more health
care resources, and face higher morbidity and mortality, resulting in an enormous economic
burden. Some studies have shown health care costs to be as much as 20% higher than those
accrued by patients without the risk factors. Patients with the metabolic syndrome have been
shown to have greater drug expenditures, more frequent hospitalizations, and higher utilization
of outpatient and physician services. When considered alone, the individual risk factor compo-
nents account for a substantial economic burden to patients, health plans, and society as a whole.
The diagnosis of the metabolic syndrome as a condition may encourage appropriate manage-
ment and thus help prevent disease progression and reduce the considerable economic impact.
List of Abbreviations: BMI, > Body Mass Index; CVD, Cardiovascular Disease; FPG, > Fasting
Plasma Glucose; HBP, High Blood Pressure; HDL-C, High-Density Lipoprotein Cholesterol;
ICD-9, International Statistical Classification of Diseases and Related Health Problems; IDF,
International Diabetes Federation; IGT, > Impaired Glucose Tolerance; LDL-C, Low-Density
Lipoprotein Cholesterol; MEPS, Medical Expenditure Panel Survey; NCEP-ATP III, Third
National Cholesterol Education Program Adult Treatment Panel; NHANES, National
Health and Nutrition Examination Survey; NMES, National Medical Expenditure Survey;
TG, Triglycerides; WHO, World Health Organization
1 Disease Overview
Although the concept of the metabolic syndrome has been debated and redefined numerous
times; it is consistently described as a collection of characteristics that cluster in patients and
appear to increase the risk of CVD and type two diabetes mellitus (Ford, 2005a; Grundy et al.,
2005). The components of the metabolic syndrome include > abdominal obesity, insulin
resistance (FPG; hyperinsulinemia; IGT), > hypertension, and > dyslipidemia (high TG and
low HDL-C). The increasing prevalence of these components and their tendency to manifest
concurrently has placed a greater emphasis on understanding, diagnosing, and effectively
managing them as a unified syndrome.
This chapter presents an overview of the metabolic syndrome, including a review of the
economic burden resulting from components.
1.1 Defining the Metabolic Syndrome
The combination of risk factors that currently describe the metabolic syndrome has been
observed since the 1920s (Joslin, 1921). Groupings of these risk factors have been given a
variety of names, including Diabetogenic Obesity, Syndrome X, Reaven’s Syndrome, Dysme-
tabolic Syndrome X (International Statistical Classification of Diseases and Related Health
Problems, ICD-9 code 277.7), Insulin Resistance Syndrome, and ‘‘the Deadly Quartet’’ (ICD-
9data.com, 2008; Vague et al., 1983). The term ‘‘metabolic syndrome’’ was first used in 1977 to
describe the association of obesity, diabetes, hyperlipoproteinemia and hyperuricemia in the
context of atherosclerosis, (Haller, 1977) as well as to associate diabetes, obesity, gout and
hypertension with hyperlipoproteinemia (Singer, 1977).
The WHO published the first formal definition of the metabolic syndrome in 1998 (Alberti
and Zimmet, 1998). Specifically, they recognized that insulin resistance in combination with
Economic Burden of the Components of the Metabolic Syndrome 64 1137
two or more of either abdominal obesity, high TG, low HDL-C, HBP or microalbuminuria, are
an important group of risk factors that predict diabetes and cardiovascular disease.
An alternative definition has been proposed by NCEP-ATP III, (2001a) and another by
the IDF (Alberti et al., 2005). They agree that abdominal obesity, insulin resistance, dys-
lipidemia, and HBP are often associated, and together they convey an increased risk of CVD
and diabetes (> Tables 64-1 and > 64-2) (Eckel et al., 2005; Grundy et al., 2004a; Lindsay
and Howard, 2004).
. Table 64-1
Clinical Identification of the Metabolic Syndrome Based on the NCEP-ATP III, IDF and WHO
criteria (Alberti and Zimmet, 1998; Grundy et al., 2004a; Alberti et al., 2005)
NCEP-ATP III IDF WHO

Required Presence of three Abdominal Obesity and two Glucose intolerance, or
or more risk factors additional risk factors diabetes, or insulin
resistance with two
additional risk factors
Risk Factors
Abdominal Waist Waist circumference depending Waist-to-hip ratio >0.9 for
Obesity circumference on ethnicity; for European men; >0.85 for women or
>102 cm for men; ancestry, 94 cm men; 80 cm BMI >30kg mg2 (either
>88 cm for women women sex)
Low HDL <40 mg dL1 for Men <40 mg dL1; women 35 mg dL1 for men,
1
men; <50 mg dL <50 mg dL1 or treatment for 39 mg dL1 for women
for women this lipid abnormality
Raised TG 150 mg dL1 >150 mg dL1 or treatment for 150 mg dL1
this lipid abnormality
High Blood SBP 130 mmHg SBP 130 mmHg or DBP 140/90 mmHg or anti-
Pressure DBP 85 mmHg 85 mmHg or treatment of hypertensive treatment
hypertension
High FPG 100 mg dL1 100 mg dL1 or diabetes 110 mg dL1
Micro- Not applicable Not applicable Albumin excretion
albuminuria 20 mg min1 or albumin/
creatinine 30 mg g1
This table summarizes the clinical characteristics of each of the three major criteria that are used to define and
diagnose the metabolic syndrome. The required threshold levels for each component risk factor of the metabolic
syndrome are presented for each of the NCEP-ATP III, IDF and WHO criteria. NCEP-ATP III the third national
cholesterol education program adult treatment panel; IDF international diabetes federation; WHO world health
organization; BMI body mass index; HDL high density lipoprotein; LDL low density lipoprotein; TG triglyceride; SBP
systolic blood pressure; DBP diastolic blood pressure; FPG fasting plasma glucose
In October of 2001, an ICD-9 code (277.7) for the metabolic syndrome (termed Dysmeta-
bolic Syndrome X) was introduced (ICD-9data.com, 2008). It denotes a constellation of
metabolic abnormalities in insulin to glucose level ratios, lipids (TG, LDL-C or HDL-C),
uric acid levels, coagulation factors and vascular physiology.
. Table 64-2
Differences in Metabolic Syndrome Definitions: NCEP-ATP III versus IDF
NCEP-ATP III IDF

Metabolic Syndrome Waist circumference equally Increased waist circumference
Diagnosis weighted with other risk factors (not required for metabolic syndrome
needed for metabolic syndrome)
Waist Circumference Single threshold Ethnic specific thresholds which
Threshold tend to be lower
Treatment of Risk Not considered. Risk factor level Considers treatment as equivalent
Factors must accord with the recommended to an abnormal measured level
threshold
FPG Requires measured FPG Diabetes diagnosis equal to FPG
<100 mg dl1 <100 mg dl1
This table outlines the relevant differences between the NCEP-ATP III and IDF criteria for defining and diagnosing
metabolic syndrome. NCEP-ATP III the third national cholesterol education program adult treatment panel; IDF
international diabetes federation
1.2 The Metabolic Syndrome Controversy
Despite the recognition of this cluster of risk factors, the specific grouping and classification
remains a topic of debate (Grundy et al., 2005; Kahn et al., 2005). Much of the controversy
stems from the existence of multiple definitions as well as the lack of firm evidence to set factor
thresholds and their joint implications for risk. Many believe that the metabolic syndrome is a
useful construct because it identifies individuals at increased risk for diabetes and CVD
(Laaksonen et al., 2002; Lakka et al., 2002). The concept of the metabolic syndrome is supported
by data showing that its components often co-exist (Greenlund et al., 2004; Kahn et al., 2005)
and are linked to CVD, diabetes, and death (Ford, 2005b; Isomaa et al., 2001; Laaksonen et al.,
2004; Lakka et al., 2002; Najarian et al., 2006; Sundstrom et al., 2006). By contrast the Joint
Statement from the ADA and the European Association for the Study of Diabetes points out that
studies have not clearly shown the impact of each factor on cardiovascular risk (Kahn et al.,
2005). Nevertheless, acknowledging the existence of the metabolic syndrome and treating it as a
whole, rather than focusing on one risk factor at a time, may be of increasing importance
as its prevalence rises (Fine, 2007; Hoerger and Ahmann, 2008).
1.3 Epidemiology
The prevalence of the metabolic syndrome has increased with more common obesity, (Flegal
et al., 2002; Ogden et al., 2006) diabetes, and an aging population (Ford, 2005a; Vasan et al.,
2005). In the US, it increased from 23% among the 1988–1994 NHANES population to 27% in
1999–2000 (> Figure 64-1) (Ford et al., 2004). There has also been an increase with age
(> Figure 64-2) (Ford et al., 2004; Scranton et al., 2007). Recent estimates of the overall
prevalence in US adults range from 18 to 35% (Ford et al., 2002, 2004, 2005a). Estimates also
tend to be higher using the IDF definition, regardless of sex or ethnicity (> Tables 64-3) (Ford,
2005a; Hollenbeak et al., 2007).
. Figure 64-1
Increasing Prevalence of the Metabolic Syndrome in US Adults (Ford et al., 2004). This figure uses
data from the National Health and Nutrition Examination Survey (NHANES) to demonstrate
that the prevalence of the metabolic syndrome among the overall population, as well as
among both men and women, has increased over the years. Unadjusted prevalences, and
relative increases are presented for each group
. Figure 64-2
Prevalence of the Metabolic Syndrome Increases with Age (Ford et al., 2004). This figure uses
data from the National Health and Nutrition Examination Survey (NHANES) to demonstrate that
the prevalence of the metabolic syndrome increases with age in both men and women.
Prevalence data are presented from both the NHANES 1988–1994 and 1999–2000 samples
. Table 64-3
Prevalence of the Metabolic Syndrome by Sex and Ethnicity (Ford, 2005a)
Men (%) Women (%)

African- Mexican- African- Mexican-
Overall Caucasian American American Overall Caucasian American American
NCEP- 35.4 24.5 40.3 34.4 31.5 36.4 44.0 34.5
ATP III
IDF 41.9 27.1 50.6 40.7 34.4 38.8 46.2 37.1
This table presents the prevalence of the metabolic syndrome, defined using both the NCEP-ATP III and IDF
definitions according to sex and ethnicity. Prevalence data are presented for both men and women across
the overall, Caucasian, African-American and Mexican-American populations. NCEP-ATP III the third national
cholesterol education program adult treatment panel; IDF international diabetes federation
In a recent study using NHANES data most individuals had the minimum three risk
factors for the metabolic syndrome (55%), 32% had four and 13% had all five, with the most
common risk factors being abdominal obesity and dyslipidemia (Fitch et al., 2007). A separate
analysis of data from NHANES 1999–2000 revealed that each of the risk factor components
have a higher prevalence in men and people of Mexican origin (Ford and Giles, 2003; Ford
et al., 2004). An 8-year follow-up of obese and non-obese patients in the San Antonio Heart
Study revealed that abdominal obesity, as indicated by elevated > waist circumference,
was associated with an increased incidence of the metabolic syndrome (> Figure 64-3) (Han
et al., 2002).
1.4 Clinical Consequences and Burden of Illness
Many studies have documented the association of abnormal lipid values with the risk of CVD
(Rubins et al., 1996; Stanek et al., 2007; Taylor et al., 2004). Furthermore > hyperglycemia is
not only a known risk factor for diabetes, but also for CVD even without diabetes, (Levitan
et al., 2004) and may account for more than 2 million deaths worldwide from ischemic heart
disease or stroke (Danaei et al., 2006). The increased risk of CVD resulting from hypertension
has been extensively documented (Castelli, 1999; O’Donnell et al., 1997). The rise in obesity
has also contributed to the increase in prevalence of other diseases including diabetes, CVD,
HBP, osteoarthritis, and several types of cancer (Eckel et al., 2005; Zimmet et al., 2001).
Obesity also diminishes life expectancy (Flegal, 2005; Grundy et al., 2004a).
Although the relationships between the individual risk factors for the metabolic syndrome
and clinical outcomes are well established, their relative contribution to the burden associated
with the metabolic syndrome is still debated (Giannini and Testa, 2003; Kahn et al., 2005).
Nonetheless, many claim that synergies exist, such that the risk is greater than that given by
individual factors (Wilson et al., 2005). This relationship between an increased number of risk
factors and adverse outcomes is well established (Isomaa et al., 2001; Klein et al., 2002).
Furthermore, both overall and cardiovascular mortality have been found to be significantly
higher in subjects with the metabolic syndrome (> Figure 64-4) (Isomaa et al., 2001).
. Figure 64-3
Abdominal Obesity Predicts the Development of the Metabolic Syndrome – Adjusted 8-year
Incidence of the Metabolic Syndrome from the San Antonio Heart Study (Han et al., 2002). This
figure presents data from the San Antonio Heart Study that demonstrates the relationship
between abdominal obesity and the incidence of the metabolic syndrome in both obese and
non-obese patients
. Figure 64-4
The Metabolic Syndrome is Associated with Increased CV Morbidity and Mortality (Isomaa et al.,
2001). This figure demonstrates that the metabolic syndrome is associated with an increased
prevalence of cardiovascular heart disease (CHD), myocardial infarction (MI), and stroke. This
figure also demonstrates that both the all-cause and cardiovascular mortality rates are greater in
patients with the metabolic syndrome as compared to those without
2 Economic Burden of the Metabolic Syndrome
The high prevalence, morbidity and mortality associated with the metabolic syndrome imply
that there are important economic consequences (Brixner et al., 2007). Regardless of the
definition used, there is clear consensus that the increasing prevalence of the metabolic
syndrome will have an enormous impact on medical costs associated with related health
outcomes such as diabetes and CVD (Alberti and Zimmet, 1998; Alexander et al., 2003; Ford
and Giles, 2003; Grundy et al., 2004b).
In 2005 CVD was estimated to cost $152 billion in lost productivity and $242 billion in
direct medical expenditures, resulting in a total estimated cost of $394 billion to the US
economy (AHA, 2005). CVD is also the leading cause of death in the US, responsible for nearly
40% of all deaths (CDC, 2005). Patients with diabetes also accrue greater hospital and other
healthcare resource utilization, with overall costs that are more than double those incurred by
patients without diabetes (Hogan et al., 2003).
Strong evidence of the economic burden of the metabolic syndrome comes from Medicare
claims data and large, nationally-representative datasets such as the National Medical Expen-
diture Survey (NMES), the Medical Expenditure Panel Survey (MEPS), and NHANES. Two
studies in particular present a thorough analysis of the health care costs associated with the
metabolic syndrome and its component risk factors.
In one of the first efforts to study the relationship between the metabolic syndrome, its
constituent risk factors, and long-term costs, 10-year data from nearly 4,000 individuals aged
65 years or older in the Cardiovascular Health Study were examined (Curtis et al., 2007). Using
the NCEP-ATP III definition of the metabolic syndrome, the authors found that these
individuals had more inpatient stays and a greater number of primary care visits, resulting
in 20% higher Medicare costs. The differences in inpatient stays, outpatient visits, visits
to primary care providers, and costs to Medicare Part A and Part B were all statistically
significant.
That study used log-linear regression analyses to examine the relationship of costs to the
metabolic syndrome and its components (Curtis et al., 2007). All models controlled for
demographics, smoking status, and LDL-C level. The first model included the components
of the metabolic syndrome individually according to the NCEP-ATP III criteria (low HDL-C,
and increased waist circumference, TG, HBP, and FPG) in order to gauge the independent
effect of each condition on 10-year medical costs. The second model replaced the individual
components with a single composite measure as an indicator of the metabolic syndrome, to
determine the effect of the syndrome itself on costs. Their results showed that of the individual
components in Model 1, waist circumference, low HDL-C, and HBP were significant pre-
dictors, indicating 14.9%, 15.8% and 20.4% greater costs, respectively. When the metabolic
syndrome composite measure was added to the model in the absence of the individual
components (Model 2) it predicted a 29.6% increase in costs. This higher predicted increase
in cost may point to the potential impact on health care costs when the metabolic syndrome is
considered and treated in lieu of its individual component risk factors.
Using similar methods, another study (Thorpe and Howard, 2006) drew on MEPS,
NHANES and NMES data to explore the change in prevalence and costs among Medicare
beneficiaries from 1987 to 2002. Using the metabolic syndrome as a case study, hypertension,
diabetes, and hyperlipidemia combined were found to be responsible for 16% of the increase
in health care spending among Medicare beneficiaries over that time period (7, 5 and 4%,
respectively).
The burden associated with the metabolic syndrome the also modeled in one study using a
Markov technique to predict the incidence of cardiovascular events and diabetes, and their
associated costs (Caro et al., 2007). The model predicted that among patients with metabolic
syndrome according to the NCEP-ATP III definition, approximately 11% would have onset of
diabetes within 3 years, and this would grow to 23% by 7 years. Modeling out to 10 years, 31%
would suffer onset of diabetes and the model predicted that the risk of an acute myocardial
infarction or stroke was nearly 4% over that decade. Another study that included older patients
found that over 14 years the myocardial infarction rate was as high as 18% (Todaro et al., 2005).
Cumulative costs of new onset diabetes, incident myocardial infarction and incident stroke were
estimated at $20,000, $55,000 and $37,000 respectively (Caro et al., 2007), which accounted for
an additional $6,200, $2,200 and $1,300 respectively per person in the cohort.
It has been shown that most of the cost of cardiovascular disease borne by employers is
concentrated in the one-third of the working population with the metabolic syndrome. One
study estimated that working-age individuals with the metabolic syndrome had significantly
higher medical costs than those without: $626 per member per month compared to $367 per
member per month. Of the $259 in excess costs, 20% was estimated to be a result of additional
cardiovascular events and the rest due to the ongoing expense of managing cardiovascular
disease and diabetes (Fitch et al., 2007).
Drug expenditures are also much greater for patients with the metabolic syndrome. The
spending on prescriptions drugs used to treat components of the metabolic syndrome
accounts for up to 30% of total drug expenditures in some cases (Medco, 2007). An analysis
of claims from approximately 2 million adult patients found that individuals taking medica-
tions for the risk factors associated with the metabolic syndrome had annual drug expendi-
tures that were more than four times those of all other patients (Medco Health Solutions).
2.1 Obesity
Obesity has long been associated with greater health care expenditures. A recent study (Thorpe
et al., 2005) estimated that private healthcare spending attributable to obesity increased from
2% (about $3.6 billion) in 1987 to 12% (about $36.5 billion) in 2002. Medical expenditures
attributable to obesity in adults accounted for 6% of total health expenditures in the United
States, or approximately $92.6 billion (calculated in 2002 dollars) (Finkelstein et al., 2003).
Another study found that the direct health care costs attributable to obesity were approxi-
mately $64 billion, and that indirect costs add another $59 billion (> Table 64-4). This study
also found that most obesity-related health care costs are due to co-morbidities such as
diabetes, hypertension, and coronary heart disease (Wolf and Colditz, 1998).
Research suggests that the average obese adult increases annual medical expenditures by
$732 (or 37%) per year (Finkelstein et al., 2003). Compared to normal weight individuals
(body mass index, BMI less than 25 kg m2), moderately obese persons (BMI 30–35 kg m2)
require 14% more physician visits, while in the severely obese (BMI > 35 kg m2) this
increases to 25% more (Finkelstein et al., 2005). The number of physician visits and pharmacy
dispenses have also been shown to increase with BMI (Thompson et al., 2001). Obese
individuals are also approximately three times more likely to have at least one hospitalization
(Raebel et al., 2004). A study of a nationally representative sample of 19,648 individuals ages
54–69 years demonstrated that hospitalization rates increase with BMI (> Figure 64-5)
(Andreyeva et al., 2004).
. Table 64-4
Annual Direct and Indirect Health Care Costs (in billions of 2001 USD) Attributable to Obesity
by Disease (Wolf and Colditz, 1998)
Obesity comorbidity Direct costs Indirect costs

Type II Diabetes $40.1 $38.0
Coronary heart disease $8.8 –
Hypertension $4.1 –
Osteoarthritis $5.3 $15.9
Gallbladder disease $3.2 $0.2
Breast, endometrial, colon cancer $2.6 $4.7
TOTAL $64.1 $58.8
This table presents the annual direct and indirect costs in billions of US dollars that are attributable to obesity.
Total costs, along with the costs associated with six major comorbidities of obesity are presented. Obesity defined
as BMI 29 kg m2. Referent group’s BMI was 20 kg m2 for gallbladder disease, <21 kg m2 for coronary heart
disease, <22 kg m2 for diabetes and colon cancer, and <23 kg m2 for hypertension
. Figure 64-5
Hospitalization Rates Increase with BMI (Andreyeva et al., 2004). This figure presents
hospitalization data (mean #) from a large nationally representative sample according to varying
levels of body mass index
It has been estimated that expenditures for weight loss medications in the United States
were $362 million in 2002 (Encinosa et al., 2005). Persons with BMI greater than 30 kg m2
had six times the number of filled prescriptions for anti-diabetics and more than three times
the number of cardiovascular medications (Finkelstein et al., 2005). The net effect of greater
physician, hospital, and pharmaceutical utilization that accompany elevated BMI is an in-
crease in the cost of care (> Table 64-5).
Obesity is also associated with significant indirect costs. Obese individuals are more likely to
be absent from work and experience restrictions in mobility and activity. A recent study demons-
trated that obese men were 1.7 times more likely, and women 1.6 times, to have seven or more
work absences due to illness than their normal weight counterparts (Finkelstein et al., 2005).
. Table 64-5
Health Care Costs in Relation to BMI
Body Mass Index, BMI (kg m2)

Population 20–24.9 25–29.9 30–34.9 35–39.9 40
US ages 18–64, employed full-time Male: Male: Male: Male: Male:
(n = 20,329) (Finkelstein et al., 2005) $1,351 $1,520 $1,743 $1,920 $2,942
Female: Female: Female: Female: Female:
$1,956 $2,451 $3,027 $3,505 $3,315
US ages 54–69 (n = 19,648) (Andreyeva et al., $4,089 $4,270 $5,075 $5,967 $8,224
2004)
Health plan ages 35–64 (n = 1,286) $1,641 $1,805 $2,232
(Thompson et al., 2001)
This table summarizes the results of three separate studies that present the overall per-person cost of health care
according to body mass index (BMI) level
. Figure 64-6
Missed Work Days According to Obesity and Disease (2001b). This figure presents the results
of a study that estimated the number of work days missed in obese and non-obese
individuals due to heart disease, hypertension and diabetes
Many of these lost work days among obese individuals are a result of CVD diabetes
(> Figure 64-6).
Although obese individuals represent nearly half of US diabetics, they are responsible for
56% of diabetes-related costs. Obesity increases the cost of diabetes care by an average of $700
per year. Obese individuals also represent 34% of the dyslipidemia population but are
responsible for 52% of dyslipidemia-related costs (Finkelstein et al., 2007).
2.2 Hypertension
According to recent data from the AHA, the annual expenditures for office visits, labora-
tory tests related, and medications for the treatment of hypertension were approximately
$37 billion (American Heart Association, 2007). The major driver of hypertension-related
medical expenditures is ambulatory care. It was estimated that in 2004 38 million physician
visits and 3 million hospital outpatient visits were due to hypertension (Hing et al., 2006).
Direct costs associated with cardiovascular complications of hypertension are substantial.
Using 1998 data from the Health Care Financing Administration, it was estimated that
direct medical expenditures attributable to hypertension were $109 billion (Hodgson and
Cai, 2001). Using data from the 1996 MEPS, one study estimated that the national expenditure
for antihypertensive medications among persons without cardiovascular conditions was
$9 billion, of which 18% was spent on diuretics and beta blockers, 65% on calcium-channel
blockers or angiotensin-converting enzymes, and 18% on other medications (Xu et al., 2003).
The indirect costs of hypertension are also extensive. One study found that employees with
hypertension lost nearly $12 billion in wages due to missed workdays in 1996 (Druss et al.,
2001). Another study explored the major drivers of productivity losses for six large employers
located throughout 43 states, representing almost 375,000 employees. They estimated that
chronic maintenance for essential hypertension was the second most costly condition (after
angina pectoris), averaging $160 per employee annually. Employee absence and short-term
disability losses due to hypertension were responsible for 43% of the health and productivity-
related expenditures to employers in 1999 (Goetzel et al., 2004).
2.3 Dyslipidemia
The costs associated with treating dyslipidemia are significant, especially when considering the
cost of the newer cholesterol-lowering HMG-COA reductase inhibitors (statins). Statins
represented three of the top 15 prescribed drugs in terms of volume in 2000, accounting for
over 6% of pharmaceutical utilization, 7% of pharmaceutical costs in managed care plans, and
more than $8 billion in sales (Lipsy, 2003). More recent data show that annual spending on the
most popular statin (atorvastatin) alone rose to $13 billion in 2006 (Smith, 2007). This
therapeutic class was at the top of global pharmaceutical sales in 2006 with over $35 billion
(IMS Health Incorporated, 2006).
2.4 Hyperglycemia
One of the most in-depth analysis to date of the economic burden of hyperglycemia is a study
of medical records and expenditure data from 1994 through 2003 for over 28,000 patients with
FPG levels above 100 mg dL1 (Nichols and Brown, 2005). This research grouped patients into
two stages of hyperglycemia: stage 1 FPG 100–109 mg dL1, or stage 2 110–125 mg dL1.
Patients with higher FPG were in poorer health as determined using multiple measures
relevant to the metabolic syndrome. Specifically, hyperglycemia was associated with the
presence of CVD use of antihypertensive and lipid-lowering drugs, higher BP, lower HDL-C,
higher TG, and greater BMI. In fact, nearly two-thirds of individuals with stage 2 FPG had at
least two of the metabolic syndrome characteristics: hypertension, low HDL-C, or elevated TG
(Nichols and Brown, 2005). When controlling for age, sex, and comorbidities, annual phar-
maceutical costs were significantly higher with elevated FPG ($1,093 for stage 2, $1,004 for
stage 1, $939 for normal). Differences in total costs were also significant: $4,556 for stage 2
versus $4,388 for normal. While only 1 in 10 patients who remained normal (N ¼ 26,309)
presented any of the three metabolic syndrome components measured (HBP, lower HDL-C,
elevated TG), 32% of those who progressed to diabetes over the course of the study did
(p < 0.001) (Nichols and Brown, 2005).
Not surprisingly, this trend was also reflected in costs, with patients who remained in
the normal group costing $3,785 per year compared to $4,459, $5,307 and $6,568 in stage 1,
stage 2, and diabetes, respectively. Finally, a multivariate analysis showed that when controlling
for age, sex, smoking history, BMI, HBP, HDL-C, TG and LDL-C, each 1 mg dL1 increase in
FPG contributes an additional $10 to annual per-patient costs. It is worth noting, however,
that when CVD, depression, and history of stroke were added to the model, the contribution
of FPG to costs lost statistical significance (Nichols and Brown, 2005).
Studies ranging across managed care organizations of various sizes throughout the US
found that patients with poorer glycemic control had more frequent and more expensive
admissions, higher diabetes-related costs, higher resource utilization, and higher total costs. A
review of eight studies that compared patients with good glycemic control to those with poor
control (using various definitions) found the savings to range from $182 to 1,536 (2005
dollars) per patient per year, with the average around $800 (Stephens et al., 2006). Research
into lifestyle interventions for individuals with elevated FPG or impaired glucose tolerance has
found that it is cost-effective to screen overweight people for prediabetes and then implement
a lifestyle intervention (Hoerger et al., 2007).
Costs of care are greater in patients with diabetes (Vijan and Hayward, 2003), especially
when hypertension or cardiovascular disease are also present (> Table 64-6).
. Table 64-6
Cardiovascular Comorbidity and Costs in Diabetes
Population No Diabetes Diabetes

US population (Hogan et al., 2003) $5,642 $13,243
Adults from eight primary care clinics in Wisconsin (French No High High No High High
et al., 2005) BP BP BP BP
$2,856 $4,156 $7,019 $9,500
Managed care patients (Nichols and Brown, 2002) NO CVD CVD No CVD CVD
$2,562 $6,396 $4,402 $10,172
This table presents the results of three separate studies that estimated the per-patient costs among patients with
and without diabetes, BP high blood pressure; and CVD cardiovascular disease
Summary Points
The risk factor components of the metabolic syndrome have been extensively studied,
defined and debated, however their inherent relationship justifies the classification of the
metabolic syndrome as a legitimate disease.
The metabolic syndrome and its risk factor components are highly prevalent, and this
prevalence has been on the rise.
The presence of the metabolic syndrome and its risk factor components is associated with
increased resource utilization, morbidity and mortality.
The health consequences associated with the presence of each of the risk factor compo-
nents of the metabolic syndrome have an enormous impact on health care costs and
expenditures.
The diagnosis and treatment of the metabolic syndrome as a single condition as opposed
to a coincidental clustering of distinct risk factors, may have the potential to prevent the
disease progression and reduce the economic burden associated with each of the compo-
nent risk factors.
References
AHA. (2005). Heart Disease and Stroke Statistics: 2005 Finkelstein E, Brown DS, Trogdon JG, Segal JE, Ben-
Update. American Heart Association, Dallas, TX. Joseph R. (2007). Value Health. 10(S1): S45–S51.
Alberti KG, Zimmet P, Shaw J. (2005). Lancet. 366: Finkelstein E, Fiebelkorn C, Wang G. (2005). Am J
(9491)1059–1062. Health Promot. 20(1): 45–51.
Alberti KG, Zimmet PZ. (1998). Diabet Med. 15(7): Finkelstein EA, Fiebelkorn IC, Wang G. (2003). National
539–553. medical spending attributable to overweight and
Alexander CM, Landsman PB, Teutsch SM, Haffner SM. obesity: how much, and who’s paying? Health
(2003). Diabetes. 52(5): 1210–1214. Aff (Millwood). (Suppl Web Exclusives): W3-219–
American Heart Association. (2007). Metabolic W3-226.
Syndrome – Statistics. Retrieved on November 19, Fitch K, Pyenson B, Iwasaki K. (2007). Value Health. 10
2007, from http://www.americanheart.org/down (S1): S21–S28.
loadable/heart/1168553793520META07.pdf. Flegal KM. (2005). Physiol Behav. 86(5): 599–602.
Andreyeva T, Sturm R, Ringel JS. (2004). Obes Res. Flegal KM, Carroll MD, Ogden CL, Johnson CL. (2002).
12(12): 1936–1943. JAMA. 288(14): 1723–1727.
Brixner D, Said Q, Kirkness C, Oberg B, Ben- Ford ES. (2005a). Diabetes Care. 28(11): 2745–2749.
Joseph R, Oderda G. (2007). Value Health. Ford ES. (2005b). Diabetes Care. 28(7): 1769–1778.
10(S1): S29–S37. Ford ES, Giles WH. (2003). Diabetes Care. 26(3):
Caro JJ, O’Brien JA, Hollenbeak CS, Spackman E, Ben- 575–581.
Joseph R, Okamoto L, Paramore LC. (2007). Value Ford ES, Giles WH, Dietz WH. (2002). JAMA. 287(3):
Health. 10(S1): S12–S20. 356–359.
Castelli WP. (1999). Am J Obstet Gynecol. 180(6 Pt 2): Ford ES, Giles WH, Mokdad AH. (2004). Adults Diabetes
S349–S356. Care. 27(10): 2444–2449.
CDC. (2005). Preventing Heart Disease and Stroke: French MT, Mundt MP, Fleming M, Zavala SK. (2005).
Addressing the Nation’s Leading Killers. Centers J Intern Med. 258(1): 45–54.
for Disease Control, Atlanta. Giannini E, Testa R. (2003). Arch Intern Med. 163(22):
Curtis LH, Hammill BG, Bethel MA, Anstrom KJ, 2787–2788.
Gottdiener JS, Schulman KA. (2007). Diabetes Goetzel RZ, Long SR, Ozminkowski RJ, Hawkins K,
Care. 30(10): 2553–2558. Wang S, Lynch W. (2004). J Occup Environ Med.
Danaei G, Lawes CM, Vander Hoorn S, Murray CJ, 46(4): 398–412.
Ezzati M. (2006). Lancet. 368(9548): 1651–1659. Greenlund KJ, Zheng ZJ, Keenan NL, Giles WH, Casper
Druss BG, Marcus SC, Olfson M, Tanielian T, Elinson L, ML, Mensah GA, Croft JB. (2004). Arch Intern Med.
Pincus HA. (2001). Health Aff (Millwood). 20(6): 164(2): 181–188.
233–241. Grundy SM, Brewer HB Jr., Cleeman JI, Smith SC Jr.,
Eckel RH, Grundy SM, Zimmet PZ. (2005). Lancet. 365 Lenfant C. (2004a). Circulation. 109(3): 433–438.
(9468): 1415–1428. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel
Encinosa WE, Bernard DM, Steiner CA, Chen CC. RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ,
(2005). Health Aff (Millwood). 24(4): 1039–1046. Smith SC, Jr Spertus JA, Costa F. (2005). Cardiol
Expert Panel on Detection, Evaluation, and Treatment of Rev. 13(6): 322–327.
High Blood Cholesterol in Adults. (2001a). JAMA. Grundy SM, Hansen B, Smith SC Jr., Cleeman JI,
285(19): 2486–2497. Kahn RA. (2004b). Circulation. 109(4): 551–556.
Fine M. (2007). Value Health. 10(Suppl 1): S2–S3. Haller H. (1977). Z Gesamte Inn Med. 32(8): 124–128.
Han TS, Williams K, Sattar N, Hunt KJ, Lean ME, Ogden CL, Carroll MD, Curtin LR, McDowell MA,
Haffner SM. (2002). Obes Res. 10(9): 923–931. Tabak CJ, Flegal KM. (2006). JAMA. 295(13):
Hing E, Cherry D, Woodwell D. (2006). Adv Data. 374: 1549–1555.
1–33. Raebel MA, Malone DC, Conner DA, Xu S, Porter JA,
Hodgson TA, Cai L. (2001). Med Care. 39(6): 599–615. Lanty FA. (2004). Arch Intern Med. 164(19):
Hoerger TJ, Ahmann AJ. (2008). J Manag Care Pharm. 2135–2140.
14(1 Suppl C): S2–S14. Rubins HB, Robins SJ, Collins D. (1996). Am J Cardiol.
Hoerger TJ, Hicks KA, Sorensen SW, Herman WH, 78(5): 572–575.
Ratner RE, Ackermann RT, Zhang P, Engelgau Scranton RE, Bozeman SR, Burton TM, Hoaglin DC,
MM. (2007). Diabetes Care. 30(11): 2874–2879. Sirko S, Hollenbeak CS, Wilson PW. (2007). Value
Hogan P, Dall T, Nikolov P. (2003). Diabetes Care. 26(3): Health. 10(S1): S37–S44.
917–932. Singer P. (1977). Diagnosis of primary hyperlipoprotei-
Hollenbeak CS, Spackman E, Ben-Joseph R, Okamoto L, nemias. Z Gesamte Inn Med. 32(9): 129–133.
Luce BR, Schwartz JS, Sullivan S. (2007). Value Smith DG. (2007). Am J Manag Care. Suppl. 3: S68–S71.
Health. 10(S1): S4–S11. Stanek EJ, Sarawate C, Willey VJ, Charland SL, Cziraky MJ.
ICD-9data.com (2008). ICD-9-CM Database. from (2007). Curr Med Res Opin. 23(3): 553–563.
http://www.icd9data.com/2008/Volume1/240-279/ Stephens JM, Botteman MF, Hay JW. (2006). J Manag
270-279/277/277.7.htm. Care Pharm. 12(2): 130–142.
IMS Health Incorporated. (2006). Leading therapy Sundstrom J, Riserus U, Byberg L, Zethelius B, Lithell H,
classes by global pharmaceutical sales. Retrieved Lind L. (2006). BMJ. 332(7546): 878–882.
October 26, 2007, from http://www.imshealth.com/ Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA.
ims/portal/front/articleC/0,2777,6599_80528184_ (2004). Circulation. 110(23): 3512–3517.
80530441,00.html. Thompson D, Brown JB, Nichols GA, Elmer PJ, Oster G.
Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, (2001). Obes Res. 9(3): 210–218.
Nissen M, Taskinen MR, Groop L. (2001). Diabetes Thorpe KE, Florence CS, Howard DH, Joski P. (2005).
Care. 24(4): 683–689. Health Aff (Millwood). Suppl Web Exclusives:
Joslin E. (1921). JAMA. 76: 79–84. W5-317–W5-325.
Kahn R, Buse J, Ferrannini E, Stern M. (2005). Diabetes Thorpe KE, Howard DH. (2006). Health Aff (Millwood).
Care. 28(9): 2289–2304. 25(5): w378–w388.
Klein BE, Klein R, Lee KE. (2002). Diabetes Care. 25(10): Todaro JF, Con A, Niaura R, Spiro A, 3rd, Ward
1790–1794. KD, Roytberg A. (2005). Am J Cardiol. 96(2):
Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, 221–226.
Salonen JT, Lakka TA. (2002). Am J Epidemiol. Vague J, Vague P, Tramoni M, Vialettes B. (1983). Tohoku
156(11): 1070–1077. J Exp Med. 141: 147–159.
Laaksonen DE, Niskanen L, Lakka HM, Lakka TA, Vasan RS, Pencina MJ, Cobain M, Freiberg MS,
Uusitupa M. (2004). Ann Med. 36(5): 332–346. D’Agostino RB. (2005). Ann Intern Med. 143(7):
Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, 473–480.
Kumpusalo E, Tuomilehto J, Salonen JT. (2002). Vijan S, Hayward RA. (2003). Ann Intern Med. 138(7):
JAMA. 288(21): 2709–2716. 593–602.
Levitan EB, Song Y, Ford ES, Liu S. (2004). Arch Intern Wilson PW, D’Agostino RB, Parise H, Sullivan L,
Med. 164(19): 2147–2155. Meigs JB. (2005). Circulation. 112(20): 3066–3072.
Lindsay RS, Howard BV. (2004). 4(1): 63–68. Wolf AM, Colditz GA. (1998). Obes Res. 6(2): 97–106.
Lipsy RJ. (2003). Am J Manag Care. 9(2): S39–S58. Xu KT, Moloney M, Phillips S. (2003). Am J Manag Care.
Medco. (2007). Humanomics: understand the cost of 9(8): 529–536.
cutting edge healthcare. Drug Trend Report. http:// Zimmet P, Alberti KG, Shaw J. (2001). Nature.
medco.mediaroom.com/index.php?s=64& cat=5. 414(6865): 782–787.
Najarian RM, Sullivan LM, Kannel WB, Wilson PW, (2001b). The Hidden Competitive Edge. Employers
D’Agostino RB, Wolf PA. (2006). Arch Intern Med. Health Coalition: 1–12. http://www.ehcaccess.org/
166(1): 106–111. store.asp
Nichols GA, Brown JB. (2002). Diabetes Care. 25(3): (Medco Health Solutions). News release: Proprietary
482–486. research reveals: metabolic syndrom – the costliest
Nichols GA, Brown JB. (2005). Diabetes Care. 28(9): condition you’ve never heard of afflicts nearly
2223–2229. one in four Americans. Retrieved February 21,
O’Donnell CJ, Ridker PM, Glynn RJ, Berger K, Ajani U, 2008. http://phx.corporate-ir.net/phoenix.zhtml?
Manson JE, Hennekens CH. (1997). Circulation. c=131268&p=irol-newsArticle print&ID=706992&
95(5): 1132–1137. highlight
65 Zinc Deficiency and DALYs in
India: Impact Assessment and
Economic Analyses
A. J. Stein . M. Qaim . P. Nestel
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
1.1 Micronutrient Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
1.2 Zinc Deficiency, Its Causes and Its Extent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153
1.3 The Need to Measure the Burden of Zinc Deficiency Correctly . . . . . . . . . . . . . . . . 1154
2 Zinc Deficiency and DALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154

2.1 The DALY Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
2.1.1 Application and Strengths of the Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
2.1.2 The Calculation of DALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1156
2.2 General Criticism of DALYs and Methodological Differences . . . . . . . . . . . . . . . . . . . . 1157
2.2.1 Discounting of DALYs and Future Life and Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1157
2.2.2 The Use of Disability Weights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158
2.2.3 The Basis for Calculating the Average Remaining Life Expectancy . . . . . . . . . . . . . . 1159
2.2.4 The Exclusion of Age Weights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159
2.2.5 Arguments in Favor of the DALY Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1160
3 Calculating the Loss of DALYs Due to Zinc Deficiency . . . . . . . . . . . . . . . . . . . . . . . . 1160

3.1 Outcomes and Target Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161
3.2 Size of the Relevant Target Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161
3.3 Mortality Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161
3.4 Remaining Life Expectancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1162
3.5 Incidence Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
3.5.1 Incidence Rates of the Sequelae of Zinc Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
3.5.2 Incidence Rates and Prevalence Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1164
3.6 Disability Weights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1165
3.7 Duration of the Relevant Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1166
4 Using DALYs for Impact Assessment and Economic Analyses . . . . . . . . . . . . . . . . . 1166

4.1 General Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1166
4.2 The Example of Biofortification in India . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1166
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1167

1152 65 Zinc Deficiency and DALYs in India: Impact Assessment and Economic Analyses
Abstract: Although less obvious than outright lack of sufficient food, > micronutrient
malnutrition represents an economic and public health problem in many countries. Over
the last years > zinc deficiency has emerged as another major micronutrient deficiency, with a
large proportion of the population being at risk, especially in the developing world. However,
simple quantification of the number of people who suffer from a condition fails to take
account of the depth of the problem. For comparison, monitoring or impact assessment
purposes as well as > cost-effectiveness or more general economic analyses, the health loss of a
condition needs to be measured in a more comprehensive index.
In this chapter the concept of disability-adjusted life years (> DALYs) is explained and a
framework for its application to zinc deficiency is provided. DALYs were developed by the
World Bank in collaboration with the World Health Organization (WHO) and are today used
by many relevant organizations and for analyses in very different fields, in particular at the
global level or in developing countries. By weighting the loss of an individual’s functioning
due to ill health – relative to death and complete health – DALYs allow measuring morbidity
and mortality in a single index that can be aggregated and compared across different
conditions. The methodology is explained and discussed, and general data and parameters
to calculate the loss of DALYs due to zinc deficiency are reported for the example of India.
List of Abbreviations: AADO, average age of death or onset of disease; cf, confer; DALY,
disability-adjusted life year; FAO, Food and Agriculture Organization; > GBD, global burden
of disease; GDP, gross domestic product; IZiNCG, International Zinc Nutrition Consultative
Group; N/A, not applicable; > QALY, quality-adjusted life year; r, discount rate; RDI, recom-
mended dietary intake; SEAR-D, countries in the WHO’s South-East Asia region with high
child and high adult mortality; t, time; UN, United Nations; US$, United States Dollar; WHO,
World Health Organization; WTP, willingness-to-pay; YLD, years lived with disability; YLL,
years of life lost; yr, year; ZnD, zinc deficiency
1 Introduction
1.1 Micronutrient Deficiencies
Over 800 million people in developing countries are undernourished because they do not eat
enough to meet their daily energy requirements (FAO, 2005). Moreover, many of these people
go to bed hungry. The social and economic costs of inadequate food intake directly affect those
who endure this hunger, and indirectly society at-large, which is acknowledged by academics,
policy makers and the general public (Arcand, 2001; McGovern, 2001; Sachs et al., 2004;
Strauss and Thomas, 1998; UN, 2000; WHO, 2001).
A monotonous diet that is insufficient in quantity and does not meet energy requirements
will invariably be inadequate in quality too, but increasing energy intake through increased
consumption of staple foods will not necessarily ensure adequate quality. The notion of good
diet quality is especially pertinent for intakes of vitamins and minerals that are collectively
known as micronutrients. Micronutrients are essential for cell functioning and survival.
Prolonged low micronutrient intakes result in recognized and documented clinical outcomes,
and in some cases death, but these outcomes reflect the extreme end of the sequelae that ensues
as an individual goes from being replete to deplete.
The > prevalence of florid clinical micronutrient deficiencies has greatly fallen over the last
50–70 years due to both improved agricultural production and access to health care (World
Bank, 2006). While the prevalence of clinical deficiencies declined, and the diagnostic tools
Zinc Deficiency and DALYs in India: Impact Assessment and Economic Analyses 65 1153
improved, it became increasingly apparent that there were very large numbers of individuals
with subclinical micronutrient deficiencies in which no signs and symptoms were present. The
latter is important because even subclinical deficiencies can impact on morbidity and mortal-
ity (World Bank, 2006), hence the notion of hidden hunger.
As the link between micronutrient deficiencies and child survival became increasingly
apparent, policy makers have been compelled to consider the public health ramifications –
including the economic implications – of controlling micronutrient deficiencies (Behrman
et al., 2004; FAO, 2005; World Bank, 2006). Partly because they were relatively easy to diagnose,
the focus has been on controlling iodine, iron and vitamin A deficiencies (ACC/SCN, 2000).
Because the underlying causal factors for iron deficiency are similar to that for zinc deficiency,
and the fact that zinc is needed in nearly all metabolic pathways in the body, it soon became
apparent that zinc deficiency was also very likely to be a public health problem of enormous
proportions in developing countries (Prasad, 2003). And indeed the World Health Organi-
zation identified zinc deficiency as one of the top five risk factors contributing to the burden
of disease in developing countries with high mortality rates (WHO, 2002).
1.2 Zinc Deficiency, Its Causes and Its Extent
One third of the global population is estimated to be zinc deficient (Hotz and Brown, 2004).
Zinc deficiency can develop due to inadequate intakes, increased requirements, malabsorption,
impaired utilization or increased losses (> Box 65-1). Zinc intakes will be inadequate if the zinc
content of food is low or it is bound to some other compound (notably phytates) that makes it
unavailable for absorption. Zinc requirements are increased in during pregnancy. Diseases such
as diarrhea and some drugs can result in reduced absorption of zinc. Other drugs can bind zinc,
thus impairing its utilization. Infections in general result in the sequestration of zinc in the liver,
thus decreasing circulating levels of this trace mineral in the body. Finally, disease or other
conditions that are associated with bone or muscle atrophy can also increase the losses of
endogenous zinc from the body; furthermore, conditions that perturb intestinal functions may
affect the body’s ability to maintain zinc status (Hotz and Brown, 2004).
Box 65‐1 Key Facts on Zinc in Nutrition and Health
Zinc is present in virtually every tissue in the body and plays a central role in the correct
functioning of the immune system, growth and development. Consequently, infants and young
children who are growing rapidly are most vulnerable to becoming deficient. Deficiency results
when there is an inadequate intake of absorbable zinc that can develop from inadequate dietary
intakes, increased requirement (during pregnancy and lactation), as well as malabsorption,
impaired utilization or increased losses of zinc as a result of pathological conditions that affect
the integrity of the gut. Deficiency causes stunting, poor appetite, recurrent infections (especially
diarrhea and pneumonia) and delayed wound healing due to low immune function. About one
third of the global population is estimated to be zinc deficient, with deficiency most widespread
in South and Southeast Asia. Poor health related to zinc deficiency also affects economic
productivity in later life. For instance, estimates for India indicate a lower bound for the economic
loss due to zinc deficiency of US$ 1.74 billion – or 0.25% of gross domestic product.
In absolute terms zinc deficiency is most widespread in Asia because of the large number of
people living in this region. Indeed, just under three-quarters of the population in the WHO
SEAR-D region – i.e., India, Bangladesh, Myanmar, North Korea, Nepal, Bhutan and the
Maldives – were calculated to consume less than the US recommended dietary intakes (RDIs)
for zinc (WHO, 2002; > Figure 65-1). More specifically Hotz and Brown (2004) estimated that
one-quarter of the Indian population were at-risk of inadequate zinc intakes, putting India in
the ‘‘high’’ risk category for zinc deficiency (> Table 65-1). Hence, zinc deficiency in India
clearly warrants further analyses, from both the biological and economic perspectives.
1.3 The Need to Measure the Burden of Zinc Deficiency Correctly
Knowing how many people are at risk of zinc deficiency is a first and important step to
ascertain the extent of the problem. However, a head-count approach can neither show the
depth or severity of the problem – as encountered with head-count measurements in
the poverty literature (cf. Sen, 1976) – nor does it allow for comparisons to be made
between the severity of ill health from zinc deficiency and other public health problems.
Likewise, summing up the magnitude of various health problems to obtain an overall burden
of disease is not possible with a head-count approach alone.
In assessing the impact of a public health program – or in continuous monitoring – it may
be misleading to simply look at the change in the prevalence of zinc deficiency: the
intervention may reduce the severity of the ill-health outcomes of the deficiency although
the absolute number of cases may remain the same.
In establishing the cost-effectiveness of a public health program, using the effect of
zinc deficiency on mortality rates (e.g., to express the cost per death averted) may also
be misleading: a disease or deficiency may result in many cases with severe but non-lethal
health outcomes, while another may result in fewer but more severe health outcomes or
even deaths. In the first case the program may improve the lives of many people consider-
ably (e.g., reduce morbidity) but not save any lives, while in the latter case the program
may prevent a few deaths but not affect the severity of the morbidity.
Finally, to carry out purely economic analyses, e.g., by assessing the productivity loss due to
a deficiency, merely knowing the number of people who are zinc deficient does not say
anything about the extent to which their productivity may be affected. Hence, simply
looking at the prevalence or > incidence of zinc deficiency or at mortality rates is not very
informative.
The forgoing has shown that zinc deficiency is a global public health problem, particularly in India.
It has explained the need for a better economic indicator that captures both the extent and severity
of the problem. The rest of this chapter explains the concept of disability-adjusted life years
(DALYs) and puts forward a framework for its application to zinc deficiency in India.
2 Zinc Deficiency and DALYs
2.1 The DALY Methodology
2.1.1 Application and Strengths of the Methodology
As explained above, head-count approaches to measure ill-health are not satisfactory because
they do not capture the severity of a condition. One concept that addresses this issue is the
. Figure 65-1
Zinc deficiency worldwide. This figure shows for different regions in the world the percentage of people having insufficient zinc intakes (by US
standards); India belongs to the SEAR-D region where this share is highest. Region code: AFR African Region; AMR Region of the Americas; EMR Eastern
Mediterranean Region; EUR European Region; SEAR South-East Asia Region; WPR Western Pacific Region. Mortality strata: A, very low child, very low
adult; B, low child, low adult; C, low child, high adult; D, high child, high adult; E, high child, very high adult. RDIs recommended dietary intakes. Source:
After WHO (2002)
Zinc Deficiency and DALYs in India: Impact Assessment and Economic Analyses
65
1155
. Table 65-1
Zinc deficiency in India and its neighbors
Country Total population (millions) At risk of ZnD (%) At risk of ZnD (millions)
India 982 25.9 254
China 1,263 14.1 178
Pakistan 148 11.1 16
Bangladesh 125 50.4 63
Myanmar 44 34.6 15
Nepal 23 21.3 5
Sri Lanka 18 44.7 8
Total 2,604 20.8 540
This table shows the total population size of India and its neighbors and the percent of the population of each of
these countries that is at risk of zinc deficiency, as well as the absolute number of people in this region who are at
risk of zinc deficiency (by the standards of the International Zinc Nutrition Consultative Group). ZnD zinc
deficiency. Source: Hotz and Brown (2004)
disability-adjusted life years (DALYs) approach that builds on the idea of quality-adjusted life
years (QALYs). The World Bank, in collaboration with the WHO, developed the DALYs
methodology and introduced DALYs as a measure for the global burden of disease (GBD)
(World Bank, 1993). The use of DALYs was further popularized following the work of Murray
and Lopez (1996); nowadays, the approach is also often used by other international organiza-
tions (e.g., FAO, 2004; UN-SCN, 2004) and in a diverse set of contexts, e.g., civil war and
sanitation infrastructures (Collier and Hoeffler, 2004; Rijsberman, 2004). DALYs are used
particularly in global or developing country settings (c.f. Fox-Rushby, 2002). In the context of
dietary deficiencies in India, DALYs were used to determine the cost-effectiveness of > biofor-
tification (Stein et al., 2006, 2007, 2008) and the human and economic cost of micronutrient
malnutrition (Stein and Qaim, 2007).
The strength of the DALY methodology is that it includes both the severity – what
economists may refer to as its depth – and the incidence – or width – of a condition. This is
done through the use of disability weights that define the extent of the loss of an individual’s
function with each adverse health outcome relative to death (100% loss) and complete health
(no loss). This relative weighting means that the combined health losses due to morbidity and
mortality can be measured in one single index, and the latter is comparable across different
conditions. The duration of the adverse health outcomes are counted in life years. With this,
the burden of disease, or of a particular dietary deficiency, can be expressed as the aggregate
number of DALYs that are lost due to the condition(s) of interest, i.e., as the sum of the years of
life lost (YLL) due to the condition-related mortality and the sum of years lived with disability
(YLD) that is due to the condition (Murray and Lopez, 1996).
2.1.2 The Calculation of DALYs
Because the severity – or the level of disability – is weighted in the YLD (relative to the YLL),
the basic rationale underlying the DALY concept can be represented as:
Burdenof disease ¼ DALYslost ¼ YLL þ YLDweighted
This burden of disease needs to be calculated and aggregated for each target group (i.e., each
relevant age and gender group) that is affected by the condition – as incidence and severity
may differ between different groups – and future health losses need to be discounted.
Following Zimmerman and Qaim (2004) and Stein et al. (2005), the revised formula can
then be represented more formally as:
X X X
1 erLj 1 erdij
DALYslost ¼ Tj Mj þ T j Iij D ij
j r i j r
Where Tj is the total number of people in target group j, Mj is the mortality rate associated
with the condition in target group j, Lj is the average remaining life expectancy for target group
j (i.e., if persons in that target group live 1 year shorter they lose one DALY), Iij is the incidence
rate of condition i in target group j, Dij is the disability weight for condition i, in target group j
(ranging from 1 to 0, with 1 representing a complete loss of functioning and 0 perfect health),
dij is the duration of the condition i in target group j (for permanent conditions dij equals the
average remaining life expectancy Lj), and r is the discount rate for future life years.
2.2 General Criticism of DALYs and Methodological Differences
The DALY approach has not been without criticism (e.g., Allotey et al., 2003; Anand and
Hanson, 1998; Arnesen and Nord, 1999; Groce et al., 1999; Lyttkens, 2003; Olsen et al., 2002;
Richardson, 1999). In this section the main points of critique are discussed and the modifica-
tions that have been made to the original methodology to address some of the issues are
explained. A more detailed discussion can be found in Murray and Lopez (1996) and Fox-
Rushby (2002).
2.2.1 Discounting of DALYs and Future Life and Health
> Discounting DALYs (and thus future life and health) is a contentious issue in the literature.
The main reproach to discounting DALYs is that it is unfair toward future generations because,
with discounting, saving one DALY next year is worth less than saving one DALY today and
saving one DALY in 20 years is – at present – worth even less (> Figure 65-2). This issue has
been discussed by Murray and Lopez (1996) and Tan-Torres Edejer et al. (2003, p. 67) who
explained succinctly:
" The logic for discounting costs is that the value of a unit of consumption to individuals and
society decreases over time, for three possible reasons. First, individuals take into account the
fact that they might not be alive to benefit from future consumption, and society takes into
account the possibility of catastrophe – the possibility that any or all interventions might at some
point in the future become valueless due to the technology becoming obsolete, climate change
or social chaos, for example. Second, people and society might simply prefer consumption now
to consumption in the future – called the pure rate of time preference or, sometimes, myopia.
Third, if it is expected that incomes will increase, the marginal welfare gain from an additional
unit of consumption will be lower in the future, when people are richer, meaning that any given
increase in consumption is more valuable now than in the future. Accordingly it is standard
practice to discount future costs to their present values to allow for differences in the value of
one extra unit of consumption over time.
. Figure 65-2
The impact of discounting DALYs. This figure illustrates the impact of discounting DALYs by
showing how the present value of 100 DALYs diminishes the higher the discount rate (r) and the
more years the saving of these DALYs lies ahead in the future (t); without discounting (r = 0%) the
current equivalent of 100 DALYs that are saved in the future is also 100 DALYs. DALYs:
disability-adjusted life years. Source: Adapted from Stein (2006)
It is now usual practice to use a discount rate of 3% in DALY calculations (Murray and Lopez,
1996; Stein et al., 2005; Tan-Torres Edejer et al., 2003; WHO, 2002; World Bank, 1993).
Nevertheless, when calculating DALYs it is considered good practice to carry out sensitivity
analyses in which the discount rate is varied and includes a 0% rate (Murray and Lopez, 1996;
Stein, 2006). Sensitivity analysis can be used both to illustrate the impact of the choice of discount
rate on the final results and to facilitate comparisons across different programs and studies.
2.2.2 The Use of Disability Weights
The use of disability weights has also been criticized because they neither value the
intrinsic value of the life of a person suffering from a condition, nor question their potential
contribution to society or their capacity to realize individual achievements and to have a
fulfilled life. Disability weights merely measure the loss of function of individuals, i.e., the
degree to which they are unable to achieve their full physical and cognitive potential.
The disability weights used in the GBD project were derived at a meeting convened at the
WHO, in which a rigorous consultative protocol was followed; the results matched closely the
pooled results of similar previous exercises (Arnesen and Nord, 1999; Murray and Lopez,
1996). Subsequent studies have found that the approach of putting person trade-off questions
to a group of experts is sufficiently robust and can yield comprehensive and coherent disability
weights (Baltussen et al., 2002; Stouthard et al., 2000). As most decisions in public health
imply a certain trade-off between one treatment or group of patients against another, disability
weights contribute to greater transparency and objectivity. Allotey et al. (2003), however, note
that it may be necessary to assess their general validity and to adapt disability weights to
particular settings. The disability weights reported below for India are the outcome of a
workshop – with experts from the Indian subcontinent – in which the disability weights
used in the GBD project (Murray and Lopez, 1996) were used as benchmarks to set the
appropriate disability weights to use in a developing country context (Stein et al., 2005).
One of the more serious reproaches to the use of disability weights is that they discriminate
against the disabled because they imply that saving the lives of disabled people saves fewer
DALYs than that of fully functional individuals (Anand and Hanson, 1998; Arnesen and Nord,
1999). Yet this problem does not actually arise because when calculating the YLL no disability
weights are applied, i.e., 1 year of life lost from premature mortality counts the same for all
people irrespective of whether they are disabled. A more detailed discussion of the use of
disability rates, including a justification for the use of disability weights is given by Stein
(2006), and the concept as such is explained well by Tan-Torres Edejer et al. (2003).
2.2.3 The Basis for Calculating the Average Remaining Life Expectancy
In the GBD project a hypothetical general life expectancy was used to derive the average
remaining life expectancies (Lj). This general life expectancy was based on the longest observed
life expectancy of 82.5 years for Japanese women – adjusted to 80 years for men because of the
biological difference in survival potential (Murray and Lopez, 1996). The use of a standardized
approach was necessary because the GBD project undertook to measure the burden of all
diseases and injuries at once at a given point in time, i.e., for the average remaining life
expectancies a world without diseases and accidents had to be assumed. Moreover, because the
GBD was calculated for the entire world, this approach ensured inter-regional equality: no
matter where a premature death occurred – be it in a rich country with a long-living
population or in a poor country with a low national average life expectancy – general life
expectancy counted the same in terms of the number of DALYs lost. However, the gender
differentiation has provoked criticism because of the inherent inequality and the potential
ethical implications if decisions in the field of health are based on biological – or genetic –
factors (Lyttkens, 2003).
For analyses of individual conditions at a national level, such as zinc deficiency in India,
the issue of which life expectancy to apply (the national one or a theoretical maximum life
expectancy, possibly differentiated between men and women) can be circumvented because
eradicating the condition probably only has a minor impact on national average life expec-
tancy and, therefore, national life tables can be used (Stein, 2006). More details are given in the
section on ‘‘Calculating the loss of DALYs due to zinc deficiency’’.
2.2.4 The Exclusion of Age Weights
A departure from the DALY formula used by Murray (1996) is that no age weights are included
in the formula presented here, which is taken from Zimmermann and Qaim (2004). Murray
had proposed age-based weights to value the lives of young, productive adults higher than the
lives of infants and the elderly, i.e., more DALYs are lost if a disease is suffered by a 33 year old
person than if the same disease is suffered by a 11 year old child or a 66 year old individual, and
more DALYs are saved if the life of a 33 year old person is extended by 5 years than if the life of
either the child or the elder individual is extended by 5 years. Murray justified this approach
based on studies on the social and individual willingness to pay for health care, and the
contribution of young adults to social welfare and their role as ‘‘care-givers’’ for their children
and perhaps also their parents.
Age weights have been criticized on various grounds (Anand and Hanson, 1998;
Richardson, 1999; Williams, 1999), not least because weighting an individual’s social
importance implies an ethical value judgment and could represent an opening of Pandora’s
Box (Lyttkens, 2003) that leaves the question where to stop with the weighting (Stein, 2006):
are doctors or film stars more important than other people, or orphans less? By not using age
weights (or using unity weights for all individuals) this problem can be reduced. Because even
if Musgrove (2000) rightly points out that treating all age groups equally is not a value-free
judgment either, the ethical ramifications of not using age weights are less far reaching. Given
the concerns outlined here, it is also noteworthy that in their sensitivity analyses of the GBD
calculations Murray and Lopez (1996) had changed the age-weighting assumptions.
2.2.5 Arguments in Favor of the DALY Approach
As explained above, the DALY formula presented here is a modification of the original one to
counter some of the general criticisms of the DALY methodology. While quantifications in the
field of public health will inevitably be controversial, it is nevertheless often expedient to do
the calculations – and DALYs are a transparent and widely used way of doing so. In particular,
DALYs differ from other economic measures of disease because – unlike, for instance, the cost-
of-illness or willingness-to-pay (WTP) approaches that aim at approximating the impact of
ill-health through monetary quantification – they are not influenced by the earnings of indivi-
duals (or the national product). Hence, DALYs are more equitable. (In the case of cost-of-illness
analyses higher incomes of individuals increase the benefit of avoiding or curing a disease that
affects them – e.g., against controlling a disease that affects poorer individuals. Hence, one result
of such analyses may be that curing the more affluent members of a society (or the citizens in
richer countries) should take precedence over saving the lives of the poor. Similar outcomes are
possible with WTP approaches, as health typically has a positive income elasticity of demand,
i.e., the more individuals earn the more they are willing to pay for health.)
While standardization can help to reduce the equity issue of these alternative approaches,
it cannot quantify the actual burden of ill-health. DALYs, however, can be used for both: they
measure the burden of ill-health directly and, by attaching a standard monetary value to a
DALY, they can also be used for monetary approximations of the economic burden of a disease
(see ‘‘Using DALYs for impact assessment and economic analyses’’).
3 Calculating the Loss of DALYs Due to Zinc Deficiency
In its World Health Report 2002 the WHO reported the number of DALYs that are lost due to
various risk factors. According to this report it was estimated that in 2000 worldwide over 28
million DALYs were lost due to zinc deficiency; 9.6 million of which were in the countries in
South-East Asia that have high child and high adult mortality rates, including India. In terms
of DALYs lost, zinc deficiency was ranked among the top five risk factors that contribute to the
burden of disease in high mortality developing countries; these were underweight (15% of the
burden), unsafe sex (10%), unsafe water, sanitation and hygiene (5.5%), indoor smoke from
solid fuels (3.7%) and zinc deficiency (3.2%) (> Figure 65-3).
In an application of the methodology outlined above and largely based on the data presented
below, Stein et al. (2007) calculated that zinc deficiency in India resulted in 2.8 million DALYs lost
in 2004. This is less than the WHO estimated loss of 9.6 million DALYs in South-East Asia – where
India is the biggest country. It is important to note, however, that the World Health Report
reported the burden of zinc deficiency at the regional level and not the country level. Moreover,
apart from the methodological differences explained above, and the perhaps more conservative
assumptions presented in this section, the World Health Report did not directly calculate the loss
of DALYs for zinc deficiency. Instead, the burden of zinc deficiency was based on attributing a
share of the DALYs lost due to other, related conditions. (‘‘Worldwide, zinc deficiency is
responsible for approximately 16% of lower respiratory tract infections, 18% of malaria and
10% of diarrheal disease.’’ WHO, 2002, p. 55.).
This section describes the data required for calculating the number of DALYs lost due to zinc
deficiency. While special reference is made to India, the requirements would be essentially the
same also in other country contexts. Much of the information presented here draws on Stein et al.
(2005) who summarize the outcomes of a series of workshops held in 2003 and 2004 at which
nutritionists and economists discussed and substantiated the scientific basis for the recommen-
dations. An overview of the data requirements and data sources is given in > Table 65-2, and an
illustration of how DALYs are lost with different health outcomes is given in > Figure 65-4.
3.1 Outcomes and Target Groups
Zinc deficiency increases the risk of young children contracting diarrhea, pneumonia that is a
severe acute respiratory infection, and growth faltering manifested as stunting or short stature.
The increased susceptibility to diarrhea and pneumonia affects both infants – defined as
children below 1 year old – and young children – age 1 through 5 years, while the onset of
stunting affects only infants. Thus, the incidence rates of the above three conditions in the two
age groups are needed. Furthermore, it is assumed that both diarrhea and pneumonia result in
a certain percentage of fatalities.
3.2 Size of the Relevant Target Groups
The size of the two target groups – infants and young children – can be derived from
population and demographic statistics of international organizations or official national
sources. For India updated national census data is available online (Census, 2007).
3.3 Mortality Rates
The mortality due to zinc deficiency per se is unknown, but both diarrhea and pneumonia
result in a certain percentage of fatalities. Jones et al. (2003) estimated that at least 4% of
. Figure 65-3
The ten leading risk factors that contribute to the burden of disease in high mortality developing
countries. This figure illustrates the importance of zinc deficiency as a public health problem in
high mortality developing countries by showing its contribution to the burden of disease in
percent, together with the contribution of the other nine leading risk factors (including iron
deficiency, another micronutrient deficiency) that contribute to the burden of disease in these
countries. Source: After WHO (2002)
mortality among children under-5 years old in low-income countries could be prevented if the
intake of zinc was adequate. Hence, mortality due to zinc deficiency in children under 5 years
old in India can be approximated by multiplying the overall mortality rate of children under
5 years old by 0.04. The under-five mortality rate for India in 2005 was 74 per 1,000 live births
(UNDP, 2007; UNICEF, 2007; WHO, 2007a; World Bank, 2007a). Because mortality rates for
children under-5 years old are given as the number of deaths per 1,000 live births, the target
group for which the mortality rate needs to be applied is the number of live births and not the
number of children under 5 years old.
3.4 Remaining Life Expectancy
Of the three adverse functional outcomes caused by zinc deficiency, only stunting is permanent.
This means that the duration of stunting dij equals the average remaining life expectancy Lj.
. Table 65-2
Data requirements and data sources to calculate DALYs for zinc deficiency in India
Target
Condition i group j Tj Mj or Iij Dij AADO Lj or dij r
Diarrhea Infants 0.47 0.20 3/365
<1 year
Children 0.23 0.15 4/365
1–5 yrs Use
census N/A
Pneumonia Infants 0.12 0.30 4/365
data
<1 yrs
3%
Children 0.20 4/365
1–5 yrs
Stunting Infants Derive from (i) zinc (i) 0.001 <1 Calculate from
<1 yr deficiency (ii) 0.0001 year AADO * and
(ii) stunting standard
Increased Use data on 0.04 * under five (1.00) <1 life tables
mortality live births mortality rate year
This table shows what data are needed to calculate DALYs for zinc deficiency in India, suggesting possible sources
where the data are not provided. DALYs disability-adjusted life years; Tj total number of people in target group j; Mj
mortality rate associated with zinc deficiency in target group j; Lj average remaining life expectancy for target
group j; Iij incidence rate of condition i in target group j; Dij disability weight for condition i in target group j; AADO
average age of death or onset of disease; dij duration of the condition i in target group j; r discount rate for future
life years; N/A not applicable. Source: Adapted from Stein et al. (2005)
Standard life tables are used to calculate the average remaining life expectancy, and thus also to
calculate the DALYs lost due to mortality. These tables are available from the WHO (2007b)
and are shown graphically in > Figure 65-5. In zinc deficiency stunting is assumed to start at
the age of 6 months (Stein et al., 2005). Most of the deaths among children under 5 years old in
India is among infants (Census, 2007); thus, the age of death for children under-5 years old
can be set before the first birthday (Stein, 2006). This means that the duration of stunting and
the average remaining live expectancy for zinc deficiency-related child mortality in 2005 was
on average 63 years for both sexes.
3.5 Incidence Rates
3.5.1 Incidence Rates of the Sequelae of Zinc Deficiency
Because the incidence rates of diarrhea, pneumonia and stunting due to zinc deficiency are not
known, a share of the general incidence rates has to be attributed to zinc deficiency. By
combining information on the average number of diarrhea episodes per year and the share
of zinc deficiency therein, Stein et al. (2005) calculated that the incidence rate for diarrhea
due to zinc deficiency was 0.47 for infants and 0.23 for young children. Similarly, the incidence
rate for pneumonia due to zinc deficiency was estimated to be 0.12 for both infants and
young children.
. Figure 65-4
Illustration of how the loss of DALYs is calculated. This figure illustrates how the loss of DALYs is
calculated by showing this loss on columns that represent the duration of a theoretical life. The
60 “rows” of each column represent life years; light rows represent healthy life years, black rows
represent DALYs lost. In case (a) the individual has a healthy life of 60 years with no DALYs lost. In
case (b) the individual dies prematurely at the age of one and, thus, loses 59 DALYs. In case (c)
the individual suffers from stunting from the age of 1 year onwards, but as the disability weight
for stunting is very small, the individual loses only a fraction of a DALY in each of the remaining
years (altogether 0.06 DALYs). In case (d) the individual suffers a 4-day-bout of pneumonia at the
age of 5 years. During these 4 days the individual is disabled to 20% (disability weight of 0.2). If
these 4 days, in which a partial loss of good health occurs, are put in relation to a year, 0.002
DALYs are lost. (This is for illustration purposes only, therefore neither are DALYs discounted to
the present, nor is it considered that live expectancy increases over an individual’s life span (see
> Figure 104-5) but it is assumed to be fix at 60 years.) DALYs disability-adjusted life years
For stunting two approaches can be used to determine the incidence rate due to zinc
deficiency. First, assume that all infants with zinc deficiency are at-risk of being stunted. In
other words, the incidence rate of zinc deficiency is used as the incidence rate of stunting.
Second, assume that without zinc deficiency all stunted infants become one centimeter taller
than otherwise, that is the incidence rate of stunting is used as the incidence rate of zinc
deficiency (Stein et al., 2005). The approach chosen determines the disability weights used, as
explained in the next section.
3.5.2 Incidence Rates and Prevalence Rates
A potential problem in using the first approach is that zinc deficiency is usually reported as a
prevalence rate rather than incidence rate. However, the two rates are connected. Given the
assumption that stunting is permanent and sets in during infancy, the incidence rate can be
derived from the prevalence rate for zinc deficiency because the reference period in each case is
. Figure 65-5
Average remaining life expectancies in India in 2005. This figure illustrates how the average
remaining life expectancy rises directly after infancy and then slowly falls again, indicating for
each age and gender group the average remaining life expectancy. For those people who survive
the various risks to their life at various ages, when they get older their average remaining life
expectancy diminishes at a slower rate, thus explaining why, for instance, males have a
remaining life expectancy of about 65 years when they are 1 year old, but on average can still
expect to live over 12 years when they are 65 years old. Source: After WHO (2007b)
1 year: as many infants as are stunted (i.e., the prevalence rate) became so during the same year
(i.e., the incidence rate). Where the prevalence rate is not specifically given for infants, an
approximation is still possible: because stunting is permanent, the prevalence rate for a group
comprising several age groups can also be used for each age group alone, i.e., also for infants.
(For instance, if 45% of children under-5 years old are stunted then 45% of those aged 4 years are
stunted, and 45% of those aged 3 years, and 2 years, and one year are stunted as well – and so are
45% of the infants.) This approach, however, neglects demographic changes (like lower birth
rates over time), which is why it is only an approximation. Prevalence data on stunting among
children in India are available in the National Family Health Surveys, and the most recent survey
gives the prevalence rate of stunting among children under the age of 3 years to be 38%
(IIPS, 2007).
3.6 Disability Weights
The 2003–2004 expert consultation (Stein et al., 2005) assigned a disability weight for diarrhea
of 0.2 for infants and 0.15 for young children, and 0.3 and 0.2 for pneumonia among
infants and young children, respectively. For stunting, two sets of disability weights were
agreed upon, depending on the approach used to determine incidence. If the incidence rate of
stunting is derived from the incidence of zinc deficiency, and if it is assumed that with
adequate zinc intake zinc-related stunting will disappear, then the disability weight is 0.001.
If it is assumed that adequate zinc intakes will reduce all stunting by 1 cm then the disability
weight is 0.0001.
3.7 Duration of the Relevant Diseases
The experts at the workshop set the average duration of diarrhea among infants in a develop-
ing country like India at 3 days, and that for young children at 4 days. For pneumonia the
average duration was set at 4 days for both infants and young children (Stein et al., 2005). The
annual figures were derived by dividing these durations, which are expressed in days, by 365
days to obtain the duration of the diseases as fractions of a year. Because stunting is permanent
its duration was simply calculated from standard life tables as described in the section on
‘‘Remaining life expectancy.’’
4 Using DALYs for Impact Assessment and Economic Analyses

4.1 General Issues
Once the loss of DALYs due to zinc deficiency has been calculated the result can be used
both to illustrate the burden of disease provoked by the deficiency and to assess the impact of
a zinc intervention. The latter is done by comparing the number of DALYs lost with and
without the intervention – although care must be taken to control for possible confounding
factors.
Going one step further, the number of DALYs that could be saved through an intervent-
ion can be juxtaposed on the cost of its implementation to arrive at the cost per DALY
saved. For an ex ante analysis, the impact of the intervention can be simulated and then
compared with its expected cost. In this case the uncertainty associated with ex ante
analyses should be taken care of, for example, by calculating the impact of the intervention
based on a pessimistic and an optimistic scenario and also by using pessimistic and optimis-
tic assumptions for projecting the development of the related costs. To approximate
the economic burden of a disease on society, or to carry out a cost-benefit analysis,
DALYs can also be valued monetarily. Then, by adding up the loss of DALYs in monetary
terms, the total corresponding financial loss can be off-set against suitable parameters, like
the gross domestic product (GDP), to illustrate the magnitude of the problem (Stein and
Qaim, 2007).
4.2 The Example of Biofortification in India
Biofortification refers to the use of plant breeding to accumulate essential micronutrients

in the edible parts of staple crops. Using the framework described in this chapter and using
a pessimistic and an optimistic scenario, Stein et al. (2007) projected that zinc biofortification
. Table 65-3
Impact and cost-effectiveness of zinc biofortification of rice and wheat in India
Scenario Pessimistic Optimistic

DALYs lost in the status quo (million) 2.8
Reduction of burden of ZnD (%) 20 51
Cost-effectiveness (US$/DALY saved) 7.31 0.73
This table shows the results of an analysis of the impact and cost-effectiveness of zinc biofortification on the
burden of zinc deficiency in India; the burden of zinc deficiency is expressed in million DALYs lost, the impact is
expressed in a percent reduction of this burden and the cost-effectiveness ratio is given in US$/DALY saved, i.e., it
indicates how much it costs to save one DALY through this particular intervention. DALYs disability-adjusted life
years; ZnD zinc deficiency. Source: Stein et al. (2007)
of rice and wheat could reduce the burden of zinc deficiency in India by 20–50%. Further-
more, contrasting the corresponding gain of DALYs with the costs of this intervention, they
indicated that the cost-effectiveness of this approach falls into the range of 1–7 US$ per
DALY saved – whereas similar projections for zinc fortification of wheat flour produced
a range of 5–7 US$/DALY saved (> Table 65-3), and zinc supplementation, which could
be necessary in rice-eating regions of India, was projected to cost at least 17 US$/DALY
saved (Tan-Torres Edejer et al., 2005; converted from international dollars). Based on
these results Stein and Qaim (2007) calculated that a lower bound for the economic
loss caused only by zinc deficiency in India in 2004 was US$ 1.74 billion – or 0.25% of the
Indian GDP.
Summary Points
Zinc deficiency is a recognized public health problem in India and many other developing
countries.
Zinc deficiency is among the top five risk factors for the loss of healthy live in developing
countries with high mortality rates.
Zinc deficiency causes diarrhea, pneumonia and stunting in children under 5 years old; it
also results in death.
Disability-adjusted life years (DALYs) are a major unit of measurement in health
economics.
One DALY lost is equivalent to the loss of 1 year of healthy life.
DALYs are units of ill health that measure the health loss due to both mortality and
morbidity.
DALYs capture both the extent and severity of a disease.
DALYs allow summing up the burdens to society of different diseases.
DALYs can be used to quantify the health loss of each of the outcomes of zinc deficiency.
Calculating the impact and cost-effectiveness of zinc interventions can be based on DALYs.
First projections support the idea that zinc biofortification could be a viable approach to
reduce DALY losses.
In the context of India, the estimated cost-effectiveness of zinc biofortification of rice and
wheat compares favorably with other public health interventions.
References
ACC/SCN (2000). Fourth Report on the World Nutrition Lancet. 362:65–71. http://dx.doi.org/10.1016/
Situation. United Nations Administrative Committee S0140-6736(03)13811-1.
on Coordination, Sub-Committee on Nutrition, Lyttkens CH. (2003). Eur J Health Econ. 4: 195–202.
Geneva. http://www.unsystem.org/SCN/Publications/ http://dx.doi.org/10.1007/s10198-003-0169-2.
rwns/4RWNS.html. McGovern G. (2001). UN Chron. 38: 24–27. http://www.
Allotey P, Reidpath D, Kouamé A, Cummin R. (2003). un.org/Pubs/chronicle/2001/issue3/0103p24.html.
Soc Sci Med. 57: 949–958. http://dx.doi.org/ Murray CJL, Lopez AD (eds.) (1996). The Global Burden of
10.1016/S0277-9536(02)00463-X. Disease. Global Burden of Disease and Injury Series,
Anand S, Hanson K. (1998). World Dev. 26: 307–310. Vol. 1., Harvard University, Cambridge, MA. http://
http://dx.doi.org/10.1016/S0305-750X(97)10019-5. www.hup.harvard.edu/catalog/MURGLO.html.
Arcand JL. (2001). Econ Soc Dev. Paper No. 147. Food Musgrove P. (2000). Health Policy Plann. 15: 110–115.
and Agriculture Organization of the United Nations, http://dx.doi.org/10.1093/heapol/15.1.110.
Rome. http://www.fao.org/DOCREP/003/X9280E/ Olsen JA, Richardson J, Dolan P, Menzel P. (2002). The
X9280E00.HTM. Moral Relevance of Personal Characteristics inSet-
Arnesen T, Nord E. (1999). Br Med J. 319: 1423–1425. ting Health Care Priorities. Working Paper No. 17.
Baltussen RMPM, Sanon M, Sommerfeld J, Würthwein Health Economics Research Programme, Oslo Univ,
R. (2002). Health Econ. 11: 155–163. http://dx.doi. Oslo. http://www.hero.uio.no/publications.html.
org/10.1002/hec.658. Prasad AS. (2003). Br Med J. 326: 409–410. http://dx.doi.
Behrman JR, Alderman H, Hoddinott J. (2004). org/10.1136/bmj.326.7386.409.
Hunger and Malnutrition. Copenhagen Consensus, Richardson J. (1999). Age Weighting and Discounting:
Copenhagen. http://www.copenhagenconsensus.com/ What Are the Ethical Issues? Working Paper
Default.aspx?ID=223. No. 109. Centre for Health Program Evaluation,
Census. (2007). Census of India. Registrar General & Monash University, West Heidelberg. http://www.
Census Commissioner, New Delhi. http://www. buseco.monash.edu.au/centres/che/che-publications.
censusindia.gov.in/. html#1999.
Collier P, Hoeffler A. (2004). The Challenge of Rijsberman F. (2004). The Water Challenge.
Reducing the Global Incidence of Civil War. Copenhagen Consensus, Copenhagen. http://www.
Copenhagen Consensus, Copenhagen. http://www. copenhagenconsensus.com/Default.aspx?ID=228.
copenhagenconsensus.com/Default.aspx?ID=221. Sachs JD, McArthur JW, Schmidt-Traub G, Kruk M,
FAO. (2004). The State of Food Insecurity in the Bahadur C, Faye M, McCord G. (2004). Brookings
World 2004. Food and Agriculture Organization of Pap Econ Act. 1: 117–240. http://www.brookings.
the United Nations, Rome. http://www.fao.org/sof/ edu/press/Journals/2004/brookingspapersonecono
sofi/. micactivity12004.aspx.
FAO. (2005). The State of Food Insecurity in the Sen AK. (1976). Econometrica 44: 219–232. http://dx.
World 2005. Food and Agriculture Organization of doi.org/10.2307/1912718.
the United Nations, Rome. http://www.fao.org/sof/ Stein AJ. (2006). Micronutrient Malnutrition and the Im-
sofi/. pact of Modern Plant Breeding on Public Health in
Fox-Rushby JA. (2002). Disability Adjusted Life Years India. Hohenheim University, Stuttgart. http://www.
(DALYs) for Decision-Making? An Overview of the uni-hohenheim.de/ub/opus/volltexte/2006/157/.
Literature. Office of Health Economics, London. Stein AJ, Meenakshi JV, Qaim M, Nestel P,
ISBN 978-1899040377. Sachdev HPS, Bhutta ZA. (2005). Analyzing the
Groce NE, Chamie M, Me A. (1999). Int Rehabil Health Benefits of Biofortified Staple Crops by
Rev. 49: 12–15. http://www.rehab-international. means of the Disability-Adjusted Life Years
org/publications/rehabilitationreview.html. Approach: A Handbook. HarvestPlus Technical
Hotz C, Brown KH. (eds.) (2004). Food Nutr Bull. Monograph No 4. International Food Policy Re-
25: S91–S204. http://www.unu.edu/unupress/food/ search Institute, Washington, DC. http://www.
fnb25-1s-IZiNCG.pdf. harvestplus.org/pubshp.html#tech.
IIPS. (2007). National Family Health Survey (NFHS-3), Stein AJ, Meenakshi JV, Qaim M, Nestel P, Sachdev HPS,
National Fact Sheet: India. International Institute for Bhutta ZA. (2008). Soc Sci Med. 66: 1659–1870.
Population Sciences, Mumbai. http://www.nfhsindia. http://dx.doi.org/10.1016/j.socscimed.2008.01.006.
org/. Stein AJ, Nestel P, Meenakshi JV, Qaim M. S.chdev HPS,
Jones G, Steketee RW, Black RE, Bhutta ZA, Morris SS, Bhutta ZA. (2007). Public Health Nutr. 10: 492–501.
Bellagio Child Survival Study Group. (2003). http://dx.doi.org/10.1017/S1368980007223857.
Stein AJ, Qaim M. (2007). Food Nutr Bull. 28: 125–134. UNICEF. (2007). Monitoring and Statistics. UNICEF,
http://www.inffoundation.org/FNB/FNBindexNEW. New York. http://www.unicef.org/statistics/.
html. WHO. (2001). Macroeconomics and Health: Investing in
Sachdev AJ, Stein HPS, Qaim M. (2006). Nat Biotechnol. Health for Economic Development. World Health
24: 1200–1201. http://dx.doi.org/10.1038/ Organization, Geneva. http://whqlibdoc.who.int/
nbt1006-1200b. publications/2001/924154550X.pdf.
Stouthard MEA, Essink-BotM-L, Bonsel GJ. (2000). Eur J WHO. (2002). The World Health Report 2002. World
Public Health. 10: 24–30. http://dx.doi.org/10.1093/ Health Organization, Geneva. http://www.who.int/
eurpub/10.1.24. whr/2002/en/.
Strauss J, Thomas D. (1998). J Econ Lit. 36: 766–817. WHO. (2007a). WHOSIS (WHO Statistical Information
http://www.aeaweb.org/journal/contents/june1998. System). World Health Organization, Geneva.
html. http://www.who.int/whosis/.
Tan-Torres Edejer T, Aikins M, Black R, Wolfson L, Hutu- WHO. (2007b). Life Tables for WHO Member States.
bessy R, Evans DB. (2005). Brit Med J. 331:1177. World Health Organization, Geneva. http://www.
http://dx.doi.org/10.1136/bmj.38652.550278.7C. who.int/whosis/database/life_tables/life_tables.cfm.
Tan-Torres Edejer T, Baltussen R, Adam T, Hutubessy R, Williams A. (1999). Health Econ. 8: 1–8. http://dx.doi.
Acharya A, Evans DB, Murray CJL. (2003). org/10.1002/(SICI)1099-1050(199902)8:1:1::AID-
Making Choices in Health: WHO Guide to Cost- HEC3993.0.CO;2-B.
Effectiveness Analysis. World Health Organization, World Bank. (1993). World Development Report 1993.
Geneva. http://www.who.int/choice/book/. World Bank, Washington, DC. http://go.worldbank.
UN. (2000). United Nations Millennium Declaration. org/J6RBXR2BM0.
General Assembly Resolution 55/2 of 8 September. World Bank. (2006). Repositioning Nutrition as Central
United Nations, New York. http://www.un.org/ to Development. World Bank, Washington, DC.
millennium/declaration/ares552e.htm. http://go.worldbank.org/UGPWFYHNU0.
UN-SCN. (2004). 5th Report on the World Nutrition World Bank. (2007a). Development Data & Statistics.
Situation. United Nations System, Standing Com- World Bank, Washington, DC. http://www.
mittee on Nutrition, Geneva. http://www.unsystem. worldbank.org/data/.
org/SCN/Publications/html/RWNS.html. Zimmermann R, Qaim M. (2004). Food Policy. 29:
UNDP. (2007). Statistics of the Human Development 147–168. http://dx.doi.org/10.1016/j.foodpol.2004.
Report. United Nations Development Programme, 03.001.
New York. http://hdr.undp.org/en/statistics/.
Impacts
2.5 Immune Disorders, Viral,
Bacterial, Microbiological,
Infectious and Parasitic
Diseases
66 The Impact of Infectious
Diseases on the Development
of Africa
A. Boutayeb
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174
2 The Burden of Infectious Diseases in Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175

2.1 Major Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1176
2.1.1 HIV/AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178
2.1.2 Diarrheal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179
2.1.3 Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179
2.1.4 Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179
2.1.5 Respiratory Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180
2.1.6 Preventable Sexually Transmitted Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180
2.1.7 Neglected Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180
3 Impact of Infectious Diseases on the Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181

3.1 Sectorial Impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181
3.1.1 Impact on Health Indicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181
3.1.2 Impact on Economic Indicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182
3.1.3 Impact on Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1184
3.2 Global Impact on Economic and Human Development . . . . . . . . . . . . . . . . . . . . . . . . . 1185
4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1186
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1187

1174 66 The Impact of Infectious Diseases on the Development of Africa
Abstract: Despite the success of vaccination programs for polio and some childhood diseases,
other diseases like HIV/AIDS, malaria, tuberculosis, acute respiratory infections and diarrheal
disease are causing high mortality rates in Africa. However, mortality figures give only a partial
measure of the toll asked by infectious diseases, and the global burden includes also health
impact measured by disabilities, deformities, loss of productivity, care and treatment caused
by a multitude of diseases like lymphatic filariasis, leishmaniasis, schistosomiasis, sleeping
sickness and others. The impact of infectious diseases can be traced according to economic
performance of African countries, showing that 34 out of 53 countries are classified as low-
income economies. The disease burden is, however, more devastating since it affects all
components of human development, including income, health and education.
The impact of infectious diseases on African countries is no longer a crisis only for the
healthcare sector, but presents a challenge to all sectors. It has the potential to reverse those
gains made in human development in the last few years. Consequently, beyond health issues,
these diseases should and must globally be seen as a development concern, affecting education
and knowledge acquisition, income and social status, productivity and economic growth and
other direct and indirect components of human development such as gender equality and
human rights.
For health strategies to be successful, international solidarity and public-private partner-
ships are needed to tackle the problems of shortage and lack of treatments, resistance and the
need for new drugs, vaccines and diagnostic procedures. However, the output of international
initiatives will remain limited without the national and local implication.
List of Abbreviations: AIDS, Acquired Immune Defense System; CVD, Cardio Vascular
Disease; DALY, Disability Adjusted Life Years; DNDi, The > Drug for Neglected Diseases
Initiative; DOTS, > Directly Observed Therapy Strategy; FAO, Food and Agriculture Organi-
zation; FIND, The > Foundation for Innovative New Diagnostics; GAVI, > Global Alliance for
Vaccines and Immunization; GDI, > Gender-related Development Index; GDP, Gross Domes-
tic Product; GEM, > Gender Empowerment Measure; GFFATM, > Global Fund to Fight
AIDS, Tuberculosis and Malaria; HDI, > Human Development Index; HHVI, The
> Human Hookworm Vaccine initiative; HIV, Human Immunodeficiency Virus; HPI,
Human Poverty Index; MDG, > Millennium Development Goals; MMV, The > Medicines
for Malaria Ventures; ND, Neglected Disease; SARS, Severe Acute Respiratory Syndrome; STD,
Sexually Transmitted Disease; TB Alliance, The Global Alliance for Tuberculosis Drug Devel-
opment; UNAIDS, United Nations AIDS; UNDP, United Nations Development Program;
WHO, World Health Organization; YLD, Years Lived with Disability; YLL, Years of Life Lost
1 Introduction
Infectious diseases continue to be the major causes of mortality in Africa. Well known existing,
emerging and re-emerging diseases like malaria, tuberculosis, HIV/AIDS, cholera, meningitis,
hepatitis, schistosomiasis, lymphatic filariasis, sleeping sickness, Ebola, SARS and others are
causing suffering and mortality to a wide population in developing countries in general, and in
Africa in particular (WHO, 2003a).
Beyond mortality statistics, different methods can be considered to quantify the burden of
disease expressed in terms of socio-economic costs such as productivity losses, care and
treatment, hospitalization and handicap. In order to overcome the specific problems of each
The Impact of Infectious Diseases on the Development of Africa 66 1175
. Table 66-1
Deaths and burden (DALYs) caused by infectious diseases, in thousands, 2002 (WHO, 2003b)
World Africa
Cause/disease Deaths DALYs Deaths DALYs
HIV/AIDS 2821 86072 2203 (78%) 66772 (78%)
Malaria 1222 44716 1087 (89%) 39165 (88%)
Respiratory diseases 3845 90252 1071 (28%) 32703 (36%)
Diarrhea 1767 61095 695 (39%) 22992 (38%)
Tuberculosis 1605 35361 303 (19%) 8230 (23%)
Total 11260 317496 53595 (48%) 169862 (48%)
Data worked from the WHO statistics, by kind permission of the World Health Organization
Nearly 50% of deaths and DALYs caused by infectious diseases in 2002 occurred in Africa
country, the most used method is the approach that measures the global burden of disease in
terms of Disability Adjusted Life Years (DALYs) which is a combination of Years of Life Lost
(YLL) through premature death, and Years Lived with Disability (YLD). Thus, DALY is
thought of as one lost year of healthy life (Mathers et al., 2007) (> Table 66-1).
Worldwide, nations are economically classified into two groups as developed and devel-
oping countries according to their level of development. Sometimes, a third group is specified
as least developed countries. Using the per capita income, the World Bank has introduced
four levels of income, namely: high-income, higher-middle-income, lower-middle-income
and lower income (World Bank, 2003). Considering a broader definition of development
that supplement income by other components like levels of health and education, the
United Nations have developed five main composite indices to measure the average achieve-
ments in basic human development (human development index (HDI)), gender-related
development index (GDI), > human poverty indices (HPI-1 and HPI-2) and the gender
empowerment measure (GEM). HDI is the most used index giving a summary measure of
human development, allowing a yearly comparison between countries around the world and
indicating the relative ranking evolution in time of each country. HDI is a three dimensional
composite index obtained as a mean of three indicators weighed equally: health (life expec-
tancy at birth), standard of living (GDP per capita) and education (literacy and enrolment)
(UNDP, 2006).
In this chapter, we consider the impact of infectious diseases on the development of
African countries, showing that, beyond health issues, these diseases should and must globally
be seen as a development concern, affecting education and knowledge acquisition, income and
social status, productivity and economic growth and other direct and indirect components of
human development such as gender equality and human rights.
2 The Burden of Infectious Diseases in Africa

According to the World Health Organization report (WHO, 2003b), it has been estimated that,
in 2002, nearly 60% of the 57 million total reported deaths in the world and approximately 47%
of the global burden of disease is attributable to chronic diseases and cardiovascular diseases
. Figure 66-1
Disease burden (DALYs) among adults by broad cause, selected subregions, 2002
(WHO, 2003b). In Africa, the burden of communicable diseases is higher than those of
non communicable diseases and injuries, whereas, in other regions, the burden of non
communicable diseases is predominant. Reproduced by kind permission of the World Health
Organisation
(CVDs) in particular. Deaths caused by > non communicable diseases dominate the mortality
statistics in five out of six regions of the World Health Organization. The exception is Africa
where deaths caused by HIV/AIDS, malaria, tuberculosis and other > communicable diseases
are predominant (> Figure 66-1).
2.1 Major Infectious Diseases
With malnutrition as a common contributor, the five biggest infectious killers in Africa are
acute respiratory infections, HIV/AIDS, diarrhea, malaria and tuberculosis, responsible for
nearly 80% of the total infectious disease burden and claiming more than 6 million people per
year. In five out of six WHO regions, the burden of non communicable disease is greater than
that of communicable diseases. The exception is Africa where communicable diseases are
predominant (> Table 66-2).
Despite the success of vaccination programs for polio and many childhood diseases,
malaria, tuberculosis, HIV/AIDS and others are still out of control in the majority of
African countries. Children remain at high risk. Indeed, in 2002, of the 57 million deaths
reported worldwide, 10.5 million deaths were among children of less than 5 years of age,
of which 98% were in developing countries in general and in Africa in particular (WHO,
2003a, b, 2004, 2005) (> Table 66-3). Consequently, while life expectancy at birth reached
78 years for women in developed countries, it fell back to less than 46 years in sub-Saharan
Africa.
. Table 66-2
Deaths by causes in WHO regions, estimates for 2002, in thousands (WHO, 2003b)
Non
Communicable diseases, maternal and perinatal communicable
Cause conditions and nutritional deficiencies diseases Injuries
WHO regions
Africa 7779 2252 747
The Americas 875 4543 540
Eastern 1746 2030 391
Mediterranean
Europe 567 8112 803
South-East 5730 7423 1467
Asia
Western 1701 9000 1231
Pacific
World 18416 33424 5188
% of total 32.3% 58.6% 9.1%
deaths
Reproduced by kind permission of the World Health Organisation
This figure shows the predominance of communicable diseases in Africa by opposition to the rest of the world
where non communicable diseases are prevalent
. Table 66-3
Leading causes of deaths in children in developing countries in 2002 (WHO, 2003a)
Condition Numbers (in thousands) % of all deaths

Perinatal conditions 2375 23.1%
Lower Respiratory Infections 1856 18.1%
Diarrheal diseases 1566 15.2%
Malaria 1098 10.7%
Measles 551 05.4%
Congenital anomalies 386 03.8%
HIV/AIDS 370 03.6%
Pertussis 301 02.9%
Tetanos 185 01.8%
Protein-energy malnutrition 138 01.3%
Other causes 1437 14.0%
Total 10263 100%
Reproduced by kind permission of the World Health Organisation
Lower respiratory infections, malaria, diarrhea, measles, AIDS and other infectious diseases are the leading causes
of child mortality in developing countries and in Africa in particular. They affect life expectancy and human
development of African countries in general
2.1.1 HIV/AIDS
The number of people affected by HIV/AIDS is exponentially increasing, passing from

10 million cases in 1990 to more than 25 million cases in 1996 and reaching 42 million in
2002 (> Figure 66-2). Around 75% of all cases are taking place in Africa.
. Figure 66-2
HIV/AIDS cases have skyrocketed. In 12 years time, the number of cases affected by HIV/AIDS
worldwide has increased more than four-fold. In 2002, about three-quarter of all cases occurred
in Sub-Saharan Africa. Reproduced by kind permission of UNDP
In 2005, 38.6 million [33.4–46.0] people were living with HIV worldwide, 4.1 million [3.4–
6.2] became newly infected and 2.8 million [2.4–3.3] lost their lives to AIDS. If the present trend
is maintained, by 2020 AIDS will have caused more deaths than any other disease > epidemic in
history. Moreover, beyond mortality figures and beside the disease considered as a public health
challenge, HIV/AIDS is becoming a real problem of development. In Africa and especially in
countries with high > prevalence of HIV/AIDS, devastating consequences are already strikingly
apparent not only on health systems and health indicators but also in terms of income and
productivity, education and knowledge, human rights and gender equality (UNAIDS, 2006).
Nearly 80% of the 3 million global deaths from HIV/AIDS that occurred by the end of 2002
were in sub-Saharan Africa, dramatically cutting life expectancy and leaving a legacy of millions
of orphans. Seven countries had a prevalence of HIV over 20% (UN, 2004).
2.1.2 Diarrheal Disease
It is well known that diarrhea is among the leading causes of mortality and morbidity in
children in developing countries generally and in Africa particularly. Using different methods
and sources of information, several authors have attempted to evaluate the burden of this
disease. Despite the differences existing between estimates, they all show a declining trend in
mortality figures but a relatively stable morbidity. (Rohde and Northrup, 1976; Snyder and
Merson, 1982; NVD, 1986; Bern et al., 1992; Murray et al., 2001; Kosek et al., 2003; WHO,
2003a) (> Table 66-4).
. Table 66-4
Disease burden due to diarrhea worldwide
Deaths per
Authors year Period covered and data used in the review
Rohde and Northrup (1976) 5 million Author’s data, 1976
Snyder and Merson (1982) 4.6 million Review of data published between 1954 and 1979
NVD-US Institute of 3.5 million Based on published data and field experience
Medicine (1986)
Bern et al (1992) 3.3 million Using data published between 1980 and 1990
Murray et al (2001) 1.4 million Data analysis in 2000
Kosek et al (2003) 2.5 million Using data published between 1992 and 2000
WHO (2003a) 1.9 million Report: Global defence against the infectious disease
threat, data 2001
Various estimates provided by different authors who have tempted to evaluate the disease burden caused by
diarrhea diseases. They all show a declining trend in mortality but morbidity remains relatively stable
2.1.3 Malaria
The WHO statistics indicate that malaria claims more than 1 million lives a year. Beyond
mortality, the disease affects more than 300 million every year with a high handicapping rate.
Children, pregnant women and vulnerable people in general are the most exposed. Moreover,
malnutrition and other diseases like pulmonary infections constitute favourable environment
for the spread of malaria. Countries in tropical Africa bear the brunt of malaria, accounting for
more than 90% of all cases occurring worldwide each year (Ruxin et al., 2005).
2.1.4 Tuberculosis
Tuberculosis is among the top ten causes of global mortality (Dye, 1999; Borgdorff et al.,
2002). It has been estimated that approximately one-third of the world’s population is infected
with tuberculosis bacillus, and that each year 8 million people develop tuberculosis disease and
about 2 million die of the disease. Once more, the highest > incidence rates are found in Africa
and South-East Asia. The HIV/AIDS epidemic and multi-drug resistance have worsened the
tuberculosis situation over the last two decades. Tuberculosis is a leading killer of people with
HIV, and 80% of tuberculosis patients are HIV positive in countries with high prevalence of
HIV (Dye, 1999; Ruxin et al., 2005; Laxminarayan et al., 2007) (> Table 66-5). However,
despite the importance of weakened immunity due to HIV/AIDS, the global reductions in
immunity caused by malnutrition, diabetes, co-infections, drug use, alcoholism, and the stress
of poverty an migration could be as great if no greater than those caused by HIV/AIDS (Currey
et al., 2007).
. Table 66-5
The 22 countries the most affected by tuberculosis (Laxminarayan et al., 2007)
Number of countries by region Total Deaths HIV + deaths Excluding HIV + deaths
Africa (9 countries) 609986 444289 201760
Asia (9 countries) 987231 81826 888859
South America (3 countries) 74209 7148 69061
Europe (1 country) 34144 2902 31242
Total (22 countries) 1705612 536162 1205513
African countries are the most affected by the co-infections of HIV and tuberculosis
2.1.5 Respiratory Infections
According to WHO estimates, Respiratory infectious diseases were the first cause of mortality
from infectious diseases in 2001, responsible for nearly 4 million deaths. In 2002, lower respira-
tory infections caused nearly 2 million deaths in children, ranking at the second leading cause. In
Africa, this disease caused more than one million deaths and nearly 33 million DALYS in 2002.
2.1.6 Preventable Sexually Transmitted Diseases
Worldwide, in 1999, preventable sexually transmitted diseases (STD) caused about 350 million
infections in the population aged 15–49. However, in the era of AIDS and the high level of
politicisation and priority given to HIV, other sexually transmissible diseases may receive less
attention. For instance, North African countries are known to have high prevalence of STD
and relatively low prevalence of HIV/AIDS (Boutayeb, 2006).
Although tools of prevention have been available for decades, congenital syphilis is still
endemic in many African countries. In 1999, there were some 4 million cases of syphilis among
adults in sub-Sahara Africa compared to 4 million cases in south and south-east Asia and
3 million cases in Latin America and the Caribbean (Berman, 2003; Hawkes et al., 2003;
Peeling and Ye, 2003; Schmid, 2003).
2.1.7 Neglected Diseases
Beyond mortality figures, the health impact of a number of infectious diseases can be
measured by severe and permanent disabilities and deformities affecting approximately
1 billion people in the world and causing millions of DALYs. Africa is particularly concerned
with these diseases. Indeed, lymphatic filariasis, leishmaniasis, schistosomiasis, sleeping sick-
ness, dengue, Chagas disease, Buruli ulcer and others are responsible for impaired childhood
growth, mental retardation, blindness, amputation and diverse > disability conditions
(Derouich and Boutayeb, 2006; Boutayeb, 2007; See details in the chapter The Burden of
> Neglected Diseases in Developing Countries of this book).
3 Impact of Infectious Diseases on the Development
3.1 Sectorial Impact
3.1.1 Impact on Health Indicators
In Africa, respiratory diseases, HIV/AIDS, diarrhea, malaria, tuberculosis and other infectious
diseases are directly affecting health and demographic indicators such as mortality rates,
life expectancy, and sex and age distributions. In particular, millions of healthy years are
amputated from African populations due to infectious diseases (> Figure 66-3). Globally, in
. Figure 66-3
Loss of life expectancy due to HIV/AIDS. From 2000 to 2005 Zimbabwe, Botswana, Swaziland and
Lesotho have lost respectively 35, 28, 28 and 24 years in life expectancy due to HIV/AIDS.
Reproduced by kind permission of UNDP
1995–2000, 38 African countries had a mean life expectancy of 47 years, representing tens of
years of loss attributable to infectious diseases.
In the most affected countries by HIV/AIDS, life expectancy declined by 12.1 years during the
period 1995–2000 and it is expected to decline by 29.4 years by 2010–2015. More generally, deaths
and especially infant mortality are ravaging sub-Saharan Africa (> Table 66-6). The impact of
infectious diseases on health indicators affects individuals, households, communities and the
whole nation (hospitalisation, healthcare, orphan hood). In sub-Saharan Africa, HIV/AIDS
and related diseases are mobilizing more than half of all hospital beds. In some countries,
30%–50% of hospital admissions and around 50% of out-patient visits are due to malaria
which is also responsible for more than 30% of hospital deaths. Many African countries have
lost a large part of their healthcare workforce due to AIDS and other infectious diseases. In
other countries, midwives and health workers are affected by infectious diseases (UN, 2004).
. Table 66-6
Estimated and projected impact of HIV/AIDS on mortality indicators in the seven most affected
countries in Africa
1995–2000 2010–2015
Life expectancy at birth (years)
Without AIDS 62.3 67
With AIDS 50.2 37.6
Absolute difference 12.1 29.4
Number of deaths (millions)
Without AIDS 3 3
With AIDS 5 10
Absolute difference 2 6
Infant mortality rate (per 1000)
Without AIDS 55.4 40.7
With AIDS 66.1 54.6
Child mortality rate (per 1000)
Without AIDS 80.2 56.9
With AIDS 108.8 100.2
Reproduced by kind permission of UNDP
In Africa in general and in the most affected countries in particular, HIV/AIDS is seriously affecting life expectancy,
rates of mortality and child mortality. If the current trend is not reversed or at least stabilised then African countries
will be exposed to a catastrophe
3.1.2 Impact on Economic Indicators
Worldwide, about 2 billion people have inadequate or no access to life-saving treatments.

More than 80% of these deprived people are living in developing countries where infectious
diseases constitute serious impediments to economic development by reducing productivity,
setting aside saving possibilities and slowing economic growth in general. In many African
countries, the quasi totality of public health expenditure is a consequence of infectious
diseases. For instance, in tropical rural areas with limited access to preventive and curative
health facilities, malaria can have devastating consequences on agriculture households by a
simple episode that coincides with a plantation or harvest season. It is estimated that malaria
costs Africa more than US$12 billion a year, slowing its economic growth by 1.3% annually
(Bartram et al., 2005). Contrary to the majority of diseases, HIV/AIDS kills and disables adults
in the best productive part of their lives, affecting business, investment, industry and agricul-
tural sustainability. African agriculture labour force is particularly affected (> Figure 66-4).
. Figure 66-4
Reduction in African agriculture labour force due to HIV/AIDS, as estimated in 2000 and
projected for 2020 (UNAIDS, 2006). If the present trend is maintained, by 2020, HIV/AIDS will
have caused more than a 25% reduction in agriculture labour force in some African countries.
Reproduced by kind permission of UNAIDS

causes over 3 million livestock deaths each year and an annual loss of US$4.5 billion in
agriculture. Similarly, gains following lymphatic filariasis elimination are expected to ap-
proach US$4 billion per year. More globally, infectious diseases are reducing families’ income
and slowing economic growth as indicated by the recent report released by the World Bank on
tuberculosis control, showing that besides deaths, tuberculosis costs more than US$3.3 billion
annually in lost productivity though important economic benefit is at hand (Laxminarayan
et al., 2007) (> Table 66-7).
At the moment, it is difficult to estimate precisely the real economic impact that
infectious diseases are having on the whole African continent. However, many studies have
attempted to evaluate the disease burden case by case or country by country. In the case of
HIV/AIDS, the cost was estimated to be between 11.7 and 35.1% of the GNP in Africa
. Table 66-7
Costs and Economic Benefit of TB Control Strategies in Sub-Saharan African countries, in billions
of dollars (2006–2015) (Laxminarayan et al., 2007)
Sustained DOTS (relative to no DOTS) Costs Benefits Ratio

Africa 12.24 129.44 [112.81–146.07] 11 [9–12]
Africa High HIV+ 9.45 97.59 [85.83–109.35] 10 [9–12]
Africa Low HIV+ 2.79 31.85 [26.89–36.80] 11 [10–13]
High Burden African countries 7.70 81.06 [71.34–90.77] 11 [9–12]
African countries can make important economic benefits by controlling TB through a sustained DOTS strategy. The
ratio between benefit and cost can be greater than 10
(Macroeconomics, 2001). Other figures were given by different organisms like the World
Health Organization (WHO, 2003b), The European Parliament (2005), The World Bank
(World Bank, 2003), and UNAIDS (UNAIDS, 2006).
3.1.3 Impact on Education
As stressed in the Millennium Development Goals, education is essential for human develop-
ment and needs to be enhanced especially in sub-Saharan African countries. Unfortunately,
malaria, tuberculosis, HIV/AIDS and infectious diseases in general, are reversing the trend
towards the achievement of universal primary education in most African countries. In Africa,
less than 65% of children are enrolled in primary school and thousands of enrolled children
will prematurely leave school under the pressure of infectious diseases, including orphans,
disabled, impoverished and those who withdraw to look after ill members of their families
(UNICEF, 2005; UNAIDS, 2006; UNESCO, 2007) (> Table 66-8). During the period
1999–2004, orphaned children represented 12.3% of all children under age 18 in sub-Saharan
Africa and the percentage of child labour reached 41% in West and Central Africa (UNICEF,
2005). More globally, these diseases are seen to have a four-fold impact on education. They
affect the cognitive ability of children, the capacity of teachers, the upbringing of families and
the efficiency of staff and managers. For instance, HIV prevalence among South African
. Table 66-8
Impact of orphanhood on school attendance among 10–14 years-olds (%) (UNAIDS, 2006)
West: 9 Central: 6 Eastern: 9 Southern: 10 All: 34

Percentage in school countries countries countries countries countries
Non-orphan 67 75 70 88 74
Orphan 58 69 54 84 69
Double orphan 57 58 49 80 64
Ratio double versus .86 .94 .72 .90 .87
non orphan
Reproduced by kind permission of UNAIDS
In African countries, orphan children are more likely to miss school than others
teachers reaches 21% among those aged 25–34 and 13% among those aged 35–44, whereas in
the Zambian school system, over 60% of teacher absence is due to HIV/AIDS (illness, care for
ill family members, family funeral, etc..) (UNAIDS, 2006).
Malaria is the leading cause of mortality in the under-five African children. Consequently, it
affects the education capacity of African countries. Similarly and on top of high mortality figures,
with a median of 3.2 episodes per child-year, diarrhea is highly affecting school attendance.
3.2 Global Impact on Economic and Human Development
As indicated in the previous sections, infectious diseases are globally affecting economic and
human development of African countries. Malaria is responsible for 10% of Africa’s disease
burden and the current GDP is thought to be 32% lower than it would have been without
malaria. Consequently, in Africa, malaria is seen both as a disease of poverty and a cause of
poverty. The devastating impact of HIV/AIDS is recognised in the majority of national human
development reports as stressed in the South Africa human development report 2003 (South
Africa, 2003), the Zimbabwe human development report 2003 (Zimbabwe, 2003) and the
Malawi human development report 2005 (Malawi, 2005). These reports give details of the
impact of HIV and AIDS on household welfare, orphaned children, the extended family,
educational and health sectors, agricultural production, business and public service delivery.
They also stress that HIV/AIDS and its far-reaching consequences mean that the disease is no
longer a crisis only for the healthcare sector, but presents a challenge to all sectors. It has the
potential to reverse those gains made in human development in the last few years.
Economically, 34 African countries belong to the lower-income group, 12 are lower-
middle-income countries, only eight countries are classified as higher-middle-income and
no African country has reached the high-income level.
Sadly and more interestingly, it can be seen from the UNDP report 2006 (UNDP, 2006)
that infectious diseases are affecting all components of human development (HD) in African
countries. Indeed, no African country belongs to the ‘‘High HD’’ group, almost all of the ‘‘Low
HD’’ countries at the bottom of the index table are in sub-Saharan Africa, and the remaining
African countries occupy uncomfortable places among the ‘‘Medium HD’’ group.
Moreover, in 15 years (1990–2006), the most affected African countries by infectious
diseases in general and by HIV/AIDS in particular have lost tens of places in the human
development ranking.
In 2001, the Commission on Macroeconomics and Health provided empirical evidence on
how investing in health can achieve economic development and poverty reduction. It was
estimated that eight million lives per year could be saved by essential interventions against
infectious diseases and nutritional deficiencies by 2010, resulting in economic benefits adding
up to more than US$360 per year by 2015. In the same spirit, the United Nations (UN)
Millennium Summit adopted in 2001 the Millennium Development Goals (MDGs) by fixing
eight goals to be reached in 2015. Preventing the spread of HIV/AIDS, tuberculosis, malaria,
and other infectious diseases is one of the goals. However, mid-way, most African countries,
have made little (if any) headway in preventing and controlling infectious diseases like HIV/
AIDS, malaria, tuberculosis, diarrhea, respiratory disease and a multitude of the so-called
neglected diseases. Opposite to that, wars and conflicts are financed at the expenses of disease
control as it can be sadly noticed from the amount of US$7 billion that African governments
dedicated to military spending in 1999 (Mashelkar, 2005).
4 Conclusions
In African nations, millions of people live with less than 1$ a day and on fragile and often
remote rural ecosystems, most of them lack access to basic health services and safe drinking
water. Moreover, many countries, being heavily indebted, affect less than 1% of the national
global budget to health, and few governments are putting science, technology and innovation
at the centre of their strategies.
Considering the treatment cost of communicable and chronic diseases, and the level of
poverty, the most affected countries are unable to cope with the burden of disease. For health
strategies to be successful, international solidarity and public-private partnerships are needed
to tackle the problems of shortage and lack of treatments, resistance and the need for
new drugs, vaccines and diagnostic procedures. In this direction, several programmes have
already been launched such as the Global Fund to Fight AIDS, Tuberculosis and Malaria
(GFFATM), Global Alliance for Vaccines and Immunization (GAVI), The medicines for
Malaria Ventures (MMV), the Global Alliance for TB Drug Development (TB Alliance),
The Human Hookworm Vaccine initiative (HHVI), the Foundation for Innovative New
Diagnostics (FIND), the Drug for Neglected Diseases Initiative (DNDi), Stop TB, Roll back
Malaria, etc. . .. However, this global strategy is insufficient without the national and local
implication. Health decision makers, non governmental organizations (NGOs), research
institutions, community groups and individuals must join their efforts in order to attenuate
the incidences of specific diseases, control the spread of epidemics and development of
complications, and optimise the health management of human and material resources.
Stressing that treatment has been the most neglected element in developing countries
where almost 6 million people will die from AIDS in the near future if they do not receive
treatment, the WHO report 2004 calls for a comprehensive HIV/AIDS strategy that links
prevention, treatment, care and long-term support. The objective fixed by WHO and its
partners to provide 3 million people in developing countries with antiretroviral therapy by
the end of 2005 was far to be reached, suggesting that more effort and efficient measures are
needed. It is also hoped that combined efforts between donor nations and affected countries
will provide the US$2–3 billion per year required to scale up the response against malaria in
endemic areas. Similarly, although 16 million patients have been treated so far with the WHO-
recommended directly observed therapy strategy (DOTS), yet more than half of those affected
by tuberculosis still do not have access to this treatment, especially those living in the Nine
African countries the most affected by tuberculosis. However, an indisputable economic
benefit is predicted from a sustained DOTS and global plan strategy as indicated by the
World Bank report (Laxminarayan et al., 2007). A recent cost-benefit analysis by WHO
showed that achieving the global MDG target in water and sanitation would bring substantial
economic gain in both health and other benefits (consequences of reduction in diarrheal
episodes): each $1 invested would yield an economic return between $3 and $34 depending on
region. The health-related costs avoided would reach $7.3 billion per year, and the annual
value of adult working days gained as a result of less illness would be almost $750 million.
Last but not least, tens of thousands of deaths can be avoided in Africa, and billions of
dollars saved by reducing the impact of respiratory diseases and the so-called neglected
diseases such as schistosomiasis, intestinal helminth infections, trachoma, dengue and others.
Meanwhile, by the dawn of the third millennium, a Japanese woman can expect to receive,
on average, care and medications worth about US$550 per year and much more if needed.
Whereas, a woman in the least developed African countries can expect, on average, medicines
worth about US$3 per year. Consequently, a woman in sub-Saharan Africa is 100 times more
likely to die in pregnancy or childbirth than is a woman in Western Europe.
Summary Points
Infectious diseases are causing about 15 million deaths annually with more than 80% in
Africa
Low-income economies is the group of countries where the annual per capita income is
less than 600 dollars
Tuberculosis is the second leading infectious disease, causing about 2 million deaths every
year
Malaria is responsible for one million deaths annually almost exclusively happening in
Africa
HIV/AIDS, appeared about 25 years ago, this disease has become a real development
problem, causing about 3 million deaths annually, responsible for more than 7% of the
global disease burden (DALYs)
Diarrheal disease is the third leading cause of child mortality, killing about 1.5 million
children every year
Respiratory Diseases constitute the second killer of children with nearly two million deaths
annually
Neglected Diseases is the name given to a multitude of diseases, including lymphatic
filariasis, leishmaniasis, schistosomiasis, sleeping sickness, dengue, Chagas disease, Buruli,
ulcer, trachoma and others
Infectious diseases are reducing life expectancy in many African countries. For instance,
the reduction due HIV/AIDS is between 25 and 35 years in Botswana, Swaziland and
Zimbabwe
The economic cost of HIV/AIDS is estimated to be between 11.7 and 35.1% of the GNP in
Africa
causes over 3 million livestock deaths each year and an annual loss of US$4.5 billion in
agriculture
Malaria costs Africa more than US$12 billion annually
References
Bartram J, Lewis K, Lenton R, Wright A. (2005). Lancet. Boutayeb A. (2007). Developing countries and neglected
365: 810–812. diseases: challenges and perspectives. Int J Eq
Berman SM. (2003). Bull World Health Organ. 82: Health. doi: 10.1186/1475-9276-6-20.
433–438. Currey B, Quamruzzaman Q, Rahman M. (2007). Lan-
Bern C, Martines J, de Zoysa I, Glass RI. (1992). Bull cet. 371: 1401–1403.
World Health Organ. 70: 705–714. Derouich M, Boutayeb A. (2006). Appl Math Comput.
Borgdorff MW, Floyd K, Broekmans JF. (2002). Bull 177: 528–544.
World Health Organ. 80: 217–227. Dye C. (1999). Int J Tub Lung Disease. 4: 146–152.
Boutayeb A. (2006). Trans R Soc Trop Med Hyg. 100: European Parliament (EP). (2005). Report on major and
191–199. neglected diseases in developing countries. Available
at http://www.europarl.europa.eu (accessed at South Africa. (2003). Human development report.

8 December 2007). Available at http://www.undp.org.za (accessed at
Hawkes S, Miller S, Rechenbach L, Nayyar A, Buse K. 8 December 2007).
(2003). Bull World Health Organ. 82: 417–423. UNESCO. (2007). Education for all in least developed
Kosek M, Bern C, Guerrant RL. (2003). Bull World countries. Available at shttp://unesdoc.unesco.org
Health Organ. 81: 197–204. (accessed at 8 Dec 2007).
Laxminarayan R, Klein E, Dye C, Floyd K, Dareley S, UNICEF. (2005). The state of the world’s children. The
Adeyi O. (2007). Economic Benefit of Tuberculosis United Nations Children’s Fund, New York.
Control. The World Bank, Washington, DC. United Nations. (2004). World population prospects.
Malawi HDR. (2005). Reversing HIV/AIDS in Malawi. United Nations, Geneva.
United Nations Development Programme, UNAIDS. (2006). The impact of AIDS on people
Washington, DC. and societies. Available at http://data.unaids.org
Mashelkar RA. (2005). Innov Strat Today. 1: 16–32. (accessed at 20 January 2008).
Mathers CD, Ezzati M, Lopez AD. (2007). Measuring UNDP. (2006). Human development indicators. Avail-
the burden of neglected tropical diseases: the global able at http://hdr.undp.org (accessed at 8 December
burden of disease framework. PLOS Negl Trop Dis. 2007).
doi: 10.1371/journal.pntd.0000114. World Bank. (2003). Sustainable development in a dy-
Murray CJL, Lopez AD, Mathers CD, Stein C. (2001). namic world. Available at http://www.worldbank.
The Global Burden of Disease 2002 Project. Word org (accessed at 20 January 2008).
Health Organization, Geneva. WHO. (2003a). Global defence against the infectious
NVD. (1986). Establishing Priorities volume 2. Institute diseases threat. World Health Organization, Geneva.
of Medicine, Washington, DC. WHO. (2003b). World Health Organization annual
Peeling RW, Ye H. (2003). Bull World Health Organ. 82: report. Available at http://www.who.int/whr/2003/en
439–446. (accessed at 20 January 2008).
Rohde JR, Northrup RS. (1976). Ciba Foundation WHO. (2004). World Health Organization annual
Symposium Acute Diarrhoea in Children. Elsevier, report. Available at http://www.who.int/whr/2004/
Amsterdam, pp. 339–365. en (accessed at 20 January 2008).
Ruxin J, Paluzzi JE, Wilson PA, Tozan Y, Kruk M, WHO. (2005). World Health Organization annual
Teklehaimanot A. (2005). Lancet. 365: 618–621. report. Available at http://www.who.int/whr/2005/
Schmid G. (2003). Bull World Health Organ. 82: en (accessed at 20 January 2008).
402–409. Zimbabwe HDR. (2003). Redirecting our responses to
Snyder JD, Merson MH. (1982). Bull World Health HIV and AIDS. United Nations Development
Organ. 60: 605–613. Programme, Washington, DC.
67 Measuring the Global Burden
of Tuberculosis
I. Onozaki . N. Ishikawa . D. A. Enarson
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190
2 Global TB Burden and its Trend . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1192
3 How the Burden is Estimated . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1192

3.1 Incidence as an Indicator of Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1192
3.2 Estimation of Incidence Using Different Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1195
3.3 Estimation of Incidence from Annual Risk of TB Infection . . . . . . . . . . . . . . . . . . . . . . . 1198
3.4 Estimation of Incidence from Disease Prevalence Surveys . . . . . . . . . . . . . . . . . . . . . . . . . 1198
3.5 Estimation of Incidence from Vital Registrations of Deaths . . . . . . . . . . . . . . . . . . . . . . . 1199
3.6 Estimation of Trends in Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1200
4 Prevalence as an Independent Indicator for Millennium

Development Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1200
4.1 How to Detect TB Cases in the Community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
4.2 Culture Examinations are Recommended to Measure TB Burden
and to Confirm TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1204
4.3 High Risk Groups and Their Role in Resurgence of TB . . . . . . . . . . . . . . . . . . . . . . . . . . . 1205
4.4 Prevalence Survey Brings Other Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1205
5 Delay Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1205
6 New Technology for Screening and Diagnosis to Measure the Burden . . . . . . . . . . 1205
7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206
8 Case Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1209

1190 67 Measuring the Global Burden of Tuberculosis
Abstract: There are several ways to measure the burden of TB. Estimated TB incidence and
its rate have been utilized as the most popular indicators of TB burden since 1997. According
to the WHO’s estimation of the global TB burden, there were 9.2 million new TB cases in
2006 with 1.7 million deaths due to TB. Although the estimated global incidence rate stabilized
or began to fall slowly, the number of new cases was still increasing because population growth
had a greater effect on the number of cases than did the declining rate of TB.
However, for each individual country, the uncertainty of the incidence estimation became a
concern for monitoring and evaluating the progress of the TB situation at the country level.
Methods for estimating current burden were reviewed. An important limitation is that the
current estimation of the burden, incidence, is mainly based on the notification data from
countries and assumption of case detection rate. Very few countries have scientific data to
estimate the epidemiological situation and trend. It is essential to strengthen routine recording
and reporting systems, and surveillance, to improve the estimates of burden and trend. However,
as the current surveillance systems are not always reliable in many countries where TB is common,
it is recommended that a prevalence survey be conducted every 5–10 years. Prevalence itself is one
of the MDG’s indicators, and survey findings can be utilized to evaluate trends derived from
routine surveillance. Combinations of prevalence surveys and notification data might be the best
method to measure disease burden. Although a prevalence survey is costly and labour intensive, it
may be a great help to a country in improving TB control policy. Surveys made in some countries
might help neighbouring countries with similar situations to understand their epidemiological
status of TB through interpretation of routine surveillance data. By adding delay analysis, much
insight can be gained into the quality and use of TB services.
List of Abbreviations: BCG, Anti- Tuberculosis vaccine containing the Bacille de Calmette et
Guérin used by the expanded immunization programme worldwide; CDR, Case Detection
Rate; DALYs, Disabled Adjusted Life-Years; DOTS, The brand name of a comprehensive TB
control program recommended by the WHO and Stop TB Partnership originated from Directly
Observed Treatment, Short Course; HBC, High-burden country where the absolute number of
TB incident cases is high. 22 HBCs comprise 80% of the Global TB burden; HIV, Human
Immuno-deficiency Virus; IGRAs, Interferon gamma release assays; MDGs, > Millennium
Development Goals; MDR TB, Multidrug-Resistant Tuberculosis. TB that is resistant, at a
minimum, to the two major anti-TB drugs Rifampicin and Isoniazid; NTP, National TB
Control Program; TB, Tuberculosis; WHO, World Health Organization; XDR TB, Extensively
Drug Resistant Tuberculosis, which is MDR but also resistant to any fluoroquinolone and any
second-line anti-TB injectables, namely Amikacin, Kanamycin or Capreomycin
1 Introduction
The Burden of Tuberculosis (TB) usually refers to the epidemiological burden and is measured
by disease incidence, prevalence and/or mortality, and infection prevalence, and incidence
(annual risk). It may also be measured by economic indicators such as medical expenditure on
TB and economic loss due to TB. Until the early 1990s, short-course chemotherapy, a
rifampicin-containing regimen had been believed to be too expensive for developing
countries. However, the cost effectiveness of TB control was demonstrated by estimating the
number DALYs saved by its activities, and the World Bank started to invest in TB control
(Murray et al., 1991; World Bank, 1993). This marked the turning of the tide in terms of
international assistance to TB control with the adoption of DOTS as the international
standard for TB services (WHO, 1994; WHO Tuberculosis programme, 1994).
Measuring the Global Burden of Tuberculosis 67 1191
Since 1997, the WHO publishes the Global TB report every year with estimates of disease
incidence, prevalence and mortality at global, regional and national levels (WHO, 2008). The
indicators are shown in absolute numbers and rates per 100,000 population. High burden
countries (HBCs) for TB have been designated based on the absolute number of the estimated
new TB cases per year, or incidence, in a country. Since then, the WHO’s estimation of TB
incidence has been widely used to reflect the burden. According to the Global TB report of
2008, there were an estimated 9.2 million new cases in the world in 2006 (139 per 100,000
population) including 4.1 million smear positive cases. Twenty-two HBCs account for 80% of
the global TB burden in terms of incidence (WHO, 2008).
For each country, smear positive incidence per 100,000 population has been the most
popular indicator to express a country’s TB burden for a decade. Because one of the two
pillars of international outcome targets was to detect 70% or more of existing smear
positive cases (a case detection rate of 70% or more), along with a treatment success rate
of 85% or more (WHO Tuberculosis programme, 1994), countries have become more
interested in incidence. It is estimated that detecting 70% of incident cases and curing
85% of them will cause the TB burden to be halved in 8–12 years (in the absence of HIV)
(Styblo and Bumgarner, 1991). The CDR target became a vital force to push countries to
improve their case finding and their surveillance systems. It is also a visible indicator at
the global level to demonstrate and monitor progress. In 2006, the global estimation of
the case detection rate of smear positive TB was 61% and 77 countries met the 70% target
(WHO, 2008).
However, as DOTS, and better TB services expanded in countries, several questions were
raised concerning the extent to which these estimations are reliable especially at the country
level. We observed several discrepancies even within the 22 HBCs: Myanmar achieved 70%
detection in 2003, and efforts on further expansion of the service obtained 100% or more
CDR consecutively in 2005, 2006 and 2007; Vietnam has been achieving both CDR and
treatment success targets since 1997. However, it experienced no decline of case notification;
despite extensive efforts, most African countries such as Nigeria, Ethiopia, Tanzania and
Uganda fell far short of the 70% CDR target. Is the disease burden in Asian countries
underestimated? Is it overestimated in African countries? How do countries reliably dem-
onstrate impact of intervention in terms of decline of incidence? The uncertainty over the
current approach to estimation of TB burden has created much discussion, and several
countries are now showing interest in surveys to understand the epidemiological burden
more accurately.
Current global targets and indicators for TB control have been developed within
the framework of the MDGs as well as by the Stop TB Partnership and the WHO’s World
Health Assembly (Stop TB Partnership, 2006). The impact targets are to halt and reverse TB
incidence by 2015 and to halve the prevalence and death rates by 2015 compared with a
baseline of 1990. Although it is questionable how accurately we can estimate a 1990 baseline, it
is notable that a measurable indicator derived from community surveys, namely disease
prevalence, became one of the indicators of the MDGs. Disease prevalence surveys began
to be promoted to more accurately determine the TB situation in countries (Dye et al.,
2008; WHO, Western Pacific Region, 2007), even as serious limitations of tuberculin surveys
began to be recognized (Dye, 2008; Reider, 1995).
In this chapter, we first summarize the current estimation of the global TB burden by the
WHO. Second, we try to provide an overview of current methods to measure burden, and, third,
we discuss what might be the best way for a country to measure its TB burden especially in
resource poor high burden settings.
2 Global TB Burden and its Trend
The WHO estimated that there were 9.2 million new cases of TB in 2006 (139 per 100,000
population) including 4.1 million smear positive cases (WHO, 2008). Although HIV is often
thought to be the cause of the resurgence of TB (Corbett et al., 2003), 0.7 million HIV-positive
cases make up only 8% of the total TB cases. However, the African Region has the highest
incidence per capita (363 per 100,000 population), while the Western Pacific and the South
East Asian Regions accounted for more than half of the incidence, 55%. Twenty-two countries
designated as HBC accounted for 80% of the incidence, and 50% of those incident cases in the
22 HBC, 3.8 million, were in the top three countries: India, China and Indonesia (WHO, 2008;
> Table 67-1).
The magnitude of the TB burden in each country can also be expressed as the incidence
rate (WHO, 2008; > Figure 67-1). Higher incidence rates were observed mostly in countries in
Africa, South East Asia and the Former Soviet Union. HIV co-infection, poverty and recent
experiences of social instability seem to be major factors contributing to the high burden of TB
in these countries. There were 29 countries that were estimated to have the highest incidence
rate of all TB (300 or more per 100,000 population). All but three (Cambodia, East Timor and
Kiribati) were countries in the African continent. The high incidence rates in African countries
are partially explained by a high rate of HIV co-infection (Corbett, 2003). This may also
explain the higher mortality in the African Region; while the African Region accounted for
31% of the incidence, it accounted for 39% of TB deaths.
According to WHO estimates of global incidence of TB per capita, the incidence rate
peaked around 2003 and appears to have stabilized or begun to decline slowly, while the
mortality and disease prevalence rate began to decline earlier because these factors respond
more quickly to the expansion of case detection and treatment (WHO, 2008; > Figure 67-2).
Among 134 countries that have a reliable series of case notification reports for the decade
1997–2006, data from 93 countries indicate that the incidence rate was falling. However,
globally, the slow decline of the incidence rate was overwhelmed by population growth in
actually increasing the numbers of cases (the estimated incidence in 2005 was 9.1 million,
while that of 2006 was 9.2 million). Decline of HIV prevalence in the general population in
high HIV prevalence countries in Africa was mainly contributing to the declining incidence
rate of TB in the region as well as that in the world.
Recently, the threat of MDR and XDR TB has started to attract significant attention. While
most drug sensitive TB can be cured with a 6-month chemotherapy regimen costing 20$ per
course, MDR and XDR TB are often fatal and require 2 years for treatment with a cost that is
100 times more expensive than that of drug sensitive TB. Therefore, MDR and XDR TB can be
proposed as a significant part of the global burden; it is estimated that 490,000 MDR TB cases
emerged in 2006, and 40,000 of those were XDR TB (The WHO/IUATLD Global Project on
Anti-Tuberculosis Drug Resistance Surveillance, 2008).
3 How the Burden is Estimated
3.1 Incidence as an Indicator of Burden
As an indicator to decide HBC, the incidence of all TB is usually calculated from the
estimation of smear positive incidence in most resource-limited countries, as diagnosis of
. Table 67-1
Epidemiological burden of TB, 2006 estimated by WHO
Incidence Prevalence Mortality HIV prev.* in

Incident TB
All forms Smear positive All forms All forms cases
Population Number Per Number Per Number Per Number Per
1000s 1000s 100,000 pop 1000s 100,000 pop 1000s 100,000 pop 1000s 100,000 pop %
India 1,151,751 1933 168 867 75 3,445 299 325 28 1.2
China 1,320,864 1,311 99 590 45 2,658 201 201 15 0.3
Indonesia 228,864 534 234 240 105 578 253 88 38 0.6
South Africa 48,282 454 940 184 382 482 998 105 218 44
Nigeria 144,720 450 311 198 137 890 615 117 81 9.6
Bangladesh 155,991 351 225 158 101 610 391 70 45 0.0
Ethiopia 81,021 306 378 136 168 520 641 68 83 6.3
Pakistan 160,943 292 181 131 82 423 263 55 34 0.3
Philippines 86,264 248 287 111 129 373 432 39 45 0.1
DR Congo 60,644 237 392 105 173 391 645 51 84 9.2
Russian Federation 143,221 153 107 68 48 179 125 24 17 3.8
Vietnam 86,206 149 173 66 77 194 225 20 23 5.0
Kenya 36,553 141 384 56 153 122 334 26 72 52
Measuring the Global Burden of Tuberculosis
UR Tanzania 39,459 123 312 53 135 181 459 26 66 18

Uganda 29,899 106 355 46 154 168 561 25 84 16
Brazil 189,323 94 50 59 31 104 55 7.6 4.0 12
Mozambique 20,971 93 443 39 186 131 624 24 117 30
Thailand 63,444 90 142 40 62 125 197 13 20 11
67
1193
1194
67
Incidence Prevalence Mortality HIV prev.* in

Incident TB
All forms Smear positive All forms All forms cases
Population Number Per Number Per Number Per Number Per
1000s 1000s 100,000 pop 1000s 100,000 pop 1000s 100,000 pop 1000s 100,000 pop %
Myanmar 48,379 83 171 37 76 82 169 6.1 13 2.6
Zimbabwe 13,228 74 557 30 227 79 597 17 131 43
Cambodia 14,197 71 500 31 220 94 665 13 92 9.6
Afghanistan 26,088 42 161 19 73 60 231 8.3 32 0.0
High burden countries 4,150,313 7,334 177 3,265 79 11,899 286 1,330 32 11
African Region 773,792 2,808 363 1,203 155 4,234 547 639 83 22
American Region 899,388 331 37 165 18 398 44 41 4.5 6.4
Eastern Mediterranean 544,173 570 105 256 47 826 152 108 20 1.1
Region
European Region 887,455 433 49 194 22 478 54 62 7.0 3.0
South East Asian Region 1,721,049 3,100 180 1,391 81 4,975 289 515 30 1.3
Western Pacific Region 1,764,231 1,915 109 860 49 3,513 199 291 17 1.2
Global 6,590,088 9,157 139 4,068 62 1,424 219 1,656 25 7.7
*HIV
This table shows epidemiological burden of TB in 2006 by incidence, prevalence, and mortality
smear positive TB is mostly standardized and available in most countries. Smear positive TB is
said to account for 45% of all TB, even though it has been shown that this proportion varies
widely in different population groups. High HIV prevalent countries are given a lower
proportion with the assumption that the smear positive accounts for 35% of TB incidence
among HIV positives (Corbett et al., 2003; Dye et al., 1999; WHO, 2008).
Although TB incidence is theoretically measurable by a prospective study, it is practically
impossible as it is necessary to have a very large population to follow up because cases of TB
disease occur only in hundreds per 100,000 a year in the general population even where TB is
most frequent. Moreover, because there is no suitable biomarker to detect all TB cases
accurately especially in resource poor settings. Thus it is no possible to measure TB incidence
directly in the general population. Some may argue that it is easy to study the incidence of
smear positive tuberculosis. However, because some cases may convert to negative without
treatment prior to regular examination, and because other serious cases may die very quickly,
it might be difficult to catch all smear positive incident cases as smear positive TB patients
(Toman, 2004). Moreover, to accurately determine the incidence of smear positive tuberculo-
sis must take account of that fact that some patients with smear negative TB might progress to
smear positive without treatment, but carrying out such as study would be unethical. It is not
feasible to estimate the incidence by direct measurement. We need alternative methods to
measure burden and to estimate incidence.
The current estimations of the TB burden by the WHO are based principally on four
different methods and their combinations: notification data with an assumption concerning
the case detection rate (1); annual risk of TB infection using the Styblo ratio (2); prevalence
from surveys with the assumption of an average disease duration (3); and TB mortality from
vital registration data used together with case fatality rate (4). The method(s) selected for
making estimates for a specific country depend(s) upon the availability of study results and
quality of data. They use the following parameters:
1. Incidence = case notification/estimated proportion of cases detected.
2. Incidence (smear positive) = > annual risk of infection (ARI) (%) 50/100,000.
3. Incidence = prevalence/average duration of condition.
4. Incidence = TB deaths/proportion of incident cases that die (case fatality rate).
We will discuss each method in the following four sections.
3.2 Estimation of Incidence Using Different Methods
Disease prevalence and tuberculin surveys have been conducted in a limited number of
countries (WHO, Western Pacific Region, 2007), and most developing countries do not
have reliable mortality data from vital registration that covers the whole population. There-
fore, incidence for the majority of countries is estimated from notification data, routine
surveillance, with assumptions of the case detection rate. Although the WHO’s estimates are
the best guess of the country burden with careful review of all available information, it may
cause confusion in countries as they calculate one of their key target indicators of CDR by
dividing their notification by the incidence estimation that was estimated using an assumption
of CDR for the country.
In countries where access to medical services is good for most of the population and where
functional disease surveillance exists, notification is considered to be a reliable indicator of
1196
. Figure 67-1
Estimated TB incidence rate, 2006. Source: Figure 1.3 in page 20 in Global Tuberculosis Control 2008 (World Health organization 2008). This figure shows
the estimated incidence rate over the world. Higher incidence rates were observed mostly in countries in Africa, South East Asia and the
67
Former Soviet Union.
. Figure 67-2
Estimated global prevalence, mortality and incidence rates, 1990–2006. Figure 1.20 in Global
Tuberculosis Control 2008 (World Health Organization 2008). This figure shows estimated global
prevalence, mortality and incidence rates. WHO estimates of global incidence of TB per capita,
the incidence rate peaked around 2003 and appears to have stabilized or begun to decline
slowly, while the mortality and disease prevalence rate began to decline earlier
disease incidence. The private sector and laboratories are also included in the surveillance
system in many of such countries in order to catch as many TB cases as possible. The burden of
disease can be estimated correctly through the routine surveillance system in these countries,
and this is ideal. However, it is obvious that this method cannot be applied in most TB
endemic developing countries, where the surveillance system is weak. Not only does the TB
service fail to reach every segment of the population, such as migrants, the very remote, and
the urban poor, but the surveillance system often does not even cover public medical facilities
outside the disease control services (such as teaching hospitals or central hospitals) nor does it
cover the growing private sector.
In these settings, when data from other methods is not available, it is necessary to make a best
assumption of the case detection rate. A baseline case detection rate was established in a series of
consultation workshops in each WHO region in 1997, country by country (Dye et al., 1999).
If a country has some model or pilot areas of DOTS with improved access and quality of
care, the case notification rate of those areas might be considered as a standard, assuming their
case detection rate is high. However, such projects might be more likely to be implemented in
very remote or hot spots where high incidence is expected or may attract clients from outside
the area. Whether the results can be generalized to the entire country should be carefully
discussed.
While continuous efforts are essential to expand services to reach those vulnerable patients
without access, it is important to make efforts to improve the current disease surveillance
system. However, since it may take years to establish it in most developing countries, it is
necessary to have alternative ways to estimate the burden.
3.3 Estimation of Incidence from Annual Risk of TB Infection
Although the annual risk of TB infection (ARI) available from tuberculin surveys used to be
utilized as a key indicator of TB epidemiology (Cauthen et al., 2002), using ARI to estimate TB
incidence is no longer recommended (Dye, 2008; Dye et al., 2008). ARI available from a
tuberculin survey has been utilized to estimate TB incidence through applying Styblo’s rule: a
1% ARI was considered to be equivalent to a smear positive TB incidence of 50/100,000
(Styblo, 1985). However, the results of recent tuberculin surveys are hardly interpretable
without any anti-mode to distinguish infected from non-infected both in BCG vaccinated
and non-vaccinated individuals. High BCG coverage also hampers the interpretation of
studies. It has been very difficult to estimate ARI from most recently conducted tuberculin
surveys (Dye et al., 2008; National Center for Tuberculosis and Leprosy Control, 2005; Reider,
1995). Moreover, it has been shown that the Styblo model does not fit the epidemiological
situation in many countries where surveys were recently conducted (van Leth et al., 2008;
National Center for Tuberculosis and Leprosy Control, 2005). One smear positive patient may
not infect as many as was estimated; circulation of the infection may be occurring in
populations far from children such as in factories in urban areas; schoolchildren might be
better protected from TB infection than the general population. Disease incidence previously
estimated by using ARI from tuberculin surveys seems to be underestimated. The WHO and
its technical task force no longer recommend using a tuberculin survey to estimate TB disease
incidence.
However, although the tuberculin survey is not recommended to measure the burden, it
might help to estimate epidemiological trends in a country if a series of surveys can be
conducted in comparable ways.
> Interferon-gamma release assays (IGRAs) introduce a new technology to diagnose latent
infection of TB, and results are less affected by BCG vaccination and infections with myco-
bacteria other than tuberculosis (Lalvani, 2007; Pai et al., 2004). They may be expected to be
utilized for surveys to determine the TB infection rate in the population. However, the
technical stability of handling IGRAs with a large number of samples from a survey is still a
concern in resource poor settings. Observations of conversion and reversion of results of
IGRAs suggest that what is being measured by tuberculin test and by IGRAs may be different
(Menzies et al., 2007). Moreover, there marked limitations because of the necessity of taking
blood by veno-puncture where the majority of children (those who are negative) cannot
obtain any benefit from the survey examination. Therefore, infection surveys with IGRAs
among children are not recommended. Development of less invasive, simpler examinations to
determine infection is essential.
3.4 Estimation of Incidence from Disease Prevalence Surveys
Like incidence, prevalence is a direct measure of illness in a population. Although measuring

incidence is extremely difficult, prevalence can be measured in a single population study, and a
series of studies can indicate a trend. Although disease prevalence surveys were conducted
widely until 1970, the national level data was available only from Asian countries until recently
(World Health Organization, Western Pacific Region, 2007). Since active case detection has
not been encouraged for decades because of questions of cost and effectiveness, prevalence
surveys that use the same methodology were also suspended. However, many countries are
showing interest in disease prevalence surveys to identify the TB burden, incidence, and to
determine the real CDR there. However, countries should be aware that to estimate the
incidence even with a quality prevalence survey is extremely difficult and may be unreliable.
When smear positive disease prevalence from a survey was used to estimate incidence,
prevalence was traditionally divided by two with the assumption that the average duration of a
smear positive condition was 2 years. However, successful treatment greatly reduces average
duration, drug resistant disease and inadequate treatment may prolong it and HIV infection
may also change the average duration of disease, by rapid progression and death in advanced
cases. It is necessary to provide country specific disease duration while also considering
various factors such as service coverage, HIV prevalence and MDR TB prevalence. For most
HBCs, it is necessary to consider six different scenarios: three kinds of patients with different
treatment; patients who received DOTS, patients who received non-DOTS treatment, and
those who received no treatment; and each of them with and without HIV. This process must
always be applied when making such estimates as prevalence is a product of incidence and
disease duration.
The proportion of patients who received non-DOTS or treatment in the private sector
without notification might be available from a population-based prevalence survey. However,
it is difficult to estimate treatment results, or average time to smear conversion. When
treatment through non-DOTS accounts for a large proportion of the patients being treated
in a country, it may affect the estimation of incidence.
For patients who cannot afford or do not have access to any modern treatment, a historical
observation of 2 years is often given to the non-HIV positive. The WHO estimation gives
6 months to HIV positives, considering the rapid progress of disease without treatment
(WHO, 2008). However, this assumption among the HIV negative patients is no longer
reliable in the chemotherapy era. Characteristics of non-detected may be different from
those detected; among those who do not have access to chemotherapy, some are too ill to
visit the TB service and die earlier, while some stay in the community without taking action
longer because they are not seriously ill. For HIV positive patients, disease duration might be
longer than 6 months. Results of intensified case detection through screening cannot explain
such a short duration of illness of 6 months (Cheng et al., 2008; Kimerling et al., 2002; Wood
et al., 2007).
Therefore, even if a very high quality prevalence study is conducted in a country, the
estimated incidence for a country is not easily calculated. For the 2006 estimates, disease
duration (= prevalence/incidence ratios of smear positive cases) provided to countries by the
WHO varies from 0.8 to 2.4 years, with an average of 1.46 years.
3.5 Estimation of Incidence from Vital Registrations of Deaths
Mortality itself has been a popular indicator of the TB burden, and it is one of the MDGs
indicators. When we know the case fatality rate among TB patients in a specific population or
in a whole country through a study, the case fatality rate can be used to estimate TB incidence
from TB mortality.
The numbers of deaths during treatment are regularly reported to national TB programs
and to the WHO. Increase of deaths during TB treatment alarmed TB programs in the 1990s
so that they paid attention to HIV associated TB, before they were able to provide HIV testing
to TB patients. MDR and X-DR TB also threaten TB patients with increasing treatment failure
and deaths. However, in the era of short-course chemotherapy, the majority of deaths are not
from TB/HIV or MDR/XDR TB; they are from those with delayed or no access to TB services,
diagnosis and treatment. In countries with a working vital registration for deaths, any death
should be reported with the cause(s) of death documented by a doctor’s certificate; and the
police or local government even has the obligation to conduct an autopsy when the cause of
death is uncertain. However, reliable vital registrations for deaths to cover sufficient popula-
tions are not available in most TB endemic countries, so the number of reported TB deaths is
hardly available not only to measure the TB burden, but also to the estimate incidence.
The verbal autopsy is a method that can be used to clarify the proportion of TB deaths
among all deaths. It is conducted to review registered deaths to improve the accuracy of the
cause of death statistics (Gajalakshmi et al., 2002; Jha et al., 2006). Some proportion of deaths
by ‘‘unknown cause’’ may be reclassified as TB deaths. However, sensitivity and specificity of
verbal autopsy have not been accurately assessed, and a very large sample size is necessary to
conduct a study for a rare event such as TB death (Yang et al., 2006). Incidence estimation
from mortality is applied only in a few countries.
3.6 Estimation of Trends in Incidence
Once the estimation of incidence has been established with the consensus of experts, estima-
tion of change gives incidence for a given year. Notification data, data from routine country
surveillance, and regional trends (trends of other countries in the surrounding area) are
usually used to estimate change in a country. When there are supportive studies such as
prevalence surveys, tuberculin surveys and HIV prevalence studies among the general popula-
tion as well as among TB patients, those are taken into account to calibrate surveillance data.
4 Prevalence as an Independent Indicator for Millennium

Development Goals
Many countries are now showing interest in conducting TB disease prevalence surveys to
determine the country’s epidemiological situation more accurately in order to combat disease,
while funding agencies and donors also want to determine the impact of their efforts and
investment on the burden of the disease. Countries’ primary interest seems to be to estimate
incidence from a prevalence study, since a key target of CDR is based on incidence. However,
although a series of disease prevalence surveys may provide evidence, countries should
understand that the estimation of incidence from prevalence is difficult as we discussed in
previous sections in this chapter.
MDGs impact targets are to halt and reverse TB incidence by 2015 and to halve prevalence
and death rates by 2015 compared with the baseline of 1990 (STOP TB Partnership, 2006).
Although, once again, it is questionable how accurately we can estimate a 1990 baseline, it is an
important advance that a measurable indicator obtained from a community study, prevalence,
has been adopted as one of the indicators of progress toward the MDGs. Prevalence, measurable
by a prevalence survey, can be an independent indicator of TB burden, while other indicators are
hardly measurable in most TB endemic countries due to the currently weak surveillance system.
It also has the advantage that prevalence changes quickly in response to the expansion and/or
improvement of the service that detects and treats patients more frequently and earlier; short-
term impact can be observed as well. Moreover, it is the prevalence and not the incidence that
determines the probability of transmission in a community.
Countries with an estimated TB prevalence of more than 100 per 100,000 are encouraged to
conduct a TB prevalence survey or a series of such surveys, as these are likely to be beneficial in
assessing disease burden and trends, and in optimising planning for TB control (China Tubercu-
losis Control Collaboration, 2004; World Health Organization, Western Pacific Region, 2007).
However, it is essential to standardize survey methods to have accurate estimation and to
make international comparison possible. Two major challenges here are screening strategy for
bacteriological examination and the availability of culture examinations. There are also major
technical limitations to diagnose extra-pulmonary TB and TB in children through community
surveys. Therefore, the TB prevalence survey is recommended to target pulmonary TB among
adults aged 15 or more. A guidebook on TB prevalence surveys was published by the Western
Pacific Regional Office of the WHO, and it is available through the Internet (World Health
Organization, Western Pacific Region, 2007).
A prevalence survey is usually recommended only in countries with high prevalence,
because a very large number of samples is necessary in a country in those with lower
prevalence, and because countries with a high burden of TB often don’t have a notification
or surveillance system with proven accuracy and completeness. Although the necessary sample
size should be calculated according to established epidemiological methods, a rough idea of
the necessary number of study participants for a single survey is available by answering the
question: ‘‘How many participants are necessary to catch 100 target cases?’’: If a country
expects a smear positive prevalence of 200/100,000, we need 50,000 participants in a survey to
detect 100.
However, if we would like to measure the impact of control efforts, decline of TB
prevalence, by performing two surveys within some interval, at least 50–60% more partici-
pants are necessary in each survey to show a 30% decline with statistical significance.
4.1 How to Detect TB Cases in the Community
If we could provide smear, culture and chest radiography for all, theoretically, all pulmonary
cases could be identified. Moreover, old TB cases with sequelae such as destroyed lung can be
detected by chest radiography as a disease burden. However, it is frequently not feasible to
conduct all examinations for all in a large-scale survey, considering limited resources. A typical
survey in a high burden setting may require 100,000 culture examinations. High cost and the
significant demand for laboratory capacity could be major constraints. Alternative approaches
should be sought with current technologies depending on the availability of resources. Since a
TB disease prevalence survey usually targets bacteriologically confirmed pulmonary TB cases
in the community, different screening options could be considered (> Table 67-2):
Screening method I: Sputum collections from all participants for smear.

Screening method II: Symptom screening by interview and sputum collection from those
with suspected TB symptoms.
Screening method III: Screening by chest radiography and sputum collections from those
with abnormal shadows.
Screening method IV: Screening by tuberculin test, and further examinations including
sputum examinations from those with positive reaction.
The method of no screening (to take sputum from every participant for smear) is aimed at not
missing any sputum positive patients in the community without screening (Method I)
(Sebhatu et al., 2007). It might be the most economical and technically feasible way in a
resource-limited setting to detect all smear positive cases in the community. Two or three
sputum samples should be taken from every participant. Only smear positive cases can be
detected by this method. Although the workload of the laboratory could be a limitation of this
method, sputum samples can be screened by fluorescent microscope to cope with a large
number of samples. Other limitations of this method are uncertainty of the quality of sputum
sample collection from real TB patients and possible lower positive predictive value due to the
low prevalence of bacteriologically positives. Additional examinations such as culture and/or
chest radiography may be required to confirm a case. Further study is necessary prior to
conducting a national prevalence survey only by Method I.
Sputum collection from study participants with symptoms compatible with TB such as
chronic cough for 2 or 3 weeks or more identified by interviews (Method II) had been
considered a reasonable approach, because it is a standard method of screening in routine
. Table 67-2
How to detect TB cases in the community
Smear
negative TB
Screening Smear Culture suggestive
method positive positive by X-ray Weakness
No N.A. Theoretically Not feasible N.A. Possible low positive
screening all due to high predictive value
(sputum lab workload
from all)
Suspected Interview 30–70% Less than N.A. Low sensitivity
TB 50%
symptoms
Chest X ray Chest Most Most Possible Cost Capacity of X ray
abnormality radiography reading, Potential for
overdiagnosis
TB infection Tuberculin Probably Most, but N.A. Very high positive rate in
test most limited in most HBCs in adults,
high HIV 3 days after injection
settings
Gamma Most Most N.A. Cost, Time, Blood taking
interferon from vein
assay
This table shows the different screening options to detect TB cases in the community and the weakness of each
option
case detection practice by NTP in resource-limited countries. And it has been used as a
methodology of active case detection in the community. However, past prevalence surveys
showed that the sensitivity of symptomatic screening of ‘‘TB suspects’’ by interview is very
limited; only 30–70% of smear positive prevalent cases in the community can be identified by
interviews (den Boon et al., 2006; Gopi et al., 2006; National Center for Tuberculosis and
Leprosy Control, 2005). Characteristics of patients who show up at a clinic to seek a treatment
and those of patients staying in the community are different. A survey with a screening
methodology only by interviews is not recommended even in resource-limited settings
because it underestimates the prevalence.
Chest radiography is usually used as a screening method for bacteriological examinations
in prevalence surveys (Method III). Sputum samples are collected from participants with a
chest radiography abnormality. Chest radiography is a very sensitive examination to screen
TB, but the appearance of TB in chest radiography is not specific (Koppaka and Bock, 2004).
Inter-reader discordance is not negligible. Sputum examinations should be performed from
those with any abnormal findings, since a significant number of bacteriologically positive
patients are detected from ‘‘TB healed’’ and ‘‘disease other than TB’’ categories. Therefore,
sputum collection only from ‘‘TB suspects’’ by radiographic findings underestimates the
prevalence. The limitation of chest radiography screening is highlighted especially in high
HIV prevalent settings; according to the experiences in an intensified TB case detection
program among the HIV positive, bacteriologically positive TB patients are detected among
those without having any abnormality in a chest radiograph (Bakari et al., 2008; Day
et al., 2006).
Method IV may be applied when a survey in children is conducted. As TB disease develops
only in those infected, it is not necessary to examine those not infected. However, as already
discussed, there are clear limitations to the tuberculin test both in sensitivity and specificity.
Tuberculin negative often does not mean non-infected. Tuberculin negative TB is especially
common among those infected with HIV (Cobelens et al., 2006). It is difficult to apply this
screening method even for a survey among children in high TB burden settings. A waiting time
of 3 days to read the result after tuberculin injection is also a constraint in a community survey.
Recently, there has been a proposal to use new technology for screening instead of the
tuberculin test; IGRAs have the potential to detect latent TB infection and TB disease with
high sensitivity. However, the high cost and technical requirements of this method are
constraints for a large-scale survey. Moreover, as it requires veno-puncture to collect blood,
it is an invasive examination and it cannot be justified to introduce it in a prevalence survey
from an ethical point of view.
Considering the advantages and disadvantages of the screening methods discussed above,
currently, a combination of Methods II and III is recommended for the survey in TB endemic
countries. The combination of interview to ask about symptoms and chest radiography is
recommended as a screening strategy; sputum samples should be collected from those with
any abnormality in chest radiography and those with symptoms that make them suspects for
TB regardless of chest radiographic findings (WHO, Western Pacific Region, 2007). TB
patients who are ill but without clear chest radiographic abnormality can be detected by this
combined strategy. Having this combined screening strategy is also expected to contribute to
quality sputum sample collection. Theoretically, there may be asymptomatic TB patients
without any chest radiographic abnormality that cannot be identified by this strategy. But
these are expected to be very limited in proportion, and there is no way to diagnose these
cases by the medical service.
4.2 Culture Examinations are Recommended to Measure TB Burden

and to Confirm TB
There is a debate over whether smear positive TB is enough to measure the TB burden or
not. Experience shows that the proportion of smear positive cases among all those bacterio-
logically positive in the community detected by prevalence surveys has been declining
(Hong, 1995; National Center for Tuberculosis and Leprosy Control, 2005; Tupasi et al.,
1999; > Table 67-3). Smear negative and culture positive cases are more than smear positive
. Table 67-3
Whether is smear positive TB enough to measure the TB burden or not?
Year X-ray active Bac(+) Smear(+) S(+)/B(+) (%)

Cambodia 2002 1,928 901 269 30
China 1990 523 177 134 76

2000 367 160 122 76
Philippines 1983 2,900 860 660 77

1997 4,200 810 310 38
Republic of Korea 1965 5,100 940 690 73

1975 3,300 760 480 63
1985 2,200 480 240 50
1995 1,000 220 90 41
(Prevalence /100,000 population)
This table shows that the proportion of smear positive cases among all those bacteriologically positive in the
community detected by prevalence surveys has been declining
in most surveys where culture examinations are systemically conducted. This was observed
not only in recent surveys in Asia, but also in national surveys in Japan in the 1950s–1960s
(Omura et al., 1962; Yamaguchi, 1955) and in the Kolin Study in Czechoslovakia where only
29% of new bacteriologically positive cases were smear positive (Styblo et al., 1967). Quality
TB service, DOTS, might have removed smear positive TB cases from the community
efficiently enough to decrease smear positive TB prevalence. However, if we do not measure
those underlying smear negative/culture positives, we may not be able to determine the real TB
burden in the community. Especially under the Stop TB strategy, since all TB cases are targeted
in detection and treatment, it is recommended that culture examination should be adopted in
prevalence surveys as much as possible. There are other advantages of culture examination: it
can identify mycobacterium other than TB that is frequently observed in immuno-compro-
mised individuals and those with a history of TB treatment; the drug susceptibility pattern of
patients in the community is available through culture, and it may help the NTP if it does not
have national surveillance data.
4.3 High Risk Groups and Their Role in Resurgence of TB
Countries may have a concentrated epidemic of TB in some high-risk populations such as

migrants, prisoners and intravenous drug users (IVDUs). However, a prevalence survey in a
country often targets only residents or registered populations. When TB among those high-
risk populations is considered to account for a significant proportion of the country’s
prevalence, it is necessary to review the survey design if those populations are properly
included in a survey. Another feasible option might be to estimate the TB prevalence and
number of those high-risk populations independently by other sources and studies, and add
those when we estimate country prevalence from the prevalence survey.
4.4 Prevalence Survey Brings Other Benefits
As a community survey, prevalence surveys can be used to provide more information than
simply of the burden of disease. For example, some risk factors such as tobacco use and socio-
economic status, and patients’ behaviour and the utilization of the health system (for example,
patient’s tendency to first seek TB treatment in the private sector) are often investigated. In
addition, the sex ratio between notification and prevalence is also of interest. And, delay
analysis (described immediately below) can also be conducted as part of a prevalence survey.
However, since it costs 1 million dollars to conduct a typical single survey to estimate
country burden, and because a prevalence survey is very labour intensive, it should be
discussed whether a country can afford to increase the sample size 50–60% to detect the
impact in a country, or whether we should aim for this kind of impact analysis only at sub-
regional, regional and global levels.
5 Delay Analysis
Delay analysis of individual patients can be conducted comparatively easily and provides the
information on the service quality and its use. It measures the duration from onset of the
disease to starting treatment against TB and analyzes the process of the health seeking behavior
of TB patients and diagnosis. Longer duration (delay) before diagnosis and treatment shows
the delayed health seeking behavior of the patients (= patient delay) or the poor quality of
services (= health service delay). This leads to more severe TB disease in individual patients
and increased transmission in the community. As a result, delay analysis can be a useful tool to
measure the TB burden in terms of time duration (= delays) of the process before diagnosis
and treatment, and also changes of the delays through various interventions, though it has a
limitation due to recall bias (uncertain memory about the illness by patients). The Eastern
Mediterranean Region of WHO recently conducted the comparative study among seven
countries, using this method (WHO/EMRO, 2006).
6 New Technology for Screening and Diagnosis to Measure

the Burden
In the near future, the development of molecular bacteriology may bring a new approach to
screen study participants and to diagnose TB (STOP TB Partnership Retooling Task Force,
2007). Highly sensitive and non-invasive screening examination in combination with a new
culture system such as liquid culture may have the potential to detect all targeted cases, smear
positive, culture positive, culture negative, pulmonary, extra-pulmonary and childhood TB.
7 Conclusion
According to the WHO’s estimation of the global TB burden, there were 9.2 million new TB
cases in 2006 with 1.7 million deaths due to TB. Although the estimated global incidence rate
stabilized or began to fall slowly, the number of new cases was still increasing because
population growth exceeded the declining rate of this disease.
However, for each individual country, the uncertainty of the incidence estimation became
a concern to monitor and evaluate the progress of the TB situation at country level. There are
several ways to measure the burden of TB. It is essential to strengthen the routine recording
and reporting system and surveillance, in order to estimate the burden and its trend. However,
as the current surveillance system is not always reliable in most TB endemic countries,
conducting a prevalence survey is recommended every 5–10 years. Prevalence itself is one of
the MDGs indicators, and survey findings can be utilized to calibrate routine surveillance.
Combinations with prevalence survey and notification data might be the best method to
measure the disease burden right now. Although a prevalence survey costs a lot and it is labor
intensive, it may help a country considerably to improve TB control policy. Although a
prevalence study cannot be implemented in every country, studies conducted in some
countries will help neighbouring countries with similar situations to understand their epide-
miological status of TB through the interpretation of routine surveillance data.
8 Case Study
One Country’s efforts to have more accurate measurement of TB burden – CAMBODIA.

In the National TB survey in Cambodia, 2002, BCG scar and Tuberculin surveys, presence
of BCG scar and tuberculin test results were analyzed in children aged between 1 year and
15 years. 5,835 children without BCG scar and 5,886 with BCG scar were examined. The
proportion of children with BCG scar is higher in the younger age group.
There was no obvious anti-mode to separate populations of infected and non-infected
children in any age category (> Figure 67-3), while tuberculin among TB patients provided a
clear histogram (> Figure 67-4).
ARI was calculated by two different methods: One was with the conventional cut off point
of 10 mm; the other was with a mirror image with 16 mm obtained by a survey of tuberculin
reactions among TB patients. There were significant differences between the results using these
two methods. It is consequently very difficult to determine estimated ARI (> Table 67-4).
If we applied Styblo’s rule to estimate the smear positive TB incidence rate with a point
estimate for ARI of 2.8% obtained, the incidence rate for Cambodia would be estimated at
140 (2.8 50), and that was almost equivalent to the case notification rate in Cambodia,
141/100,000 in 2002, while the WHO’s estimated incidence at that time was 256/100,000.
However, no one assumed because of this that Cambodia had achieved 100% CDR in 2002; the
estimation of the TB burden by tuberculin must not have been valid. For the disease
prevalence survey, 22,160 participants aged 10 or more underwent an interview and chest
. Figure 67-3
Tuberculin reaction among children, age 5–9
. Table 67-4
Annual risk of TB infection by different methods
Cut-off 10 mm 16 mm mirror
Age group Point estimate 95% Cl Point estimate 95% Cl
1–4 0.76% 0.44–1.33 0.25% 0.08–0.85
5–9 2.34% 1.85–2.95 1.15% 0.80–1.68
10–14 3.03% 2.51–3.61 1.37% 1.02–1.84
Total 2.80% 2.37–3.28 1.32% 1.02–1.70
Source: National Center for Tuberculosis and Leprosy Control, 2005
radiograph, and those with cough for 3 weeks or more and/or any abnormality in X-ray were
asked to submit two sputum specimens for smear and culture.
Eighty-one smear positive and 190 smear negative/culture positive cases were detected.
The prevalence of smear positive TB was 269/100,000 population, only half of the WHO’s
estimation, 548/100,000, while the prevalence of bacteriologically positive TB was as high as
898/100,000. These results suggest that DOTS was working to decrease the smear positive
prevalence in the community. Not only the number and rate, but also the pattern of age
distribution of patients suggested that the program was working. Since 1997, the WHO had
been attributing to Cambodia an increasing trend of TB incidence mostly due to the spread of
HIV infection in the 1990s. However, according to the survey results, the trend was corrected
from ‘‘increasing’’ to ‘‘declining,’’ following the Western Pacific Regional trend, although the
estimation was still as high as 220/100,000 in 2006. The NTP learned several unexpected things
from the survey: as smear positive TB made up only 30% of bacteriologically positive cases, the
prevalence of all TB seemed to be higher than the WHO’s estimation; Only 62% of smear
positive cases and 39% of bacteriologically positive cases complained of cough for 3 weeks or
more; although females accounted for 50% of case notifications in Cambodia, the prevalence
. Figure 67-4
Tuberculin reaction of TB Patients Kg Chlanang and Kg Thom Provinces, Cambodia, 2003
. Figure 67-5
Prevalence of bacteriologically positive TB by age and sex
of smear positive in males was 2.6 times higher than that in females (> Figure 67-5). In
addition, the prevalence in older persons was extremely high. These findings helped the NTP
and partners to develop further plans to expand and improve TB services (National Center for
Tuberculosis and Leprosy Control, 2005).
Summary Points
The burden of TB can be described in various ways, such as epidemiological burden and
financial burden.
Estimated disease incidence and its rate have been the most popular indicators of TB
burden since 1997 when the WHO began to publish the estimates every year. There were
an estimated 9.2 million new TB cases (139/100,000 population) and 1.7 million deaths
globally in 2006, according the most recent estimation by WHO.
The estimated global incidence rate was reported to have stabilized or begun to fall slowly
after a peak in 2003. However, as population growth exceeds the decline in incidence, the
number of new cases is still increasing.
For an individual country, it is often difficult to have an accurate estimation of the
incidence due to limited reliability and coverage of case notification through the routine
disease surveillance system. As services expand, discrepancies have been noted between
estimates of incidence and notification rates in several countries.
Tuberculin surveys are no longer recommended to measure TB burden, while disease
prevalence surveys are promoted for countries with expected prevalence of smear positive
TB of 100 or more per 100,000, in order to have more accurate figures with which to
measure the TB situation.
Prevalence is not only an indicator that is measurable by a community survey, but also one
of the indicators of the MDGs. A series of prevalence surveys can provide a measure of
trend and may show the impact of control efforts. The results of successive surveys can also
be utilized to evaluate the data on trend derived from routine surveillance.
It is essential for countries to make continuous efforts to improve their disease surveillance
system, since it is cost efficient and an ideal way to measure the disease burden of TB as
well as other diseases.
References
Bakari M, Arbeit RD, Mtei L, Lyimo J, Waddell R, China Tuberculosis Control Collaboration. (2004).
Matee M, Cole BF, Tvaroha S, Horsburgh CR, Lancet. 364: 417–422.
Soini H, Pallangyo K, von Reyn CF. (2008). BMC Cobelens F, Egwaga SM, van Ginkel T, Muwinge H,
Infect Dis. 8: 32. Matee MI, Borgdorff MW. (2006). Clin Infect Dis.
Cain KP, Kanara N, Laserson KF Vannarith C, 43: 634–639.
Sameourn K, Samnang K, Qualls ML, Wells CD, Corbett EL, Watt CJ, Walker N, Maher D, Williams BG,
Varma JK. (2007). Int J Tuberc Lung Dis. Raviglione MC, Dye C. (2003). Arc Intern Med. 163:
11: 1008–1013. 1009–1021.
Cauthen GM, Pio A, ten Dam HG. (2002). Bull World Day JH, Charalambous S, Fielding KL, Hayes RJ,
Health Organ. 80: 503–511. Churchyard GJ, Grant AD. (2006). Int J Tuberc
Chheng P, Tamhane A, Natpratan C, Tan V, Lay V, Sar B, Lung Dis. 10: 523–529.
Kimerling ME. (2008). Int J Tuberc Lung Dis. den Boon S, White NW, van Lill SW, Borgdorff MW,
12 (Suppl 1): 54–62. Verver S, Lombard CJ, Bateman ED, Irusen E,
Enarson DA, Beyers N. (2006). Int J Tuberc Lung Styblo K, Bumgarner JR. (1991). Tuberculosis Surveillance
Dis. 10: 876–882. Research Unit Progress Report: 2: pp. 60–72.
Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Styblo K. (1991). Epidemiology of Tuberculosis, 2nd ed.
(1999). JAMA. 282: 677–686. KNCV Tuberculosis Foundation, Hague, The
Dye C. (2008). Bull World Health Organ. 86: 4. Netherlands.
Dye C, Bassil A, Bierrenbach AL, Broekmans JF, Styblo K. (1985). Bull Int Union Tuberc Lung Dis. 60:
Chadha VK, Glaziou P, Gopi PG, Hosseini M, 117–119.
Kim SJ, Manissero D, Onozaki I, Rieder HL, The WHO/IUATLD Global Project on Anti-Tuberculosis
Scheele S, van Leth F, van der Werf M, Williams Drug Resistance Surveillance. (2008). Anti-Tuberculosis
BG. (2008). Lancet Infect Dis. 8: 233–243. drug resistance in the world, Report No.4. World
Gajalakshmi V, Peto R, Kanaka S. Balasubramanian S. Health Organization, Geneva.
(2002). BMC Public Health 2: 7. Toman K. (2004). In: Toman’s Tuberculosis Case Detec-
Gopi PG, Subramani R, Sadacharam K, Narayanan PR. tion, Treatment and Monitoring: Questions and
(2006). Int J Tuberc Lung Dis. 10: 343–345. Answers, 2nd ed. World Health Organization, Geneva,
Hong YP, Kim SJ, Lew WJ, Lee EK, Han YC. (1995). Int J pp. 66–71.
Tuberc Lung Dis. 2: 27–36. Tupasi TE, Radhakrishna S, Rivera AB, Pascual ML,
Jha P, Gajalakshmi V, Gupta PC, Kumar R, Mony P, Quelapio MI, Co VM, Villa ML, Beltran G, Legaspi
Dhingra N, Peto R; RGI-CGHR Prospective Study JD, Mangubat NV, Sarol JN Jr., Reyes AC,
Collaborators. (2006). PLoS Med. 3(2): e18. Sarmiento A, Solon M, Solon FS, Mantala MJ.
Kimerling ME, Schuchter J, Chanthol E, Kunthy T, (1999). Int J Tuberc Lung Dis. 3: 471–477.
Stuer F, Glaziou P, Ee O. (2002). Int J Tuberc Lung van Leth F, Vander Werf MJ, Borbodorff MW. (2008).
Dis. 6: 988–994. Bull World Health Organ. 86: 20–24.
Koppaka R, Bock N. (2004). In: Toman’s Tuberculosis WHO Tuberculosis Programme. (1994). Framework
Case Detection, Treatment and Monitoring: Ques- for Effective Tuberculosis C control. World Health
tions and Answers, 2nd ed. World Health Organiza- Organization, Geneva.
tion, Geneva, pp. 51–60. WHO, EMRO. (2006). Diagnostic and treatment delay
Lalvani A. (2007). Chest. 131: 1898–1906. in tuberculosis, an in-depth analysis of the health-
Menzies D, Pai M, Comstock G. (2007). Ann Intern Med. seeking behaviour of patients and health system
146: 340–354. response in seven countries of the Eastern Mediter-
Murray CJ, DeJonghe E, Chum HJ, Nyangulu DS, ranean Region. WHO, EMRO, Cairo.
Salomao A, Styblo K. (1991). Lancet. 338(8778): Wood R, Middelkoop K, Myer L, Grant A, Whitelaw AD,
1305–1308. Lawn SD, Kaplan G, Huebner R, McIntyre J,
National Center for Tuberculosis and Leprosy Control. Bekker LG. (2007). Am J Respir Crit Care Med.
(2005). National tuberculosis prevalence survey, 175: 87–93.
2002, Cambodia. Phnom Penh: Royal Government World Bank. (1993). World Development Report 1993:
of Cambodia, Ministry of Health, Phnom Penh. Investing in Health, Oxford University Press,
Omura T, Oka H, Kumabe H, Kobayashi A. (1962). Bull New York, pp. 25–29.
World Health Organ. 26: 19–45. World Health Organization. (2008). WHO Report 2008,
Pai M, Riley LW, Colford JM. Jr. (2004). Lancet Infect Global Tuberculosis Control: Surveillance, Planning,
Dis. 4: 761–776. Financing. Geneva.
Reider HL. (1995). Tubercle Lung Dis. 76: 114–121. World Health Organization, Western Pacific Region.
Sebhatu M, Kiflom B, Seyoum M, Kassim N, Negash T, (2007). Assessing Tuberculosis Prevalence Through
Tesfazion A, Borgdorff MW, van der Werf MJ. Population-based Surveys. Manila.
(2007). Bull World Health Organ. 85: 593–599. http://www.wpro.who.int/NR/rdonlyres/F49273CB-4CAB-
STOP TB Partnership Retooling Task Force. (2007). 4C38-B1E3–500108BA4A97/0/AssessingTBprevalence.
New Technology for Tuberculosis Control: A Frame- pdf.
work for their Adoption, Introduction and Imple- World Health Organization. (1994). TB: A Global Emer-
mentation. World Health Organization, Geneva. gency, WHO Report on the TB Epidemic. World
STOP TB Partnership. (2006). The Global Plan to Stop Health Organization, Geneva.
TB, 2006–15. World Health Organization, Geneva. Yamaguchi M. (1955). Bull World Health Organ. 13:
Styblo K, Dankova D, Drapela J, Galliova J, Jezek Z, 1041–1073.
Krivanek J, Kubik A, Langerova M, Radkovsky J. Yang G, Rao C, Ma J, Wang L, Wan X, Dubrovsky G,
(1967). Bull World Health Organ. 37: 819–874. Lopez AD. (2006). Int J Epidemiol. 35: 741–748.
68 Burden of Tuberculosis:
Serbian Perspectives
Z. Gledovic . H. Vlajinac . T. Pekmezovic . S. Grujicic-Sipetic .
A. Grgurevic . D. Pesut
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1212
2 The Burden of Tuberculosis in Serbia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1213

2.1 Incidence and Incidence Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1213
2.2 Mortality and Mortality Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1215
3 Disability Adjusted Life Years (DALY) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1217
4 Serbian Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1218
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1219

1212 68 Burden of Tuberculosis: Serbian Perspectives
Abstract: > Tuberculosis still remains the largest single infectious cause of death among
young persons and adults, and continues to be a major public health problem in many parts
of the world. TB > incidence in Serbia, very high in the 1950s (about 350/100,000 population),
significantly decreased in subsequent years and fell below 50/100,000 in the last decade of the
twentieth century. As a result of deteriorating social and economic conditions during the 1990s, TB
incidence leveled off at an annual average of 34.6/100,000 in the period 1992–2002. During the same
period childhood tuberculosis incidence rates in Serbia tended to fall, which could be explained by
the decreasing trend in overall tuberculosis incidence and the good control program including
chemoprophylaxis of young household contacts. TB mortality in Serbia showed a significant
decreasing trend from the 1950s, even in the period 1992–2002 in which the average annual
mortality rate was 4.1/100,000. The decrease in > DALY caused by TB in Serbia, from 1992 to
2002, was the result of a lower death rate. This means that, in addition to the improvement of
primary prevention, which is very important, the improvement of secondary prevention, consisting
of early diagnosis and adequate treatment, is needed to prevent premature death. The good
organization and efficient work of anti-tuberculosis dispensaries in Serbia, the low frequency of
HIV/AIDS, the low frequency of Mycobacterium tuberculosis resistant strains and the implemen-
tation of the > DOTS strategy explain how in the 1990s, during a period of social and
economic crisis, TB incidence did not increase and TB mortality continued to drop. Thanks
to the intensification of health care activities regarding TB control from 1998, the epidemio-
logical situation of TB in Serbia is not expected to deteriorate in the future despite the
anticipated inevitable increase of HIV/AIDS.
List of Abbreviations: AIDS, acquired immunodeficiency syndrome; BCG, bacillus calmette-
guérin; DALY, disability adjusted life years; DOTS, directly observed therapy; GBD, global burden
of disease study; GFTAM, global fund of tuberculosis, AIDS & malaria; HIV, human immuno-
deficiency virus; MDR-TB, multidrug resistant tuberculosis; PCR, > polymerase chain reac-
tion; TB, tuberculosis; > YLD, years lived with disability; > YLL, years of life lost; WHO,
World Health Organization
1 Introduction
Today, when the human race has reached a state of intellectual and technological sophistica-
tion, the war on the most primitive species on earth – microbes – continues to be waged.
Tuberculosis is one such microbial disease that has been known since the beginning of
recorded history. Robert Koch’s discovery of Mycobacterium tuberculosis in 1882 was one of
the landmarks in the history of microbiology, which enabled the introduction of powerful
anti-TB drugs to control this disease.
Over 30 years ago, the prospect of eradicating tuberculosis seemed quite possible. Al-
though the rates had fallen to very low levels in the developed world, the optimism of that time
was short-lived. Tuberculosis remains a global emergency because of a lack of understanding
of the details of its pathogenesis and the difficulty in identifying the nature of protective
immune mechanisms. Our failure to control tuberculosis results from our lack of understand-
ing of the mechanisms of latency and persistence, and the reasons for the failure of the vaccine
currently available. Estimates of the protective efficacy of this vaccine vary from 0 to 80%.
The apparent failure of antimicrobial chemotherapy to control the TB epidemic increases
our need to understand the epidemiology of this disease. In recent years, traditional methods
in epidemiology have been augmented by molecular typing methods. Genetic sequence
analysis using PCR offers the potential for nonculture identification (Fletcher et al., 2001).
Burden of Tuberculosis: Serbian Perspectives 68 1213
The natural history of tuberculosis is complex. Primary infection occurs in people without
specific immunity, generally children and young adults. The initial infection can occur at any
time during childhood, but adolescence is the peak time of risk. Any condition affecting the
integrity of the immune system will increase the chance of infection following initial contact.
The very young, patients with HIV infection, diabetic patients, those on corticisteroids, and
those undergoing chemotherapy for cancer fall into this category. Poor nutrition and alcohol
abuse can be added to the list.
Prevalence studies from most parts of the world suggests that tuberculosis is more a disease
of males than of females. The male to female ratio of TB cases reported to public health
authorities worldwide is approximately 2:1(Thorson and Diwan, 2001). It is not known
whether this is a genuine difference in incidence, the result of underreporting of female
cases, or a combination of both.
Tuberculosis has long been regarded as the disease of the poor, the homeless and the
marginalized. Recent studies indicate that the relationship between poverty and disease is not
straightforward. The incidence of the disease is increasing in many industrially-developed
countries, particularly among the poor, ethnic minorities, prisoners and other institutionalized
persons, and the socially and geographically isolated. In developing countries, millions of people
are disadvantaged by poverty, and recent health sector reforms are not entirely in their interest.
Ninety-five percent of all TB cases and 98% of all deaths caused by TB occur in the developing
countries, especially those in Sub-Saharan Africa and parts of Asia (India, China, Indonesia).
Eighty percent of all incident TB cases were found in 22 countries, with more than half the
cases occurring in five South-East Asian countries. Nine of the ten countries with the highest
incidence rates were in Africa. Prevalence of TB/HIV co-infection worldwide is 0.2% (Dye
et al., 1999).
The global burden of tuberculosis remains enormous, mainly because of poor control
in South-East Asia, Sub-Saharan Africa, and Eastern Europe, and because of high rates of
M. tuberculosis and HIV coinfection in some African countries (Corbett et al., 2003).
The regular decline in TB notification rates has leveled off or reversed in recent years in
both the USA and in Europe where relevant differences between Central/Eastern and Western
countries have become more and more apparent. The main consequences of sub-optimal TB
control in Eastern Europe (the Baltic states, Romania, the Russian Federation) are the export
of TB and MDRTB through immigration (Migliori and Centis, 2002).
Tuberculosis still remains the largest single infectious cause of death among young persons
and adults and continues to be a major public health problem in many parts of the world.
The World Health Organization (WHO) in 1993 declared TB a global emergency. At
the beginning of the twenty first century WHO estimates that M. tuberculosis has infected
about 2 billion people around the world, that is one in every three, with 8 million new cases
and 2.9 million deaths annually. At least 1 million cases occur annually in children, with
450,000 tuberculosis-associated deaths (Dye et al., 1999).
2 The Burden of Tuberculosis in Serbia
2.1 Incidence and Incidence Trends
The analysis of incidence data for tuberculosis in Serbia over the period 1956–2002 was done
for Central Serbia excluding the provinces of Kosovo and Vojvodina. The sources of morbidity
data were the annual reports of the Institute of Lung Diseases and Tuberculosis in Belgrade,
which is the reference centre for diagnosis and treatment of tuberculosis in Serbia. Incidence
includes active new or relapsed cases of pulmonary tuberculosis. We have assumed that these
data were a good approximation of all active cases in Serbia. Population denominator data for
the period 1956–2002 were obtained according to the official estimate carried out on the basis
of national censuses (1953, 1961, 1971, 1981, 1991 and 2002) with extrapolation. The average
population of Central Serbia in the period 1956–2002 was 5.9 million. Refugees who came to
Serbia during 1990s from other parts of Former Yugoslavia as a result of the civil war were not
counted as part of the population when incidence rates were calculated.
Due to the great differences in incidence rates at the beginning (324.0 per 100,000) and the
end (34.8 per 100,000) of the period 1956–2002 it was inappropriate to calculate average
values of incidence rates (> Figure 68‐1).
The increase of incidence in the first 2 years of the period studied was the result of the
difficulties at the beginning of the notification process. After 1958 there is a steady decline in
the incidence rates. (y = 335.964e 0.0592, F = 526.59, p = 0.000). Exponential fit is used to
express the speed of decline.
Bearing in mind the worsening social and economic conditions in Serbia during the last
decade of the twentieth century caused by the war in Former Yugoslavia, the economic
sanctions imposed on Serbia by the United Nations, and population migration, we observed
the epidemiological situation of TB in the period 1992–2002 separately (Gledovic et al.,
2006b). In that period the average annual tuberculosis incidence rate was 34.6 per 100,000
persons (95% CI: 33.2–35.8) for both sexes. The rate for men was 43.9 per 100,000 (95% CI:
42.1–45.7) and for women, 25.3 per 100,000 (95% CI: 24.3–24.6). These rates were near or
even below the European average. Compared to other Eastern European countries, they were
similar to the incidence rates in Bulgaria, two times lower than the rates in Russia, and three
times lower than those in Romania (WHO, 1998). TB incidence varied in 25 geographical
regions in Serbia from 7.2 per 100,000 to 74.6 per 100,000. The incidence was highest in
regions with the greatest number of refugees from Bosnia and Herzegovina (near its border)
where the highest TB rates were registered in Former Yugoslavia, and in the two regions
adjacent to Kosovo, where, according to past data, TB incidence was higher than in other parts
of Serbia (Jovanovic et al., 2007).
In Serbia, TB incidence increased with age. In both sexes, the highest incidence rates were
registered in those over 65 years of age (Gledovic et al., 2006b). Tuberculosis in Serbia was
more frequent in males than in females, and the male to female ratio was almost 2:1, similar to
the male/female ratio worldwide (Murray and Lopez, 2000).
In the period 1992–2002, TB incidence rates in Serbia leveled off (y = 28.8588 + 3.3975x
0.07292x2 + 0.0449x3, F = 3.44, p = 0.081), after a long period of falling off during the
previous decades and this trend has continued in the years since 2002 (Gledovic et al., 2000;
Jovanovic et al., 2007). This change in the incidence trend could be expected as a result of the
above-mentioned deteriorating social and economic conditions in Serbia during the 1990s
(Vlajinac et al., 1997). The prevalence of HIV infection, even if we take into account that it was
most probably underestimated, was not high enough to have a significant impact on TB
incidence (Wong, 2002). In the period 1985–2002, there were 886 AIDS cases in Serbia, and
1,378 HIV-infected people without symptoms were reported (Gledovic et al., 2006b).
In the European Community the incidence rates of tuberculosis have steadily fallen, but in
several countries during the 1990s an increase in incidence was registered in foreign-born
persons, and the country of birth of the TB patients is the most influential factor explaining
the variability of TB incidence rates (Decludt, 2002). These cases were responsible for 51% TB
. Figure 68‐1
Tuberculosis incidence rates in Serbia in the period 1956–2002
cases in Switzerland, 41% in the Netherlands and Sweden and 38% in Denmark (Raviglione
et al., 1995). In the USA, from the middle of the twentieth century, incidence rates decreased
about 6% a year, but from 1985 an upward trend in incidence rates of tuberculosis due to the
AIDS epidemic was observed (WHO, 1995).
As tuberculosis in children reflects the prevalence of the disease in adults as well as current
transmission rate, special attention was focused on TB in children from 0 to 14 years old. In
the period 1992–2002, 280 children (0–14 years) in Serbia were reported as having been
diagnosed with tuberculosis. The average annual incidence rate was 1.79 per 100,000 (95% CI:
0.92–3.13). Childhood tuberculosis accounts for about 5% of the reported cases of tuberculo-
sis in Serbia (Gledovic et al., 2006a). A similar percentage was observed in France (Gaudelus,
2002) but the percentage in the United States was lower (Starke, 2004). The gender ratio of
childhood TB in Serbia of 0.8:1 (129 boys and 151 girls) is similar to this ratio in other
countries (Datta and Swaminathan, 2001). In Serbia, tuberculosis was more frequent in
children from 5 to 14 years old (77.5%) than in those from 0 to 4 years old, which is the
opposite of findings in other countries (Datta and Swaminathan, 2001).
In the period 1992–2002, childhood tuberculosis incidence rates in Serbia tended to drop
(y = 2.412–0.088x; P = 0.010) (> Figure 68‐2), which may be explained by the decreasing trend
in overall tuberculosis incidence at the beginning of the period when notification began, and
the good control program including chemoprophylaxis of young household contacts.
2.2 Mortality and Mortality Trends
TB mortality rates were calculated using the official data of the Republican Institute for
Statistics. Rates are based on all tuberculosis deaths.
Population denominator data for the period 1956–2002 were obtained from the official
estimate carried out on the basis on national censuses (1953, 1961, 1971, 1981, 1991 and 2002)
with extrapolation. In the period 1956–2002 mortality rates decreased from 76.4 per 100,000
(88.0 per 100,000 in males, 65.3 per 100,000 in females) in 1956 to lowest value of 0.9 per
. Figure 68‐2
Incidence trend of childhood tuberculosis in Serbia in the period 1992–2002
100,000 in 1982 (1.3 per 100,000 in males and 0.6 per 100,000 in females). After that mortality
rates varied and in 1996 they were 6.4 per 100,000 in males and 2.7 per 100,000 in females.
Over the entire period studied mortality rates decreased (y = 50.3745e 0.0732, F = 126.78,
p = 0.000). Deviation from the steady rate of decline in 1969 may be explained by the epidemic
of influenza (type A2, Hong Kong) in Serbia within the pandemic wave of influenza in the
world. The slight increase of TB mortality in 1961 and 1981 was at a lower level and there is no
adequate explanation for this (> Figure 68‐3).
Comparing exponential fit coefficients it can be concluded that mortality rates declined
faster than incidence rates in the period observed.
In the period 1992–2002 the average annual mortality rate was 4.1 per 100,000 (95% CI 3.7–
4.5), 6.0 per 100,000 (95% CI; 5.4–6.6) in males and 2.3 per 100,000 (1.9–2.6) in females. The
average TB mortality rate in Serbia was below the European average (Dye et al., 1999). In Serbia,
mortality rates increased with age in both men and women. The highest rates were in those over
65 years of age. The male to female ratio in TB mortality rates was 3:1 (Gledovic et al., 2006b).
Although it could be expected that the deteriorating performance of the economy during
1990s would have an adverse effect on TB mortality, TB mortality rates in Serbia significantly
declined in the period 1992–2002 (y = 4.2920 + 0.6015x–0.1596 x2 + 0.090x3, F = 68.74,
p = 0.000). The fall in the death rate from TB is continuing (Jovanovic et al., 2007). This is a
. Figure 68‐3
Tuberculosis mortality rates in Serbia in the period 1956–2002
pattern similar to that already seen in many other parts of the world. TB incidence and
mortality are only weakly correlated across Europe. In low-incidence countries in Western
Europe, a high proportion of cases occur in elderly people who die from other causes while
undergoing treatment for TB. In Eastern European countries, mortality is markedly reduced
by drug therapy. The decreasing mortality trend in Serbia can be ascribed to better therapy
thanks to the good organization and efficient work of anti-tuberculosis dispensaries. DOT was
applied for the first time in Serbia in 1992 and its use has steadily expanded since that time. In
the period observed, more than 80% of cases were successfully cured. Also the frequency of
Mycobacterium tuberculosis resistant strains was low. Initial and acquired resistance to izonia-
zid or izoniazid and rifampicin and other drugs was 6.3% (range, 2.6–11.5%) and 5.3%
(range, 2.7–8.3%) respectively (Atanaskovic-Markovic et al., 2003).
In the period 1992–2002, tuberculosis was reported in 11 children, 5 boys and 6 girls. The
average annual childhood tuberculosis mortality rate was 0.1 per 100,000 (95CI; 0.01–0.56). The
mortality rates for both boys and girls were higher in the age group 0–4 than in the age group 5–14
(Gledovic et al., 2006a). Childhood tuberculosis mortality rates fell, although that decrease was
not statistically significant. One of the reasons for the low mortality rates in children might be the
low incidence rates in the youngest (0–4 years old), who are at greatest risk to develop severe and
most fatal forms of disease. In the period 1992–2002 the percentage of BCG–vaccinated children
was 94% on average (BCG vaccination is mandatory for infants in Serbia) (The Republic Health
Institute, 2003). There is some evidence that BCG vaccination is effective against disseminated
forms of the disease in childhood (Cooper et al., 2003; Datta and Swaminathan, 2001). Properly
conducted short-course multi-drug treatment in Serbia is accepted as a treatment of choice for
TB cases in adults as well as in children (Shingadia and Noveli, 2003).
3 Disability Adjusted Life Years (DALY)
DALY is the aggregation of years of life lost (YLL), and a year lived with disability (YLD) at the
population level and thus reflects the ‘‘burden of disease’’ among the population. The method
used in this study for estimating DALY was largely based on that developed for the Global
Burden of Disease (GBD) study (Murray and Lopez, 1996, 2000). The average duration for TB
in the region of the former socialist economies (FSE) region was assumed to be 6 months in the
GBD study, and we used the 6 months duration of TB disability for the YLD calculation (the
average duration of treatment was 6 months).
The TB burden for the period 1992–2002, expressed as YLD, YLL, and DALY, was
estimated for Central Serbia and the province of Vojvodina, which together comprised
7.7 million inhabitants on average. DALY rates per 1,000 population were greater for males
than for females, and increased with ageing. The average DALY rate for males was highest in
the age group from 55 to 64 years and, for females, in those aged 65 and over (> Table 68‐1).
During the period observed, DALY rates significantly decreased in both males (y = 0.668–
0.021x, P = .0090 and females (y = 0.273–0.012x, P = .008), (> Figure 68‐4).
The burden of tuberculosis in Serbia according to YLD, YLL and DALY was three times
higher for males than for females. The total TB burden (DALY) in Serbia in the period 1992–
2002 has been decreasing thanks to decreasing TB mortality. This means that, in addition to
the improvement of primary prevention, which is very important, the improvement of
secondary prevention, consisting of early diagnosis and adequate treatment, is needed to
prevent premature death (> Table 68‐2).
. Table 68‐1
YLD, YLL, and DALY per 1,000 population from TB in Serbia: average values, 1992–2002
Sex No. cases No. deaths YLD YLL DALY

Males 1658.4 221.0 0.057 0.638 0.702
Females 1003.0 86.3 0.037 0.226 0.263
YLD years lived with disability; YLL years of life lost; DALY disability adjusted life years
. Figure 68‐4
DALY rates from TB in Serbia in the period 1992–2002, rhomb-male; quadrant-female
. Table 68‐2
Incidence, YLD, DALY and YLD/DALY ratio for tuberculosis in Serbia excluding Kosovo and
Metohia, and in EURO regions
Region Incidence per 1,000 YLD per 1,000 DALY per 1,000 YLD/DALY %
Serbia 0.34 0.05 0.50 11%
EURO 0.56 0.21 1.83 11%
EUROA 0.17 0.05 0.15 33%
EURO B 0.62 0.31 2.03 15%
EURO C 1.16 0.55 4.51 12%
EURO A – Andorra, Austria, Croatia, Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland,
Israel, Italy, Luxemburg, Malta, Monaco, The Netherlands, Norway, Portugal, San Marino, Slovenia, Spain, Sweden,
Switzerland, the United Kingdom. EURO B (B1) – Albania, Bosnia and Herzegovina, Bulgaria, Georgia, Poland,
Romania, Slovakia, The Former Yugoslav Republic of Macedonia, Turkey, Serbia and Montenegro, (B2) – Armenia,
Azerbaijan, Kyrgyzstan, Tajikistan, Turkmenistan, Uzbekistan. EURO C – Belarus, Estonia, Hungary, Kazakhstan,
Latvia, Lithuania, the Republic of Moldavia, the Russian Federation, Ukraine
4 Serbian Perspective
It is now widely recognized that understanding why tuberculosis remains a major killer among
infectious diseases worldwide requires links between advances in biomedical knowledge and
the wider social and economic dynamics of disease epidemiology.
In recent times, the emphasis has moved away from didactic principles of tuberculosis
‘‘control’’ to community- and patient-centered health services, based on analysis of local
factors affecting case finding and adherence to therapy. Although WHO is urging governments
to adopt its five-point DOTS strategy, there is increasing evidence that numerous social
factors, differing in various communities, must receive serious consideration for the effective
control of this preventable and treatable disease.
In order to cope more successfully with tuberculosis in Serbia, the National TB Control
Program was created in 1998. Since 2004 all activities for TB control at national level have been
achieved within the framework of the project ‘‘TB control in Serbia by implementation of the
DOTS strategy and outreach services for vulnerable populations,’’ which was financed by the
Global Fund of Tuberculosis, AIDS & Malaria (GFATM). The main goal of the study was to
reduce TB incidence in the country to 25 per 100,000 population by the end of 2009, by
strengthening health care capacities for TB control, by implementation of the DOTS strategy
throughout the country, by improvement of TB control in population groups at high risk for
TB, and by prevention of MDR TB. Thanks to these activities, TB incidence in Central Serbia
and Vojvodina fell from 37 per 100,000 in 2003 to 29 per 100,000 in 2006, and the planned
implementation of the DOTS strategy was achieved. In 2007, the requisite conditions were set
up for the improvement of diagnosis, treatment and follow-up of MDR TB.
Thanks to these health care activities, it can be expected that the epidemiological picture of
TB in Serbia will not deteriorate in the future despite the anticipated inevitable increase of
HIV/AIDS.
Summary Points
After the steady decline of TB incidence rates in the period 1992–2002 leveled off.
The average TB incidence rate in Serbia is below the European average.
Childhood tuberculosis accounts for 5% of TB cases in Serbia.
TB mortality in Serbia is decreasing significantly.
The total TB burden (DALY) in Serbia in the period 1992–2002 has decreased thanks to
declining mortality.
References
Atanaskovic-Markovic Z, Bjegovic V, Jankovic S, Kocev N, Decludt B. (2002). Rev Prat. 52: 2106–2010.
Laaser U, Marinkovic J, et al. (2003). Burden of Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC.
Disease and Injury in Serbia. Belgrade: Ministry of (1999). JAMA. 282: 677–686.
Health of the Republic of Serbia: 2003. Available from Fletcher H. (2001). Curr Opin Pulm Med. 7: 154–159.
URL: www.sbds.sr.gov.yu. Gaudelus J. (2002). Rev Prat. 52: 2133–2138.
Cooper WO, Boyce TG, Wright PF, Griffin MR. (2003). Gledovic Z, Grgurevic A, Pekmezovic T. (2006a). Pediatr
Bull World Health Org. 81: 821–826. Infect Dis J. 25: 269–270.
Corbett E, Watt C, Walker N, Maher D, Williams BG, Gledovic Z, Jovanovic M, Pekmezovic T. (2000). Int J
Raviglione MS, Dye C. (2003). Arch Intern Med. Tuberc Lung Dis. 4: 32–35.
163: 1009–1021. Gledovic Z,Vlajinac H, Pekmezovic T, Grujicic-Sipetic S,
Datta M, Swaminathan S. (2001). Pediatr Respir Rev. 2: Grgurevic A, Pesut D. (2006b). Am J Infect Control.
91–96. 34: 676–679.
Jovanovic D, Skodric-Trifunovic V, Markovic-Denic l, Starke JR. (2004). Semin Respir Crit Care Med. 25:
Stevic R, Vlajinac H. (2007). Int J Tuberc Lung 353–364.
Dis. 11: 647–651. The Republic Health Institute. (2003). Belgrade Annual
Migliori GB, Centis R. (2002). Monaldi Arch Chest Dis. Report. 1992–2002.
57: 285–290. Thorson A, Diwan VK. (2001). Curr Opin Pulm Med. 7:
Murray CJL, Lopez AD (eds.). (1996). The Global Burden 165–169.
of Disease: a Comprehensive Assessment of Mortal- Vlajinac H, Marinkovic J, Kocev N, Adanja B, Pekmezovic
ity and Disability from Diseases, Injuries and Risk T, Sipetic S, Jovanovic D. (1997). J Epidemiol Com-
Factors in 1990 and Projected to 2020. Global Bur- mun Health. 51: 106–109.
den of Diseases and Injury Series, Vol. 1, Harvard Wong T. (2002). Rapid Assessment of Serbia HIV/AIDS/
University Press, Cambridge, pp. 125–133. STI Surveillance System. Field Investigation Report.
Murray CJL, Lopez AD. (2000). Health Econ. 9: 69–82. CPHA, Belgrade.
Raviglione MC, Snider DE, Kochi A. (1995). JAMA. 273: World Health Organization. (1998). Global Tuberculosis
220–226. Control. WHO, Geneva, 273p.
Shingadia D, Noveli V. (2003). Lancet Infect Dis. 3: World Health Organization. (1995). Wkly Epidemiol
624–632. Rec. 70: 224–236.
69 DALYs and Diarrhea
R. Oria . R. Pinkerton . AAM Lima . R. L. Guerrant
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222
2 Importance of Disability in Addition to Mortality: Definitions of Terms:

DALYs, QALYs, YPLL, YLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1223
3 Potential Importance of Long-Term Effects of Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . 1224
4 Relevance to Cost Effective Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227
5 Potential Evolutionary Relevance of DALYs to Human Genetics . . . . . . . . . . . . . . . . . . 1229
6 Importance to Solving one of the Greatest Health Problems Stemming

from Poverty: Enteric Infections from Inadequate Water and Sanitation . . . . . . . . . 1230
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1231

1222 69 DALYs and Diarrhea
Abstract: Burden of disease assessments must incorporate both years of life lost and years lost
to disability. This is especially important for diseases that have long-term effects in addition to
early life mortality. Such is increasingly recognized to be the case for early childhood diarrhea,
especially in impoverished areas. Although dramatic improvements have been made in
reducing childhood diarrhea mortality, the morbidity (illness) rates persist, and have likely
lasting effects on children’s physical and even cognitive development. Hence, even though data
are limited, existing evidence suggests that these long-term effects of early childhood diarrhea
on child development and thus cause potentially lifelong “disability” may be substantial.
Although several approaches have been used to assess these disability and mortality impacts,
including “Quality adjusted life years” and “Disability adjusted life years,” the latter (DALYs)
have gained widespread use. We review this evidence and provide a range of estimates from
published information on the “DALY impact” of early childhood diarrhea.
List of Abbreviations: ApoE4, apolipoprotein E4; CAT-1, cationic arginine transporter 1;
DALY, disability-adjusted life years; EAEC, enteroaggregative Escherichia coli; ECD, early
childhood diarrhea; HAART, highly active antiretroviral therapy; HAZ, height-for-age z scores;
HIV, human immunodeficiency virus; HST, Harvard step test; IL-8, interleukin-8; IQ,
intelligence quotient; ORNT, oral rehydration and nutrition therapy; ORT, oral rehydration
therapy; QALY, quality-adjusted life years; SD, standard deviation; TB, tuberculosis; TONI III,
test of nonverbal intelligence, version III; WISC, Wechsler intelligence scale for children; YLD,
years lost to disability; YPLL, years of potential life lost
1 Introduction
Assessing the importance of diseases or conditions that alter the health and well being of
people necessitates a broad understanding of health as well as the ways it can be altered.
Attempts at quantifying the impact of health altering conditions (and hence the “value” or
worth of interventions that avoid these impacts or optimize “health”) require not only
counting the causes of death, but also the ages affected (hence the “years of potential life
lost,” YPLL). However, morbidity (i.e., illnesses or impaired quality of life without death) must
also be counted. This requires a full understanding of “good health” that includes a sense of
well being that may even include such issues as “stress” or a sense of control in one’s life, as well
as freedom from overt “disease” (Bosma et al., 1997). It must also incorporate a sense of ability
to achieve one’s full human potential, both physically and cognitively, and a sense of meaning,
fulfillment and richness in life. This “achieving of one’s full human potential” becomes
important in assessing the long-term impact of early childhood conditions such as enteric
infections and their consequent symptoms of overt diarrhea or covert impairment of long-
term physical and cognitive development, the latter potentially lasting for a lifetime.
As premature deaths are reduced, morbidity gains much greater importance relative to
mortality. Though quality of life is increasingly appreciated by those who age and lose
functions and quality, the potential life-long impact of conditions that affect an entire lifetime
is far greater. Thus, the “years lost to disability” (YLD) become increasingly important when
assessing the impact of conditions that affect human development from early childhood. Such
is the importance of early childhood intestinal infections from inadequate water and sanita-
tion in impoverished conditions, relevant to 1.2–2.4 billion people (i.e., 17–40% of the world’s
population), respectively, who lack these basic necessities (Mara, 2003).
DALYs and Diarrhea 69 1223
2 Importance of Disability in Addition to Mortality:

Definitions of Terms: DALYs, QALYs, YPLL, YLD
(> Table 69-1)
An understanding of the true (or nearest approximation of) global burden of diarrheal
diseases and enteric infections in pediatric populations in the developing world (especially
in children under five years of age) is critical to effective planning of public health policies to
prevent or diminish their effects on children’s development. Although mortality from early
childhood diarrhea (ECD) has been dramatically reduced by oral rehydration therapy (ORT),
the persisting poverty and lack of water and sanitation amidst the fastest growing populations
(Guerrant and Blackwood, 1999) leave morbidity (illness) rates as high or higher than ever
(Kosek et al., 2003). Consequently, as we understand the potentially lifelong impairment
of cognitive as well as physical development, the calculation of the global burden of disease
from diarrhea and intestinal infections may be far greater than previously estimated (Guerrant
et al., 2002).
. Table 69-1
Means of assessing burdens of disease
QALYs Quality adjusted life years

DALYs (= YPLL + YLD) Disability adjusted life years
YPLL Years of potential life lost
YLD Years lost to disability
The construction of standard health measurements (and predictive models) to quantify

the burden of disease (and estimate changes over time) has provided a new rationale to
accomplish a more cost-effective and equitable use of health resources (allocation of health
professionals, medications, vaccines, infrastructure and equipment) and for prioritizing the
economic investments toward the most important public health needs and health impact.
The establishment of measurable health and economic indicators, such as QALYs and DALYs,
to estimate the global burden of disease, has also provided an important epidemiological tool
to health officials and policy makers to design new road maps and to define time windows to
optimize the most effective prevention and control measures (such as immunizations
or improved water and sanitation) and treatment (such as ORT, oral rehydration and
nutrition therapy (ORNT), micronutrients, macronutrients, and antimicrobials) strategies
based on endemic environments and risk groups.
QALYs (Quality-Adjusted Life Years) have been designed to assess individual preference to
different non-fatal health outcomes that might result from a specific intervention, therefore
helping to identify types of disability, impairment and handicap (Morrow and Bryant, 1995).
However, their utility has been more restricted to high income countries; since more refined
measurements of disability diminish in importance when juxtaposed against attempts to the
account for preventable burdens of premature deaths and long-term disabilities in developing
countries. In addition, the usually high cost of these quality-based studies and subjective
assignments of this index reduce its feasibility to estimate quality of life in poor settings. Thus
QALYs not only suffer problems of subjective value assignments that vary substantially with
who makes the choices, they also do not capture the broader benefits (externalities) that may
accrue to society, family or friends (Guerrant et al., 2004).
In 1995–1996, the Global Burden of Disease Programme called for DALY (Disability-
Adjusted Life Years) estimates for many diseases, which was followed subsequently by WHO,
the World Bank and other agencies to rank the burden (King et al., 2005). DALYs incorporate
not only age-specific mortality (as years of potential life lost (YPLL) to fatality) but also
includes the reduction of the quality of life due to disabilities and handicap (e.g., years lost to
disability (YLD)). In calculating DALYs, a healthy “non-disabled” state is assign as 0 and death
is defined as 1; in between the different degrees of disability are found. This measurement
greatly simplifies the calculation of disease burden and ensures comparability between popu-
lations. The losses from disability and premature death are combined to define the final DALY
value, which allows the evaluation of short and long-term consequences on the quality of life.
This kind of measurement is therefore appropriate to understand the impact of chronic and
debilitating diseases that do not kill (with low mortality rates) but are either chronic or cause
long-term morbidity or disability.
Neuropsychiatric illnesses (such as depression, dementia, and schizophrenia), rheumatic
diseases (such as arthritis and neuropathic conditions) and neurovascular diseases (such as
atherosclerosis and diabetes) may have a more chronic course and thus have a greater YLD
impact than that due to YPLL. These debilitating chronic conditions are far more costly over
the long term due to the staggering toll of disability, hospitalization and life-long medications.
The improvement of health worldwide has reduced the mortality rates, which in turn lead to
increase in longevity. Aging populations, especially in the developed world, are therefore more
subjected to chronic diseases or greater disease risk such as with Clostridium difficile antibiotic-
associated colitis, which has a distinct increased risk with increasing age and likely impairs
quality of life more than currently appreciated.
3 Potential Importance of Long-Term Effects of Diarrhea
According to Murray and Lopez, (Lopez et al., 2006) diarrhea ranks second only to respiratory
illnesses among the top three causes of DALYs worldwide. The global DALY for diarrheal
diseases is estimated to be 99.6 million. If iron-deficiency and protein-energy malnutrition are
added to this number (both are commonly seen with enteric infections), this number
approximates 145 million total DALYs. For instance, malnutrition was found to be the
major risk factor responsible for the greatest loss of DALYs (15.9%), together with poor
water and sanitation (6.8%). Pruss et al. (2002) estimated DALYs due to diarrheal illnesses
(related to poor hygiene and sanitation) to be 82,196,000 DALYs per year, with the total
amount of 2,213,000 deaths worldwide (especially in sub-Sahara Africa). The lack of potable
water and adequate distribution systems in the developing world clearly pose the greatest risk
of water-borne enteric illnesses and diarrhea (Lee and Schwab, 2005).
Although trends of declining mortality due to diarrheal illnesses have been reported in
children under five years old, morbidity rates have not declined (Kosek et al., 2003; Parashar
et al., 2003). However, there is considerable uncertainty in all-cause mortality in low-income
countries in the sub-Saharan Africa (Lopez et al., 2006). In contrast to aging populations with
chronic illnesses, who are admitted to hospitals and health centers and have medical records
which contribute to population statistics, children who silently survive following repeated or
persistent intestinal infections and diarrhea early in life but are never hospitalized or otherwise
brought to medical attention have physical and cognitive impairment or chronic disabilities
that remain obscured or uncounted if not completely undiscovered. Mortality rates due to
diarrhea and malnutrition in children under five years old, thus likely represent only a tip of
the iceberg (Guerrant et al., 2005). Children’s developing their full potential as productive
adults might be forever lost if a critical time window (the first two years of life) for brain
development is compromised by debilitating and malnourishing diarrhea. Diarrhea and
enteric infections might disrupt intestinal barrier function and therefore reduce the supply
of critical nutrients (such us zinc, fatty acids or iron) to the developing brain, thus jeopardiz-
ing the development of normal brain plasticity. For example, zinc deficiency in Latin America,
Africa and Asia, was projected to be responsible for over 453,000 deaths (4.4% of childhood
deaths) and 1.2% of the burden of disease (3.8% among children between 6 mo and 5 yo) in
2004, mostly in Africa (Fischer Walker et al., 2008). The global burden of other micronutrient
deficiencies and their interactions with each other are not well established. In addition,
diarrhea and enteric infections may increase the risk for or worsen the effects of micronutrient
deficiencies or environmental toxins such as low-dose chronic exposure to lead; for example,
zinc deficiency may contribute to increased lead absorption (Levander, 1979; Oria et al., 2007).
Our studies in a Brazilian cohort of shantytown children under active surveillance for
diarrheal illnesses since birth suggest that heavy burdens of enteric illnesses early life (depicted
by higher number and duration of diarrheal episodes in the first two years of life) are
associated with long-term physical (Guerrant et al., 1999a; Moore et al., 2001) and cognitive
deficits into schooling years (Guerrant et al., 1999a; Lorntz et al., 2006; Moore et al., 2000,
2001; Niehaus et al., 2002). These prolonged cognitive and growth deficits remain significantly
associated with early childhood diarrhea (ECD) even after controlling for several confounding
factors (such as maternal education, breast feeding and household income). Shown in
> Table 69-2 are the published evidence that early childhood diarrhea and enteric parasitic
infections in just the first two years of life have profound, lasting effects on child development.
> Table 69-3 summarizes the magnitude of these estimates just from our studies in North-
eastern Brazil, which, given the documented secular improvements in this population over
time (Moore et al., 2000) probably represent a “best case” scenario. These correlate with
just the average burden of diarrhea in the first two years of life alone and include an estimated
8.2 cm growth shortfall by age 7 years old, an approximate 2–10 point decrement in IQ, an
impaired fitness score that equates to a 17% decrement in work productivity, and an approxi-
mate 12 month delay in schooling (Guerrant et al., 1999, 2002; Lorntz et al., 2006; Moore et al.,
2001; Niehaus et al., 2002). In addition, early childhood diarrhea was the best single predictor
of age at starting school and age-for-grade as well as cognitive impairment; the next best
“surrogate” predictor (as it reflects ECD) of schooling was height-for-age Z scores at 2 years
old (Lorntz et al., 2006).
Checkley and colleagues found significant negative correlations between diarrhea episodes
in the first two years of life and height-for-age z scores (HAZ) in Peruvian children living in
urban slums. Children afflicted with diarrhea 10% of the time (during the first two years) were
1.5 cm shorter than children without diarrhea history (Checkley et al., 1998, 2003). Moore
et al. found a mean 3.6 cm decrement in height at the age of 7 years old in children with a
previous history of diarrhea (mean = 9.1 episodes) in the first 24 months in life (Moore et al.,
2001). Chronic malnutrition (defined by stunting: below -2 SD under reference values) early
in life may also independently affect cognitive performance during late childhood (Pinkerton
et al., 2008). Although malnutrition-induced cognitive deficits during the schooling years may
be ameliorated with early interventions (Tarleton et al., 2006), malnutrition combined with
. Table 69-2
Evidence for lasting disability effects from early childhood diarrhea
Disease Outcome References

Growth shortfalls
Cryptosporidial infections and Increased diarrhea morbidity and nutritional Agnew et al.
persistent diarrhea shortfalls for up to 18 months (1998)
Lima et al.
(2000)
Newman
et al. (1999)
Cryptosporidium hominis is more common Bushen et al.
than C. parvum in favela children and is (2007)
associated with heavier infections and greater
growth shortfalls, even in the absence of
symptoms
Cryptosporidial infections and 0.95–1.05 cm growth deficits at 1 year later Checkley
at <6 months of age and in stunted et al. (1998)
children
Early childhood diarrhea (0–2 y.o.) Lasting growth shortfalls persisting at 3.6 cm Moore et al.
at 7 y.o. (additive to 8.2 cm with intestinal (2001)
helminths at 0–2 y.o.)
At 24 months of age, Peruvian children were Checkley
2.5 cm shorter than the US National Center for et al. (2008)
Health Statistics/World Health Organization
growth reference. A diarrheal prevalence
of 2.3% in the first 24 months of life explained
2–27% of this growth deficit
ECD 0–2 leads to 1.13 risk of stunting for every Checkley
5 illnesses et al. (2008)
Fitness impairment
Early childhood diarrhea (0–2 y.o.) Impaired fitness scores (assessed by Stephenson
the Harvard Step Test, HST) 4–7 years later et al. (1993)
(by 4–8.2% for median and high diarrhea Ndamba
burdens, respectively; for comparison, fitness et al. (1993)
scores improved 6.9% 4 months after Guerrant
albendazole treatment of schoolboys in Kenya et al. (1999a)
and a 4.3% increase in HST scores correlated
with a 16.6% in sugarcane cutters in
Zimbabwe
Cognitive impairment
Early childhood diarrhea (0–2 y.o.) Impaired cognitive function at 6–9y.o. by Guerrant
McCarthy Draw-a-design (p = 0.017 when et al. (1999a)
controlling for early childhood helminthic
infections), and WISC coding and reverse digit
span testing (p = 0.045)
Disease Outcome References

Impaired Test of Nonverbal Intelligence Niehaus
(TONI III) scores at 6–10y.o. when controlling et al. (2002)
for maternal education, breastfeeding
duration, and early helminthic infections, and
WISC coding and digit span scores were lower
in children who had one or more persistent
diarrheal illnesses in their first 2 years of life
This study suggests a disproportional Patrick et al.
impairment in semantic but not phonetic (2005)
fluency in a subset of children with heavy
burdens of diarrhea in their first 2 years of
life even when controlling for maternal
education, breastfeeding, and child
schooling. The data show the potential
influences of early childhood diarrhea on
language development
School performance
Early childhood diarrhea (0–2 y.o.) Delayed age at starting school and older Lorntz et al.
age-for-grade, independent of maternal (2006)
education, socioeconomic status, other
illnesses and of also significant effects (of ECD)
on height for age Z scores (i.e., stunting) at 0,
2, or 7 years of age (p < 0.02, N = 77) late
starters also are 2-fold more likely to have
experienced cryptosporidial infections in their
first 2 years of life
Early childhood diarrhea (ECD) correlated with Lorntz et al.
growth shortfalls and impaired cognitive (2006)
functioning. The study document effects of early
childhood diarrhea on later school readiness and
performance and hence potential long-term
human and economic costs of ECD
diarrheal illnesses or intestinal infections in the first years of life may additively and irreversibly
impair cognitive development in children living in poor settings (Guerrant et al., 2002). Thus
the vicious cycle of repeated diarrheal diseases and enteric infections with malnutrition must
now include developmental impairment of growth, cognition and schooling and even as noted
below drug malabsorption as depicted in > Figure 69-1.
4 Relevance to Cost Effective Analyses
The now growing evidence that the lasting disability effects of diarrheal infections and
malnutrition early in life point necessitate a reassessment of the global DALYs attributed to
these often “overlooked and neglected” diseases. The vicious cycle of malnutrition and
. Table 69-3
Estimated magnitude of the lasting disability effects from early childhood diarrhea (ECD) in just
the first 2 years of life on growth, fitness, cognition and schooling 4–7 years later
Lasting
disability Magnitude of disability Reference
Growth Most prominent on HAZ at 2yo; but persisting to 8.2 cm Moore et al. (2001)
shortfalls difference at 7yo
Fitness Approximating 17% work productivity Guerrant et al. (1999a)
impairment Ndambe et al. (1993)
Cognitive Approximating 2–10 IQ points Guerrant et al. (1999a)
impairment Niehaus et al. (2002)
School Approximately 12 months behind in age-for-grade by third Lorntz et al. (2006)
performance grade; Also delayed age at starting school
. Figure 69-1
Vicious cycle of enteric infection and developmental shortfalls
diarrhea interact to compound the burden of both afflictions, where each aggravates or
worsens the other. Recently, new calculations of the cost of chronic helmintic infections,
often with anemia, diarrhea and undernutrition, suggest the necessity of changing the DALY
for schistosomiasis from 0.5 to 2–15% disability (King et al., 2005). Current DALY estimates
for diarrheal disease approximate 100 million, with more than 95% derived just from
mortality. If only 5% of children who experienced an average of 4–8 episodes of diarrhea
in their first two years of life in the lowest disability scenario, this would increase the global
DALY for diarrhea by 100 million (Guerrant et al., 2002). Based on others’ and our data, we
suggest herein that the disability burden of enteric illnesses associated with malnutrition
likely outweighs even the still troubling mortality due to diarrhea, especially if we include
growth and cognitive deficits. Furthermore, cognitive and growth deficits can be seen with
intestinal infections (with protozoa and bacteria as well as with helminths) without overt
symptomatic diarrhea (Checkley et al., 1998; Steiner et al., 1998). These effects likely relate
to intestinal malabsorption, which has been documented with subclinical intestinal infec-
tions (Guerrant et al., 1999b, 2008). Such impaired absorptive function may also compro-
mise nutrient and drug bioavailability, leading to increased resistance to HIV, tuberculosis,
and malaria therapy, which rely on long-term regimens to eradicate or control the infection
(Bushen et al., 2004).
5 Potential Evolutionary Relevance of DALYs to Human

Genetics
> Table 69-4 summarizes two examples of genetic alleles that appear to determine the
impact of enteric infections. We have recently described the remarkable protective role
played by the human genetic allele ApoE4 (that predisposes to Alzheimer’s Disease as well
as to cardiovascular risk). This potentially devastating gene (in later life) may actually be in
our human gene pool because it is protective against heavy diarrhea burdens in early
childhood and their consequences of lasting cognitive impairment (Oria et al., 2005, 2006,
2007). Of even greater interest, understanding the cellular effects of this gene (such as the
upregulation of an arginine transporter Colton et al., 2001, 2002; Czapiga and Colton, 2003)
may provide clues to novel approaches to nutrient therapy. Furthermore, perinatal stressors, such
as malnutrition and diarrhea may increase the risk of high cholesterol levels later in life, thus
putting children with heavy burdens of malnourishing diarrhea at greater risk for cardiovascular
diseases later in life (Oria et al., 2007; Victora et al., 2008). The global burden of cardiovascular
diseases has been growing especially in developing countries (emergent countries such as Brazil
and India), (Lawes et al., 2008) where malnourished children are more prone to obesity when
life style changes (Prentice, 2006). Hence the full impact of early childhood diarrheal illnesses
likely extends far beyond DALY calculations to include an evolutionary impact of the human gene
pool itself.
The second example is that of the proinflammatory allele at the 251 position in the
human IL-8 promoter. This allele is not only associated with overt diarrheal symptoms
in travelers infected with enteroaggregative E. coli (Jiang, 2003) (of potential relevance to
EAEC causing inflammation and malnutrition as well Steiner et al., 1998), but also with C.
difficile colitis (Jiang, 2006) and even with ulcer and carcinoma with H. pylori infections
(Garza-Gonzalez, 2007). Hence, we are just beginning to appreciate the tremendous interac-
tions of enteric infections with long-term outcomes in humans, but even with the evolution of
our human genome itself.
. Table 69-4
Examples of genetic determinants of impact of enteric infections
Apo E4:
Associated with increased risk for Alzheimer’s and cardiovascular disease
Protective against diarrhea and its cognitive impairment (Oria et al., 2005, 2007)
Upregulates arginine-selective uptake via the CAT-1 (cationic aminoacid) transporter (Czapiga and
Colton, 2003; Colton et al., 2001)
Intestinal inflammation and the proinflammatory allele at 251 in the IL-8 promoter:
Associated with enteroaggregative E. coli diarrhea (Jiang et al., 2003)
Associated with C. difficile colitis (Jiang et al., 2006)
Associated with H. pylori, ulcers and gastric carcinoma (Garza-Gonzalez et al., 2007)
6 Importance to Solving one of the Greatest Health Problems

Stemming from Poverty: Enteric Infections from Inadequate
Water and Sanitation
In conclusion, a full and accurate assessment of the true, potentially lifelong burden of early
childhood diarrhea and intestinal infections is imperative in order to place the appropriate
priority on interventions that can so effectively ameliorate or avoid these burdens. Such is the
importance of the DALY calculations that strive to account for years lost to disability as well as
for years of life lost. Despite the greatly reduced mortality from childhood diarrhea, the illness
rates continue unabated, with a potentially even greater morbidity impact when combined
with food scarcity that now threatens the poorest millions of children around the world. Thus
the societal (and even familial and personal) impact of impaired development for most of the
world’s poorest children approaches or even exceeds that of the declining mortality from
diarrheal diseases, certainly for global DALY recalculations but perhaps even for the costly
familial and personal suffering that may accompany significant impairment of a child’s normal
development. Shown in > Table 69-5 are the ranges of revised DALY calculations for diarrhea,
using the standard formulas with age-weighting and discounting at 3%, with all disability
falling into the lowest “class” (of 0.096). These calculations were published in Guerrant et al.
(2002) and held mortality and morbidity in >4-year olds fixed. In the 5 scenarios shown, the
first shows the original assumptions of just 1 week of “disability” for diarrheal illness 3.6 attacks
per child per year. The second through fifth scenarios show how even only 5% (to 25%) of
children affected by a disability “class” of 0.096 (the only one available for these formulas) for
durations of 25–81.25 years (i.e., a lifetime) results in a two to six-fold increase in the global DALY
calculation. The basis for this range of estimates derives from the very limited data suggesting a
linear decrement in cognitive performance at 6–9 years of age from increasing diarrhea burdens in
the first two years of life, the average of which approximates 2–10 IQ points with the average
diarrhea burden in children living in an urban shantytown in northeast Brazil (Guerrant et al.,
1999, 2002; Lorntz et al., 2006; Niehaus et al., 2002).
Hence, we must see the far greater importance of adequate water and sanitation, poverty
relief, and any effective interventions that can ameliorate or prevent these devastating early
childhood infections and illnesses. Only with accurate assessments can such critical policy and
investment decisions be made that will be so profoundly important to enabling children in
greatest need to meet their full human potential.
. Table 69-5
Revised DALY calculationsa
Attack rate/year at 0–4yo Proportion disabled Duration of durability DALYs ( 106)

3.6 1 0.02 100.9
1 0.17 81.25 451.3
1 0.25 81.25 616.8
1 0.10 25.00 217.7
1 0.05 81.25 207.2
i.e., A long-term impact of only 1–2% more than doubles the global diarrhea DALY
a
Guerrant et al. (2002)
Summary Points
Data are increasingly showing long-term consequences of early childhood diarrhea for
physical and cognitive development.
A recent multi-country analysis documents an adjusted increased odds of stunting by 1.13
(i.e., 13%) for every 5 episodes of diarrhea over the first 2 years of life (i.e., every 2.5
illnesses per child-year) (Checkley et al., 2008).
Stunting at age 2 years old (like diarrhea in the first 2 years of life) predicts later cognitive
impairment (Mendez and Adair 1999) and HAZ-2 may be the best predictor of human
capital (Victora et al., 2008).
Mounting evidence shows that intestinal infections lead to malnutrition and that malnu-
trition worsens intestinal infections thus documenting a “vicious cycle” for child develop-
ment. (i.e., bad water collides with bad diets to impair child development and human
potential) (Guerrant et al., 2008).
DALY calculations that have here-to-fore focused on mortality and only acute diarrheal
symptoms thus will need substantial corrections as data on long-term impact become available.
Understanding the terms to define disease burden is relevant to police makers and health
officials to assign short and long-term societal cost-effects of child morbidity.
The reciprocal cycle of diarrhea and malnutrition amplifies the burden of diarrheal disease
to a level not ever considered before.
Novel scientific evidence requires the revisit of global DALYs calculation for diarrheal
diseases.
The understanding of evolutionary traits for human survival may highlight gene candi-
dates for diarrheal disease susceptibility and to design preventive measures.
Solving the greatest health problems requires multi-focused attention to water, sanitation,
behavior, microbes, genetics and intestinal repair micronutrients and nutrients in order to
reduce the diseases of poverty.
References
Agnew DG, Lima AA, Newman RD, et al. (1998). J Infect Checkley W, Epstein LD, Gilman RH, Black RE,
Dis. 177: 754–760. Cabrera L, Sterling CR. (1998). Am J Epidemiol.
Bosma H, Marmot MG, Hemingway H, Nicholson AC, 148: 497–506.
Brunner E, Stansfeld SA. (1997). BMJ. 314: 558–565. Checkley W, Epstein LD, Gilman RH, Cabrera L, Black
Bushen OY, Davenport JA, Lima AB, et al. (2004). Clin RE. (2003). Am J Epidemiol. 157: 166–175.
Infect Dis. 38: 1764–1770. Czapiga M, Colton CA. (2003). J Neuroimmunol. 134:
Bushen OY, Kohli A, Pinkerton RC, et al. (2007). Trans R 44–51.
Soc Trop Med Hyg. 101: 378–384. Fischer Walker CL, Ezzati M, Black RE. (2008). Feb 13.
Checkley W, Buckley G, Gilman RH, Assis AMO, Eur J Clin Nutr. doi:10.1038/ejcn.2008. 9: 1–7
Guerrant RL, Morris SS, Molbak K, Valentiner- PMID:18270521.
Branth P, Lanata CF, Black RE and The Childhood Garza-Gonzalez E, et al. (2007). BMC Cancer. 7: 70.
Malnutrition and Infection Network. (2008). Int J Guerrant DI, Moore SR, Lima AA, Patrick PD, Schorling
Epidemiol. 37 (4): 816–830. JB, Guerrant RL. (1999a). Am J Trop Med Hyg. 61:
Colton CA, Brown CM, Cook D, et al. (2002). Neurobiol 707–713.
Aging. 23: 777–785. Guerrant RL, Blackwood BL. (1999). Clin Infect Dis. 28:
Colton CA, Czapiga M, Snell-Callanan J, Chernyshev 966–986.
ON, Vitek MP. (2001). Biochim Biophys Acta. Guerrant RL, Kosek M, Lima AA, Lorntz B, Guyatt HL.
1535: 134–144. (2002). Trends Parasitol. 18: 191–193.
Guerrant RL, Kosek M, Moore S, Lorntz B, Brantley R, Moore SR, Lima AA, Schorling JB, Barboza MS, Jr.,
Lima AA. (2002). Arch Med Res. 33: 351–355. Soares AM, Guerrant RL. (2000). Int J Infect Dis.
Guerrant RL, Lima AAM, Barboza M, et al. (1999b). 4: 179–186.
Mechanisms and impact of enteric infections. Proceed- Morrow RH, Bryant JH. (1995). Am J Public Health. 85:
ings of the 2nd International Rushmore Conference on 1356–1360.
Mechanisms in the Pathogenesis of Enteric Diseases. Mendez MA, Adair LS. (1999). J Nutr. 129(8):
MT. RUSHMORE, South Dakota. 1555–1562.
Guerrant RL, Lima AAM, Moore SR, Lorntz B, Patrick Ndamba J, Makaza N, Munjoma M, Gomo E, Kaondera
PD. (2004). Potential Long-Term Consequences of KC. (1993). Ann Trop Med Parasitol. 87: 553–561.
Early Childhood Enteric and Parasitic Infections. Newman RD, Sears CL, Moore SR, et al. (1999). J Infect
The Infectious Etilogy of Chronic Diseases, The Dis. 180: 167–175.
National Academies Forum on Microbial Threats, Niehaus MD, Moore SR, Patrick PD, et al. (2002). Am J
Washington DC, pp. 83–92. Trop Med Hyg. 66: 590–593.
Guerrant RL, Oria R, Bushen OY, Patrick PD, Houpt E, Oria RB, Patrick PD, Blackman JA, Lima AA, Guerrant
Lima AA. (2005). Clin Infect Dis. 41(Suppl. 8): RL. (2007). Med Hypotheses. 68: 1099–1107.
S524–S530. Oria RB, Patrick PD, Zhang H, et al. (2005). Pediatr Res.
Guerrant RL, Oriá RB, Moore SR, Oriá MO, Lima AA. 57: 310–316.
(2008). Nutr Rev. 66(9): 487–505. Oria RB, Vieira CMG, Pinkerton RC, et al. (2006). Nutr
Jiang ZD, et al. (2003). J. Infect. Dis. 188: 506–511. Res. 26: 427–435.
Jiang ZD. et al. (2006). Am. J. Gastroenterol. 101: Patrick PD, Oria RB, Madhavan V, et al. (2005). Child
1112–1116. Neuropsychol. 11: 233–244.
King CH, Dickman K, Tisch DJ. (2005). Lancet. 365: Parashar UD, Bresee JS, Glass RI. (2003). Bull World
1561–1569. Health Organ. 81: 236.
Kosek M, Bern C, Guerrant RL. (2003). Bull World Pinkerton R, Lima AAM, Moore SR, Niehaus M, Oria
Health Organ. 81: 197–204. RB, Guerrant RL. (2008). International Research in
Lawes CM, Vander HS, Rodgers A. (2008). Lancet. 371: Infectious Disease. Presented May 29, NIH,
1513–1518. Bethesda, MD.
Lee EJ, Schwab KJ. (2005). J Water Health. 3: 109–127. Prentice AM. (2006). Int J Epidemiol. 35: 93–99.
Levander OA. (1979). Environ Health Perspect. 29: Pruss A, Kay D, Fewtrell L, Bartram J. (2002). Environ
115–125. Health Perspect. 110: 537–542.
Lima AA, Moore SR, Barboza MS, Jr., et al. (2000). Steiner TS, Lima AA, Nataro JP, Guerrant RL. (1998).
J Infect Dis. 181: 1643–1651. J Infect Dis. 177: 88–96.
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray Stephenson LS, Latham MC, Adams EJ, Kinoti SN,
CJ. (2006). Lancet. 367: 1747–1757. Pertet A. (1993). J Nutr. 123: 1036–1046.
Lorntz B, Soares AM, Moore SR, et al. (2006). Pediatr Tarleton JL, Haque R, Mondal D, Shu J, Farr BM, Petri
Infect Dis J. 25: 513–520. WA. Jr. (2006). Am J Trop Med Hyg. 74: 475–481.
Mara DD. (2003). Public Health. 117: 452–456. Victora CG, Adair L, Fall C, et al. (2008). Lancet. 371:
Moore SR, Lima AA, Conaway MR, Schorling JB, Soares 340–357.
AM, Guerrant RL. (2001). Int J Epidemiol. 30:
1457–1464.
70 The Burden of Rotavirus
Acute Gastroenteritis in
Europe
J. Bilcke . P. Van Damme . P. Beutels
1 Introduction: Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1234
2 Rotavirus Disease Burden in Europe: the Available Data . . . . . . . . . . . . . . . . . . . . . . . 1235

2.1 Symptomatic Cases Not Requiring Professional Medical Care . . . . . . . . . . . . . . . . . . . . . 1235
2.2 Ambulatory Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1235
2.3 Emergency Department Visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1236
2.4 Hospitalizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1236
2.5 Nosocomial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1236
2.6 Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1237
3 Considerations Regarding Interpretation and Comparison of

Reported Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1237
3.1 Seasonality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1239
3.2 Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1239
3.3 Case Definitions and Study Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1239
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1240

1234 70 The Burden of Rotavirus Acute Gastroenteritis in Europe
Abstract: > Rotavirus (RV) is the leading cause of severe > gastroenteritis in children under
5 years of age. In this chapter we will document the burden of > rotavirus gastroenteritis
in the 27 countries of the European Union.
Data on rotavirus disease burden is lacking for about half of the countries of the European
Union. The available data for the other half show differences that do not necessarily reflect
country-specific differences, but that may also be due to differences in study characteristics
and quality. Based on the available literature, the annual > incidence of RV disease in the
European Union ranges from 0.06–4.15% of the children aged <5 years seeking > ambulatory
care, 0–2.65% of the children aged <5 years visiting emergency departments, 0.03–1.19% of
the children aged <4/5 years being hospitalized for rotavirus, and 0.5–14 children per million
children aged <3/5 years that die due to RV infection. Information on children experiencing
disease but not seeking professional medical care is lacking for the European Union. Studies
on > nosocomial RV > infections are numerous, but difficult (if not impossible) to interpret
and compare, because of very different methodologies and contexts.
List of Abbreviations: AGE, acute gastroenteritis; EU, European Union; GP, general practi-
tioner; ICD-9, > International Classification of Disease, ninth edition; NRV, nosocomial
rotavirus infection; O, outpatient visit; P, pediatrician; PROTECT, Pediatric ROTavirus Euro-
pean CommiTee; RV, rotavirus; RVGE, rotavirus gastroenteritis
1 Introduction: Background
Rotavirus (RV, > Table 70-1) is the leading cause of severe gastroenteritis in children under
5 years of age (Parashar et al., 2003). Although it is widely accepted that by the age of five years,
every child is infected at least once by RV (e.g., Dennehy, 2007; Glass et al., 2006; Parashar
et al., 2003; Van Damme et al., 2006), not all of these infections are symptomatic (e.g., Fischer
et al., 2002; Mata et al., 1983; Simhon et al., 1985; Velazquez et al., 1996). Only a proportion of
children infected with RV suffer from diarrhea and/or vomiting, which ranges from mild
episodes for which no medical care is sought, to very severe episodes which may lead, if
untreated, to dehydration and death. In developing countries, a substantial number of
children die due to RV (de Zoysa and Feachem, 1985; Parashar et al., 2006). In developed
countries, RV related deaths are uncommon, but a substantial disease burden still exists (de
Zoysa and Feachem, 1985; Parashar et al., 2006). As in temperate areas (e.g., Europe), rotavirus
. Table 70-1
Key facts of Rotaviruses
Virus that causes almost half of the cases of gastroenteritis (symptoms of diarrhea and/or
vomiting) in young children throughout the world
After first infection, subsequent infections generally less severe
Treatment: rehydration
Highly contagious (oral transmission), so that improving hygiene often not sufficient to reduce
spread of the disease
Now, oral rotavirus vaccines are on the market, preventing disease (not infection)
Some key facts about rotavirus, rotavirus disease, treatment and prevention
The Burden of Rotavirus Acute Gastroenteritis in Europe 70 1235
gastroenteritis (RVGE) occurs in winter epidemics together with influenza and respiratory
syncytial virus bronchiolitis, it often creates temporary capacity problems in the health care
system (Van Damme et al., 2006).
2 Rotavirus Disease Burden in Europe: the Available Data
In this chapter we will document the burden of RVGE in the 27 countries of the European
Union. More detailed information about clinical features, transmission and pathogenesis of
rotavirus can be found in another chapter in this book, entitled The economic burden of
rotavirus diarrhea in Taiwan.
A recent study (PROTECT, 2006) documented rotavirus burden in the European Union
(EU), based on a literature search for the period 1994–2005. We updated this search for the
years 2006 and 2007, by doing a search with the same strings (‘‘rotavirus’’ ‘‘country name’’ and
‘‘epidemiology’’) in Pubmed. Only papers in English, French, Spanish and German were
considered. The results are described below. Note that, unlike the paper from the PROTECT
group (PROTECT, 2006), we do not consider clinical trials, because they often use strictly
controlled study design and therefore may not be representative for what happens in the
general population. Also, we restrict ourselves to original studies estimating incidences
directly, and thus exclude incidences inferred indirectly from other countries (as for instance
reported by Parashar et al., 2003; Soriano-Gabarro et al., 2006).
The disease burden of rotavirus infection is presented hereafter in different categories,
according to the type of health care sought when infected (no professional medical care,
ambulatory care, emergency department visit or hospitalization). Nosocomial RV infections
and RV related deaths are addressed separately.
2.1 Symptomatic Cases Not Requiring Professional Medical Care
This encompasses children who are infected by rotavirus and may show symptoms (diarrhea
and/or vomiting), but for whom no professional medical care is sought. By our knowledge,
there is no information on the size of this group for (any country of) the European Union.
Although it is often stated that by the age of 5 every child is infected at least once by RV, no
study in Europe exists about how many of them experienced a > symptomatic infection.
Prospective community based studies of symptomatic RV infection performed in countries
outside the EU report annual estimates in children aged <2 ranging from 6–78% (China
(Zheng et al., 1989) respectively Mayan Indian children in Guatemala (Mata et al., 1983)).
Huet et al., 2007 estimated the proportion of children with RVGE who do not seek medical
care to be 41.4%, based on the incidence observed in day care centers in Lyon (Floret et al.,
2006). Clearly, more information is needed.
2.2 Ambulatory Care
Depending on the study, this includes RV related visits to general practitioners, pediatricians
and/or outpatient visits. Annual incidence for RV infected children aged <5 years seeking
ambulatory care ranges from 0.06% (Sweden) to 4.15% (Germany) (> Table 70-2).
. Table 70-2
Annual incidence of rotavirus related ambulatory care
Austria (Fruhwirth et al., 2001a; Fruhwirth et al., 2001b) P 0.84

3
Belgium (Van Damme et al., 2007) 1.59
Belgium (Bilcke et al., 2008) GP&P&O 3.2
3
France (Van Damme et al., 2007) 1.45
Germany (Fruhwirth et al., 2001a; Ehlken et al., 2002) P 4.1
3
Germany (Van Damme et al., 2007) 4.18
3
Italy (Van Damme et al., 2007) 2.28
Netherlands (de Wit et al., 2001a; de Wit et al., 2001b) GP 0.761
Netherlands (de Wit et al., 2001a; de Wit et al., 2001b) GP 0.462
3
Spain (Van Damme et al., 2007) 2.19
3
Sweden (Van Damme et al., 2007) 0.06
3
United Kingdom (Van Damme et al., 2007) 1.59
Annual incidence of rotavirus related ambulatory care (number of visits/100 children), for children <5 years of age
(unless stated otherwise). Incidence includes visits to general practitioner (GP), pediatrician (P) and/or outpatient
visits (O)
1
children < 1 year of age
2
children 1–4 years of age
3
includes visits to GP and/or P, depending on country (Van Damme et al., 2007)
2.3 Emergency Department Visits
All but two (Belgium (Bilcke et al.) and Spain (Cilla et al., 2000)) estimates for the incidence of
RV related emergency department visits come from a single multi-centre study (Van Damme
et al., 2007) (> Table 70-3). In Germany and one study for Belgium RV related emergency
department visits without subsequent admittance to hospital are regarded as a rare event. In
the other study for Belgium and the other countries, annual incidence of RV related emergency
department visits without subsequent admittance to hospital ranges between 0.19% (United
Kingdom) and 2.65% (France) of the children aged < 5 years.
2.4 Hospitalizations
Annual incidence of RV related hospitalizations ranges from 0.03% (Austria) to 1.19%

(Ireland) of the children aged <4/5 years (> Table 70-4).
2.5 Nosocomial Infections
A large number of studies report on incidence rates of nosocomial rotavirus infections (NRV,
reviewed in Chandran et al., 2006; Gleizes et al., 2006; PROTECT, 2006). The reported
incidence rates show a large variation: incidence per 1000 hospitalization days in EU countries
ranges for instance from 0.23 (Foppa et al., 2006) to 16 (Piednoir et al., 2003). This variation is
due to differences in the case definition (i.e., RV infection occurring 48–72h after admission),
. Table 70-3
Annual incidence of rotavirus related emergency department visits

Belgium (Bilcke et al., 2008) NA1
Germany (Van Damme et al., 2007) NA2
Spain (Cilla et al., 2000) 2.23
Annual incidence of rotavirus related emergency department visits without subsequent admittance to hospital
(number of visits/100 children), for children <5 years of age (unless stated otherwise)
1
national databases did not include rotavirus related emergency department visits without subsequent admit-
tance to hospital, suggesting this would be a rare event in Belgium
2
all eligible children who presented to the emergency department were referred to hospital
3
children < 4 years of age in the Basque autonomous region
methodology, targeted age group, the length of the study, whether or not a community
outbreak was occurring, the season in which the study was done, and the location of the
study (Chandran et al., 2006). Therefore it is difficult, if not impossible, to compare the
burden of disease between studies (Chandran et al., 2006).
2.6 Deaths
Only five European countries estimated their rotavirus mortality rate (> Table 70-5). Annual
incidence of RV related deaths ranges from 0.5 to 14 per million children (note that these
minimum and maximum values are estimates for a single country!).
3 Considerations Regarding Interpretation and Comparison

of Reported Data
Based on the available literature, the annual incidence of RV disease in the European Union
ranges from 0.06% (Sweden) to 4.15% (Germany) of the children aged < 5 years seeking
ambulatory care, 0% (Germany) to 2.65% (France) of the children aged < 5 years visiting
emergency departments, 0.03% (Austria) to 1.19% (Ireland) of the children aged < 4/5 years
being hospitalized for rotavirus, and 0.5–14 children per million children aged < 3/5 years that
die due to RV infection (France). There is no information for the EU on children experiencing
disease but not seeking professional medical care. Studies on nosocomial RV infections are
numerous, but difficult (if not impossible) to interpret and compare, because of very different
methodologies and contexts (Chandran et al., 2006).
Caution for interpretation and comparison of reported data should not only be confined
to nosocomial RV infections. There is a range of points one should keep in mind when
interpreting the reported data for the EU.
. Table 70-4
Annual incidence of rotavirus related hospitalizations
Austria (Fruhwirth et al., 2001a) 0.031

Austria (Rendi-Wagner et al., 2006) 0.766
Belgium (Bilcke et al., 2008) 0.685
Denmark (Fischer, 2001) 0.28
Denmark (Fischer et al., 2007) 0.24
0.25
Finland (Vesikari et al., 1999) 0.6
France (Fourquet et al., 2003) 0.21
Germany (Van Damme et al., 2007) 0.50
Germany (Fruhwirth et al., 2001a; Ehlken et al., 2002) 0.3
Hungary (Szucs et al., 1999) 0.84
Ireland (Lynch et al., 2001) 1.19
Netherlands (de Wit et al., 2000) 0.27
0.09
Poland (Mrukowicz et al., 1999) 0.31
Spain (Visser et al., 1999; Cilla et al., 2000; Gil et al., 2004) 0.1
0.25
0.31
Sweden (Johansen et al., 1999) 0.371
United Kingdom: England (Ryan et al., 1996) 0.52
Annual incidence of rotavirus related hospitalizations (number of hospitalisations/100 children), for children
<5 years of age (unless stated otherwise)
1
children <4 years of age
First of all, there is an enormous lack of data: no data on RV disease burden were found
with our search strategy for about half of the EU countries (Bulgaria, Cyprus, Czech Republic,
Estonia, Greece, Latvia, Lithuania, Luxembourg, Malta, Portugal, Romania, Slovakia and
Slovenia). Studies on RV disease burden in these countries may be absent, or may not have
been found due to restrictions of our search strategy. For instance, as our search strings were
English, papers not (partially) published in English were not included. The available data on
the other half of the EU countries may not be representative for the whole of the EU, and
should preferably be interpreted on the country-level, rather than the EU level.
Secondly, differences in RV disease burden estimates between countries do not necessarily
reflect country-specific differences; they may also be the consequence of differences in one or
more of following study characteristics:
. Table 70-5
Annual incidence of rotavirus related deaths
Belgium (Bilcke et al., 2008; Bilcke et al., 2007) 51

Finland (Vesikari et al., 1999) 0.7–1.8
Finland (Salo et al., October 2007) 12
France (Fourquet et al., 2003) 0.5–1.6
France (Tran, 2006) 141
France (Huet et al., 2007) 4
Ireland (Lynch et al., 2001) 1.92
United Kingdom: England&Wales (Crowley et al., 1997) 2.32
United Kingdom: England&Wales (Jit et al., 2007) 51,2
Annual incidence of rotavirus related deaths (number/million children), for children <5 years of age (unless stated
otherwise)
1
children < 3 years of age
2
indirectly obtained
3.1 Seasonality
In temperate climates (as in Europe), RV infection occurs in winter peaks (Koopmans and
Brown, 1999). As some studies measured incidence in such a winter epidemic (and not a full
year), these estimates are likely to overestimate the annual incidence.
3.2 Age
Incidence of symptomatic RV infection is highly age dependent. Symptomatic infection is low

in children aged 0–5 months, peaks in children aged 6–11 months, remains high in children
aged 12–23 months and drops to low levels thereafter (de Zoysa and Feachem, 1985).
Consequently only studies reporting on incidence rates for the same or similar age groups
can be compared. (Studies focusing on children < 2 years of age are likely to report higher
incidences compared to studies on children < 5 years of age.)
3.3 Case Definitions and Study Methodology
Different definitions were used to identify RV related ambulatory care, hospitalizations,

nosocomial infections and deaths. Regarding ambulatory care, it is not clear whether every
study included all possible primary health care available. Some studies report on children with
RVGE visiting general practitioners only, whereas others also include the ones visiting pedia-
tricians. If not all available primary health care is included, the reported incidences of
ambulatory care (> Table 70-2) are likely to be an underestimation. To determine the
incidence of RV related hospitalizations some studies used (national) hospital discharge data
using the ICD-9 code for RVGE, whereas other (often regional) studies used laboratory
confirmed data. Clearly, the former can lead to underestimation of the real disease burden
(Hsu et al., 2005; Riordan and Quigley, 2004), whereas the problem with the latter is that
laboratory confirmation of RV infection is often not standard practice and hence not exhaus-
tive. Moreover, it is not sure to which extent regional data can be generalized to the national
level. As indicated above, variation in methodology for the estimation of nosocomial RV
infection is so large that interpretation and comparison of the estimates is often difficult, if not
impossible (Chandran et al., 2006). Only five countries estimated RV related deaths, despite
the fact that it is the most severe outcome of rotavirus infection, and highly important for
estimating disease burden and evaluating the cost-effectiveness of rotavirus vaccines (Bilcke
et al., 2007; Jit and Edmunds, 2007). Death certificates are not often available, and therefore
RV deaths are sometimes indirectly derived (e.g., proportion of AGE (acute gastroenteritis)
deaths attributable to RV), see > Table 70-5. Different estimation methods can lead to
different annual numbers of RV related deaths, even within a single country (e.g., France,
> Table 70-5). If one were to disregard these differences, take the range of estimates in
> Table 70-5 and multiply it by the 25 million children <5 years in the 27 EU countries
(Eurostat), it translates in a highly speculative estimated range of 12.5–364 children per year,
corresponding roughly to a loss of 875–25500 life years per year. Efforts to document
accurately RV related deaths in EU are therefore necessary.
A last point one should keep in mind when looking at the reported RV disease burden, is
the difference in quality of the studies (e.g., small versus large sample size) and risk of bias.
Although such differences are difficult to quantify, one should be aware of this.
Summary Points
Data on rotavirus disease burden is lacking for about half of the countries of the European
Union. The available data for the other half show differences that do not necessarily reflect
country-specific differences, but that may also be due to differences in study characteristics
and quality. (> Table 70-6).
Based on the available literature, the annual incidence of RV disease in the European
Union ranges from:
0.06–4.15% of the children aged < 5 years seeking ambulatory care.
0–2.65% of the children aged < 5 years visiting emergency departments.
. Table 70-6
Rotavirus disease in Europe: current data
Rotavirus disease in Europe results each year in:

0.06–4.15% of children aged < 5 years seeking ambulatory care
0–2.65% of the children aged < 5 years visiting emergency departments
0.03–1.19% of the children aged < 4/5 years being hospitalized for rotavirus
and 0.5–14 children per million children aged < 3/5 years that die due to RV infection
Information on children experiencing disease but not seeking professional medical care is lacking
Information on nosocomial infections is difficult to interpret and compare
Summary of the available data on rotavirus disease in the 27 countries of Europe. Note that for about half of the
27 countries no information was available
0.03–1.19% of the children aged < 4/5 years being hospitalized for rotavirus.
0.5–14 children per million children aged < 3/5 years that die due to RV infection.
Information on children experiencing disease but not seeking professional medical care
is lacking for the EU.
Studies on nosocomial RV infections are numerous, but difficult (if not impossible) to
interpret and compare, because of very different methodologies and contexts.
References
Bilcke J, Van Damme P, Beutels P. (2008). Med Decis Fourquet F, Desenclos JC, Maurage C, Baron S. (2003).
Making. doi:10.1177/0272989X08324955 Arch Pediatr. 10: 861–868.
Bilcke J, Van Damme P, De Smet F, Hanquet G, Van Fruhwirth M, Heininger U, Ehlken B, Petersen G,
Ranst M, Beutels P. (2008). Eur J Ped 167(12): Laubereau B, Moll-Schuler I, Mutz I, Forster J.
1409–1419. (2001a). Pediatr Infect Dis. J 20: 784–791.
Bilcke J, Beutels P, De Smet F, Hanquet G, Van Ranst M, Fruhwirth M, Karmaus W, Moll-Schuler I, Brosl S,
Van Damme P. (2007). KCE reports vol.54C. Mutz I. (2001b). Arch Dis Child. 84: 393–397.
accessed November 6th 2008 Gil A, Carrasco P, Jimenez R, San-Martin M, Oyaguez I,
Chandran A, Heinzen RR, Santosham M, Siberry GK. Gonzalez A. (2004). Vaccine 22: 2221–2225.
(2006). J Pediatr. 149: 441–447. Glass RI, Parashar UD, Bresee JS, Turcios R, Fischer TK,
Cilla G, Perez-Trallero E, Lopez-Lopategui MC, Gilsetas Widdowson MA, Jiang B, Gentsch JR. (2006).
A, Gomariz M. (2000). Epidemiol Infect. 125: Lancet. 368: 323–332.
677–683. Gleizes O, Desselberger U, Tatochenko V, Rodrigo C,
Crowley DS, Ryan MJ, Wall PG. (1997). Commun Dis Salman N, Mezner Z, Giaquinto C, Grimprel E.
Rep CDR Rev 7: R82–R86. (2006). Pediatr Infect Dis J. 25: S12–S21.
de Wit MA, Koopmans MP, Blij van der JF, van Duynho- Hsu VP, Staat MA, Roberts N, Thieman C, Bernstein DI,
ven YT. (2000). Clin Infect Dis. 31: 698–704. Bresee J, Glass RI, Parashar UD. (2005). Pediatrics.
de Wit MA, Koopmans MP, Kortbeek LM, van Leeuwen 115: 78–82.
NJ, Bartelds AI, van Duynhoven YT. (2001a). Emerg Huet F, Largeron N, Trichard M, Miadi-Fargier H,
Infect Dis. 7: 82–91. Jasso-Mosqueda G. (2007). Vaccine. 25: 6348–6358.
de Wit MA, Koopmans MP, Kortbeek LM, van Leeuwen Jit M, Edmunds WJ. (2007). Vaccine. 25: 3971–3979.
NJ, Vinje J, van Duynhoven YT. (2001b). Clin Infect Jit M, Pebody R, Chen M, Andrews N, Edmunds WJ.
Dis. 33: 280–288. (2007). Hum Vaccin. 3: 23–26.
de Zoysa I, Feachem RG. (1985). Bull World Health Johansen K, Bennet R, Bondesson K, Eriksson M,
Organ 63: 569–583. Hedlund KO, De Verdier Klingenberg K, Uhnoo I,
Dennehy PH. (2007). Vaccine 25: 3137–3141. Svensson L. (1999). Acta Paediatr. 88: 20–23.
Ehlken B, Laubereau B, Karmaus W, Petersen G, Koopmans M, Brown D. (1999). Acta Paediatr. 88: 14–19.
Rohwedder A, Forster J. (2002). Acta Paediatr. 91: Lynch M, O’Halloran F, Whyte D, Fanning S, Cryan B,
769–775. Glass RI. (2001). Pediatr Infect Dis J. 20: 693–698.
Fischer TK. (2001). Acta Paediatr. 90: 1073–1075. Mata L, Simhon A, Urrutia JJ, Kronmal RA, Fernandez R,
Fischer TK, Valentiner-Branth P, Steinsland H, Perch M, Garcia B. (1983). J Infect Dis. 148: 452–461.
Santos G, Aaby P, Molbak K, Sommerfelt H. (2002). Mrukowicz JZ, Krobicka B, Duplaga M, Kowalska-
J Infect Dis. 186: 593–597. Duplaga K, Domanski J, Szajewska H, Kantecki M,
Fischer TK, Nielsen NM, Wohlfahrt J, Paerregaard A. Iwanczak F, Pytrus T. (1999). Acta Paediatr. 88:
(2007). Emerg Infect Dis. 13: 855–859. 53–60.
Floret D, Lina B, Pinchinat S, Billaud G, Ait-Belghiti F, Parashar UD, Hummelman EG, Bresee JS, Miller MA,
Largeron N, Bellemin B, Trang CN, Fau C, Gaspard Glass RI. (2003). Emerg Infect Dis. 9: 565–572.
C, Mamoux V, Marcelon L. (2006). Eur J Pediatr. Parashar UD, Gibson CJ, Bresse JS, Glass RI. (2006).
165: 905–906. Emerg Infect Dis. 12: 304–306.
Foppa IM, Karmaus W, Ehlken B, Fruhwirth M, Piednoir E, Bessaci K, Bureau-Chalot F, Sabouraud P,
Heininger U, Plenge-Bonig A, Forster J. (2006). Brodard V, Andreoletti L, Bajolet O. (2003). J Hosp
Infect Control Hosp Epidemiol. 27: 633–635. Infect. 55: 190–195.
PROTECT. (2006). Epidemiol Infect. 134: 908–916. Van Damme P, Wielen Van der M, Ansaldi F, Desgrand-
Rendi-Wagner P, Kundi M, Mikolasek A, Mutz I, Zwiauer champs D, Domingo JD, Sanchez FG, Gray J,
K, Wiedermann U, Vecsei A, Kollaritsch H. (2006). Haditsch M, Johansen K, Lorgelly P, Lorrot M,
Wien Klin Wochenschr. 118: 280–285. Parez N, Reschke V, Rose M. (2006). Lancet Infect
Riordan FA, Quigley T. (2004). J Infect. 49: 13–16. Dis. 6: 805–812.
Ryan MJ, Ramsay M, Brown D, Gay NJ, Farrington CP, Van Damme P, Giaquinto C, Huet F, Gothefors L, Max-
Wall PG. (1996). J Infect Dis. 174 Suppl 1: S12–S18. well M, Wielen Van der M. (2007). J Infect Dis. 195
Salo H, Ollgren J, Linna M, Sintonen H, Kilpi T. (2007). Suppl 1: S4–S16.
Economic evaluation of rotavirus vaccination in Velazquez FR, Matson DO, Calva JJ, Guerrero L, Morrow
Finland. poster, EUPHA, Helsinki. AL, Carter-Campbell S, Glass RI, Estes MK,
Simhon A, Mata L, Vives M, Rivera L, Vargas S, Ramirez Pickering LK, Ruiz-Palacios GM. (1996). N Engl J
G, Lizano L, Catarinella G, Azofeifa J. (1985). J Med. 335: 1022–1028.
Infect Dis. 152: 1134–1142. Vesikari T, Rautanen T, Von Bonsdorff CH. (1999). Acta
Soriano-Gabarro M, Mrukowicz J, Vesikari T, Verstraeten Paediatr. 88: 24–30.
T. (2006). Pediatr Infect Dis J. 25: S7–S11. Visser LE, Cano Portero R, Gay NJ, Martinez Navarro JF.
Szucs G, Uj M, Mihaly I, Deak J. (1999). Acta Paediatr. (1999). Acta Paediatr. 88: 72–76.
88: 61–65. Zheng BJ, Lo SK, Tam JS, Lo M, Yeung CY, Ng MH.
Tran MN. (2006). Survey of the deaths due to acute (1989). J Clin Microbiol. 27: 2083–2090.
gastro-enteritis avoidable with the rotavirus vaccine,
France, poster, EPIET Scientific Seminar, Menorca.
France, Nov 2004–Mar 2005.
71 The Economic Burden of
Rotavirus Diarrhea: Taiwan
Perspectives
Kow-Tong Chen
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1244
2 Classification and Characterization of Rotavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1245
3 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1245
4 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1246
5 Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1246
6 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1247
7 Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1247
8 Treatment and Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1248
9 Cost of Illness Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1248
10 Rotavirus Disease and Socio-Economic Burden in Taiwan . . . . . . . . . . . . . . . . . . . 1251

10.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1251
10.2 Outpatient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1251
10.2.1 Burden of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1252
10.3 Inpatient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1252
10.3.1 Disease Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1253
10.3.2 Economic Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1254
10.4 Economic Benefits of Rotavirus Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1255
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1259
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1260
Costs Calculated Among Inpatient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1260

1244 71 The Economic Burden of Rotavirus Diarrhea: Taiwan Perspectives
Abstract: Worldwide, rotavirus is the principal cause of diarrheal illness in young children.
Rotavirus > infection causes significant morbidity and mortality, often inflicting emotional
distress and financial burden on the family and the society.
Disease surveillance has revealed that the incidence of rotavirus infections in infants and
young children is similar in both developing and developed countries. Despite so, the burden
of mortality is most pronounced in the poorest countries with limited healthcare access, while
morbidity is of greater significance in the developed countries. Asia’s diverse populations and
economies therefore present a full spectrum of disease burden. The main drivers of rotavirus
burden are direct costs (e.g., hospitalizations) and indirect costs (e.g., loss of productivity).
Indirect costs are substantial in industrialized counties. The estimated annual social and
medical costs due to rotavirus infections in the United States were over US $1 billion
and US $264 million, respectively, demonstrating a clear emphasis of indirect over direct
cost. In contrast, the estimated annual social and hospital costs for rotavirus-associated
admission in Taiwan were US $13.3 million and US $10.4 million, respectively, showing
the equivalence in direct and indirect cost burden.
Although few countries have evaluated its economic impact or considered the potential
> cost effectiveness (CE) of rotavirus > universal mass vaccination (UMV), the magnitude of
rotavirus disease burden is recognized. Rotavirus vaccine could markedly alleviate the ensuing
disease toll on both society and the economy but to maximize its benefits, it will be important
to increase its coverage.
List of Abbreviations: AGE, > acute gastroenteritis; ARSN, > Asian Rotavirus Surveillance
Network; BNHI, Bureau of National Health Insurance; CE, cost effectiveness; COI,
cost-of-illness; GAVI, > global alliance for vaccine and immunization; ICD-9 CM codes,
International Classification of Disease, ninth edition, Clinical Modification Code (ICD-9
CM Code); LOS, > length of stay; OPD, out-patient department; ORT, > oral rehydration
therapy; RT-PCR, reverse transcription-polymerase chain reaction; SH, > sentinel hospital;
UMV, universal mass vaccination; WHO, World Health Organization
1 Introduction
Rotavirus is the most common cause of severe gastroenteritis and dehydration in young
children in both industrialized and developing countries. A World Health Organization
sponsored review of rotavirus studies found that 20–70% of all hospitalizations and 20% of
deaths from diarrhea were attributable to rotavirus (de Zoysa and Feachem, 1985). Rotavirus
infects all children in early life and although most first infections cause mild diarrhea, 15–20%
need treatment at a clinic, and 1–3% lead to dehydration needing hospitalization (Cook et al.,
1990). The virus can be identified in 15–35% of children younger than 5 years treated in
outpatient settings for diarrhea and in 25–55% of those hospitalized (Jain et al., 2001). About
600,000 children die every year from rotavirus, mainly in developing countries, and this figure
represents about 5% of all deaths in children younger than 5 years (Parashar et al., 2006).
Mortality is great in south Asia and sub-Saharan Africa, about 1 in 200 children borne in these
regions will die of rotavirus (Jain et al., 2001). Although most studies of rotavirus deaths
have extrapolated numbers from global rates of diarrheal deaths, several investigators have
specifically assessed risk factors, and pathological findings of the deceased clearly established
rotavirus to be an important causative agent (Lynch et al., 2003).
The Economic Burden of Rotavirus Diarrhea: Taiwan Perspectives 71 1245
Cost-of illness studies are a subset of studies measuring disease burden, years of life
lost and money cost (Bloom et al., 2001). Patient, and family, providers, payers, and society
perspectives have been used to estimate the economic burden of a disease. Cost estimated
have been defined for national population or selected samples, and have estimated patient
direct (e.g., medical cost) and indirect (e.g., loss of productivity) costs. In this chapter,
we used the data on the economics of rotavirus gastroenteritis in Taiwan to illustrate the
direct cost of health care services for rotavirus diarrhea, as well as indirect costs to the
individual patient.
2 Classification and Characterization of Rotavirus
Rotaviruses are members of the family Reoviridae. These viruses causing acute gastroenteritis
were recognized as a collective pathogen affecting humans and animals world-wide (Flewett
and Woode, 1978). In 1974, Thomas Henry Flewett suggested the name rotavirus after
observing that, viewed through an electron microscope, a rotavirus particle looks like a
wheel (rota in Latin) (Flewett and Woode, 1978). Rotaviruses occur in five groups (serogroups
A-E) but only groups A-C infect human and of multiple serotypes within each group. Group A
is by far the most common with sporadic episodes due to group C, group B is limited largely to
China. Rotavirus is characterized by the presence of 11 segments of double-stranded RNA
surrounded by three shells (an outer capsid, inner capsid, and core) (Estes, 2001). Strains are
routinely typed by their two outer capsid protein that elicit neutralizing antibodies and
determine serotype, the VP7, a glycoprotein or G protein and VP4, a protease-cleaved protein
(P-protein). The G- and P-protein form the basis for a dual typing system (e.g., P[8], G3), with
G serotypes often determined by enzyme immunoassay and the P genotype by reverse
transcription-polymerase chain reaction (RT-PCR). Only five strains are commonly detected
(P[8], G1; P[4], G2; P[8], G3; P[8], G4; and P[8], G9) (Gentsch et al., 2005).
Reassortment is a process by which cells infected with two viruses can yield mixed progeny
with gene segments derived from each parent strain – has been used in the laboratory
to develop new > vaccine (Greenberg et al., 1981). Animal strains from monkeys (rhesus
RRV) (Kapikian et al., 1996), cows (Clark et al., 1996; Clements-Mann et al., 1999) and lambs
(Kapikian et al., 2001) that are naturally attenuated for human beings have been cultured with
human strains to yields reassortants. The selected progeny viruses contain ten genes from the
animal strain, which maintain the property of attenuation, and one gene encoding the outer
capsid proteins, representing the common human serotypes.
3 Epidemiology
Rotavirus infection is a single most important cause of diarrheal illness in young children in
both industrialized and developing countries. Rotavirus infects all children in early life and
although most first infections cause mild diarrhea, 15–20% need treatment at a clinic, and
1–3% lead to dehydration needing hospitalization (Cook et al., 1990). The virus can be
identified in 15–35% of children younger than 5 years treated in outpatient settings for
diarrhea and in 25–55% of those hospitalized (Kosek et al., 2003). A previous report estimated
globally that about 110 million episodes of gastroenteritis require home care, 25 million
require clinic visits, 2 million require hospitalizations, and 352,000–592,000 (median 440,000)
deaths of children <5 years of age annually attributed to rotavirus (Parashar et al., 2006).
Mortality is great in south Asia and sub-Saharan Africa, with more than 100,000 deaths
every year occurring in India alone (Jain et al., 2001). Although the estimated number of
deaths from diarrhea has fallen strikingly over the past two decades as a result of improved
treatment with oral rehydration therapy (ORT) and sanitation and water interventions, the
number of deaths from rotavirus has not decreased as much (Kosek et al., 2003). Acute
gastroenteritis (AGE) caused by rotavirus infection in children can significantly impact
their families and society and result in increased medical expenditures, lost productivity,
childcare and pain and suffering.
The rotavirus infection financial burden is various among different countries. For
example, annual cost of rotavirus disease in Hong Kong (Chan et al., 1998), Sweden (Johansen
et al., 1999), USA (Tucker et al., 1998) is US$ 1.2 million, US$ 1.8–2 million, and
US $1 billion, respectively.
4 Clinical Features
Rotavirus infection is a sporadic, seasonal, often severe gastroenteritis of infants and

young children. The clinical spectrum of rotavirus infection can last 2–7 days. The clinical
presentations vary from subclinical infection to mild diarrhea and severe illness. The ratio of
symptomatic and asymptomatic cases are 4 to 1 (Velazquez et al., 1993). The clinical pictures
of rotavirus infection are characterized by vomiting, fever and a profuse watery diarrhea
with loss of fluid and electrolytes. Aggressive rehydration with oral or intravenous fluids can
correct these imbalances and sustain a child until the diarrhea stops. Rotavirus infection has
occasionally been found in pediatric patients with a variety of other clinical manifestations,
but the virus is probably coincidental rather than causative in theses conditions (David, 2004).
Newborn babies can be infected in the nursery, but these infections are often asymptomatic,
perhaps because of the protective effect of circulating maternal antibodies (Kilgore et al.,
1996). However, first infection in children 3–24 months of age most often lead to vomiting,
then watery diarrhea that is sometimes accompanied by fever.
5 Transmission
Rotavirus is transmitted by the fecal-oral route. A small infectious dose (<100 virus particles)
facilitates spread from person to person or possibly via airborne droplets (Kapikian et al.,
2001). Given rotavirus shedding at a level of 109 per ml, as little as 0.1ml of stool contamination
could contain an infectious dose. Such tiny quantities are invisible and easily retained on skin.
Although hand washing is effective as a disinfectant in the case of rotavirus (Estes et al., 1979),
infections are easily transmitted from person to person either directly or via contamination of
objects and surfaces. Vomit is also a significant route for transmission; 30 million particles may
be shed by vomiting and rotavirus may survive for up to 9 days in the air (Caul, 1994).
Proximity to vomit at the time of vomiting may be a route of exposure.
Person-to-person transmission is favored by closed setting such as hospitals, care homes.
Once rotavirus has been introduced within those settings, rotavirus is to be spread. Rotavirus
is a major cause of > nosocomial diarrhea of newborns and infants (Rodrigues et al., 2007).
In industrialized countries, nosocomially acquired rotavirus affected approximately the same
number of children as community-acquired illness (Berner et al., 1999). The risk of infants
acquiring a nosocomial rotavirus infection is constant throughout the hospital course, an
average of 0.01 episode per day (Cone et al., 1988). Increasing time in the hospital is directly
related to the constant risk of nosocomial rotavirus infection.
Most (70%) immunocompetent children experiencing primary infection are reported to
cease shedding rotavirus within 20 days of the onset of symptoms and some (30%) of them
may have detectable virus for more than 25 days (Richardson et al., 1998).
6 Pathogenesis
Rotavirus infects the mature absorptive enterocytes in the proximal two thirds of the ileum,
and is thought to cause diarrhea by several mechanisms. Once ingested, rotavirus not
neutralized by stomach acid attaches to the proximal small intestine. During the incubation
period of 18–36 h, the virus enters epithelial cells where it first elaborates a potent enterotoxin.
Enterotoxin is a non-structural protein (NSP4) which is elaborated in epithelial cells. It is
thought that the enterotoxin triggers an intracellular Caþþ- dependent signaling pathway,
which leads to an increased membrane permeability to electrolyte. And then goes on after
18–36 h to destroy the mature villus enterocytes of the small intestine with subsequent
sloughing of the villus epithelium and proliferation of the secretory crypt cells, results in
reduced absorptive capacity of the gut, leading to fluid and electrolyte loss into lumen.
Epithelial dysfunction also leads expression of certain digestive enzymes such as sucrase
and isomaltase, and the osmotic pull of accumulated sugar in the small intestine further
exacerbates fluid loss. In addition, destroy the mature villus enterocyte of the small intestine
and crypt hyperplasia, extensive damage, and shedding of massive quantities of virus
(1012 particles per gram) in stools are noted (Ball et al., 1996). Secondary transient disacchar-
ides deficiency, and inflammation in the lamina propria are observed. Lastly, rotavirus seems
to activate the secretomotor neuron of enteric nervous system that stimulate secretion of fluid
and solutes, an effect recently found to be mediated via vasoactive intestinal peptide (Kordasti
et al., 2004). Rotavirus infection has been thought to be localized exclusively in the small
intestine, but several findings have demonstrated that rotavirus can be detected in the blood
(Blutt et al., 2003), organ (Pang et al., 1996), and cerebrospinal fluid (Lynch et al., 2001),
although the clinical implications of these findings remain unclear.
7 Immunity
The mechanisms responsible for immunity to rotavirus infection and illness are not completely
understood. It was observed that first infections after the neonatal period were generally
symptomatic, few children had severe or moderately severe disease on re-infection, and repeat
disease was uncommon after the second infection (Velazquez et al., 1996). These findings
provide the scientific rationale to judge that this protective immunity could be induced by live
oral vaccine. Local immunity in the gut seems critical but it is hard to measure and is of short
duration. Therefore, circulating immunoglobulin A antibodies have been used as the best proxy
for vaccine takes (Grimwood et al., 1988). However, vaccines that have been very marginally
immunogenic have nonetheless been very efficacious in field trials, so large clinical trails have
become the only secure means to ensure the effectiveness of a vaccine (Jiang et al., 2002).
Studies in monkeys suggest that the passive transfer of circulating antibodies can
confer protection against infection, a finding that provides the scientific basis for considering
the future use of parenteral vaccine (Westerman et al., 2005). Waning immunity leaves
elderly people susceptible to rotavirus infections and outbreaks have occurred in nursing
homes and hospitals.
8 Treatment and Prevention
The primary aim of treatment of rotaviral gastroenteritis is to replace fluids and electrolytes
lost by vomiting and diarrhea (Sazawal et al., 1991). Most cases are readily managed with oral
rehydration treatment, but clear liquid and hypocaloric (dilute formula) diets for more that
48 h are not advisable in uncomplicated viral gastroenteritis, because starvation depresses
digestive function and prolong the diarrhea. Some 1–2% of children admitted with rotavirus
infection present with shock and peripheral cyanosis. The patient in fluid and electrolyte loss
and incorrect with oral rehydration, or the patient in severely dehydrated, or in shock,
intravenous fluids must be given immediately. A handful of reports exist of cases whose
cerebrospinal fluid contained rotavirus particles during acute illness.
Despite marked improvement in water quality, sanitation, and hygiene, the fact that the
incidence of rotavirus diarrhea has not decreased substantially during the past decade suggests
that immunization may be the most promising prevention strategy (Ehreth, 2003). Vaccines
currently under development have the potential to reduce morbidity and mortality due to
rotavirus infection (Vesikari et al., 2006, 2007). Vaccine was identified as the best method for
rotavirus prevention in the 1980s, and development of effective rotavirus vaccines has
continued to be listed as a high priority for the World Health Organization (WHO) and the
Global Alliance for Vaccine and Immunization (GAVI) (World Health Organization, 2000).
Two vaccines from GlaxoSmithKline (Rotarix) and Merck (RotaTeq) have been licensed in
several countries (Glass et al., 2006). Rotarix is derived from a single serotype G1 human
rotavirus strain attenuated by multiple passages in cell culture. Like natural infection in
children, Rotarix appears to induce cross-protection against G9 strains; this finding suggests
that Rotarix will be suitable against a range of the common serotypes (Vesikari et al., 2007).
Vaccines derived from animal strain of simian (RotaShield) or bovine (RotaTeq) origin appear
to require a combination of reassortant strains to ensure adequate protection against the
common serotypes (Berstein et al., 1995). RotaTeg is an oral, live pentavalent (G1, G2, G3, G4,
and P[8]) human-bovine (WC3) reassortant rotavirus vaccine. Both Rotarix and RotaTeg are
administrated as an oral liquid in buffer as two dose (Rotarix) or three doses (RotaTeg) to
babies, with the first dose given at 6–14 weeks of age.
9 Cost of Illness Analysis
Rotavirus infections in children generates a variety of costs for the health care system, families
of those infected, and society as a whole, including increased medical expenditures, other costs
to households for care of children, lost productivity, and pain and suffering caused to children
and their families. In an era of scarce public resource, policymakers have become increasing
interested in justifying regulatory and expenditure decisions in term of dollar-valued costs and
benefits. Economic logic is based on the notion of scarcity, according to which needs outstrip
resources. As resources are scarce it is necessary to make choice not just on which needs should
be met and which should not be, but also on assessing up to which point several different
needs should be met. In developing countries, as healthcare uses resources which are then no
longer available for food and house. In developed countries, they have more resources, but also
have increasing higher offer of new technologies which can not be all simultaneous acquired.
Public health analysts have responded to this emphasis by producing estimates of the dollar
costs of morbidity and mortality associated with various illnesses (Ernst and Hay, 1994; Rice
et al., 1992; Weiss et al., 1992).
> Cost-of-illness (COI) studies are a type of economic study common in the medical
literature, particular in specialist clinical journal. The aim of a COI is to evaluate the economic
burden illness impose on society as a whole in terms of the consumption of health care
resources and production losses. The implicit assumption was that the economic costs of
illness represented the economic benefits of a health care intervention had it eradicated the
illness (Tarricone, 2006). COI studies have been widely debated and its usefulness as a
decision-making tool has been questioned by many health economists. Nevertheless, COIs
are among the commonest economic studies in healthcare, and it is widely believed that
estimating the total social cost of an illness is useful aid to policy decision making (Bloom
et al., 2001).
All methods of economic evaluation value both input and consequences following the
same three-stop road: identify input and consequences; measure input and consequences
using appropriate physical units; valuate input and consequences. Problems are encountered
in all three phases. Some items are difficult to identify as some healthcare interventions have
hidden or unknown costs and consequences. Not all costs and consequences can be measured
in appropriate physical units as some interventions have intangible consequences such as
reduction of pain. Other programs use inputs which are equally difficult to quantify such
as hi-tech Know-how. COI studies can be described according to the epidemiological data
used (prevalence vs. incidence approach), methods chosen to estimate the economic costs
(top-down vs. bottom-up), the temporal relation between the initiation of the study and
data collection (retrospective vs. prospective studies) (Koopmanschap, 1998; Rice, 1994;
Tarricone, 2006).
Prevalence versus incidence approach: it is required the clear description of a prevalence-
or incidence-based approach to measuring resource use, cost and time frame. If the results are
to be used for cost control, prevalence-based costing is appropriate; this method identifies
the main components of current expenditures and forgone resource and identifies possible
targets for economy. If the analysis is aimed at making decisions about which treatment or
research strategy to implement, the incidence-based approach is more appropriate because
it provides the basis for predictions about the likely saving from programs that reduce
incidence or outcomes.
Top-down versus bottom-up method: the method for capturing resource use should
be described. The bottom-up strategy is evaluated on the basis of the populations used
and the samples and sources of specific services used for estimates. In the bottom-up
approach, the estimation of costs can be to estimate the quantity of health inputs used and
to estimate the unit costs of the inputs used. The costs are then estimated by multiplying unit
costs by the quantities. The advantage of bottom-up is the data collected from study subjects
which provide more reliable data. The disadvantage is the data needed and available will vary
with the scope of the study. The top-down strategy of aggregating population sample data
is examined for data completeness and sources for mortality, morbidity, hospitalizations,
ambulatory visits, pharmaceuticals and the like. The advantages of top-down are one can
avoid the risk that the sum of treatment of individual diseases, but are likely to present
misallocation of costs. The disadvantage of top-down is to underestimate or over-estimate
total direct costs and the exclusion of cost categories that are not included in national health
care expenditures (e.g., transportations).
Retrospective versus prospective studies: In retrospective COI studies, all the relevant
events have already occurred when the study is initiated. Conversely, in prospective COI
studies the relevant events have not already occurred when the study is initiated. The major
advantage of retrospective COI is that they are less expensive and time consuming that those
performed prospectively. However, retrospective COIs can only be carried out when sufficient
data are available. The appropriate method for measuring the dollar value of lives lost owing to
morbidity and mortality has been the subject of much controversy. The approach adopted
depends on the purpose of the analysis.
COI is estimated by identifying the cost-generating components and by attributing a
monetary value to them. The monetary value is the opportunity cost, the value of the forgone
opportunity to use in a different way those resources that are used or lost due to illness. COI
studies are typically divided into two main categories: core cost which resulting directly from
the illness and other related cost including non-health costs of illness. Within each category,
there are direct costs (for which payments are made) and indirect costs (for which resources
are lost) (Rice, 1994). Direct costs are generally estimated as product of two components:
number of services and unit price or charges. Indirect costs include morbidity and mortality
costs. Morbidity costs are the value of reduced or lost productivity due to the disease.
Mortality costs are the product of the number of deaths from the disease and the expected
value of an individual’s future earnings with gender and age taken into account.
COI analysis is different from any other economic evaluation analysis because it basically
does not compare costs with outcome. The main objectives are (Ernst and Hay, 1994; Rice,
1994; Tarricone, 2006): (1) To assess the economic burden of illness to society. This would give
information about the amount of scarce resources consumed because of illness and, along with
epidemiological data on morbidity and mortality may help ranking diseases according
to global burden. (2) To identify the main cost components and their incidence over total
costs. This would help health policy maker defining and/or limiting. (3) To identify the
actual clinical management of illness at a national level. This would help policy makers and
mangers to analyze the production function used to combine inputs and/or intermediate
services to deliver the final output that could range from a single product, such as hospitaliza-
tion to an entire therapeutic pattern which encompasses multiple medical services. Inefficient
and/or ineffective functions can then be put forward and may represent the base for the
re-engineering of the whole process in case of inefficiencies, and for the reassessment of
the clinical strategy as it happens for the evidence-based medicine. Clinical guidelines may
for instance be one of the final products in this case, that is whenever the identification of the
clinical management of illness is judged ineffective or too diverse in the same country. (4) To
explain the variability of costs. In this case, statistical analysis can be performed to check
whether there is a relationship between costs variability and variables, such as those related the
illness (e.g., severity), to the patient (e.g., demographic variables) or to the health care
providers (e.g., teaching hospitals versus district hospitals).
Estimating the burden of specific diseases by means of COI studies is done frequently.
However, the usefulness of COI studies has been disputed repeatedly. Some authors
argue that this type of study does not deliver relevant information for healthcare policy
(Shiell et al., 1987), while others are more optimistic (Hodgson, 1989). However, these results
would help managers to feed the planning process with more accurate information as to the
future provision of service, since knowing the cost drivers that explain – at least partially – the
consumption patterns of services can be very useful when planning the provision of health care
services.
Socioeconomic studies have their limitations and caution must be exercised in their
interpretation. The cost per unit of service as well as the value of resources used in the
treatment of diarrhea is often hard to quantify with sufficient accuracy. Calculating the cost
of an illness requires information on all major direct expenditures as well as indirect costs.
In industrialized countries, mortality due to intestinal infections is minimal; as a result, the
decision to introduce rotavirus vaccines will be based on its ability to reduce morbidity and
health care costs associated with rotavirus infection. As effective rotavirus vaccines become
available, policy makers will have to make decisions regarding the relative cost and benefit of
vaccination, in addition to considering its clinical effectiveness. In doing so, they must
systematically consider the economic burden of disease, the impact of vaccination on health
and economic outcomes and the net cost of vaccination and compare the costs of vaccination
to health benefits.
10 Rotavirus Disease and Socio-Economic Burden in Taiwan
10.1 Background
Taiwan government-run national health insurance program, in which enrollment is manda-

tory, was implemented in 1995. By 1999, approximately 96% of Taiwan’s population was
covered by the program (Bureau of National Health Insurance, 2006). The national health
insurance program provides comprehensive coverage, including inpatient care, ambulatory
care, laboratory tests, prescription drugs, and certain nonprescription drugs, dental services,
traditional Chinese medicine, and certain preventive services. A co-payment is required for
ambulatory care, inpatient care, and pharmaceuticals. However, services for catastrophic
diseases, child birth, and preventive health care as well as medical services are offered in
specific mountain areas or on offshore islands for low-income households and veterans who
are exempt from the co-payment. The Bureau of National Health Insurance (BNHI) in Taiwan
maintains an extensive database on all inpatient and outpatient visits, including their medical
diagnoses and medical expenditure.
10.2 Outpatient
Lu et al. (2006) extracted the medical and administrative records of all pediatric
patients <5 years old with the principle diagnosis of acute gastroenteritis (AGE) who were
seen in the outpatient department (including emergency rooms) of three study hospitals in
Taiwan between March 2001 and February 2002. Only those whose stool specimens were
tested for both rotaviral antigen by monoclonal antibody incorporated enzyme-linked immu-
nosorbent assay according to manufacture’s instructions (Rotaclone, Meridian Diagnostic,
Cincinnati, OH, USA) and bacterial agents by culture were taken into account. The total
number of rotavirus infection was estimated by multiplying the total number of AGE cases in
<5 years old children form the Bureau of Taiwan National Health Insurance (BNHI) database
and the percentages of laboratory confirmed rotavirus infections. The medial care expenses
reimbursed by BNHI associated with each visits for these patients were extracted from the
Bureau of Taiwan National Health Insurance database according to ICD-9 CM codes. The co-
payment data (US $1.5–3.0 for outpatient) were included in medical cost estimation. Nation-
wide total medical cost attributable to rotavirus infection in 2001 were estimated by multi-
plying the average BNHI reimbursement per AGE patient with estimated annual case numbers
of rotavirus infections. The monetary values in New Taiwan dollars (NT$) were converted into
United States dollars (US$) based on the average exchange rate in 2001.
10.2.1 Burden of Disease
It was estimated the positive rate of rotavirus infection was 15–35% of AGE outpatient
in <5 year old children; an estimated 255,600–596,400 episodes of rotavirus infections
in children <5 years old sought outpatient medical care in 2001 in Taiwan. The esti-
mated medical expenses due to rotavirus infection in children <5 years old were
US $2.8–6.4 million (US $10.8 255,600–596,400) for outpatients in 2001 in Taiwan.
Costs estimated in this study are only direct medical costs for outpatient care but indirect
costs are not counted.
10.3 Inpatient
For creating awareness of rotavirus disease burden and assess the potential value of rotavirus
vaccines currently under development, data on the disease burden associated with rotavirus
infection in Taiwan were estimated from sentinel hospital surveillance data (Chen et al., 2005).
Sentinel hospital (SH) surveillance was established at four hospitals in the Northern (National
Taiwan University Hospital, Taipei, Veteran General Hospital, Taipei), Central (Veteran
General Hospital, Taichung), and Southern (Veteran General Hospital, Kaohsiung) regions
of Taiwan during the period of April 1, 2001 to March 31, 2003 among patients less than
5 years of age who were hospitalized for diarrhea. Children were enrolled who had either
gastroenteritis defined by vomiting and/or diarrhea or diarrhea alone defined as the passing
of two or more liquid or semi-liquid stools or based upon the clinical history provided by
the mother.
The economic burden study data were collected at the same four sentinel hospitals.
Information of the cost related to each child’s diarrhea episode was obtained from the
families, and families were given a symptom diary to complete during the 10 days after
recruitment (while the child is hospitalized or after discharge). The families were encouraged
to return the diary in a prestamped, preaddressed envelop after 10 days. Information recorded
in the symptom diary included the length of stay (LOS), visit to other health care providers,
extra travel costs, cost of additional diapers used, other miscellaneous costs (e.g., food
supplements of nonprescription remedies), time off work required by family members as
result of the child illness, and the respective estimated hourly, daily, weekly, or monthly salary
lost. The families were telephoned 5 days after the date of admission if the child had been
discharged from hospital and again 10 days after admission. During these phone calls,
the details of the various costs were recorded together with other information related to the
child’s illness. If the child still had diarrhea after the day-10 contact, an additional contact was
made 5 days later (Chen et al., 2007).
The cost analysis incorporated both monetary time costs whenever applicable. Rotavirus
diarrhea-related costs include direct expenditures for medical care and medical costs. In this
study, the direct expenditures for medical care included costs and charges (as proxy for cost)
for hospitalization, outpatient services and medications. Information on drugs indirectly
related to rotavirus diarrhea such as treatment for candidiasis was difficult to obtain and
not taken into consideration. Indirect costs arising from morbidity and mortality included the
value of time lost from work by caretakers.
The flow chart of estimated costs is shown in > Figure 71-1. Costs were estimated from
two perspectives – social costs (total medical direct costs þ total indirect costs) and private
costs (total indirect costs þ total family expenditure). Each of these aforementioned costs
was calculated as Appendix. Cost data are presented as total and mean (SD), unless otherwise
specified. The costs were calculated for the following etiological groups: only rotavirus
positive, only bacteria positive, both rotavirus and bacteria positive, and any cause. All costs
are expressed in 2002 US dollars.
10.3.1 Disease Burden
During the 2-year study period, 2,702 children hospitalized for diarrhea were invited to
participate in the study, and of these, 2,600 (96.2%) families provided the complete symptom
diary (1,498 during the first year and 1,102 during the second year). The major signs
and symptoms shown by hospitalized were diarrhea (94%), fever (63%), vomiting (58%),
dehydration (51%). Compared with patients with nonrotavirus diarrhea, patients with rota-
virus diarrhea were more likely to experience vomiting and dehydration, but less likely to have
bloody stools and they experienced the same mean duration of hospitalization (> Table 71-1).
We plotted the total number of hospital admission each month for gastroenteritis due to all
cases and for gastroenteritis due to rotavirus infection (> Figure 71-2). Rotavirus-related
hospital admissions occurred year-round, but the largely monthly variability in rates. We
plotted the cumulative distribution of cases of rotavirus diarrhea by age (> Figure 71-3).
Rotavirus-related hospitalizations were uncommon during the first 3 months of life,; 35% of
children were hospitalized by age 1 year, and 60% of cases of rotavirus diarrhea occurred in
children <2 years old. Overall, rotavirus was detected in 43% (1,113/2,600) of the tested
specimens, 11% (282/2,600) of specimens were positive for bacteria, and 2.5% (63/2,600) were
positive for enteric adenoviruses (> Table 71-2).
Of the 1,113 rotavirus-positive specimens, 1,015 were positive for rotavirus only, 80 were
positive for both rotavirus and bacteria, and 18 were positive for rotavirus and adenovirus. Of
the 202 specimens positive for bacteria and negative for rotavirus, 200 were positive for
bacteria only, two were positive for bacteria and adenovirus. Thirty-nine specimens were
positive for adenovirus only. No enteric pathogens were detected in 1,246 (48%) patients.
Rotavirus was detected year-round. Rotavirus disease was most common among children
7–23 month old. The estimated burden of rotavirus disease-associated hospitalization in this
study appears similar to Japan (6.6%) (Nakagomi et al., 2005). The most common rotavirus
strain present was P[8]G9 strain (37% of strains), followed by P[8]G1 (31%), P[4]G2
(10%), P[9]G3 (9.3%), and P[8]G4 (3.7%). In addition, 9.3.% of strains were nontypable
(> Table 71-3).
. Figure 71-1
Flow chart of cost estimated (From Chen et al. (2007) with permission)
10.3.2 Economic Burden
Costs were calculated for the different etiological groups: only rotavirus positive (n = 1,015),
only bacteria positive (n = 202), rotavirus- and bacteria- positive (n = 80), and any cause
(n = 2,600). > Table 71-4 illustrates the total cost of hospitalization among the 2,600 children.
The estimated total burden of medical care between April 2001 and March 2003 represents US
$686,750, $195,352, $77,929 and $1,699,399 among children with only rotavirus positive, only
bacteria positive, rotavirus- and bacteria-positive, and any cause, respectively. Of these, 45%
were caused by rotavirus-associated diarrhea and 16% by bacteria-associated diarrhea. Further
US $188,057, $52,215, $20,886 and $470,774 represents the indirect costs among children
with only rotavirus positive, only bacteria positive, rotavirus- and bacteria- positive, and any
cause, respectively. Thus, up to 45% (US $973,620) can be considered the total burden of
rotavirus-associated diarrhea in the study population.
> Table 71-5 provides a breakdown for costs at the single patient level. The estimated
single burden of medical care in hospitalized children between April 2001 and March 2003 is
US $676 (381), $967 (543), $975 (549) and $653 (367) among children with only rotavirus
positive, only bacteria positive, rotavirus- and bacteria-positive, and any cause, respectively.
Further, US $185 (145), $258 (202), $261 (205) and $181 (141) represents the indirect costs in
a child with only rotavirus positive, only bacteria positive, rotavirus- and bacteria-positive,
and any cause, respectively. For patients with positive rotavirus test results, the mean (SD)
total social cost of a rotavirus-associated hospital admission was US $861 (484) derived from
the mean (SD) total direct cost of US $676 (381) and the mean (SD) total indirect cost of US
$185 (145). The mean (SD) total SH cost was US $569 (320) and the mean total family
expenditure was US $294 (181). Thus, up to 43% (US $294) was paid by the family. This cost
represents ~40% of the monthly salary (US $720/month) of an unskilled or service worker,
. Table 71-1
Demographic characteristics, clinical symptoms, and hospital of admission for 2,600 children
<5 years old with diarrhea in Taiwan, 1 April 2001 through 31 March 2003
Patients with rotavirus Patients with rotavirus

positive diarrhea negative diarrhea Total
Variable (n = 113) (n = 1,487) (n = 2,600)
Demographic characteristics
Age, mean (SD), months 23.0 (15) 20.2 (15) 21.4 (15)
Male sex 671 (60) 885 (60) 1,556 (60)
Clinical symptom
Fever 713 (64) 934 (63) 1,647 (63)
Vomiting* 805 (72) 701 (47) 1,506 (58)
Diarrhea 1,046 (94) 1,407 (95) 2,453 (94)
Bloody stool* 191 (17) 410 (28) 601 (23)
Dehydration* 613 (55) 713 (48) 1,326 (51)
Seizure 30 (2.7) 38 (2.6) 68 (2.6)
Region, hospital of admission, city
Northern
National Taiwan University 204 (18) 348 (23) 552 (21)
Hospital, Taipei
National Veteran General 302 (27) 380 (26) 682 (26)
Hospital, Taipei
Central, National Veteran 289 (26) 411 (28) 700 (27)
General Hospital, Taichung
Southern, National Veteran 318 (29) 348 (23) 666 (26)
General Hospital, Kaohsiung
Note: Data are no (%) of children, except where noted. *P < 0.01 by Chi-square test (From Chen et al. (2005) with
permission)
and the cost represents 5.9% of the gross national income of $11,517 per capita. It should be
emphasized that the present study has only assessed costs of episodes of rotavirus diarrhea that
require hospital admission and does not include costs associated with diarrhea episodes for
both outpatients and children cared for in the home.
10.4 Economic Benefits of Rotavirus Vaccination
Observations of the natural history of rotavirus infection noted that a child’s first infection
with rotavirus occurs in life, is usually the most clinically severe, and results in immunity
against subsequent illness. Perspective studies subsequently showed that this protective
immunity against severe disease is boosted by subsequent infections. Therefore, the adminis-
tration of an attenuated rotavirus strain early in life will mimic the initial natural infection and
induce immunity. In Taiwan, routine immunizations of children are government funded
through a system of public health centers. Only a small percentage of children receive their
. Figure 71-2
Children with diarrhea admitted to the hospital in Taiwan, by month, April 2001 through March
2003. The number of children with rotavirus diarrhea is shown (From Chen et al. (2005) with
permission)
. Figure 71-3
Children with acute gastroenteritis admitted to the hospital in Taiwan, by age, April 2001
through March 2003 (From Chen et al. (2005) with permission)
. Table 71-2
Pathogens isolated from children <5 years old with gastroenteritis admitted to hospital in
Taiwan, 1 April 2001 through 31 March 2003
Pathogens Number (%) of children (n = 2,600)

Rotavirus 1,113 (43)
Bacteria 282 (11)
Adenovirus 63 (2.5)
Non-pathogen identified 1,246 (47.9)
Note: Among children with mixed infections, 76 were infected with rotavirus and bacteria; 18 were infected with
rotavirus and adenovirus; two were infected with bacteria and adenovirus; and four were infected with rotavirus,
adenovirus, and bacteria (From Chen et al. (2005) with permission)
. Table 71-3
Rotavirus strains isolated from children <5 years old with diarrhea admitted to hospital in
Taiwan, 1 April 2001 through 31 March 2003
Strain Number (%) of children (n = 300)

P[8]G1 92 (31)
P[4]G2 31 (10)
P[8]G3 28 (9.3)
P[8]G4 11 (3.7)
P[8]G9 110 (37)
Untypable 28 (9.3)
From Chen et al. (2005) with permission
routine vaccinations privately. The rationale for vaccination mainly from the social health
perspective is that, if the social health cost could be shown to be substantial, there would be
a greater likelihood that the government would consider introducing a rotavirus vaccine into
the routine immunization schedule in the future. However, by documenting costs incurred by
the family during their child’s illness (i.e., the total family expenditure), we are also able to
provide some indication of the additional costs incurred by families with children infected by
rotavirus who use the highly subsidized National Health Insurance system (NHI) system.
According to the data from the NHI system, between April 2001 and March 2003, there
were 84,219 children, aged <15 years, were hospitalized with diarrhea. Of these, 3,052 were
hospitalized in the four sentinel hospitals in this study. We estimated that during the
24-month period from 1 April 2001 through 31 March 2003, 85% (2,600/3,052) of all general
pediatric admissions were associated with diarrhea due to any cause by the age of 5 and the
cumulative risk of hospitalization was 71,586 (84,219 85%) children. The annual number
of pediatric admissions (<5 years old) to hospitals due to rotavirus infection during this
24-month period was 30,782 (71,586 43%) admissions (15,391 admissions over a 12-month
period). Under this assumption, it is estimated that for the direct cost, the annual cost related
to rotavirus diarrhea was US $2.8–6.4 million for outpatients and US $10.4 million (total
direct cost, US $676 15,391) for admission. The corresponding estimates of the annual
. Table 71-4
Total social and private costs of rotavirus, bacteria, any-cause diarrhea, and hospital admission
for 2,600 children <5 years old with diarrhea in Taiwan, 1 April 2001 through 31 March 2003
Only R (+) Only B (+) R and B (+) Any cause

Cost variables (n = 1,015) (n = 202) (n = 80) (n = 2,600)
Direct costsa 686,750 195,352 77,929 1,699,399
Inpatient cost 364,106 107,118 42,847 890,333
Outpatient cost 23,325 4,596 1,838 59,748
Total family expenditureb 299,319 83,638 33,244 749,314
Family cost paid to SH 190,298 53,368 21,136 476,394
Total other family costsc 109,021 30,270 12,108 272,920
Indirect costs 188,057 52,215 20,886 470,774
Caregiver’s time costs 188,057 52,215 20,886 470,774
Total social costd 874,807 247,567 98,813 2,170,169
Total private coste 487,376 135,853 54,130 1,220,088
f
Total SH cost 577,729 165,082 65,821 1,426,475
Data are total costs in US dollars. One US dollar equals 35.0 new Taiwan dollars. R rotavirus; B bacteria (From Chen
et al. (2007) with permission)
a
Inpatient cost þ outpatient cost þ total family expenditure
b
Family SH cost þ total other family costs
c
Total costs of co-pay for other health care providers paid by family, travel costs, such as diapers and medications
d
Total direct cost þ total indirect cost
e
Total family expenditure þ caregiver’s time costs
f
Total inpatient cost þ total outpatient cost þ total family SH cost of co-payment
social cost and the annual family expenditure are US $13.3 million (US $861 15,391) and
US $4.5 million (US $294 15,391) for admission, respectively. If a rotavirus vaccine could
reduce medical attention rate by 84% and admission rates by 96% (Vesikari et al., 2007), direct
medical costs could at least be reduced by US $2.4–5.5 million for outpatients and US $9.98
million for admission. A similar estimate is obtained using the estimate that the annual
number of hospitalizations due to rotavirus is about 15,000. The annual number of live births
in Taiwan is about 226,000 (thus, the number of children aged 0–4 years is about 1,130,000).
It is estimated that the cumulated incidence of 6.6% of rotavirus infection among children less
than 5 years old in Taiwan.
Hong Kong has similar socioeconomic environment and approach to healthcare delivery
with Taiwan (Nelson et al., 2005). The authors compared the economic burden of Taiwan for
rotavirus hospitalization among children to that of Hong Kong region. The estimates of direct
and indirect costs were derived from data on the disease burden of rotavirus-associated
hospital admissions with detailed cost data. On the basis of a birth cohort of 50,000 infants
and the assumption that 4.6% of the general pediatric admissions were associated with
rotavirus infection, it is estimated that the annual costs related to rotavirus infection are
US $4.09 million for Authorized hospitals. The addition of direct and indirect costs, the annual
social cost and annual family expenditures are US $4.3million and US $0.25 million, respec-
tively. The direct medical and social costs for admission were US $10.4 and $13.3 million,
. Table 71-5
Social and private mean costs of rotavirus, bacteria, and any-cause diarrhea in Taiwan
Cost variables Only R (+) Only B (+) R and B (+) Any cause
a
Direct costs 676 (381) 967 (543) 975 (549) 653 (367)
Inpatient cost 359 (215) 530 (317) 536 (321) 342 (205)
Outpatient cost 23 (6) 23 (6) 2 (6) 23 (6)
b
Total family expenditure 294 (181) 414 (255) 416 (258) 288 (177)
Family cost paid to SH 187 (116) 264 (164) 264 (169) 183 (113)
Total other family costsc 107 (67) 150 (94) 152 (97) 105 (65)
Indirect costs 185 (145) 258 (202) 261 (205) 181 (141)
Caregiver’s time costs 185 (145) 258 (202) 261 (205) 181 (141)
d
Total social cost 861 (484) 1,224 (688) 1,236 (695) 834 (468)
Total private coste 480 (271) 671 (379) 677 (382) 469 (265)
Total SH costf 569 (320) 817 (459) 823 (463) 548 (308)
Length stay, mean (SD), days 4.4 (3.3) 6.2 (3.5) 6.3 (3.6) 4.3 (3.6)
Data are total mean (SD) in US dollars. One US dollar equals 35.0 new Taiwan dollars. Note: R rotavirus; B bacteria;
SH sentinel hospitals (From Chen et al. (2007) with permission)
a
Inpatient cost þ outpatient cost þ total family expenditure
b
Family SH cost þ total other family costs
c
Total costs of co-payment for other health care providers paid by family, travel costs, such as diapers and
medications
d
Total direct cost þ total indirect cost
e
Total family expenditure þ caregiver’s time costs
f
Total inpatient cost þ total outpatient cost þ total family SH cost of co-payment
respectively. For a birth cohort of 230,000 infants, the equivalent hospitalization and social
costs would equal US $20.4 and US $21.5 million, respectively. Our hospital and social costs
were much lower than these estimates, mainly because they reflect differences in the calcula-
tions of direct cost. Because hospitalizations account for the largest proportion of costs of
rotavirus-associated illness to the health care system, it will be important to assess the
effect of a rotavirus vaccine on rates of hospitalization when more data become available
(Podewils et al., 2005).
Summary Points
Rotavirus is the most important cause of acute gastroenteritis in young children in both
developed and developing countries. Rotavirus infection causes significant morbidity and
mortality.
Rotavirus infection imposes a significant economic burden in Taiwan.
Although the introduction of a safe and effective rotavirus vaccine may not prevent all
rotavirus-associated hospital admissions, it could result in significant cost savings for the
Taiwanese government and families.
COI was the first economic evaluation technique used in the health field. COI can be a
good economic tool to inform decision makers if it is considered from another perspective.
To do that the design of the COI study must be innovative, capable of measuring the true cost
of society, to identify the different subjects who bear the costs and to explain cost variability.
Appendix
Costs Calculated Among Inpatient
1. Total direct costs included total SH costs and total family expenditure:
(1) Total SH costs = SH inpatient cost þ SH outpatient cost þ SH ward follow-up cost
(2) SH inpatient cost = (total number of days in SH hospital) (cost of a general pediatric
SH hospital bed bed/day); where the SH calculates bed costs by using full cost estimates.
All four sentinel hospitals conducted similar calculations on an annual basis. The
pediatric costs are calculated for pediatric beds. The latter figure was used to calculate
SH inpatient costs and was estimated by escalating 2001–2001 cost data to 2002–2003
price levels > Table 71-6. All costs, including medications and diagnostic tests, are
included in the per diem cost
(3) SH outpatient cost = (number of Hospital outpatient department (HOPD) visits offi-
cial cost/HOPD visit) þ (number of a Accident & Emergency [A&E] visit official
cost/A&E visit), which includes all visits related to the same episode of gastroenteritis
that required admission and occurred either before or after hospitalization
(4) SH ward follow-up (WFU) cost = (number of WFU visits) (official cost/WFU)
2. The total family expenditure included all co-payments made by the family to the SH
hospitals or clinics (family SH costs) and total family costs and was calculated as follows:
(1) Family SH costs = (total days in SH hospital) (official cost of co-pay a pediatric SH
bed per day paid by family) þ (number of WFU visits) (official cost of co-pay per
WFU paid by family) þ (number of OPD visits official cost of co-pay per OPD visit
. Table 71-6
Sentinel Hospital and private healthcare costs per visit used to calculate social and private costs
of the disease burden associated with rotavirus infection in Taiwan
Cost variables Paid by NHISa Paid by family

General pediatric bed per day (four patients in each room) 15 (512) 0
General pediatric bed per day (two patients in each room) 15 (512) 45 (1,580)
Ward follow-up 10 (352) 0
General outpatient department 7 (250) 3 (100)
Note: Data are expressed in US dollars (Taiwan dollars). One US dollar equals 35.0 new Taiwan dollars; NHIS:
National Health Insurance System (From Chen et al. (2007) with permission)
a
Data were obtained from the National Health Insurance Bureau (August 2006) and were estimated by escalating
2001–2003 cost data to 2002–2003 price level
paid by family) þ (number of A&E visits official cost of co-pay per A&E visit paid
by family)
(2) Total family costs = family ‘‘other provider’’ cost þ family travel costs þ family ‘‘other
related’’ costs
(3) Family ‘‘other provider’’ costs = actual cost of co-payment for any other provider costs,
including cost of non-SH hospital treatment (bed, consultation fees, and medications)
(4) Family travel costs = actual cost of bus fare, taxi, or mileage to visit hospitals (SH or
non-SH) or outpatient service (SH service or non-SH) because of the child’s illness
(5) Family ‘‘other related’’ costs = actual for food supplements and nonprescription
remedies þ actual costs for additional day care þ actual cost for extra diaper use þ actual
costs for miscellaneous items (families were shown how to record these various costs in
the symptom diary at the time of recruitment)
(6) Total indirect costs were calculated as the mother’s time cost þ father’s time cost þ other’s
time cost, where mother’s time cost = (hour/day off work) (mother’s estimated hour/day
salary); and father’s time cost = (hour/day off work) (father’s estimated hour/day salary);
and other’s time cost = (hour/day off work) (other’s estimated hour/day salary). Parents
were asked to record in the symptom diary all time taken off from paid employment
References
Ball JM, Tian P, Zeng CQ-Y, Morris AP, Estes MK. Clark HF, Offit PA, Ellis RW, Krah D, Shaw AR, Eiden JJ,
(1996). Science. 272: 101–104. Pichichero M, Treanor JJ. (1996). Arch Virol. 12:
Berner R, Schumacher RF, Hameister S, Forster J. (1999). (Suppl)187–198.
Acta Paediatr Suppl. 426: 48–52. Clements-Mann ML, Makhene MK, Mrukowicz J,
Berstein DI, Glass RI, Rodgers G, Davidson BL, Sack DA. Wright PF, Hoshino Y, Midthun K, Sperber E,
(1995). JAMA. 73: 1191–1196. Karron R, Kapikian AZ. (1999). Vaccine. 17:
Bloom BS, Bruno DJ, Maman DY, Jayadevappa R. (2001). 2715–2725.
Pharmacoeconomics. 19: (2)207–213. Cone R, Mohan K, Thouless M, Corey L. (1988). Pediatr
Blutt SE, Kirkwood CD, Parreno V, Warfield KL, Infect Dis. J. 7: 103–109.
Cicarlet M, Estes MK, Bok K, Bishop RE, Cook SM, Glass RI, LeBaron CW, Ho MS. (1990). Bull
Conner ME. (2003). Lancet. 362: 1445–1449. World Health Organ. 68: 171–177.
Bresee J, Fang ZY, Wang B, Nelson EA, Tam J, Soenarto Y, David LH. (2004). In: David LH (ed.) Control of
Wilopo SA, Kilgore P, Kim JS, Kang JO, Lan WS, Communicable Disease Manual. American Public
Gaik CC, Moe K, Chen KT, Jiraphongsa C, Health Association, Washington, DC, pp. 224–227.
Ponguswanna Y, Nguyen VM, Phan VM, Le TL, de Zoysa I, Feachem RG. (1985). Bull World Health
Hummelman E, Gentsch JR, Glass RI. (2004). Organ. 63: 569–583.
Emerg Infect Dis. 10: 988–995. Ehreth J. (2003). Vaccine. 21: 4105–4117.
Bureau of National Health Insurance. (2006). The Ernst RL, Hay JW. (1994). Am J Public Health. 84:
National Health Insurance Annual Statistical Re- 1261–1264.
port, 2004. Accessed on 15 August 2006 by http:// Estes MK. (2001). In: Knipe DM, Howley PM (eds)
www.nhi.gov.tw/00english/e_index.htm. Fields Virology, 4th ed. Lippincott-Raven, Philadel-
Caul EO. (1994). Lancet. 343: 1240–1242. phia, PA, pp. 1747–1786.
Chan PK, Tam JS, Nelson EA, Fung KS, Adeyemi-Doro Estes MK, Graham DY, Smith EM, Gerba CP. (1979).
FA, Fok TF, Cheng AF. (1998). Epidemiol Infect. J Gen Virol. 43: 403–409.
120: 321–325. Flewett TH, Woode GN. (1978). Arch Virol. 57: 1–23.
Chen KT, Chen PY, Tang RB, Huang YF, Lee PI, Yang JY, Gentsch JR, Laid AR, Bielfelt B, Griffin DD, Banyai k,
Chen HY, Bresee J, Hummelmen E, Roger RI. Ramachandran PM, Jain V, Cunliffe NA, Nakagomi
(2005). J Infect Dis. 92: s44–s48. O, Kirkwood CD, Fisher TK, Parashar UD, Bresee JS,
Chen KT, Fan SF, Tang RB, Huang YF, Lee PI, Chen PY, Jiang B, Glass GI. (2005). J Infect Dis. 192(Suppl 1):
Tang CW, Chen HC. (2007). Vaccine. 25: 4266–4272. S146–S159.
Glass RI, Parashar UD, Bresee JS, et al. (2006). Lancet. Parashar UD, Gibson CJ, Bresee JS, Glass RI. (2006).
368: 323–332. Emerg Infect Dis. 12: 304–306.
Greenberg HB, Kalica AR, Wyatt RG, Jones RW, Kapikian Podewils LJ, Antil L, Hummelman E, Bresee J, Parashar
AZ, Chanock RM. (1981). Proc Natl Acad Sci USA. UD, Rheingans R. (2005). J Infect Dis. 192:
78: 420–424. s133–s145.
Grimwood K, Lund JC, Coulson BS, Hudson IL, Rice DP. (1994). Lancet. 344: 1519–1520.
Bishop RF, Barnes GL. (1988). J Clin Microbiol. Rice DP, Kelman S, Miller LS. (1992). Hosp Community
26: 732–738. Psychiatry. 43: 1227–1232.
Hodgson TA. (1989). Health Policy. 11: 57–60. Richardson S, Grimwood K, Gorrell R, Palombo E,
Jain V, Parashar UD, Glass RI, Bhan MK. (2001). Indian Barnes G, Bishop R. (1998). Lancet. 351: 1844–1848.
J Pediatr. 68: 855–862. Rodrigues A, de Carvalho M, Monteiro S, Mikkelsen CS,
Jiang B, Gentsch JR, Glass RI. (2002). Clin Infect Dis. 34: Aaby P, Mølbak K, Fischer TK. (2007). Pediatr Infect
1351–1361. Dis J. 26: 233–237.
Johansen K, Bonnet R, Bondessen K, Eriksson M, Sazawal S, Bhatnager S, Bhan MK, Sakena SK, Arora NK,
Hedlund KO, De Verdier Klingenberg K, Uhnoo I, Aggarwal SK, Kashyap DK. (1991). J Pediatr Gastero-
Svensson L. (1999). Acta Paediatr. 88: 20–23. enterol Nutr. 12: 461–468.
Kapikian AZ, Hoshino Y, Chanock RM (2001). In: Knipe Shiell A, Gerard K, Donaldson C. (1987). Health Policy.
DM, Howley PM (eds.) Fields Virology, 4th ed. 8: 317–323.
Lippincott Williams & Wilkins, Philadelphia, PA, Tarricone R. (2006). Health Policy. 77: 51–63.
pp. 1787–1834. Tucker AW, Haddix AC, Bresee JS, Holman RC, Parashar
Kapikian AZ, Hoshino Y, Chanock RM, Perez-Schael I. UD, Glass GI. (1998). JAMA. 279: 1371–1376.
(1996). J Infect Dis. 174(Suppl): S65–S72. Velazquez FR, Calva JJ, Lourdes Guerrero M, Mass D,
Kilgore PE, Unicomb LE, Gentsch JR, Albert MJ, Glass RI, Pickering LK, Ruiz-Palacios GM. (1993).
McElroy CA, Glass RI. (1996). Pediatr Infect Dis J. Pediatr Infect Dis J. 12: 54–61.
15: 672–677. Velazquez FR, Matson DO, Calva JJ, Guerrero L, Morrow
Koopmanschap MA. (1998). Pharmacoeconomics. 14: L, Carter-Campbell S, Glass RI, Estes MK, Pickering
143–148. LK, Ruiz-Palacios GM. (1996). N Engl J Med. 335:
Kordasti S, Sjovall H, Lundgren O, Svensson L. (2004). 1022–1028.
Gut. 53: 952–957. Vesikari T, Karvonen A, Prymula R, Schuster V, Tejedor
Kosek M, Bern C, Guerrant RL. (2003). Bull World JC, Cohen R, Meurice F, Han HH, Damaso S,
Health Organ. 81: 197–204. Bouckenooghe A. (2007). Lancet. 370: 1757–1763.
Lu CY, Lauderdale TL, Fang YU, Wang CY, Ho YH, Vesikari T, Matson DO, Dennehy P, Damme PV,
Hung CL, Chang LY, Lee CY, Huang LM. (2006). Santosham M, Rodriguez Z, Dallas MJ, Heyse JF,
BMC Infect Dis. 6: 176. Goveia MG, Black SB, Shinefield HR, Christie CD,
Lynch M, Lee B, Azimi P, Gentsch J, Glaser L, Gilliam S, Ylitalo S, Itzler RF, Coia ML, Onorato MT,
Chang HG, Ward R, Glass RI. (2001). Clin Infect Adeyi BA, Marshall GS, Gothefors L, Campens D,
Dis. 33: 932–938. Karvonen A, Watt JP, O’Brien KL, DiNubile MJ,
Lynch M, Shieh WJ, Tatti K, Gentsch JR, Ferebee-Harris T, Clark HF, Boslego JW, Offit PA, Heaton PM.
Jiang B, Guarner J, Bresee JS, Greenwald M, Cullen S, (2006). N Engl J Med. 354: 23–33.
Davies HD, Trevenen C, Zaki SR, Glass RI. (2003). Weiss KB, Gergen PJ, Hodgson TA. (1992). N Engl J Med.
Clin Infect Dis. 37: 1327–1333. 326: 862–866.
Nakagomi T, Nakagomi O, Takahashi Y, Enoki M, Suzuki T, Westerman LE, McClure HM, Jiang B, Almond JW,
Kilgore PE. (2005). J Infect Dis. 192: S106–S110. Glass RI. (2005). Proc Natl Acad Sci USA. 102:
Nelson EA, Tam JS, Yu LM, Ng YC, Bresee JS, Poon KH, 7268–7273.
Ng CH, IP KS, Mast TC, Chan PK, Parashar UD, World Health Organization. (2000). Report of the
Fok TF, Glass RI. (2005). J Infect Dis. 192: s64–s70. Meeting on Future Directions for Rotavirus Vaccine
Pang XL, Joensuu J, Vesikari T. (1996). Pediatr Infect Dis Research in Developing Countries. World Health
J. 15: 543–545. Organization, Geneva, Switzerland, pp. 1–56.
72 Disease Burden of Dengue
Fever and Dengue
Hemorrhagic Fever
J. A. Suaya . D. S. Shepard . Mark E. Beatty . J. Farrar
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1264
2 Dengue Disease Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1265

2.1 Current Knowledge of Dengue Disease Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1266
2.2 Challenges Measuring Dengue Disease Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1268
2.2.1 A. Major Gaps in Defining, Diagnosing, and Measuring the Impact
of Dengue Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1268
2.2.2 B. Major Gaps in Dengue Case Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1272
2.2.3 C. Major Gaps in Understanding Special Regions and Populations
at Risk of Dengue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1274
3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1276
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1276

1264 72 Disease Burden of Dengue Fever and Dengue Hemorrhagic Fever
Abstract: Dengue is a rapidly growing public health problem in tropical and sub-tropical
regions of the world. These countries are less economically developed and collectively have a
current population in excess of three billion and characteristically very high population
growth. Quantifying the epidemiological and economic burden of dengue is key to formulat-
ing policy decisions on research priorities, prevention programs, clinical training for manage-
ment of the disease, and the introduction of new technologies such as vaccines, vector control,
diagnostics or drugs. This paper describes current knowledge and gaps in measuring global
dengue burden and suggests a framework for developing research priorities. There are a
number of major challenges. These include lack of uniform application of the World Health
Organization (WHO) case definition, limited access to or standardization of dengue diagnos-
tic tests, misdiagnosis, lack of systematic reporting of dengue cases to WHO, limited surveil-
lance and reliable reporting systems, and limited public awareness in endemic regions and
incidence of infection among travelers. The published literature contains few studies on
dengue disease burden and hence a great deal of research and allocation of limited public
health resources is done in the absence of reliable evidence to guide these decisions.
List of Abbreviations: CFR, case-fatality rate; DALYs, disability adjusted life years; DDB,
dengue disease burden; DF, dengue fever; DHF, dengue hemorrhagic fever; DSS, dengue shock
syndrome; ELISA, enzyme-linked immunosorbent assay; EUR, European region; ICT, immu-
nochromatographic test; PCR, polymerase chain reaction; PDVI, Pediatric Dengue Vaccine
Initiative; QALYs, quality adjusted life years; SD, standard deviation; US, United States of
America; WHO, World Health Organization
1 Introduction
Dengue is a rapidly growing public health problem in tropical and sub-tropical countries,
where the majority of the world’s population resides. The majority of individuals in these
nations are economically disadvantaged, living in regions with rapidly growing populations,
economic migration, rapid urbanization, and are usually simultaneously faced with multiple
public health problems. All these issues encourage the spread of the Aedes mosquito and
hence of dengue. Few affected countries have the resources to combat the reemergence
and global spread of dengue when faced with these challenges (Gubler and Meltzer, 1999;
Halstead, 1999, 2005).
With a total population of approximately three billion people living in endemic areas
(World Health Organization (WHO), 2006c) and with roughly 120 million travelers to these
regions each year, (World Tourism Organization, 2005) a large share of the world’s population
is at risk of dengue infection. Two estimates project that there are approximately 100 million
cases of dengue fever annually (Halstead, 1988; Rigau-Pérez and Gubler, 1999; World Health
Organization (WHO), 2002) corresponding to an incidence rate of 2.5–5%. These cases result
in hundreds of thousands of hospitalizations, often overwhelming already stretched hospitals
as a result of the explosive nature of the outbreaks and about 50,000 deaths each year (Gubler
and Meltzer, 1999). The spectrum of dengue infection ranges from asymptomatic infection
to death. Clinical presentations of dengue fever (DF) include a mild non-localizing fever
syndrome, or influenza-like illness, and classic dengue, or break-bone fever. Severe manifesta-
tions immediately following the febrile phase in 1–2% of DF cases include dengue hemor-
rhagic fever (DHF) (a febrile illness followed by abnormally low platelet counts, egress
Disease Burden of Dengue Fever and Dengue Hemorrhagic Fever 72 1265
of plasma into the pleural and abdominal cavities and hemorrhagic symptoms), and dengue
shock syndrome (DSS) (DHF with evidence of systemic hypoperfusion). Death occurs rarely
in the febrile phase; it is most commonly the result of hypoperfusion following the develop-
ment of DHF. Between 250,000 and 500,000 people develop DHF and DSS each year (Deen
et al., 2006).
Mildly symptomatic DF is usually treated in an ambulatory care setting, while the more
severe forms require inpatient management. Although more than 90% of patients who
develop DHF or DSS have serologic evidence of a previous dengue infection, it is not possible
to predict which DF patients will progress to these more serious forms, complicating the triage
and medical management of patients. Given the large geographic distribution of the virus and
large numbers of persons with symptomatic infection, dengue infection can have a significant
impact on the health care systems of the countries involved and on their economies, especially
during epidemics. As dengue spreads around the world these epidemics are often explosive
(as recently experienced in Indian Ocean, Cambodia, and Brazil) (Epidemic and Pandemic
Alert and Response (EPR) and World Health Organization (WHO), 2006, 2008; International
Federation of Red Cross and Red Crescent Societies, 2007). The inpatient care of patients with
severe dengue is very labor intensive which puts an enormous strain on the health care system
to manage the large increase in the number of patients with dengue, and also pressurizes the
system to cope with the normal work load.
Quantifying the dengue disease burden (DDB) is key to formulating policy decisions on
research priorities, prevention programs, clinical training for management of the disease,
allocation of resources in the face of intermittent explosive epidemics and the introduction of
new technologies. Reliable diagnosis and reporting of dengue would allow better understand-
ing of the true disease burden posed by dengue in a world of competing public health issues.
DDB estimations can be used for multiple purposes. First, they provide the basis for compar-
isons of dengue burden within and across geographical locations and time periods. Second,
these DDB estimations can help country-level, regional, and global public health authorities to
make informed decisions on resource allocations through the comparison of the DDB with
that of other competing public health issues. Accurate estimates of DDB may serve to justify
donor funding, set priorities for research, and accelerate the development of dengue vaccines.
Third, a comprehensive understanding of DDB will be essential to formulation of rational
immunization policies by governments and public health entities should a vaccine candidate
be proven adequately efficacious. Finally it is likely that the twenty-first century will be
characterized as a period of globalization, migration, urbanization, climate change and
changing demographics, and hence dengue is truly a disease of the this century. The Aedes
mosquito life style lends itself to the urbanization seen today in Asia and Latin America, and
potentially in the future of Africa as well. With climate change altering the areas of the world
where Aedes mosquito can thrive, and the patterns of acquired immunity requiring two
infections for severe disease means human migration plays a significant factor. This chapter,
which is based on a scientific working paper, (Suaya et al., 2007b) identifies gaps in current
knowledge of dengue disease burden in an effort to encourage research in these areas.
2 Dengue Disease Burden
DDB indicates the human cost of disease that is not yet prevented or fully treated. It can be
expressed in terms of total case counts of symptomatic dengue infections classified by severity
(DF, DHF, and DSS), and other epidemiologic indices such as, case-fatality rate, and number
of deaths during a period of time. In addition to these epidemiological indicators, disease
burden can be expressed as a single health indicator such as Quality Adjusted Life Years
(QALY) (Zeckhauser and Shepard, 1976) or Disability Adjusted Life Years (DALY) (Murray,
1994). Internationally, DALY computations are most often employed. The disease burden
imposed by dengue and the potential benefits of any intervention, such as vaccination, can
then be expressed in terms of DALYs lost or saved and cost per DALY lost or saved. Dengue
cases can be classified as fatal and non-fatal case. The number of DALYs lost per fatal case will
be a function of gender and the age of death. The number of DALYs lost per non-fatal dengue
case is a function of the duration of the illness episode and the decrement in quality of life
during the episode.
2.1 Current Knowledge of Dengue Disease Burden
Dengue is endemic in all WHO Regions except the European Region (EUR) (World Health
Organization (WHO), 2006d). > Figure 72‐1 shows the global number of cases reported by
year and the characteristic cyclical variations due to high epidemic and low post-epidemic
years. In each year through 1976, fewer than 40,000 cases from fewer than 15 countries
were reported annually to WHO (World Health Organization (WHO), 2006c). In 1974,
WHO developed the first dengue diagnostic and management guidelines (Deen et al., 2006).
> Figure 72‐1 shows that the lowest number of cases was reported in 1979 and the highest
number in 2002 with 110,000 and 1,300,000 cases reported, respectively.
. Figure 72‐1
Dengue cases: global annual number of cases reported and number of countries reporting to
WHO by year, 1955–2005
> Figure 72‐2 shows both the annual global number of dengue deaths and the number of
countries reporting them. There were similar cyclical variations in the number of deaths
coinciding with epidemic and non-epidemic years. After 1977, the year with the lowest
reported number of dengue deaths was 1978 (with 807 fatalities) and the year with the highest
number was 1983 (with 6,031 fatalities). The majority of both total cases and deaths have been
reported from Southeast Asia and the Western Pacific.
A number of studies have attempted to estimate the DDB in terms of DALYs. For example,
the DDB was estimated in Puerto Rico for the period 1984–1994 (Meltzer et al., 1998).
Estimations were based on both the dengue cases and deaths reported to the national
surveillance system and on age-group expansion factors used to control for under-reporting.
The authors estimated an average loss of 658 DALYs per million population per year
and concluded that this burden was comparable to that attributed to meningitis, hepatitis,
malaria, tuberculosis, the childhood cluster of diseases (polio, measles, pertussis, diphtheria,
and tetanus), or intestinal helminthiasis. This is of the same order of magnitude as tuberculo-
sis in Latin America and the Caribbean. A study in Southeast Asia estimated a loss of
420 DALYs per million population per year, comparable to that of meningitis (390 DALYs
per million population per year), twice the burden of hepatitis, and one-third of the burden
imposed by HIV-AIDS in the region (Shepard et al., 2004). Two studies for Thailand estimated
that country’s DDB at a loss of 427 and 465 DALYs per million population per year
for 2001 and for the period 1999–2002 (Anderson et al., 2007; Clark et al., 2005) and
estimated that dengue illness may account for 15% of DALYs lost to all febrile illnesses
(Anderson et al., 2007).
. Figure 72‐2
Dengue deaths: global annual number of deaths reported and number of countries reporting to
WHO by year, 1955–2005
The Disease Control Priorities Project has recently published the global burden of disease
for 2001–2003 (Cattand et al., 2006). It estimated the global DDB as 528,000 DALYs for the
year 2001. This corresponds to a burden of 264 DALYs per million population per year for two
billion people living worldwide in areas at risk of dengue.
2.2 Challenges Measuring Dengue Disease Burden
Global estimations of DDB are considered uncertain due to a number of factors listed in
(> Table 72‐1) and discussed below.
. Table 72-1
Challenges measuring dengue disease burden
A. Major gaps in defining, diagnosing, and measuring dengue illness

Lack of uniform application of WHO case definition
Limited capabilities and standards of dengue laboratories
Limited accuracy of rapid tests
Misdiagnosis
Limited knowledge of quality of life during a dengue episode
B. Major gaps in dengue case reporting
Lack of uniform criteria to report dengue cases to WHO
Limited role of surveillance and reporting systems
Underreporting of non-fatal dengue cases
Misclassification in dengue case reporting
Underreporting of fatal dengue cases
C. Major gaps in understanding special regions and populations
Limited public knowledge in major regions at risk
Limited knowledge about dengue in travelers
2.2.1 A. Major Gaps in Defining, Diagnosing, and Measuring the Impact

of Dengue Illness
2.2.1.1 Lack of Uniform Application of WHO Case Definition

WHO has published guidelines for dengue diagnosis, classification, and management, which
have been adapted by WHO regional offices (World Health Organization (WHO), 1997).
Investigators have reported difficulties applying the case definition because of its complexity
and the limited ability to explain observed patterns of disease (Balmaseda et al., 2005; Deen
et al., 2006; Rigau-Perez, 2006). Because of these difficulties and the need to use categories
relevant to their needs for dengue planning and management, some countries have instituted
their own case definitions (Deen et al., 2006).
2.2.1.2 Limited Capabilities and Standards of Dengue Laboratories

Test kits for anti-dengue IgM antibodies are commercially available. Their accuracy appears to
vary with the clinical context in which they are used (Guzmán and Kourı́, 2004). Tests for virus
by cell culture or nucleic acid detection (e.g., polymerase chain reaction (PCR)) require
commercial or research laboratories to produce test materials (e.g., cells, primers, serotype
specific antibodies) (Pediatric Dengue Vaccine Initiative (PDVI), 2006). Given the complexity
of these viral identification methods, quality and quality control of testing varies (Pediatric
Dengue Vaccine Initiative (PDVI), 2006). Laboratory capabilities, infrastructure, technical
expertise and research capacity need to be improved (Guzmán and Kourı́, 2004). Very few
patients with dengue ever have a diagnostic test performed.
Scientists at a recent WHO-sponsored meeting pointed out gaps for laboratory
standards, quality control, and dengue serological diagnosis and virus isolation, as well as for
reporting and information exchange in Southeast Asian and Western Pacific countries (World
Health Organization, 2004). Similar considerations may apply to laboratories in the Americas
as suggested by an evaluation of quality control of serological diagnostic tests in major national
reference laboratories responsible for dengue surveillance and diagnosis in the region (Guzmán
et al., 2003). Though the majority of the participating laboratories had a high level of accuracy
in detecting dengue IgG and IgM antibodies, only 63% of 86 laboratories that received testing
samples between 1996 and 2001 decided to participate in this quality control project. This study
also highlighted the challenges faced by participating laboratories, such as lack of timely
availability of antigens, low sensitivity of IgM antibody testing by enzyme-linked immunosor-
bent assay (ELISA), and lack of alternative tests and techniques for dengue diagnosis. There are
few publications on quality control evaluations on laboratory performance for dengue virus
identification (such as PCR) or isolation.
Regions with imported dengue, such as the United States of America (US) and the
European Union, may face additional challenges. Since dengue is not common in these
areas, laboratory testing for dengue may not be readily available and the disease may be
overlooked as a cause of symptoms among ill returning travelers. For example, as part of a
quality control evaluation, 20 serum samples were sent in 2002 to 18 European laboratories to
be tested for the presence of dengue virus-specific IgM and IgG antibodies (Donoso Mantke
et al., 2004). Laboratories reported concurrent and correct results for 71% of the IgG-positive
samples and 89% of the IgG-negative samples. However, though 97% of the IgM-negative
samples showed concurrent and correct results, only 58% of the IgM-positive samples had
concurrent and correct results. These findings highlight the need for quality control and
improvements in dengue testing in most countries including those with where dengue is
primarily imported.
2.2.1.3 Limited Accuracy of Rapid Tests

A recent meta-analysis of 11 studies of rapid dengue diagnostic assays evaluated the perfor-
mance of immunochromatographic test (ICT) manufactured by one company. The meta-
analysis showed a wide spectrum of sensitivity ranging from 0.45 to 1.0, and specificity,
ranging from 0.57 to 1.0. These findings suggest that tests may have limited accuracy (Blacksell
et al., 2006). Additionally, the cost of rapid tests may be a barrier to widespread use in
developing countries. There is little else in the published literature describing the performance
of other available rapid diagnostics tests for dengue.
2.2.1.4 Misdiagnosis
Despite the publication of clinical guidelines, dengue can be misdiagnosed leading to both
under-diagnosis and over-diagnosis. Given the lack of specificity of dengue symptoms,
clinicians can confuse dengue with other infections such as influenza, enterococus, chikungu-
nya, leptospirosis, typhoid, malaria, influenza, and in some cases even viral hemorrhagic fevers
(Halstead, 1997). Moreover, dengue infection as an undifferentiated febrile illness may
represent a large share of all the symptomatic dengue (Phuong et al., 2006). For example, in
a study in a dengue endemic province in Vietnam, 34% of patients with acute undifferentiated
fever visiting primary care facilities actually had laboratory-diagnosed dengue. Indicating
symptomatic dengue infection may account for a large proportion of fever cases seen in
general practice but have few distinguishing clinical signs or symptoms (Phuong et al., 2006).
A study reviewing the medical records for a period of 6-months in Laredo, Texas in 1999
showed that only 50% of the patients with clinical suspicion of dengue were diagnosed as such
(Centers for Disease Control and Prevention (CDC), 2001). Misdiagnosis is particularly more
likely if there are other febrile diseases with similar clinical characteristics occurring concomi-
tantly. In Barbados in 1995 and 1997, the majority of the febrile patients with suspected
leptospirosis actually had laboratory-diagnosed dengue as the cause of their fever. Conversely,
some cases of suspected dengue had leptospirosis (Levett et al., 2000). In another study, during
a dengue outbreak in Bangladesh, about 18% of suspected dengue cases were laboratory
negative for dengue and proved to have leptospirosis (LaRocque et al., 2005).
Misdiagnosis can be influenced by treatment guidelines. For example, while WHO guide-
lines for the treatment of febrile children aged 2 months–5 years are useful to ensure that
children with fever and no alternative explanation are empirically treated for malaria, this
guideline may contribute to misdiagnosis of dengue, particularly in areas of low malaria
transmission or where physicians are not routinely using malaria smears to confirm the
diagnosis (Beatty et al., 2007; Malik et al., 2005).
Results for most current dengue tests are not available for days or weeks after the clinical
consultation, diagnosis, empiric treatment, and case resolution. Rapid dengue testing may
improve the situation, but the cost of the test may be a disincentive and issues of test reliability
and validity have not been entirely resolved. In addition, even in those countries with adequate
laboratory facilities, cross reactivity between anti-dengue antibodies and other Flavivirus
antibodies (such as Yellow Fever, West Nile virus, St Louis encephalitis, and Japanese Enceph-
alitis) can confound accurate diagnosis. Furthermore, prior immune response to these Flavi-
viruses can result in boosting of pre-existing Flavivirus antibodies during a second Flavivirus
infection (original antigenic sin), further contributing to the problem of confirming dengue
diagnosis in areas of the world where multiple Flaviviruses co-circulate.
2.2.1.5 Limited Knowledge of Quality of Life during a Dengue Episode

Quality of life during a dengue episode has not been studied systematically or comprehensively
until recently. Therefore, all earlier published studies estimating dengue disease burden have
used assumptions or expert opinions to measure the likely quality of life of a non-fatal dengue
episode (Anderson et al., 2007; Cattand et al., 2006; Clark et al., 2005; Meltzer et al., 1998;
Shepard et al., 2004). However, a recent multi-country study has analyzed the type and
quantity of health domains affected and the quality of life during dengue illness as the
intermediate steps to quantify the DALYs lost for a non-fatal dengue case (Suaya et al.,
2007a). Results from two countries, Malaysia and Panama, have been published to date
(Armien et al., 2008; Lum et al., 2008). To measure health domains affected, the study used
the health module of the World Health Survey (EuroQOL Group, 1990; World Health
Organization (WHO), 2008) to survey on eight health domains: pain and discomfort,
mobility, interpersonal activities, sleep and energy, affect, self-care, cognition, and vision.
One to three questions with a five-point response scale (none, mild, moderate, severe, and
extreme) were used to survey each health domain investigated. Overall quality of life during
the illness was assessed with the EuroQOL’s 100-point thermometer visual scale, in which zero
corresponds to death and 100 to perfect health (EuroQOL Group, 1990). A unique feature of
the study in Malaysia was a daily survey of the patient’s quality of life during the illness.
In Panama, a cohort of 130 ambulatory dengue patients, the majority of them adults,
reported having an average of 3.6 (SD2.3) of health domains that were severely to extremely
affected. The quality of life during the illness was seriously impaired and averaged only 33% at the
lowest point, implying a loss of up to 67% of the equivalent of perfect health (Armien et al., 2008).
In Malaysia, the average number of health domains reported to be moderately to extremely
affected was 6.2 (SD1.3) in 124 hospitalized patients and 5.0 (SD1.2) in 83 ambulatory
patients, which included both children and adults (Lum et al., 2008). The quality of life
during the illness was also seriously impacted. As > Figure 72-3 shows, quality of life followed
. Figure 72‐3
Quality of life during a dengue illness episode (adapted from Lum et al. 2008)
a U-shaped curve. A radical decrease in the quality of life was observed in all of the patients
from the onset of symptoms, with the lowest point (equivalent to a loss of 60% of the
equivalent of perfect health) between the third and seventh days of illness. After the lowest
point, patients experienced a progressive recovery of the quality of life. The average duration of
the impairment was well beyond the number of days of fever (5 and 7 days, respectively), and
the quality of life was 9 days for ambulatory patients (n = 83) and 13 days for hospitalized
patients (n = 124). As shown in > Figure 72‐3 ambulatory patients had, on average, a lesser
decrease in their quality of life and a faster recovery to normality.
Despite these recent empirical studies on quality of life, the calculation of disease burden in
DALYs requires additional refinements, such as conversion from visual analogue scales (e.g.,
the EuroQOL’s 100-point thermometer visual scale used in these studies) to time tradeoff
utilities (O’Leary et al., 1995; Salomon and Murray, 2004). Furthermore, as dengue also affects
children, it is necessary to validate the ability of parents to act as a child’s proxy to quantify
quality of life (Prosser et al., 2007).
2.2.2 B. Major Gaps in Dengue Case Reporting
2.2.2.1 Lack of Uniform Criteria to Report Dengue Cases to WHO

In the Americas region, dengue cases are reported to WHO stratified by severity (e.g., DF or
DHF). However, in Southeast Asia and the Western Pacific regions, dengue cases are reported
without classification by severity, because case ascertainment is based on hospital admission
(World Health Organization (WHO), 2006d). Thus, while some countries report only severe
dengue cases, others attempt to report all, and still others report only laboratory confirmed
cases (World Health Organization (WHO), 2000). This lack of uniform reporting makes it
difficult to perform meaningful international comparisons and aggregations.
2.2.2.2 Limited Role of Surveillance and Reporting Systems

The majority of national surveillance systems depend mainly on hospital-based reporting with
individual case reporting by hospital staff whose primary responsibilities lie elsewhere. Less
information is obtained from clinics, and still more limited data are reported from private
sector medical practices. In Southeast Asia, for example, notification is barely enforced and the
number of cases of communicable diseases, such as, the proportion of the dengue disease
burden dealt with in the private sector is unknown (Zaidi et al., 2004). In the Americas,
surveillance systems are also generally passive. While this system may be sufficient to detect
outbreaks, the data gathering is unlikely to represent the true incidence of disease in these
countries (World Health Organization (WHO), 2006a).
2.2.2.3 Underreporting of Non-fatal Dengue Cases

There are a number of factors that contribute to the underreporting of dengue. First, the time
required to collect a sample and complete a report form may be a disincentive to a busy
healthcare provider. Second, there is little benefit to the evaluating physician or individual
patient because results will often not be available for days to weeks after the acute visit that led
to the sample collection. Third, while notification of suspected dengue to public health
authorities (communicable disease units) may be legally required in most of the affected
countries, is it rarely enforced. Finally, surveillance systems usually have logistic and budgetary
constraints and all samples may not be tested. In addition, quality of testing techniques may
vary, calling into question the reliability of reported results. Thus, underreporting of dengue
cases, and probably even of deaths due to dengue, is a major concern.
Evidence of underreporting of dengue cases is evident in studies conducted in Brazil,
Indonesia, Puerto Rico, and Thailand. In Belo Horizonte, Southeastern Brazil, the level of
reporting of hospitalized suspected dengue cases was estimated to be 63% between 1997 and
2002 (Duarte and França, 2006). As the cases recorded in the reporting system were the more
severe, the overall case fatality rate may have been consequently overestimated. In Indonesia,
the number of reported cases was compared against medical records of hospitalized DHF cases
that were admitted in four major hospitals in Bandung during 1994. Only 31% of those cases
were captured in the report (Chairulfatah et al., 2001). Similar underreporting was found in
Puerto Rico, where only 28.4% of the hospitalized DHF cases were detected by any of the
surveillance and reporting systems (Rigau-Pérez, 1999). In another study, the same author
tried to measure the burden of dengue in Puerto Rico during 1984–1994 (Meltzer et al., 1998).
To deal with the existing underreporting, it was estimated that for every dengue case reported
among children, there were about 10 additional cases not reported. Among adults, it was
estimated that for every case reported, 27 cases went unreported. In a recent study in Thailand,
underreporting was recognized and the true number was estimated as 10-fold the number
reported (Clark et al., 2005).
2.2.2.4 Misclassification in Dengue Case Reporting

Dengue cases can be misclassified as DF, DHF, and DSS at the time of diagnosis because of the
lack of familiarity of medical providers with dengue as a disease or the complexity of the WHO
classification system (Deen et al., 2006). This is important because the severity of dengue
disease is a predictor of the use of health care services and of medical care costs (Suaya et al.,
2003). Correct classification is important epidemiologically because the WHO suggests calculat-
ing the dengue case-fatality rate (CFR) by dividing the number of deaths by the number of DHF
cases (World Health Organization (WHO), 1997). If classification is not uniform, CFR compar-
isons across countries may be misleading. In a study in Puerto Rico, only 17 DHF and 3 DSS cases
were identified among 986 dengue disease hospitalizations reported through the surveillance
system during 1990–1991. A review of the hospital records of those patients, however, found that
88 and 14 of them had clinical diagnosis of DHF and DSS, respectively (Rigau-Pérez, 1997). The
reviews of medical records identified about five times more severe dengue cases than were
reported to the routine surveillance system. Another review of the medical records of dengue
patients during the 2002 epidemic in Taiwan, found that 71% of the patients admitted with DHF
were discharged with a diagnosis of dengue fever only (Lee et al., 2006). If appropriate allocation
of resources to address issues of dengue reporting is to occur, better recognition and accuracy in
classification of dengue disease and improved reporting is needed.
2.2.2.5 Underreporting of Fatal Dengue Cases

Reports of dengue deaths may be intuitively assumed more accurate than reports for non-fatal
dengue cases. During the 1998 dengue epidemic in Puerto Rico, there were 17,000 reported
cases of dengue and 19 deaths for which dengue was confirmed or probable. For the same year,
however, only five dengue deaths are shown in the WHO DengueNet, the WHO-sponsored
internet-based system for the global surveillance of dengue fever and DHF (World Health
Organization (WHO), 2006c). This single time-point finding indicates a four fold under-
reporting to WHO of laboratory-diagnosed dengue deaths. In addition, there were 31 more
deaths for which dengue was initially suspected but could not be confirmed because the virus
was not identified by virus isolation or immunohistochemical staining of tissue, the patient
died before seroconversion, and no other explanation for the death was identified (Rigau-
Perez et al., 2002). Had these deceased patients had a convalescent sample it is highly likely that
some of them would have seroconverted and classified as dengue. Difficulties in reporting and
classification that occurred in Puerto Rico are likely to occur in other dengue endemic
countries. Additional factors that may further interfere with confirmation and reporting of
dengue deaths to WHO might include political and economic concerns regarding the possible
impact on tourism.
2.2.3 C. Major Gaps in Understanding Special Regions and Populations

at Risk of Dengue
2.2.3.1 Limited Public Knowledge in Major Regions at Risk

Data on DDB is limited for dengue endemic regions that have a significant portion of the
world’s population: India, China, and sub-Saharan Africa.
India. One billion people (15% of the world’s population) reside in India. India’s popula-
tion is twice that of Southeast Asia (the region containing Thailand, Cambodia, and Vietnam)
which currently reports the most dengue-related deaths world-wide. Despite that India has
many regions with comparable environmental conditions, the number of reported dengue
cases and deaths is only a fraction of those reported in Southeast Asia.
Additionally, an increasing number of laboratory-diagnosed dengue cases in India are
secondary infections (Vijayakumar et al., 2005). Despite generally being considered an urban
disease, outbreaks of dengue are increasingly reported in rural areas, increasing the population
that is at risk (Dhar et al., 2006; Jamaluddain and Saxena, 1997; Kumar et al., 2001; Ratho et al.,
2005; Sharma et al., 2000). Prior to 2005, dengue surveillance had been very limited in India
(World Health Organization (WHO), 1994). A study concerning the dengue epidemic in
Chennai in 2001 suggested that the surveillance system was unlikely to generate proper
information on the epidemiology of the disease (Kabilan et al., 2005). In 2004, a WHO
initiative called for promoting improvement on dengue surveillance as part of the Integrated
Disease Surveillance Program in India, strengthening laboratory networking and quality
assurance, and reviewing case definitions (World Health Organization (WHO), 2003). In
2005 dengue case reporting became mandatory. Although improvements are being made, the
national surveillance system is still passive, with only 12,317 dengue cases and 184 dengue
deaths provisionally reported in 2006 (National Vector Borne Disease Control Programme
(NVBDCP), 2008). These figures represent a dengue fever incidence of 1 per 100,000, a
significantly lower rate than reported in Southeast Asian countries. The current gaps in
epidemiologic data and surveillance in India make the dengue disease burden in India
uncertain. Despite this, dengue is one of the listed causes of death and hospitalization
among children in India (Vector Control Research Center ICoMR, 2006).
China. One billion three hundred million people (20% of the world’s population) live in
China. Roughly one fifth of China’s land mass, including some of the more densely populated
regions, lies in tropical climes where dengue transmission is known to occur. Published reports
on dengue outbreaks detailed the reemergence of dengue in the 1980s and 1990s (Fan et al.,
1989; Qiu et al., 1991, 1993). However, since 2003, data from WHO does not include cases in
China, (World Health Organization (WHO), 2006c) making the documentation of DDB in
this country difficult.
Sub-Saharan Africa. The DDB in Africa remains poorly defined. Travelers visiting and
military personnel stationed in Africa have been identified with laboratory-diagnosed dengue
infections, indicating that the virus is circulating (Centers for Disease Control and Preven-
tion (CDC), 2005; Sharp et al., 1995). Several seroprevalence and fever studies conducted
in sub-Saharan Africa have identified past evidence of the dengue virus transmission in
many sub-Saharan countries including Senegal, Kenya, Cameroon, Djibouti, Sudan and
Burkino Faso. These studies reported lower seroprevalence rates, 10–34%, than those seen
in other tropical countries, such Haiti, Brazil, and Thailand (Halstead et al., 2001; Teixeira
et al., 2002; Tuntaprasart et al., 2003). As expected, higher prevalence levels are noted among
urban residents compared to rural residents (Collenberg et al., 2006; Ibrahim et al., 2002;
Kuniholm et al., 2006; Morrill et al., 1991; Rodier et al., 1996; Saluzzo et al., 1986). In addition
periodic outbreaks of dengue fever have been reported in the region (Ibrahim et al., 2002;
Johnson et al., 1982; Rodier et al., 1996; Saluzzo et al., 1986). Without systematic surveillance
and serosurveys with appropriate sample schemes to give a fair representation of the disease
burden in the population, current DDB in Africa may remain poorly defined. Moreover if
dengue is an endemic problem in sub-Saharan Africa, increasing urbanization will increase the
burden of disease as large populations are placed at risk.
2.2.3.2 Limited Knowledge About Dengue in Travelers

According to the World Tourism Organization, 125.4 million international tourists visited
countries where they may be at risk for acquiring dengue infection (World Tourism Organi-
zation, 2005). Depending on the population studied and the laboratory methods used,
serological evidence of recent dengue infection was found in 7–45% of febrile travelers
returning from endemic areas (López-Vélez et al., 1996; Schwartz et al., 1996; Yabe et al.,
1996), confirming that dengue is an important cause of fever in this group. Because it explains
a substantial proportion of fevers in returning travelers, dengue may have a significant
economic impact in non-dengue endemic countries due to days lost from work. However,
given the spectrum of clinical illness, not all patients may seek medical attention or receive
diagnostic testing. As a result, underreporting of dengue infection occurs even in developed
countries. Moreover, not all travelers diagnosed with dengue may be reported to public health
authorities. In the US where dengue fever reporting is not required nationally, less than 100
patients with laboratory-diagnosed dengue are reported to the US Centers for Disease Control
and Prevention each year. However, we can estimate the level of underreporting using the
available literature. During the period of 1 Jan 2001 through 31 December 2004, seven
residents of the United States were diagnosed with dengue after returning from Thailand
(Centers for Disease Control and Prevention (CDC), 2005). According to the World Tourism
Organization, 2,012,077 US tourists visited Thailand during the same time period, (World
Tourism Organization, 2006) giving a rate of 3.5 dengue infections per 1 million visitors to
Thailand. However, among a prospective cohort of Dutch travelers, 0.7% of travelers from
Southeast Asia experienced symptomatic, laboratory-diagnosed (anti-dengue IgM serocon-
version) dengue infections (Cobelens et al., 2002). If the risk of acquiring dengue infection is
similar for Dutch and US travelers visiting Southeast Asia, for each dengue case reported to the
US Centers for Disease Control and Prevention there may be 5,000 additional unreported but
symptomatic dengue cases. This is, however, a conservative estimate since the US, unlike
Holland, shares a border with a dengue endemic country, Mexico.
Personnel deployed in dengue endemic areas during humanitarian emergencies and
conflicts are at a higher risk of dengue infection than regular travelers, since they usually
live in areas with higher transmission rates and usually stay in those areas longer than a tourist.
For example, during a 5-month deployment as part of the United Nations Mission in Haiti,
32% of 249 personnel with febrile illness had dengue infection (Gambel et al., 1999).
3 Conclusions
Existing knowledge about global dengue disease burden is limited. Although data for every
health condition are imperfect, the constraints on data are particularly important for condi-
tions such as dengue for which morbidity is relatively important compared to mortality and
for which confirmatory diagnostic tests are difficult, expensive and not widely available.
Registration data for deaths, while imperfect, usually tend to be better than those for
morbidity. Also, censuses provide a check on overall death rates not available for morbidity
data. Because dengue occurs in epidemics and treatment requires highly skilled medical
personnel, the health system may become overloaded. As a result, treatment of other condi-
tions requiring the same personnel and facilities may be adversely affected.
Though population-based studies with active surveillance are the gold standard for burden
estimations, their large cost and limited generalizability to other populations, settings and
time, make alternative methods necessary. Several complementary study designs may provide
reliable estimates of disease burden in dengue endemic countries. These include: (1) capture-
recapture studies from incomplete, but independent reports of dengue cases; (2) estimating
expansion factors from both populations under active surveillance and comparisons between
data in medical records and aggregate statistics from representative institutions to correct for
the level of misreporting to public health authorities; (3) treatment patterns from outbreak
estimations; and (4) laboratory analyses of cases and deaths classified under other cases that
could have included dengue.
Reliable data obtained from these different approaches could provide the foundation for
modeling to correct for under-diagnosis, misdiagnosis, underreporting and other limitations
of existing dengue incidence.
Well-planned standardized protocols for dengue disease burden studies in multiple
countries could provide more complete and comparable data across countries, as was recently
noted for rotavirus (World Health Organization (WHO), 2006b). Dengue disease burden
estimates will facilitate cost-effectiveness analyses of new diagnostic, preventive, and thera-
peutic technologies.
Summary Points
Dengue is a viral acute disease transmitted by a mosquito.

Dengue is a growing public health problem in tropical and sub-tropical regions.
The affected countries have a current population in excess of three billion.
Quantifying the epidemiological and economic burden of dengue is key to formulating
policy decisions on research priorities, prevention programs, clinical training for manage-
ment of the disease, and the introduction of new technologies such as vaccines, vector
control, diagnostics or drugs.
There is limited knowledge of global dengue disease burden.
There are a number of major challenges in measuring its disease burden.
The challenges include: lack of uniform application of the WHO case definition, limited
access to or standardization of dengue diagnostic tests, misdiagnosis, lack of systematic
reporting of dengue cases to WHO, limited surveillance and reliable reporting systems, and
limited public awareness in endemic regions and incidence of infection among travelers.
Underreporting of dengue cases (both fatal and non-fatal) is probably the most important
barrier to obtaining accurate assessments.
Acknowledgments
The scientific paper (Suaya et al., 2007b), which served as a background document for this
chapter was supported in part by the Pediatric Dengue Vaccine Initiative (PDVI). The
preparation of this chapter was supported by the endowment of the Schneider Institutes for
Health Policy, Brandeis University. For comments and assistance, the authors are indebted to
Chrisann Newransky, MS, Clare Hurley, MM, Rana Sughayyar, MS, and Binod Sah, MD
(Brandeis University, U.S.A.), Lucy Lum, MD (University Malaya, Malaysia), Bill Letson, MD
(PDVI, Korea) and Axel Kroeger, MD (Special Programme for Research and Training in
Tropical Diseases, (TDR), WHO Switzerland).
References
Anderson KB, Chunsuttiwat S, Nisalak A, et al. (2007). Collenberg E, Ouedraogo T, Ganamé J, Fickenscher H,
Lancet. 369: 1452–1459. Kynast-Wolf G, et al. (2006). J Med Virol. 78:
Armien B, Suaya JA, Quiroz E, et al. (2008). Am J Trop 683–692.
Med Hyg. 79(3): 364–371. Deen JL, Harris E, Wills B, et al. (2006). Lancet. 368:
Balmaseda A, Hammond SN, Pérez MA, et al. (2005). 170–173.
Am J Trop Med Hyg. 73: 1059–1062. Dhar S, Malakar R, Ghosh A, Kundu R, Mukhopadhyay M,
Beatty ME, Hunsperger E, Long, et al. (2007). Emerg Banerjee R. (2006). Indian J Dermatol. 51: 57–59.
Infect Dis. 13(2): 308–310. Donoso Mantke O, Lemmer K, Biel SS, et al. (2004).
Blacksell SD, Doust JA, Newton PN, Peacock SJ, Day NP, J Clin Virol. 29: 105–112.
Dondorp AM. (2006). Trans R Soc Trop Med Hyg. Duarte HH, França EB. (2006). Rev Saude Publica.
100: 775–784. 40: 134–142.
Cattand P, Desjeux P, Guzmán MG, Jannin J, Kroeger A, Epidemic and Pandemic Alert and Response (EPR),
et al. (2006). Tropical Diseases Lacking Adequate World Health Organization (WHO). (2006). Chi-
Control Measures: Dengue, Leishmaniasis, and kungunya and Dengue in the South West Indian
African Trypanosomiasis, Chap. 23. Disease Control Ocean. http://www.who.int/csr/don/2006_03_17/
Priorities in Developing Countries, 2nd ed. Oxford en/index.html. Accessed 30 May 2008.
University Press, New York, pp. 451–466. Epidemic and Pandemic Alert and Response (EPR), World
Centers for Disease Control and Prevention (CDC). Health Organization (WHO). (2008). Dengue/
(2001). MMWR Morb Mortal Wkly Rep. 50: 57–59. dengue Haemorrhagic Fever in Brazil. http://www.
Centers for Disease Control and Prevention (CDC). who.int/csr/don/2008_04_10/en/index.html.
(2005). MMWR Morb Mortal Wkly Rep. 54: 556–558. Accessed 30 May 2008.
Chairulfatah A, Setiabudi D, Agoes R, van Sprundel M, EuroQOL Group. (1990). Health Policy. 16: 199–208.
Colebunders R. (2001). Acta Trop. 80: 111–115. Fan WF, Yu SR, Cosgriff TM. (1989). Rev Infect Dis. 11
Clark DV, Mammen MP Jr, Nisalak A, Puthimethee V. (Suppl. 4): S847–853.
(2005). Am J Trop Med Hyg. 72: 786–791. Gambel JM, Drabick JJ, Swalko MA, Henchal EA,
Cobelens FG, Groen J, Osterhaus AD, Leentvaar- Rossi CA, Martinez-Lopez L. (1999). Mil Med.
Kuipers A, Wertheim-van Dillen PM, Kager PA. 164: 300–302.
(2002). Trop Med Int Health. 7: 331–338. Gubler DJ, Meltzer M. (1999). Adv Virus Res. 53: 35–70.
Guzmán MG, Kourı́ G. (2004). Int J Infect Dis. 8: 69–80. Pediatric Dengue Vaccine Initiative (PDVI). (2006). PDVI
Guzmán MG, Pelegrino JL, Pumariega T, et al. (2003). diagnostic programs. http://www.pdvi.org/Newsletter_
Rev Panam Salud Publica. 14: 371–376. files/PDVIDiagnostics.htm. Accessed 26 Sept 2006.
Halstead SB. (1988). Science. 239: 476–481. Phuong HL, de Vries PJ, Nga TT, Giao PT, Hungle Q,
Halstead SB. (1997). In: Gubler DJ, Kuno G (eds.) et al. (2006). BMC Infect Dis. 6: 123.
Dengue and Dengue Hemorrhagic Fever. CAB Prosser LA, Hammitt J, Keren R. (2007). Pharmacoeco-
International, Wallingford, UK, pp 23–44. nomics. 25: 713–726.
Halstead SB. (1999). Lancet. 353: 1100–1101. Qiu FX, Chen QQ, Ho QY, Chen WZ, Zhao ZG,
Halstead SB. (2005). Emerg Infect Dis. 11: 740–741. Zhao BW. (1991). Am J Trop Med Hyg. 44: 364–370.
Halstead SB, Streit TG, Lafontant JG, et al. (2001). Am J Qiu FX, Gubler DJ, Liu JC, Chen QQ. (1993). Bull World
Trop Med Hyg. 65: 180–183. Health Organ. 71: 349–359.
Ibrahim SA, Mustafa OM, Mukhtar MM, et al. (2002). Ratho RK, Mishra B, Kaur J, Kakkar N, Sharma K.
Trop Med Int Health. 7: 442–449. (2005). Indian J Med Sci. 59: 519–527.
International Federation of Red Cross and Red Crescent Rigau-Pérez JG. (1997). Rev Panam Salud Publica. 1:
Societies. (2007). Cambodia: Dengue Fever. Infor- 381–388.
mation Bulletin. July 10, 2007. http://www.ifrc.org/ Rigau-Pérez JG. (1999). P R Health Sci J. 18: 337–345.
docs/appeals/rpts07/KHdg07100701. pdf Accessed Rigau-Perez JG. (2006). Lancet Infect Dis. 6: 297–302.
30 May 2008. Rigau-Perez JG, Ayala-Lopez A, Garcia-Rivera EJ, et al.
Jamaluddain M, Saxena VK. (1997). J Commun Dis. 29: (2002). Am J Trop Med Hyg. 67: 355–362.
169–170. Rigau-Pérez JG, Gubler DJ. (1999). Lancet. 353: 1101.
Johnson BK, Ocheng D, Gichogo A, et al. (1982). East Afr Rodier GR, Gubler DJ, Cope SE, et al. (1996). Trans R
Med J. 59: 781–784. Soc Trop Med Hyg. 90: 237–240.
Kabilan L, Balasubramanian S, Keshava SM, Satyanar- Salomon JA, Murray CJL. (2004). Health Econ. 13:
ayana K. (2005). Indian J Pediatr. 72: 919–923. 281–290.
Kumar A, Sharma SK, Padbidri VS, Thakare JP, Saluzzo JF, Cornet M, Castagnet P, Rey C, Digoutte JP.
Jain DC, Datta KK. (2001). J Commun Dis. 33: (1986). Trans R Soc Trop Med Hyg. 80: 5.
274–281. Schwartz E, Mendelson E, Sidi Y. (1996). Am J Med. 101:
Kuniholm MH, Wolfe ND, Huang CYH, et al. (2006). 516–520.
Am J Trop Med Hyg. 74: 1078–1083. Sharma SN, Raina VK, Kumar A. (2000). J Commun Dis.
LaRocque RC, Breiman RF, Ari MD, et al. (2005). Emerg 32: 175–179.
Infect Dis. 11: 766–769. Sharp TW, Wallace MR, Hayes CG, et al. (1995). Am J
Lee MS, Hwang KP, Chen TC, Lu PL, Chen TP. (2006). Trop Med Hyg. 53: 89–94.
J Microbiol Immunol Infect. 39: 121–129. Shepard DS, Suaya JA, Halstead SB, et al. (2004). Vac-
Levett PN, Branch SL, Edwards CN. (2000). Am J Trop cine. 22: 1275–1280.
Med Hyg. 62: 112–114. Suaya JA, Chai PF, Shepard DS, Lum L. (2003).
López-Vélez R, Pérez-Casas C, Vorndam AV, Rigau J. Resource Utilization of Hospitalized Dengue
(1996). Eur J Clin Microbiol Infect Dis. 15: 823–826. Infected Children in Malaysia. Paper presented at
Lum LCS, Suaya JA, Tan LH, Sah BK, Shepard DS. the Annual Meeting, Academy for Health
(2008). Am J Trop Med Hyg. 78(6): 862–867. Services Research and Health Policy, TN, USA,
Malik EM, Eltahir HG, Ahmed ES. (2005). East Mediterr June 2003.
Health J. 11: 753–761. Suaya JA, Shepard D, Armien B, et al. (2007a). Am J Trop
Meltzer MI, Rigau-Pérez JG, Clark GG, Reiter P, Med Hyg. 77: 9.
Gubler DJ. (1998). Am J Trop Med Hyg. 59: Suaya JA, Shepard DS, Beatty ME. (2007b). Dengue
265–271. burden of disease and cost of illness. In: Scientific
Morrill JC, Johnson BK, Hyams C, et al. (1991). J Trop Working Group: Report on Dengue. World Health
Med Hyg. 94: 166–168. Organization on behalf of the Special Programme
Murray CJ. (1994). Bull World Health Organ. 72(3): for Research and Training in Tropical Diseases.
429–445. Geneva, pp. 35–49. TDR/SWG/08.
National Vector Borne Disease Control Programme Teixeira MG, Barreto ML, Costa MCN, Ferreira LDA,
(NVBDCP). (2008). Directorate General of Health Vasconcelos PVC, Cairncross S. (2002). Tro Med
Services, Ministry of Health and Family Welfare, Int Health. 7: 757–762.
Government of India. Dengue Cases and Deaths Tuntaprasart W, Barbazan P, Nitatpattana N,
Since 2001. http://www.nvbdcp.gov.in/dengueC&D. Rongsriyam Y, Yoksan S, Gonzalez JP. (2003).
html. Accessed 26 Sept 2007. Southeast Asian J Trop Med Public Health. 34:
O’Leary JF, Fairclough DL, Jankowski MK, Weeks JC. 564–568.
(1995). Med Decis Making. 15: 132–137.
Vector Control Research Center ICoMR. (2006). Dengue World Health Organization WHO/WPRO/SEARO.
and Dengue Hemorrhagic Fever. http://www.pon. (2004). Wkly Epidemiol Rec. 79(6): 57–62. http://
nic.in/vcrc/deng.html. Accessed 15 October 2006. www.who.int/wer/2004/en/wer7906.pdf.
Vijayakumar TS, Chandy S, Sathish N, Abraham M, World Health Organization (WHO). (2006b). Wkly Epi-
Abraham P, Sridharan G. (2005). Indian J Med demiol Rec. 81: 349–356.
Res. 121: 100–107. World Health Organization (WHO). (2006c). Dengue-
World Health Organization (WHO). (1994). Division of Net http://www.who.int/csr/disease/dengue/den-
Communicable Diseases Partnership for Child De- guenet/en/index.html. Accessed 25 Sept 2006.
velopment. International Conference on Dengue World Health Organization (WHO). (2002). Dengue
Haemorrhagic Fever. Report of WHO/ICMR/DBT and Dengue Haemorrhagic Fever. Fact sheet
meeting and National Brainstorming Session on N 117. April 2002; http://www.who.int/mediacen-
Dengue, National Institute of Virology. World tre/factsheets/fs117/en/print.html. Accessed 26 Sept
Health Organization, Geneva, p. 7. WHO/CDS/ 2006.
MIM/94.1. World Health Organization (WHO). (2006d). Tropical
World Health Organization (WHO). (1997). Dengue Diseases Research (TDR). Strategic Direction for
Haemorrhagic Fever: Diagnosis, Treatment, Preven- Research: Dengue. http://www.who.int/tdr/diseases/
tion and Control, 2nd ed. WHO, Geneva. dengue/direction.htm. Accessed 26 Sept 2006.
World Health Organization (WHO). (2000). Dengue and World Health Organization (WHO). (2008). World
Dengue Hemorrhagic Fever. Global Surveillance of Health Survey Instruments and Related Documents.
Epidemic Prone Infectious Diseases. WHO, Geneva. World Health Organization, Geneva. http://www.
World Health Organization (WHO). (2006a). Dengue- who.int/healthinfo/survey/instruments/en/index.html.
Net Implementation in the Americas. Report of a Accessed 15 Jan 2008.
WHO/PAHO/CDC Meeting, San Juan, Puerto Rico, World Tourism Organization. (2005). Tourism High-
9–11 July 2002. http://www.who.int/csr/resources/ lights. 2005.
publications/dengue/WHO_CDS_CSR_GAR_2003_8/ World Tourism Organization. (2006). Compendium of
en/index.html. Accessed 26 Sept 2006. Tourism Statistics. www.world-tourism.org/statis-
World Health Organization (WHO). (2003). Communi- tics/index.htm. Accessed 25 Sept 2006.
cable Diseases and Disease Surveillance Dengue Re- Yabe S, Nakayama M, Yamada K, et al. (1996). Kansen-
port. Proceedings of the Meetings on Vector Borne shogaku Zasshi. 70: 1160–1169.
Disease Surveillance with Special Focus on Dengue- Zaidi AKM, Awasthi S, DeSilva HJ. (2004). BMJ. 328:
Net at Delhi and Bangalore Organized by NICD in 811–815.
Collaboration with WR India, CSR/ Hq. SEARO Zeckhauser R, Shepard D. (1976). Law Comtemp Probl.
under USAID/WHO/Hq. 40(4): 5–45.
73 Cost-Effectiveness of a
Dengue Vaccine in Southeast
Asia and Panama: Preliminary
Estimates
D. S. Shepard . J. A. Suaya
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282
2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1283
3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1289
4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1291
5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1293
Summary points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1294

1282 73 Cost-Effectiveness of a Dengue Vaccine in Southeast Asia and Panama: Preliminary Estimates
Abstract: To ascertain the economic feasibility of a pediatric tetravalent dengue vaccine, we

developed and calibrated a cost-effectiveness model of vaccinating children at 15 months in
Southeast Asia and Panama using a societal perspective. We assumed that full immunization
would require two doses. In Southeast Asia, the gross cost per vaccinee would be US $8.28.
Due to projected savings in dengue treatment, the net cost per capita would be 89% below the
gross cost. The cost per disability adjusted life year (DALY) saved by a pediatric vaccine would
be $50, making the potential vaccine highly cost-effective. In Panama, where we assumed a
higher price per dose ($5), the gross cost per vaccinee would be $19.70 for infants and $26.70
in a catch up program for adults. As projected treatment costs are higher, however, averaging
$154.27 when discounted to the time of vaccination, the estimated cost offsets would be 178%
of vaccination costs for infants and 138% for adults. Thus the dengue vaccination appears to
be cost saving under our most likely assumptions. Many uncertainties remain, however, until
more epidemiological and economic data are obtained and vaccine development proceeds
further.
List of Abbreviations: CS, cost saving; DALYS, disability adjusted life years; DF, dengue fever;
DHF, dengue hemorrhagic fever; DPT3, diphtheria pertussis tetanus (dose 3); DSS, dengue
shock syndrome; GAVI, Global Alliance for Vaccines and Immunization; GNI, gross national
income; HBV, hepatitis B vaccine; HIB, hemophilus influenza B; PAHO, Pan American Health
Organization; SE Asia, Southeast Asia; WHO, World Health Organization
1 Introduction
Dengue is a mosquito-borne disease which threatens half the world’s population (Strobel and
Lamaury, 2001). Epidemiological publications and surveillance reports have documented the
sobering increase in cases and deaths from dengue (Strobel and Lamaury, 2001) and its spread to
new areas, such as the Middle East and the US states of Texas (Gubler, 1998), (Centers for Disease
Control, 2002) and Hawaii (Centers for Disease Control, 2002), and Paraguay (BBC, 2007). In the
Americas, major outbreaks occurred in 2002 and 2007 with about one million cases reported in
each outbreak (Pan American Health Organization, 2008) greatly increasing the importance
of effective control programs. As of 2008, the National Institutes of Health have a product
in Phase 1 testing, and both Glaxo Smith Kline and Sanofi Pasteur have candidate vaccines in
Phase 2 clinical testing, and other developers are conducting laboratory research (Pediatric
Dengue Vaccine Initiative (PDVI), 2008). To help guide stakeholders around continued invest-
ment in the development and potential use of a dengue vaccine, this paper uses and extends the
authors, previous work on its cost-effectiveness in Southeast Asia (SE Asia) (Shepard et al., 2004).
Periodically, economic analyses are conducted to guide public support for vaccine
development in both industrialized (Stratton et al., 2001) and developing countries (Insti-
tute of Medicine, 1986), (Shepard et al., 1995), including previous cost-effectiveness studies
of dengue (Shepard and Halstead, 1993), (Shepard et al., 2004). Insufficient economic
analysis may have delayed the adoption of Hepatitis B vaccine (HBV) in developing
countries (Muraskin, 1995). To minimize such risks with a pneumococcal pneumonia
vaccine, a study on its cost-effectiveness is informing plans to greatly expand its use to
low- and middle-income countries (Sinha et al., 2007).
Assuming a pediatric dengue vaccine proves safe and effective, here we first examine
whether it would be economically viable in the regional context of SE Asia. This region, the
Cost-Effectiveness of a Dengue Vaccine in Southeast Asia and Panama: Preliminary Estimates 73 1283
focus of our earlier study (Shepard et al., 2004), has traditionally witnessed the highest
incidence; the disease primarily strikes children and has been the site of major epidemics in
the past 20 years (World Health Organization (WHO), 1997). The ten countries in SE Asia
(Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand,
and Vietnam) had a combined population in 1999 of 529 million persons (Population
Reference Bureau, 2001). From 1997 through 2001, these countries officially reported to the
World Health Organization (WHO) 1.2 million cases of dengue fever (DF) or dengue
hemorrhagic fever (DHF), a life-threatening form of the disease, while the actual burden is
projected to be far higher (Gubler and Meltzer, 1999). Our target population in SE Asia, the
cohort of 11.6 million children who reached the age of 15 months sometime in 2001, was
based on births in 1999 (United Nations, 2000, 2001).
Our analysis next shows how our earlier framework (Shepard et al., 2004) can be applied to
a national context. As a recent publication about Panama provides a comprehensive assess-
ment of the cost of dengue in that country (Armien et al., 2008), we have selected it for
illustration. Panama also illustrates the growing problem of dengue in the Americas. In
Panama, dengue was re-introduced in 1985 and the country has experienced transmission
since 1993. In 2005, the country experienced its worst epidemic since 1993, with over 5,482
dengue cases, 7 dengue hemorrhagic fever cases, and 5 deaths reported (Armien et al., 2008).
For both areas, this paper (1) estimates the health benefits of offering dengue vaccination
to annual child cohorts in that region, (2) determines the annual cost of that strategy, and
(3) projects potential revenues to vaccine producers from sale of a pediatric dengue vaccine
(Mahoney and Maynard, 1999). Our analysis is designed to inform the many stakeholders in
vaccine development, including national governments, donors, research institutes, vaccine
producers, and financing intermediaries such as the Vaccine Fund, which supports the
activities of the Global Alliance for Vaccines and Immunization (GAVI) (Global Alliance for
Vaccines and Immunizations, 2002). The stakeholders interact because investment decisions
by donors and producers on vaccine development depend, in part, on the potential utilization
and revenue from a vaccine if it is developed.
Through this paper, we illustrate the choices facing policy makers. They must decide not
only whether to recommend use of a dengue vaccine if available, but also the appropriate
target population – specifically adults and infants. Addressing these questions highlights the
needs and challenges in obtaining the needed data and predictions. Uncertainties affect many
key parameters – the degree of under-reporting of dengue, the exact loss in quality of life, the
mixture of treatment sites, and the cost, efficacy, period of protection, and side effects of a
potential vaccine. For this reason, our approach is primarily didactic and our results and
sensitivity analyses are necessarily preliminary. To address these limitations, we also indicate
a research agenda for more definitive findings.
2 Methods
We conducted this economic analysis using standard approaches to cost-effectiveness analysis

(Shepard and Thompson, 1979), (Gold et al., 1996) to derive the cost per Disability Adjusted
Life Year (DALY) saved (World Bank, 1993). Each DALY saved represents 1 year of healthy
life gained due to postponement of mortality and/or reduction in rate or severity of morbidity.
To estimate the potential benefits of vaccination, we first constructed a conceptual model of
. Figure 73-1
Disease model of dengue and transition rates for SE Asia. The disease model shows the
possible transition from a member of the general population to death from dengue hemorrhagic
fever, with probabilities of favorable and unfavorable outcomes at each branch
dengue and calibrated it based on existing literature (> Figure 73-1) (Shepard et al., 2004).
This proved important because terminology between dengue infections and dengue cases or
dengue fever versus dengue hemorrhagic fever is sometime inconsistent. It also provided the
basis for disease modeling, where each rectangle represents a model state.
In adapting this framework to Panama, we used the number of reported cases in 2005, 2006,
and 2007 by age as of mid-2008 (Panama Ministry of Health, 2008). Due to reporting lags, data
for 2007 were still preliminary. Reported cases are widely believed to understate the true
burden. We calculated projected cases by multiplying the reported cases times six, the expan-
sion factor estimated by the Ministry of Health (Armien et al., 2008). As 2005 was an epidemic
year for Panama, the two subsequent years had fewer cases. Nevertheless, dengue has been
increasing steadily in the Americas (Pan American Health Organization, 2008). For that reason,
we chose to calibrate this model from the most recent three years, rather than earlier data. In
2005, Panama had a population of 3.2 million persons and a per capita gross national income
(GNI) of $4,630; it projected 32,934 clinical cases, of which 456 were hospitalized and 5 were
fatal (Armien et al., 2008).
To convert numbers of cases into population-based rates, we projected the population of
Panama for 2006 and 2007 based on its growth rate of 1.528% per year (Central Intelligence
Agency, 2008). As long term projections showed that the proportion of the population in
the age group in which most dengue cases fall (ages of 15–59) would barely change through the
year 2050 (United Nations, 2005), we applied the overall population growth rate to each group
for our limited projection to the year 2006. We chose that year as it was not an epidemic year
and had data for the full year.
. Table 73-1
Selected dengue indicators for Panama by year, 2005–2007
Indicator 2005 2006 2007

Reported dengue cases 5,489 4,323 3,527
Projected dengue cases 32,934 25,938 21,162
Estimated population 3,228,186 3,277,513 3,327,593
Projected dengue cases per 100,000 population 1,020 791 636
Projected dengue infections per person per year 4.3% 3.3% 2.6%
Life expectancy at birth (years) 75.0 75.0 75.0
Projected lifetime infections per person (undisc) 3.188 2.473 1.987
Projected lifetime cases per person (undiscounted) 0.765 0.594 0.477
Projected lifetime cases per person (discounted) 0.293 0.230 0.188
> Table 73-1 reports selected indicators for Panama by year from 2005 through 2007. As
the life expectancy at birth of Panama is 75 years, we projected lifetime cases by multiplying
the average incidence of projected clinical cases times the life expectancy. As only 24% of
infections are estimated to be clinical cases (Shepard et al., 2004), we projected lifetime
infections by dividing the clinical cases by 24%.
> Figure 73-2 shows the rates of reported dengue cases by age and year for 2005 through
2007. Whereas in SE Asia dengue affects primarily children (Shepard et al., 2004), in Panama
the highest incidence is in adults.
To understand the lifetime pattern of dengue, we calculated the cumulative number of
projected dengue cases by age for Panama. This involved using the aforementioned expan-
sion factor and the period of risk within each age interval. As an approximation, we ignored
deaths within each age group except the last, so each closed interval had a 5-year period of
risk. For the last, open-ended interval, we assumed a 10-year period of risk, approximating
to the discounted life expectancy at age 70. > Figure 73-3 plots these cumulative rates by year.
While the cumulative rates differ among the 3 years, the relative patterns by age are extremely
stable.
As we wanted to examine the effect of vaccinations at different ages, we needed to estimate
the proportion of expected lifetime average clinical cases that occurred after each specified
age category after birth, without adjustment for mortality over the lifespan. As shown in
> Figure 73-4, this proportion declines steadily from 100% at birth to 0% by age 65. As
the benefits of trying to vaccinate persons aged 65 and above would be very low; however,
this simplifying assumption of no adjustment for mortality is reasonable. If a more complex
analysis were conducted with adjustment for mortality, the proportion would decline to a
small fraction, but not necessarily zero, at age 65. While these proportions could be structured
by age group, the cumulative proportions differed by no more than one percentage point
among age groups, so average proportions were used here instead.
Our time horizon for the analysis was the lifetime for the cohort, which, for Panama, we set
to the country’s life expectancy of 75 years (World Bank, 2008). With the expected average
annual dengue infection rate of 3.5%, Panama has two thirds of the corresponding rate for SE
. Figure 73-2
Rate of reported dengue cases in Panama by age and year. With square marks for 2005, circles
for 2006, and triangles for 2007, the graph shows that all 3 years show similar patterns of
age-specific incidence rates of reported dengue cases, with the highest rates being among those
aged 55–59 years
Asia of 5%. We adopted a societal perspective for evaluating costs and benefits. As Panama’s
official currency is the US dollar, we kept all economic analyses in 2005 US dollars.
Our reference for all economic analyses was the current situation, i.e., no dengue vaccina-
tion exists and dengue remains a threat despite ongoing vector control programs. The vector
control program entails varying levels of public education, inspection of potential breeding
sites, elimination or appropriate management of larval habitats, and insecticidal measures
against larvae and adults.
Because of the predominance of adult cases, we considered two alternative vaccination
scenarios. The first would vaccinate children as they pass through the routine health care
system at about age 1 year, as was assumed for SE Asia (Shepard et al., 2004). The second is a
catch up program, in which vaccination is offered to persons aged 15–64.
In adapting our model from SE Asia to Panama, there were three major changes. First, the
major difference in the share of cases being hospitalized is substantially lower in Panama.
Second, we were able to estimate treatment costs from the recent study from Panama (Armien
et al., 2008), rather than the literature. The resulting costs per case proved higher than the
earlier estimates for SE Asia based on earlier international literature (Shepard et al., 2004).
Third, the annual rate from ‘‘population’’ to ‘‘infection,’’ based on 2006 data, was 3.3% in
Panama, compared to 5% in SE Asia.
. Figure 73-3
Modeled projected dengue cases in Panama up to specified age, by year. With square marks
for 2005, circles for 2006, and triangles for 2007, the lines show that the modeled cumulative rate
of dengue infections rises in a similar way among age categories for the 3 years. An individual
could potentially experience up to four infections, one of each dengue serotype
Other factors remained the same as our previous model from SE Asia. We assumed that
vaccination would be 95% efficacious in providing lifetime protection against each of the four
dengue virus serotypes (Shepard et al., 2004), reducing the recipient’s annual risk of infection
to 0.165%. Vaccination would have negligible side effects. The quality of life values were based
on losses per day (compared to perfect health) of 0.81 and 0.85, for DF and DHF, respectively
(Gubler and Meltzer, 1999). In both areas, we assumed that children would be vaccinated with
two doses.
In SE Asia, we projected a mixed distribution system (both public and private) and two-
tiered prices from experience with HBV. For children vaccinated in public sector, the first dose
would coincide with the visit for measles vaccination, generally given at the average age of
9–12 months (Centers for Disease Control, 2002). The second, requiring a separate visit,
would occur around 18 months, the age just prior to the period of risk. For children vaccinated
in the private sector, we assumed that neither dose would coincide with an existing vaccination
and each thus dose would require a separate visit. Based on the current vaccination coverage
for DPT3 in SE Asia, we assumed that 85% coverage would be achieved at full implementation,
and 0.25 additional doses would be procured for each dose administered to compensate for
an estimated 20% wastage rate (UNICEF, 1998).
. Figure 73-4
Modeled percentage of dengue cases beyond each specified age category per person alive
(based on 2005–2007 data). This graph shows the percentage of cases beyond each age category,
normalized to the average rate, falls with age. The pattern is the inverse of the modeled
cumulative incidence rate
In Panama, a middle-income country in a region where governments traditionally buy

vaccines through a revolving vaccine fund, we assumed a single national price. Our base case
assumption used a bulk price of $5 per dose to parallel the assumed bulk price for pneumococcal
conjugate vaccine for children (Sinha et al., 2007). While the price of the pneumonia vaccine is
substantially higher in industrialized countries, a price of $5 per dose should allow widespread
adoption in a middle-income country, such as Panama, and, in large volume, may cover the
marginal cost of production. Financing could come from any combination of government,
households, donors, insurers, and social insurance systems. As fair pricing is one of the criteria
affecting the societal contribution, ranking and reputation of international vaccine manufacturers
(Menou et al., 2008), companies have good reasons to set affordable prices in developing countries.
On top of the vaccines, users would need syringes and services. To adjust for inflation and
higher prices in Panama than SE Asia, we estimated that syringes would cost $0.10 each. Costs
per contact of labor, overhead, vaccine distribution, and storage for administering the vaccine
would be $7 per contact, twice the original level (Shepard et al., 1995). The model ‘‘dis-
counted’’ health benefits (expressed as DALYs) and costs saved from vaccination at an annual
real (net of inflation) rate of 3% per year.
We performed sensitivity analyses of key variables and assumptions in SE Asia. First, we

varied the vaccine price per dose in SE Asia over the range of $0.25 (the current price of HBV
under the Vaccine Fund) to $10, which is twice the base price. It should be noted that the price
at which HBV started to be used in the public sector in developing countries was $1.50
(Mahoney and Maynard, 1999). Second, we varied the rate of clinical disease above and below
our best estimate based on alternative values of Gubler and Meltzer’s (1999) ‘‘multiplier’’ that
projects actual cases from reported cases. Third, we also examined a ‘‘least cost-effective
scenario’’ with the lowest infection rate, a low vaccine efficacy (85%), the highest public sector
vaccine price ($1.50), and only 85% of children served through the public sector.
In Panama, we considered a price range of $1–10 per dose, where the lower bound is
comparable to the public sector price for long established vaccines, while the upper bound
is twice the estimated bulk price. We also considered alternative expansion factors, assuming
that the projected number of cases per reported case could range from 2 (giving the lowest
number of cases) to 10, based on the broad range of expansion factors in the international
literature (Suaya et al., 2007).
To best adapt our model to available data from Panama, we focused our model of impact
around projected clinical cases. Thus, averaging across hospital and ambulatory cases, both
fatal and non-fatal we derived the direct cost of treating one clinical case (the sum of medical
and non-medical direct costs) and the indirect cost per case. We then discounted these to
present value based on the age of the vaccines (1 year for infants, and 15–64 for adults,
weighted according to their shares in the Panama population in 2005). We used the incidence
rate in 2006 (our middle year), alternative expansion factors for under-reporting, and
assumed vaccine characteristics to estimate the number of cases averted and associated health
benefits (in DALYs) and dollars gained.
3 Results
The baseline disease burden of dengue in SE Asia for the cohort is 0.42 DALYs per 1,000
population, of which 52% is due to premature mortality and 48% to acute morbidity. The
baseline gross cost of treatment is $99 per 1,000 population per year. Although DHF con-
stitutes only 6% of clinical cases, it represents 68% of the disease burden and 67% of the
treatment costs. In SE Asia, the dengue vaccination program would cost $50 per DALY saved
under the base assumptions (> Table 73-2). This cost-effectiveness ratio is the cost to buy
. Table 73-2
Cost-effectiveness of dengue vaccination in SE Asia under alternative DHF rates and costs of
vaccine in the public sector (US$/DALY gained)a
Public sector vaccine price per dose

DHF per 100,000 population $0.25 $0.50 $1.00 $1.50
36 $438 $499 $622 $683
72 $19 $50 $111 $41
108 CS CS CS CS
a
The base case values for this sensitivity analysis are bolded. CS denotes cost saving (i.e., vaccination costs less than
the status quo)
a year of good health. The lower that ratio, the more favorable the health intervention.
The calculated ratio also means that each $1 million invested in dengue vaccination
would save 20,000 DALYs. The sensitivity value shows that the cost-effectiveness ranges
from 0 to 100,000.
In SE Asia, under our most likely assumptions, vaccination reduces both the mortality and
morbidity burdens of disease by 82%, saving 0.34 DALYs per 1,000 population per year. The
incremental cost of vaccinating one child against dengue would be $4.85 in the public sector,
$39.10 in the private sector, and $8.28 overall. Since each child would receive two doses, the
cost per dose would be $4.14. The gross cost per 1,000 population of the vaccination program
would be $154. This cost is relatively low because children must be vaccinated during just
1 year of their life, but that cost is allocated over the entire population. The net cost per 1,000
population, $17, is 89% below the gross cost because of the savings in health care costs from
fewer dengue cases. In aggregate, when fully implemented in SE Asia, dengue vaccination
would cost $81.7 million per year, save $72.7 million in treatment, and have a net cost of
$9.0 million. It would save 182,000 DALYs per year.
In Panama, the incremental cost of vaccinating one person against dengue would be $19.70
for an infant and $26.70 for an adult (> Table 73-3). The adult cost is higher because the adult
needs two incremental contacts with the health care system, whereas the child needs only one.
Even ignoring the cost offsets, the vaccine is relatively cost-effective, at $2,069 and $2,574 per
DALY in infants and adults, respectively. The cost offsets are more substantial than those in SE
Asia as the costs of dengue treatment are higher, based the recent empirical study (Armien
et al., 2008). The cost offsets represent 178% of vaccination costs for infants and 138% for
adults. Thus, with the cost offsets included, the vaccine becomes cost saving.
. Table 73-3
Economic evaluation of dengue vaccination in Panama under most likely assumptions
Item Infants Adults

Expansion factor for cases (projected/reported) 6 6
Projected lifetime cases per person (discounted) 0.2304 0.2510
Vaccine efficacy 95% 95%
Projected lifetime cases averted per person vaccinated 0.2189 0.2384
(disc.)
Disease burden per discounted case (DALYs) 0.0435 0.0435
Disease burden averted per person vaccinated (DALYs) 0.0095 0.0104
Gross cost per person vaccinated (US$) $19.70 $26.70
Direct cost per discounted case $154.27 $154.27
Projected lifetime direct cost averted per person vaccinated $33.77 $36.78
Net cost per person vaccinated -$14.07 -$10.08
Total cost per discounted case (direct and indirect) $359.14 $359.14
Projected lifetime total cost averted per person vaccinated $78.62 $85.63
Cost-effectiveness, ignoring offsets (US$/DALY) $2,069 $2,574
Cost-effectiveness, including offsets (US$/DALY) CSa CSa
Benefit-cost ratio 4.0 3.2
a
CS denotes ‘‘cost saving,’’ so vaccination offsets more than its costs
. Table 73-4
Economic analysis of dengue vaccination in Panama under alternative expansion factors and
vaccine prices
Vaccine price per dose
Include $1 $5 $10
Expansion factor cost offsets Infants Adults Infants Adults Infants Adults
Cost-effectiveness (US$/DALY gained)
2 Yes CS $1,284 $2,660 $4,177 $6,598 $7,792
No $3,056 $4,831 $6,207 $7,723 $10,145 $11,339
6a Yes CS CS CS CS CS $233
No $1,019 $1,610 $2,069 $2,574 $3,382 $3,780
10 Yes CS CS CS CS CS CS
No $611 $966 $1,241 $1,545 $2,029 $2,268
Benefit-cost ratio
2 Yes 2.7 1.7 1.3 1.1 0.81 0.73
6a Yes 8.1 5.1 4.0 3.2 2.4 2.2
10 Yes 13.5 8.5 6.7 5.3 4.1 3.6
a
The most likely values corresponding to the most likely assumptions are bolded
> Table 73-4 reports the sensitivity analysis for Panama. For most values of the vaccine-
price and expansion factor, the vaccine is cost saving. Even under the least favorable combi-
nation of the expansion factor (two times reported cases) and vaccine price ($10 per dose),
the vaccine would have borderline cost-effectiveness for a middle income country.
4 Discussion
Cost-effectiveness. Cost-effectiveness interpretations should first relate to other health inter-

ventions as a whole. The cost-effectiveness ratio for a dengue vaccine in SE Asia ($50 per DALY
saved) is comparable to the most favorable public health programs for children, which each
cost less than $100 per DALY saved (i.e., control of respiratory infections, perinatal conditions,
diarrheal disease, pertussis, polio, measles, tetanus, malaria, malnutrition, and vitamin A
deficiency). It is 20 times more favorable than the treatment of leukemia (World Bank, 1993).
Next, a dengue vaccine should be judged against other approaches to prevention, particu-
larly environmental control. By contrast to the cost per DALY of $50 for vaccination, the
published cost-effectiveness ratio for an environmental management approach to dengue
prevention and control ($3,139 per DALY), derived from the Singapore experience, was far
less favorable (Shepard and Halstead, 1993). While a pediatric dengue vaccine would be
expected to confer virtual lifelong immunity, environmental management, must be delivered
repeatedly each year to the entire population as part of an integrated vector control strategy,
with associated high recurrent costs. With few exceptions, sustained control or prevention of
dengue virus transmission by vector control has not been achieved in recent decades, mainly
due to operational constraints including weaknesses of program delivery, continuity and
coverage, and over-reliance on insecticidal control methods, especially those targeting adult
mosquitoes. Control programs have generally failed to engage communities in sustainable
behavior change that prevents the creation of, or controls larval habitats.
We estimate that after many cohorts have been vaccinated, vaccinations would be at least as
effective as current vector control programs, and could supplant them for purposes of preventing
dengue transmission. To estimate the potential savings, we assembled the most recent available data
on dengue vector control. As dengue is primarily an urban disease, more urbanized countries had
higher spending. Annual cost per 1,000 population was $15 in Indonesia (1998), $81 in Thailand in
1994 (Sornmani and Okanurak, 1995), $188 in Thailand in 1998, $240 in Malaysia (2002), and
$2,400 in Singapore (2000) (unpublished data, World Health Organization for Indonesia and
Thailand; Ministry of Health, Malaysia; Ministry of the Environment, Singapore). For 1997, among
14 Latin American countries, corresponding spending on control ranged from $20 to 3,560 with a
median $260 (Pan American Health Organization (PAHO), 1999). For 17 Caribbean islands in
1990, the corresponding expenditure ranged from $140 to 8,490 with a median of $1,340 (Nathan,
1993). As control costs were predominantly for personnel, we used the same methodology applied
for vaccination costs to compute the average expenditure on environmental control for SE Asia.
In 2001 prices, this unweighted average was $66 per 1,000 population. Thus, if vaccination allowed
at least a one third reduction in spending on environmental control, it would be cost saving.
In Panama, as noted, we found that the dengue vaccination would be cost saving under the
most likely values. An upper threshold of three times the GDP per capita is recommended by
WHO to identify interventions that are ‘‘cost-effective’’ in low- and middle-income countries
(World Health Organization, 2008). The factor of three incorporates the human element in
cost-effectiveness – societies value years of healthy life for more than just their productivity
value. Even the least favorable cost-effectiveness ratio, $11,339, is less than three times
Panama’s per capita GNI.
Vaccination costs. One of the most critical questions in pharmaco-economics concerns
the price of the product. That price must satisfy the opposing needs of the consumers and the
producers of a product. It must be high enough to satisfy the needs of the producer. That is, it
must cover at least the amortized development and production costs plus a return competitive
with other alternatives. On the other hand, it must be low enough that the public sector could
purchase the vaccine on a large scale. This analysis for SE Asia suggested that our base case price
per dose ($0.50 in public sector and $10 in private sector) could meet these two objectives. The
proposed public price exceeds the cost per dose of older vaccines in the Expanded Programme
on Immunization, but is below the price of those most recently introduced (e.g., HBV and
Hib), suggesting it is a plausible average over the vaccine’s anticipated lifetime. The hypothe-
sized private price is comparable to existing private sector prices in SE Asia, e.g., $9.51 per dose
for Hib and $13.59 for the Japanese encephalitis in Malaysia manufactured by Biken (Cardosa,
M.J. personal communication, June 2003). Both industry and government representatives at a
major dengue conference understood the rationale for two-tiered prices of these magnitudes
(Almond et al., 2002). Under a national program, governments would purchase vaccines from
producer via tender, with negligible commissions and fees.
The full cost per dose (weighted average of the public and private sectors, including labor
and overhead) of $4.14 for SE Asia lies within the range ($0.50–6.00) of reported cost per dose
in a systematic review of studies of expanding vaccination coverage (Pegurri et al., 2005).
The analysis indicated that the vaccine price was also a critical variable in Panama.
Without considering treatment costs, the cost-effectiveness tripled as the assumed price
rose. With Panama being a middle-income country, dengue vaccination is clearly cost-effective
at the most favorable and most likely prices assumed in this analysis, but may not necessarily
be cost-effective at the least favorable (higher) assumed price.
Limitations and results of sensitivity analyses. The greatest limitations in our model are
uncertainties in its parameters. Multivalent vaccines have not yet reached the level of develop-
ment to know their efficacy, duration and type of protection, and side effects. Incomplete
reporting leads to uncertainty about the current burden of dengue. Our sensitivity analysis
showed that even with less favorable vaccine performance and disease incidence, vaccination
remained cost-effective in SE Asia.
Sensitivity analyses showed that the two factors that most affected the cost-effectiveness of
a dengue vaccine were: (1) the price per dose of vaccine, and (2) the incidence of DHF. The low
incidence of DHF in SE Asia (36 per 100,000 population per year) corresponds to half of
the base case values for each age group, with an overall annual infection rate of 2.5%. The
intermediate value (72) corresponds to the central values described in > Figure 73-1. The high
incidence (108) corresponds to an infection rate of 6% (16% for those under 15 years, and 3%
for those 15 and above) and 30% of infections being clinical cases. Higher rates of infection would
be impossible over the long run, as they would require reinfections with the same serotype.
If the incidence of DHF were high enough and the price were low enough, savings in treatment
of DF and DHF would more than offset the costs of vaccination. With the highest incidence of
DHF, vaccination is actually cost saving (CS) for all four prices shown and, in fact, for any price
per dose up to $1.73. The highest incidence and lowest price achieve the greatest savings.
The cost-effectiveness ratio under least favorable assumptions in > Table 73-2 ($683 per
DALY) and the cost-effectiveness ratios for poorer vaccine performance ($788 and $960
per DALY) all fall in the same category as several other public health programs in adults
(e.g., control of diabetes and motor vehicle injuries) (World Bank, 1993). Moreover, these
cost-effectiveness ratios are less than the region’s per capita GNI of $1,083 – another bench-
mark for cost-effective interventions.
Extension to other regions and population groups. The cost-effectiveness of vaccinations, like
that of other preventive programs, is roughly proportional to the disease burden. While
dengue has been endemic in SE Asia for decades, it returned to the Americas in 1980 and
spread in Brazil, Venezuela, Mexico, and other countries. In the United States, 102 cases of DF
were reported from Hawaii in 2001, the first outbreak on that island in 56 years (Centers for
Disease Control, 2002). Similar cost-effectiveness analyses could examine the extension of
vaccination to other countries, to older children and various adult ages in endemic countries,
as well as to travelers, and members of the military from non-endemic countries.
5 Conclusions
Several factors contributed to preliminary results favoring the development and subsequent use
of a dengue vaccine in SE Asia. First, at a projected price of $0.50 per dose in the public sector,
the dengue vaccine would be relatively inexpensive. This projection was based on the recent
success of large public sector procurement through the Vaccine Fund in driving down the price
of HBV to half of this level. It also counted on donor involvement in effectiveness testing, large
public sector procurement, with concomitant low marketing overhead, to provide the producer
with a means to reduce unit costs of production and distribution, thereby increasing overall
profitability. Second, by assuming that dengue vaccination would be linked with the last dose of
the Expanded Program on Immunization, a high (85%) coverage rate seemed reasonable.
In Panama, the similarity of preliminary results between targeting adults and infants as
vaccines was striking. Several differences between the two age groups happened to counterbal-
ance one another. An adult program was assumed to accept any adult aged 15–64. The average
age of those vaccinated would be about 40 years, just prior to the age of highest incidence (age
50). The use of discounting favors focusing on adults because their lag between vaccination
and peak disease is small, but for infants is large. This advantage for adults is offset by a smaller
fraction of projected lifetime clinical cases averted, due to a substantial portion of the disease
occurring before adult vaccination. If a vaccine did not provide protection that lasts over
multiple decades, then adult vaccination would clearly be preferable.
Several types of research are needed to address the data uncertainties. More studies on disease
burden, utilization of health services, and cost of illness, particularly population-based investiga-
tions, can help clarify incidence, patterns and costs of treatment, and outcomes. Definitive
data on vaccine performance must await Phase III and IV field studies. Vaccine prices depend
on manufacturers’ judgments about achieving financial and public recognition goals.
Summary points
We developed and calibrated a cost-effectiveness model of vaccinating children at

15 months in SE Asia and Panama.
We selected a societal perspective.
We assumed that full immunization would require two doses.
As our most likely assumptions, we assumed prices per dose of $0.50 and $10 each in the public
and private sectors, respectively, in SE Asia, and a uniform price of $5 per dose in Panama.
The gross cost per 1,000 population (of all ages) of the vaccination program would be US
$154 in SE Asia.
Projected savings in dengue treatment were projected to offset 89% of vaccination cost in
SE Asia, reducing the net cost per capita to only $17 per 1,000 population.
The cost per disability adjusted life year (DALY) saved by a pediatric vaccine would be $50
in SE Asia, making the potential vaccine highly cost-effective.
In Panama, due to higher treatment cost, a moderately priced vaccine would be cost saving
for both infants and adults; the result is even more favorable than being highly cost-
effective.
From a benefit cost perspective, a moderately priced dengue vaccine in Panama would also
be economically advantageous, with estimated benefits equal to 4.0 and 3.2 times the costs
for infants and adults, respectively.
In countries such as Panama where dengue affects primarily adults, both infant and adult
vaccinations are advantageous strategies.
Eventually, vaccination may allow countries to reduce spending on environmental control.
Acknowledgments
The preparation of this chapter was supported in part by the endowment of the Schneider
Institutes for Health Policy, Brandeis University, Waltham, MA, USA. The authors are
indebted to Gladys Guerrero, MD, MPH, and Dennys Rodriguez of the Department of
Epidemiological Surveillance of the Panama Ministry of Health for providing epidemiological

data from Panama, to Blas Armien, MD, of the Gorgas Memorial Institute, Panama, for
assistance with analysis of these data, and to Clare L. Hurley, MM, of Brandeis University
for editorial assistance.
References
Almond J, Clemens J, Engers H, Halstead SB, Khiem HB, CE142/17 (Eng.) for 142nd Session of the Executive
Pablos-Mendez A, Pervikov Y, Tram TT. (2002). Committee, Washington, D.C., USA, 23–27 June 2008.
Vaccine. 20: 3043–3046. Pan American Health Organization, World Health
Armien B, Suaya J, Quiroz E, Sah B, Bayard V, Marchena L, Organization, Washington, DC. http://www.reliefweb.
Campos C, Shepard D. (2008). Am J Trop Med Hyg. int/rw/RWFiles2008.nsf/FilesByRWDocUnidFilename/
79: 364–371. ASIN-7F3PF4-full_report.pdf/$File/full_report.pdf.
BBC. (2007). Dengue sparks Paraguay emergency. Accessed 22 May 2008.
London http://news.bbc.co.uk/2/hi/americas/6407287. Panama Ministry of Health. (2008). Dengue cases by
stm. Accessed 2 March 2007. health region and age group, 2005–2007. [Casos de
Centers for Disease Control. (2002). Notice: dengue fever dengue según region de salud por grupo de edad,
in Hawaii. http://www.cdc.gov/travel/other/dengue- 2005–2007]. Directorate of General Health, Depart-
hawaii-oct2001.htm. Accessed 23 January 2002. ment of Epidemiology, Panama.
Central Intelligence Agency. (2008). Panama. The world Pediatric Dengue Vaccine Initiative (PDVI). (2008). Den-
factbook. Langley, VA, Central Intelligence Agency. gue vaccines. Pediatric Dengue Vaccine Initiative,
https://www.cia.gov/library/publications/the-world- Seoul, Korea. http://www.pdvi.org/vaccines/vaccine.
factbook/geos/pm.html. Accessed June 25, 2008. htm www.pdvi.org.
Global Alliance for Vaccines and Immunizations. (2002). Pegurri E, Fox-Rushby JA, Walker D. (2005). Vaccine.
http://www.vaccinealliance.org/ Accessed 29 January 23:1624–1635.
2002. Population Reference Bureau. (2001). http://www.prb.
Gold MR, Siegel JE, Russell LB, Weinstein MC. (1996). org/Content/NavigationMenu/Other_reports/
Cost-Effectiveness in Health and Medicine. Oxford 2000–2002/sheet1.html. Accessed 18 August 2002.
University Press, New York. Shepard D, Suaya J, Halstead S, Nathan M, Gubler D,
Gubler D, Meltzer M. (1999). Adv Virus Res. 53: 35–70. Mahoney R, Wang D, Meltzer M. (2004). Vaccine.
Gubler DJ. (1998). Clin Microbiol Rev. 11: 480–496. 22: 1275–1280.
Institute of Medicine. (1986). New Vaccine Develop- Shepard D, Thompson M. (1979). Public Health Rep. 94:
ment: Establishing Priorities, vol. II: Diseases of 535–543.
Importance in Developing Countries. National Shepard D, Walsh J, Kleinau E, Stansfield S, Bhalotra S.
Academy Press, Washington, DC. (1995). Vaccine. 13: 707–714.
Mahoney RT, Maynard JE. (1999). Vaccine. 17: 646–652. Shepard DS, Halstead SB. (1993). In: Jamison DT,
Menou V, Hornstein A, Lipton-McCombie E. (2008). Mosley WH, Measham AR, Bobadilla JL (ed.)
Access to medicine index (Report prepared by the Disease Control Priorities in Developing Countries.
Innovest Healthcare Team). Netherlands Access to The World Bank, Oxford University Press, New
Medicine Foundation, Haarlem. http://atmindex. York, pp. 303–320.
org/download/67. Sinha A, Levine O, Knoll M, Muhib F, Lieu T. (2007).
Muraskin W. (1995). The War Against Hepatitis B: Lancet. 369: 389–396.
A History of the International Task Force on Hepa- Sornmani S, Okanurak K. (1995). Social and economic
titis B Immunization. University of Pennsylvania impact of dengue haemorrhagic fever in Thailand.
Press, Philadelphia. Social and Economic Units, Faculty of Tropical
Nathan MB. (1993). J Am Mosq Control Assoc. 9: 1–7. Medicine Mahidol University.
Pan American Health Organization (PAHO). (1999). Stratton K, Durch JS, Lawrence RS (ed.). (2001). Vac-
A Blueprint for Action for the Next Generation: cines for the 21st Century: A tool for Decision
Dengue Prevention and Control. http://www.paho. Making. National Academy Press, Washington DC.
org/English/HCP/HCT/hct-136–99.doc Accessed 29 Strobel M, Lamaury I. (2001). Rev Med Interne. 22:
January 2002. 638–647.
Pan American Health Organization. (2008). Dengue: Prog- Suaya JA, Shepard DS, Beatty ME. (2007). Dengue:
ress Report. Provisional Agenda Item 4.10, document burden of disease and costs of illness. Working
paper 3.2. In: Report of the Scientific Working New York. http://www.un.org/esa/population/publi-
Group meeting on Dengue, Geneva, 1–5 October cations/WPP2004/2004Highlights_finalrevised.pdf.
2006 (TDR/SWG/07). Special Programme for Research World Bank. (1993). World Development Report: Invest-
and Training in Tropical Diseases (TDR), WHO, www. ing in Health. World Bank, Washington, DC.
who.int/tdr, Geneva, Switzerland, pp 35–49. World Bank. (2008). World development indicators.
UNICEF. (1998). The state of the world’s children. www.worldbank.org. Accessed 1 June 2008.
http://www.unicef.org/sowc98/tab1.htm. Accessed 29 World Health Organization (WHO). (1997). Dengue
January 2002. Hemorrhagic Fever. Diagnosis, Treatment, Preven-
United Nations. (2000). Expected births for 2001. In. tion and Control. World Health Organization,
Statistics Division. http://unstats.un.org/cgi-bin/ Geneva.
cdbdemo.exe. Accessed 29 January 2002. World Health Organization. (2008). Cost-Effectiveness
United Nations. (2001). Social indicators. Statistics Divi- Thresholds. Choosing Interventions that are Cost
sion. http://www.un.org/depts/unsd/social/popula- Effective (WHO-CHOICE). In World Health Orga-
tion.htm. Accessed 29 January 2002. nization, Geneva. http://www.who.int/choice/costs/
United Nations. (2005). World Population Prospects. The CER_thresholds/en/index.html. Accessed 29 June
2004 Revision (ESA/P/WP.193). United Nations, 2008.
74 Burden of Sexually
Transmitted Chlamydia
trachomatis Infections
L. M. Niccolai . D. Berube
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1298
2 Global Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1299
3 Burden in Developed World . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1300
4 Disparities in Burden by Sex, Age, and Race . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1303

4.1 Women Have a Higher Observed Prevalence of Infection . . . . . . . . . . . . . . . . . . . . . . . . . 1303
4.2 Adolescents and Young Adults are Most Affected by C. trachomatis
Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1304
4.3 Racial and Ethnic Minorities are Disproportionately Affected by
C. trachomatis Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1304
5 Burden of Repeat C. trachomatis Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306
6 Increasing Burden of C. trachomatis Infections? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307
7 Burden of Associated Sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1308

7.1 Women Suffer Negative Long-Term Consequences as a Result of
C. trachomatis Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1308
7.2 C. trachomatis is Associated with High Economic Burden . . . . . . . . . . . . . . . . . . . . . . . . . . 1309
7.3 Infection with C. trachomatis Causes Increased HIV Transmission
and Acquisition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1309
8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1309
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1310

1298 74 Burden of Sexually Transmitted Chlamydia trachomatis Infections
Abstract: Chlamydia trachomatis (C. trachomatis) infections are the most common bacterial
sexually transmitted disease in the world, and therefore these infections constitute an enor-
mous public health problem. Globally, over 90 million new infections occur annually and a
higher burden of disease is found in resource poor countries, perhaps due to limited access to
care and treatment. In developed countries, C. trachomatis infection is the most common
reportable disease, and risk also varies along socioeconomic factors. Younger individuals have
higher burden of disease due to a variety of factors including physiological, psychological, and
structural reasons, and racial/ethnic minorities have a higher burden for reasons that are not
entirely clear but likely to be multifaceted. Women bear a disproportionate burden of negative
health consequences of C. trachomatis infections including pelvic inflammatory disease,
chronic pelvic pain, and infertility. The cost associated with treating infections and their
sequelae is substantial. Infection with C. trachomatis also contributes increased HIV transmis-
sion. Recent evidence of increasing C. trachomatis > prevalence has been reported, and this
necessitates immediate efforts to better understand these trends in order to implement
effective control measures. Continuing and improving existing control efforts are required
to reduce the burden of C. trachomatis infections.
List of Abbreviations: CDC, Centers for Disease Control and Prevention; C. trachomatis,
Chlamydia trachomatis; HIV, Human Immunodeficiency Virus; LGV, Lymphogranuloma
Venereum; NAAT, Nucleic Acid Amplification Test; PID, Pelvic Inflammatory Disease; STD,
Sexually Transmitted Disease; STI, Sexually Transmitted Infection; UK, United Kingdom; US,
United States
1 Introduction
The sexually transmitted disease known as chlamydia is caused by infection with Chlamydia
trachomatis bacteria. The C. trachomatis genus is sub-divided into different biovars: the
lymphogranuloma venereum (LGV) biovar that causes a different sexually transmitted infec-
tion (STI) also known as LGV, and the trachoma biovar that includes the genotypes that cause
genital tract and ocular diseases. The focus of this chapter will be on the sexually transmitted
trachoma biovar that causes urogenital chlamydial disease. While LGV is also an important
STI, its burden is less than that of chlamydia and has different epidemiology, so it will not be
discussed in detail.
> Sexual transmission of C. trachomatis can occur during vaginal, oral, or anal sexual
contact. The same genotypes can also be transmitted by a mother to her newborn during
delivery, causing eye conjunctivitis and/or pneumonia. Transmissibility in sexual partnerships
is estimated to be approximately 70% from both men to women and women to men (Quinn
et al., 1996). C. trachomatis infections are often asymptomatic, up to 75% of the time, and
more often asymptomatic in women than in men. When symptomatic, C. trachomatis
produces non-specific and generally mild symptoms. In women, signs and symptoms may
include cervicitis, urethritis, endometritis, and acute salpingitis. In men, signs and symptoms
may include urethritis, epididymitis, prostatitis, and proctitis. Long term consequences in
women include pelvic inflammatory disease, tubal scarring, chronic pelvic pain, and infertili-
ty, and in men, Reiter’s syndrome.
Diagnosis of urogenital chlamydial infections may be performed using swab specimens from
the endocervix or vagina in women and urethral swabs in men, or using urine specimens
Burden of Sexually Transmitted Chlamydia trachomatis Infections 74 1299
from both men and women. On these specimens, C. trachomatis may be detected by culture,
antigen detection (including direct immunoflourescence or enzyme immunoassays), DNA
hybridization, and nucleic acid amplification tests (NAATs). While cell culture is often consid-
ered the ‘‘gold standard,’’ its use is often impractical owing to the need for technical expertise,
specimen storage and transport, and a cell culture system. The other methods are both more
practical and less expensive, and the NAATs have superior sensitivity and specificity compared to
the non-amplification methods. The recommended treatment regimen for uncomplicated
chlamydial infections is either azithromycin (1 g single dose orally) or doxycycline (100 mg
twice a day for 7 days orally). Both treatments have equal efficacy (>95%) and rare adverse
events. Though doxycycline is less expensive, azithromycin is often preferred because of the
simplicity of the single dose regimen, ensuring higher compliance.
Because of the high frequency of asymptomatic infection and the long-term negative
health consequences, > screening for C. trachomatis been an important focus of chlamydia
control programs in many parts of the world. Recent advances in nucleic acid amplification
tests that can be performed on urine specimens (and thus outside of clinical settings) and the
availability of single dose treatment have made this more feasible. The goal of chlamydia
control has been to shorten the duration of infection, thereby improving reproductive health
for women and interrupting disease transmission.
2 Global Burden
Sexually transmitted C. trachomatis infections are a major source of morbidity throughout the
world in developing and industrialized countries alike. According to the World Health
Organization, the estimated number of new cases among adults in 1999 exceeded 90 million,
making C. trachomatis the most common bacterial STI pathogen (Gerbase et al., 1998). The
greatest burden of disease is found in South and South East Asia (>40 million new cases), in
large part reflecting the dense populations of large countries in this area of the world, followed
by sub-Saharan Africa (>15 million new cases) (> Figure 74-1).
In addition to a greater burden of disease due to larger population sizes, prevalence
estimates also suggest that individuals in developing countries are at greater risk for
C. trachomatis infections. Though variability in diagnostics, > surveillance, reporting, and
targeted populations make international comparisons difficult, a recent report from World
Health Organization summarized key differences across a variety of countries (Gerbase et al.,
1998; WHO, 2007). Studies of pregnant women from around the world indicate a greater risk
in S. and S. East Asia and Africa compared to Europe and North America. For example,
prevalence estimates among pregnant women in the five African countries of Cape Verde,
South Africa, Gabon, Central African Republic, and Tanzania range from 6 to 13%, and
estimates in the two Asian countries of Thailand and India are 6 and 17%, respectively. In
contrast, prevalence estimates among pregnant women in seven European countries range
from 3 to 8%, and in the US, the prevalence is estimated to be 8% (CDC, 2007). Perhaps the
best evidence for regional differences throughout the world comes from a single study that
used similar methodology to estimate C. trachomatis prevalence in women from ten different
areas on four continents (Franceschi et al., 2007). Cross-sectional > population-based surveys
were conducted between 1993 and 2004 among non-pregnant women age 15–44 years in
Nigeria, Columbia, Argentina, Vietnam (two areas), China, Thailand (two areas), Korea, and
Spain. Over 5,000 women were included. Findings revealed C. trachomatis prevalence ranged
. Figure 74-1
Global burden of C. trachomatis infections by world region (WHO, 2007). The burden of
C. trachomatis infections is highest in South and Southeast Asia and Sub-Saharan Africa due to
the populous nature of countries in these regions
from <2% in Spain, Korea, and Thailand, 2–4.9% in China and Vietnam, and 5% in
Columbia, Argentina, and Nigeria. These data further support evidence of a lower prevalence
in more developed countries.
Collectively, these findings demonstrate a higher prevalence of C. trachomatis disease in
more resource poor settings. This may reflect, at least in part, structural factors related to
access to care and treatment. Individuals in resource poor settings may have lowered access
to care and treatment, resulting in longer duration infections and therefore more transmission
in the community. Furthermore, limited infrastructure for population-based and targeted
screening, inadequate laboratory facilities for diagnosis, and limited treatment supplies for
patients and their sexual contacts can also result in a higher burden of disease.
3 Burden in Developed World
Despite a somewhat lower prevalence of C. trachomatis in developed countries compared to

resource poor settings, C. trachomatis is still common in both general and at-risk populations
in developed nations, thereby constituting an important public health problem. A systematic
review of studies that examined the prevalence of C. trachomatis in European women reported
prevalence estimates ranging from 1% in Spain to 6% in France and UK (Wilson et al., 2002).
In the US, a total of 1,030,911 cases of C. trachomatis were reported in 2006 (CDC, 2007). This
was the first time over 1 million cases had been reported in the US surveillance system, and
this represents a continued and steady increase in the number of detected and reported cases
(discussed in greater detail below, see Increasing Burden). This makes C. trachomatis the
most common bacterial STI in the US. The estimated annual number of cases in the US
is approximately 3 million, which far exceeds the number of reported cases because many cases
are asymptomatic and remain undiagnosed (Weinstock et al., 2004) (see > Figure 74-2).
Over half of these infections are estimated to occur among persons age 15–24 years.
. Figure 74-2
Estimated total burden of C. trachomatis in United States. The total number of reported
C. trachomatis infections in the US exceeds 1 million, but this is just a fraction of the total
estimated burden due to undiagnosed infections
> Table 74-1 shows examples of research studies, organized by population and setting,
providing estimates of the burden of C. trachomatis. This list is not comprehensive or

systematically selected; rather, key studies that are qualitatively representative of the larger
body of literature were selected. As shown in the table, prevalence varies by setting and
population. Among regionally or nationally representative population-based samples,
C. trachomatis > positivity estimates typically range from approximately 2 to 11%. For
example, among a nationally representative sample of sexually active young adults in the
US, prevalence was estimated to be 4% (Miller et al., 2004). In London UK, the estimate was
11%; the higher prevalence in this study likely reflects the selective focus on an urban area
(Fenton et al., 2001). Among clinic-based samples, prevalence estimates are somewhat higher,
typically ranging from 7 to 18%. Higher prevalence estimates in clinics compared to popula-
tion-based representative samples may be due to higher representation of people seeking care
for symptoms or other known risk factors for infection. For example, among men in four US
cities seeking care at health clinics, drug treatment or detention centers, prevalence was 7%
(Gaydos et al., 2006). Among youth recruited from similar settings (e.g., health clinics,
detention centers) in Washington State, prevalence was 9% among women and 5% among
men (Marrazzo et al., 1997). Prevalence of C. trachomatis is often equally high, e.g., 7–16%,
among individuals that are considered to be in ‘‘high-risk’’ groups, defined behaviorally and
sociodemographically. For example, among men and women entering prisons in California
the prevalence is estimated 7% (Bernstein et al., 2006). Among disadvantaged young women
entering a national job training program in US, the prevalence was estimated 10–12% (Joesoef
and Mosure, 2006a). These groups have higher prevalence estimates than population-based
representative samples as well, perhaps due to the over-representation of racial/ethnic minori-
ties and individuals from impoverished backgrounds which are associated with STI risk
and prevalence.
. Table 74-1
Burden of C. trachomatis infections in select populations
Reference Population Prevalence

Population-based samples
Bakken et al. Population-based registry in Central Norway 1990–2003 6–11%
(2006) examining results at time of first test (n = 28,599) among
women
15–23%
among men
Fenton et al. Population-based sample of young adults in London, UK 11%
(2001) (n = 143)
Miller et al. (2004) Nationally representative sample of sexually active young 4%
adults age 18–26 in AddHealth study US (n = 14,322)
Klausner et al. Population based sample of young, low-income women in 3%
(2001) northern California US (n = 1,439)
van Valkengoed Random sample of patients of 16 general practices in 3% among
et al. (2000) Amsterdam Netherlands mailed test kits (n = 4,810) women
2% among
men
Clinic- or community-based samples
Gaydos et al. Men attending adolescent primary care clinics, school-based 7%
(2006) health clinics, street-based outreach venues, community-
based organizations, drug treatment centers, and detention
centers in Baltimore, Denver, San Francisco and Seattle US
(n = 17,712)
Griesinger et al. Female urban adolescents in Berlin Germany presenting for 7%
(2007) gynecologic care (n = 521)
Marrazzo et al. Youth age 21 years or less at nontraditional sites including 9% among
(1997) CBOs, school-based health centers, teen clinics, detention women
centers in Washington US (n = 10,118) 5% among
men
Niccolai et al. Pregnant adolescent recruited from ten health care clinics in 18%
(2003) Connecticut US, 1998–2000 (n = 203)
Rowhani-Rahbar Men attending public STD clinics in Connecticut US (n = 4,990) 15%
et al. (2006)
High-risk samples
Bernstein et al. Men and women newly entering six California US prisons 7%
(2006) (n = 1,270)
Joesoef and Disadvantaged women age 16–24 entering a national job 10–12%
Mosure, (2006a) training program in US (n = 106,377)
Joesoef and Disadvantaged men age 16–24 entering a national job 8%
Mosure, (2006b) training program in US (n = 51,478)
Kahn et al. (2005) Adolescents in 14 juvenile detention centers in US 16% among
(n = 131,296) women
6% among
men
Burden of Sexually Transmitted Chlamydia trachomatis Infections

74 1303

Menon-Johansson Young male inmates in UK 13%
et al. (2005)
Other
Burstein et al. Students at three urban public middle schools attend school- 21% among
(1998) based health clinic in Maryland US (n = 213) women
2% among
men
Cohen et al. (1999) Junior and senior high school students at eight urban public 12% among
schools in Louisiana US (n = 4,805) women
6% among
men
Debattista et al. Men who have sex with men attending gay venues in Brisbane 4%
(2002) Australia (n = 184)
Renton et al. Women presenting for termination of pregnancy in UK 9%
(2006) (n = 863)
The prevalence of C. trachomatis infection varies by setting and population. UK United Kingdom; US United States
4 Disparities in Burden by Sex, Age, and Race
4.1 Women Have a Higher Observed Prevalence of Infection
A variety of data sources demonstrate a higher burden and greater risk of C. trachomatis
infection in women compared to men. US CDC surveillance data from 2006 demonstrate that the
overall burden of reported chlamydial infection among women was almost three times as high as
the rate among men (516 cases per 100,000 females vs. 173 cases per 100,000 males) (CDC, 2007).
As shown in > Table 74-1, when similar screening patterns are applied to both men and
women, the prevalence of infection is often higher in women. Among high school students in
Louisiana, the prevalence was 12% in females and 6% in males (Cohen et al., 1999). Among
disadvantaged young adults in the US entering a job training program, observed prevalence
among women was 10–12% compared to 8% among men (Joesoef and Mosure 2006a,b).
There are at least two reasons for the observed differences between men and women. First,
sex differences in the burden of many STI partly reflect increased susceptibility in women due
to physiological differences between males and females (Ehrhardt et al., 1999). More efficient
transmission from men to women may be due to more extended contact with pathogens after
sexual exposure among women (e.g., infected semen remains in the vagina) and increased
exposed surface area of susceptible cells (e.g., cervix vs. urethra). Increased biologic suscepti-
bility among women can explain the higher prevalence observed in several studies when men
and women undergo similar screening patterns. (However, it should also be noted that the
gender difference in transmissibility for C. trachomatis may not be as great as for other STI.)
Another likely significant contributor to the higher observed burden of C. trachomatis among
women is different screening patterns that result in a > detection bias and underestimation of
the true burden of infection among men. This explains the greater number of reported cases
among women than men (reflecting observed burden, not true risk as described above).
Because of the disproportionate burden of negative health effects in women and because
women are more likely to have contact with the health care system than men for reproductive
health services, women are more likely to be tested for C. trachomatis and therefore detected
with infection than men. However, the advent of urine based testing for infection that can
be used in both men and women is likely to increase the frequency of diagnosis in men because
testing can be done outside of health care settings by non-clinicians.
4.2 Adolescents and Young Adults are Most Affected by

C. trachomatis Infections
Differences in burden of C. trachomatis are also often observed by age, with younger age
groups having a higher burden. Surveillance data based on case reports in the US indicate the
highest age-specific rates of chlamydia in 2006 were among women age 15–19 years (2,863 cases
per 100,000 females) and 20–24 years (2,797 cases per 100,000 females) (CDC, 2007). Rates drop
off quickly after those age groups (e.g., to 1,141 cases per 100,000 females among women age 25–
29 years). A similar pattern by age is observed for men though the rates are lower overall. Similar
patterns also emerge from non-surveillance data reports. For example, among female inmates
entering California prisons in 1999, women age 25 years had a prevalence of 8.9%, women age
26–30 years had a prevalence of 4.3%, and women age >30 years had a prevalence of 2.6%
(Bernstein et al., 2006). In another study of women entering a national job training program in
USA from 1998 to 2004, prevalence estimates of C. trachomatis were 13% among women age
16–17 years, 11% among those age 18–19 years, 10% among ages 20–21, and 7% among ages
20–24 (Joesoef and Mosure, 2006a).
The greater burden of C. trachomatis among younger women may partially reflect differ-
ential screening. Screening guidelines in the US recommend annual testing of sexually active
women age 25 years or less regardless of risk factors [CDC, 2007], so this population probably
undergoes more frequent screening. However, there are also biological, psychological, social,
and structural reasons why younger women have higher rates of many STI and C. trachomatis
in particular. Younger women may be biologically more susceptible to STI due to cervical
ectopy (Lee et al., 2006). This is the condition in which the cervix still displays exposed
columnar epithelium, not yet replaced by squamous epithelium as adolescents transcend
through puberty into adulthood, which are the target cells for C. trachomatis. Cognitively,
adolescents are less able to conceptualize the long-term impact of current actions that may
increase risk-taking sexual behaviors, and many adolescents do not perceive themselves to be
at risk for STI (Shrier, 2004). Behaviorally, adolescents are less likely to use condoms consis-
tently and more likely to have higher rates of partner turnover (Shrier, 2004). Finally, many
adolescents do not access sexual healthcare services due to lack of transportation, inability to
pay, or concerns about confidentiality (McKee et al., 2006; Thrall et al., 2000). This can result
in longer duration of infection and continued transmission in networks of younger popula-
tions. For all of these reasons, adolescents and young adults may be at true increased risk for
C. trachomatis infections. This is of concern because younger women have the greatest
potential loss from the negative reproductive health consequences of C. trachomatis infections.
4.3 Racial and Ethnic Minorities are Disproportionately Affected by

C. trachomatis Infections
It is virtually universally observed that racial/ethnic minority groups (e.g., African-Americans,

Latinos) have higher rates of C. trachomatis infections compared to whites. For example, data
from the National Longitudinal Study of Adolescent Health (Add Health) during 2001–2002,
which includes a nationally representative sample of young adults age 18–26 years living in the
US, reported an overall prevalence of 4.2% but dramatic differences by race (Miller et al.,
2004). This study found that the prevalence among black women was 14% compared to 2.5%
among white women. Other studies have shown similar patterns: data for men and women in
the national job training program for disadvantaged youth show a 4-fold higher prevalence
among black men compared to white men and a 2-fold greater difference for black women
compared to white women (Joesoef and Mosure, 2006a,b). Rates were also elevated for
other racial/ethnic minority groups including Asian/Pacific Islanders, American Indians,
and Latinos.
These consistent and dramatic differences in the burden of C. trachomatis infections are of
tremendous concern. These differences are likely to be real rather than artifacts of screening as
described above for sex and age. For example, differences that have been observed in repre-
sentative US samples are not subject to detection or reporting biases because all selected
individuals are similarly screened (Miller et al., 2004). Reasons for these disparities are not
always clear, but are likely to be complex and the result of many factors. Since there is no
reason to suspect biological differences in susceptibility, it is more likely that race and ethnicity
are markers of fundamental determinants of health status, such as poverty, access to care, and
health seeking behaviors. There is some evidence to support this. Data from the Add Health
study that includes a nationally representative sample of young US adults were examined with
respect to health insurance coverage, health care seeking behaviors, and chlamydial infections
(Geisler et al., 2006). Data were also available by race/ethnicity. This study found remarkable
differences in C. trachomatis positivity by race: 13% among black and Native Americans, 7%
among Hispanic, and 2% among white and Asians. This study also found that health
insurance coverage differed significantly by race/ethnicity for both men and women, and
that coverage was inversely associated with chlamydia prevalence. For example, blacks
were more likely to not have health insurance than whites (20 vs. 15% among women and
25 vs. 20% among men). In this same sample, not having health insurance was also signifi-
cantly associated with C. trachomatis; men who had health insurance for greater than 12
months had 43% reduced likelihood of C. trachomatis positivity compared to those with no
insurance, and the reduced likelihood was 36% among women. The same pattern was
observed for health care seeking behaviors assessed by asking about usual source of care
(e.g., primary care, emergency room, etc.).
Another explanation for differences in C. trachomatis prevalence by race/ethnicity lies in a
network approach. Because STI are transmitted in the context of a sexual dyad, and sexual dyads
are often changing, understanding the broader connections between individuals in sexual net-
works is often necessary to understand transmission dynamics of STI. In other words, to
understand which individuals are vulnerable to STI, it is important to examine not only their
own risks but also the risks of their partners, their partners’ partners, and others in the sexual
networks. Using this network analytic approach, investigators have found that African Amer-
icans’ higher STI rate can be explained in part by the patterns of sexual networks within and
between different racial/ethnic groups (Laumann and Youm, 1999). They identified two sexual
network factors pertaining to partner selection that explain higher rates of STI among African-
Americans. First, they found that partner choice among African-Americans was more highly
dissortative compared to whites, meaning that among African-Americans there is more mixing
between core individuals (those with more sex partners) and peripheral individuals (those
with fewer sex partners) compared to whites; this results in higher prevalence among African-
Americans. Second, STI prevalence remains high within African-American populations because
their choice of sex partners was more segregated, that is, African-American are more likely to have
African-American sex partners and to remain segregated from other (lower prevalence) racial/
ethnic groups. These findings remained consistent after controlling for behavioral risk factors
(e.g., number of partners). Thus, there is compelling evidence for a network explanation for
higher STI rates among African-Americans. Regardless of the cause, racial disparities in STI are
dramatic and troubling, and therefore warrant additional research for an increased understand-
ing and a targeted public health response.
5 Burden of Repeat C. trachomatis Infections
Though estimates vary depending on populations and measures, it is clear from a substantial
body of literature that repeat C. trachomatis infections are also common. In other words, many
individuals who are diagnosed with C. trachomatis will be diagnosed with another infection at
some point in time (see > Table 74-2).
. Table 74-2
Burden of repeat C. trachomatis infections in select populations

Whittington et al. Young women seeking health care in five US cities 7% at 4 months
(2001) (n = 1,194)
Golden et al. Men and women in a treatment trial in Washington 13% at 19 weeks (in
(2005) US (n = 2,751) control arm)
Fortenberry et al. Adolescent females seeking care in Indiana US 18% within 6 months
(1999) (n = 490)
Blythe et al. (1992) Adolescent females receiving GYN care in Indiana 38% within mean
US (n = 1,308) 9.7 months
LaMontagne et al. Women age 16–24 in UK (n = 592) 24% per year
(2005)
Hillis et al. (1994) Retrospective analysis of case report data in 7–14% within 12 months
Wisconsin US
Niccolai et al. Adolescent women in Connecticut US (n = 411) 57% within mean 4.7
(2007) years
The prevalence of repeat C. trachomatis infections is high. UK United Kingdom; US United States
For example, in a five-city study of teenage and young adult women attending reproduc-
tive health, STD, and adolescent medicine clinics, 7% had repeat C. trachomatis 4 months after
the initial diagnosis (after excluding the possibility of treatment failures by conducting a test-
of-cure visit at 1-month after the initial diagnosis) (Whittington et al., 2001). In a study of
male and female STD clinic patients, 20% had repeat C. trachomatis during a mean follow-up
of 335 days (Rietmeijer et al., 2002). In another study of female adolescents with an initial
infection attending STD and community-based primary care clinics, 18% were C. trachomatis-
positive again within 6 months, and 20% were C. trachomatis-positive within 7–12 months
(Fortenberry et al., 1999). Rates of > repeat infections range from 20 to 50 per
100 person-years of follow-up (LaMontagne, 2005; Niccolai et al., 2007; Rietmeijer et al., 2002;
Whittington et al., 2001). The burden of repeat infections is also high: 26–53% of all diagnoses
are repeat infections (Blythe et al., 1992; Niccolai et al., 2007; Rietmeijer et al., 2002). The
amount of time between initial and repeat infections is relatively short, with estimates ranging
from 5 to 11 months (Fortenberry et al., 1999; Niccolai et al., 2007; Whittington et al., 2001).
A recent report using multiple data sources for a cohort of young women followed for a mean
of 4.7 years found that 57% of study participants experienced a repeat infection (Niccolai
et al., 2007). Clearly, repeat C. trachomatis infections comprise a substantial health burden
among women and possibly higher than generally recognized.
6 Increasing Burden of C. trachomatis Infections?
Recently, there have been several reports of increases in the burden of C. trachomatis from
countries with active screening programs. One of the earliest reports of this trend came from
Sweden in 2002. Using both case reports and laboratory data, Gotz et al. reported an increase
in positivity from 4.1% in 1994 to 5.4% in 1999 (Gotz et al., 2002). In the United States,
similar trends have been reported. US data from women age 15–24 years in family planning
clinics reported increases in 5 of 10 US Public Health Service planning regions (CDC, 2007).
The most dramatic increases were observed in the region that includes the states of Alaska,
Idaho, Oregon, and Washington, where widespread screening and treatment programs for
chlamydia began in 1988. During the first 9 years of the program, from 1988 to 1996,
chlamydia positivity among women age 15–24 declined from 10.3 to 4.0%, a greater than
60% decline (CDC, 2007). However, during the following 8 years, there was a 46% increase in
chlamydia positivity from 3.9% in 1997 to 5.7% in 2004.
Whether these trends represent a true increase in burden of C. trachomatis or reflect some
other change is an important and unanswered question. In addition to a true increase in
prevalence, increases in positivity could be due to improved laboratory testing technology
reflected in the switch to using tests with higher sensitivities (NAATs), or a shift toward screening
higher-risk women. Several studies have examined these potential effects to better understand
the trend of increasing positivity. For example, in the Swedish study mentioned above, increas-
ing positivity occurred both in labs that had and had not switched to more sensitive tests,
therefore, the increase could not be attributed to greater detection due to improved laboratory
techniques (Gotz et al., 2002). The authors concluded that the increase in the number of
reported infections reflected ‘‘a real increase in prevalence.’’ In another analysis of data from
the US, investigators were able to examine the risk characteristics of the tested population over
time and to adjust for the type of test used (Fine et al., 2008). They observed that the proportion
of tested women with demographic, clinical, or sexual risk behavior characteristics associated
with an increased risk of chlamydial infection remained stable or decreased over time, and they
adjusted chlamydia positivity to account for use of more sensitive laboratory tests. After carefully
controlling for the potential effects of changing laboratory test characteristics and demographic
and sexual risk behaviors of tested populations, they showed an independent 5% per year
increase in chlamydia positivity over this 8-year period. Thus, the authors concluded that a true
increase in chlamydia prevalence may have occurred.
Additional studies provide further evidence of a true increase in C. trachomatis prevalence.
Another explanation for a true increase that is supported by data from the experience in British
Columbia, Canada. Since 2002, trends of increasing case reports have been observed (Brunham
et al., 2005). In 2005, Brunham et al. reported a decline in the case rate from 216/100,000 in 1991
to 104/100,000 in 1997, followed by an increase to 193/100,000 in 2003. They also reported a
similar trend for repeat C. trachomatis infections, with an increase from approximately
2/100,000 during 1989–1995 to 53/100,000 in 1996. This change reflects a 4.6% increase per
year since 1989. This increase in case reports that appears to be driven by increases in repeat
infections suggests a possible explanation that has been termed the ‘‘arrested immunity
hypothesis’’ (Brunham and Rekart, 2008). This hypothesis puts forth the idea that rising
case rates are due to earlier detection and treatment of infection that interferes with the
development of protective immune responses. In Canada, as in many parts of the developed
world, control programs have involved aggressive screening efforts for early detection and
treatment of infection since the 1980s. Earlier detection and treatment has likely reduced the
duration of infection in many individuals, resulting in lowered immune response and lower
antibody production. This, in turn, may have resulted in greater susceptibility to reinfection at
the population level and hence the increased number of reported chlamydia cases. Other
possible explanations for a true increase in prevalence could be changes in individual beha-
viors or sexual network dynamics. Reasons remain unclear at this point, and investigation into
these important shifts should be a priority.
7 Burden of Associated Sequelae
7.1 Women Suffer Negative Long-Term Consequences as a Result

of C. trachomatis Infections
The burden of sequelae associated with C. trachomatis infections are summarized in

> Table 74-3. C. trachomatis infections are an important preventable cause of pelvic inflam-
matory disease (PID), chronic pelvic pain, tubal infertility, and ectopic pregnancies
among women (Stamm, 1999). Lower genital tract infection with C. trachomatis frequently
ascends to the upper reproductive tract where permanent damage (e.g., scarring) can occur.
It is estimated that inadequately treated chlamydial infections may cause PID in 20–40% of
. Table 74-3
Burden of sequelae associated with C. trachomatis infections among women
Examples
Health Chronic pelvic pain
Tubal scarring
Pelvic inflammatory disease
Infertility
Ectopic pregnancy
Psychosocial Stigma
Concern about health effects
Anxiety about sex partner reaction
Economic Estimated 1.5 billion (US 1994)
HIV risk 2- to 5-fold increased risk of HIV acquisition
women (Stamm, 1999), and that among women with PID, 20% may develop tubal infertility
(Westrom et al., 1992). There is evidence that the long-term negative health effects of genital
C. trachomatis are more closely linked to repeat infections than to initial infections. Epidemi-
ologic studies have also shown increased risk for ectopic pregnancies and PID among women
with repeat infections. In one study, the risk for PID among women with two infections was
increased 4-fold compared to women with one infection, and the risk among women with
three or more infections was increased 6-fold (Hillis et al., 1997). Women also suffer immedi-
ate psychological consequences after a C. trachomatis diagnosis, including stigma associated
with STI, uncertainty about reproductive health effects, and anxiety about partners’ reactions
to the diagnosis (Duncan et al., 2001).
7.2 C. trachomatis is Associated with High Economic Burden
The economic burden associated with C. trachomatis is substantial. In 1994 US dollars, it was
estimated that the direct cost of C. trachomatis infections was $1.5 billion (IOM, 1997). This
estimate includes the cost of health care services, laboratory services, treatment for infections
and associated sequelae. The direct cost of pelvic inflammatory disease which is often caused
by C. trachomatis is $3.1 billion.
7.3 Infection with C. trachomatis Causes Increased HIV Transmission

and Acquisition
Several studies have documented increased HIV risk associated with C. trachomatis infections
(Wasserheit, 1992). The increased risk is often estimated to be 2- to 5-fold. For example, in a
study among female sex workers in Africa, presence of C. trachomatis infection was associated
with a 3.6-fold increase in likelihood of HIV seroconversion after controlling for potential
confounding by sexual behavior (Laga et al., 1991). It is also noteworthy that the proportion of
HIV infections attributable to non-ulcerative STI like C. trachomatis is likely to be greater than
the proportion attributable to ulcerative STI despite lower relative risk because of their higher
prevalence in the population.
8 Conclusion
In sum, it is clear from a large and growing body of evidence that C. trachomatis infections
constitute an important public health problem due to their burden, disproportionate impact
on vulnerable populations, and their sequelae. The possibility that the burden of infections is
increasing in countries that have been implementing screening programs for control is also of
concern. Continued efforts to understand biological and behavioral risks and the larger social
and cultural contexts in which infections are transmitted are critical, and applying this
knowledge to prevention and control is a public health priority. Improved access to screening
and treatment in developing countries is also needed to reduce the high burden in these
settings. Reducing the burden of C. trachomatis infections will have a positive impact
on women’s reproductive health in particular and the overall health of general populations
as well.
Summary Points
C. trachomatis is the most common bacterial sexually transmitted disease in the world, and
therefore these infections constitute an enormous public health problem.
The true burden of C. trachomatis infections is unknown due to substantial number of
undiagnosed infections and/or under-reporting.
The burden of C. trachomatis is especially high in resource poor countries, perhaps due to
limited access to care and treatment.
In developed countries, C. trachomatis infections are most common among adolescents
and young adults, and among racial/ethnic minorities.
Women bear a disproportionate burden of negative health consequences of C. trachomatis
infections including pelvic inflammatory disease, chronic pelvic pain, and infertility.
Additional burdens include high cost on the health care system and increased HIV
transmission.
Recent evidence of increasing C. trachomatis prevalence has been reported.
References
Bakken IJ, Norbdo SA, Skjeldestad FE. (2006). Sex Fine D, Dicker L, Mosure D, Berman S. (2008). Sex
Transm Dis. 33: 26–30. Transm Dis. 35: 47–52.
Bernstein KT, Chow JM, Ruiz J, Schachter J, Horowitz E, Fortenberry JD, Brizendine EJ, Katz BP, Wools KK,
Bunnell R, Bolan G. (2006). Am J Public Health. 96: Blythe MJ, Orr DP. (1999). Sex Trans Dis. 26: 26–32.
1862–1866. Franceschi S, Smith J, Brule van den A, Herrero R,
Blythe MJ, Katz BP, Batteiger BE, Ganser JA, Jones RB. Arslan A, Anh PTH, Bosch FX, Hieu NT, Matos E,
(1992). J Pediatrics. 121: 487–493. Posso H, Qiao YL, Shin HR, Sukvirach S, Thomas
Brunham RC, Pourbohloul B, Mak S, White R, JO, Snijders PJF, Munoz N, Meijer CJLM. (2007).
Rekart ML. (2005). J Infect Dis. 192: 1836–1844. Sex Transm Dis. 34: 563–569.
Brunham RC, Rekart ML. (2008). Sex Transm Dis. 35: Gaydos CA, Kent CK, Rietmeijer CA, Willard NJ,
53–54. Marrazzo JM, Chapin JB, Dunne EF, Markowitz
Burstein GR, Waterfield G, Joffe A, Zenilman JM, LE, Klausner JD, Ellen JM, Schillinger JA. (2006).
Quinn TC, Gaydos CA. (1998). Sex Transm Dis. Sex Transm Dis. 33: 314–319.
25: 395–402. Geisler WM, Chyu L, Kusunoki Y, Upchurch DM,
Centers for Disease Control and Prevention. (2007). US Hook EW III. (2006). Sex Transm Dis. 33: 389–396.
Department of Health and Human Services, Gerbase AC, Rowley JT, Heymann DHL, Berkley SFB,
Atlanta GA. Piot P. (1998). Sex Transm Inf. 74: S12–S16.
Cohen DA, Nsuami M, Martin DH, Farley T. (1999). Golden MR, Whittington WLH, Handsfield HH,
Pediatrics. 104: 1281–1285. Hughes JP, Stamm WE, Hogben M, Clark A,
Debattista J, Clementson C, Mason D, Dwyer J, Argent S, Malinski C, Helmers JRL, Thomas KK, Holmes
Woodward C, Dean J, Buks L, Copley M, Hinwood KK. (2005). N Eng J Med. 352: 676–685.
G, Benfield C, Walton P. (2002). Sex Transm Dis. 29: Gotz H, Linback J, Ripa T, Arneborn M, Ramstedt K,
216–221. Ekdahl K. (2002). Scand J Infect Dis. 34: 28–34.
Duncan B, Hart G, Schoular A, Bigrigg A. (2001). BMJ. Griesinger G, Gille G, Klapp C, von Otte S, Diedrich K.
322: 195–199. (2007). Clin Microbiol Infect. 13: 436–439.
Ehrhardt AA, Bolan G, Wasserheit JN. (1999). In: Hillis SD, Owens LM, Marchbanks PA, Amsterdam LE,
Holmes KK et al. (eds.) Sexually Transmitted MacKenzie WR. (1997). Am J Obstet Gynecol. 176:
Diseases. McGraw-Hill, New York. 103–107.
Fenton KA, Copas A, Mitchell K, Elam G, Carder C, Institute of Medicine. (1997). National Academy Press,
Ridgway G, Wellings K, Erens B, Field J, Washington DC.
Johnson AM. (2001). Sex Transm Infect. 77: Joesoef MR, Mosure DJ. (2006a). Sex Transm Dis. 33:
194–198. 571–575.
Joesoef MR, Mosure DJ. (2006b). Sex Transm Dis. 33: Quinn TC, Gaydos C, Shepherd M, bobo L, Hook EW
636–639. III, Viscidi R, Rompalo A. (1996). JAMA. 276:
Kahn RH, Mosure DJ, Blank S, Kent CK, Chow JM, 1737–1742.
Boudov MR, Brock J, Tulloch S. (2005). Sex Transm Renton A, Thomas BM, Gill S, Lowndes C, Taylor-
Dis. 32: 255–259. Robinson D, Patterson K. (2006). Int J STD AIDS.
Klausner JD, McFarland W, Bolan G, Hernandez FM, 17: 443–447.
Lemp GF, Cahoon-Young B, Morrow S, Ruiz J. Rietmeijer CA, Van Bemmelen R, Judson FN, Douglas
(2001). J Infect Dis. 183: 1087–1092. JM Jr. (2002). Sex Transm Dis. 29: 65–72.
Laga M, Nzila N, Goeman J. (1991). AIDS. 5: S55–S63. Rowhani-Rahbar A, Niccolai LM, Dunne DW, Green S,
LaMontagne SD, Baster K, Emmett L. (2005). Determi- Jenkins H, Khoshnood K. (2006). Int J STD AIDS.
nants of chlamydia re-infection: the role of partner 17: 453–458.
change and treatment [abstract]. In: Program and Shrier LA. (2004). Adolesc Med Clin 15: 215.
Abstracts of the 16th Biennial Meeting of the Inter- Stamm WE (1999). In: Holmes KK (eds.) et al. Sexually
national Society for Sexually Transmitted Diseases Transmitted Diseases. McGraw-Hill, New York, NY.
Research, Amsterdam, The Netherlands, Abstract Thrall JS, McCloskey L, Ettner SL, Rothman E, Tighe JE,
TO-404. Emans SJ (2000). Arch Pediatr Adolesc Med.
Laumann EO, Youm Y. (1999). Sex Transm Dis. 26: 154: 885.
250–261. van Valkengoed IGM, Morre SA, Brule van den AJC,
Lee V, Tobin JM, Foley E. (2006). J Fam Plann Reprod Meijer CJLM, Deville W, Bouter LM, Boeke AJP.
Health Care. 32: 104. (2000). Sex Transm Infect. 76: 375–380.
Marrazzo JM, White CL, Krekeler B, Celum CL, Wasserheit JN. (1992). Sex Trans Dis. 19: 61–77.
Lafferty WE, Stamm WE, Handsfield HH. (1997). Weinstock H, Berman S, Cates W Jr. (2004). Perspect Sex
Ann Intern Med. 127: 796–803. Reprod Health. 36: 6–10.
McKee MD, Fletcher J, Schechter CB. (2006). J Adolesc Westrom L, Joesoef R, Reynolds G, Hagdu A, Thompson
Health. 39:183. SE. (1992). Sex Transm Dis. 19: 185–192.
Menon-Johansson AS, Winston A, Matthews G, Wilson JS, Honey E, Templeton A, Paavonen J, Mardh
Portsmouth S, Daniels D. (2005). Int J STD AIDS. P-A, Stary A, Stray-Pedersen B. (2002). Hum
16: 799–801. Reprod Update. 8: 385–394.
Miller WC, Ford CA, Morris M, Handcock MS, Whittington WL, Kent C, Kissinger P, Oh MK,
Schmitz JL, Hobbs MM, Cohen MS, Harris KM, Fortenberry JD, Hillis SE, Litchfield B, Bolan GA,
Udry JR. (2004). JAMA. 291: 2229–2236. St. Louis ME, Farley TA, Handsfield HH. (2001). Sex
Niccolai LM, Ethier KA, Kershaw TS, Lewis JB, Transm Dis. 28: 117–23.
Ickovics JR. (2003). Am J Obstet Gynecol. 188: World Health Organization Department of HIV/AIDS.
63–70. (2007). http:/www.who.int/docstore/hiv/GRSTI/003.
Niccolai LM, Hochberg AL, Ethier KA, Lewis JB, html.
Ickovics JR. (2007). Arch Pediatr Adol Med. 161:
246–251.
75 Disease Burden from
Group A Neisseria
meningitidis Meningitis in
Hyperendemic Countries of
the African Meningitis Belt
C. Suraratdecha . C. Levin . F. M. LaForce
1 Group A Neisseria meningitidis Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1314
2 Incidence, Case-Fatality, and Disability Rates of Group A

Meningococcal Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1316
3 Disease Burden Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317
4 Economic Burden of Group A Meningococcal Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . 1318
5 Disease Burden Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318
6 Methodological and Data Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318
7 Applications of the Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1320
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1321

1314 75 Disease Burden from Group A Neisseria meningitidis
Abstract: Neisseria meningitidis meningitis is a devastating illness characterized by the sudden

onset of intense headache, high fever, nausea, vomiting, photophobia, and stiff neck. The
disease has a high mortality rate and is associated with long-term neurological defects such as
deafness and recurrent seizures. > Epidemics of group A meningococcal meningitis continue
to pose an important public health problem for sub-Saharan Africa. The last major epidemic
occurred in 1996–1997, with more than 180,000 reported cases and 20,000 deaths. During
2006 and 2007 Burkina Faso suffered more than 45,000 cases of group A meningococcal
meningitis. Using the population-based incidence and bacteriologic data from Niger to
estimate disease burden in seven hyperendemic countries (Mali, Burkina Faso, Niger, Nigeria,
Chad, Sudan, and Ethiopia), over a 10-year period, group A N. meningitidis is estimated to
cause about 1.1 million cases of meningitis, 133,000 deaths, 317,000 disabilities, and 12 million
disability-adjusted life years lost in the population 0- to 40-year-old > cohorts. Over the last
few years a major effort has been under way to control epidemic meningococcal disease in
Africa through the development, testing, licensure, and introduction of new conjugate me-
ningococcal > vaccines. The Meningitis Vaccine Project, a partnership between PATH and the
World Health Organization, is developing an affordable meningococcal A > conjugate vaccine
that will be introduced at public health scale in 2009. Wide-scale introduction of the menin-
gococcal A conjugate vaccine is expected to eliminate these epidemics.
List of Abbreviations: CFR, > case-fatality rate; DALYs, disability-adjusted life years; Men A,
meningococcal A; Men Ps, meningococcal polysaccharide; PCR, > polymerase chain reaction;
WHO, World Health Organization; WHO-CHOICE, choosing interventions that are cost
effective; YLD, years lost due to disability; YLL, years of life lost
1 Group A Neisseria meningitidis Meningitis
Bacterial meningitis continues to be a major health problem in sub-Saharan Africa. Green-

wood (2004) estimated that 200,000 cases and 70,000 deaths occur annually from bacterial
meningitis due to Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningi-
tidis in African children under 5 years of age. Of these three agents, only the meningococcus
has the ability to cause large epidemics, particularly in the African meningitis belt (Mar et al.,
1979; Makela et al., 1992; Moore, 1992).
Meningococcal meningitis is an infection of membranes surrounding the brain and spinal
cord and presents clinically with acute onset of intense headache, high fever, nausea, vomiting,
photophobia, and stiff neck (> Table 75-1). The disease carries a high mortality rate, particu-
larly if treatment is delayed, and long-term neurological defects. The first outbreak of
meningococcal meningitis was described in Geneva, Switzerland, in 1805, but it was not
until 1887 that N. meningitidis was isolated and identified as the causative agent. The first
outbreak in Africa occurred in soldiers in Algiers in 1840 (Chalmers and O’Farrell, 1916). The
disease appeared in North Africa and the sub-Saharan region of Africa in the 1880s in an area
that became known as the African meningitis belt, which extends from Ethiopia in the east to
Senegal in the west (> Figure 75-1; WHO, 1998). For more than 100 years, sub-Saharan Africa
has suffered periodic meningitis epidemics in this so-called ‘‘meningitis belt.’’ The human toll
from these epidemics has been enormous; for example, the 1996 epidemic resulted in more
than 180,000 reported cases and 20,000 deaths.
The primary goal of this chapter is to provide an estimate of the disease burden due to
group A Neisseria meningitidis in the hyperendemic countries of the African meningitis belt.
. Table 75-1
Key features of acute bacterial meningitis in sub-Saharan Africa
1. Bacterial meningitis is a severe acute infection of the membranes lining the brain and spinal cord
2. Bacterial meningitis is a very serious infection; despite antimicrobial treatment, mortality rates
are about 10%
3. Most bacterial meningitis is by three bacteria: pneumococci, meningococci, and Haemophilus
influenzae
4. Only meningococci are capable of causing large epidemics
5. Sub-Saharan Africa is the home for 95% of global systemic meningococcal infections
6. Over 85% of meningococcal isolates in sub-Saharan Africa belong to one group, group A
7. There is no group A meningococcal disease in Europe or North America
8. The currently available vaccine to protect against meningococci is meningococcal
polysaccharide
9. Conjugate vaccines have been shown to induce a better and longer-lasting immune response
than polysaccharide vaccines. Conjugate vaccines against group A meningococci are being
developed
This table lists the key facts of bacterial meningitis in sub-Saharan Africa due to meningococci
. Figure 75-1
African meningitis belt countries. The figure illustrates hyperendemic countries and
non-hyperendemic countries in the African meningitis belt where group A meningococcal
meningitis has been reported, and their population size
The chapter will review published data and present a method used to estimate the disease
burden of group A meningococcal meningitis in hyperendemic countries. Estimates will be
summarized, as well as limitations of the method.
2 Incidence, Case-Fatality, and Disability Rates of Group A

Meningococcal Meningitis
Quantifying the meningococcal disease burden in Africa is not a simple task. While there have
been many descriptive studies of meningitis in sub-Saharan Africa, only a few are population
based and even fewer link bacteriologic information with individual cases over time. Most
published data are hospital based and/or descriptions of outbreaks of meningococcal menin-
gitis. These epidemics occur over a relatively short period of time and are characterized by very
high attack rates. For example, using the data from a sentinel site in Khartoum, Sudan, Salih
et al. (1990) reported an annual incidence rate of 1,679 per 100,000 inhabitants during a large
epidemic due to group A N. meningitidis (February–August 1988). About a third of the cases
were under 9 years old. In the Savannes region of Togo between December 1996 and May 1997,
the cumulative attack rate from group A N. meningitidis was 581 per 100,000 population
(Aplogan et al., 1997). The Upper East, Upper West, and Northern regions of Ghana reported
an attack rate of meningococcal disease of 550 per 100,000 population at the end of the
epidemic in 1997 (Woods et al., 2000).
Even in the absence of dramatic epidemics the > endemic case rates are high when compared
to Europe and the United States. Data from the Bobo-Dioulasso region of Burkina Faso collected
during the periods of May 2002–April 2003 and March 2004–February 2005 showed that annual
incidence rates of group A meningococci were 2.7, 6.3, 7.8, and 2.6 per 100,000 in children under
1 year, 1–4 years, 5–14 years, and 15 years and older, respectively (Traore et al., 2006). The attack
rates in various areas of Zaria, Northern Nigeria, from March to May 1977 ranged from 0 to 11.9
per 1,000 inhabitants, with an average of 3.6 per 1,000 (Greenwood et al., 1979). Using the
retrospective data from 16 health centers in two Northern districts (Atacora and Donga) of
Benin from 1998 to 2001, Fourn et al. (2004) estimated an increase in crude incidence rates from
85 to 567 per 100,000 in Atacora and 71 to 619 per 100,000 in Donga. During the huge 1996
outbreak in Nigeria with more than 115,000 cases, almost three quarters of the patients were
under 15 years; 11% were above 30 (Mohammed et al., 2000). These data show the enormous
variability in rates, depending largely on whether data were collected during an epidemic.
The only comprehensive population-based analysis of bacterial meningitis in the African
meningitis belt was done at Centre de Recherche Médicale et Sanitaire (CERMES) in Niamey,
Niger, after the meningitis epidemic in 1995–1996 (Campagne et al., 1999). The bacteriology
laboratory at CERMES is the national reference laboratory for Niger, with more than 30 years
of experience in the bacteriologic analysis of > cerebrospinal fluid specimens. Data are
rigorously maintained during epidemic (1994–1995) and inter-epidemic (1981–1993 and
1996–1997) periods and reviewed on a regular basis. Baseline incidence rates are high in
the population 0–29 years of age, and during epidemics the rates soar ten fold in this
age group. About five percent of all cases of meningococcal meningitis in epidemic and
inter-epidemic periods occur in infants, while 90% of cases occur in 1- to 29-year-olds.
The incidence of group A N. meningitidis varies annually. While the crude meningitis
incidence rate is 100.8 per 100,000 per year, the rate for N. meningitidis is 55.3 cases per
100,000 per year, with 85.6% of meningococcal infections due to Serogroup A (> Table 75-2).
. Table 75-2
Incidence rates per 100,000, case-fatality and disability rates (%) of group A Neisseria meningitidis
in Niamey, Niger (1981–1996)
Total per
Age (years) 100,000
<1 1–4 5–9 10–14 15–19 20–29 30–39 40
Incidence rates
Inter-epidemic 32.0 27.6 37.1 31.8 26.5 9.3 4.7 2.9 22.1
years
Epidemic year 210.9 398.6 400.5 399.8 398.1 103.7 54.0 9.4 309.7
Case-fatality 19.3 12.0 9.0 7.6 5.2 22.9 22.2 41.7 11.6
rate
Disability rate 24.0 24.0 24.0 24.0 24.0 24.0 24.0 24.0 24.0
This table presents the data on age-specific incidence rates during epidemic and non-epidemic years, case-fatality
rates, and disability rates of group A N. meningitidis from the study in Niamey, Niger, during 1981–1996 that were
used in the estimates of disease burden (Campagne et al., 1999)
The case-fatality rate (CFR) was 11.6% on average, and residual morbidity after meningitis
was 24% (Bovier et al., 1999; Parent du Châtelet et al., 2001).
3 Disease Burden Model
Since the reported epidemic incidence rates in Niamey are similar to those reported from
other areas in the African meningitis belt (Campagne et al., 1999), the population-based
epidemiologic data from Niamey were extrapolated to other hyperendemic countries. The
estimate was based on 2009 cohort population data of hyperendemic countries (Burkina Faso,
Chad, Ethiopia, Mali, Niger, nine states of Nigeria, and Sudan) from 0 to 40 years, which were
derived from the United Nations Department of Economic and Social Affairs, Population
Division (United Nations Population Division, 2007). A cohort model in which the total
number of meningococcal meningitis cases was calculated for each age cohort using age-
specific incidence and CFR was developed using data from > Table 75-2. All 0- to 40-years age
cohorts were followed over the 10-year period to account for variation in incidence rates
during epidemic and inter-epidemic years. The model assumed that an epidemic cycle occurs
every 10 years. Since the model used the population data in 2009 and the last major epidemic
occurred in 1996–1997, the model replaced the age-specific incidence rates in the 8th year in
the cycle in the model by epidemic rates. The susceptible population was adjusted over time
for infections and deaths from other causes using the age-specific mortality rates to avoid
double counting of meningococcal meningitis cases.
Disability-adjusted life years (DALYs) were calculated as the sum of the years of life lost
(YLL) and years lost due to disability (YLD) associated with chronic sequelae associated with
deafness, seizure disorder, and motor deficits (Lopez et al., 2001). YLLs were estimated from
the WHO life tables for hyperendemic countries (WHO, 2006). Age-specific mortality rate was
calculated and weighted average among seven hyperendemic countries. The disability weight
for average chronic sequelae due to meningitis of 0.183 was used in YLD calculation.
4 Economic Burden of Group A Meningococcal Meningitis
The medical cost associated with meningococcal meningitis was projected over a 10-year
period, consisting of diagnostic studies, outpatient care, and inpatient care. All cost estimates
are presented in 2007 US dollars. The cost of treating a case of meningitis is $80 and is based
on a Ministry of Health study conducted in Burkina Faso during the 2002 meningitis epidemic
(Ministry of Health and Burkina Faso, 2003) and the Choosing Interventions that are Cost
Effective (WHO-CHOICE) model. The total costs per case at the district level ranged from $67
to 90 and included initial consultation visit, the hospitalization and costs of supporting the
hospitalized family member, laboratory, and transportation costs. Using the WHO-CHOICE
model (WHO, 2002), and assuming the ratio of urban to rural patients is 3:1, an outpatient
visit in the urban area costs $10.42 and each hospital day costs $32.08 per day. In the rural area,
one outpatient visit costs $6.14 and an inpatient day costs $18.85 per day. The model further
assumes that all cases were seen (outpatient), all urban cases were hospitalized, and only one
third of the total rural patients were hospitalized. Cost of antibiotics for the non-hospitalized
cases is $10. An average estimated cost is $77.68 per case.
To estimate the diagnostic costs, the following guidelines were followed. The clinical
guideline in Burkina Faso is to perform a lumbar puncture in all suspected meningitis cases
in endemic years. In the model, an average cost of diagnostic is $15. It is assumed that lumbar
puncture is performed in 50% of endemic cases and in 10% of epidemic cases. A lumbar
puncture kit costs $2, Gram stain costs $0.60, latex agglutination costs $15.60, and polymerase
chain reaction (PCR) costs $6 for a negative sample or $12 for a positive sample (Chanteaux,
2005, unpublished).
5 Disease Burden Estimates
The total > high-risk group (up to 40 years old) in hyperendemic countries in 2009 is
projected at 201 million. Extrapolation of the Niger data and adjustment of age-specific
incidence rates during endemic and epidemic years to reflect the epidemiological pattern of
meningococcal meningitis that appears in cycles of approximately 8–12 years produced a
burden estimate of group A meningococcal meningitis of 1,105,836 cases over the 10-year
period. When case-fatality rates, disability rates, and DALY formula were applied to the total
case estimates at 0% discount rate, 133,586 deaths, 316,657 disabilities, and 12,172,860 DALYs
were derived. The estimate of disease burden from group A meningococcal meningitis is
110,584 cases annually, ranging from 44,409 during non-epidemic years to 669,835 in epi-
demic years (year 8 in > Figure 75-2). The decennial estimate of economic cost as a result of
these cases is $111,213,294 (or $11 million per year, on average) from treatment, laboratory,
and diagnostic testing costs. > Table 75-3 summarizes disease burden and economic burden of
group A meningococcal meningitis in discounted and undiscounted values.
6 Methodological and Data Considerations
Epidemic meningitis is a major public health problem in sub-Saharan Africa. Virtually all of
the meningitis epidemics with incidence rates greater than 100 per 100,000 have been caused
by a specific pathogen, group A Neisseria meningitidis. Despite the general acceptance of the
. Figure 75-2
Group A meningococcal meningitis cases by year. This figure shows the number of group A
Neisseria meningitidis cases estimated from the disease burden model by year. The model
assumed that the epidemic would occur in year 8 of the 10-year cycle
. Table 75-3
Estimated disease burden and economic burden of group A Neisseria meningitidis in hyperen-
demic countries over the 10-year period
YLL YLD DALYs Economic burden (USD)

0% discount 8,404,432 3,768,428 12,172,860 111,213,294
3% discount 4,409,696 1,963,576 6,373,272 109,982,969
This table provides the estimates of discounted (3% discount rate) and undiscounted YLL, YLD, DALYs, and
economic burden due to group A N. meningitidis in population 0–40 years old over a 10-year period. DALYs
disability- adjusted life years; YLD years lost due to disability; YLL years of life lost
public health importance of epidemic meningitis, ascertaining and quantitating the meningo-
coccal disease burden is not simple. There have been many descriptive studies of meningitis in
sub-Saharan Africa, but, as mentioned earlier, only a few are population-based with bacterio-
logic confirmation of cases, and there was only one study that spanned epidemic and inter-
epidemic periods.
Meningitis surveillance in African meningitis belt countries varies greatly in quality. For
the most part, African surveillance systems can identify major epidemics of meningococcal
meningitis but cannot precisely determine either the total number of cases during an epidemic
or the number of meningitis cases during inter-epidemic periods. Country surveillance data
are often fragmented, poorly codified, and of limited value to epidemiologists. Some countries
such as Burkina Faso and Niger have well developed systems that rapidly identify meningitis
epidemics; many others have limited capabilities. To improve meningitis surveillance, major
efforts have been made in recent years, and beginning in 2003, the Meningitis Vaccine Project
has sponsored an effort at WHO’s Multi Disease Surveillance Center in Ouagadougou to collect,
codify, and analyze meningitis data from Niger, Burkina Faso, and Mali. Comprehensive
sets of data are now available from Niger (1986–2004), Burkina Faso (1996–2004), and
. Figure 75-3
Burkina Faso meningitis cases, 1996–2007. This figure shows the annual reported cases of
meningitis in Burkina Faso from 1996 to 2007 (Ministry of Health and Burkina Faso, 2003, WHO)
Mali (1992–2004). > Figure 75-3 shows the meningitis incidence data for Burkina Faso from
1996 to 2007. These data clearly show the seasonal distribution and the wave-like nature of
meningococcal epidemics in these countries. Epidemics occur across 2 or 3 years, with
intervals of quiescence that last 5–7 years. Incidence rates during epidemics can soar to
more than 500/100,000 population.
The temporal characteristics of epidemics are very predictable; the hot, dry, and dusty
conditions during the first 4 months of the calendar year serve as the climatologic backdrop
for the annual burst of cases of meningococcal meningitis. While these new data are a major
improvement, they do not provide information on disease rates by pathogen because of the
absence of case-based surveillance data that link individual cases with bacteriologic data.
7 Applications of the Model
The analytic approach described in this paper is one such method that can be used to
demonstrate the impact of disease control strategy through estimating the burden of group
A meningococci that could be averted by implementing vaccination strategies. Over the last
20 years, control of epidemic meningitis has emphasized surveillance and reactive mass
> immunizations with the meningococcal polysaccharide (Men Ps) vaccine. A successful
reactive vaccination strategy requires major investments in infrastructure and resources such
as real-time surveillance data, accurate bacteriologic information, availability of vaccine, and
rapid implementation of district-based vaccinations. More often than not, immunizations are
given in the latter phase or after the epidemic with discouraging results. Because Men Ps
vaccine is ineffective in infants and toddlers under 2 years, and has no effect on colonization,
these emergency mass vaccination campaigns must be repeated on a regular basis. Currently, it
is estimated that meningitis belt countries spend about US $20 million annually responding to
meningococcal outbreaks.
Through an innovative partnership, the Meningitis Vaccine Project has developed an
affordable (US $0.40/dose) Men A conjugate vaccine manufactured at the Serum Institute of
India (LaForce et al., 2007). Conjugate vaccines are more immunogenic than > polysaccharide
vaccines, they prime immunological memory, can be confidently used in children under 1 year
of age, and have been shown to induce herd immunity. The vaccine will be given as a single
dose to all 1- to 29-year-olds, a strategy that is expected to generate strong herd immunity and
rapid control of group A N. meningitidis infections. Introduction at public health scale is
expected in 2009. It is important for countries to be aware of current disease burdens so that
they can estimate the cost and potential savings that may accrue with the introduction of more
potent vaccines such as Men A conjugate vaccine.
Summary Points
Group A Neisseria meningitidis is the most important cause of epidemic meningitis in sub-
Saharan Africa.
Reactive vaccination strategies with meningococcal > polysaccharide vaccine have not
eliminated epidemics.
There are limited population-based data on the incidence and the etiology of bacterial
meningitis in Africa.
The most complete data set is from Niger (1981–1996), which shows a meningococcal
group A incidence rate of about 50 cases per 100,000; comparable incidence rates for all
meningococcal infections in the United States is 0.3 cases per 100,000.
The model predicts that, over 10 years, there are more than 1.1 million cases of meningo-
coccal group A meningitis.
Introduction of a new conjugate meningococcal vaccine in mass vaccination campaigns of
high-risk population (1- to 29-year-olds) is expected to generate herd immunity and
eliminate these epidemics.
References
Aplogan A, Batchassi E, Yakoua Y, Croisier A, Aleki A, LaForce FM, Konde K, Viviani S, Preziosi MP. (2007).
Schlumberger M, Molina S, Sidatt M, Kaninda AV. Vaccine. 25 (Suppl. 1): A97–A100.
(1997). Sante. 7(6): 384–390. Lopez AD, Salomon J, Ahmad O, Murray CJL, Mafat D.
Bovier P, Wyss K, Au H. (1999). Soc Sci Med. 48(9): (2001). Life Tables for 191 Countries: Data, Meth-
1205–1220. ods, and Results. Global Programme on Evidence
Campagne G, Schuchat A, Djibo S, Ousséini A, Cissé L, for Health Policy Discussion Paper Series: No. 9.
Chippaux JP. (1999). Bull World Health Organ. 77 World Health Organization, Geneva.
(6): 499–508. Makela PH, Takala AK, Peltola H, Eskola J. (1992).
Chalmers AJ, O’Farrell WR. (1916). J Trop Med Hyg. 29: J Infect Dis. 165 (Suppl. 1): S2–S6.
101–116, 117–129. Mar ID, Denis F, Cadoz M. (1979). Pathol Biol. (Paris) 27
Fourn L, Makoutodé M, Ouendo M, Tounkara B. (2004). (9): 543–548.
Sante. 14(3): 153–159. Ministry of Health, Burkina Faso. (2003). Recherche
Greenwood B. (2004). In: Parry E (ed.) Principles of operationelle sur la gratuite de la prise en charge
Medicine in Africa, 3rd ed. Cambridge University des patients atteints de meningite cerebro-spinale au
Press, Cambridge, UK, pp. 305–315. Burkina Faso.
Greenwood BM, Bradley AK, Cleland PG, Haggie MH, Mohammed I, Nasidi A, Alkali AS, Garbati MA, Ajayi-
Hassan-King M, Lewis LS, Macfarlane JT, Taqi A, Obe EK, Audu KA, Usman A, Abdullahi S. (2000).
Whittle HC, Bradley-Moore AM, Ansari Q. (1979). Trans R Soc Trop Med Hyg. 94(3): 265–270.
Trans R Soc Trop Med Hyg. 73(5): 557–562. Moore PS. (1992). Clin Infect Dis. 14(2): 515–525.
Parent du Châtelet I, Gessner BD, da Silva A. (2001). World Health Organization. (1998). Control of Epidemic
Vaccine. 19(25–26): 3420–3431. Meningococcal Disease. WHO Practical Guidelines,
Salih MA, Ahmed HS, Karrar ZA, Kamil I, Osman KA, 2nd ed. WHO, Geneva. http://www.who.int/csr/
Palmgren H, Hofvander Y, Olcén P. (1990). Scand J resources/publications/meningitis/whoemcbac983.
Infect Dis. 22(2): 161–170. pdf. Accessed 7 Mar 2008.
Traore Y, Njanpop-Lafourcade BM, Adjogble KL, World Health Organization. (2002). Statistical Informa-
Lourd M, Yaro S, Nacro B, Drabo A, Parent du tion System (WHOSIS). Africa D Total population,
Châtelet I, Mueller JE, Taha MK, Borrow R, births and mortality rates; Unit costs for base case
Nicolas P, Alonso JM, Gessner BD. (2006). Clin analysis: WHO African Region – D, Country specific
Infect Dis. 43(7): 817–822. hospital costs, WHO CHOICE.
United Nations Population Division. (2007). World World Health Organization. (2006). Life Tables for
Population Prospects: The 2006 Revision. United WHO Member States. WHO, Geneva. http://www.
Nations, New York. who.int/whosis/database/life_tables/life_tables.cfm.
Woods CW, Armstrong G, Sackey SO, Tetteh C, Bugri S, Accessed 7 Mar 2008.
Perkins BA, Rosenstein NE. (2000). Lancet. 355
(9197): 30–33.
76 DALYs in Chronic Hepatitis C :
A Paneuropean Perspective
U. Siebert . A. Conrads-Frank . R. Schwarzer . B. Lettmeier .
G. Sroczynski . S. Zeuzem . N. Mühlberger
1 Key Facts Hepatitis C Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1324
2 Review of Existing DALY Data and Calculation of the Contribution of

Cirrhosis and Liver Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326
3 Revised Evaluation of the HCV Burden of Disease after Inclusion of

Cirrhosis and Liver Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331
4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1332
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333

1324 76 DALYs in Chronic Hepatitis C : A Paneuropean Perspective
Abstract: > Hepatitis C virus (HCV) is one of the leading causes of chronic liver disease with
serious sequelae such as end-stage cirrhosis and liver cancer. However, few burden of disease
data that consider health-related quality of life are available for Europe.
The objective of this evaluation was to summarize available data on the HCV-related
burden of disease under consideration of the reduction in quality of life for countries of the
WHO European region.
We analyzed available data on disability-adjusted life years (> DALY) and life years lost to
disability (> YLD). Literature and international health databases were systematically searched
for HCV-related data on DALY and YLD. If no HCV-specific data were available, these were
calculated via HCV-attributable fractions.
HCV-specific DALY data were only available for hepatitis C without cirrhosis and liver
cancer and for all cause cirrhosis and liver cancer. The calculation via HCV-attributable
fractions yielded that approximately 1.2 million DALYs were lost due to HCV in 2002 in the
WHO European region, of which about one sixth can be attributed to quality-of-life im-
pairment. About 95% of the DALYs were accumulated by patients in advanced disease stages.
Our results emphasize the public health relevance of hepatitis C and highlight the
importance and the potential benefit of preventive antiviral treatment. The variation of
DALY figures indicate the potential of inequality of health services across the countries of
the WHO European region that should be investigated further. The finding that HCV-specific
data are not available suggests that the crisis is not yet fully perceived on the European level.
List of Abbreviations: AF, Attributable fractions, in this chapter used for the fraction of cases
of liver cirrhosis and liver cancer, that are caused by HCV infection; > ALT, Serum alanine
aminotransferase. A liver enzyme that is an indicator of liver disease; DALY, > Disability
adjusted life years; GBD, WHO Global Burden of Disease Project (GBD); HBV, > Hepatitis B
virus; HCV, Hepatitis C virus; > ICD-10, The International Statistical Classification of Dis-
eases and Related Health Problems 10th; ICD-10 Code B20-B24, ICD-10 Code for human
immunodeficiency virus (HIV) disease; ICD-10 Code C16, ICD-10 Code for malignant
neoplasm of the stomach; RNA, Ribonucleic acid; > SF-36, Short Form 36 (health survey
questionnaire), a generic quality-of-life profile instrument; WHO, World Health Organiza-
tion; YLD, > Life years lost to disability; > YLL, Years of life lost from premature death
1 Key Facts Hepatitis C Virus
Hepatitis C virus (HCV) discovered in 1989.

Hepatitis C is a leading cause of chronic liver disease with life-threatening sequelae such as
end-stage liver cirrhosis and liver cancer.
15–25% of HCV infections progress to severe liver disease.
Progression is often silent, and therefore, many cases are diagnosed at a late stage, when
therapeutic options are already limited (‘‘Silent Killer’’).
In late stages, liver transplantation is the only therapeutic option. With early detection,
antiviral treatment can prevent about 60% of complications. Pegylated interferon combined
with ribavirin is the state of the art treatment.
Transmission is via blood to blood contact. Infections decreased with introduction of
routine blood screening in 1991.
Many patients have been infected prior to the 1990s (‘‘Awakening Giant’’).
DALYs in Chronic Hepatitis C : A Paneuropean Perspective 76 1325
The hepatitis C virus (HCV) was discovered in 1989 and identified as one of the leading
causes of chronic liver disease with serious sequelae such as end-stage cirrhosis and liver cancer
(Lauer and Walker, 2001). According to expert estimates, HCVaccounts for 20% of cases of acute
hepatitis, 70% of cases of chronic hepatitis, 40% of cases of end-stage cirrhosis, 60% of cases of
hepatocellular carcinoma, and 30% of liver transplants (European Association on the Studies on
the Liver, 1999) in industrialised countries. The World Health Organization (WHO) has esti-
mated that as many as two thirds of the liver transplants in the developed world are due to HCV
infection (World Health Organization, 1999a). In the US, a consensus conference named HCVas
the primary reason for liver transplantation (National Institute of Health, 2002).
These figures show that hepatitis C causes a major public health problem and poses a huge
burden of disease on society. The burden of disease results from premature death through
severe liver disease and from impairment in quality of life. Quality of life was initially assumed
to be affected primarily in the minority of patients with advanced disease, where HCV may
cause end-organ damage in a number of different organ systems. The vast majority of patients
with only mild liver disease were described as ‘asymptomatic’ and their quality of life was
assumed to be unaffected by the infection (Anonymous, 1997; European Monitoring Centre
for Drugs and Drug Addiction, 2004; Spiegel et al., 2005). This position has been revised since
a number of studies revealed that HCV per se causes a broad array of symptoms and
diminishes health related quality of life even in the absence of advanced liver disease (Foster
et al., 1998; Siebert et al., 2003; Siebert et al., 2005; Spiegel et al., 2005; Hollander et al., 2006;
Lang et al., 2006; von Wagner et al., 2006). As Spiegel et al. summarize in a systematic review of
quality of life studies, patients with HCV score lower than uninfected controls across all scales
of the Short Form 36 (SF-36) regardless of liver histology or ALT (serum alanine aminotrans-
ferase) levels. Quality-of-life impairment is detectable in persons who have never used drugs,
but was found to be greatest in intravenous drug users, which indicates that HCV is not the
sole reason for quality of life reduction in patients with chronic hepatitis C (Foster et al., 1998;
European Monitoring Centre for Drugs and Drug Addiction, 2004; Gjeruldsen et al., 2006).
Most frequent complaints associated with HCV infection comprise neuropsychiatric and
gastrointestinal disorders, algesia and dysesthesia (Lang et al., 2006). Quality of life was
shown to improve significantly with successful antiviral treatment (Spiegel et al., 2005).
Today, it is commonly accepted that HCV-related quality of life impairment must be taken
into account in order to assess the true burden of the disease.
Most estimates of burden of disease reflect provisional expert consensus opinion. Moti-
vated by the uncertainty of present burden of disease estimates and a lack of reliable data with
which to prioritize public health measures, an international working group was established to
assist the WHO in estimating the global burden of disease associated with HCV infection (The
Global Burden of Disease Working Group, 2004). However, important results from this
working group are still preliminary or pending.
A summary measure for the burden of disease, designed to compare premature death and
disability from various diseases across countries, was introduced by the WHO Global Burden
of Disease Study (GBD). This measure is the DALY, the disability-adjusted life years. We
focused on this measure for our present study.
In the following, we present a review that we performed with the objective to (1) search for
and summarize the data on HCV-related burden of disease in terms of DALY that are presently
available for countries of the WHO European region and (2) where the DALY do not include
the impact of the late stages of cirrhosis and liver cancer, to estimate this contribution through
HCV-attributable fractions from DALY for all-cause cirrhosis and all-cause liver cancer.
2 Review of Existing DALY Data and Calculation of the

Contribution of Cirrhosis and Liver Cancer
The primary goal of our review was to retrieve nationally representative data that are
comparable across countries. Therefore, we performed a systematic literature search in Med-
line, PreMedline and Embase, combining search terms for disease (‘‘hepatitis C’’ or ‘‘HCV’’),
burden of disease related outcomes and geographic regions. We defined the disease as a
documented HCV infection, determined by circulating viral RNA without restrictions to
co-infections. Additional index search terms related to the disease included ‘‘cirrhosis’’,
‘‘hepatocellular carcinoma’’, and ‘‘liver cancer’’. As outcome of interest related to burden of
disease, we searched for quality of life and focused on data for DALY. We searched for
publications concerning Europe, or one of 22 countries in the WHO European region
(Austria, Belgium, the Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary,
Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Romania, Russia, Spain, Sweden,
Switzerland, Turkey, and the United Kingdom).
Since HCV was first discovered in 1989, we restricted our search to documents published
since then. A final update of the literature search was performed in October 2006. Documents
in languages other than English or German were excluded.
In addition to the systematic literature search, we reviewed reference lists of retrieved
publications, searched websites of national and international organizations, e.g., Centers for
Disease Control and Prevention (US), Deutsche Stiftung Organtransplantation – German
Foundation for Organ Transplantation, European Association for the Study of the Liver,
European Centre for Disease Prevention and Control, European Liver Transplant Registry,
European Commission, The Statistical Office of the European Communities, Eurosurveil-
lance, National Institutes of Health (US), Organization for Economic Co-operation and
Development, WHO. We also consulted with experts from health organizations and pharma-
ceutical companies to obtain data from national sources.
For multi-causal disease outcomes such as liver cirrhosis or liver cancer, the data were
reported only in aggregated form, while cause-specific data were missing. Therefore, our
approach was to use attributable fractions (AF) to calculate the number and proportion of
cases specifically related to HCV infection. Using this methodology, the number of cases
attributable to HCV was derived by multiplying the total number of cases of the multi-causal
disease outcome with the HCV-attributable fraction. HCV-attributable fractions used in our
work were derived from a recent publication by Perz et al. (Perz et al., 2006), who estimated
the attributable fractions of cirrhosis and hepatocellular carcinoma due to HBV and HCV
infections for WHO sub-regions. We preferred attributable fractions as derived by Perz et al. to
AFs recently derived by other researchers (Parkin, 2006) because the attributable fractions
derived by Perz et al. do not rely on estimates of the HCV prevalence and corresponding
relative risks of exposure in the source populations, which at present are major sources of
uncertainty. The use of region-specific AFs is a simplification that may not have a strong
influence on regional burden of disease estimates, but could yield inaccurate results for single
countries.
To describe quality-of-life-related burden of disease, we used DALY and years lost due to
disability (YLD) (Murray, 1994; Murray and Lopez, 1994; Murray and Lopez, 1997; Mathers
et al., 2003; Anonymous et al., 2006; Sassi, 2006). The DALY was introduced by the WHO
Global Burden of Disease Study (GBD) to compare death and disability from various disorders
across countries. It is a summary measure of population health that combines years of life lost
from premature death (YLL) and years of ‘healthy’ life lost by being in a state of poor health or
disability (YLD). One DALY can therefore be thought of as one lost year of ‘healthy’ life and
the goal of a health intervention is to minimize DALYs. DALYs for a disease are calculated as
the sum of YLL in the population and YLD for incident cases of the health condition. The
incidence perspective for YLD is chosen to match the perspective of YLL, which measures the
incident stream of life years lost due to deaths.
Our systematic literature search yielded several studies investigating health related quality
of life in patients with hepatitis C. However, none of the studies estimated the burden of
disease resulting from HCV-related quality-of-life impairment for a whole country or region
in Europe.
Burden of disease data considering quality of life were only reported by the WHO Global
Burden of Disease Project (GBD) (World Health Organization). Available data comprised year
2002 country-specific DALY (World Health Organization, 2004a) and region-specific YLD
estimates (World Health Organization, 2004b).
The WHO GBD reported DALYs and YLD only for hepatitis C without cirrhosis and liver
cancer (World Health Organization, 2004a). Therefore, DALYs and YLD resulting from HCV-
related cirrhosis and liver cancer were calculated by weighing given data for all cause cirrhosis
and liver cancer with HCV-attributable fractions.
Retrieved and calculated DALY figures along with country-specific absolute numbers and
rates, both overall and separately for HCV-related hepatitis, cirrhosis and liver cancer are
presented in an evidence table (> Table 76-1). In addition, attributable fractions used to derive
HCV-specific values, data sources, and calculation steps are listed.
Based on our calculations, almost 1.2 Million DALYs were lost in the WHO European
region due to HCV in 2002, which corresponds to an overall rate of 134.54 DALYs per 100 000
residents. The majority of DALYs (81%) were lost due to HCV-related cirrhosis. HCV
accounted for 35% of the cirrhosis and 30% of the liver cancer DALYs in the WHO European
region. These figures vary substantially across countries. Among countries with data for HCV,
cirrhosis and liver cancer, the lowest value is 25 DALY per 100 000 (Iceland) and the highest
value is 443 DALY per 100 000 (Moldova).
In addition, data are presented as a choropleth map of the WHO European region
compiled in the software SAS (release 9.1 by SAS Institute Inc., Cary, NC, USA), where the
map categories represent rounded data quartiles (> Figure 76-1). The map shows the distri-
bution of HCV-related DALY rates in countries of the WHO European region. Countries with
low HCV-related DALY rates (<= 68 DALYs per 100 000) include Iceland, Ireland, Israel,
Malta, Netherlands, Norway, San Marino, Sweden, Macedonia, and Turkey. Countries with
high HCV-related DALY rates (>155 DALYs per 100 000) include Croatia, Germany, Hungary,
Kazakhstan, Kyrgyzstan, Moldova, Romania, Russia, Slovenia, Tajikistan, Turkmenistan,
Ukraine and Uzbekistan. The countries with high rates are located in the East (east of Finland
and Belarus and north of the Black Sea, and in a range of countries between Slovenia and
Ukraine), whereas countries with low rates are disseminated throughout the region. Germany,
with a value of 156 DALY per 100 000 (just above the threshold), is the only Western European
country in the group of the highest DALY range.
Because the DALY measure combines aspects of mortality and quality of life, we looked at
YLD (the disability component of the DALY measure) separately. YLD data were available for
the WHO European region, but not for individual countries. HCV-related YLD were calcu-
lated similarly to HCV-related DALY, using the regional HCV attributable fractions for
cirrhosis (35%) and liver cancer (30%) derived from our DALY calculation. According to
1328
. Table 76-1
DALY and DALY rates related to HCV in countries of the WHO European region in 2002
76
Hepatitis Cirrhosis Liver cancer All
DALYS attr. to Total DALYS attr. to Total DALYS attr. to DALYS attr. to
HCV DALYS AF HCV DALYS AF HCV HCV
Countries of the WHO Population per per per
European Region (’000) n n % n 100,000 n % n 100,000 n 100,000
Albania 3,141 81 34 4960 15 744 23.6883 825 26.2708
Andorra 69 7 134 38 51 73.8103 50 44 22 31.6535 80 115.8265
Armenia 3,072 35 6694 34 2276 74.0917 2656 15 398 12.9672 2710 88.2120
Austria 8,111 398 24341 38 9249 114.0353 5435 44 2391 29.4813 12039 148.4245
Azerbaijan 8,297 527 23463 34 7977 96.1512 5551 15 833 10.0361 9337 112.5361
Belarus 9,940 89 26913 34 9151 92.0596 3965 15 595 5.9839 9835 98.9423
Belgium 10,296 656 25332 38 9626 93.4966 4638 44 2041 19.8225 12323 119.6868
Bosnia and Herzegovina 4,126 97 8016 34 2725 66.0514 5583 15 837 20.2958 3659 88.6864
Bulgaria 7,965 263 20362 34 6923 86.9196 7398 15 1110 13.9329 8296 104.1517
Croatia 4,439 100 19749 38 7505 169.0782 3284 44 1445 32.5563 9049 203.8786
Cyprus 796 371 38 141 17.7280 423 44 186 23.3892 327 41.1173
Czech Republic 10,246 64 28833 38 10956 106.9362 7631 44 3358 32.7708 14378 140.3361
DALYs in Chronic Hepatitis C : A Paneuropean Perspective
Denmark 5,351 85 14892 38 5659 105.7492 1912 44 841 15.7216 6586 123.0644
Estonia 1,338 20 5724 34 1946 145.4489 601 15 90 6.7375 2056 153.6581
Finland 5,197 160 12061 38 4583 88.1801 2578 44 1134 21.8241 5878 113.0885
France 59,850 1816 140576 38 53419 89.2549 53237 44 23424 39.1387 78659 131.4282
Georgia 5,177 7 21203 34 7209 139.2458 4055 15 608 11.7497 7824 151.1245
Germany 82,414 7971 264492 38 100507 121.9532 45230 44 19901 24.1475 128379 155.7728
Greece 10,970 445 7413 38 2817 25.6814 13269 44 5838 53.2245 9100 82.9596
Hungary 9,923 187 93358 34 31742 319.8883 7594 15 1139 11.4799 33068 333.2497
Iceland 287 4 82 38 31 10.8223 83 44 36 12.6654 71 24.7890
Ireland 3,911 124 2448 38 930 23.7904 1223 44 538 13.7567 1592 40.7147
Israel 6,304 735 3142 38 1194 18.9415 1486 44 654 10.3701 2583 40.9750
Italy 57,482 11195 110240 38 41891 72.8766 70278 44 30922 53.7947 84009 146.1472
Kazakhstan 15,469 1203 75553 34 25688 166.0636 9489 15 1423 9.2012 28314 183.0427
Kyrgyzstan 5,067 97 31659 34 10764 212.4291 2956 15 443 8.7506 11305 223.0992
Latvia 2,329 40 6419 34 2183 93.7094 1171 15 176 7.5413 2398 102.9673
Lithuania 3,465 84 12646 34 4300 124.0892 1175 15 176 5.0874 4560 131.6078
Luxembourg 447 12 1122 38 426 95.3598 211 44 93 20.7319 531 118.6912
Malta 393 11 242 38 92 23.4585 98 44 43 11.0163 146 37.2949
Monaco 34 1 62 38 23 68.5757 24 44 10 30.4847 35 102.4308
Netherlands 16,067 361 12723 38 4835 30.0908 4167 44 1833 11.4108 7029 43.7469
Norway 4,514 90 3671 38 1395 30.9093 754 44 332 7.3497 1817 40.2499
Poland 38,622 1097 93738 34 31871 82.5203 17908 15 2686 6.9552 35654 92.3152
Portugal 10,049 1656 29519 38 11217 111.6304 5502 44 2421 24.0930 15294 152.2001
Moldova 4,270 243 53605 34 18226 426.7966 3025 15 454 10.6249 18923 443.1102
Romania 22,387 162 159426 34 54205 242.1225 20090 15 3014 13.4608 57381 256.3088
Russian Federation 144,082 6158 677009 34 230183 159.7589 84009 15 12601 8.7460 248942 172.7788
San Marino 27 0 24 38 9 33.5571 14 44 6 23.0311 16 57.1033
Serbia and 10,535 220 24606 9174 220 2.0876
Montenegro
Slovakia 5,398 22621 34 7691 142.4789 3207 15 481 8.9125 8172 151.3914
Slovenia 1,986 27 12094 38 4596 231.4278 1118 44 492 24.7736 5115 257.5791
Spain 40,977 6592 64195 38 24394 59.5307 32520 44 14309 34.9186 45295 110.5363
Sweden 8,867 417 6237 38 2370 26.7296 3136 44 1380 15.5628 4167 46.9904
76
1329
1330

76
Hepatitis Cirrhosis Liver cancer All
DALYS attr. to Total DALYS attr. to Total DALYS attr. to DALYS attr. to
HCV DALYS AF HCV DALYS AF HCV HCV
Countries of the WHO Population per per per
European Region (’000) n n % n 100,000 n % n 100,000 n 100,000
Switzerland 7,171 185 10302 38 3915 54.5874 3767 44 1657 23.1094 5757 80.2770
Tajikistan 6,195 3707 23172 34 7878 127.1734 899 15 135 2.1771 11720 189.1861
Macedonia 2,046 37 2365 34 804 39.3128 1908 15 286 13.9942 1128 55.1223
Turkey 70,318 5913 50473 34 17161 24.4046 15060 15 2259 3.2126 25333 36.0261
Turkmenistan 4,794 1186 28496 34 9689 202.0972 2853 15 428 8.9275 11302 235.7542
Ukraine 48,902 919 224442 34 76310 156.0483 26395 15 3959 8.0963 81188 166.0233
United Kingdom 59,068 2414 114459 38 43494 73.6345 19702 44 8669 14.6764 54577 92.3978
Uzbekistan 25,705 5600 132821 34 45159 175.6793 9089 15 1363 5.3038 52122 202.7670
ALL 877,887 63496 2733544 35 957389 109.0561 532544 30 160219 18.2505 1181105 134.5395
The Hepatitis C Virus (HCV) can cause acute hepatitis and chronic hepatitis with potential long-term consequences cirrhosis and liver cancer. Disability adjusted life years (DALY) are
derived from WHO GBD (World Health Organization, Global Burden of Disease Project) data. DALY resulting from hepatitis (column 3) represent original WHO data. These data
excluded cirrhosis and liver cancer. Liver cancer and cirrhosis DALY attributable (attr.) to HCV represent WHO GDB data weighted by population attributable fractions (AF). Population
size data used to calculate DALY rates were derived from the WHO GDB project as well. Figures highlighted in italics represent external input data, figures in standard font indicate
calculated results
Data sources:(a) WHO GBD data 2002 available at: http://www3.who.int/whosis/burden/estimates/2002Rev/2002RevCountries/DthDALY2002.zip(b) Population attributable fractions:
Perz JF, Armstrong GL, Farrington LA, Hutin YJ and Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.
J Hepatol 2006;45:529–38
. Figure 76-1
HCV-related DALY rates in countries of the WHO European region in 2002. Source: Calculated
from WHO GBD data (World Health Organization, 2004a)
the calculation, HCV caused 200 104 YLD in the WHO European region in 2002. Of those
6250 (3%) were due to hepatitis C without cirrhosis or liver cancer, 191 537 (96%) were due to
HCV-related cirrhosis and 2317 (1%) were due to HCV-related liver cancer.
3 Revised Evaluation of the HCV Burden of Disease after

Inclusion of Cirrhosis and Liver Cancer
The inclusion of the estimated HCV-related fraction of DALY from all-cause cirrhosis and liver
cancer changes the picture dramatically. According to our calculations, HCV caused approxi-
mately 1.2 million DALYs in the WHO European region in 2002. Comparing this figure to DALY
reported by the WHO GBD study for other diseases reveals that hepatitis C is a major health
problem, almost the size of HIV/AIDS (ICD-10 Code B20-B24) or stomach cancer (ICD-10
Code C16), each with about 1.4 million DALY in 2002 (World Health Organization, 2004c).
A closer look on YLD (the disability component of the DALY measure) reveals that about one
sixth of the HCV-related DALY burden (200 104 YLD) are due to quality-of-life impairment.
However, the YLD account for disability in incident cases only. Quality of life reductions for
patients, who suffer from the disease but have been detected in the past, are not included.
DALY differ in a wide range between countries. High DALY figures are predominantly
found in Eastern countries. Since YLD contribute only one sixth to the DALY, they are unlikely
to explain the differences between countries. Differences in the second DALY component, YLL
(life years lost due to premature death) are therefore a more likely reason for DALY variation.
The strong geographic variation of DALY may be partially explained by differences in
prevalence, but also younger age at death is likely an important contribution. Deviating health
care standards or differences in the distribution of competing and synergistic risk factors
should be considered as explanations for geographic variations in age at death. For example,
HCV-related death rates might be lower in countries with high prevalence of hepatitis B
(World Health Organization, 1999b), whereas they might be higher in countries with a high
alcohol consumption (Peters and Terrault, 2002). Specifically, heavy alcohol consumption was
shown to be associated with higher risks of cirrhosis, liver cancer and death in patients with chronic
hepatitis C (Shepard et al., 2005; Perz et al., 2006). Involvement of other risk factors or co-
morbidities can not be excluded. Heterogeneous data quality may add to geographical variation.
About 95% of the HCV-related DALYs were accumulated by patients in advanced disease
stages (cirrhosis or liver cancer). This high percentage emphasizes the importance and potential
benefit of preventive antiviral treatment. However, it also suggests that quality of life im-
pairment caused by HCV infection per se (Foster et al., 1998; Spiegel et al., 2005; Hollander
et al., 2006; Lang et al., 2006; von Wagner et al., 2006) might not be relevant from a burden of
disease perspective. However, this cannot be concluded with certainty, as it is unclear what
conditions and aspects are covered by the disability weight of 0.075 (Mathers et al., 2003) that
was used for the calculation of hepatitis C related DALYs in the GBD study. It should also be
realized that estimating YLD and subsequently DALYs was the most complex component of the
GBD study, requiring a broad set of input data from a multitude of sources (Mathers, 2005).
Results for single countries might therefore be surrounded with considerable uncertainty.
A limitation of our analysis is the use of regional instead of country-specific HCV
attributable fractions. This may not have a strong influence on regional burden of disease
estimates, but may yield inaccurate results for single countries. Since all parameters of our
calculations are revealed, though, country-specific estimates can easily be revised by the
interested reader when better data become available.
The considerable geographic variation of DALY should be examined in further research.
Reliable and comparable data for prevalence and mortality across countries need to be
identified for that purpose. Competing risks and differences in health care for hepatitis C
patients, for example access to state-of-the-art antiviral treatment or availability of liver
transplantations, should be evaluated as well (Lettmeier et al., 2008).
4 Conclusion
Presently, the only data allowing a consistent cross-country comparison of burden of disease
resulting from HCV-related premature death and quality of life impairment are DALYs and
YLD estimated by the WHO GBD study in 2002.
According to our additional calculations based on these data and HCV-attributable
fractions of cirrhosis and liver cancer, hepatitis C is a major health problem in the WHO
European region, comparable in magnitude to HIV/AIDS or stomach cancer. Our results
underline the importance and potential benefit of preventive antiviral treatment.
The burden of disease differs strongly across the countries of the WHO European region,
with highest values in eastern countries. This variation indicates the potential of inequality of
health services across counties that should be investigated further. The lack of data demon-
strates that the full extent of the hepatitis C crisis is not yet fully perceived in Europe.
Summary Points
According to our calculations, HCV caused approximately 1.2 Million DALYs (life years
lost through premature death or impairment of quality of life) in the WHO European
region in 2002.
One sixth of these DALYs can be attributed to quality of life impairment.
Hepatitis C is a major health problem, comparable to HIV/AIDS or stomach cancer each
with about 1.4 million DALY.
About 95% of the HCV-related DALY were accumulated by patients in advanced disease
stages (cirrhosis of liver cancer), which underlines the importance and potential benefit of
preventive antiviral treatment.
The burden of disease expressed in DALY differs strongly across countries, with highest
values in eastern countries. Countries with highest HCV-related DALY rates (>155 DALYS
per 100 000) are Croatia, Germany, Hungary, Kazakhstan, Kyrgyzstan, Moldova, Romania,
Russia, Slovenia, Tajikistan, Turkmenistan, Ukraine and Uzbekistan. Further research
regarding the causes of the variation is needed.
The lack of data demonstrates that the full extend of the hepatitis C crisis is not yet fully
perceived in Europe.
Acknowledgments
This project was supported in part by an unrestricted research grant from Hoffmann La-Roche
Ltd., Basel, Switzerland. The authors had complete and independent control over study design,
analysis and interpretation of data, report writing, and publication, regardless of results.
References
Anonymous. (1997). Hepatology. 26: 2S–10S. Lettmeier B, Mühlberger N, Schwarzer R, Sroczynski G,
European Association on the Studies on the Liver Wright D, Zeuzem S, Siebert U. (2008). J Hepatol.
(EASL). (1999). J Hepatol. 31(Suppl 1): 3–8. 49: 528–536.
European Monitoring Centre for Drugs and Drug Addic- Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray
tion (EMCDDA), Jager J, Limburg W, Kretzschmar CJL (2006). Global Burden of Disease and Risk
M, Postma M, Wiessing L. Hepatitis C and injecting Factors. Oxford University Press, New York. Also
drug use: impact, costs and policy options. Mono- available from: http://www.dcp2.org/pubs/GBD.
graph 7 [monograph on the Internet]. Lisbon: Eu- Mathers CD, Bernard C, Moesgaard Iburg K, Inoue M,
ropean Monitoring Centre for Drugs and Drug Ma Fat D, Shibuya K, Stein C, Tomijima N, Xu H.
Addiction; 2004 [cited 2007 Sept]. Available from: Global Burden of Disease in 2002: data sources,
http://www.emcdda.eu.int/?nnodeid=428. methods and results. Global Programme on Evi-
Foster GR, Goldin RD, Thomas HC. (1998). Hepatology. dence for Health Policy Discussion Paper No. 54
27: 209–212. [monograph on the Internet]. World Health Orga-
Gjeruldsen S, Loge JH, Myrvang B, Opjordsmoen S. nization, Geneva, Switzerland 2003, revised 2004
(2006). Nord J Psychiatry. 60: 157–161. [cited: 2006 Oct]. Available from: http://www.who.
Hollander A, Foster GR, Weiland O. (2006). Scand J int/healthinfo/paper54.pdf.
Gastroenterol. 41: 577–585. Mathers CD. Uncertainty and data availability for the
Lang CA, Conrad S, Garrett L, Battistutta D, Cooksley global burden of disease estimates 2000–2002 [mono-
WG, Dunne MP, Macdonald GA. (2006). J Pain graph on the Internet]. 2005 [cited 2007 Mar].
Symptom Manage. 31: 335–344. Available from: http://www.who.int/healthinfo/publi-
Lauer GM, Walker BD. (2001). N Engl J Med. 345: 41–52. cations/boduncertaintypaper2002.pdf.
Murray CJ. (1994). Bull World Health Organ. von Wagner M, Lee JH, Kronenberger B, Friedl R,
72: 429–445. Sarrazin C, Teuber G, Herrmann E, Zeuzem S.
Murray CJ, Lopez AD. (1994). Bull World Health Organ (2006). J Viral Hepat. 13: 828–834.
72: 481–494. World Health Organization. The Global Burden of Dis-
Murray CJ, Lopez AD. (1997). Bull World Health Organ ease project: results for 2002 and earlier years, meth-
75: 377–381. ods, documentation and publications. Manuals,
National Institute of Health (NIH). (2002). Hepatology. resources and software for carrying out national
36: S3–S20. burden of disease studies [website on the Internet].
Parkin DM. (2006). Int J Cancer. 118: 3030–3044. [cited 2007 Mar]. Available from: http://www.who.
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. int/healthinfo/bodproject/en/index.html.
(2006). J Hepatol. 45: 529–538. World Health Organization. Hepatitis C [monograph on
Peters MG, Terrault NA. (2002). Hepatology. the Internet]. 1999a [cited 2006 Oct]. Available
36: S220–S225. from: http://www.who.int/immunization/topics/
Sassi F. (2006). Health Policy Plan. 21: 402–408. hepatitis_c/en/index.html/.
Shepard CW, Finelli L, Alter MJ. (2005). Lancet Infect World Health Organization. (1999b). J Viral Hepat.
Dis. 5: 558–567. 6: 35–47.
Siebert U, Sroczynski G, on behalf of the German Hepa- World Health Organization. Mortality and burden of
titis C Model (GEHMO) Group and the HTA Expert disease estimates for WHO member states in 2002
Panel on Hepatitis C. (2003). [Antiviral therapy for [database on the Internet]. 2004a [updated N.N.;
patients with chronic hepatitis C in Germany. Eval- cited 2006 Oct]. Available from: http://www3.who.
uation of effectiveness and cost-effectiveness of ini- int/whosis/burden/estimates/2002Rev/
tial combination therapy with Interferon/ 2002RevCountries/DthDALY2002.zip.
Peginterferon plus Ribavirin. Series of the German World Health Organization. Estimates of Years Lost due
Institute for Medical Documentation and Informa- to Disability by sex, cause and WHO Region for
tion commissioned by the Federal Ministry of 2002 [monograph on the Internet]. 2004b [cited
Health and Social Security]. Vol. 8. DIMDI, Köln. 2007 Mar]. Available from: http://www.who.int/en-
Siebert U, Sroczynski G, on behalf of the German Hepa- tity/healthinfo/statistics/gbdwhoregionyld2002.xls.
titis C Model (GEHMO) Group and the HTA Expert World Health Organization. Estimates of DALYs by
Panel on Hepatitis C. (2005). Int J Technol Assess sex, cause and WHO Region for 2002 [monograph
Health Care. 21: 55–65. on the Internet]. 2004c [cited Mar 2007]. Available
Spiegel BM, Younossi ZM, Hays RD, Revicki D, from: http://www.who.int/healthinfo/statistics/
Robbins S, Kanwal F. (2005). Hepatology. 41: gbdwhoregiondaly2002.xls.
790–800.
The Global Burden of Disease Working Group. (2004).
J Clin Pharmacol. 44: 20–29.
77 Economics and Vaccines
J. Bos . M. Postma
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1336
2 Modeling Economic Evaluations of Vaccines: Methodological Issues . . . . . . . . . . 1338
3 Cost-Effectiveness of Vaccine Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1340

3.1 Childhood Cluster Diseases Vaccination Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1340
3.1.1 Measles, Mumps and Rubella (MMR) Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1341
3.1.2 Diphtheria, Tetanus, Pertussis and Polio (DTPP) Vaccination . . . . . . . . . . . . . . . . . . . 1343
3.1.3 Varicella Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1343
3.2 Vaccination Campaigns Against Respiratory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1345
3.2.1 Hemophilus influenzae Type B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1345
3.2.2 Pneumococcal Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1346
3.2.3 Meningococcal Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1346
3.2.4 Influenza Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347
3.3 Vaccination Campaigns Against Sexually Transmitted Infections
and Other Vaccine-Preventable Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347
3.3.1 Hepatitis B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347
3.3.2 Human Papilloma Virus (HPV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1348
3.3.3 Hepatitis A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1348
3.3.4 Rotavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1349
4 Discussion and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1349
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1350

1336 77 Economics and Vaccines
Abstract: Infectious diseases are an important cause of mortality and morbidity, causing
approximately 27% of the total disease burden in > DALY. A large part of DALY lost due to
infectious diseases could be prevented by improving existing vaccination programs for the
population. Diseases such as > childhood cluster diseases, hepatitis A and B, respiratory
infections caused by influenza, pneumococcal and meningococcal infections, and Hemophilus
influenzae type B, are for a large part preventable by current vaccines.
The implementation of new vaccine programs or/and strategies is often a costly process
with long term consequences. Vaccination programs often concern a large part of the popula-
tion, and have a large budget impact. Once a vaccination program has started, it is (due to
equity reasons) extremely difficult to cease the program. To gain a better understanding of the
potential impact on health benefits and costs of a vaccine intervention, health-economic
evaluations are frequently used, which estimate the future impact on health gains and costs.
Health-economic evaluations are mostly presented as one of the following four types of
analysis: cost-minimization, cost-benefit, cost-effectiveness and cost-utility analysis. In this
chapter, we provide an overview of the main techniques and challenges associated with health
economic evaluations of vaccination programs, such as the choice of the model. Additionally,
an overview of health economic evaluations that have been performed on currently imple-
mented vaccination strategies is presented. From our analysis it follows that vaccine programs,
and especially those against childhood cluster diseases, and vaccination of elderly against
influenza are amongst the world’s most cost-effective interventions.
List of Abbreviations: BCG, bacillus Calmette-Guérin; CBA, > cost benefit analysis; > CEA,
cost effectiveness analysis; > CMA, cost minimization analysis; DALY, disability adjusted life
year; > DTPP, diphtheria, tetanus, pertussis and poliomyelitis; > Hib, Hemophilus influenzae
type b; > HPV, human papilloma virus; > IPV, inactivated poliomyelitis vaccine; > MMR,
measles, mumps and rubella; > OPV, oral poliomyelitis vaccine; > QALY, quality adjusted life
year; > WTP, willingness to pay; > VZV, varicella zoster virus
1 Introduction
Despite the discovery of vaccines that helped to eradicate smallpox, the launch of a global
campaign to eradicate poliomyelitis, and support the control of measles, diphtheria and other
diseases, infectious diseases remain the leading cause of death in developing countries (WHO,
2007).
Worldwide, infectious diseases are an important cause of mortality and morbidity, causing
approximately 27% of the total disease burden in DALY (Authors calculation based on WHO,
2004 data). A large part of DALY lost due to infectious diseases could be prevented by
improving existing vaccination programs for the population. Diseases such as childhood
cluster diseases, hepatitis B, TB, respiratory infections caused by influenza, pneumococcal
and meningococcal infections, Hemophilus influenzae type B, are for a large part preventable by
current vaccines but still lead to a large burden of disease and mortality. > Table 77-1 provides
an overview of the global burden of disease caused by infectious diseases.
The implementation of new vaccine programs or/and strategies is an often costly process
with long term consequences, due to the fact that (1) vaccination strategies often involve
vaccination of large parts of the population and (2) once a vaccination program has started, it
is (due to equity reasons) extremely difficult to cease the program. Additionally, in most cases,
Economics and Vaccines 77 1337
. Table 77-1
Overview of major infectious diseases and DALY burden worldwidea
All Causes 1.490.125.643

Communicable conditions 403.490.600
Infectious and parasitic diseases 308.887.251
Tuberculosis 34.735.908
STDs excluding HIV 11.347.067
HIV/AIDS 84.457.784
Diarrheal diseases 61.966.183
Childhood-cluster diseases (Pertussis, Poliomyelitis, Diphtheria, Measles, 41.479.543
Tetanus)
Meningitisa 6.191.790
Hepatitis B 2.170.326
Hepatitis C 1.003.682
Malaria 46.485.868
Tropical-cluster diseases: Trypanosomiasis, Chagas disease, Schitomiasis, 12.245.452
Leishmaniasis, lymphatic filariasis, onchocerciasis
Leprosy 198.778
Dengue 615.529
Japanese encephalitis 709.219
Trachoma 2.328.780
Intestinal nematode infections 2.951.341
Respiratory infections
Lower respiratory tract infections, Upper respiratory tract infections, Otitis 94.603.349
media
Noncommunicable diseases 697.815.295
Injuries 181.991.119
Adapted from (Gwatkin and Guillot, 1998)
a
Total does not add up since we omitted DALY burden due to perinatal conditions and nutritional deficiencies
decisions with regards to vaccination programs are public health policy decisions, making
rational decision making a must. A better understanding of the potential impact of an
intervention will enable policy makers to prioritize intervention in public healthcare, so that
the available funds are spend in such a way that health care gains are being maximized. As a
result, in an increasing number of countries, for new interventions to successfully apply for
reimbursement, not only their clinical effectiveness has to be proven, but also their cost-
effectiveness (Cookson and Mc Daid, 2003).
For the estimation of potential costs and benefits of the introduction of a new public
health program, health-economic evaluations are frequently used, which estimate the future
impact on health gains and costs. Health-economic evaluations are mostly presented as one of
four types of analysis: cost-minimization analysis (CMA), cost-benefit analysis (CBA), cost-
effectiveness analysis (CEA) and cost-utility analysis (CUA), of which the latter two are used
most often. In cost-minimization analysis, the interventions under study are assumed to have
similar efficacy and equal effectiveness. Only relevant costs are compared, and the cheapest
intervention is assumed to be the most efficient. In cost-benefit analysis, the benefits of the
intervention are expressed in monetary values, usually as the individual’s willingness to pay
(WTP) for a certain risk reduction in morbidity or mortality due to a new medical interven-
tion (Johannesson and Meltzer, 1998). Concern over the monetary valuation of the resulting
human lives, led to the development of cost-effectiveness analysis as an alternative. In cost-
effectiveness analysis, benefits of the intervention are expressed in a natural outcome measure,
such as averted infections or life years gained. In cost-effectiveness analysis, differences in
quality of life are not valued. Another form of cost-effectiveness analysis is cost-utility analysis,
where health gains are corrected for the quality of life of the patient. Health benefits are then
mostly expressed as quality adjusted life years (QALYs) or other denominators, such as
disability adjusted life years (DALYs) (Johannesson and Meltzer, 1998).
In a growing number of countries, such as the Netherlands, United Kingdom, Australia,
and Canada, these evaluations are being used to guide policy making on the introduction on
new public vaccination programs (Cookson and Mc Daid, 2003). For instance, the decision of
the Netherlands to vaccinate all infants with meningococcal C vaccine on the age of 14 months
was a direct effect of the health-economic analysis (Welte et al., 2005).
2 Modeling Economic Evaluations of Vaccines:

Methodological Issues
In economic evaluations of healthcare interventions, net costs are related to health gains, and
expressed as a ratio such as the cost-effectiveness ratio of net costs per life-year gained. Net costs
are estimated by subtracting the savings on averted infectious diseases’ treatment costs from the
costs of the vaccines and the investment costs in administration and infrastructure. Both costs
and health gains are corrected for the time of occurrence using an annual > discount rate.
Vaccine interventions usually have the following features, which might set them apart from
other interventions in public health:
1. Preventative character: Although therapeutic vaccines are being developed against certain
forms of cancer for instance, most vaccines are given as prophylaxis. Some infectious
diseases, such as hepatitis B and HPV infections, have an impact on the occurrence of
severe complications much later on in life. This might pose a challenge to the analyst, since
often long time frames of analysis need to be modeled.
2. Large scale, hence often large budgetary impacts: Whereas economic evaluations of other
pharmaceuticals often target individual patients (or small patient populations), vaccine
interventions in most cases concern a larger part of the population, causing the intervention
to have a large budgetary impact. Therefore, when assessing these interventions, budget
impact and allocation of the total budget will form an important aspect of the final decision.
3. Targeted against infectious diseases: Although some exceptions exist, (for instance vaccines
are being developed against cancer) most vaccines target specific infectious diseases. Due
to the communicable character of the agents causing disease, all indirect effects of removal
of the pathogen from the population on those not vaccinated should also be included
in the model. This is a challenge for the analyst, since the transmission mechanism of
the causing agent needs to be assessed and included in the analysis. Additionally, an
intervention against an infectious disease will gradually be subject to diminishing marginal

returns. This occurs since vaccinating the population leads to a diminished > force of
infection, causing the incidence of disease to drop. So, as the coverage of the vaccination
program increases, more and more persons need to be vaccinated in order to prevent a
single case of disease. This may well cause a paradox, in which eradication of disease is even
more costly than disease control by selected vaccination strategies.
4. Incongruent timing between costs associated with the intervention and the resulting health
benefits: Some diseases, such as HPV infections or hepatitis B infections have an impact on
the occurrence of severe complications much later in life. Thus, a large time gap might
exist between the costs of the intervention and the expected benefits of the intervention.
Using equal discount rates for costs and health effects might have a large impact on the cost-
effectiveness ratio of the vaccine. In a recent consensus statement on vaccination programs for
preventing Hepatitis B, Beutels et al. (2002) re-iterate that discounting health effects signifi-
cantly and negatively affects estimated cost-effectiveness of vaccination programs with long
term effects.
In economic evaluations, it is good practice to use data from clinical trials. However, it
has been argued that for the evaluation of vaccine programs, effectiveness data from clinical
trials are not transferable to a real life setting (Clemens et al., 1996; Edmunds et al., 1999).
Since vaccine trials are small in relation to population based vaccination programs, they can
only provide an estimate of the individual efficacy of the vaccine and do not give a good
estimate for the overall effectiveness of a mass vaccination campaign in the population. By
vaccinating a large group in the population, the circulation of the bacteria or virus will
diminish, leading to a reduction of disease beyond the direct effects of vaccination. As a
consequence, the force1 of infection diminishes. So, by mass vaccination, a certain level of
protection is also offered to those in the population who are not vaccinated (Edmunds et al.,
1999). This phenomenon is called > ‘‘herd immunity’’ – not correcting for it may cause an
underestimation of the effect of the intervention (Edmunds et al., 1999). Another consequence
of a diminished force of infection is that infections will occur at a later age. This shift in age-
specific incidence can have great implications for public health, especially for diseases that
have worse outcome when occurring at a later age (for instance varicella zoster infections)
(Beutels et al., 2002).
Cost-effectiveness analyses of vaccination programs that assess the transmission of disease,
use either a static or a dynamic transmission model. The difference between a static or a
dynamic model lies in the assumption of the value of the force of infection. A static model
assumes that the force of infection is a constant, while in a transmission dynamic model the
force of infection is a function of the number of infectious individuals in the population
(Edmunds et al., 1999). In the latter, herd immunity effects of mass vaccination on the force
infection are taken into account. Also, in transmission dynamic models the effects of vaccina-
tion on for instance the age-specific incidence rate are assessed. In > Table 77-2, an overview is
presented of the most important model types and characteristics.
1
The force of infection is defined as the per-susceptible rate of infection. The force of infection can be calculated
approximately by dividing the incidence by the number of susceptibles
. Table 77-2
Key characteristics of the models (Bos et al., 2008)
Key assumption Model type Main features

Static Constant force of infection Decision analysis/ Simple
Markov model Minimal data requirements
Dynamic Force of infection is a function (Age-structured) Complex
of the fraction infected compartmental Needs detailed data on
model transmission dynamics
Able to evaluate impact of herd
immunity
Accounts for shift in age-
specific incidence rates
Gives insight in shifts in cost-
effectiveness ratio over time
3 Cost-Effectiveness of Vaccine Interventions
In this section, we will provide an overview of most common vaccination programs in

developed countries, their cost-effectiveness and the cost-effectiveness models used for the
analysis. A large number of vaccines have been in use in public health interventions for quite
some time, as is illustrated in > Table 77-3 (which is by no means exhaustive).
The cost-effectiveness of an intervention is usually measured compared to the do-nothing
alternative. A number of these vaccines have been in use for a long period of time, making the
cost-effectiveness of these vaccines is difficult to measure. The effects of the vaccine on the
epidemiology and transmission of disease depend highly on the fact that a vaccine has been
given for a very long period in time before starting the analysis. Therefore, it is impossible to
calculate the cost-effectiveness against the do-nothing scenario. Additionally, the decision to
vaccinate against these diseases has been made a long time ago, in a time where health
economic evaluations of public health interventions were not performed. However, cost-
effectiveness studies on adaptations of those vaccines, for instance different formulations
with less side-effects and/or higher efficacy, are frequently used by policy makers.
3.1 Childhood Cluster Diseases Vaccination Programs
This category consists of vaccination programs against common childhood diseases, such as
measles, mumps, diphtheria, tetanus, poliomyelitis, rubella, and pertussis. Cost-effectiveness
analysis of the original interventions with Measles, Mumps, Rubella vaccine (MMR) and polio
and Diphtheria, Tetanus and Pertussis (DTP) vaccines have only been performed to a limited
extend. These childhood vaccines are commonly cited to be among the most cost-effective
interventions, and have resulted in the saving of millions of lives of infants and young children
(WHO, 2008). A recent study estimated that a one-week ‘‘supplemental immunization
activity’’ against measles carried out in Kenya in 2002 – in which 12.8 million children were
vaccinated – would result in a net savings of US$12 million over the following ten years; during
. Table 77-3
Introduction of first generation vaccines
Year of introduction first generation

Vaccine vaccine for human use
Smallpox 1798
Rabies 1885
Plague 1897
Diphtheria 1923
Pertussis 1926
Tuberculosis (BCG) 1927
Tetanus 1927
Yellow fever 1935
Injectable Polio vaccine (IPV) 1955
Oral Polio vaccine (OPV) 1962
Measles 1964
Mumps 1967
Rubella 1970
Hepatitis B 1981
Influenza 1953
Hepatitis Aa 1995
Hemophilus influenza type B 1992
Pneumococcal conjugate vaccine 2000
Pneumococcal vaccine polysaccharideb 1948
Meningococcal C vaccine 1999
Meningococcal A, Y, W135 and C vaccine 2005
Adapted from Plotkin and Mortimer (1994)
a
and
b
Baker (2007) and Austrian (1981)
which it would prevent 3,850,000 cases of measles and 125,000 deaths. In the United States,
cost-benefit analysis indicated that every dollar invested in a childhood disease vaccine dose
saves US$2 to US$27 in health expenses (WHO, 2008).
3.1.1 Measles, Mumps and Rubella (MMR) Vaccination
Since the vaccines against measles, mumps and rubella are usually given in the MMR
combination vaccine, we will discuss both health-economic analyses of single vaccine inter-
ventions, such as revaccination after an outbreak of measles, as well as the cost-effectiveness of
MMR vaccine. Few studies have been undertaken to assess the cost-effectiveness of the MMR
vaccine since it’s introduction in general vaccination programs in the second half of last
century. Most studies focus on adaptations of existing formulations, or changes in target
population. A single study from 1985 was found that compared vaccination with MMR
vaccine to the do-nothing scenario in the US, and found the intervention to be cost-saving
(White et al., 1985). Without an immunization program, an estimated 3,325,000 cases of
measles would occur as compared to 2,872 actual cases in 1983 with a program. Instead of an
expected 1.5 million rubella cases annually, there were only 3,816 actual cases. Mumps cases
were lowered from an expected 2.1 million to 32,850 actual cases. Without a vaccination
program, disease costs would have been almost $1.4 billion. Expenditures for immunization,
including vaccine administration costs and the costs associated with vaccine reactions, totaled
$96 million. The resulting benefit-cost ratio for the MMR immunization program was
approximately 14:1. The savings realized due to the use of the combination vaccine rather
than single antigen vaccines totaled nearly $60 million (White et al., 1985).
3.1.1.1 Measles Vaccine

Despite the lack of formal cost-effectiveness studies, measles vaccination is cited to be among
the most cost-effective public health interventions implemented world-wide. (WHO, 2008) A
few studies have been conducted on the cost-effectiveness of additional vaccination in the case
of a measles outbreak, or on measles eradication strategies. Stover et al. (1994) assessed the
cost-effectiveness of a program to identify and immunize susceptible hospital employees
during a measles outbreak. In three US hospitals, they compared blind MMR vaccination
with targeted MMR vaccination to only those at risk (being those born from 1957 onwards).
Their analysis showed that a directed MMR immunization program was projected to be cost-
effective compared to universal MMR vaccination of all hospital employees. However, no
formal transmission model was used, making it difficult to assess the effects of vaccinating
hospital workers on the transmission of measles, mumps or rubella to the patient population.
Sellick et al. (1992), also showed targeted measles immunization for susceptible workers to be
more cost-effective than universal vaccination.
A few studies were found that assessed the cost-effectiveness of improved measles control
or measles eradication within the general population. Pelletier et al. (1998) studied the benefit-
cost ratio of two-dose measles vaccination of infants in Canada, using a transmission dynamic
model. Zwanziger et al. (2001) used a static approach to evaluate the economic impact of
increasing measles immunization rates in the United States. They examined the relationship
between measles incidence and the immunization rate and converted it to a linear model,
which was linked to a decision analysis model to assess the cost-effectiveness. The decision
analysis study by Shiell et al. (1998) used similar methodology to assess the cost-effectiveness
of measles vaccination to prevent school-based outbreaks in Australia, finding favorable cost-
effectiveness.
A study by Gay et al., used a transmission dynamic model to assess the impact of adding a
second booster dose of measles vaccine for infants aged 18 months or 5 years to the national
vaccination program in Canada (Gay et al., 1998). Their model analyzed the transmission
between five different age groups over time. The results of this modeling study showed that a
combination of a catch-up campaign and a booster vaccine for infants would have an immedi-
ate impact in reducing the transmission of measles, whereas adding only a routine second dose
would still allow endemic transmission between older infants for at least 10–15 years.
Beutels and Gay (2003) analyzed the costs and benefits of the eradication of measles, using
a transmission dynamic model that simulated ten different measles vaccination strategies for a
hypothetical west-European country. The conclusion of this analysis was that very high
(>95%) coverage two-dose vaccination is optimal, irrespective of past vaccination coverage.
Additionally, the addition of a catch-up campaign to this two-dose vaccination strategy would
be cost-saving in the case of low historical coverage (<70%). Miller et al. developed a static
model for analyzing measles eradication interventions in the US (Miller et al., 1998), estimat-
ing that measles eradication would save an estimated US$ 45 million. However, in this study
the transmission of measles was not incorporated giving little insight in the coverage rates
needed for eradication, timing of eradication and potential age-shifts.
3.1.1.2 Mumps and Rubella Vaccines

Few economic evaluations have been performed of these vaccines. A review study done by
Hinman et al. (2002), showed that in total five economic analyses of Rubella vaccine and seven
economic analyses of MMR vaccine had been performed in developed countries. This review
study indicated that the comparability of the individual study results was hampered by a lack
of standardization in study design and methods used. The results of these studies showed
favorable cost-effectiveness for rubella and MMR vaccines, supporting the decision to include
this vaccine in national vaccination programs.
3.1.2 Diphtheria, Tetanus, Pertussis and Polio (DTPP) Vaccination
No specific studies were found evaluating DTP or DTPP vaccines. However, separate evaluation
of pertussis vaccination and polio vaccines were found. A number of evaluations of pertussis
vaccine were found comparing acellular pertussis vaccine with whole cell pertussis vaccine,
where the latter vaccine formulation would have a higher incidence of side-effects (Beutels
et al., 1999; Caro et al., 2005; Ekwueme et al., 2000; Tormans et al., 1998). Additionally, several
studies analyze the impact of a pertussis booster vaccine given later in the infants life (Edmunds
et al., 2002; Iskedjian et al., 2004; Purdy et al., 2004; Stevenson et al., 2002). All studies, except
the study by Edmunds et al., used a static transmission model. All studies on whole cell pertussis
versus acellular vaccine showed that the acellular vaccine was more cost-effective, since all
studies projected higher efficacy rates for the acellular vaccine (Caro et al., 2005).
A small number of studies were found that evaluated the effects of increasing efforts to
eradicate polio (Bart et al., 1996; Kahn and Ehreth, 2003; Thompson and Duintjer Tebbens,
2006, 2007). In general, these studies concluded that the eradication of polio would be cost-
effective. A study by Thompson (Thompson and Duintjer Tebbens, 2006) concluded that the
poliomyelitis vaccination program in the US is a highly cost-effective intervention, responsible
for the prevention of hundreds of thousands of cases of paralytic poliomyelitis and premature
deaths, and has yielded net economic benefits exceeding US$180,000 million. In another study
by Thompson et al., a dynamic transmission model was used to assess the costs and benefits of
worldwide polio eradication versus controlling poliomyelitis levels by increasing vaccine
coverage (Thompson and Duintjer Tebbens, 2007). Their study supports the completion of
eradication now, instead of controlling poliomyelitis.
3.1.3 Varicella Vaccination
Varicella zoster virus (VZV) is a herpes virus that causes both varicella (commonly known as
chickenpox) and herpes zoster. When a person becomes infected for the first time with VZV, it
results in varicella, which is a mild illness (although severity increases with age). After the
initial Varicella infection, VZV becomes latent in the dorsal root ganglia and can reactivate
after a long period to cause herpes zoster (Miller et al., 1993). Reactivation occurs in 15–25%
of individuals, of which over 70% are adults (Brisson et al., 2000). Zoster is associated with
severe morbidity (hospitalization occurs in 4% of cases, median duration of hospitalization of
18 days) and significant case fatality (0.07% of cases), making herpes zoster an essential issue
to be considered when analyzing the epidemiology of VZV (Brisson et al., 2000).
The precise relationship between varicella and zoster incidence is still unclear, it has been
suggested that varicella can decrease the risk of zoster by boosting specific immunity to VZV
(Brisson et al., 2000). This relationship implies that a reduction of VZV in the population may
have adverse effects on the incidence of zoster. By reducing the exposure to natural varicella
and shifting the average age of infection upwards, widespread vaccination would have two
potentially adverse consequences. Firstly, the severity of varicella illness increases with age.
Therefore infant vaccination avoids mostly ‘‘cheap’’ cases of varicella in infants, but partly
replacing them by more ‘‘expensive’’ older cases. Secondly, the incidence of herpes zoster
(shingles) at older ages temporarily increases if (1) periodical exposure to wild-type VZV
infection (i.e., exposure to infectious children) boosts immunity to zoster, and (2) break-
through varicella cases occur on a limited scale with relatively low infectiousness (Brisson
et al., 2000). These effects may have a profound effect on the cost-effectiveness and morbidity
caused by VZV (Postma et al., 2003).
A live attenuated VZV vaccine has been available since the middle of the 1970s. Currently
in the United States and Japan varicella vaccination is included in the childhood immuniza-
tion schedule (Postma et al., 2003). Several health economic studies have been performed on
the introduction of this vaccine for infants. Thiry et al. (2003) reviewed economic evaluations
of varicella vaccination, identifying ten studies on infant vaccination. The studies showed cost-
savings from the societal perspective (benefit-to-cost ratios varying from 1.6 to 6.9). From the
societal perspective it was primarily vaccine price and averted unproductive days by parents
(indirect costs averted) caring for sick children that determined cost savings. However, all
these studies excluded the impact of zoster on the analysis, and used no formal dynamic
transmission model.
A study by Edmunds et al. (2002) on the cost-effectiveness of Varicella vaccination of
infants in Canada was the first to take the potential increase in zoster into account (Brisson
and Edmunds, 2002). The inclusion of zoster influenced their results, raising baseline net costs
per life-year gained by almost 200%. They estimated that universal infant vaccination may
increase the incidence of zoster by 13% (during an analytic period of 30 years and discounted
at 3%). We do note that the relationship between VZV infection and zoster as specified by
Brisson and Edmunds (2002) has been challenged (Seward et al., 2002). Other theories
suggest, for example, subclinical reactivation of VZV with uncertain impact on zoster.
Previously, Edmunds et al. (2001) analyzed the epidemiological and economical burden of
herpes zoster and its complications (in particular, after herpetic neuralgia) for England and
Wales. They estimated that direct medical costs of zoster amounted to almost €70 million
annually (€1.3 per citizen).
Adolescent varicella vaccination has also been studied. Banz et al. (2003), Beutels et al.
(1999), and Brisson and Edmunds (2002) all indicated superior pharmacoeconomic profiles
for vaccinating 12-year-olds as opposed to infants. Brisson and Edmunds (2002) conclude that
the attractiveness of preteen vaccination from an economic perspective remains robust under
varying plausible parameter, model and methodological, assumptions. For example, the
impact of including zoster is very limited in preteen vaccination, as transmission of varicella
occurs mostly through contact with very young children who continue to be infected under
this strategy. Obviously, if combined with screening, only those 10–12 year olds at risk are
targeted (approximately 10%), limiting the budget impact of vaccination.
To conclude, there is still considerable uncertainty around the interaction between Vari-
cella vaccination and zoster. The potential adverse effects of Varicella vaccination on increa-
ses in the incidence of zoster could reverse the cost-effectiveness ratio of universal infant
vaccination. Therefore, it is important to consider alternative vaccination strategies that show
less sensitivity to the inclusion of potential effects on zoster, such as adolescent booster
vaccination.
3.2 Vaccination Campaigns Against Respiratory Diseases
Currently, vaccines are being used against Hemophilus influenzae type B, pneumococcal and
meningococcal infections, and influenza. Additionally, the > BCG vaccine against TB is still
being used for TB proxylaxis. However, since there is still considerable discussion on the
efficacy and duration of protection of BCG vaccine in the prevention of TB, we decided not
to discuss vaccines against TB in this section.
3.2.1 Hemophilus influenzae Type B
Vaccination against Hemophilus influenzae type b (Hib) has been introduced in most Western
countries in the early nineties. The choice to introduce the vaccine in the routine childhood
vaccination programs was justified by it’s high incidence of between 20 and 69 per 100,000
infants <5 years (Akumu et al., 2007). Prior to vaccination, Hemophilus influenzae type B was
the most common cause of meningitis, causing in the US annually more than 20,000 cases of
invasive disease (Hay et al., 1987). The case fatality rate of Hemophilus influenzae type B
meningitis is approximately 5%. A number of economic evaluations have been performed in
developed countries, showing a favorable cost-effectiveness. Martens et al. (1991) calculated a
break-even price for the vaccine of US$ 7 for the use of the vaccine in the infant immunization
program of the Netherlands. A favorable benefit to cost-ratio was found for Hib vaccination in
Slovenia, (Pokorn et al., 2001) of 1.38, (including indirect costs. The cost-effectiveness ratio of
Hib vaccination is highly dependent on the epidemiology. A similar study performed in
Moscow showed a higher cost-effectiveness ratio of €10,842 per DALY averted as opposed
to cost-savings (Platonov et al., 2006). However, this cost-effectiveness ratio is still acceptable
in Western countries.
Additionally, a number of studies have been performed in countries in Africa and South-
America (Akumu et al., 2007). A study by Akumu et al. (2007), indicated that the incidence of
Hemophilus influenzae type b meningitis would decrease from 71 per 100,000 to 8, indicating
massive health benefits for this intervention. Broughton (2007) analyzed the potential cost-
effectiveness of introducing Hib vaccination in the infant immunization program in Indone-
sia. His model indicated that Hib vaccination of infants would result in averting over 76,000
cases of invasive disease per year, saving approximately 7,150 lives. The incremental cost-
effectiveness of such a program would be US$ 67 per DALY. These indicate the potential
impact of Hib vaccination in the prevention of invasive disease such as bacteremia and
meningitis, and should make policy makers aware of the massive health benefits that could
be saved by introducing the Hib vaccine in endemic areas.
3.2.2 Pneumococcal Vaccines
Basically, two types of pneumococcal vaccines exist: polysaccharide vaccines primarily

intended for elderly populations and conjugate vaccines primarily intended for infant vacci-
nations. Many western countries have now large-scale polysaccharide vaccination programs
for the elderly in place. A recent analysis on the cost-effectiveness of this pneumococcal
vaccine in the elderly in ten European countries revealed that high potential for favorable
cost-effectiveness exist (Evers et al., 2007). For these countries cost-effectiveness ranged from
€3,000 to 5,000 up to a maximum of €20,000 per QALY gained. In the USA, pneumococcal
vaccination of elderly is cost-effective, potentially even if the age-limit for vaccination would
be lowered from 65 years down to 50 years (Sisk et al., 2003).
A number of studies have been performed on the cost-effectiveness of a conjugate
pneumococcal vaccine in infants, which potentially prevents meningitis, bacteremia, and otitis
media. These studies have shown conflicting results. A recent review by Beutels et al. (2007)
reviewed 15 studies from Finland, UK and Wales, US, the Netherlands, Spain, Switzerland,
Germany, Australia and Italy. The study found a range of results ranging from cost-saving
from the societal perspective (studies from Spain and Germany) to €101,452 per LYG in
Canada. The largest difference between the studies was found to be the inclusion or exclusion
of herd immunity effects on the adult population. Whitney et al. found a decline in invasive
pneumococcal disease in adults after the introduction of pneumococcal conjugate vaccination
of infants, (Whitney et al., 2003) leading to additional life years gained and medical and
indirect costs saved due to the occurrence of herd immunity. To illustrate the impact of the
inclusion of herd immunity on the results, a study by Bos et al. in 2004 showed a base-case
cost-effectiveness of €71,703 per QALY without considering the potential effects of herd
immunity, whereas the cost-effectiveness ratio improved to €15,600 per QALY when herd
immunity effects were considered. Of the available studies, favorable cost-effectiveness ratios
were found in Spain, Germany, Canada, the Netherlands (after inclusion of herd immunity
effects), and for the UK it was found to be on the upper limit of cost-effective interventions.
3.2.3 Meningococcal Vaccines
Vaccines against subtypes Neisseria meningitidis A, C, Y and W135 are currently available.
Meningococcal infections, such as meningitis and septic shock are associated with high mortality
rates of up to 35% and complications. Survivors often suffer from neurological or physical
sequelae. A number of studies have been performed on the cost-effectiveness of meningococcal C
vaccination, which has been introduced in a number of countries, such as Australia, UK, and the
Netherlands. A review by Welte et al. (2005), analyzed studies from Canada, the Netherlands, UK,
Australia, Portugal, Switzerland. The cost-effectiveness of the interventions was dependent
mainly on the age of the vaccinated infant, and the incidence of meningococcal disease. Since
infants aged >12 months only need a single dose of vaccine in order to build immunity against
the pathogen, and younger infants need three doses to boost their immune system, vaccination
of the first group will be more affordable. The cost-effectiveness of a single dose intervention
ranged from €19,000 per QALY in Switzerland to €2,600 per QALY in the Netherlands, with the
main differences found in the incidence of disease. The three dose scenario was analyzed to be
less cost-effective, with cost-effectiveness ratios ranging from €55,000 per QALY in Switzerland,
to €21,700 per QALY in the Netherlands.
3.2.4 Influenza Vaccines
Influenza has been frequently referred to as ‘‘the last great uncontrolled plague of mankind,’’
Elderly persons are at increased risk of developing influenza-related complications which
require complex healthcare and might lead to mortality. By 1997, all but three countries in
the European Union had universal vaccination programs for citizens aged ≥65 years. In a
review by Postma et al. (2002), an overview is given of health economic studies on influenza
vaccination of the elderly in developed countries. The studies provided remarkably similar
results. Benefit to cost ratios ranging from 0.7 to 50 were found, indicating that in most
instances the benefits of influenza vaccination of the elderly outweigh the costs associated with
the program. Even in the study were a benefit to cost ratio of 0.7 was found, the cost-
effectiveness ratio was still below the acceptable threshold for cost-effectiveness. In particular,
influenza vaccination among elderly people at higher risk, such as the chronically ill elderly, is
generally found to be cost saving.
A number of studies have been performed on the cost-effectiveness of influenza vaccination
of healthy working adults. The results of these studies are not homogeneous; some studies report
cost savings, whereas other studies report no economic benefits at all. Most differences in
outcome are related to whether indirect costs due to work loss are included in the analysis,
the efficacy of the vaccine in relation to the dominant influenza strains in the year of analysis,
and the severity of the influenza epidemic (Postma et al., 2002). A review of 11 studies reported
in western countries found that eight of the studies reported cost-savings against three studies
that reported no economic benefit (Postma et al., 2002). Another review study, by Wood et al.
(2000) also noted the disparity in results between the various economic studies, but also
concluded that the published studies seem to suggest that influenza vaccination in the healthy,
working adult would be a cost-effective health intervention, at least from the perspective of
an employer.
Some studies have analyzed whether vaccination of healthcare workers to protect high-risk
patients would be a cost-effective strategy. A review by Burls et al. (2006) found that most cost-
effectiveness studies did not take the effects on patient transmission into account and therefore
underestimated the cost-effectiveness of the intervention. The study by Burls et al. estimated
that vaccination of healthcare workers to protect high-risk patients would be a highly cost-
effective intervention, with a CER between cost-saving and 405 GBP per LYG.
3.3 Vaccination Campaigns Against Sexually Transmitted Infections

and Other Vaccine-Preventable Viruses
3.3.1 Hepatitis B
Hepatitis B virus (HBV) infection is still an important public health problem, despite the
availability of an effective vaccine for several decades now. According to the WHO recom-
mendation for universal routine vaccination many countries of high and intermediate en-
demicity have implemented routine vaccination. Implementation of such programs is often
done at the infant age or young adolescent age, with a combined catch-up program. Favorable
cost-effectiveness of implementing these programs has been evidenced broadly (Beutels,
2001), (Beutels et al., 2002). For example, the specific Italian implementation of vaccination
in 1992 of a combined universal infant schedule and catch-up of 12-years olds was chosen after
careful examination of economic data (Bonanni et al., 2003).
Discussions on introducing universal vaccination for infants and/or adolescents are
currently going on in countries that currently only vaccinate selected target populations
(such as the UK and the Netherlands) and in developing countries for which vaccination
becomes feasible due to recent price reductions.
3.3.2 Human Papilloma Virus (HPV)
Recently, two Human papilloma virus vaccines have been registered for prophylactic use. Trials
have proved efficacy up to 5 years; long-term effectiveness has yet to be demonstrated in
follow-up of the initial trails and post-marketing research. Both vaccines have proven to be
highly effective against HPV-types 16 and 18, that are associated with 70% of cervical cancers
worldwide (Paavonen et al., 2007; Parkin and Bray, 2006). Slight differences seem to exist
between both vaccines, potentially influencing exact cost-effectiveness profiles of both. In
particular, one is quadrivalent, also protecting against genital warts caused by types 6 and 11
(Gardasil), whereas the other is bivalent only, but claiming higher likelihood for long-term
protection (Frazer, 2007). Various cost-effectiveness analyses have already been performed,
generally building on cost-effectiveness analyses for cervical cancer screening (Dasbach et al.,
2006). Notably, vaccination is assumed to be implemented on top of the existing screening
programs. All cost-effectiveness models for the HPV-vaccines generally assume no deteriora-
tion in the coverage of the screening. Additional vaccination of young teenage boys might be
considered, but is less likely to be cost-effective (Dasbach et al., 2006).
Approximately 20 publications are now available on the cost-effectiveness of HPV-
vaccination. For effectiveness, most of these models build on the observations in the trials
for HPV-infections of the vaccine-types, rather than ‘‘hard endpoints’’ such as pre-cancerous
stages and cervical cancer. Generally, acceptable cost-effectiveness of around US50,000 per
QALY or lower are estimated for vaccinating young teenage girls. One concern generally
expressed from the cost-effectiveness analyses is that a slight deterioration in the coverage of
screening could easily offset the savings and health benefits of vaccination. So, implementation
of vaccination should be combined with campaign to sustain screening coverage rates, and
such costs should be included in the cost-effectiveness analyses of vaccination.
3.3.3 Hepatitis A
Hepatitis A vaccines have been available for over a decade. With the disease impact primarily
affecting developing rather than developed countries, the picture of universal vaccination
differs strongly from Hepatitis B. In particular, many developed countries have strategies
implemented on vaccinating risk groups, such as ethnic minorities and travelers to Hepatitis A
endemic regions. In a recent review, none of the cost-effectiveness studies yet being performed
for the Hepatitis A vaccine were done for a developing country (Anonychuk et al., 2008). Cost-
effectiveness studies have up to now primarily evaluated targeted vaccination, such as vacci-
nating antibody-negatives only, prison inmates and the military (Jefferson et al., 1994).
Additionally, some studies have been done specifically addressing the cost-effectiveness of
vaccinating chronic Hepatitis C patients with Hepatitis A vaccine (Jacobs et al., 2002).
Findings indicate that favorable cost-effectiveness is highly unlikely the older the patient is and
if antibody screening is performed prior to vaccination. More cost-effectiveness studies are
needed and standardization of the approach should be enhanced.
3.3.4 Rotavirus
After initial drawbacks on the use of rotavirus vaccines due to suspected intussusception,
recently two vaccines are being marketed worldwide (Rotarix and RotaTeq). Safety and efficacy
have been shown in various clinical trials for the respective 2- and 3-dose schedules (Vesikari
et al., 2006). Rotavirus infection is considered to be the most prevalent cause of acute
gastroenteritis globally. Currently, the vaccine is initially considered for the developed world,
where mortality and serious morbidity is relatively low. A small number of cost-effectiveness
studies have been done on rotavirus vaccination, however these publications either lack
comparability by using QALYs or do not include the full scale of savings and health gains
(Widdowson et al., 2007). In particular, due to lack of valid data, rotavirus episodes without
hospitalization are not yet factored into the models, leading to underestimation due to the
omission of potential work loss of parents. In the absence of more robust information on these
aspects, models are yet very sensitive to mortality assumed for rotavirus. Typically, mortality is
assumed at approximately 1 per 100,000 infants annually, however valid registrations of
rotavirus deaths may be lacking in many countries.
Generally, from the cost-effectiveness analyses it appears that rotavirus vaccination may
not be highly cost-effective, with cost-effectiveness ratios varying from €50,000 to 100,000 per
QALY from the health-care payer perspective (Jit and Edmunds, 2007). Only marginally better
ratios were found from the societal perspective for England and Wales (Jit and Edmunds,
2007). If however from the societal perspective parental work and QALY losses are included
related to those cases of disease without health-care services visits involved, cost-effectiveness
may improve dramatically. For the Belgium situation cost-saving potentials were reported
(Bilcke et al., 2007). Cost-effectiveness ratios are highly sensitive to the QALY impact assumed.
Up to now only one study is available on the specific quality-of-life aspects of rotavirus
infection (Sénécal et al., 2006). In particular, a prospective study was designed in Canada to
estimate QALY-impacts for the infants involved and the caregivers using the Health Utilities
Index and the Visual Analogue Scale. However, more research is needed to further underpin
this crucial parameter in rotavirus cost-effectiveness analysis. Also, we note that further
discussions on including QALY impacts for caregivers are required and that current standards
for cost-effectiveness analysis do not include QALY loss with caregivers.
4 Discussion and Conclusion

In this chapter, we have provided a brief overview of the main challenges that are associated
with modeling the economic impact of vaccines. Often, the vaccines are given as prophylaxis,
and concern a very large part of the population. The latter implies that the budget impact is a
prominent issue to consider prior to the introduction of new vaccination programs. Moreover,
it is difficult to stop a program once it has been started, due to reasons of equity. Therefore,
with assessing these interventions, budget impact and allocation of the total budget forms an
important aspect of the final decision.
Most vaccines yield benefits not only for the direct beneficiary, but also for the non-
vaccinated population. This phenomenon, called herd immunity, is an important aspect of
vaccines. Lastly, due to the preventative character of vaccine interventions, benefits might
occur later in life, which should be valued according to the preferences of the population.
Vaccine interventions are a public health decision, affecting many citizens directly, and
have long term budgetary consequences. Therefore, decision regarding new vaccination
programs should consider all aspects of the intervention carefully. To assess the economic
and health impact of the intervention, health economic studies such as cost-effectiveness
analysis are being used. By using cost-effectiveness analysis, decision makers gain an under-
standing of those interventions that provide best value for money and that should be
prioritized in order to maximize the utility gains in the population.
In this chapter, we have provided an overview of health economic evaluations of most
vaccines that have been introduced in the developed world. Most of the vaccines that have been
introduced all exhibit favorable cost-effectiveness ratios, ranging from cost saving or highly cost-
effective for childhood cluster vaccines, Hemophilus influenzae type b vaccine, influenza vacci-
nation for the elderly, meningococcal C vaccine and hepatitis A and B vaccine for infants. For
some vaccination programs, the cost-effectiveness is very sensitive to changes in certain
assumptions, such as the relation with zoster for the varicella vaccine, the occurrence of
herd immunity with the pneumococcal conjugate vaccine for infants, and whether or nor
screening rates for cervical cancer will decline as a result of HPV vaccination. Each of these
assumptions has the potential to change an intervention from cost-effective towards not cost-
effective or vice versa. Although the cost-effectiveness studies are extremely sensitive to
changes in these assumptions they serve a clear purpose in showing decision makers the
impact of such changes.
It is worth noting that most of the vaccine interventions prior to the 1990s have been
implemented with only limited guidance of health economic studies. However, there are signs
that economic evaluations are increasingly being used for guidance on whether or not to
implement a new vaccination program. Welte et al. (2005) investigated whether or not health
economic data played a role in the decision to start national vaccination programs against
meningococcal C infections, and found a clear relationship between increasing incidence rates
for meningococcal C infections and the commissioning of an health economic study on
vaccination. This indicates that health economic studies are starting to play a more important
role in decision making on the introduction of new vaccination programs. However, it needs
to be kept in mind that, health economic data are only a single consideration next to for
instance equity, or ethical reasons.
Summary Points
Infectious diseases are an important cause of mortality and morbidity, causing approxi-
mately 27% of the total disease burden in DALY. A large part of DALY lost due to infectious
diseases could be prevented by improving existing vaccination programs for the popula-
tion. Diseases such as childhood cluster diseases, hepatitis A and B, respiratory infections
caused by influenza, pneumococcal and meningococcal infections, and Hemophilus influ-
enzae type B, are for a large part preventable by current vaccines.
The implementation of new vaccine programs or/and strategies is a costly process with
long term consequences. To gain a better understanding of the potential impact on health
benefits and costs of a vaccine intervention, health-economic evaluations are frequently

used, which estimate the future impact on health gains and costs.
In economic evaluations of vaccination campaigns, models are frequently used to assess
the population effects of the vaccination campaign. Vaccine trials are small in relation to
population based vaccination programs, they can only provide an estimate of the individ-
ual efficacy of the vaccine and do not give a good estimate for the overall effectiveness of a
mass vaccination campaign in the population. By vaccinating a large group in the
population, the circulation of the bacteria or virus will diminish, leading to a reduction
of disease beyond the direct effects of vaccination.
Vaccination campaigns, especially those against childhood cluster diseases, and influenza
vaccination in the elderly are amongst the most cost-effective interventions.
Vaccine interventions prior to the 1990s have been implemented with only limited
guidance of health economic studies. However, health economic studies are starting to
play a more important role in decision making on the introduction of new vaccination
programs.
References
Akumu A, English M, et al.(2007). Bull World Health Brisson M, Edmunds WJ. (2002). Vaccine. 20:
Organ. 85(7): 511–518. 1113–1125.
Anderson RM, May RM. (1991). Infectious Diseases of Brisson M, Edmunds WJ, et al.(2000a). Vaccine. 18:
Humans; Dynamics and Control. Oxford University 2775–2778.
Press, New York. Brisson M, Edmunds WJ, et al.(2000b). Epidemiol Infect.
Anonychuk A, Tricco A, et al.(2008). Pharmacoeco- 125: 651–669.
nomics. 26: 17–32. Broughton E. (2007). J Public Health (Oxf). 29(4):
Austrian R. (1981). Proc Am Philos Soc. 125(1): 46–51. 441–448.
Baker CJ. (2007). N Engl J Med. 357: 1757–1759. Burls A, Jordan R, et al.(2006). Vaccine. 24(19):
Banz K, Wagenpfeil S, et al.(2003). Vaccine. 21: 4212–4221.
1256–1267. Caro J, Getsios D, et al.(2005). Pediatr Infect Dis
Bart K, Foulds J, et al.(1996). Bull World Health Organ. J. 24(Suppl): S75–S82.
74: 35–45. Caro JJ, Getsios D, et al.(2005). Pediatr Infect Dis
Beutels P. (2001). Health Econ. 10: 751–774. J. 24(5 Suppl): S48–S54.
Beutels P, Bonanni P, et al.(1999). Vaccine. 17(19): Clemens J, Brenner R, et al.(1996). JAMA 275: 390–397.
2400–2409. Cookson R, Mc Daid D. (2003). Health Policy 63:
Beutels P, Edmunds WJ, et al.(2002). Pharmacoeco- 133–139.
nomics. 20: 1–7. Dasbach E, Elbasha E, et al.(2006). Epidemiol Rev 28:
Beutels P, Gay NJ. (2003). Epidemiol Infect. 130(2): 88–100.
273–283. Edmunds WJ, Brisson M, et al.(2001). Vaccine. 19:
Beutels P, Thiry N, van Damme P. (2007). Vaccine. 25(8): 3076–3090.
1355–1367. Edmunds WJ, Brisson M, et al.(2002). Vaccine. 20:
Bilcke J, Beutels P, et al. (2007). Cost-Effectiveness of 1316–1330.
Rotavirus Vaccination of Infants in Belgium. KCE, Edmunds WJ, Medley GF, et al.(1999). Stat Med. 18:
Brussels. 3262–3282.
Bonanni P, Pesavento G, et al.(2003). Vaccine. 21: Ekwueme DU, Strebel PM, et al.(2000). Arch Pediatr
685–691. Adolesc Med. 154: 797–803.
Bos JM, van Alphen L, et al.(2008). ‘‘The use of model- Evers S, Ament A, et al.(2007). Eur J Clin Microbiol. 26:
ling in the economic evaluation of vaccines. Expert 531–540.
Rev Pharmacoeconomics Outcomes Res. 2(5): Frazer I. (2007). Int J Infect Dis. 11: S10–S16.
443–455. Gay NJ, Pelletier L, et al.(1998). Vaccine. 16(8): 794–801.
Gwatkin DR, Guillot M. (1998). The Burden of Tropical Sénécal M, Brisson M, et al. (2006). Quality of Life
Diseases Among the Poorest and Richest 20% of the Lost Associated with Rotavirus Gastroenteritis in
Global Population. TDR/ER/RD/96.1, World Health Canadian Families: A Prospective Community
Organization. Based Study. 7th Canadian Immunization Confer-
Hay J, Daum R, et al.(1987). Pediatrics 80(3): 319–329. ence, Winnipeg.
Hinman AR, Irons B, et al.(2002). Bull World Health Seward JF, Jumaan AO, et al. (2002). JAMA. 287:
Organ 80(4): 264–270. 2211–2222.
Iskedjian M, Walter JH, et al.(2004). Vaccine. 22: Shiell A, Jorm LR, et al.(1998). Aust N Z J Public Health.
4215–4227. 22(1): 126–132.
Jacobs R, Koff R, et al. (2002). Am J Gastroenterol. 97: Sisk J, Whang W, et al. (2003). Ann Intern Med. 138.
427–434. Stevenson M, Beard S, et al.(2002). Vaccine. 20:
Jefferson T, Behrens R, et al. (1994). Vaccine. 12: 1778–1786.
1379–1383. Stover BH, Adams G, et al. (1994). Infect Control Hosp
Jit M, Edmunds W. (2007). Vaccine. 25: 3971–3979 Epidemiol. 15(1): 18–21.
Johannesson M, Meltzer D. (1998). Health Econ. 7(1): Thiry N, Beutels P, et al. (2003). Pharmacoeconomics. 21:
1–7. 13–18.
Kahn MM, Ehreth J. (2003). Vaccine. 21: 702–705. Thompson KM, Duintjer Tebbens RJ. (2006). Risk Anal.
Martens L, ten Velden G, et al. (1991). Ned Tijdschr 26: 1423–1440.
Geneeskd. 135(1): 16–20. Thompson KM, Duintjer Tebbens RJ. (2007). Lancet.
Miller E, Marshall R, et al.(1993). Rev Med Microbiol. 4: 369: 1363–1371.
222–230. Tormans G, Van Doorslaer E, et al. (1998). Eur J Pediatr.
Miller MA, Redd S, et al. (1998). Vaccine. 16(20): 157: 395–401.
1917–1922. Vesikari T, Matson D, et al. (2006). N Engl J Med. 354:
Paavonen J, Jenkins D, et al.(2007). Lancet. 369: 23–33.
2161–2170. Welte R, Trotter CL, et al. (2005). Pharmacoeconomics.
Parkin D, Bray F. (2006). Vaccine. 24: S11–S25. 23(9): 855–874.
Pelletier L, Chung P, et al. (1998). Vaccine. 16(9): White CC, Koplan JP, et al. (1985). Am J Public Health.
989–996. 75: 739–744.
Platonov A, Griffiths U, et al. (2006). Vaccine. 24(13): Whitney G, Farley M, et al. (2003). N Engl J Med. 348:
2367–2376. 1737–1746.
Plotkin SA Mortimer EA. (1994). Vaccines, 2nd ed. W.B. WHO. (2007). The World Health Report 2007 – A safer
Saunders Company, New York. future: global public health security in the 21st
Pokorn M, Kopac S, et al. (2001). Vaccine. 19(25–26): century.
3600–3605. WHO. (2008). Immunisation fact sheet Nr 288.
Postma M, Jansema P, et al. (2002). Drugs. 62(7): Widdowson M, Meltzer M, et al. (2007). Pediatrics 119:
1013–1024. 684–697.
Postma MJ, Bos JM, et al. (2003). Eur J Health Econ. Wood S, Nguyen V, et al. (2000). Pharmacoeconomics.
Purdy KW, Hay JW, et al. (2004). Clin Infect Dis. 39: 18(2): 173–183.
20–28. Zwanziger J, Szilagyi PG, et al. (2001). Health Serv Res.
Sellick JA, Jr., Longbine D, et al. (1992). Ann Intern Med. 36(5): 885–909.
116(12 Pt 1): 982–984.
78 Economic Costs and
in Polio Eradication: A
Long-Run Global Perspective
M. M. Khan
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354
2 How Do We Calculate the Costs and the Effectiveness? . . . . . . . . . . . . . . . . . . . . . . . 1356

2.1 Estimating Polio Cases With and Without Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . 1357
2.1.1 Choosing a Flexible Equation for Empirical Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1357
2.1.2 Using the Estimated Equation for Prediction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1358
2.2 Estimating the Disability Adjusted Life Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1359
3 Deriving the Cost Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1360

3.1 Cost Parameters for Routine Polio Immunization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1360
3.1.1 Price of Vaccine and Cost per Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1361
3.2 Cost Parameters for Polio Eradication Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1363
4 Global Cost and Effectiveness of Polio Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1363

4.1 Number of Polio Cases Averted and Dalys Saved . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1363
4.1.1 Calculating the Effectiveness of Polio Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1366
4.2 Net Cost of Routine Polio Immunization and the
Cost-Effectiveness Ratios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1368
4.3 Cost-Effectiveness of Polio Eradication Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1369
5 Conclusions and Policy Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1370
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1371

1354 78 Economic Costs and Disability-Adjusted Life Years in Polio Eradication
Abstract: This paper estimates the costs and effectiveness of polio immunization and eradi-
cation activities from long-term global perspective. The effectiveness of immunization
has been expressed in terms of Disability Adjusted Life Years (> DALYs) averted over the
years 1970–2050 and the aggregate effectiveness was calculated using 2007 present values. The
projected annual numbers of polio cases without vaccination were obtained from polio case-
loads in pre-vaccination era in the USA and in Europe. Costs of routine polio immunization
and eradication activities were also expressed in terms of 2007 dollars. The results indicate that
polio immunization will prevent more than 42 million cases of polio, four million paralysis
and 855 thousand deaths over the years 1970–2050. In terms of 2007 dollars, the aggregate
global cost of polio immunization over 1970–2050 will exceed $123 billion. Despite the high
cost of the program, direct medical care cost savings associated with polio prevention are so
high that the program becomes cost-saving at the global level. Excepting for few low income
countries in Africa and South-east Asia, routine polio immunization remains a > highly cost-
effective intervention for all countries of the world. Even for poorer countries, polio immuni-
zation and eradication activities remain cost-effective. However, very poor countries will
require continued financial assistance to help achieve the full economic benefit of polio
immunization and eradication.
List of Abbreviations: AFP, acute flaccid paralysis; AFR, Africa region of WHO; AMR, region
of the Americas; DALY, disability adjusted life years; EMR, eastern mediterranean region;
> EPI, expanded program for immunization; EURO, European region; GNI, > gross national
income; ICD10, International Classification of Disease version 10; > IPV, inactivated polio
vaccine; NIDs, National Immunization Days; > OPV, oral polio vaccine; SEAR, south-east
Asia region; WPR, western pacific region; YLD, years lost due to disability for the incident
cases of health conditions; YLL, years of life lost due to premature death
1 Introduction
The World Health Assembly in 1988 adopted a set of strategies to eradicate polio by the year
2000. The eradication program consisted of a number of specific interventions and targets:
immunization of 90% or more children against polio with four doses of Oral Polio Vaccine
(OPV) by 12 month of age as part of the Expanded Program on Immunization (EPI);
conducting National Immunization Days (NIDs) to provide two doses of OPV to all children
less than 5 years and strengthening surveillance and laboratory investigation of suspected polio
cases. It was suggested that the NIDs be carried out for at least three consecutive years and all
countries should conduct surveillance and laboratory investigation of any case of Acute
Flaccid Paralysis (AFP) for children less than 15 years and any case of polio at any age. If
the surveillance system identified transmission of wild poliovirus in a geographic area, the
plan required immediate adoption of mop-up campaigns to vaccinate children with two extra
doses of OPV.
The eradication activities adopted have shown significant accomplishments since 1990.
> Figure 78‐1 shows the time trend of total global cases reported from 1980 to 2007 and over
the years the number of cases declined at a very rapid rate. The reported case-load of
confirmed polio exceeded 50,000 per year in 1980 (the actual case count, including the ones
without any long-term symptoms, could be as much as ten times the reported numbers) and
expansion of regular polio immunization helped reduce the case-load by more than 50% to
Economic Costs and Disability-Adjusted Life Years in Polio Eradication 78 1355
. Figure 78‐1
Global total of polio cases by year: 1980–2007
about 23,000 by 1990 (WHO, 2000). Adoption of polio eradication strategies in early 1990s
further reduced the number of reported cases and by the year 2000 polio cases dipped below
the three thousand level (WHO, 2002). Although the plan was to eradicate polio by the year
2000 (CDC, 1998), the average number of polio cases remained at around 1,600 over the
years 2000–2007. This is despite the fact that the number of polio endemic countries, i.e.,
countries with indigenous wild poliovirus presence, reduced from 50 in 1999 to 20 in 2001. By
early 2008, only four countries, Nigeria, India, Pakistan and Afghanistan remained polio
endemic (WHO, 2008).
According to the World Health Organization (WHO) calculations, polio cases in 2005
were responsible for loss of 13,261 Disability Adjusted Life Years (DALYs) compared to about
5.7 million DALYs lost due to pertussis and 9.8 million due to measles (Mathers and Loncar,
2006). The low burden of polio in 2005 clearly shows dramatic success of polio immunization
and eradication activities. It is important to point out that a significant part of polio related
loss of DALYs in 2005 was due to premature deaths. For example, the burden of polio in
Americas was 2,361 DALYs in 2005 and all of it was due to premature deaths. Most of these
cases were in the age group 45 years old or older indicating that many of the polio-related
deaths in 2005 were the result of polio transmission that happened prior to early 1960s.
It became clear by mid-1990s that polio eradication cannot be achieved by 2000 as planned
and a new target date of 2005 was set. Polio outbreaks during 2003–2005 again frustrated the
polio eradication target-date. In November 2007, high-level polio consultation agreed to
intensify immunization activities in the remaining endemic countries to stop poliovirus
transmission for good (WHO, 2008). To complicate the polio eradication efforts further,
poliovirus importation affected another ten countries during 2006–07 and clearly global polio
eradication certification date must be pushed back by few additional years and is not expected
before 2010 at the earliest.
Despite the fact that polio eradication has remained elusive, significant progress has
been made in controlling polio through regular and intensive immunizations. At this stage
of polio control, focusing the discussion narrowly on eradication strategies is probably

counter-productive. Preventing polio require continued vigilance in terms of immunization
coverage and outbreak responses. Given the uncertainty associated with eradication and high
levels of health benefits derived from regular polio immunization, policy makers should
emphasize continued polio immunization in general.
This paper demonstrates that polio immunization program itself has been one of the
greatest success stories of modern public health interventions. If we consider the > economic
costs and health benefits of regular polio immunization activities alone, the benefits clearly are
high enough to justify continuation of polio vaccination in the longer run, irrespective of polio
eradication status. A separate analysis can be conducted to examine the benefits and costs of
polio eradication. To better understand the success of polio control strategies, analyses should
subdivide the interventions into two discrete sets of activities: control of polio through regular
immunization and supplemental and/or intensive polio vaccination for eradication.
After the successful global eradication, regular polio immunization will not be required
and the world will save money by stopping polio vaccination altogether. Complete cessation of
polio vaccination, although feasible in post-eradication era, may not be a practical option any
more. Fear of accidental and intentional reintroduction of poliovirus in the environment
made many countries, especially the developed world, unwilling to discontinue polio immu-
nization. In this sense, financial benefit of eradication may not be fully realized and from
policy perspective it is much more important to discuss the long-run > financial costs and
benefits of continued polio immunization rather than eradication.
This paper is an attempt to estimate the long-run global economic costs and effectiveness
of polio vaccination program. Since the polio control strategies have been divided into control
and eradication activities, the paper will also discuss potential incremental costs and benefits
of polio eradication. This involves estimating the economic costs of intensive supplementary
immunization, establishment of surveillance system and laboratories and final certification
cost of polio eradication. The estimation of benefits in terms of health outcomes require
estimation of deaths and paralysis prevented due to the immunization program. The WHO
suggested method (Murray and Lopez, 1996) will be used to convert pre-mature deaths and
cases of paralysis prevented into Disability Adjusted Life Years (DALYs). On the cost side,
vaccine and vaccine delivery costs will be considered. Since the prevention of polio cases saves
medical resources, net cost of immunization will be derived by subtracting the medical care
costs from the cost of the immunization program.
2 How Do We Calculate the Costs and the Effectiveness?
This paper is a > cost-effectiveness analysis of polio vaccination and eradication. The effec-
tiveness of polio vaccination is defined as the polio cases averted (paralysis and deaths
averted). To obtain an estimate of the cases averted, we need to derive the number of cases
that would have occurred if there were no vaccinations. Cases of polio without vaccination
were estimated from the historical data on polio cases in the USA and Italy. Cost-effectiveness
of eradication was estimated by assuming that eradication will allow discontinuation of
vaccination. So, the future vaccination cost saved becomes the benefit of polio eradication
activities. It is also assumed that a small number of hard-to-prevent cases can be prevented
only through eradication activities.
To estimate the global health outcomes and costs related to polio immunization and
eradication, this study will use the WHO region-specific estimates for the analysis. The WHO
divided the world into six regions: African region (AFR), Region of the Americas (AMR),
Eastern Mediterranean Region (EMR), European Region (EUR), South-East Asia Region
(SEAR) and Western Pacific Region (WPR). For each of the regions, the study estimates the
number of cases one would have expected if there were no polio vaccination. The predicted
case-load allows estimation of number of deaths and disability averted due to polio vaccina-
tion. The medical care costs and other associated costs will also be derived by using region-
specific average cost information.
2.1 Estimating Polio Cases With and Without Vaccination
To estimate the number of cases averted since the introduction of vaccination program, time
series modeling was carried out to predict the number of polio cases with and without
vaccination. The prevalence of polio prior to the introduction of polio vaccination was used
to derive the yearly cases if there was no vaccination.
For each of the WHO regions, efforts were made to collect incidence rate of polio prior to
the introduction of vaccines. For the Region of the Americas (AMR), information was
collected on population, population under five and the polio cases from 1912 to 1954 for
USA. From the polio cases reported, rate per 100,000 children were derived so that we can
use the rates to project polio cases in the whole of AMR in absence of vaccination. For the
European Region, time series data for pre-vaccination period were obtained for Italy.
The Chinese rates are also available for about 25 years prior to 1970, but the incidence rates
reported for China are clearly too low. It is likely that polio cases were underreported by a wide
margin for China and for other developing countries of the world. Even in South America
the rates were underreported by as much as 80% (Musgrove 1989). Therefore, to predict the
cyclical changes in polio incidence pattern, it will be better to use the information from a
country with relatively more reliable data. For most of the regions of the world, we have used
Italy’s time pattern of polio rates over the pre-vaccination years. The reported cases for each
of the regions were inflated to make the reported rates equal to predicted rates on the average
for the pre-immunization years in each of the regions.
2.1.1 Choosing a Flexible Equation for Empirical Analysis
One problem with statistical prediction of polio incidence rates is its relatively high year-to-
year variability. The incidence rate per 100,000 children varied from less than 30 to more than
300 in the USA over the 43 pre-vaccination years. Therefore, to project the incidence rates in
the future, we need a flexible time series modeling technique, which will allow frequent ups
and downs within a short time frame. If we use the average incidence rate of pre-vaccination
period, it will distort the cost-effectiveness ratios because in an analysis with long time
horizon, both costs and effectiveness are affected significantly by the timing of the costs and
outcomes.
Another problem with time series modeling is that predicted values tend to become either
explosive or asymptotic when the period of prediction is long. For our analysis, it is important
to identify a model that will allow cyclical ups and downs over the years, for at least
30–40 years in the future, in a predictive model. Polio incidence numbers are such that after
a high incidence rate in a year it tends to go down for sometime before increasing again.
After examining the nature of polio incidences during the pre-vaccination years, it was decided
to use a > Fourier series model for projecting polio cases. The advantage of the Fourier series
is that since it is based on sine and cosine functions, it can actually show the ups and downs
expected in the future. Moreover, the series can indicate abrupt changes in the function. The
model applied for the time series analysis of polio incidence rates is described below.
Assume that the time series of incidence rates is represented by a vector [R]. At the
first stage, we need to standardize the elements of the vector by finding the mean and
standard deviation of the elements. The new vector defined after standardization becomes
[Y]. Therefore,
Ri m
Yi ¼
s
where m = mean value of Ri, and s = standard deviation of Ri
The time series analysis is then carried out on Y values. The functional form we have used
is:Yi ¼ a Cosðw1 tÞ þ b Sinðw1 tÞ þ e1
In this equation, w is the splicing factor and a and b are the parameters to be estimated. We
start the analysis by choosing a very low value for w, such as 0.00001. Given the small w, we
find a and b so that the sum of squared residuals are minimized, i.e., using the standard
regression approach, we want to minimize
X
½Yi a Cosðw1 tÞ b Sinðw1 tÞ2
After obtaining the minimizing values of a and b, both the predicted values of Y, say F1, and
the error terms (E1) were retrieved for further analysis. At the second stage, the residual values
were used as the dependent variable and the earlier stage w value was multiplied by about 10.
With the new value of w, again the sum of squared errors was minimized by finding a new set
of values of a and b. The error terms (E2) and the predicted values (F2) from the second stage
are retained if the standard deviation of the error term after the second stage is lower than the
standard deviation of the error term from the first stage. The iterations are continued till the
reduction in the standard deviation of the error term is not significantly different from that in
the previous stage. If we stop our iterations at the nth round, the predicted Y value becomes
^ ¼ F 1 þ F 2 þ F 3 þ ::::::: þ Fn
Y
Since the addition of sine and cosine values can represent many different types of irregular
functions, the predicted values should be very close to the actual values of polio incidence rates.
Nonlinear regression module of standard statistical package programs can be used to find
the estimates of the parameters. Once the parameters are derived, the error terms are
calculated and another nonlinear regression is run with the error terms as the dependent
variable. The SPSS non-linear regression module was used to estimate the above function.
2.1.2 Using the Estimated Equation for Prediction
The estimated Fourier function can now be used to predict the > standardized values of
polio incidence rates expected without vaccination. The problem with too long prediction
period is that the estimates become less and less reliable as we move further and further
away from the actual data points. This is especially a problem for polio because the
pre-vaccination rates are available for the years prior to 1960s and so we need to predict
the rates for about 100 years. To reduce errors due to long time frame, polio incidence rates
were predicted for no more than 30 years and the actual reported points plus 30 predicted
points were used repeatedly to find the incidence rates beyond the 30-year limit. For the
estimation of costs and effectiveness of polio control, we have used projected incidence rate of
polio till 2050.
The actual number of polio cases by WHO regions is available since early 1970s but the
reported incidence rates are quite unreliable. For example, the incidence rates reported for
China in 1970s was only about 10% of Italy’s rate in pre-vaccination era. In fact, polio cases
were underreported in all regions of the world including Americas and Europe but the degree
of underreporting is likely to be low for the later two regions, where more active surveillance
systems were in place before 1970. For estimating the number of cases averted, we have
assumed that for all WHO regions expecting Americas and Europe the number of cases
averted should be close to zero for the years 1970–1975. The reported average number
of polio cases for these years were multiplied by a fixed factor to make the average equal to
the average of predicted values. The same fixed factor was used to adjust the whole series of
reported numbers. A comparison of the number of cases expected (derived by using Fourier
series) since 1970 with the corrected actual number of cases has been used as the number of
acute polio cases prevented through immunization.
2.2 Estimating the Disability Adjusted Life Years
We have used WHO proposed method for estimating the Disability Adjusted Life Years (DALYs)
for polio cases (ICD10 code A80). The WHO method estimates the years lost due to premature
deaths and the years lost due to lameness or paralysis. Therefore, by using the number of acute
polio cases averted, we need to derive the number of paralysis and deaths averted per year.
In WHO methodology, surveillance data on laboratory confirmed cases of wild virus
infection in symptomatic persons were used to estimate global polio cases. The infections lead
to lameness in some children and the Years Lived with Disability (YLDs) were calculated for the
paralysis cases by assuming that the age at onset is 2.5 years for all regions except Africa (2.4 years
for Africa). Since we are using the WHO method of estimating DALYs, we will simply use the
parameters WHO has used in their estimation of Global Burden of Disease. The disability
associated with polio is assumed to continue over the lifetime of the individual. To calculate
the YLDs due to lameness, WHO used a > disability weight of 0.369. The methodology of
obtaining disability weights has been discussed in Murrey and Lopez (1996).
In our study, we do not have information on paralysis cases by year, especially for the years
prior to 1970s. To get an estimate of paralysis cases without vaccination in pre-vaccination era,
we have used one study that reported the probabilities of paralysis and central nervous system
problems for North America and Western Europe in 1960s. Over the years 1964–1967, WHO
received information on the isolation of viruses from different countries of the world. The data
for North America and Europe are relatively complete and can be used to define the
probability of paralysis and death. The reported numbers from these two regions indicate
that 20.8% of all polio cases create disease of central nervous system and 10.27% cases lead to
paralysis (Cockburn and Drozdov, 1970).
The WHO also assumes that the number of deaths from polio is equal to 10% of
the lameness and other nervous system attack cases. We have used the same assumption to
derive the number of deaths due to polio (WHO, 2006). Given the estimates of paralysis
and nervous system attacks cases, the number of deaths can be projected using the above
parameters. Years of life lost due to pre-mature death is based on DALY assumption on
life expectancy at age 3 years, which is 77.8 years or 30.9 discounted years without age-
weighting. Since the YLDs and YLLs are distributed over a long period of time, all health
outcomes and costs were converted into values specific to the year 2007. Again, using
the method followed by the WHO, discount rate chosen for the analysis was 3%. For each
of the years, the estimated numbers of deaths were multiplied by the number of years lost
due to death to get the total YLLs. Although the standard life expectancy at age three
was 77.8 years, the duration of disability was assumed to be about 10 years shorter on the
average. Therefore, discounted value of years of disability of a polio case becomes about
29.6 years. For the years of life saved prior to 2007, a multiplicative factor was used and after
2007, the discount factor was applied.
3 Deriving the Cost Parameters
3.1 Cost Parameters for Routine Polio Immunization
The aggregate economic cost of routine immunization will be derived for all years starting
from 1970 to 2050. In early 1970s, polio immunization was being strengthened and imple-
mented around the world. In routine immunization programs, polio is not the only vaccine
being delivered and so the cost of polio immunization can be estimated by appropriately
apportioning the routine immunization cost to polio component. The economic savings
associated with complete cessation of polio vaccination can also be approximated by using
the average cost per dose for non-vaccine cost items plus the cost of procuring and handing
the vaccine.
> Table 78‐1 below lists the cost of polio immunization reported by various country
level studies. One striking aspect of the numbers in the table is the wide variability of
polio immunization cost across different countries of the world. Cost per dose in New York
City immunization program was about $114 in 1993 prices while the number was less than
$1.50 for many poor developing countries. Since the costing studies used different approaches
of costing, it is important to identify cost parameters for country-groups (based on income
per capita of countries) when all resources used in the delivery of immunization services
are accounted for. One cost component is the vaccine cost and although the cif price of
vaccines should not vary significantly across countries, in-country handling and process-
ing costs differ widely based on its economic status. Although Bart et al. (1996) made an
attempt to define the vaccine and non-vaccine cost differences between developed and
developing countries, global cost estimates can be further improved by defining the average
cost by economic status of countries and by geographic regions. For estimating the polio
immunization cost for a geographic region, a weighted average of country-group costs will
be used.
For each of the regions of the world, proportion of population living in income-based
country categories (low income, middle income, upper-middle income and high-income)
were used as weights to derive the region-specific cost parameters (World Bank, 2006).
. Table 78‐1
Cost per dose for polio immunization activities as reported by costing studies from different
countries of the world
Year Vaccine Other Inflation Other cost/

of cost per cost per factor, 2007 dose in 2007 Source of cost
Country study dose dose prices prices information
Morocco 1999 $0.10 $1.12 1.245 $1.394 Kaddar et al. (1999)
Bangladesh 1999 $0.13 $1.04 1.245 $1.295 Kaddar et al. (2000);
Khan and Yoder
(1998)
Philippines 1990 $0.15a $1.61 1.586 $2.553 Brenzel and Claquin
(1994)
Tanzania 1990 $0.11a $0.78 1.586 $1.237 Brenzel and Claquin
(1994)
Mauritania 1990 $0.12a $0.87 1.586 $1.380 Brenzel and Claquin
(1994)
Turkey 1990 $0.15a $2.36 1.586 $3.743 Brenzel and Claquin
(1994)
Burkina 1990 $0.10a $1.65 1.586 $2.617 Brenzel and Claquin
Faso (1994)
USA (NY 1993 $5.00a $109 1.435 $156 Fairbrother and
City) DuMont (1995)
Developing 1993 $0.11b $1.51 1.435 $2.167 Bart et al. (1996)
countries
Developed 1993 $4.58b $5.09 1.435 $7.304 Bart et al. (1996)
countries
a
These studies did not report vaccine cost separately. Assumed vaccine cost, including in-country handling, has
been used
b
Cost per dose includes wastage related costs. Wastage is assumed to be 33% of vaccine doses delivered for
developing countries and 10% for developed countries
This table shows polio vaccine prices and other costs associated with administering polio vaccination in different
countries of the world. Since the costing studies were conducted at different points in time, reported costs were
adjusted to express all numbers in terms of 2007 prices. Annual inflation rates for the years 1990–2007 were
obtained for the USA and the inflation rates were used for the adjustment
3.1.1 Price of Vaccine and Cost per Dose
Procurement price of OPV in recent years has increased quite significantly due to low production
capacity and uncertainty about OPV demand in the near future and using this level of interna-
tional price will distort the costing exercise. To ensure that we are considering the economic cost
of resources used in costing the polio programs, OPV procurement price in 2001 may be
considered the opportunity cost of the vaccine. The UNICEF procurement office
reported that a dose of OPV in 2001 was about $0.09, equivalent to inflation adjusted price of
$0.11 per dose in 2007.
With this international price of vaccines, we have to add resource costs related to handling,
transportation and wastage of the vaccines (see costing methodology used by Liu et al. 2002).
For the low-income countries of the world, the minimum vaccine cost should be about $0.15 after
adding all these additional cost items. From > Table 78‐1, we can say that the average cost of
administering vaccine per dose (other costs) is about $1.30 for low-income countries and so the
total cost per dose becomes $1.45 including the vaccine cost. Allowing proportionate increase in
costs based on the average income of the group of countries, the cost of polio vaccine per dose
becomes $3.46 for middle-income countries, $9.22 for upper-middle income countries and $15.15
for high-income countries of the world. The cost for high-income countries already includes the
cost of using IPV in the regular immunization program and no further adjustments in the cost
numbers will be needed for this country-category.
> Table 78‐2 shows the country-group specific weights used for the derivation of average
cost per dose of polio-vaccine administered by geographic regions (the WHO regions).
. Table 78-2
Cost of administering polio vaccination, including the vaccine costs, by WHO regions for the
year 2007
Percent of population living in countries categorized as

Low Middle Upper-middle High- Average cost per
WHO regions income income income income dose
African region 88 6 6 0 $2.04
Americas 2 20 40 38 $10.17
Eastern 60 34 5 1 $2.66
Mediterranean
European region 4 48 4 44 $8.75
South-east Asia 80 20 0 0 $1.85
Western Pacific 81 5 5 9 $3.17
Cost of administering or delivering a dose of polio depends on the average income levels of countries. In low-
income countries, cost of delivering vaccines becomes low mainly due to low labor costs. To find the average cost
per dose of polio vaccine delivered for a geographic region, costs per dose by income category of countries were
multiplied by the percent of population in the geographic region living in that category of countries. Average cost
of delivering a dose of polio vaccine for low-income, middle income, upper-middle income and high income
countries were multiplied by the population proportions mentioned in columns 2–5. Weighted averages of the
costs are shown in the final column of the table
The calculated average costs per dose are also reported in the table. Note that cost per dose
administered includes vaccine wastage, which is relatively high for developing countries of the
world. The cost parameters derived and reported in the table are used in estimating the global
cost of polio vaccination through regular immunization programs.
To find the total cost of polio vaccination, we also need information on > vaccine cover-
age rate by country groups or by regions. It is assumed that the vaccine coverage in develo-
ped countries increase from about 60% in 1970 to about 90% by the year 2000. In many
developed countries, vaccine coverage (crude) remained around 60% in early 1970s and due
to low coverage in some countries. The average coverage rate among high income countries
after 2000 is assumed to be at 95%. For developing countries of the world, the coverage
of three doses of polio vaccine was only 15% in 1970, which increased to 60% in 1985 and 80%
in 1995. After that the coverage is assumed to remain at 90% level.
3.2 Cost Parameters for Polio Eradication Program
The eradication program has five distinct components: the supplementary immunization
activities (> NIDs and SNIDs), AFP Surveillance, AFP Surveillance laboratory costs, mopping
up immunization activities, polio eradication certification activities. These activities are
organized in different countries and regions at different points in time depending upon the
progress in routine immunization coverage and success in reducing polio incidence rates. For
example, polio eradication campaign was introduced in the Americas in 1986, when a 5-year
intensive immunization program was adopted. The eradication activities in South Asia and
Africa did not start before 1995. Since the cost of eradication occurred in different years,
appropriate > discounting factors must be used to derive the eradication costs in terms of
2007 prices.
Bart et al. (1996) reported some cost parameters related to intensive polio immunization.
They assumed a cost of $0.18 per dose for developing countries and $5.64 per dose for
developed countries (in 1993 prices). In this paper, cost parameters are defined for four
categories of countries using the costs reported in the literature (Bart et al., 1996; Jian et al.,
1998; Levin et al., 2000a,b). The estimated cost per dose delivered through intensive immuni-
zation programs for low-income, middle-income, upper-middle income and high-income
countries were found to be $0.30, $1.14, $2.94 and $6.77 respectively. Using the same
population weights in > Table 78‐2, weighted cost per dose of polio through intensive
programs becomes: $0.51 for Africa, $3.98 for Americas, $0.78 for Eastern Mediterranean,
$3.66 for Europe, $0.47 for South East Asia and $1.06 for Western pacific.
Excepting for the South East Asian Region (SEARO), no other WHO regions report the
cost of eradication activities. For SEARO, we have used the costs reported by the WHO and for
other regions, eradication costs were estimated using the assumptions used by Bart et al.
(1996) on start date of the campaign, coverage of vaccination, etc. For example, we have
assumed that in Eastern Mediterranean Region, eradication activities began in 1992 targeting
10% of children and in South East Asia it began in 1994 covering 90% of children.
4 Global Cost and Effectiveness of Polio Vaccination

The parameters described in sections II and III above are presented in > Table 78‐3 below.
These parameters will be used to calculate the global cost of polio immunization.
4.1 Number of Polio Cases Averted and Dalys Saved
Using the parameters reported in > Table 78‐3 and the estimates of number of polio cases in all
the six WHO regions, we can calculate the number of polio cases averted and the number of
deaths prevented through routine immunization and eradication programs.
> Figure 78‐2 shows the actual and predicted values of polio incidence rates (per 100,000
children below 5 years of age) for USA during the pre-vaccination period. Note that the
predicted values almost perfectly predict the actual observations. The estimated polio inci-
dence rate function was used to project the number of cases without vaccination for the
Americas. Similarly, incidence rates of polio in Italy for pre-vaccination period (1924–1963)
were used to predict the polio incidence rates for European and other regions of the world
. Table 78-3
Parameters used for the estimation of costs and effectiveness of polio vaccination and eradica-
tion activities
Parameters for measuring cost and effectiveness Parameter values

Proportion of polio cases likely to become paralyzed 0.1027
Proportion of polio cases with other nervous system attacks 0.1053
Duration of paralysis (discounted years) 68 years (29.6 years)
Disability weight used for paralysis 0.369
Case fatality rate (per 100 polio cases) 2
Years of life lost due to premature death (discounted years) 78 years (30.9 years)
Routine immunization cost parameters (in 2007 prices) for
Low-income countries $1.45
Middle-income countries $3.46
Upper-middle income countries $9.22
High income countries $15.15
Eradication program cost parameters (in 2007 prices) for
Low-income countries $0.30
Middle-income countries $1.14
Upper-middle income countries $2.94
High income countries $6.77
Medical care cost per year per case and percent of cases utilizing medical care for (% utilization
rates are in parentheses)
Low-income countries $504 (20%)
Middle-income countries $2,364 (40%)
Upper-middle income countries $5,400 (65%)
High income countries $30,000 (80%)
This table shows the parameters used in this paper to calculate the costs and effectiveness of polio immunization
program. First seven rows report the parameters needed to calculate the health outcomes related to polio. Almost 10%
of polio cases lead to long-term paralysis and another 10% are afflicted with other types of nervous system attacks.
Those who are paralyzed, the duration of paralysis is considered to be 68 years. Disability weight indicates the loss of
health associated with a disease. The WHO assumed that the disability weight for polio-related paralysis is 0.369, i.e.,
living with paralysis for 1 year is equivalent to living in perfect health for (1–0.369) = 0.631 year. Cost of immunization
per dose and medical care cost of polio cases are also reported. In this paper, medical care cost is defined by the median
income of countries in the category. For high-income countries in Americas, medical care cost per year is considered
$30,000 (equivalent to Bart et al. (1996) medical cost numbers for developed countries). For other high income
countries, medical care cost per case of polio paralysis or nervous system attack is considered $18,000 per year
(AFR, SEAR, WPR and EMR). The Fourier series estimation predicted the observed incidence
rates for Italy almost perfectly.
As mentioned in the method section, the estimated Fourier series were used to predict
polio incidence rates for all the years from 1912 to 2050. > Figure 78‐3 shows the predicted
incidence rates per 100,000 children based on US incidence data for pre-vaccination years.
This predicted series indicates the incidence of polio that would have occurred without polio
immunization in the Americas.
. Figure 78-2
Actual and predicted polio incidence rates in the USA, 1912–1955
. Figure 78‐3
Observed and predicted polio incidence rates without vaccination in the Americas: 1912–2050
4.1.1 Calculating the Effectiveness of Polio Vaccination
The effectiveness of polio vaccination is simply the difference between the projected polio
cases without vaccination and actual polio cases with vaccination. The population of the world
was about 6,055 million in 2000 and it is expected to increase to 8,560 million in 2050.
If the polio cases prevented are calculated for each of the six regions of the world, global total
of polio cases prevented over the years 1970–2050 (without discounting) becomes about
42 million. More than four million paralysis cases will be potentially averted by 2050 and
immunization will also avert another four million cases of other nervous system attacks. The
undiscounted number of deaths prevented due to successful vaccination and eradication over
the years should be about 855 thousands.
Given the number of deaths and disabilities, we are now in a position to convert these health
outcomes into DALYs. It should be noted that all the deaths and disabilities are not prevented in
the same year and therefore, we need to express the health outcomes in terms of 2007 values. In
other words, all the health outcomes prior to 2007 will be multiplied by the discount factor and
all the health outcomes after 2007 will be divided by the discount factor. As mentioned earlier,
we will use a discount rate of 3%, the rate used by the WHO in their DALY calculations.
To illustrate the DALY calculation steps followed, let us look at the data set used for Africa
Region. > Table 78‐4 shows data on actual incidence and projected polio incidence without
. Table 78‐4
Adjusted incidence and projected incidence without polio immunization with DALY calculations
for Africa region (1981–1990)
Cases Paralysis Deaths YLDs YLLs

Polio prevented, prevented prevented prevented^ prevented DALYs
cases* (2) = [pred- (3) = [(2) (4 ) = [2% (5) = [(3)* (6) = [(4)* prevented
Year (1) (1)] *0.1027] of (2)] 0.369*29.6] 30.9] (7) = [(5) + (6)]
1981 62,865 27,698 2,845 576 31,071 17,803 48,874
1982 58,455 45,021 4,624 936 50,502 28,936 79,438
1983 45,990 90,773 9,322 1,888 101,823 58,342 160,165
1984 44,520 96,675 9,929 2,011 108,443 62,135 170,578
1985 59,025 73,835 7,583 1,536 82,823 47,455 130,278
1986 51,375 80,788 8,297 1,680 90,623 51,925 142,548
1987 41,730 100,118 10,282 2,082 112,306 64,348 176,654
1988 68,145 72,749 7,471 1,513 81,605 46,758 128,363
1989 46,440 131,840 13,540 2,742 147,890 84,737 232,626
1990 63,420 98,752 10,142 2,054 110,774 63,470 174,244
*Adjusted for underreporting of polio cases
This table shows the total number adjusted polio cases in column 2 and the number of cases averted in column 3.
Cases averted have been estimated by projecting the number of cases that would have occurred in absence of
polio immunization and subtracting the adjusted incidence number from the estimate. The numbers of averted
cases were used to find the number of paralysis and deaths averted. Years lost due to premature mortality (YLL)
has been derived from the estimates of deaths averted and Years lost due to disability (YLD) has been derived from
paralysis cases averted. The calculations in the table ignored the loss of health associated with other nervous
system attack cases
vaccination for the years 1981–2000. Prior to 1981, it is assumed that polio vaccination
was not effective enough to avert any case. This actually underestimates the effectiveness
of polio vaccination as the immunization program obviously had some impact on preventing
polio before 1980. Also, if a particular year shows high incidence of polio (adjusted number
due to underestimation of cases), higher than or equal to the projected incidence without
vaccination, number of cases prevented in that year also becomes zero. The DALY numbers
are by year by geographic region and to get an aggregate measure of effectiveness of
polio immunization, we need to add the DALY values together. Since the DALYs prevented
are distributed over a long period of time, we have used 2007 as the base year and all DALY
values were adjusted so that the aggregate number becomes same as the equivalent DALYs
saved in 2007 alone. As before, 3% discount factor was used for the conversions.
For each of the WHO regions, similar calculations were carried out for the years
1970–2050 and for each of the years number of cases prevented and other health out-
comes were derived. The discounted values of DALYs were calculated from the health
outcome information and the numbers are presented in > Table 78‐5.
Note from > Table 78‐5 that DALYs averted are relatively high for the Americas and
the reason for this is mainly due to two factors: first, the reported incidence of polio were
. Table 78‐5
Estimated health impacts of routine polio immunization in the WHO regions, 1970–2050 (in
thousands of years)
Discounted Discounted
YLDs prevented YLLs prevented YLDs YLLs
(w/o (w/o (discount (discount Discounted
WHO regions discounting) discounting) rate 3%) rate 3%) DALYs
Africa 7,003.91 4,013.04 5,517.02 4,006.52 9,523.54
Americas 10,409.08 5,964.11 10,263.97 5,880.97 16,144.94
Eastern 4,812.82 2,757.61 4,387.16 2,513.72 6,900.88
Mediterranean
Europe 4,687.57 2,686.99 6,349.54 3,638.11 9,987.65
South-east 10,045.09 5,755.55 8,147.97 4,668.56 12,816.53
Asia
Western 8,798.11 5,041.07 8,138.98 4,663.41 12,802.39
Pacific
Global total 45,756.58 26,218.37 42,804.64 25,371.29 68,175.93
This table summarizes the estimates of health outcomes expressed in terms of DALYs due to routine polio
immunization by the six WHO regions of the world. Both discounted and undiscounted values are presented
higher in the Americas than in other regions of the world during the pre-vaccination period and
second, the prevention of deaths and disability happened in the Americas much earlier than
any other regions of the world. Since the discounted values are expressed in terms of 2007, all
deaths and disabilities averted prior to 2007 are inflated by the discount factor.
It should also be mentioned that in the calculations above we have used the number of
symptomatic polio cases even though almost all children are likely to be infected with poliovirus
if not immunized. Since the number of deaths has been estimated from the number of paralytic
polio cases, the case fatality rate becomes relatively low, about 2% of all symptomatic polio cases.
4.2 Net Cost of Routine Polio Immunization and the

Cost-Effectiveness Ratios
> Table 78-6 reports the costs of vaccination and medical care cost savings achieved through
routine immunization due to the prevention of polio cases and polio related medical care costs
in six regions of the world. All costs are expressed in terms of 2007 prices and 2007 values.
. Table 78‐6
Aggregate net cost of routine polio immunization and cost per DALY averted for all years over
1970–2050 expressed in terms of 2007 values
Net cost of Discounted

Cost of routine Medical care routine polio DALYs Net cost
immunization costs averted immunization averted per DALY
WHO regions (millions) (millions) (millions) (thousands) averted
Africa $8,729 $4,039 $4,690 9523.54 $492.5
Americas $44,959 $194,478 $149,519 16,144.94 Negative
Eastern $7,776 $6,691 $1,085 6,900.88 $157.2
Mediterranean
Europe $30,412 $107,719 $77,307 9,987.65 Negative
South-east $13,038 $4,502 $8,536 12,816.53 $666.0
Asia
Western $18,677 $28,882 $10,205 12,802.39 Negative
Pacific
Global $123,591 $346,311 $222,720 68,175.93 Negative
In this table, net costs of routine polio immunization have been derived by WHO regions. Net cost is defined as the
cost of routine polio immunization minus the medical care costs averted due to the prevention of polio cases. In
the final column of the table, cost per DALY is shown. Note that the cost per DALY is negative for the whole world
taken together and for three regions of the world
To convert past and future costs in terms of 2007 values (time preference adjustment),
discount rate of 3% was used. The table also shows the cost-effectiveness ratios for the six
regions as well as for the whole world using DALYs averted as the effectiveness measure.
Estimating the cost of routine immunization is straightforward; we can simply multiply
the cost per dose with the total number of polio doses administered. Number of doses
administered is obtained by multiplying the number of infants (less than a year) in a region
with vaccine coverage rate and then with four (four doses of vaccine). Calculation of medical
care cost savings is much more involved. Paralysis cases need medical care over the life time
and not all cases seek medical attention. Given the assumption on medical care utilization
rates for paralysis cases by country-categories (see > Table 78‐3), number of cases which would
otherwise seek medical care in any year can be derived by obtaining the cumulative number of
averted paralysis cases over the previous 67 years.
The aggregate global economic cost of routine immunization over the years 1970–2050
would be about $123.6 billion in terms of 2007 values while the medical care cost averted
on the global scale will be about $346 billion. If we consider a very long-term perspective,
continuation of routine polio immunization is actually cost saving for three regions of
the world: Americas, Europe and Western Pacific. Therefore, if risk of polio exists, it will be
irrational for these regional countries not to continue with polio immunization. Even
for poorer regions of the world, Africa, Eastern Mediterranean and South-east Asia, net cost
per DALY averted are relatively low. The cost-effectiveness ratio for South-east Asia was $666
per DALY averted, the highest cost-effectiveness ratio among all the six regions of the
world. Therefore, even if eradication activities were not in place (or were not feasible), it
makes perfect economic sense to continue with the routine immunization in the long run.
Medical care cost savings on the global scale will be more than enough to pay for the
immunization cost.
For the whole world taken together, the net cost of polio immunization becomes negative.
Therefore, polio immunization remains a highly desirable intervention if we consider the
whole world as one unit. In South-East Asia, the intervention appears least cost-effective
among all the six regions. One of the reasons for this relatively high cost-effectiveness ratio is
the lower medical care cost associated with polio cases and lower probability of seeking care
for polio. Over time, health-seeking behavior of population will change and may make the
polio immunization relatively more cost-effective.
4.3 Cost-Effectiveness of Polio Eradication Activities
To calculate the cost-effectiveness of polio eradication, we assume that the eradication

campaign conducted in different regions of the world can successfully eradicate wild polio
transmission and vaccination will not be needed to protect population from wild poliovirus.
In this sense, the benefit of eradication activities is the cost-savings achieved by discontinua-
tion of polio vaccination as well as prevention of few hard-to-protect cases through supple-
mental vaccination activities.
> Table 78‐7 reports the cost-effectiveness polio eradication activities by the WHO regions.
The method of calculation of the costs and effectiveness is similar to the approach followed for
routine program but successful eradication has one additional component, the cost savings due
to discontinuation of routine immunization. It is assumed that countries will not stop polio
immunization in all areas and 50% of routine program will continue after eradication certifi-
cation. The year of polio eradication certification is assumed to be 2015.
> Table 78‐7 indicates that polio eradication activities will be cost savings for the whole
world taken together, even if 50% of regular polio immunization continues after the certifica-
tion date. However, the estimates show wide regional variability. For example, in South-east
Asia, polio eradication activities show very high cost-effectiveness ratio, almost $8,000 per
DALY averted, if polio immunization cannot be stopped altogether after certification.
If routine polio immunization is completely discontinued after 2015, the net cost becomes
negative for all the regions of the world. Therefore, polio eradication activities will be
cost-saving in the long-run if complete cessation of polio immunization is feasible after
. Table 78-7
Cost-effectiveness ratios for polio eradication activities expressed in 2007 values (assumed date
of eradication 2015)
Vaccine Medical
Eradication cost care cost Net cost of DALYs averted Net
cost savings savings eradication by eradication cost/
WHO regions (millions) (millions) (millions) (millions) (thousands) DALY
Africa $1,826 $1,572 $8 $246 112.6 $2185
Americas $73 $5,169 $1,002 $6,098 70.11 Negative
Eastern $1,227 $1,221 $86 $80 51.98 Negative
Mediterranean
Europe $2,195 $2,640 $418 $863 44.66 Negative
South-east $2,887 $1,952 $37 $898 112.64 $7,972
Asia
Western $5,766 $5,130 $198 $438 97.71 $4,482
Pacific
Global $13,974 $17,684 $1,749 $5,459 489.70 Negative
This table shows the cost-effectiveness ratios of eradication activities by WHO regions. Column 2 reports the costs
associated with eradication activities. Polio eradication will potentially allow discontinuation of routine polio
vaccination and vaccine costs will be saved in the post-eradication years. This savings are shown in column 3.
Column 4 shows the estimates of medical care cost savings for few hard-to-reach cases, which can be reached and
prevented by eradication activities. Net cost of eradication is shown in column 5 (costs minus the savings). Net
costs per DALY averted by polio eradication activities are reported in the final column
certification. Without complete cessation of polio immunization, the eradication cost

incurred may be better used elsewhere to improve the health status of population in a more
effective manner.
5 Conclusions and Policy Implications
Polio eradication program has shown significant progress towards polio free world since
1985. At this point in time, it is important to examine the costs and effectiveness of
polio vaccination and eradication programs. This will be helpful to policy makers to design
and advocate future eradication activities for other infectious diseases. In this study, estimates
of costs and health effects of polio vaccination and eradication are presented by con-
sidering a very long time frame, from 1970 to 2050. Economic evaluation of control and
eradication of infectious diseases should consider long time horizon as eradication activities
continue to provide health benefits long after the complete cessation of eradication and
control activities.
In this paper, health outcomes are measured in terms of deaths averted, years of life saved
due to the prevention of premature death and years of disability averted due to the prevention
of paralysis. Cost parameters were also derived by country-categories defined by economic
status of countries. In discussing policy alternatives at the global level, economic status based
country categorization provides more realistic policy directions. The analysis of the paper
indicates a number of important results and policy implications.
Summary Points
Routine polio immunization will prevent more than 42 million polio cases over the years
1970–2050. Total number of paralysis and deaths averted through the program should be
about four million and 855 thousand respectively. Polio vaccination strategy is clearly one
of the most effective public health interventions the world has ever seen.
The number of polio cases and polio endemic countries has declined very rapidly over
the last 20 years due to the successful implementation of polio vaccination and eradication
strategies. Although the global cost of polio immunization is quite high, more than $123
billion (in 2007 values) for the period 1970–2050, the benefits and health outcomes are
also high. In fact, at the global scale, routine polio immunization is cost-saving.
The WHO defines an intervention as highly cost-effective if the cost per DALY averted
is less than the Gross National Income (GNI) per capita of the country or the region.
The cost-effectiveness ratios of routine polio immunization suggest that the program will
be highly cost-effective in all countries in Africa with GNI per capita of $492 or more.
The average GNI per capita of African countries was about $850 in 2006 but 22 countries
in Africa had GNI per capita below $492 in 2006. For these very poor countries, interna-
tional financial assistance will be needed to ensure continued and effective implementation
of polio immunization and eradication activities.
For all countries in the Eastern Mediterranean, routine polio immunization is a > highly
cost-effective intervention. Cost per DALY averted becomes only $157 for this region and
all countries in the region had GNI per capita of more than $157.
Like Africa, the cost-effectiveness ratio of routine polio immunization in South-east Asia
was also relatively high, about $666 per DALY averted. Again, some of the countries in
this region will require international assistance in implementing the polio immunization
program. However, the relatively high cost-effectiveness ratio in the region is due to low
utilization of medical care services by polio and paralysis cases. With rapid economic
progress in India, utilization rate of medical care services is likely to expand, lowering
the net cost per DALY averted for the whole region.
Polio eradication has remained elusive and the health outcomes of eradication activities,
over and above the routine polio immunization, are relatively low. Despite the low health
outcomes of eradication, eradication activities were cost-saving in three regions of the
world, namely, the Americas, Eastern Mediterranean and Europe. If countries stop routine
polio immunization completely after eradication, the interventions will be cost savings for
all regions of the world.
If polio eradication cannot be achieved within the next 5 years or so, emphasis should shift
towards strengthening routine polio immunization as the program remains highly cost-
effective with or without eradication.
From the developed countries’ point of view, it is economically justifiable to help the poor
countries to adopt and continue with effective polio immunization programs. Polio
control provides such a high level of cost savings for the high-income countries, less
than half of the cost savings can fully fund polio vaccination in the developing world.
Allocating only 10% of the net savings of high-income countries will help to fund 20% of
polio vaccination costs in the developing world. High-income countries, for protecting
their own net savings generated through the eradication of polio, should become actively
involved in the strengthening the global immunization program.
References
Bart KJ, Foulds J, Patriarca P. (1996). Bull World Health Liu X, Levin A, Makinen M, Day J. (2002). OPV vs IPV:
Organ. 74(1): 35–45. Past and Future Choice of Vaccine in the Global
Brenzel L, Claquin P. (1994). Soc Sci Med. 39(4): Polio Eradication Program. Partnerships for Health
527–536. Reformplus Project, February.
CDC. (1998). JAMA. 279(2): 103–104. Mathers C, Loncar D. (2006). Updated projections of
Cockburn WC, Drozdov SG. (1970). Bull World Health global mortality and burden of disease, 2002–2030:
Organ. 42: 405–417. Data sources, methods and results. Evidence and
Fairbrother G, DuMont KA. (1995). Am J Public Health. information for policy working paper, World Health
85(12): 1662–1665. Organization, Geneva, November.
Jian Z, Jing-jin Y, Rong-zhen Z, et al. (1998). Int J Health Murray CJL, Lopez AD, (eds.). (1996). The Global
Plan Manage. 13: 5–25. Burden of Disease: A Comprehensive Assessment
Kaddar M, Levin A, Dougherty L, Maceira D. (2000). of Mortality and Disability from Diseases, Injuries
Costs and Financing of Immunization Programs: and Risk Factors in 1990 and Projected to 2020.
Findings of Four Case Studies. Partnerships for Harvard University Press, Cambridge.
Health Reform Project, Abt Associates Inc., May. Musgrove P. (1989). Is Polio Eradication in the Americas
Kaddar M, Mookherji S, DeRoeck D, Antona D. (1999). Economically Justified? in Health Economics: Latin
Case Study on the Costs and Financing of Immuni- American Perspectives, Pan American Health Orga-
zation Services in Morocco. Special Initiatives Re- nization, Scientific Publication no. 517.
port number 18, Partnerships for Health Reform World Bank. (2006). World Development Report 2007.
Project, Abt Associates Inc., September. Washington DC.
Khan M, Yoder R. (1998). Expanded Program on Immu- World Health Organization. (2000). Global Polio Eradi-
nization in Bangladesh: Cost, Cost-effectiveness, cation Initiative: Strategic Plan 2001–2005. Geneva.
and Financing Estimates. Technical Report number World Health Organization. (2002). Endgame issues for
24, Parnerships for Health Reform Project, Abt the global polio eradication initiative. Technical
Associates Inc., September. Consultative Group to Global Eradication of Polio,
Levin A, Ram S, Afsar A, et al. (2000a). The Cost- Clinical Infectious Diseases. 34: 1 January.
effectiveness of Mixes of Operational Approaches to World Health Organization. (2006). Global Program on
Polio Eradication: Findings of Two Case Studies. Spe- Evidence for Health Policy (GPE), “Global burden
cial Initiatives Report Number 32, Partnerships for of Poliomyelitis in the year 2000”, Global Burden of
Health Reform Project, Abt Associates Inc., October. Disease 2000 Notes, Draft 15-08-06.
Levin A, Ram S, Kaddar M. (2000b). The Impact of the World Health Organization. (2008). Conclusions and
Polio Eradication Campaign on the Financing of Recommendations of the Advisory Committee on
Routine EPI: Finding of three Case Studies. Special Poliomyelitis Eradication, Geneva, 27–28 November
Initiative Report number 27, Partnerships for 2007. Weekly Epidemiological Record. Year 83,
Health Reform Project, Abt Associates Inc., March. number 3, 18 January, pp. 25–35.
79 Financial Burdens and
in Echinococcosis
P. R. Torgerson
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1374
2 Human Clinical Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1376
3 Economic Effects of Echinococcosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1378
4 Calculating the DALY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1381

4.1 Disability Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1381
4.2 Years Lived with Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1381
4.3 Survival Analysis and AE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1383
5 Modeling Uncertainty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1384
6 The Global Burden of Echinococcosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1386
7 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1387
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1387
Key Facts About Echinococcosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1388

1374 79 Financial Burdens and Disability-Adjusted Life Years in Echinococcosis
Abstract: Human echinococcosis is a severe zoonotic parasitic disease which can be fatal if left
untreated. Two forms of the disease exist, namely > cystic echinococcosis (CE) caused by
Echinococcus granulosus and > alveolar echinococcosis (AE) caused by E. multilocularis have a
widespread distribution. Both forms of the disease are characterized by slow-growing, space-
occupying lesions which most commonly occur in the liver with clinical features similar to
those of a tumor. The disease results in financial burdens due to the direct costs of treatment
and indirect costs due to morbidity effects such as decreased employment. Although this
review primarily targets human disease, CE also has significant animal health costs which can
add to the overall burden of disease in society. Most of the burden of disease occurs in lower
income countries. A number of studies have demonstrated that both the financial costs of the
disease and the burden of disease in terms of DALYs are substantial in endemic areas and in a
few communities, such as pastoralists in Tibet, echinococcosis can be amongst the highest
contribution to total burden of disease. On a global scale the disease burden may rival that of
many better known diseases such as African trypanosomiaisis and onchocerciasis. CE is also
largely preventable and often highly cost effective to do so. Despite this, echinococcosis
remains a neglected disease.
List of Abbreviations: AE, alveolar echinococcosis; CE, cystic echinococcosis; DALY, disability
adjusted life year; HCC, hepatocellular carcinoma; OIE, World Organization for Animal
Health (Office International des Epizooties); PAIR, puncture-aspiration-injection-respiration;
YLD, years of life lived with disability (a component of the DALY); YLL, years of life lost
(a component of the DALY)
1 Introduction
Human echinococcosis is caused by infection of the > larval stage of a number of tapeworm
species (Eckert and Deplazes, 2004). Cystic echinococcosis (CE) caused by the larval stage of
Echinococcus granulosus is by far the most important on a global scale. Some pathogenic
genotypes are now being recognized as separate species such as E. ortleppi (McManus
and Thompson, 2003). Alveolar echinococcosis (AE) is caused by the larval stage of
E. multilocularis can be important locally. Human infections with E. vogeli and E. oligathus
results in polycystic echinococcosis. Relatively few cases have been described and they were all
in Latin America.
CE is a condition of livestock and humans, arising from the ingestion of infective eggs of
the cestode Echinococcus granulosus. Dogs are the primary > definitive hosts for this parasite,
with livestock acting as > intermediate hosts and humans as aberrant intermediate hosts
(> Figure 79-1). The outcome of infection in livestock and humans is cyst development in the
liver, lungs, or other organ system. The distribution of E. granulosus is considered worldwide,
with only a few areas such as Iceland, Ireland, and Greenland believed to be free of autoch-
thonous human CE (Torgerson and Budke, 2003). However, CE is not evenly distributed
geographically (> Figure 79-2). The United States has very few cases with most human cases
being in immigrants. The same is true for several countries of Western and Central Europe,
although in some countries such as Italy and Spain there is still significant transmission to
humans. In many parts of the world, however, CE is considered an > emerging disease. For
example, in the former Soviet Union and Eastern Europe, there have been dramatic increases in
the number of observed cases in recent years (Torgerson et al., 2002, 2003, 2006). Additionally,
Financial Burdens and Disability-Adjusted Life Years in Echinococcosis 79 1375
. Figure 79-1
Life cycle of Echinococcus granulosus. This demonstrates how E. granulosus is transmitted. It is a
cestode parasite which naturally transmits between dogs (the small, none pathogenic adult is
in the intestine) and farm animals (where larval cysts grow in the liver and other organs). Dogs
are infected through eating offal containing the larval cysts (or hydatid cysts). Humans and
livestock are infected through the ingestion eggs passed in the faces of dogs. Image supplied
by the Institute of Parasitology, Zurich
in other regions of the world, such as parts of China, the geographical distribution and extent of
CE is greater than previously believed (Chai, 1995). There are also substantial numbers of cases
in much of Latin America and the parasite is endemic to Australia. The parasite is widespread in
the Middle East and much of sub-Saharan Africa. CE not only causes severe disease and possible
death in human patients, but also results in economic losses due to treatment costs, lost wages,
and livestock associated production losses (Torgerson, 2003).
Echinococcus multilocularis is found throughout the northern hemisphere (> Figure 79-3).
The larval stage of this parasite causes AE (Eckert and Deplazes, 2004). Naturally the parasite
cycles between the definitive hosts foxes and small rodents. Dogs are also suitable definitive
hosts. Humans can be aberrant hosts (> Figure 79-4) and human infection arises
. Figure 79-2
Global distribution of zoonotic forms of Echinococcus granulosus. This shows the world-wide
distribution of Echinococcus granulosus with very few areas being free of the parasite.
Image supplied by the Institute of Parasitology, Zurich
from ingestion of eggs. Human AE consists of a space occupying lesion and the primary lesion
is nearly always found in the liver. The metacestode is slow growing but locally is highly
invasive. In late stage cases the metacestode will metastasize to distant organs and, untreated,
the disease has a 90% or greater fatality rate (Ammann and Eckert, 1996). In Europe the
disease has a widespread distribution in central and Eastern Europe. AE can be found
throughout much of Turkey and the disease is endemic in much of the former Soviet
Union. In western China in certain communities very high human prevalences are seen
(Budke et al., 2004). The disease also has a sporadic occurrence in Hokkaido Japan (Kimura
et al., 1999). E. multilocularis is widespread in North America although human AE cases are
rare and have been largely confined, for example, to particular communities in Alaska (Rausch
et al., 1990; Stehr-Green et al., 1988).
2 Human Clinical Disease
The initial phase of CE is asymptomatic with small, well-encapsulated cysts. After an unde-
fined period of several months to years, the infection may become symptomatic as a space-
occupying lesion. However, 60% of infections will remain asymptomatic (Eckert and
Deplazes, 2004; Kern, 2003). The liver is the most common organ involved, usually with
over two thirds of cysts (> Figure 79-5). The lungs are infected in about 20% of cases,
with other organ involvement accounting for less than 10% of cases (> Figure 79-6). The
treatment options for CE include surgical removal of the lesions and in many parts of
the world CE is the most common reason for abdominal surgery. Surgery has a success
. Figure 79-3
Life cycle of Echinococcus multilocularis. This demonstrates how E. multilocularis is transmitted. It
is a cestode parasite which naturally transmits between dogs or foxes (the small, none
pathogenic adult is in the intestine) and small rodents (where larval cysts grow in the liver and
other organs). Dogs or foxes are infected through predating. Image supplied by the Institute of
Parasitology, Zurich
rate of up to 90% (Eckert and Deplazes, 2004; Kern, 2003). An alternative to surgery is the
PAIR technique, (WHO, 1996). Chemotherapy, using benzimidazoles, has also been used
successfully (Kern, 2003). In calcified cysts, there is an indication for a wait and see approach
to treatment.
AE, due to the metacestode stage of E. multilocularis, is an often-fatal condition if
untreated. The cyst is multivesicular and highly infiltrative locally. The primary site of
metacestode development is almost exclusively the liver. Secondary metastasis may form in
a variety of adjacent or distant organs in longer standing cases, making surgical management
difficult. Patients present with cholestatic jaundice and/or epigastric pain, fatigue, weight loss,
hepatomegally or abnormal routine laboratory findings (Ammann and Eckert, 1996; Eckert
and Deplazes, 2004). Treatment options include partial and radical surgical resection for
localized lesions in combination with long-term chemotherapy using benzimidazoles. Recent
studies have suggested that modern treatment methods have substantially improved the
. Figure 79-4
Global distribution of Echinococcus multilocularis. This shows that Echinococcus multilocularis is
confined to the northern hemisphere. This is significant concern in Europe that the parasite is on
the increase as the fox population has increased substantially in the last 20 years, possibly as a
result of the successful rabies vaccination program. Europe is now seeing increases in the
numbers of cases of human AE. Image supplied by the Institute of Parasitology, Zurich
prognosis for this disease (Ammann and Eckert, 1996; Bresson-Hadni et al., 2000; Torgerson
et al., 2008).
Human infections with E. vogeli and E. oligathus results in polycystic echinococcosis.
Relatively few cases have been described and they were all in Latin America. In 80% of cases
the lesions involved the liver; the rest were located in the lung or single organ sites (D’Alessandro,
1997). The most common clinical presentation includes liver masses, enlarged abdomen,
abdominal pain, weight loss and fever. In about 25% of cases there are signs of biliary
hypertension and biliary obstruction. From the limited numbers of cases that have been
reported the fatality rate is at least 26%.
3 Economic Effects of Echinococcosis
In the human population it can be seen that the burden of disease will be due to the cost of
sickness and disability due to the disease and the cost of treatment. > Direct financial costs can
be estimated from the hospital costs of treatment. Indirect financial costs will include the loss
of income due to disability and other long term convalescent costs. Lost income due to
premature mortality is also possible (Torgerson, 2003). Early studies on disease burden for
echinococcosis were mainly targeted at financial losses due to the disease (Majorowski et al.,
2005; Torgerson and Dowling, 2001; Torgerson et al., 2000, 2001). This has some advantages
as the disease also has an economic effect on livestock. For humans, the financial costs
. Figure 79-5
MRI images of cystic echinococcosis. Hydatid cysts can be clearly seen as space occupying lesions
in the liver. Images from (Aliev et al., 2004) with permission
of echinococcosis not only depend on the incidence of the disease but also on the
cost of treatment. The cost of treatment can have huge variations depending on where
treatment is undertaken. In Jordan for example, a lower middle income country the cost
of treating a case of CE is on average approximately $524 (Torgerson et al., 2001).
This compares to the cost of treating a case of CE in the UK of approximately $15,000
(Torgerson and Dowling, 2001). In Switzerland the direct costs of treating a case of AE is on
average $150,000 (Torgerson et al., 2008) (based on the approximate exchange rates of April
2008). Other indirect costs have similar huge variations depending on the relative economic
output of the country where the disease occurs. Later studies, including the global burden
of CE (Budke et al., 2006) have also incorporated DALY estimates for disease burden.
An important part of the societal burden of disease is that of animal health costs. CE is a
zoonosis and many species of agricultural animals, but especially sheep are afflicted by CE. In
animals CE will result in loss of edible liver and can also result in loss of productivity such as
lowered milk production, loss of food conversion or impaired fertility (Torgerson, 2003). In
terms of financial costs on a global scale loss of animal productivity is perhaps half of the
total burden of disease. The total global burden of animal health losses is believed to be at least
. Figure 79-6
CAT scan of cerebral echinococcosis. Although CNS involvement of echinococcosis is rare, when
it does occur it can be a devastating condition. Image supplied by the Government Paediatric
Hospital, Bishkek, Kyrgyzstan
$141 million and possibly as high as $2.1 billion (Budke et al., 2006). In some communities the
loss of animal productivity may be the major financial burden on society (Torgerson et al.,
2001). The financial losses caused to the livestock industry is a strong argument for calculating
disease burden in financial terms (Carabin et al., 2005) particularly as the disease often
occurs in low income countries where livestock production may make up a substantial part
of rural income. In addition, including livestock costs in the disease burden estimates can also
substantially improve the potential cost effectiveness of disease control, especially if cost
sharing between agricultural and health sectors is undertaken. Indeed at least one study has
suggested that the financial return from disease control may be more than the cost of
implementing the program (Budke et al., 2005).
Also of importance to consider is the financial burden of controlling the disease. This can be
considerable in terms of actual expenditure. This includes the meat inspection costs and the
routine treating of dogs with anthelmintics for example. However, these costs must also be put in
the context of the costs of the disease prevented. The costs of control will also be dependent on the
government policy and stage of the control program. In New Zealand the financial costs of
control of CE were substantive, but the program was successful in eliminating the parasite from
livestock and preventing transmission. The present day costs are now relatively small and consist
of surveillance to maintain the parasite free status and the costs of treating a small number of
human cases who may have been infected some time ago when there was active transmission.
A review of the New Zealand and other programs can be found in (Craig and Larrieu, 2006).
Likewise there is a potential cost of controlling AE by periodically distributing baits containing
anthelmintics to reduce E. multilocularis in the fox population. Preliminary programs, for
example in Zurich in Switzerland (Hegglin et al., 2003) have proved to be successful, but the
long term effects of reducing transmission to humans still remains unknown.
4 Calculating the DALY
4.1 Disability Weight
Central to calculating a DALY for echinococcosis is to assign a disability weight to the

condition. The majority of cases of both AE and CE are a primary space occupying disease
of the liver. Therefore the disability weights, derived for AE and CE, are based on values for
liver cancer obtained from the original Global Burden of Disease Study as well as from the
Dutch Disability Weight (DDW) Group, which produced a set of disability weights for use in a
Western European context (Stouthard et al., 2000). Liver cancer was chosen it often results in
similar clinical symptoms (> Tables 79-1 and > 79-2). One of the main differences between
the conditions is that echinococcosis has a more chronic disease course. This is, however,
accounted for by having echinococcosis patients remain at their assigned disability weight for
a prolonged period of time. In burden studies on echinococcosis the disability weight assigned
has depended on the stage of the disease. Thus a disability weight of 0.2 (Dutch weight for
clinically disease free cancer) for patients was assigned to patients with regressed or calcified
lesions or those with mild disease. A weight of 0.239 was assigned for patients with stable
lesions. This is the Global Burden of Disease weight for pre-terminal liver cancer – (Murray,
1994). A weight of 0.809 was assigned for patients with severe and deteriorating disease
(the Global Burden of Disease weight for terminal liver cancer). Disability weights have
been assumed to be age independent because there is no evidence to suggest disparity in
clinical presentation dependent on age of onset. Standard age weighting and correction
parameters together with discount rates can be used. The age structure of the population
can be calculated from available data. For example in Switzerland the mean age of onset of AE
patients is 54 years.
4.2 Years Lived with Disability
This is dependent on the progression of the disease and is the time from the onset of morbidity
to cure or death. To calculate this modeling techniques and assumptions have been made
based on the natural history of the disease. For CE this varied between 5 years for mild lesions
to their expected lifespan for more severe lesions. The latter is justifiable even when there is
surgical cure of the disease because quality of life studies have suggested that patients never
fully recover from the disease, have a lower quality of life even if they are un aware they have
the disease and suffer substantially higher levels of unemployment (Budke et al., 2004;
Torgerson and Dowling, 2001; Torgerson et al., 2003). For AE, if treatment is available, then
chemotherapy may be required for long periods of time. Thus in Switzerland, for example
therapy is required for an average of 7 years to affect a cure and this would be the minimal time
lived with the disability (Torgerson et al., 2008). Without treatment modeling has suggested
that life expectancy of AE is between 5 and 10 years and hence in this situation it would require
a weight of 0.239 for the early part of the disease progressing to 0.809 for the terminal stage
(Torgerson et al., 2008).
Estimated life expectancy of an individual has been based on the Japanese estimated life
span in order to standardize DALYs lost in accordance with the Global Burden of Disease
Study (Murray, 1994). A model > life-table, West Level 26, has been used to estimate expected
longevity for each age. In the Tibetan study (Budke et al., 2004) a Chinese life-table
1382
79
. Table 79-1
Comparison of the presenting clinical signs of alveolar echinococcosis (AE) and cystic echinococcosis (CE) of the liver with hepatocellular carcinoma
(HCC)
Presenting clinical Jaundice Hepatomegaly Mass-related pain Lung involvement Asymptomatica

signs (%) (%) (%) (%) (%) Reference
HCC (n = 336) 42.6 83.9 56 3.2 2.1 Sithinamsuwan et al.
(2000)
AE (n = 30) 43 23 20 3 7 Vuitton et al. (1996)
AE (n = 76) 25 14 25 7 14 Vuitton et al. (1996)
AE (n = 33) 21 76 60 9 – Wilson and Rausch (1980)
CE (n = 59) 7 5 42 9 36 Schaefer and Khan (1991)
This table compares the symptoms of HCC with that of the two common forms of echinococcosis. From this it can be seen that echinococcosis can present with very similar clinical
problems as does HCC
a
These cases were found incidentally in patients without clinical signs (diagnosed by chance at necropsy, laparotomy, or during ultrasound examination for other reasons such as
pregnancy), other categories were diagnosed clinically and confirmed radiologically
Financial Burdens and Disability-Adjusted Life Years in Echinococcosis
. Table 79-2
Other presenting clinical signs of hepatocellular carcinoma (HCC) with comparison to alveolar
echinococcosis (AE) and cystic echinococcosis (CE)
Clinical signs of HCC (Sithinamsuwan et al., 2000) AE CE

GI bleeding √ √
Edema √ √
Abdominal enlargement √ √
Encephalopathy √ √
Liver abscess-like symptoms √ √
Non-specific symptoms (anorexia, nausea, vomiting, malaise, √ √
wt. loss)
Fever √ √
Anemia √ √
Ascites √ √
Cachexia √ √
Chronic liver stigmata √ √
Splenomegaly √ √
This table also illustrates why it is possible to use the symptoms of HCC to derive a disability weight for
echinococcosis. (√) indicates the clinical sign has been associated with this condition
(Lopez et al., 2000) was also utilized for comparison. The general DALY formula was employed
in the construction of DALYs specific for alveolar echinococcosis (AE) and cystic echinococ-
cosis (CE). In the Tibetan study, DALYs were constructed on the premise of solely chemother-
apeutic therapy, as this is the most common treatment modality for the region and in nearly all
cases the only treatment currently available.
4.3 Survival Analysis and AE
A recent manuscript reported the DALY due to AE in Switzerland. In this study a large data set
of 329 cases of AE spanning the last 40 years was examined. Relative > survival analysis was
undertaken and it demonstrated a substantially improved prognosis for AE for patients being
treated now compared to 40 years ago (Torgerson et al., 2008). This is due to the development
of new treatment methods. Compared to the normal Swiss population the study demonstrated
that for an average 54-year-old patients diagnosed with AE in 1970 the life expectancy was
estimated to be reduced by 18.2 and 21.3 years for men and women, respectively. By 2005 life
expectancy of patients with AE was reduced by approximately 3.5 and 2.6 years, respectively
(> Figure 79-7). This reduced life expectancy can be used as the basis for calculating the YLL.
The YLD was also calculated from examining the hospital records to determine the mean
time that affected individuals were under treatment. YLDs were calculated according to
standard methods. Standard age weightings were used and a discount rate of 3% applied.
For the scenario that no treatment would be available, the YLLs were estimated from the
survival curve from 1970 where the survival analysis indicated a considerably shortened life
expectancy. This will be a means of giving better estimates of YLLs in endemic areas where
. Figure 79-7
Comparative life expectancy at age 54 years for AE patients (--- males, females) compared to
Swiss population norms (. . .males, ----females). This figure demonstrates that the life expectancy
of AE patients has improved considerably in Switzerland in the past 30 years. This is probably
due to better surgical techniques but more importantly the use of benzimadazole chemotherapy
introduced in the mid 1970s. However in remote rural communities where poverty is widespread
such as in Tibet such treatment is not available and the prognosis remains bleak
such treatment options are not available. An example would be remote rural areas of the
Tibetan plateau where prevalences of 5% have been recorded.
In this Swiss study it was also possible to estimate the cost effectiveness of treatment. To do
this present incidence rates were used but the life expectancy of AE in the 1970s used. In this
scenario, YLDs were also calculated based on the last 2–3 years of life having a disability weight
of pre-terminal liver cancer, and the rest of life living with the disease a weight of terminal liver
cancer (0.239 and 0.809) respectively. This indicated that, although treatment costs per patient
were of the order of $150,000, because the treatment prolongs life expectancy substantially, the
cost per DALYs saved is $9,000. If this is compared to the mean annual GDP per head of
Switzerland of approximately $32,000 it is easy to argue that treatment, although expensive in
Switzerland, is nevertheless cost effective.
5 Modeling Uncertainty
> Modeling uncertainty for economic effects of echinococcosis were used initially in studies in
Tunisia and Jordan (Majorowski et al., 2005; Torgerson et al., 2001). This has many advan-
tages, most notably surveillance data from which the costs of the disease can be calculated are
not deterministic and depend, interalia upon sampling error, errors due to diagnosis and
problems with bias and underreporting. For financial costs there will be uncertainty in the
mean cost of treatment due to large variations in the treatment costs of individual patients. In
developing the DALY there is also uncertainty in terms of morbidity and mortality. In the
Tibetan study (Budke et al., 2004), the DALY for AE was developed, with disability outcomes
divided into five components (cured, improved, stable, worse, or death) based on the health
survey as well as findings from past studies where albendazole was utilized as the sole treatment
for human AE (> Table 79-3). To model uncertainty, Monte-Carlo techniques were employed.
From published data (> Table 79-3), the results of chemotherapeutic treatment of 103 AE
. Table 79-3
Outcomes due to treatment of AE with benzimadazoles. Data used in stochastic analysis of
(Budke et al., 2004)
Number in study Cured Improved Stable Worse Death Reference

5 0 1 (20%) 2 (40%) 1 (20%) 1 (20%) Wen et al. (1994)
11 2 (18%) 0 5 (46%) 3 (27%) 1 (9%) Liang et al. (1997)
35 2 (6%) 4 (11%) 25 (72%) 4 (11%) 0 Horton (1989)
37 0 11 (30%) 10 (27%) 12 (32%) 4 (11%) Ammann et al. (1994)
15 1 (7%) 12 (80%) 0 2 (13%) 0 Liu et al. (1991)
This table reviews the clinical outcome of patients with AE treated with benzimadazoles. Benzimadazoles are
drugs that can be used to kill helminth parasites. In the case of echinococcosis they can arrest the development of
the cyst and are useful as an alternative to surgical treatment
patients were used to construct a multinomial distribution for the likely outcome of treatment.
Of these 103 subjects, there was an approximate probability of 4% of cure resulting from
calcification and regression of the lesions. Patients in this category were assigned a disability
weight of 0.200 for 5 years. A probability of approximately 27% was given for having mild
disease with disability weight 0.200, a probability of approximately 41% was given for having
disease equated to a disability weight of 0.239, and a probability of approximately 22% was
given for severe disease equating to a disability weight 0.809. Patients assigned to these three
later disease states were provided with a disability weight until the end of their expected
lifespan, based on a trinomial distribution. In addition, approximately 6% of patients were
assigned the outcome of eventual death, which equates to a disability weight of 0.809 for 10
years followed by death.
Disability weights for cystic echinococcosis were assigned in a similar manner based on the
results of albendazole treatment of 547 patients from past studies (> Table 79-4).
A significant challenge in estimating the burden of echinococcosis is that of missing data.
In wealthy countries there are often good data sets from public health statistics or from
hospital records. Thus relatively accurate estimates of the incidence of disease can be made.
However, most of the burden of echinococcosis is in developing nations with 40% being in
China alone (Budke et al., 2006). In many areas even if treatment is available reporting systems
are inaccurate and hence there is likely to be significant underestimates of the true numbers
affected by the disease. This is illustrated by the estimated 75% underreporting in Chile and
Uzbekistan of cystic echinococcosis (Nazirov et al., 2002; Serra et al., 1999). For communities
where treatment is largely unavailable such as remote herdsmen communities on the Tibetan
plateau most of the data must come from carefully planned surveys which will give an
indication of point prevalences based on, for example, cross sectional ultrasound surveillance
studies. Such data can be used to model the likely number of cases in society and the disease
burden. A further problem is that even utilizing such data, ultrasound will not diagnose
. Table 79-4
Outcomes due to treatment of CE with benzimadazoles. Data used in stochastic analysis of
(Budke et al., 2004)
Number in study Cured Improved Stable Worse Death Reference

58 14 (24%) 29 (50%) 15 (26%) 0 0 Wen et al. (1994)
253 72 (28%) 129 (51%) 46 (18%) 6 (3%) 0 Horton (1989)
59 50 (85%) 5 (8%) 1 (2%) 3 (5%) 0 Chai et al. (2002)
118 97 (82%) 6 (5%) 0 15 (13%) 0 Chai et al. (2002)
59 25 (42%) 25 (4%) 9 (16%) 0 0 Nahmias et al. (1991)
Like > Table 3 this reviews the outcomes of patients with CE treated with benzimadazoles. This data was used to
estimate the probability of patients responding to treatment in a particular way and hence calculate uncertainty
estimates for the DALYs for echinococcosis
pulmonary echinococcosis and therefore this must be accounted for as this could be an
additional 10% or more cases. Estimates of the prevalence of undiagnosed cases need to be
undertaken as there is increasing evidence that ‘‘sub clinical’’ cases, i.e., those individuals who
unknowingly have echinococcosis nevertheless suffer a significantly decreased quality of life
and income reduction (Budke et al., 2004). Therefore such individuals will need to be given a
disability weight to estimate the total DALYs for the society. The uncertainty of missing data
can also be modeled using Monte-Carlo techniques. In the global burden disease study for CE
it was assumed that approximately 10% of annual cases are not officially diagnosed and do not
receive medical attention due to the socio-economic status of the patient or the seemingly sub-
clinical nature of the illness (Budke et al., 2006). Based on past studies, this is a most likely a
very conservative estimate (Budke et al., 2004; Torgerson et al., 2000, 2001). For example in
China, mass ultrasound screening in remote areas has revealed high prevalences of CE (Budke
et al., 2004), A number of these have advanced clinical disease but would not normally have
access to treatment due to poverty and remoteness from medical facilities. It has also been
widely acknowledged that human cases of CE are significantly and systematically under-
reported by the healthcare establishment even though they are recorded in the clinical records
or patient admissions. Therefore, adjustments were made to account for the substantial
underreporting of treated cases known to occur.
6 The Global Burden of Echinococcosis
A preliminary estimate of the global burden of cystic echinococcosis has now been made
(Budke et al., 2006). Data on country-specific annual reported human CE cases were obtained
from the OIE-HANDISTATUS 2 database for the years 1996–2003 and from literature
searches. Type and quality of incidence data varied by country or region. However, the
majority of data consisted of annual numbers of detected cases per susceptible population
or was converted into this form for analysis purposes. If both an OIE-reported and a literature
based value were available, the larger of the two was utilized. However, if the higher value
appeared to be from a survey evaluating a highly endemic region and was, therefore,
not applicable to the entire country, a corresponding adjustment was made. Adjustments
were also made to account for the substantial underreporting of treated cases known to occur.
For financial costs a few studies had been made and modeling demonstrated that there was a
significant linear correlation between the cost of treatment and the GDP per head of economic
output. This was used as the basis for estimating the treatment costs in countries where such
studies had not been made. In total the global burden of disease for CE was estimated at
285,782 DALYs, with financial burden of treatment and morbidity of close to $200 million.
When underreporting is taken into account this rises to as much as 1 million DALYs or more
and costs over $700 million.
Locally the burden of echinococcosis can be substantial. For example, in Shiqu county,
located on the Tibetan plateau of western China, there an extremely high prevalence of both
AE and CE. The burden of disease is approximately 51,000 DALYs in a population of 63,000 or
0.81 DALY per person. This represents an extremely high burden of disease in this population
and is amongst the highest burdens of any disease in this community (Budke et al., 2004). This
burden consisted of approximately 18,000 DALYs for CE and 33,000 for AE with financial costs
of at least $200,000 per annum (Budke et al., 2005).
The global burden of alveolar echinococcosis has not been completed but in addition to
Shiqu county (detailed above) the burden of AE in Switzerland has been estimated to be
approximately 77 DALYs at a cost of at least $3 million per annum (Torgerson et al., 2008).
The huge differences between Switzerland and Shiqu county are of course due to the much
high incidence in Shiqu and the very limited treatment options. In Switzerland, although it is
an emerging disease (Schweiger et al., 2007) with an increasing incidence, the incidence is still
low and modern but expensive treatment methods, not available in Shiqu, have dramatically
improved the life expectancy of AE and hence the YLL is quite small. However, the financial
costs in Switzerland are higher even though the burden of DALYs is much lower. This is due to
the very high treatment costs and high salaries enjoyed by Swiss residents and illustrates the
complexities and problems of reliance on a purely financial approach to burden analysis.
Echinococcosis is an emerging disease in many parts of the world and this is true of both AE
and CE. It is a neglected zoonosis although the global burden of disease may be as much as that
of diseases such as Dengue, Onchocerciasis, African Trypanosomiasis and Schistosomiasis
(Budke et al., 2006). Certainly CE is preventable by instituting the appropriate control
programs such as veterinary control of animal slaughter and regular periodic anthelmintic
treatment of dogs. Mathematical modeling has suggested that it can be highly cost effective to
control in terms of $ per DALY avoided. In addition there is a positive financial return due to
decrease costs of treating cases and increase livestock productivity (Budke et al., 2005).
Therefore control of this disease should be set as a priority. The disease has been eliminated
in a few countries but still remains a challenge elsewhere.
Summary Points
Echinococcosis is a global disease with economic effects in both humans and domestic
animals.
The global burden of disease is high with most of the burden in lower income countries.
CE and AE are emerging diseases in many areas.

Cystic echinococcosis is a preventable disease and is often highly cost effective, both
financial terms and in terms of costs per DALY averted.
Disease burden estimates both in terms of DALYs and financial estimates will indicate the
relative priority of echinococcosis control.
Financial estimates including animal health losses as well as DALY estimates means cost
sharing between agricultural and health sectors can be implemented even though control is
essentially reliant on veterinary services. This can improve apparent cost effectiveness.
Key Facts About Echinococcosis
Echinococcosis is a parasitic disease caused by parasites of the genus Echinococcus.

The disease is caused by the larval stage of the parasite. The adult stage is found in various
carnivore species. This is usually the domestic dog for Echinococcus granulosus (which
causes cystic echinococcosis) and can be dogs or foxes for E. multilocularis (which causes
alveolar echinococcosis). The adult stage is not pathogenic.
The larval stage is a space occupying cyst which is found in the intermediate host. This is
most commonly sheep or other farm animals (with Echinococcus granulosus) or small
rodents (E. multilocularis).
Dogs and foxes are infected by consumption of these cysts in, for example, discarded offal.
Intermediate hosts are infected by consuming eggs which have been excreted by carnivores
in their feces.
When humans ingest eggs, for example through contaminated food or eggs transferred by
fingers from dogs, a hydatid cyst develops. This occurs most commonly in the liver but can
also occur in the lung.
The disease is very pathogenic and without treatment can be fatal.
Treatment usually consists of surgical removal of the cyst although chemotherapy is also
possible.
The disease occurs in communities where there is interaction between dogs and livestock
or where there is substantial infection of the wild fox population.
The parasite has a global distribution but is less common in wealthy countries.
In some areas it is an important emerging disease. In Europe increasing numbers of cases
of human alveolar echinococcosis are being seen and this is associated with an increase in
the fox population. In central Asia there has been a substantial increase in cystic echino-
coccosis following the collapse of the Soviet Union.
References
Aliev MA, Baimahanov BB, Axmetov EA. (2004). In: Ammann RW, Eckert J. (1996). Gastroenterol Clin North
Torgerson PR, Shaikenov B (eds.) Echinococcosis Am. 25: 655–689.
in Central Asia: Problems and Solutions. Dauir, Ammann RW, Ilitsch N, Marincek B, Freiburghaus AU.
Almaty, Kazakhstan, pp. 176–184. (1994). Hepatology. 19: 735–742.
Bresson-Hadni S, Vuitton DA, Bartholomot B, Heyd B, Schaefer JW, Khan MY. (1991). Rev Inf Dis. 13: 243–247.
Godart D, Meyer JP, Hrusovsky S, Becker MC, Schweiger A, Ammann RW, Candinas D, Clavien P-A,
Mantion G, Lenys D, Miguet JP. (2000). Eur J Gas- Eckert J, Goostein B, Halkic N, Meuellhaupt B,
troenterol Hepatol. 12: 327–336. Prinz BM, Reichen J, Tarr PE, Torgerson PR,
Budke CM, Deplazes P, Torgerson PR. (2006). Emerg Inf Deplazes P. (2007). Emerg Inf Dis. 13: 878–882.
Dis. 12: 296–303. Serra I, Garcia V, Pizzaro A, Luzoro A, Cavada G, Lopez J.
Budke CM, Jiamin Q, Qian W, Torgerson PR. (2005). Am (1999). Rev Med Chil. 127: 485–492.
J Trop Med Hyg. 73: 2–10. Sithinamsuwan P, Piratvisuth T, Tanomkiat W,
Budke CM, Jiamin Q, Zinsstag J, Qian W, Torgerson PR. Apakupakul N, Tongyoo S. (2000). World J Gastro-
(2004). Am J Trop Med Hyg. 71: 56–64. enterol. 6: 339–343.
Carabin H, Budke CM, Cowan LD, Willingham AL, Stehr-Green JK, Stehr-Green PA, Schantz PM,
Torgerson PR. (2005). Trends Parasitol. 21: 327–333. Wilson JF, Lanier A. (1988). Am J Trop Med Hyg.
Chai J, Menghebat JW, Sun D, Liang B, Shi J, Fu C, Li X, 38: 380–385.
Mao Y, Wang X, Dolikun G, Wang Y, Gao F, Xiao S. Stouthard MEA, Essink-Bot ML, Bonsel GJ. (2000). Eur J
(2002). Chin Med J. 115: 1809–1813. Pub Health. 10: 24–30.
Chai JJ. (1995). Biomed Env Sci. 8: 122–136. Torgerson PR. (2003). Acta Trop. 85: 113–118.
Craig PS, Larrieu E. (2006). Adv Parasitol. 61: 443–508. Torgerson PR, Budke CM. (2003). Res Vet Sci. 74:
D’Alessandro A. (1997). Acta Trop. 67: 43–65. 191–202.
Eckert J, Deplazes P. (2004). Clin Microbiol Rev. 17: Torgerson PR, Carmona C, Bonifacino R. (2000). Ann
107–135. Trop Med Parasito. 94: 703–713.
Hegglin D, Ward PI, Deplazes P. (2003). Emerg Inf Dis. Torgerson PR, Dowling PM. (2001). Ann Trop Med
9: 1266–1272. Parasitol. 95: 177–185.
Horton RJ. (1989). Trans R Soc Trop Med Hyg. 83: Torgerson PR, Dowling PM, Abo-Shehada MN. (2001).
97–102. Ann Trop Med Parasitol. 95: 595–603.
Kern P. (2003). Lang Arch Surg. 388: 413–420. Torgerson PR, Karaeva RR, Corkeri N, Abdyjaparov TA,
Kimura H, Furuya K, Kawase S, Sato C, Yamano K, Kuttubaev OT, Shaikenov BS. (2003). Acta Trop. 85:
Takahashi K, Uraguchi K, Ito T, Yagi K, Sato N. 51–61.
(1999). Jpn J Infect Dis. 52: 117–120. Torgerson PR, Oguljahan B, Muminov AE, Karaeva RR,
Liang M, Ito A, Liu YH, Wang XG, Yao YQ, Yu DG, Kuttubaev OT, Aminjanov M, Shaikenov B. (2006).
Chen YT. (1997). Trans R Soc Trop Med Hyg. 91: Parasitol Int. 55: S207–S212.
476–478. Torgerson PR, Schweiger A, Deplazes P, Pohar M,
Liu YH, Wang XG, Chen YT. (1991). Chin Med J. 104: Reichen J, Ammann RW, Tarr PE, Halkik N,
930–933. Mullhaupt B. (2008). J Hepatol 49: 72–77.
Lopez AD, Salomon J, Ahmad O, Murray CJL, Mafat D. Torgerson PR, Shaikenov BS, Baitursinov KK,
(2000). Life Tables for 191 Countries: Data, Methods, Abdybekova AM. (2002). Trans R Society Trop
and Results. World Health Organization, Geneva. Med Hyg. 96: 124–128.
Majorowski MM, Carabin H, Kilani M, Bendsalah A. Vuitton DA, Bresson-Hadni S, Bartholomot B,
(2005). Trans R Soc Trop Med Hyg. 99: 268–278. Mantion G, Miguet JP. (1996). In: Uchino J,
McManus DP, Thompson RCA. (2003). Parasitology. Sato N (eds.) Alveolar Echinococcosis. Strategy for
127: S37–S51. Eradication of Alveolar Echinococcosis of the Liver.
Murray CJL. (1994). Bull WHO. 72: 429–445. Fuji Shoin, Sapporo, pp. 243–251.
Nahmias J, Goldsmith R, Schantz P, Siman M, el-On J. Wen H, Zou PF, Yang WG, Jian L, Wang YH, Zhang JH,
(1991). Acta Trop. 50: 1–10. Roger R, New C, Craig PS. (1994). Trans R Society
Nazirov FG, Ilkhamov IL, Ambekov NC. (2002). Med J Trop Med Hyg. 88: 340–343.
Uzbekistan. 2/3: 2–5. WHO. (1996). Bull WHO. 74: 231–242.
Rausch RL, Wilson JF, Schantz PM. (1990). Ann Trop Wilson JF, Rausch RL. (1980). Am J Trop Med Hyg. 29:
Med Parasitol. 84: 239–250. 1340–1355.
80 Measuring Japanese
Encephalitis (JE) Disease
Burden in Asia
W. Liu . D. Ding . J. D. Clemens . N. T. Yen . V. Porpit . Z.‐Y. Xu
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1392
2 Methodological Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394
3 Overall Burden of Disease Due to JE in China, Vietnam,

Thailand and Indonesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395
4 DALYs Lost by Age and Contribution of YLL and YLD to the Lost DALYs . . . . . . . 1396
5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1397
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1398

1392 80 Measuring Japanese Encephalitis (JE) Disease Burden in Asia
Abstract: Japanese > encephalitis is spread in virtually all Asian countries where pig rearing
and rice cultivation are common agricultural practices. Disease burden due to JE was assessed
in Shanghai, China (temperate region), Bali, Indonesia (tropical region), Northern Provinces
of Thailand (subtropical region) and Northern Provinces of Vietnam (subtropical region) by a
model of cumulative JE incidence for hypothetical cohorts in the four sites, each consisting of
100,000 newborn babies from birth through 15 years of age. The cumulative JE incidence rates
were measured by age-specific, JE incidence rates averaged from an epidemic cycle during the
pre-JE immunization eras. The model predicted 271 JE cases, 36 deaths, 81 disabilities, and
3,022 disability adjusted life years (> DALYs) lost associated with JE for the cohort in China; it
predicted 110 JE cases, 11 deaths, 30 disabilities and 1,012 lost DALYs for the cohort of
Vietnam. In Thailand, 192 cases, 33 deaths, 92 disabilities, and 3,161 lost DALYs were
estimated. In Indonesia, 63 JE cases, 6 JE deaths, 23 disabilities would occur and 1,412
DALYs would be lost due to JE. On average, disability contributes about 58–70% to the
DALYs lost in these four countries. Both years lived with disability (YLD) and years of life lost
(YLL) were higher in the 0–9 year age group. The overall disease burden due to JE is high for
all four countries. However, the burden was highest in Shanghai of the temperate region and
lowest on the tropical island of Bali.
List of Abbreviations: CSF, cerebrospinal fluid; DALYs, disability adjusted life years; IgM,
immunoglubin M; JE, Japanese encephalitis; YLD, years lived with disability; YLL, years of
life lost
1 Introduction
Japanese encephalitis (JE), a mosquito-borne viral infection, is the most important cause of
viral encephalitis in Asia. Following the successful control of poliomyelitis, JE has become a
major cause of neurological disability of children in Asia. Over 50,000 cases of JE were
reported with 10,000–15,000 deaths annually (Burke and Leake, 1988; Endy and Nisalak,
2002; Halstead and Jacobson, 2003; Vaughn and Hoke, 1992), a likely underestimate given that
JE is not a notifiable disease in most Asian countries.
JE virus belongs to the family of Flaviviridae which includes West Nile, Murray Valley,
St. Louis encephalitis, dengue fever and other viruses (Solomon et al., 2000, 2004). It is transmitted
by mosquito vectors, most commonly by the species Culex tritaeniorhynchus which lays eggs in
still water pools such as rice paddy fields or drainage ditches. Pigs are found to be the primary
amplifying host of the virus, displaying very high levels of viremia. Hence in the vast rural
regions of Asia where the farmers make a livelihood through rice cultivation and pig rearing,
JE virus finds an optimal habitat for circulation between mosquito vector and mammalian
hosts. Herons, ducks, as well as other wild and domestic birds have also been implicated in
the transmission of JE virus (Burke and Leake, 1988; Solomon et al., 2000).
Most JE infections in humans are asymptomatic (Chakraborty et al., 1981; Grossman et al.,
1973; Halstead and Grosz, 1962). Seroprevalence studies indicate an annual risk of infection in
10% of children and nearly universal exposure by adulthood in JE endemic regions (Halstead
and Jacobson, 2003). The clinical manifestations are complicated and range from simple
febrile seizure to the most severe form of encephalitis. Patients infected by JE virus initially
present with non-specific symptoms which include high fever, malaise, anorexia, nausea
and vomiting (Innis, 1996; Solomon et al., 2000). During the acute phase which usually
Measuring Japanese Encephalitis (JE) Disease Burden in Asia 80 1393
lasts 3–4 days, the patient develops a change in consciousness of different severity: from mild
clouding to stupor and coma. It is during this phase that patients frequently present for health
care. Seizures and stiff neck are frequently observed. Less commonly observed are tremor,
abnormal movements and cranial nerve involvement. Because the clinical presentation of JE
cannot be differentiated from meningoencephalitis of other etiologies, confirmation requires
either isolation of the causal virus or specific serological test to demonstrate the presence of
anti-JE virus Immunoglubin M (IgM) in the cerebrospinal fluid (CSF) or serum. Currently, in
many Asian countries, laboratory diagnosis for JE is not routinely conducted particularly at
rural hospitals, resulting in underestimation of JE disease burden in most endemic countries.
Case fatality rates also vary but on average 10–30% of JE patients die. For those that survive a
JE infection, more than a third will have a JE-related disability including intellectual, behav-
ioral, and neurological sequelae. Late sequelae after a long latent period of recovery have also
been observed (Ding et al., 2007). Thus, a major fraction of the disease burden of JE is due to
permanent disability among JE survivors, and the mere counting of JE cases and deaths is
inadequate to define the burden of JE for a sound decision-making such as introduction of JE
vaccine into public health programs.
Children between the ages of 1 and 15 years are most commonly affected (Vaughn and
Hoke, 1992). Adults can also be infected in areas where the virus is newly introduced (Tsai,
2000). Approximately 3 billion people live in JE endemic areas with 700 million children
<15 years at the highest risk (Tsai, 2000).
Knowing the true disease burden is critical for allocating limited health care resources.
Currently, the true disease burden of JE is unknown in many Asian countries due to the lack of
diagnostic facilities to properly identify JE cases. The disease is spread out through most Asian
countries and a part of Australia (Hanna et al., 1996; Igarashi, 1992). The purpose of this study
was to measure the burden due to JE in a temperate country (Shanghai, China), two
subtropical countries (Northern Provinces of Thailand and Northern Provinces of Vietnam)
and one tropical country (Bali, Indonesia).
In the current study disease burden due to JE is represented by the numbers of JE cases,
deaths and JE associated disability. These numbers are quantified by disability adjusted life
years (DALYs) that was conceptualized by the World Bank (Murray and Lopez, 1996). In
China, Thailand and Vietnam the study data were from routine reports on the acute encepha-
litis syndrome as well as the proportion of the cases confirmed by laboratory assays in a
sample. JE incidence rates were thus corrected by multiplying the number of the reported cases
by the fraction of confirmed JE in the sample.
JE is characterized by cyclic epidemics and JE outbreaks are seen every 5–15 years. During
the inter-epidemic years, JE incidence rates significantly decline. To estimate the disease
burden in an unbiased fashion, average annual JE incidence rates were calculated for the
entire epidemic cycle, which was 15 years for Shanghai, China (Ding et al., 2003) and 10 years
for Vietnam according to the routine reports. No cyclic epidemics so far have been observed in
Thailand for which an average annual rate was calculated arbitrarily for the last 10 years
immediately before the introduction of JE vaccine in 1981.
As JE is not reported in Bali, Indonesia, a hospital-based surveillance was conducted from
2001 through 2003 (Kari et al., 2006). All 10 hospitals with pediatric inpatient services on the
island were included for the surveillance. As health care in Bali is accessible and affordable and
few persons travel out of the island for care, the catchment population of the hospital-based
study is well defined. The presence of JE virus-specific IgM antibody in cerebrospinal fluid
(CSF) in patients with acute encephalitis confirmed the diagnosis of JE (Innis et al., 1989).
The annualized JE incidence rates from 2001 through 2003 were all around 6 per 100,000
among children less than 12 years of age (Kari et al., 2006). The average annualized rate of JE
during 2001–2003 was used for the study because secular change of the rate has remained
unclear.
Traditional indicators of disease burden, such as incidence and mortality collected in a cross-
sectional survey do not provide an unbiased estimate because the risk of the disease varies by
age and by year. We proposed to measure cumulative JE incidence rates in children less than
15 years of age as an approximate life-time risk, by survival analysis. The cumulative JE
incidence rate was an average of the annualized, age-specific JE incidence rates for an epidemic
cycle. The cumulative rate by age was then used to model for JE risk in a hypothetical cohort
consisting of 100,000 newborn babies over 15 years. As a significant proportion of JE disease
burden is caused by premature deaths and life-long neurological and mental disabilities
among survivors, a summary measure of DALYs is used to combine the burden caused by
morbidity, mortality and disability.
The estimate of DALYs is obtained from the addition of two components: years of life lost
(YLL) and years lived with disability (YLD). YLLs for JE were calculated by multiplying age-
specific incidence rates of JE and the case-fatality rate of acute JE illness by remaining life
expectancy at each year of age for the general population. Standard expected YLLs were
derived from the WHO standard life table, modified by country-specific estimates of the
mean age at death (Lopez et al., 2001). We assumed that life expectancy at each year of age was
not shortened by post-JE disability. YLD is estimated from an incidence perspective by
multiplying age-specific incidence by average duration of life with disability and the composite
disability weight. The disability weights for JE were published by Murray and Lopez (1996).
The age-specific incidence rates, case-fatality rates and proportion of JE associated dis-
ability reported from each country-specific study site were used in order to model comparable
country-specific disease burdens.
In Shanghai, China, where JE epidemics occurred once every 15 years before immuniza-
tion program was implemented, we took the average, annualized age-specific incidence rates
for 1952–1967. The period of 1952–1967 covered one epidemic cycle. The age-specific case-
fatality rates and non-fatal sequelae were obtained from published papers (Zhang et al., 2004).
In Vietnam, JE is endemic in the 16 high-risk districts. Before 1997, cyclic JE epidemic
occurred approximately every 10 years in Northern Vietnam (Lowry et al., 1998). The
estimated annual JE incidence rates for 1988–1997 were used to determine the average,
annualized age-specific JE incidence rates prior to JE immunization era. The time period
between 1988 and 1997 included one such epidemic cycle.
In Thailand JE outbreaks were reported in 1970s and 1980s. The national JE incidence
rates had declined since 1985. After 1990, when the JE immunization took place, the incidence
further dropped to lower than 0.5/100,000. No cyclic epidemics were reported in Thailand. JE
incidence data of the eight Northern provinces between 1981 and 1990 was thus arbitrarily
used to determine the average, annual age-specific JE incidence rates before the introduction
of JE vaccine. Using these averaged age-specific rates, we modeled the cumulative JE incidence
rate in Thailand for the pre-immunization era.
In Bali, Indonesia, JE vaccine has not been introduced yet. We used data reported from a
prospective hospital-based surveillance for JE in 2001–2003 (Kari et al., 2006). Unlike other
sites, age-specific annualized incidence rates are only available for children between 0 and
11 years of age. Thus, the model covered the age of 0–11 years for a cohort of 100,000 children
in Bali.
3 Overall Burden of Disease Due to JE in China, Vietnam,

Thailand and Indonesia
The cumulative JE incidence rates for 100,000 newborn babies from birth through 15 years of
age in China, Vietnam, and Thailand, and the rate from birth through 11 years of age in
Indonesia were shown in > Figure 80-1 It is clear that the observed JE risk was highest in
Shanghai, China, which has a temperate climate; it was the lowest in Bali, Indonesia, a tropical
island. The risk in Vietnam and Thailand were intermediate, and both countries belong to
subtropical region.
. Figure 80-1
Cumulative incidence rates of Japanese encephalitis (JE) from birth to 15 years of age (Shanghai,
China, eight Northern Provinces, Vietnam, and eight Northern Provinces, Thailand) and from
birth to 11 years of age (Bali, Indonesia). This figure showed cumulative incidence rates of JE
from birth to 15 years of age in a hypothetical cohort of 100,000 healthy newborns in China
(Shanghai), Vietnam (eight Northern Provinces) and Thailand (eight Northern Provinces); and the
cumulative incidence of JE in a hypothetical cohort of 100,000 new healthy newborns from birth
to 11 years of age in Indonesia (Bali)
. Table 80-1
JE cases, deaths, disability adjusted life year (DALY) in a hypothetical cohort of 100,000
children in China (Shanghai), Northern Provinces of Vietnam, Northern Provinces of Thailand,
and Indonesia (Bali)
Outcomes (events per 105 persons) China Vietnam Thailand Indonesia

No. of JE cases 271 110 192 63
No. of JE deaths 36 11 33 6
No. of JE disability 81 30 92 23
No. of YLLs 1,259 380 1,154 430
No. of YLDs 1,763 632 2,007 981
Total DALYs 3,022 1,012 3,161 1,412
This table showed JE cases, disabilities, deaths, and disability adjusted life year (DALY) in a hypothetical cohort of
100,000 children in the four study sites in China, Vietnam, Thailand, and Indonesia
YLLs: years of life lost; YLDs: years lived with disability; DALYs: disability adjusted life years
a
In China (Shanghai), Northern Provinces of Vietnam, Northern Provinces of Thailand, a hypothetical cohort of
100,000 children was model from birth till 15 years of age; in Indonesia (Bali), the hypothetical cohort of 100,000
children was model from birth to 11 years old
b
The age-specific, annual incidence rates were obtained from routine reports from three sites (China, Vietnam, and
Thailand). In Bali, Indonesia, we obtained all estimates from a published study of a hospital-based surveillance in
2001–2003 (Kari et al., 2006)
c
All data used to calculate cumulative incidence rates, deaths, and DALYs in the four countries represent the
disease burden estimates in pre-immunization era
d
All health outcomes are discounted at 3% per annual
In the cohort of 100,000 babies, the model predicted 271 cases, 36 deaths, 81 disabilities,
and 3,022 DALYs lost associated with JE from birth through 15 years of age (> Table 80-1) in
Shanghai, China; 110 cases, 11 deaths, 30 disabilities and 1,012 lost DALYs were estimated in
Vietnam (> Table 80-1); and 192 cases, 33 deaths, 92 disabilities, and loss of 3,161 DALYs
associated with JE were assessed for the cohort of 100,000 babies within their first 15 years
of life (> Table 80-1) in Thailand. In Bali, Indonesia, 63 JE cases, 6 JE deaths, 23 disabilities,
and 1,412 DALYs would be lost due to JE among 100,000 children during their first 11 years of
life (> Table 80-1). On average, disability contributes about 58–70% of DALYs lost in these
four countries. The overall disease burden is high for all four study sites.
4 DALYs Lost by Age and Contribution of YLL and YLD to the

Lost DALYs
Years of life lost due to JE-associated disability (YLD) contributed more to the total DALY loss
across all age groups in all study sites. In Vietnam and Indonesia, the contribution to DALYs
by YLD was higher in the 0–4 year age groups, and lower in 10–14 year age groups. On
the contrary, in Thailand greater contributions to DALYs were made by YLD in the 5–9 and
10–14 year age groups than in the 0–4 year age groups. In China, the highest DALY loss due to
YLD was found in 5–9 year age group, which was followed by the 0–4 and 10–14 year age
groups. In Vietnam, Thailand and Indonesia, loss of YLD accounted for 60–70% of total lost
DALYs across all age groups, whereas in China, YLD only accounted for about 58% of total
DALYs lost.
5 Conclusions
Disease burden due to JE was the highest in Shanghai, China located in temperate zone, and
it was lowest in tropical Bali where mosquitoes are active around the year, and other
mosquito-borne diseases (dengue fever, malaria and filariasis) are more prevalent (Ding
et al., 2007). The estimate of JE risk in Bali is more accurate because special surveillance
studies were carried out with laboratory support (Kari et al., 2006). It is unlikely that the
number of DALYs lost due to JE in Bali in 2001–2003 was under-estimated because after 2003
the number of hospitalizations due to JE in a major hospital for sentinel surveillance declined
(data not shown). The four study sites may not be representative of the respective four
countries, nor of other countries in the climatic zones in which these Asian countries are
located. Further studies are needed to explain the distribution of the disease in different
geographic regions.
Despite the fact that JE disease burden is high across the continent of Asia and JE
immunization is cost-saving (Ding et al., 2003) to public health perspectives, only a few
countries in Asia have adopted these vaccines in public health programs. Therefore JE
continues to be the most important cause of viral encephalitis among children in most
Asian countries. There are many reasons for this gap; one is the failure of insufficient
knowledge of disease burden to provide the practical information needed by policymakers
for JE vaccine introduction.
Our study has several limitations. In three of the four sites the estimation of the
disease burden relied on routine reports, which were based on statistics of the number of
hospitalizations with acute encephalitis syndrome. Laboratory diagnosis of JE was done
only for a sample of suspected JE cases. Estimation of true JE risk on the basis of laboratory
JE diagnosis for a non-randomly collected sample could be biased. In Bali, Indonesia,
we conducted hospital-based and laboratory-supported surveillance at all hospitals with
pediatric inpatient service, to capture all hospitalizations due to meningo-encephalitic syn-
dromes. As few patients go out of the island for care, the catchment population was
clearly defined; thus the incidence rate of hospitalized JE could be estimated accurately. This
kind of surveillance, however, is difficult, expensive and un-sustainable. Another limitation of
the study is that the estimation of disease burden is always retrospective, and the disease
trend in the future is usually unknown. We assessed JE risk for an epidemic cycle in 15 year
for China and in 10 years for Vietnam. However, it could be changed with a change in
socio-economic and the natural environment. The secular change of the disease needs
continuous investigations in the future. Finally, in most of our calculations, we applied the
JE disability index suggested by Murray and Lopez (0.61) (Murray and Lopez, 1996). The
arbitrary decision to use a single index for a summary estimate of disease burden may
cause bias because the case-fatality rate and fraction of disability varies in different popu-
lations and different health care systems. Moreover, it has been argued that the weights
provided by Murray and Lopez are based on subjective estimates and are not sufficiently
evidenced-based.
Summary Points
As for all infectious diseases, the risk of JE varies by age; lifetime risk should be estimated
for defining the disease burden due to JE.
As for all infectious diseases, the risk of JE varies with secular time, and cyclic epidemics are
observed; cumulative age-specific incidence and mortality rates averaged from entire
epidemic cycle should be measured for modeling the life-time risk. We used the
rates under 15 years of age because almost all JE cases in endemic populations occur in
persons under 15 years.
Clinically JE is not distinguishable from acute encephalitis of other etiologies. Laboratory
assays are necessary for JE diagnosis and thus for estimation of the disease burden.
The estimated disease burden could be biased due to poor access to health care, incomplete
JE reports, unreliable JE diagnoses, short-term surveillance, poorly defined catchment
populations and under-ascertainment of post-JE disability.
The estimated disease burden due to JE was high in all four study sites; it was highest in
Shanghai, in a temperate region, and lowest on the tropical island of Bali.
Years of life with disability (YLDs) contributed 58–70% of the total lost DALYs due to JE in
all four study sites. Post-JE disability is the major component of the disease burden.
Consideration of acute illness alone does not capture the major part of the disease burden.
The disease burden due to JE is high for all four study sites covering temperate, subtropical
and tropical regions of Asia.
JE immunization is cost-effective or cost-saving. Based on the disease burden in the
four study sites, JE immunization should be considered for all JE endemic countries of Asia.
80.1. Japanese encephalitis fact sheet
Japanese encephalitis (JE) is the main cause of viral encephalitis throughout Southeast Asia, the
Indian subcontinent, Nepal, far eastern Russia, China, Pakistan, Indonesia, the Philippines and
Papua New Guinea. It has spread across the Torres Straits into northern Australia and Pacific
islands including Guam and Saipan.
The JE virus is a member of the flavivirus group and antigenically related to West Nile, St. Louis,
Murray Valley and, to a lesser extent, Yellow Fever and Dengue agents.
JE is mosquito born, mostly by Culex tritaeniorhynchus which feeds in the evening and at night.
Pigs and aquatic birds have a high viremia for 4–6 days after being infected and are the most
important reservoir.
Children aged less than 15 years have the highest incidence of JE. Victims with encephalitis face
a mortality rate of 10–25%. Up to half of the survivors experience significant neurological
disabilities.
Acknowledgments
This project was supported by grants from Bill and Melinda Gates Children’s Vaccine Program
(CVP), Program for Appropriate Technology for Health (PATH), Seattle, WA USA (contract
number: 00-GAT.770–790–01149-LPS) and the Korean International Cooperation Agency
(KOICA), South Korea (contract number: 2003–138).
References
Burke DS, Leake CJ. (1988). In: Monath TP (ed.) The Innis BL, Nisalak A, Nimmannitya S, et al. (1989).
Arboviruses: Ecology and Epidemiology. CRC, Boca An enzyme-linked immunosorbent assay to charac-
Raton, pp. 63–92. terize dengue infections where dengue and Japanese
Chakraborty MS, Chakravarti SK, Mukherjee KK, encephalitis co-circulate. Am J Trop Med Hyg 40(4):
Mitra AC. (1981). Inapparent infection by Japanese 418–27.
encephalitis (JE) virus in West Bengal. Indian J Kari K, Liu W, Gautama K, et al. (2006). A hospital-based
Public Health 24(3): 121–7. surveillance for Japanese encephalitis in Bali, Indo-
Ding D, Kilgore PE, Clemens JD, Wei L, Zhi-Yi X. (2003). nesia. BMC Med 4: 8.
Cost-effectiveness of routine immunization to con- Lopez AD, Salomon J, Ahmad O, Murray CJL, Mafat D.
trol Japanese encephalitis in Shanghai, China. Bull (2001). Life tables for 191 countries: data, methods
World Health Organ 81(5): 334–42. and results. Geneva: World Health Organization.
Ding D, Hong Z, Zhao SJ, et al. (2007). Long-term dis- Global Programme on Evidence for Health Policy
ability from acute childhood Japanese encephalitis Discussion Paper No.9. 2001.
in Shanghai, China. Am J Trop Med Hyg 77(3): Lowry PW, Truong DH, Hinh LD, et al. (1998). Japanese
528–33. encephalitis among hospitalized pediatric and adult
Endy TP, Nisalak A. (2002). Japanese encephalitis virus: patients with acute encephalitis syndrome in Hanoi,
ecology and epidemiology. Curr Top Microbiol Vietnam 1995. Am J Trop Med Hyg 58(3): 324–9.
Immunol 267: 11–48. Murray CJL, Lopez AD. (1996). The global burden of
Grossman RA, Edelman R, Willhight M, Pantuwatana S, disease: a comprehensive assessment of mortality
Udomsakdi S. (1973). Study of Japanese encephalitis and disability from diseases, injuries and risk factors
virus in Chiangmai Valley, Thailand. 3. Human ser- in 1990 and projected to 2020. Cambridge (MA):
oepidemiology and inapparent infections. Am J Epi- Harvard School of Public Health on behalf of the
demiol 98(2): 133–49. World Health Organization and the World Bank.
Halstead SB, Grosz CR. (1962). Subclinical Japanese Solomon T, Dung NM, Kneen R, Gainsborough M,
encephalitis. I. Infection of Americans with limited Vaughn DW, Khanh VT. (2000). Japanese encepha-
residence in Korea. Am J Hyg 75: 190–201. litis. J Neurol Neurosurg Psychiatry 68(4): 405–15.
Halstead SB, Jacobson J. (2003). Japanese encephalitis. Solomon T. (2004). Flavivirus encephalitis. N Engl J Med
Adv Virus Res 61: 103–38. 351(4): 370–8.
Hanna JN, Ritchie SA, Phillips DA, et al. (1996). Tsai TF. (2000). New initiatives for the control of
An outbreak of Japanese encephalitis in the Japanese encephalitis by vaccination: minutes
Torres Strait, Australia, 1995. Med J Aust 165(5): of a WHO/CVI meeting, Bangkok, Thailand,
256–60. 13–15 October 1998. Vaccine 18(Suppl 2): 1–25.
Igarashi A. (1992). Epidemiology and control of Vaughn DW, Hoke CH, Jr. (1992). Epidemiol Rev 14:
Japanese encephalitis. World Health Stat Q 197–221.
45(2–3): 299–305. Zhang YZ, Siriayayapon P, Zhang HL, et al. (2004).
Innis BL. (1996). Japanese encephalitis. In: Porterfield JS, Situational analysis of Japanese encephalitis in Dali
ed. Exotic viral infections. London: Chapman and prefecture, Yunnan Province, China from 1992 to
Hall; 147–73. 2001. Endemic Diseases Bulletin (China) (4): 31–5.
81 Pandemic Influenza: Potential
Contribution to Disease
Burden
M. Nuño
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1402
2 The Genetic Basis of Influenza Pandemics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1403
3 The Burden of Disease Attributable to Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1404

3.1 Quantifying the Burden of Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1405
3.2 Mortality and Morbidity Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1405
3.3 Evaluating the Burden in Non-Temperate Regions of the World . . . . . . . . . . . . . . . . . . 1407
3.4 Pediatric Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1408
3.5 Socioeconomic Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411
4 Global/National Models for Evaluating the Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411

4.1 The Basic Reproduction Number . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1412
4.2 Modeling/Quantifying the Burden of Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1412
5 Learned Lessons and New Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1413

5.1 Control Measures to Combat a Pandemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1413
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1415
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1416

1402 81 Pandemic Influenza: Potential Contribution to Disease Burden
Abstract: Records of disease outbreaks resembling influenza date to the writings of Hippo-
crates (fifth century BPE). Since then, influenza has afflicted humans around the globe. The
most severe (‘‘Spanish Flu’’ > pandemic) of three major outbreaks of the twentieth century
killed approximately 20–50 million people worldwide. More recently, the global spread of
highly pathogenic bird-adapted strain H5N1 is considered a significant pandemic threat. Since
2003, a total of 379 cases and 239 deaths have been reported. This chapter provides an
overview of the genetic characteristics of the virus that elucidate its ability to continuously
evade a host’s immune system; it describes some of the approaches used to quantify the
burden of influenza and discusses their implications for the prevention and containment of
future pandemics. The preliminary findings of the studies discussed here suggest that influen-
za-related burden is highly underestimated in tropical and subtropical regions of the world.
This implicates that proper assessment of influenza-related morbidity and mortality world-
wide is essential in planning and allocating resources to protect against what could be one of
mankind’s most devastating challenges. A summary of learned lessons from past influenza
pandemics are described and new intervention strategies aim at curtailing a future pandemic
are discussed. More importantly, however, is the discussion of today’s challenges such as
antiviral resistance, limited resources in a world that is globally connected and the imminent
gap between the capacity (resources available) of developed and developing parts of the world
to respond to a pandemic.
List of Abbreviations: CDC, Center for Disease Control and Prevention; FF, DM, Currency
Code for France and Germany; Flu, Influenza; HA, Hemmaglutinin; H1N1, > H2N2, H3N2,
H5N1, Influenza A Virus Subtypes; ILI, Influenza-Like-Illness; NA, Neuraminidase; NB,
Influenza B Virus Glycoprotein; NPI’s, Non-Pharmaceutical Interventions; PB1-F2, Proapop-
totic Influenza A Virus Protein; PI’s, Pharmaceutical Interventions; P&I, Pneumonia &
Influenza; R0, Basic Reproduction Number; S-I-R Model, Susceptible-Infected-Recovered
Model
1 Introduction
Influenza (flu) is among the most ancient of pathogens of man and the most thoroughly
studied of viruses, yet their rapid evolution makes control of > epidemics and the prevention
or even mitigation of pandemics a persistent public health challenge. The replication of the flu
virus is noisy, i.e., offspring produced are remarkably variable. Flu viruses mutate continu-
ously in so-called > ‘‘antigenic drift,’’ a strategy that allows the virus to evade the least
experienced and adaptable immune systems in the human host population, the young and
the very old.
This chapter is organized as follows:
Section 1 provides a brief overview of the genetic basis for pandemics.
Section 2
Provides a historical overview of the worldwide impact of flu epidemics and pan-
demics,
Describes approaches used in assessing flu related disease burden,
Highlights studies that have quantified morbidity, mortality and socioeconomic costs
in countries around the world, and
Pandemic Influenza: Potential Contribution to Disease Burden 81 1403
Especially considers the burden in children, the most infected and infectious popula-
tion group.
Section 3 presents global and national modeling frameworks for evaluating the burden.
Section 4 discusses the learned lessons from previous flu epidemics and pandemics,
highlights new challenges facing humans today, and discusses preparation strategies for
curtailing future pandemics.
Section 5 concludes with thoughts on the future burden of flu.
2 The Genetic Basis of Influenza Pandemics
Epidemics caused by influenza viruses occur every winter in temperate regions of the globe.
The size of these epidemics varies from year to year and from place to place. Very large
epidemics associated with the widespread circulation of genetically novel influenza viruses, so-
called pandemics, are caused only by influenza viruses of a single type (type A). Influenza (flu)
virus, a member of the family Orthomyxoviridae is a segmented single-stranded RNA virus
which exists in three types, A, B and C. Only types A and B cause disease of any consequence in
humans. The genomes of both A and B viruses are comprised of eight gene segments which
code for eleven viral proteins. Ten of these are functionally similar. The NB protein is unique to
B viruses and the recently discovered PB1-F2 protein is found only in A viruses (Chen et al.,
2001; McCullers et al., 2004; Steinhauer and Skehel, 2002).
Two of these proteins, hemaglutinnin (HA) coded for by the gene segment conventionally
labeled #4, and neuraminidase (NA), coded for by the segment labeled #6, appear on the
surface of the influenza virion, and are responsible for the greater portion of the immune
response in humans. All B-type influenza viruses share variants of the same HA and NA
proteins. The > clinical attack rates for A and B type viruses are similar in children (McCullers
et al., 2004); but the overall clinical attack rate is much lower in epidemics of B-type than
A-type viruses. In addition, it has been recently demonstrated that mortality associated with
influenza B epidemics has declined about linearly over the most recent 40 years (Reichert et al.,
2007). This difference in epidemiology suggests that the circulation of influenza B viruses in
human populations is determined by population-based immunity. Reassortment(> genetic
reassortment) among human influenza B viruses is believed to be the genetic basis for sporadic
increases in observed attack rates for B-viruses (McCullers et al., 2004). A-type viruses,
however, exhibit another dimension of genetic complexity. A-type viruses circulate not only
in humans but in many non-human reservoirs, most notably aquatic birds. The sudden
appearance in A-type viruses responsible for human influenza infections of one or more
gene segments from influenza viruses that previously circulated only in non-human reservoirs
produces chimeric influenza viruses that are sufficiently immunologically novel that very
widespread illness and injury occurs among humans. It is also possible that a virus that
previously circulated only in a non-human reservoir could mutate sufficiently that it becomes
de novo capable both of producing disease in humans and being widely transmissible among
humans. Such a virus is maximally different from previous human immunological experience
(all gene segments are novel) and potentially could produce the most severe pandemics. Those
newly emergent viruses whose genomes are comprised of a substitution of only some of the
gene segments of viruses that previously circulated in humans are thought to have arisen via
reassortment during dual infections involving both a non-human and human influenza virus.
The appearance of an influenza virus with a substituted gene segment is called > ‘‘antigenic
shift’’ (Hall et al., 1973; Monto and Kioumehr, 1975; Reichert et al., 2007).
Sixteen immunologically distinguishable forms of HA (H1-H16) have been identified and
nine of NA (N1-N9). Because these two proteins are found on the surface of the virion, influenza
has long been typed by reference to these two antigens. Only three HA subtypes and two versions
of NA have been found in viruses that have circulated widely in humans. Pandemics of the
twentieth century and their dates of emergence in the northern/southern hemispheres were
caused by viruses of type H1N1 (1918/1918), H2N2 (1957/1958), and H3N2 (1968/1969). The
1918–1919 pandemic virus emerged en bloc as an avian virus the mutation and adaptation of
which permitted replication in and transmission among humans (Taubenberger et al., 2005;
Tumpey et al., 2005; Webster et al., 1992). The 1957 pandemic H2N2 virus emerged with
substitutions of the HA, NA and PB1 gene segments into the evolved H1N1 viruses from an
avian virus. The 1968 pandemic (H3N2) resulted from reassortments of the same avian
sequences into multiple lineages of the evolved H2N2 viruses resulting in substitutions of HA
and PB1 genes (Lindstrom et al., 2004). In each of the twentieth century pandemics, therefore,
both the HA and the PB1 genes were substituted. The nomenclature for distinguishing immu-
nologically and epidemiologically important influenza A-type viruses is, therefore, incomplete.
H1N1 viruses re-emerged in 1977 in what is widely believed to have been an accidental
release from a research laboratory, probably in China. Currently the subtypes H1N1 and
H3N2 are circulating widely in humans. A small number of isolates of H1N2 viruses have also
been reported. Therefore, the only A-type influenza viruses not circulating at present are those
with hemagglutinin of type 2, H2. In this context, we are all spectators to the brush with
emergence of influenza A viruses of type H5N1 including a unique-to-human-experience PB1
gene, which is widely extant in the avian reservoir, causing massive disease in domestic poultry
with a sporadic history of infecting small numbers of heavily exposed humans. With a > case
fatality rate of approximately 50%, these viruses pose the potential for a redux of the Great
Pandemic of 1918 in which 1.5–3% of humanity perished.
Records of disease outbreaks resembling influenza date from the writings of Hippocrates
(fifth century BPE). It is likely, however, that humans have suffered from influenza shortly, in
evolutionary time, after the domestication of animals in which we now recognize the circula-
tion of pathogenic influenza viruses, and in epidemic proportions since the rise of town-size
urbanizations. The pandemic of 1580 is thought to be the first ‘‘confidently identified as
(associated with) influenza’’ (Pyle, 1986); but ‘‘Clear’’ descriptions are attributed to authors in
the tenth century (Langmuir and Farr, 1976). The first epidemiological level description of an
influenza pandemic is due to William Farr who is credited with conceptualizing the burden of
influenza as the mortality in excess that expected in the pandemic of that year in London.
Detailed records begin with the pandemic of 1889–1892, with age-specific mortality, but
serologic data became available only in the 1930s.
3 The Burden of Disease Attributable to Influenza
In 1847 William Farr described the burden of flu and developed methods to quantify its
contribution to mortality (Farr, 1847; Langmuir and Farr, 1976). Since then, numerous studies
have been proposed to quantify the burden of flu in humans.
Flu outbreaks in temperate climates occur from November through April in Northern and
from May through September in Southern hemispheres. While seasonal periods characterize
flu outbreaks in Northern and Southern hemispheres, outbreaks in tropical climates are highly
irregular and therefore more difficult to predict. Flu pandemics are worldwide epidemics
that involve high morbidity and mortality resulting from major mutations in viral genome
(antigenic shift). Unlike flu epidemics, pandemics do not necessarily occur in seasonal
time. Some criteria for defining a major pandemic include the occurrence of a new emerging
virus subtype for which humans have no immunity to and effective person-to-person contact.
Three major pandemics have been observed in the last century. The first and foremost
severe, the ‘‘Spanish Flu’’ (H1N1), occurred during 1918–1919. It is estimated that 20–50
million individuals succumbed to the disease worldwide (approximately 2% of a world’s
population), more than 25% of the US population became ill and 2.5% of those infected
in the US died. The next major outbreaks, the ‘‘Asian Flu’’ (H2N2) and ‘‘Hong Kong Flu’’
(H3N2) emerged in 1957 and 1968, respectively. While the impact of these latter pandemics
was considerably mild when compared to 1918–1919 pandemic, 2 and 1 million world-
wide deaths were estimated to have come from the 1957 and 1968 pandemics, respectively
(Simonsen et al., 1998).
3.1 Quantifying the Burden of Influenza
The concept of > excess mortality was first introduced by William Farr (Farr, 1847; Langmuir
and Farr, 1976) to describe influenza epidemics in London. This approach of excess mortality
was later applied by Serfling in 1963 and various modifications of this approach are now
widely used (Serfling, 1963). Based on the excess criteria, an epidemic occurs when the
number of disease cases (mortality) exceeds the number expected. However, defining the
term epidemic may differ mildly. For instance, the US denotes an epidemic threshold for
mortality based on estimated of the expected number of deaths given in a particular week
accompanied by 95% confidence intervals around the projected estimate. With this approach,
an epidemic is reported when the upper 95% confidence interval is exceeded.
3.2 Mortality and Morbidity Burden
Prior to 1937, more than 90% of excess deaths were properly attributable to pneumonia.
However, over the following decade total excess mortality has dropped to 1/3 that level and the
fraction of the remainder attributable P&I dropped by 30%. Currently, this fraction has
dropped to below 10% making the evaluation of flu-related burden a more challenging task.
The burden associated with flu has been typically evaluated by a criterion that uses deaths
recorded by physicians as caused by pneumonia and influenza (P&I) along with other
measures such as influenza-like-illness (ILI). Excess mortality due to flu is calculated by
estimating a baseline of deaths that would be expected in the absence of flu virus activity, and
the number of deaths actually observed. This criterion, however, is not very sensitive as it fails to
evaluate flu-related deaths that could have occurred outside the specified flu season or that could
have been missed since several other diseases exhibit flu-like symptoms. Although P&I data has
been widely used to evaluate excess mortality, it seems to account for about 25% of all flu related
deaths; this suggests that estimates based on P&I may not be appropriate to measure the total
impact of influenza on mortality (Simonsen et al., 1997). Further efforts aimed to improve
excess mortality estimates due to flu have used > all-cause mortality data instead.
The Serfling methodology (and various modifications of it) has been used to parameterize
a baseline model based on statistical expectations (95% confidence interval of the baseline) by
training data from non-epidemic years. A surveillance system based on the Serfling approach
signals an epidemic whenever the observed time series data (e.g., P&I, all-cause mortality data)
exceeds the established threshold. The model assumes an average mortality described by b0, a
linear trend denoted by b1*t, 52-week cyclical period (or 52.1667 for adjusted leap years)
denoted by b2cos(2pt/52) + b3sin(2pt/52). This model can be denoted by the following
equation:
YðtÞ ¼ b0 þ b1 t þ b2 cosð2pt=52Þ þ b3 sinð2pt=52Þ þ error
where Y(t) denotes the estimated mortality for week t. Variations of this model that account
for potential deviations from a linear trend approach include a quadratic term b1*t2. We
illustrate the proportion of deaths in the United States attributed to pneumonia and influenza
(P&I) reported by the 122 cities mortality reporting system.
> Figure 81‐1 illustrates that the seasonal peaks observed for outbreaks in 1985–1989 seem
to have exceed the epidemic threshold.

The sinusoidal function across denotes the seasonal baseline that is established based on
periods outside the flu season. US estimates proposed by the Center of Disease Control (CDC)
show that each year 5–20% individuals get infected with the virus, some 200,000 individuals
get hospitalized and 36,000 die from the disease. Simonsen et al., modified this model to assess
the burden of flu on mortality based on P&I and all-cause mortality weekly data for 20 years
. Figure 81‐1
Pneumonia and influenza mortality for 122 US cities during 1985–1989
(United States: 1972–1992). This study showed that excess mortality estimates were comparable
to previous estimates that were based on monthly data (Simonsen et al., 1997). More
significantly however, this study showed that P&I excess mortality data only captured 25% of
the all-cause excess mortality estimates.
In a separate study, Simonsen et al. (Simonsen et al., 2000) estimated an average seasonal
rate of excess P&I hospitalization of 49 cases in 100,000. This study further showed that the
average risk of flu-related P&I hospitalization was twice as high during A (H3N2) seasons than
those observed during seasons dominated by subtypes H1N1 and B. Individuals of age less than
65 had a 57% of all-flu-related hospitalizations, however the average seasonal risk of flu-related
P&I hospitalization was significantly higher for this risk group. Further modifications of the
Serfling model have been implemented. Thomson et al. proposed a Poisson regression model to
predict excess cases of P&I during influenza epidemics (1979–2001). This study reported
significant influenza-related hospitalizations among elderly (50–64 years) and children younger
than 5 years old (Thompson et al., 2003). Their findings showed that a yearly average of 133,900
cases listed as P&I hospitalizations were actually associated with the flu virus. A more recent
study implemented a Poisson extension of the seasonal type model to predict excess cases of P&I
during 16 seasons of flu epidemics in France (Denoeud et al., 2007). This study showed that
morbidity data (flu-like-illness and virological data) may be used to predict excess P&I. The
implications of this study provide a real possibility of flu-related burden for countries in which
specific pneumonia and flu mortality surveillance data is simply not available.
3.3 Evaluating the Burden in Non-Temperate Regions of the World
Most studies have focused on assessing the mortality of flu in regions of the world that exhibit
temperate climates, however more recent efforts have demonstrated that burden of flu in the
tropics/subtropics is significant. Singapore’s yearly clinical infection from seasonal include are
estimated at 20% (Ng et al., 2002). In a recent study, Lee et al. (Lee et al., 2007) implemented a
linear regression model to evaluate the excess mortality due to flu pandemics of the last
century. The authors estimated an excess > mortality rate of 7.76 per 1,000 people during
May–June and October–November of 1918. Using a similar approach (Murray et al., 2006)
these estimates reached a rate of 18 per 1,000 people. Estimates of monthly excess mortality for
the 1957 pandemic yield 0.47 per 1,000 people (mid May). Although excess mortality during
the1968 pandemic seems mild when compared the 1918 and 1957 outbreaks, this pandemic
exhibited two waves. The first wave occurred in mid August with estimated monthly excess
mortality of 0.27 per 1,000 people (543 deaths in a population of 2,012,000). Excess deaths
peaked again in May–June of 1970 and with an estimated excess mortally in the order of 0.15
per 1,000 people (309 deaths in a population of 2,074,500). Most significantly, this study
showed that excess mortality estimates in Singapore are comparable, if not, higher than those
observed in temperate regions. Their 1918 pandemic estimate of 1.80% (18 deaths in 1,000
people) exceeds global estimates of 1.06% and Taiwan’s rate of 1.44% (Murray et al., 2006).
Based on the findings in Lee et al. and studies referenced therein, > Table 81‐1 summarizes the
burden of flu in the 1918–1919 pandemic and it illustrates that tropical (sub-tropical)
countries were affected more significantly than regions with temperate climates. These find-
ings show that Kenya was the most affected country with an upper bound mortality rate
estimate of 57.8%. Furthermore, four of the five highest affected countries corresponded to
countries with tropical-subtropical climates.
. Table 81‐1
Estimated deaths and mortality rates attributed to influenza during the pandemic of 1918–1919.
Countries are listed in order (highest to lowest) according to the estimated mortality rate
No. deaths (in Mortality rate (per Mortality rate ranking

Country Climate 1,000) 1,000) % (high to low)
Kenya Tropical 104–150 40–57.8 1
South Africa Subtropical 300 44.3 2
India Tropical 185 6.1–43.9 3
The Philippines Tropical 81.0–288 8.0–28.4 4
Portugal Temperate 59.0–159 9.8–26.4 5
Singapore Tropical 2.87–6.66 7.8–18.0 6
Ceylon Tropical 51.0–91.6 10.0–17.9 7
(Sri Lanka)
Spain Temperate 257–311 12.3–14.9 8
Taiwan Subtropical 25.4–52.8 6.9–14.4 9
Japan Tropical/ 368–517 6.7–9.4 10
Temperate
United States Temperate 402–675 3.9–6.5 11
Canada Temperate 50.0–51.0 6.1–6.3 12
England Temperate 116–200 3.4–5.8 13
Argentina Temperate 10.2–46.0 1.2–5.4 14
British Honduras Subtropical 1.01–2.00 2.3–4.6 15
(Belize)
Denmark Temperate 6.02–12.4 2.0–4.1 16
Australia Temperate 14.5–15.4 2.7–2.9 17
Trinidad and Tropical 0.30–1.00 0.1–0.2 18
Tobago
This table was adapted from the results presented in Lee et al. (Lee et al., 2007)
3.4 Pediatric Burden
School-age children play a significant role in spreading the flu in a population. Children touch
their noses, eyes, mouths, interact closely with other children and have contacts with members
of their family. They intensify the spread of the disease since they shed the virus for longer
periods of time and at higher virus titers than adults. In addition to their risk to others, the
inexperience immune system of children enhances their risk of developing complications from
an infection. Annual recommendations from the Center of Disease Control include the
vaccination of children aged 6 months–5 years; however more recent discussions recommend
vaccination of all-young age children.
Several studies have been reported on the burden of flu on morbidity and mortality in
children (Neutzil et al., 2002; Reichert et al., 2001; Simonsen et al., 1998). A prospective
surveillance study (1974–1999) of 1665 healthy children younger than 5 years showed annual
infection ranging between 15 and 42% (Neutzil et al., 2002). It was further shown that children
younger than 2-year of age were more likely than older children to have serious complications
such as pneumonia, croup, chonchiolitis and sepsis (Neutzil et al., 2002). A study assessing
age-associated burden of flu in epidemic and pandemic periods showed that half of flu-related
deaths during the 1968–1969, with larger proportions of those 1957–1958 and 1918–1919 were
attributed to people younger than 65 years of age. This study further showed that the high
number of cases observed in these pandemics decrease significantly in prospective outbreaks.
More particularly, they found that after each pandemic, the absolute risk of flu-related
mortality among people younger than 65 decreased from 7- to 28-fold over the following
decade during severe epidemics. In contrast, the corresponding risk reductions among those
people older than 65 years of age range from 2- to 3-fold or less (Simonsen et al., 1998).
A multiple source data study of the UK during 1995–1999 showed that on average 10% of
children contract clinical influenza while a further 20% may be asymptomatic for children
younger than 5 years old (Watkins, 2004). While vaccination is the optimal choice for
protecting young age children, and thereby, reducing the burden of flu in this group, it has
also been shown that the risk to other members of the population can be reduced through
children vaccination. Ahmed et al. showed that vaccinating young age children improved
community level protection (Ahmed et al., 2001).
So far, our discussion of the burden of flu in children has been limited to countries in
which flu outbreaks arise during the winter. However, recent studies of flu-related mortality in
tropical and subtropical regions show that burden to children in these parts of the world could
exceed the US estimates. Unlike developed countries, children in developing countries face
additional challenges such as malnutrition, higher risks associated with bacterial infections,
limited access to pharmaceuticals, limited health care, and poor living conditions (Simonsen,
2001). Studies of Cuba and Singapore reported 3–15% flu-related viral isolates in hospitalized
children (Cancio et al., 2000; Chew et al., 1998).
Intervention plans aimed at protecting high-risk, as well as, all other members of a
population against seasonal influenza have varied from country to country. Japan is the
only country that has ever adapted a vaccination program based on children rather than
adults. In a consequence to their most destructive pandemic experience in 1957 (approximately
8,000 deaths), Japan legislated a vaccination program that focused on school-age children
(7–15 years). Under this program, vaccination levels reached 80%. > Figure 81 ‐2 illustrates
decreasing mortality trends from all-cause and pneumonia related mortalities. However, this
figure also shows that as soon as vaccination measures were relaxed in 1987, flu-related
mortality increased. The rising levels of excess mortality became even more evident after
government discontinued the vaccination program in 1997. It has been estimated that the
vaccination of children in Japan prevented about 37,000–49,000 deaths per year (Reichert
et al., 2001). Other studies have shown that high (50–70%) levels of vaccination among
children can provide effective protection to other members in a community (Elveback et al.,
1976; Longini et al., 1978; Longini et al., 1988).
Chiu et al. showed that excess hospitalization in Hong Kong rates were higher that US
estimates (Chiu et al., 2002). It is evident that influenza contributes significantly to hospitali-
zation among children in both temperate and tropical regions. More particularly, these
findings illustrate that the rates reported for Hong Kong exceed those of the US and that
trends of decreasing hospitalization rates with increasing age are evident in both estimates.
> Table 81 ‐2 reports estimates of flu associated hospitalizations per 10,000 for children in
various age groups.

. Figure 81‐2
Five-year moving average of excess deaths attributed to both pneumonia and influenza (P&I)
and all-cause mortality, for Japan and the United States
. Table 81‐2
Estimated flu associated hospitalization rates per 10,000 for the US and Hong Kong
United States 1979–1993

age <1 year 190/10,000
1< age <2 80/10,000
3< age <4 32/10,000
5< age <14 9.2/10,000
Hong Kong 1998 :: 1999
age <1 year 278.5/10,000 :: 288.5/10,000
1 age <5 218.4/10,000 :: 209.3/10,000
2 age <5 125.6/10,000 :: 77.3/10,000
5 age <10 57.3/10,000 :: 20.9/10,000
10 age <15 16.4/10,000 :: 8.1/10,000
This table was adapted form Rennels et al and the findings reported in Rennels et al and Chiu et al (Rennels et al.,
2002; Chiu et al., 2002)
3.5 Socioeconomic Burden
Factors contributing to the socioeconomic burden of flu may be measured directly if they
correspond to cost of hospitalization and pharmaceuticals (e.g., vaccine, antivirals). However,
evaluating indirect costs such as loss of days of school and work, loss of productivity is
significantly more challenging. During an influenza season it is likely that a large number of
its members may be exposed to infection, particularly during the epidemic season. However,
the highest risk of hospitalization occurs among infants (younger than 1 year) and the elderly
(older than 65 years). Estimates of 90% of cases attributed to flu occur among the elderly.
Although flu is not typically reported as the cause for hospitalization, it is most certainly a
disease that sets the stage for the complication of other diseases such as pneumonia and
chronic illness. Complications of already existing chronic long standing illness due to the flu
are likely to result in increased hospitalization periods and more costly treatment, thereby
increasing the cost for each person at risk.
In the US, flu contributes approximately 1–3 billion (US) in direct medical cost each year
(US Congress, 1981). Estimates of 10–15 billion (US) for indirect costs related to mortality
include lost earnings due to illness and lost of future earnings (US Congress, 1981). A French
study (1989) estimated the direct and indirect contribution of influenza burden at FF1.9
billion (US: 300 million) and FF14.3 billion (US: 2.3 billion), respectively (Levy, 1996).
A study in Germany estimated losses from absenteeism and medical treatment attributed to
flu to almost DM2 billion (US: 1.1 billion) (Szucs, 1999). Another Dutch study further showed
that flu-related burden could be as high as DM2.6 billion (Kressin and Hallauer, 1999).
4 Global/National Models for Evaluating the Burden
Further approaches used to study the burden of flu and evaluate the role of intervention
measures to control the spread of disease involve epidemic mathematical models of disease
transmission. These models assume a deterministic, stochastic or individual-level framework
(among others) to capture the dynamics of disease transmission among individuals in a
population of study. A deterministic compartmental epidemic model makes several assump-
tions. First, a model’s behavior is determined (i.e., deterministic) precisely by initial condi-
tions and parameter values (i.e., no elements of chance are involved). For instance, an initial
population size of 500 susceptible and one infectious individual, fixed rates of disease
transmission, recovery, and mortality. Second, compartmental implies that the state of the
system is given by the number of people in each of the predetermined number of compart-
ments (epidemiological states), for instance susceptible (S), infected (I), and recovered (R).
A model is dynamic since the number of individuals in each epidemiological state (S, I, R)
changes over time. The progression to disease is captured by the rate at which susceptible
become infected and it depends on the number of currently infected hosts in a population.
Although deterministic models do not capture random events, they can be extended to
incorporate stochasticity. In this setting, events occur randomly, rather than deterministically.
Stochastic models are particularly appealing when assessing the spread of disease in small
populations where random events are likely to play an important role in the emergence
dynamics of disease. Deterministic and stochastic models that characterize individuals in a
population into subpopulations according to their current epidemiological state, for instance,
susceptible (S) and infected (I) are inappropriate to evaluate individual-level dynamics. For
instance, rather than considering the subpopulation of all susceptible, one may be interested in
accounting more specifically for age, gender or differences in risk (e.g. high-risk vs. low-risk)
among individuals in a population. The level of detail that is observed in a heterogeneous
population has been assessed using individual-level simulation models.
4.1 The Basic Reproduction Number
A key measure of the transmissibility of an infectious pathogen (i.e., flu virus) in these models
is denoted by the threshold quantity, the basic reproduction number (R0). This quantity
measures the average number of secondary cases of infection generated by one primary case in
a fully susceptible population. R0 is composed of three contributions: the susceptible popula-
tion available to have contact with a primary case (S0), the length of time (D) the primary case
is infectious to others (window of opportunity for infection), and the transmission coefficient
b (rate of effective mixing). Together this yields the following formula: R0 = b D S0. A value of
R0 equal to one or below defines a transmission threshold under which the generation of new
cases is insufficient to support spread of disease within a community. However, R0 greater than
one indicates that the infection will be able to spread in a population. A larger value of R0
suggests the possibility of a more severe pandemic outbreak. For instance, estimates of R0
between 2 and 3 were proposed for the 1918–1919 Spanish Flu pandemic (Mills et al., 2004).
4.2 Modeling/Quantifying the Burden of Influenza
Studies of the burden of past and potential future flu pandemics have been made accessible
by mathematical models that vary in complexity and address a wide range of research
challenges. A recent study reported the findings from three groups (UW/LANL, Imperial/
Pitt and VBI group) that implemented individual-based stochastic simulation models to
evaluate the effectiveness of a set of pharmaceutical and non-pharmaceutical interventions
(NPIs) in reducing the burden of a potential pandemic influenza (Halloran et al., 2008).
Comparisons were based on the simulation of a pandemic outbreak in a population similar to
that of Chicago (approximately 3.6 million people). These simulations considered the follow-
ing interventions: antiviral treatment and household > isolation of identified cases, prophy-
laxis and > quarantine of household contacts, closure of school, social distancing measures
implemented in the workplace and the overall community. This study was aimed at evaluating
the effectiveness of these measures as projected by each of the individual-based stochastic
simulation models and to assess the robustness of these results to the model assumptions. The
results from these three simulation models produced similar effectiveness of the interventions
evaluated. More particularly, this study showed that the timely intervention of these measures
reduces the final number of flu illness, for pandemics of moderate severity; all models show
that NPIs are highly effective. Moreover, school closure is predicted to be highly important in
all three model simulations. This study showed that under the levels of compliance (30–90%)
and ascertainment (60–80%) assumed in these simulations, that it is quite possible to mitigate
a pandemic, at least until a vaccine becomes available. The implications of these studies
suggest possible routes that may be used to ameliorate the burden of a potential pandemic.
However, the uncertainty involved ascertainment and compliance of cases is likely to play a
significant role in the effectiveness of the proposed social distancing and targeted measures.
5 Learned Lessons and New Challenges
Influenza has a long history of affecting human populations. It has been nearly 90 years since
the most severe flu pandemic (1918–1919) killed fifty million in a population size of two
billion. Since then, we have learned about the virus evolutionary mechanisms, treatment and
control interventions, and advances of vaccine research. Research of inter-pandemic and
pandemic outbreaks of the twentieth century have shown that the virus undergoes antigenic
shift mutations, the risk of infection and death seem to be age specific and related to a person’s
ability to mount an effective immune response. Although we have learned a great deal about
the virus, our knowledge is still limited and the threat of a pandemic is still eminent.
5.1 Control Measures to Combat a Pandemic
Many studies have been proposed to evaluate the role of single, as well as combined interven-
tion strategies that may be used to curtail the burden of a future pandemic. Although vaccine
is the optimal approach at curtailing a flu pandemic, antivirals (therapeutic and prophylaxis)
are likely to play an important role in reducing the burden. The use of multiple pharmaceuti-
cal interventions to reduce the burden of disease associated with a pandemic was evaluated in
several studies (Ferguson et al., 2005; Germann et al., 2006, Longini et al., 2004, Longini et al.,
2005). Choosing a plan that includes massive stockpiling of antivirals, targeted antiviral
prophylaxis, massive pre-vaccination of high-risk individuals or a combination of any of
these involves various levels of uncertainty and complexity. The foremost important factor in
determining the approach to be implemented is to determine the level of resources available at
the time that a pandemic virus emerges. Next, one must consider the potential complications
that involve the use of antivirals. For example, should they be implemented as treatment or
prophylaxis? Which of these two approaches is more economically efficient and likely to
provide higher levels of community protection? Are there any implications of viral resistance
with the use of antiviral treatment versus prophylaxis?
In efforts to prepare for a future pandemic, countries (worldwide) have drafted prepared-
ness plans. These efforts include pharmaceutical interventions such as antiviral treatment and
vaccine and non-pharmaceutical interventions such as isolation, quarantine, closing of public
gatherings. To this end, several studies have been proposed to evaluate the role of these various
interventions in minimizing the risk of a potential pandemic. A recent study assessed the
current preparedness plans in the US, UK and the Netherlands and simulated single as well as
combined intervention strategies during a pandemic (Nuño et al., 2007). The interventions
proposed in this study included vaccine, antiviral treatment and prophylaxis, and basic
hospital and community level transmission control measures. This study showed that while
vaccine was optimal in reducing the burden during a pandemic, antiviral and basic control
measures can be highly effective. The main findings in this study showed that the ‘‘optimal’’
plan for a particular country is contingent upon the resources available. That is, in countries
with limited pharmaceutical interventions, the use of antivirals as treatment was preferred
over prophylaxis. Moreover, in countries with little or no access to a vaccine or antivirals, the
benefits of non-pharmaceutical interventions (NPIs) such as basic transmission control
measures can be highly effective in reducing the burden due to influenza. This study proposed
that the implementation of social behavioral measures that could effectively reduce a person’s
risk of infection were significant in reducing the burden of disease.
Since the emergence of the highly pathogenic strain of avian flu H5N1 in Southeast Asia in
2003, a total of 379 cases and 239 deaths have been reported. Since its detection, the virus has
mutated from a low pathogenic to a highly pathogenic strain with limited transmission to
humans from infected poultry. Two of the three conditions necessary for a pandemic have
been met, primarily, a new strain (H5N1) has emerged for which humans have very little
immunity, strain can jump between species. The pending obstacle for a flu pandemic is its
inability to be transmitted from human to human.
This chapter presented an overview of the genetic characteristics of the flu, discussed
the properties of the virus that make it continuously challenging to humans, described some
of approaches that have been used to quantify the burden, and concluded with a discussion on
the current challenges that we face in preparing against a pandemic. As discussed, there are
several challenges involved in evaluating the accurate burden of flu; the non-specific nature
of the illness typically lends itself for an incomplete confirmation of cases that is likely to be
attributed to the flu virus. For instance, it is possible that a person may experience an infec-
tion without the presence of symptoms and therefore escape surveillance systems. It is also
possible that those infected individuals develop symptoms but choose to be cared for at home
and therefore do not report to a clinic or hospital. Aside from the challenges involved in the
surveillance and timely collection of data, this study emphasized that current methods for
evaluating the burden of influenza are applicable in some cases to countries with temperate
climates. A summary of the burden in tropical and subtropical regions of the world showed that
in fact, the burden of flu has been highly underestimated. These findings suggest that an effective
preparedness plan should be based on a global and accurate assessment of the burden. That is,
building a capacity (pharmaceutical and non-pharmaceutical interventions) that is aimed
at reducing the burden of developed and developing countries is essential for the well-being
of communities worldwide.
New limitations that have evolved from advances in treating flu include antiviral resis-
tance. A recent study showed that the benefits of antivirals during a flu pandemic are likely
to be reduced by the presence of drug resistance (Lipsitch et al., 2007). As suggested in the
evaluation of single and combined intervention plans for the US, UK and the Netherlands, Nuño
et al. showed that the strategy of implementing antivirals in treatment or as prophylaxis will
strongly depend on the level of resources available (Nuño et al., 2007). Countries with limited
resources should opt for treatment rather than prophylaxis. An overwhelming conclusion from
the studies that have evaluated various forms of interventions to curtail pandemic flu is that
vaccine is clearly the optimal choice. However, there are practical limitations with the use of a
vaccine. Foremost importantly, vaccine is unlikely to be available at the time a pandemic
virus emerges in humans, as current methods for developing a flu vaccine require several months.
Once a vaccine becomes available, it is uncertain how many doses each person would require
for protection. With current manufacturing capabilities only about one third of the US popula-
tion is likely to have access to a vaccine. Unfortunately, the level of resources that may be available
for developing countries is likely to be much lower than the US and other developed parts of
the world.
There are certainly numerous challenges that current public health systems face world-
wide with the prospect of a flu pandemic. The main challenge includes the uncertainty
involved with the use of antivirals, vaccine and non-pharmaceutical interventions. Among the
interventions that are likely to be readily available at the time of pandemic, non-pharmaceuti-
cal interventions (NPIs) will play an essential role in slowing the progression of an outbreak.
However, the success of a NPI-based approach will likely be conditional on its timely and
continuous implementation throughout the entire pandemic period (Bootsma and Ferguson,
2007; Hatchett et al., 2007; Markel et al., 2006; Markel et al., 2007). Early relaxation of these
measures could further magnify the spread of a pandemic and yield devastating levels of
morbidity and mortality. An optimal plan for preparing against a prospective flu pandemic is
contingent upon the availability of pharmaceutical resources, its potential complications and
the social demands that non-pharmaceutical interventions such as isolation, quarantine,
closing of public gathering will have in a society.
The methods described in this chapter to evaluate the burden of influenza (seasonal or
pandemic) can be easily implemented to study the spread and burden of other diseases such
as SARS, smallpox, HIV, and others. Each disease involves different challenges (latency
periods, different modes of transmission, infectiousness and mortality differences), however,
the goal from a public health perspective is similar in all. That is, to develop appropriate
methods to accurately assess the burden of disease and reduce/prevent the spread in
a population.
Summary Points
Flu-related morbidity and mortality is underestimated nationally and worldwide.

The burden of seasonal influenza based on epidemics and estimates of excess mortality and
morbidity is most significant among the young children, elderly individuals older than 65
years old, and the immunocompromised.
Methods to evaluate the burden of influenza (excess mortality) in temperate regions relies
on seasonally observed outbreaks, however evaluating the burden in parts of the world
where most people live (tropics and subtropics) is a major concern because these regions
have harbored previous pandemic strains.
Cross-country studies that accurately evaluate the burden of flu epidemics and pandemics
are essential in improving current preparedness plans and building appropriate resources
(capacity).
While vaccine is optimal for combating the flu, there are major logistical complications
with this approach:
Vaccine will unlikely be readily available at the time when pandemic flu cases arise.
Resources will be insufficient to protect the population at risk, particularly in parts of
the world that have limited-to-no access to a vaccine.
Various challenges are also anticipated with the use of antivirals. Some of the challenges
with the implementation of antivirals include:
Insufficient resources to provide protection throughout the pandemic period.
Resistance to antiviral has already been observed.
Early interruption of antivirals is likely to intensify transmission and magnify
morbidity and mortality.
Acknowledgments
Miriam Nuño was supported under the National Institutes of Health grant AI28697 (UCLA).
The author is thankful to Thomas A. Reichert and James M. Bugni and for their helpful
comments and suggestions.
Appendix
Key Facts
Pandemic influenza Epidemic influenza

Global outbreak of disease resulting from the Local epidemic caused by a virus that has already
emergence of a novel virus circulated in the human population
Associated with major mutations (antigenic Associated with minor mutations (antigenic drift)
shift)
People have no immunity against this virus People have partial immunity against this virus
40–60 millions deaths worldwide (based on 250,000–500,000 deaths worldwide (yearly)
1918–1919 pandemic estimates)
References
Ahmed F, Singleton JA, Franks AL. (2001). N Engl J Med. Hall CE, Cooney MK, Fox JP. (1973). Am J Epidemiol.
345(21): 1543–1547. 98: 365–380.
Bootsma MCJ, Ferguson NM. (2007). Proc Natl Acad Sci Halloran ME, Ferguson NM, Eubank S, Longini IM Jr,
USA. 104: 7588–7593. Cummings DA, Lewis B, Xu S, Fraser C,
Cancio R, Savon C, Abreau I, et al. (2000). Rev Argen Vullikanti A, Germann TC, Wagener D, Beckman
Microbiol. 32: 21–26. R, Kadau K, Barrett C, Macken CA, Burke DS,
Chen W, Calvo PA, Malide D, Gibbs J, Schubert U, Bacik Cooley P. (2008). Proc Natl Acad Sci USA. 105(12):
I, Basta S, O’Neill R, Schickli J, Palese P, Henklein P, 4639–4644.
Bennink JR, Yewdell JW. (2001). Nat Med. 7(12): Hatchett RJ, Mecher CE, Lipsitch M. (2007). Proc Natl
1306–1312. Acad Sci USA. 104(18): 7582–7587.
Chew FT, Doraisingham S, Ling AE, Kumarasinghe G, Karasin AI, Landgraf J, Swenson S, Erickson G, Goyal S,
Lee BW. (1998). Epidemiol Infect. 121(1): 121–128. Woodruff M, Shcerba G, Anderson G, Olsen CW.
Chiu SS, Lau YL, Chan KH, Wong WHS, Peiris JSM. (2002). J Clin Microbiol. 40(3): 101–119.
(2002). N Engl J Med. 347: 2097. Kressin BW, Hallauer JF. (1999). Deutsches Ärzteblatt.
Denoeud L, Turbelin C, Ansart S, Valleron AJ, Flahault A, 96: B275–B276.
Carrat F. (2007). PLoS ONE. 2(5): e464. Langmuir AD, Farr W. (1976). Int J Epidemiol. 5:
Elveback LR, Fox JP, Ackerman E, Langworthy A, 13–18.
Boyd M, Gatewood L. (1976). Am J Epidemiol. Lee VJ, Chen MI, Pang CS, Wong CS, Cutter J, Goh KT,
103(2): 152–165. Tambyah PA. (2007). EID. 13(7): 1052–1057.
Farr W. (1847). Tenth annual report of the Registrar Levy E. (1996). PharmacoEconomics. 9(Suppl 3): 62–66.
General. HMSO, London. Lindstrom. SE, Cox NJ, Klimov A. (2004). J Virol
Ferguson NM, Cummings DAT, Cauchemez S, Fraser C, 328: 101–119.
Riley S, Meeyai A, Iamsirithaworn S, Burke DS. Lipsitch M, Cohen T, Murray M, Levin BR. (2007). PLoS
(2005). Nature. 437(7056): 209–214. Med. 4(1): e15.
Germann TC, Kadau K, Longini IM, Macken CA. Longini IM, Halloran ME, Nizam A, Yang Y. (2004). Am
(2006). Proc Natl Acad Sci. 103(15): 5935–5940. J Epidemiol. 159(7): 623–633.
Longini IM, Nizam A, Xu S, Ungchusak K, Hanshaowor- Reichert TA, Sugaya N, Fedson DS, Glezen WP,
akul W, Cummings DAT, Halloran ME. (2005). Sci- Simonsen L, Tashiro M. (2001). N Engl J Med.
ence. 309 (5737): 1083–1087. 344(12): 889–896.
Markel H, Lipman HB, Navarro JA, Sloan A, Michalsen Rennels MB, Meissner HC. (2002). Pediatrics. 110(6):
JR, Stern AM, Cetron MS. (2007). JAMA. 298(6): e80–e80.
644–654. Serfling RE. (1963). Public Health Rep. 78: 494–506.
Markel H, Stern AM, Navarro JA, Michalsen JR, Monto Simonsen L. (2001). Int Congr Ser. 1219: 13–19.
AS, DiGiovanni C Jr. (2006). EID. 12(12): Simonsen L, Clarke MJ, Schonberger LB, Arden NH,
1961–1964. Cox NJ, Fukuda K. (1998). J Infect Dis. 178: 53–60.
McCullers JA, Saito T, Iverson AR. (2004). J Virol. 78: Simonsen L, Clarke MJ, Williamson GD, Stroup DF,
12817–12828. Arden NH, Schonberger LB. (1997). Am J Public
Mills CE, Robins JM, Lipsitch M. (2004). Nature. 432 Health. 87: 1944–1950.
(7019): 904–906. Simonsen L, Fukuda K, Schonberger LB, Cox, NJ. (2000).
Monto AS, Kioumehr F. (1975). Am J Epidemiol. 102: J Infect Dis. 181: 831–837.
553–563. Smith W, Andrewes CH, Laidlaw PP. (1933). Lancet. 222:
Murray CJL, Lopez AD, Chin B, Feehan D, Hill KH. 66–68.
(2006). Lancet. 368: 2211–2218. Steinhauer DA, Skehel JJ. (2002). Ann Rev Genet. 36:
Neuzil KM, Zhu Y, Griffin MR. (2002). J Infect Dis. 185: 305–322.
147–152. Szucs T. (1999). J Antimicrob Chemother. 44: 11–15.
Ng TP, Pwee TH, Niti M, Goh LG. (2002). Ann Acad Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G,
Med Singap. 31(2): 182–188. Fanning TG. (2005). Nature. 43: 889–893.
Nuño M, Chowell G, Gumel AB. (2007). Proc R Soc Thompson WW, Shay DK, Weintraub E, Brammer L,
Interface. 4: 505–521. Cox N, Anderson LJ, Fukuda K. (2003). JAMA.
Pyle GF. (1986). The Diffusion of Influenza: Patterns and 289: 179–186.
Paradigms. Rowman & Littlefield, Totowa, NJ. Tumpey TM, Basler CF, Aguilar PV, Zeng H,
Reichert TA, Pardo S, Valleron A-J, Tam T,Hampson A, Solórzano A, Swayne DE, Cox NJ, Katz JM,
Christensen RA, Sharma A. (2007). Trends in Taubenberger JK, Palese P, Garcı́a-Sastre A. (2005).
influenza-attributable mortality in four countries: Science. 310: 77–80.
implications for national vaccination programs. Watkins J. (2004). Int Congr Ser. 1263: 263–266.
In: Cox N, et al. (eds.) Options for the Control of Webster RG, Bean WJ, Gorman OT, Chambers TM,
Influenza VI. Elsevier, Amsterdam (in press). Kawaoka Y. (1992). Microbiol Rev. 56: 152–179
82 Prophylaxis of Healthcare
Workers in an Influenza
Pandemic
S. M. Moghadas
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1420
1.1 Antiviral Drug Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1421
2 Surge Capacity in a Pandemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1422
3 Preventive Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1423
4 Prophylaxis of Healthcare Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1425
5 Benefits, Logistical Constraints, and Consequences of Prophylaxis . . . . . . . . . . . . . . 1428

5.1 Antiviral Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1428
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429

1420 82 Prophylaxis of Healthcare Workers in an Influenza Pandemic
Abstract: The threat of an imminent influenza pandemic has galvanized global efforts to
identify effective preparedness strategies and consider securing health resources. As the
nations prepare to meet this threat, public health interventions are being carefully gauged
within the context of influenza epidemiology, populations, and healthcare systems. A pan-
demic will place enormous demands on healthcare systems that include at the center of
planning efforts the protection of healthcare workers. During an influenza pandemic, health-
care workers will be on the front lines delivering care to patients and preventing further spread
of the disease. Protecting these workers from acquiring or transmitting infection in the
hospital ward and outside the workplace is critical to containing a pandemic and limiting
morbidity and mortality of the population. Several approaches to protecting healthcare
workers include vaccination, antiviral > prophylaxis, use of personal protective equipment,
and adherence to other infection control practices. In the absence of vaccination, application
of antiviral drugs has been rationalized as the first-line defense against the > pandemic strain.
While the treatment of ill individuals is top priority in most national contingency plans,
the use of drugs as prophylaxis has been debatable. This chapter attempts to highlight the
importance of a competent healthcare system in response to an influenza pandemic, and
presents the conflicting issues that are surrounding an antiviral prophylaxis strategy. An
overview of potential benefits and limitations, logistical constraints, and clinical and epidemi-
ological consequences of healthcare worker prophylaxis is also provided.
List of Abbreviations: ESP, essential service personnel; FAO, Food and Agricultural Organi-
zation; HCW, healthcare worker; WHO, World Health Organization
1 Introduction
Influenza pandemics have occurred episodically for many centuries, with significant rates
of morbidity, mortality and socioeconomic disruption (Potter, 2001). The 1918–1919 pan-
demic, the first of the three that occurred during the last century (> Table 82-1), proved the
most devastating with an estimated 50 million deaths among countless infections worldwide
(Taubenberger and Morens, 2006). There is mounting concern that the current avian strain
H5N1, originated in Southeast Asia, may cause the next major global pandemic (Webster
et al., 2006), with a toll that could exceed that of the 1918–1919 pandemic (Cox et al., 2003;
Jennings and Peiris, 2006). The H5N1 strain has crossed the species barrier and shown the
ability to replicate and cause fatal disease in humans (WHO Avian Influenza, 2008). Since
populations are entirely immunologically naı̈ve to this deadly virus, the conditions for a
pandemic will be met through the emergence of a re-assorted viral strain that can sustain
human-to-human transmission (American College of Physicians, 2006).
Given the uncertainties regarding the timing, origin, characteristics and virulence of a
future pandemic strain, planning strategies for an effective response have become the priority
of global public health efforts. Pandemic preparedness measures encompass disease surveil-
lance, case identification and treatment, prevention of community-wide spread of disease,
maintenance of essential services, research and evaluation (WHO Checklist for Influenza
Pandemic Preparedness Planning, 2005). Specific approaches to influenza infection control
include the use of pharmaceutical products (such as vaccines and antiviral drugs), and non-
pharmaceutical measures (such as personal protective equipment and social distancing).
During seasonal influenza epidemics, vaccination has proven the most effective strategy for
Prophylaxis of Healthcare Workers in an Influenza Pandemic 82 1421
. Table 82-1
Influenza pandemics of the twentieth century
Pandemic Virus strain Estimated mortality

1918 19 A/H1N1 (Spanish flu) 50 million
1957 58 A/H2N2 (Asian flu) 2 million
1968 69 A/H3N2 (Hong Kong flu) 1 million
Influenza viral strains of pandemics in the twentieth century, with their estimated mortality worldwide (Potter,
2001; Taubenberger and Morens, 2006)
reducing the risk of infection and subsequent complications (Bridges et al., 2000; Nichol et al.,
1995). However, the unknown characteristics of a pandemic virus pose major obstacles to
developing new vaccine candidates, thereby limiting immunological control of the disease.
Social distancing measures, including quarantine/isolation, school closure, cancellation of
gatherings, and to some extent, travel restriction, have been considered as possible strategies
during a pandemic (Inglesby et al., 2006). These measures have in general only limited impact
on disease containment for several evidence-based reasons: (1) influenza viruses replicate
rapidly to transmissible levels in a relatively short period of time, usually within the first day
of exposure; (2) there is a pre-symptomatic stage associated with the disease, during which the
virus can be shed before symptoms appear; and (3) a sizable portion of infected individuals
may experience an asymptomatic infection, and transmit the virus (at a low rate) without
being clinically recognizable (Baccam et al., 2006; Fraser et al., 2004). To overcome the existing
limitations with these transmission reduction measures, response plans incorporate antiviral
drugs as an important primary tool for prevention and treatment of pandemic infections
(Democratis et al., 2006).
1.1 Antiviral Drug Use
Two groups of antiviral agents are currently available for the initial response to a pandemic
(Hayden, 2004): M2 ion channel inhibitors (amantadine, rimantadine) and the more recent
agents of neuraminidase inhibitors (zanamivir, oseltamivir). These drugs differ greatly in
their clinical pharmacology, protective and treatment efficacy, and resistance selection profiles.
The M2 inhibitors have been shown to provide partial protection as prophylaxis and to
alleviate symptoms when used for early treatment, without affecting viral shedding (Jefferson
et al., 2006). However, incidence of > drug-resistance to M2 inhibitors has been associated
with an increasing rate in seasonal epidemics, possibly through widespread or indiscriminate
use of the drugs (Bright et al., 2005). The use of neuraminidase inhibitors in interpandemic
influenza has been shown to be effective for both prevention and treatment (Halloran et al.,
2006). They are also less prone to selecting for resistant mutations than M2 inhibitors
(Moscona, 2005), and therefore offer a better option for pandemic preparedness.
A major concern of public health is the strategic use of antiviral drugs during pandemic
influenza. One plausible policy, as considered in most pandemic plans (FAO United Nations,
2008; WHO, 2008), would be to focus primarily on the treatment of ill individuals
and hospitalized patients in order to reduce morbidity and mortality of the population.
However, public health authorities are also concerned with questions related to delivery
of adequate care and maintenance of key services and public order (American College
of Physicians, 2006). To address these questions, a number of countries have included
prophylaxis of healthcare and other essential community workers in the formulation of
pandemic policies, which would require massive quantities of antiviral drugs to be stockpiled
for the duration of a pandemic. The use of drugs for treatment or prophylaxis leads to subtle,
yet very significant policy differences. While the inclusion of prophylaxis as a protective
measure attempts to maintain surge capacity in the healthcare system, it entails a prohibitively
expensive public health policy. Other factors that would significantly influence decisions
regarding prophylaxis include the severity of the pandemic strain, the availability of antiviral
drugs, and the impact of other intervention measures. Nevertheless, in the absence of vaccines,
antiviral prophylaxis has the potential to offer a protection comparable to that induced
by vaccination.
2 Surge Capacity in a Pandemic
The needs for pandemic preparedness are extensive and expensive, and appear to be beyond
the response capacity of many countries. Even in non-pandemic times, healthcare systems
in many parts of the world are stretched in meeting the need for regular services. While the
demand for healthcare services will substantially increase during a pandemic, health resources
will be more quickly depleted and there may be fewer healthcare workers available. Assuming a
viral strain with 25–35% clinical attack rate over the estimated 8–12 weeks of a pandemic
wave, a sizable portion of healthcare workers may become infected during the early stages of
disease outbreaks (Gardam et al., 2007; Lee and Chen, 2007). The consequence is clear: a
critical shortage of health personnel and care providers. While healthcare organizations often
face staff-shortage during a natural disaster, the healthcare system may experience much
higher absenteeism rates in the event of a pandemic. Considering the potentially reduced
capacity of the healthcare system, and the lack of appropriate resources that is likely to arise,
health professionals may be called upon to assume responsibilities outside their normal scope
of practice. Such responsibilities may involve further exposure to the disease, and require strict
adherence to infection control practices. In such circumstances, it is vital to ensure that
healthcare workers are adequately protected and barriers to their participation are eliminated,
especially in the presence of other potentially competing obligations that need to be addressed.
The diversity among healthcare workers and facilities makes preparation and response to
a pandemic especially challenging. Healthcare facilities are magnets for individuals with
influenza-related illness, and are at high risk of disruption during a pandemic, primarily
due to hospital outbreaks of influenza that affect both patients and staff (Salgado et al., 2002).
Such outbreaks can have serious consequences for a sustainable healthcare response: staff
shortages can result or be exacerbated; admission maybe curtailed; and increased costs may be
incurred. Published studies clearly demonstrate these outcomes (Horcajada et al., 2003;
Lundstrom et al., 2002; Malavaud et al., 2001; Munoz et al., 1999; Sartor et al., 2002; Stott
et al., 2002), and therefore preventing > nosocomial spread of influenza is crucial for mitigat-
ing the impact of a pandemic on the population. While responding to the care of influenza
patients, other health needs will continue and cannot be ignored during pandemic phases.
Conventional wisdom considers access to inpatient and outpatient care to be central to any
pandemic response. Were modern healthcare resources unavailable, ill individuals would not
be able to access antiviral drugs, antibiotics, oxygen therapy, intravenous therapy, intensive
care, and other therapies. These modern options are essentially irrelevant without personnel,
and their application requires a competent healthcare workforce, professional experience, and
practice in order to minimize possible unintended health consequences.
Epidemiological and evaluation studies of seasonal influenza outbreaks provide convinc-
ing evidence that healthcare workers are central to any containment policy (Bridges et al.,
2003), in particular to treatment and prophylaxis strategies. Given the potentially devastating
health, economic and social consequences of a pandemic, preserving the capacity to deliver
adequate, uninterrupted care to the ill is an unavoidable priority for preparedness strategies.
Defining essential staff and services is an important component of pandemic planning, and
should be integrated with the development of infection control protocols for triage, evalua-
tion, prevention, and follow-up after exposure to disease.
3 Preventive Measures
Studies of the efficacy and effectiveness of influenza vaccines during seasonal epidemics
reveal substantial benefits (> Tables 82-2 and > 82-3), including reduced illness, mortality,
hospitalization, absenteeism, costs of healthcare, and antiviral use (Bridges et al., 2000;
. Table 82-2
Effect of vaccination on healthcare personnel illness and absenteeism
Randomized trial 1 (Saxén and Reduction (due to

Virtanen, 1999) Vaccinated Controlled vaccination)
Days of lost work (due to respiratory 1 1.4 28%
infection)
Days felt unable to work (whether on 2.5 3.5 28%
or off duty)
Randomized trial 2 (Wilde et al., 1999) Vaccinated Controlled
Days of lost work (due to illness) 9.9 (per 100 21.1 (per 100 53%
persons) persons)
Total respiratory illnesses 28.7 (per 100 40.6 (per 100 29%
persons) persons)
Incidence of influenza 1.7% 13.4% 87%
Cross-sectional survey (Lester et al., Vaccinated Unvaccinated
2003)
Days of lost work (due to influenza-like 63 (per 100 69 (per 100 0.08%
illnesses) persons) persons)
Influenza-like illnesses 42 (per 100 54 (per 100 22%
persons) persons)
Days of illness 272 (per 100 374 (per 100 27%
persons) persons)
The impact of influenza vaccination on healthcare personnel illness and absenteeism was evaluated in two
randomized, placebo-controlled, double-blind trials (Saxén and Virtanen, 1999; Wilde et al., 1999), and a cross-
sectional survey (Lester et al., 2003)
. Table 82-3
Cost-effectiveness of influenza vaccination of adults aged <65
Cost-effectiveness studies Cost reductions

Healthcare provider visits 13 44%
Days of lost work 18 45%
Days of working with reduced efficiency 18 28%
Antibiotic use for influenza-like illnesses 25%
Cost reductions of influenza vaccination of adults aged <65 years associated with direct medical costs and indirect
costs due to work absenteeism (Bridges et al., 2000; Nichol et al., 1995, 2003; Nichol and Mendelman, 2004)
Lester et al., 2003; Nichol et al., 1995, 2003; Nichol and Mendelman, 2004; Saxén and Virtanen,
1999; Wilde et al., 1999). However, the extent to which vaccination is successful depends
largely on the antigenic match between the vaccine composition strains and the circulating
viral strains (Bridges et al., 2000). The impact of vaccines on a pandemic can potentially be
very significant, yet it remains to be proven in practice. While efforts are being made to
shorten the delay in vaccine availability, retarding the progression of the first pandemic wave
is essential for preventing excessive deaths and social disadvantages.
Without a pandemic strain vaccine, protection mechanisms are limited to antiviral drugs
and infection control practices. The World Health Organization (WHO) recommends the use
of non-pharmaceutical public health interventions in its updated influenza pandemic plan,
to protect healthcare workers while providing care (WHO Writing Group, 2006). This update
emphasizes the maintenance of capability/capacity for infection control and staff competency
in use of personal protective equipment, such as gowns, gloves, and surgical masks. Although
the use of such equipment may decrease the risk of transmission, the sheer number of
encounters with infectious patients over the course of a working day would likely still result
in disease transmission. Even with excellent infection control precautions, attack rates of
greater than 10% are likely to occur among healthcare workers in the absence of vaccination
(Salgado et al., 2002). Additionally, evidence suggests that infected individuals with develop-
ing or weakened immune systems (such as infants, elderly, and immunocompromised sub-
jects) may suffer from prolonged illnesses and shed virus for several weeks, which makes
transmission of the disease even more difficult to control in healthcare facilities and the
community (Salgado et al., 2002). In a pandemic scenario, this would mean that a large part
of the healthcare system, and particularly healthcare workers, will be at risk of repeated
exposure. It is well recognized that even if protected at work, healthcare workers are just as
likely as the general population to become infected outside of the workplace.
Infection spread among healthcare workers can promote institutional outbreaks (Horcajada
et al., 2003). Investigations of host factors responsible for such outbreaks show that, in addition
to suboptimal adherence to institutional infection control procedures, many affected healthcare
workers with subclinical or even full clinical disease continue to work, thereby risking disease
transmission to patients and colleagues (Salgado et al., 2002; Weingarten et al., 1989). Peer
pressure from overworked colleagues, strong work ethics, and concerns regarding financial and
employment security may motivate healthcare workers to work despite illness. Maintaining
worker and patient safety is therefore a major challenge that may not be overcome simply
by increasing emphasis upon compliance and appropriate use of personal protective measures.
For healthcare workers, this could interfere with professional skills and affect the quality of
work-related interactions. However, infection control precautions may not be adequate to

prevent the spread of disease among vulnerable healthcare workers and patients. The use of
antiviral drugs for prophylaxis has been shown to be highly (70–90%) effective in reducing
susceptibility to the disease (Halloran et al., 2006; Hayden, 2004; Monto, 2003), and decreasing
the infectivity (if infection occurs) and absenteeism due to illness or concern over exposure to
infection in the hospital ward (Lee and Chen, 2007). Although not a substitute for vaccination,
antiviral prophylaxis appears to be a valuable strategy that affords immediate protection for
individuals. Compared to vaccination, the cost of prophylaxis is prohibitive, yet far more
economical than hospitalized care.
4 Prophylaxis of Healthcare Workers
For healthcare administrators and planners, key challenges for pandemic planning will include
the degree of surge capacity necessary to maintain safe and effective delivery of healthcare,
estimates of likely attrition among healthcare workers during a pandemic, and tradeoffs
between worker and patient safety and health, such as those that may arise if antiviral drugs
are used for healthcare worker prophylaxis rather than treatment of ill individuals. The latter
issue has been a source of some controversy in preparedness strategies, as it is unclear whether
hospitals would retain control over existing antiviral stockpiles in the event of a pandemic-
related emergency. A recent study suggests that hospitals should consider stockpiling neur-
aminidase inhibitors for prophylaxis and treatment of healthcare workers (Cinti et al., 2005).
While the proposed strategy focuses primarily on the treatment of ill healthcare workers, it
emphasizes targeted prophylaxis of front-line healthcare providers. The outcome of this
strategy may be potentially significant in mitigating pandemic burden, and two recent studies
have addressed this effect through development of population dynamical models of influenza
transmission (Gardam et al., 2007; Lee and Chen, 2007). Central to these models is the
provision of antiviral treatment to the general population, by taking into account the
availability of healthcare workers that is influenced by their reduced susceptibility to infection
due to the protective efficacy of prophylaxis. Despite several limitations, these modeling efforts
demonstrate that antiviral prophylaxis can substantially decrease absenteeism rates among key
health personnel, and significantly reduce morbidity and mortality in the general population.
However, both studies indicate that policy effectiveness depends critically on adequacy of the
antiviral drug supply and the timely implementation of treatment and prophylaxis strategies.
Although several countries have followed guidelines issued by the WHO for formulating
national preparedness strategies (> Figure 82-1), there remain discrepancies in planning for
antiviral use, distribution, and priorities for treatment and prophylaxis. Most responding
plans consider immediate treatment of ill individuals upon diagnosis as a more efficient
approach to the use of drug stockpiles, and give priority to healthcare workers, essential and
public safety staff, and those who are at risk of severe complications or death. However,
antiviral prophylaxis has been a matter of ongoing debate for both logistical concerns and
clinical-epidemiological consequences of viral evolution and transmission (Democratis et al.,
2006; Lipsitch et al., 2007; Regoes and Bonhoeffer, 2006). > Figure 82-2 summarizes the likely
prophylactic use of drugs for target groups of healthcare workers and essential service
personnel in national pandemic plans published in the official websites of the Food and
Agricultural Organization of the United Nations and the WHO National Influenza Pandemic
Plans (FAO United Nations, 2008; WHO, 2008). Although recent studies provide scientific and
1426
. Figure 82-1
82
Global map of pandemic preparedness. Countries with national plans that indicate prophylaxis of healthcare workers and/or essential service staff as
part of their pandemic responses. Countries with no, or not yet determined, prophylaxis strategy in their national plans. Countries with no
published/accessible pandemic plans through official websites of the Food and Agricultural Organization of the United Nations, and the WHO National
Influenza Pandemic Plans
Prophylaxis of Healthcare Workers in an Influenza Pandemic
. Figure 82-2
Prophylactic use of antiviral drugs in national pandemic plans. Among fifty-one published
contingency plans for pandemic responses (FAO United Nations, 2008; Straetemans et al., 2007;
WHO, 2008), healthcare workers are identified as the priority group for pre-exposure (long-term)
prophylaxis in 17 national plans (Australia, Bahrain, Republic of Bulgaria, Chile, Czech Republic,
Germany, Greece, Hungary, Lithuania, Montenegro, Nicaragua, Norway, Republic of Serbia,
Sweden, Switzerland, Timor Leste, United States), and for post-exposure prophylaxis in eight
plans (Austria, Cuba, Ireland, Republic of Korea, Mexico, Philippines, Portugal, Singapore).
Essential service personnel are given priority for long-term prophylaxis in seven plans (Republic
of Bulgaria, Chile, Czech Republic, Greece, Nicaragua, Norway, Sweden), and for post-exposure
prophylaxis in six plans (Australia, Montenegro, Philippines, Portugal, Republic of Serbia,
Singapore). A number of these plans indicate that the decision on prophylactic use of drugs may
be influenced by the availability of vaccines and the size of antiviral stockpiles, in addition to the
severity of the pandemic strain. Twenty-five national plans (Belgium, Brazil, Canada, China,
Republic of Estonia, Finland, France, Hong Kong, India, Italy, Japan, Luxemburg, Nauru,
Netherlands, New Zealand, Nouvelle-Calédonie, Palau, Poland, Rwanda, Slovak Republic, South
Africa, Spain, Thailand, United Kingdom, West Bank/Gaza) indicate no specific strategy for
prophylaxis of healthcare workers or essential service personnel. Most plans suggest that the
strategic use of drugs should be re-evaluated during different phases of the pandemic, so that
necessary modifications to antiviral strategies can be made in a timely fashion
administrative frameworks for prophylaxis strategies that can effectively protect the healthcare
workforce in the face of infectious disease threats (Cinti et al., 2005; Toner and Waldhorn,
2006; Xiong et al., 2007), precise planning for antiviral use is hindered by several unknowns –
in particular, the transmissibility of the pandemic strain, effectiveness of drugs, and the impact
of other curtailing measures. There is also much uncertainty about how a novel influenza
strain would affect different populations with distinctly different mobility patterns, healthcare
expenditures, and economic structures. The nature of the next influenza pandemic cannot be
predicted with certainty, but the high mortality rates among younger adults in past pandemics
compel us to consider maximizing the protection of healthcare workers by using available
means of reducing disease transmission.
5 Benefits, Logistical Constraints, and Consequences

of Prophylaxis
Considering the limited capacity of vaccine production that is concentrated in a very few
countries (Fedson, 2003), antiviral drugs will likely be the primary control measure for several
months following the emergence of a pandemic strain. Yet more frightening, antiviral therapy
may be the only pharmaceutical option for many countries during the entire course of the
pandemic. Stockpiling adequate supplies of drugs has therefore become a critical component
of pandemic preparedness strategies. However, a major challenge is to define priority groups
and formulate antiviral policies that are most likely to optimize the health of the greatest
number of individuals in the face of an influenza pandemic.
In allocating antiviral drugs, it will be necessary to rate the relative importance of
treatment and prophylaxis in avoiding complete coverage of the population, particularly
when considering insufficient quantities of drugs, limited production capacity, and a surge
in demand for antiviral therapy with the progression of a pandemic (Democratis et al., 2006).
These contrasting factors highlight the importance of prioritizing public health policies that
maximize both short-term population-wide benefits and long-term epidemiological effects of
antiviral therapy. Published modeling studies suggest that the pandemic can be contained at
the source if early treatment of diagnosed cases is combined with targeted blanket prophylaxis
and social distancing measures (Ferguson et al., 2005; Longini et al., 2005). Significant
assumptions are embedded in the core of such models, most of which are unlikely to be
fulfilled in a real world environment, and therefore containment failure should be anticipated
in devising effective preparedness countermeasures.
Clearly, targeted strategies are needed to optimize the use of available supplies of antiviral
drugs, and precise planning should be based on pandemic-specific response goals for mitigating
the overall disease burden. Long-term prophylaxis of healthcare workers and emergency service
personnel may be beneficial in terms of reducing viral transmission between interconnected
subpopulations with high levels of exposure, thereby preventing impending institutional out-
breaks and staff demoralization, maintaining the quality and accountability of healthcare, and
decreasing mortality of the general population. However, this strategy would require a prohibi-
tively large drug stockpile, and delay the progression of the pandemic by the period for which
prophylaxis is provided. Regardless of the level of stockpiles, substantial logistical challenges will
arise for practical implementation of this strategy that need to be addressed, let alone its possible
long-term epidemiological outcomes that may be disadvantageous to the control of disease. Key
issues include, but are not limited to, determining target groups, potential regulatory barriers to
dispensing, labor consequences that may arise from targeting specific sectors in healthcare and
emergency departments but not others, and monitoring antiviral drug use, efficacy, and safety.
Targeted > post-exposure prophylaxis could provide significant benefits, but it would still require
much greater stockpiles than currently provided.
5.1 Antiviral Resistance
Although antiviral therapy appears to be crucial in any containment strategy, the emergence
of drug-resistance will impose significant threats to the effectiveness of drugs for both
treatment and prophylaxis (Moscona, 2005). Early treatment largely inhibits generation of
resistant viruses by suppressing viral replication, but results in a longer time for selection in
favor of pre-existing resistant mutants (Moghadas et al., 2008). Prophylaxis blocks the
transmission of the drug-sensitive strain more effectively, but contributes to the emergence of
resistance in the population by increasing the pressure for selection and spread of resistant
viruses (Lipsitch et al., 2007; Regoes and Bonhoeffer, 2006). The interplay between these
opposing effects appears particularly important for determining the advantages and disad-
vantages of population-specific antiviral strategies. Previous studies suggest that, in the
absence of drug-resistant viruses, targeted prophylaxis of healthcare workers can substantially
limit the community-level transmission of disease, by providing considerable protection to
those who contribute to caring for influenza patients (Gardam et al., 2007; Lee and Chen,
2007). However, should resistance emerge during the early stages of a pandemic, this strategy
may promote population-wide spread of drug-resistance through intense contacts with
patients and colleagues in the healthcare setting and contacts outside of the workplace. As
has been evident in the experience with outbreaks of Severe Acute Respiratory Syndrome
(SARS) in 2003, hospitals and other healthcare facilities are particularly important resources
for disease control, but they may also serve as ‘‘hot spots’’ for disease transmission, with
subsequent hospital-to-community spread (Loutfy et al., 2004).
The impact of the next influenza pandemic may be catastrophic worldwide, particularly
for nations with poor healthcare resources and fragile economies. Ongoing efforts may not
be sufficient to combat it or prevent every single death, but the basic tenet of pandemic
preparedness is not to miss the unprecedented opportunity provided by the increased aware-
ness of the potential devastation of the next influenza pandemic. To a large degree, it will
run its course; however, the healthcare system and society will need to prepare for a rapid and
effective response by developing system-wide contingency plans that accommodate the full
spectrum of harms related to pandemic influenza and benefits related to control activities.
Historical precedent, from both seasonal influenza epidemics and the 1918–1919 influenza
pandemic, suggests that an emergent influenza strain with high > pathogenicity would
severely tax existing health resources, and force healthcare administrators and providers
alike to make difficult decisions that may include rationing of scarce resources (e.g., antiviral
drugs, intensive care beds, and ventilators) and decisions that violate the autonomy of the
individual (e.g., forced quarantine or isolation of individuals). The ethical framework of such
decisions is complex; however, evaluation of the potential benefits, costs, and limitation of
competing strategies, as well as the resources and practices required to achieve best outcomes,
will allow planners and providers to balance the protection of community health against
individuals’ rights and freedoms in the context of influenza infection control.
Summary Points
Effective protection of healthcare workforce during an influenza pandemic is an essential
priority of pandemic preparedness endeavors, and should be based on scientific knowledge
and evidence of disease transmission, prevention, and mitigation. Such protection must
address the diversity of institutional activities with varying degrees of exposure to the disease.
Considering the nature of interaction between ill individuals and healthcare workers,
the lack or poor administration of preventive measures will leave healthcare workers highly
vulnerable to the infection, and therefore the surge capacity required to treat influenza
patients could be severely impaired.
Prophylaxis of healthcare workers is an essential protective mechanism that can maintain

the capacity to cope with the increased demand for healthcare, prevent nosocomial out-
breaks and further spread to the community, and reduce morbidity and mortality of
the general population.
An effective vaccine may not be available for several months following declaration of
a pandemic. Preparedness efforts should therefore include securing antiviral supplies,
particularly when prophylactic use of drugs is planned for limiting disease propagation
locally as well as globally.
Significant logistical challenges lie at the heart of prophylaxis strategies for healthcare
workers and essential service personnel that must be addressed. Scarce supplies of antiviral
drugs create ethical dilemmas of distribution priorities and target groups. These ethical
considerations must be taken into account for rationing of limited stockpiles.
Antiviral treatment can induce a massive selective pressure on the drug-sensitive pandemic
strain, resulting in the clinical outcome of developing drug-resistance. Prophylactic use
of drugs can substantially enhance the spread of drug-resistance in the population due to
a significant reduction in susceptibility to the drug-sensitive strain.
In order to prevent unintended epidemiological consequences of drug therapy, antiviral
strategies should be re-evaluated during the progression of the pandemic and necessary
adaptations should be rapidly implemented to prevent subsequent outbreaks of drug-
resistant infections.
In order to identify more tangible antiviral strategies with a global perspective, similarities
and differences in pandemic plans with respect to the use of antiviral drugs and priority
groups for treatment and prophylaxis should be carefully examined.
Development of appropriate mathematical models for disease management can help
evaluate the potential impact of various public health intervention strategies, optimize
health policy decisions, and maximize population-wide benefits of scarce health resources.
References
American College of Physicians. The Health Care Democratis J, Pareek M, Stephenson I. (2006). J
Response to Pandemic Influenza. Philadelphia, Antimicrob Chemother. 58: 911–915.
American College of Physicians, 2006. FAO United Nations. (2008). http://www.fao.org/avian-
Baccam P, Beauchemin C, Macken CA, Hayden FG, flu/en/national.html
Perelson AS. (2006). J Virol. 80: 7590–7599. Fedson DS. (2003). Clin Infect Dis 36: 1552–1561.
Bridges CB, Kuehnert MJ, Hall CB. (2003). Clin Infect Ferguson NM, Cummings DAT, Cauchemez S, Fraser C,
Dis. 37: 1094–1101. Riley S, Meeyai A, Iamsirithaworn S, Burke DS.
Bridges CB, Thompson WW, Meltzer MI, Reeve GR, (2005). Nature. 437: 209–214.
Talamonti WJ, Cox NJ, Lilac HA, Hall H, Fraser C, Riley S, Anderson RM, Ferguson NM. (2004).
Klimov A, Fukuda K. (2000). JAMA. 284: 839–844. Proc Natl Acad Sci USA. 101: 6146–6151.
Bright RA, Medina MJ, Xu X, Perez-Oronoz G, Gardam M, Liang D, Moghadas SM, Wu J, Zeng Q,
Wallis TR, Davis XM, Povinelli L, Cox J, Klimov Zhu H. (2007). J R Soc Interf. 4: 727–734.
AI. (2005). Lancet. 366: 1175–1181. Halloran ME, Hayden FG, Yang Y, Longini IM Jr,
Cinti S, Chenoweth C, Monto AS. (2005). Infect Control Monto AS. (2007). Am J Epidemiol. 165: 212–221.
Hosp Epidemiol. 26: 852–854. Hayden FG. (2004). Pediatr Infect Dis J. 23: S262–S269.
Cox NJ, Tamblyn SE, Tam T. (2003). Vaccine. 21: Horcajada JP, Pumarola T, Martı́nez JA, Tapias G,
1801–1803. Bayasz JM, de la Prada M, Garcı́a F, Codina C,
Gatell JM, Jiménez de Anta MT. (2003). Eur Respir J. Nichol KL, Mendelman P. (2004). Virus Res. 103: 3–8.
21: 303–307. Potter CW. (2001). J Appl Microbiol. 91: 572–579.
Inglesby TV, Nuzzo JB, O’Toole T, Henderson DA. Regoes RR, Bonhoeffer S. (2006). Science. 312: 389–391.
(2006). Biosecur Bioterror. 4: 1–10. Salgado CD, Farr BM, Hall KK, Hayden FG. (2002).
Jefferson T, Demicheli V, Rivetti D, Jones M, Di Lancet Infect Dis. 2: 145–155.
Pietrantonj C, Rivetti A. (2006). Lancet. 367: Sartor C, Zandotti C, Romain F, Jacomo V, Simon S,
303–313. Atlan-Gepner C, Sambuc R, Vialettes B, Drancourt
Jennings LC, Peiris M. (2006). Inter Med J. 36: 145–147. M. (2002). Infect Control Hosp Epidemiol. 23:
Lee VJ, Chen MI. (2007). Emerg Infect Dis. 13: 449–457. 615–619.
Lester RT, McGeer A, Tomlinson G, Detsky AS. (2003). Saxén H, Virtanen M. (1999). Pediatr Infect Dis J. 18:
Infect Control Hosp Epidemiol. 24: 839–844. 779–783.
Lipsitch M, Cohen T, Murray M, Levin BR. (2007). PLoS Stott DJ, Kerr G, Garman WF. (2002). Occup Med. 52:
Med. 4: e15. 249–253.
Longini IM Jr, Nizam A, Xu S, Ungchusak K, Hanshao- Straetemans M, Bochhols U, Reiter S, Haas W, Krause G.
worakul W, Cummings DAT, Halloran ME. (2005). (2007). BMC Public Health. 7: 236–247.
Science. 309: 1083–1087. Taubenberger JK, Morens DM. (2006). Emerg Infect Dis.
Loutfy MR, Wallington T, Rutledge T, Mederski B, Rose 12: 15–22.
K, Kwolek S, McRitchie D, Ali A, Wolff B, White D, Toner E, Waldhorn R. (2006). Biosecur Bioterror.
Glassman E, Ofner M, Low DE, Berger L, McGeer A, 4: 397–402.
Wong T, Baron D, Berall G. (2004). Emerg Infect Webster RG, Peiris M, Chen H, Guan Y. (2006). Emerg
Dis. 10: 771–776. Infect Dis. 12: 3–8.
Lundstrom T, Pugliese G, Bartley J, Cox J, Guither C. Weingarten S, Riedinger M, Bolton LB, Miles P, Ault M.
(2002). Am J Infect Control. 30: 93–106. (1989). Am J Infect Control. 17: 202–207.
Malavaud S, Malavaud B, Sanders K, Durand D, Marty WHO. (2008). http://www.who.int/csr/disease/influenza/
N, Icart J, Rostaing L. (2001). Transplantation 72: nationalpandemic/en/index.html
535–537. WHO Avian Influenza. (2008). http://www.who.int/csr/
Moghadas SM, Bowman CS, Röst G, Wu J. (2008). PLoS disease/avian_influenza.
ONE. 3: e1839. WHO Checklist for Influenza Pandemic Prepar-
Monto AS. (2003). Vaccine. 21: 1796–1800. edness Planning. (2005). http://www.who.int/csr/
Moscona A. (2005). N Engl J Med. 353: 2633–2636. resources/publications/influenza/
Munoz FM, Campbell JR, Atmar RL, Garcia-Prats J, WHO_CDS_CSR_GIP_2005_4/en/
Baxter BD, Johnson LE, Englund JA. (1999). Pediatr WHO Writing Group. (2006). Emerg Infect Dis. 12:
Infect Dis J. 18: 811–815. 81–87.
Nichol KL, Lind A, Margolis KL, Murdoch M, McFadden Wilde JA, McMillan JA, Serwint J, Butta J, O’Riordan
R, Hauge M, Magnan S, Drake M. (1995). N Engl J MA, Steinhoff MC. (1999). JAMA. 281: 908–913.
Med. 333: 889–893. Xiong W, Hollingsworth E, Muckstadt J, Vorenkamp
Nichol KL, Mallon KP, Mendelman PM. (2003). Vaccine. JVL, Lazar EJ, Cagliuso NV Sr, Hupert N. (2007).
21: 2207–2217. Infect Control Hosp Epidemiol. 28: 618–621.
83 The Burden of Human
African Trypanosomiasis
A. Shaw . J. Robays . E. M. Fèvre . P. Lutumba . M. Boelaert
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1434
2 Magnitude of the Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1434
3 Estimating the DALYs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1435
4 The Economic Burden on Households and Communities . . . . . . . . . . . . . . . . . . . . . . . . . . 1438
5 The Cost-Effectiveness of Controlling HAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1438
6 What Lessons can be Drawn for other Diseases? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1440
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1440
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1441

1434 83 The Burden of Human African Trypanosomiasis
Abstract: > Human African Trypanosomiasis (HAT), a once largely forgotten disease, is back
on the agenda. A public-private partnership between the World Health Organization (WHO),
pharmaceutical companies and international donors succeeded in curbing the recent epidemic,
but active transmission is still ongoing in several countries. The burden of the disease in affected
individuals is high. Untreated the disease is always fatal and estimates of the Disability Adjusted
Life Years (DALYs) lost per premature death range from 25 to 33 years. Even for successfully
treated patients, the burden on households and livelihoods is high – between 1.5 and 10
months’ income, even when diagnostics and HAT drugs are provided for free. Costs ranging
from $10–17 per DALY averted for case-finding and treatment places the control of T.b.
gambiense HAT firmly in the category of highly cost-effective health interventions.
List of Abbreviations: DALY, disability adjusted life year; DRC, democratic republic of
Congo; HAT, Human African Trypanosomiasis; NGO, Non-Governmental Organization;
T.b., > Trypanosoma brucei; WHO, World Health Organization; YLL, years of life lost
1 Introduction
Human African Trypanosomiasis (HAT), also known as “sleeping sickness” is one of the
neglected diseases of this world. It is endemic in 36 countries of sub-Saharan Africa where it
affects mainly the rural poor. The disease is caused by protozoa of the species Trypanosoma
brucei (T.b.) and is transmitted by > tsetse flies. Infection with such parasites eventually leads
to death in the absence of appropriate treatment, but the disease presents differently by region.
In East Africa, HAT is a zoonotic disease involving domestic animals and wildlife, caused by
T.b. rhodesiense, (> East African sleeping sickness) and cattle are often the main reservoir
(> disease reservoir in HAT). In West and Central Africa it is caused by T.b. gambiense and
transmitted in a man-fly-man cycle. HAT caused by T.b. gambiense (> West African sleeping
sickness) accounts for over 90% of all reported cases and has a much more protracted course
than the rhodesiense (or East African) type. The disease evolves in two stages, (1) an early stage
(> hematolymphatic stage of Human African Trypanosomiasis) when infection is limited to
blood and lymph circulation and that is treated with pentamidine or suramin with over 90% cure
rates, and (2) the late meningo-encephalitic stage (> meningo-encephalitic stage of Human
African Trypanosomiasis) when the parasites have invaded the central nervous system. An
arsenicum-derivative, melarsoprol, was until recently the recommended drug for this late stage,
but, because of its toxicity and as it was gradually loosing its efficacy, eflornithine is now
promoted in this indication for the treatment of the late stage of the gambiense form of the
disease (Priotto et al., 2008). Because of the lack of specific symptoms in the early stage,
patients usually consult a health professional when the disease is already well advanced and
involves the central nervous system. At that point, the patient may have irreversible brain
damage, requires the more expensive and toxic drugs and has posed a risk to other members
of the community due to his infectiousness to tsetse flies. Therefore, population screening
for HAT is the main control strategy for the gambiense form of HAT.
2 Magnitude of the Problem
During the 1940s, 1950s and 1960s large-scale control programmes based on active case detection
had succeeded in reducing the incidence of the gambiense form to some 4,000–6,000 reported
The Burden of Human African Trypanosomiasis 83 1435
cases a year during the 1960s (WHO, 2000). There were still regular outbreaks of the acute,
rhodesiense, form, with as many as 8,000 cases being reported during a single year in the
epidemic in Uganda which started in the late 1970s, but their severity was to some extent
mitigated by vector control activities. However, during the 1980s the number of reported HAT
cases increased gradually and towards the end of the 1990s disturbing evidence of a large scale
resurgence of the gambiense form of the disease began to emerge, as the number of reported
cases rose to 45,000 annually, a more than tenfold increase since the sixties. Although this
latter number might seem relatively low, when viewed against the other health problems faced
by Africa’s people, the clustering of this disease in localized foci where its burden is very heavy,
and its potential for epidemic outbreaks meant that this resurgence of sleeping sickness needed
to be treated with great seriousness. In addition the reported cases were mainly found by
passive surveillance rather than through active surveillance and were thought to represent only
the tip of a large iceberg. By the late 1990s there was a widespread general awareness that this
largely forgotten disease had made a frightening comeback and that a hidden epidemic of
sleeping sickness had been ravaging African countries.
Fortunately, this awareness was also translated into a major investment in the control of HAT
in recent years. Bilateral donors stepped up their aid (Lutumba et al., 2005) and a partnership
between WHO, private pharmaceutical companies, Non-governmental organizations (NGOs),
bilateral donors and the health services of the countries affected led to an important increase of
HAT control activities and a curbing of the case load. The recent trend in the Democratic
Republic of Congo (DRC) is shown in > Figure 83-1.
Nonetheless intensive transmission of the disease is still taking place in several areas of
Central Africa. The most recent figures published by WHO (2006) for gambiense HAT were
17,036 reported cases in 2004, which were extrapolated to an estimated worldwide annual
caseload of 50,000–70,000. Sixty-one percent of the reported cases (10,369/17,036) were from
a single country: DRC. Sudan and Angola each reported more than 1,500 cases, while 50–1,500
cases per year were reported in the Central African Republic, Chad, Côte d’Ivoire, Guinea and
Uganda. Burkina Faso, Cameroon, Equatorial Guinea, Gabon and Nigeria each reported less
than 50 cases (> Figure 83-2).
3 Estimating the DALYs

Published global estimates of the annual burden of this disease have ranged between 1.5 and
2.0 million disability-adjusted life years (DALYs) per annum (WHO, 2004), based on the
number of reported cases and using the same weightings for the burden associated with both
the chronic and acute forms. A number of recent studies have provided the basic data needed
for a more accurate global estimate. For the gambiense form, estimates of the DALY burden in
affected individuals have been made by interviewing hospital patients diagnosed with the
disease. In untreated individuals in Southern Sudan, the number of years of life lost (YLL) due
to premature mortality from HAT were estimated at 33 per death (D. McFarland, personal
communication, based on work in Trowbridge et al., 2001), in Angola the figure estimated was
30 years per death (Schmid et al., 2004) and in the Democratic Republic of Congo (DRC)
a figure of 27 years per death was obtained (Lutumba et al., 2005). The long term sequelae,
which can include neurological impairment, make the morbidity component significant as
well, even for treated patients. For rhodesiense, an initial estimate (Politi et al., 1995) based on
data from Uganda, estimated the number of DALYs incurred per premature death to be 25,
. Figure 83-1
Number of new cases reported by the national control program in Democratic Republic of
Congo (1926–2004). NC = new case. This graph shows how the number of new cases of
Human African Trypanosomiasis (HAT) gradually declined after a peak in 1930 to reach a
historical low in 1960. Then, despite ongoing control activities, the number of cases slowly
increased to reach a new peak in 1999, from that moment it was brought down again by an
intensified control program
a more recent estimate (Odiit, 2003) puts them at 31. Additionally, the acute nature of
T.b. rhodesiense results in a high burden per affected case, making the morbidity component
of the T.b. rhodesiense DALY high. These estimates show the number of DALYs caused by both
forms of the disease to be substantial, and well above those incurred by other tropical diseases
such as dengue and filariasis which receive a great deal of international attention. This reflects,
firstly, the fact that HAT is nearly always fatal in untreated individuals and secondly that the
majority of the people affected are economically active adults. For example data on rhodesiense
from Uganda showed 25% of cases occurring in those aged 20–29 years and 60% of those
affected being in the 10–39 year age group (Fèvre et al., 2008), for gambiense in DRC (Lutumba
et al., 2007a) very similar percentages were found (21 and 58%,respectively). These DALY
estimates provide us with an overall view of the impact of the disease on affected individuals,
but it should be noted that few DALY estimates have been made for HAT and that those
reported are deterministic estimates, referring to the average impact per patient. Furthermore,
the potential long term impacts of HAT on treated and cured patients have not been
investigated for either form of the disease, so the DALY estimates do not include sequelae.
Having established what the losses in infected individuals are likely to be, extrapolating
these to a national or continental scale is more problematical. So far, only one published
study (Odiit et al., 2005) has addressed this directly. Using an epidemiological model, applied
to data on the number of patients presenting in first and second stage of the rhodesiense form of
disease in south-eastern Uganda, the study concluded that for every reported death from the
disease, a further twelve remained unreported; this work has been validated in other parts of
Uganda (Fèvre et al., 2005), demonstrating that in a localized epidemic with 500 reported cases,
. Figure 83-2
Annual number of Human African Trypanosomiasis (HAT) cases reported between 2000 and
2005. This map shows how Democratic Republic of Congo, Sudan and Angola each reported
more than 1,500 cases, while 50–1,500 cases per year were reported in the Central African
Republic, Chad, Côte d’Ivoire, Guinea and Uganda. Burkina Faso, Cameroon, Equatorial Guinea,
Gabon and Nigeria each reported fewer than 50 cases (Adapted from World Health Organization
website: http://www.who.int/trypanosomiasis_african/disease/en/index.html)
approximately 300 additional cases died undiagnosed in the community. For gambiense, where
the course of the disease is much more extended and more variable, and where a large
proportion of the reported cases is usually found by exhaustive population screening, such
approach would not be applicable. Work by Robays et al. (2004) gives insight in the propor-
tion of HAT patients who are likely to missed out in active screening exercises for gambiense
HAT. This study estimated that between 40 and 50% of patients in the community are missed
by the campaign, because some individuals do not present themselves for the initial screening
and because of the poor sensitivity of some of the tests used to confirm the presence of
the parasite.
Developing an effective methodology for estimating the degree of under-reporting
for gambiense disease remains a challenge. WHO estimated the total population at risk to be
60 million in 1998 (WHO, 1998). Further work is being undertaken, remapping the foci of the
disease and refining this calculation. At the start of the 1997–2005 epidemic, when most cases
were passively detected, WHO estimated that only about one in ten HAT patients had been
found and correctly diagnosed – however, after more than 5 years of active case-finding, it is
hoped that a far higher proportion of patients have been found and treated.
Thus, while work on recalculating the global burden of HAT in terms of DALYs is ongoing,
it looks as though, despite the falling number of reported cases, the figure is likely to range
between 0.5 and 1.5 million DALYs, reflecting new research showing a higher burden per
affected individual and depending on the results of evidence-based estimates of the proportion
of unreported cases.
Recently, Lutumba et al. (2007a) have pointed to the risks when using DALYs for priority
setting in HAT. At a global level, the absolute figures do not reflect the major impact the
disease can have on local communities and regions, because the disease has such a clustered
occurrence. Secondly, it is vital that declining trends in case numbers or DALYs should not lead
to a reduction in resource allocation for HAT control because there are many documented
examples of resurgence after abrupt cessation of active screening campaigns (Lutumba et al.,
2005; Moore et al., 1999; Moore and Richer, 2001; Van Nieuwenhove et al., 2001) and indeed
the increase in cases leading to the current epidemic closely mirrored the decline in active
surveillance.
4 The Economic Burden on Households and Communities

The key to the high burden this disease places on affected households and communities lies
not just in the difficulties individuals face in obtaining a correct diagnosis and thus the
treatment required to prevent a fatal outcome, but also in its focal nature. Within these foci
the prevalence can be high, often around 1% in the absence of active screening. If intense
transmission goes unnoticed in a focus, the prevalence rates can rise relatively rapidly,
sometimes over half the population of certain villages have been found affected. Thus the
burden of this disease falls very heavily on a few locations, as argued in Lutumba et al. (2007a).
As well as often being the active adults in a household, HAT patients also require very high
levels of care, placing a further burden on the household. There have been few attempts to
quantify the full costs borne by households with HAT patients which include their care at
home and during hospital treatment, seeking a diagnosis, lost income, medical fees, transport,
etc. In the Republic of Central Africa, the cost to households containing HAT patients who
were correctly diagnosed and treated came to an amount equivalent to just under 1.5 months’
household income from agriculture (Gouteux et al., 1987). A recent study in DRC (Lutumba
et al., 2007a), where the direct costs of screening and treatment are fully subsidized by the HAT
program, undertook a detailed calculation of household costs for diagnosed and treated
patients; these came to 5 month’s household income on average, but rose to over 10 months’
income for patients with complications. Just seeking a diagnosis can be both time-consuming
and costly: a study in a rhodesiense area of Uganda showed that over 70% of patients had to
make three or more visits to a health unit before being correctly diagnosed and just over half
had to sell agricultural produce to pay for health care costs (Odiit et al., 2004). Lastly, HAT is
overwhelmingly a disease of isolated rural populations and within these populations it is the
poorer families who have the most difficulty in obtaining a correct diagnosis for their affected
family members and on whom the burden of care and the expenditures needed to deal with the
disease weigh most heavily.
5 The Cost-Effectiveness of Controlling HAT
A number of approaches can be used alone or in various combinations to control HAT –

finding and treating affected individuals, thus reducing the human reservoir of the disease,
dealing with the animal reservoir and controlling the vector.
For gambiense disease, active case-finding and treatment is essential to reduce transmission
and to find and treat affected individuals. The costs of this approach have been estimated in a
number of studies (Lutumba et al., 2005; Shaw and Cattand, 2001; Trowbridge et al., 2001;
WHO, 1998 – which provides templates showing how the costs could be calculated for various
screening strategies). The costs of screening populations range around $1–1.50 per person.
The costs of treatment are usually cited as around $100 for first stage patients and $300 for
second stage patients treated with melarsoprol, increasing to over $600 if eflornithine is used
(WHO, 1998). More recent estimates by Robays et al. (2008) in Angola put these figures at a
cost of $604 for melarsoprol and $844 for eflornithine treatment. The cost is very sensitive to
assumptions made about the cost of hospitalization (Shaw and Cattand, 2001; WHO, 1998).
Several attempts to calculate the cost of a patient-day in sleeping sickness treatment centers
have been made and these show the costs to be highly variable – estimated at around $2
in Uganda (Odiit, 2003), while a more detailed analysis showed them to be $10 in DRC and
$66 in a well-equipped treatment centre in Angola (Schmid et al., 2004). Overall, looking at
the breakdown of costs for case-finding and treatment (Shaw and Cattand, 2001, WHO, 1998),
it is clear that once the prevalence exceeds 1%, hospitalisation costs become the main
component of overall costs. Prolonged hospitalisation also places a very heavy burden on
households. The newly developed 10-day melarsoprol schedule thus represents a very welcome
improvement, making it possible to substantially reduce the cost of treatment, for example
from $12 to 7 per DALY averted in DRC (Schmid et al., 2004).
The cost-effectiveness of case-finding and treatment approaches has been calculated in several
studies (Lutumba et al., 2007b; Politi et al., 1995; Schmid et al., 2004; Shaw and Cattand, 2001;
Trowbridge et al., 2001; WHO, 1998). In southern Sudan, the cost per DALY averted was
estimated at $10 for periodic screening and $17 for emergency intervention after a 9-year interval
(Trowbridge et al., 2001). In DRC, a similar figure of $17 per DALY averted was calculated for
active case-finding and treatment using mobile teams (Lutumba et al., 2007a). A range of
situations was modeled (Shaw and Cattand, 2001), showing that for most situations the cost
fell below the $25 threshold of good value for money. This thus places HAT control firmly in
the category of highly cost-effective interventions, comparing favorably with immunization
programmes and usually cheaper, for example, than malaria control using treated bed-nets
(Goodwin et al., 2000). However, the benefit of active screening for gambiense goes beyond
simply finding and treating existing patients, to reducing the size of the human reservoir,
thus preventing new infections. Accurately quantifying this component would require epide-
miological modeling. There is ample historical evidence to show that active screening main-
tains a low prevalence, so that these costs per DALY averted would be even lower if the effect
in lowering the incidence of the disease were taken into account.
A limited number of studies have looked at the economic aspects of > vector control in HAT.
Vector control is usually undertaken alongside the above measures to find and treat affected people,
a summary of costs can be found in Shaw (2004). The costs of vector control to reduce the
transmission of HAT have been further discussed by Gouteux and Sinda (1990), Lancien (1991)
and Laveissière et al. (1994). Simarro et al. (1991) compared different combinations of both active
screeningandvectorcontrol.Shaw(1989)found > activecasefindingtobemorecost-effectivethan
vector control for the gambiense form of HAT.
For rhodesiense disease, recent research (Welburn et al., 2001) has demonstrated that cattle
are the main reservoir of the disease to a far greater extent than was previously thought. This
has opened up the possibility of treating cattle in order to control the disease in humans and
this approach is being adopted in Uganda. From the economic point of view this involves a
very interesting scenario. Since the trypanocides used to deal with the pathogens affecting
people will also attack those which affect animals, the health of the livestock population will be
improved, leading to monetary benefits which together with the costs saved by preventing the
disease in people, are likely to outweigh the costs of the control strategy (Shaw, 2004). Thus a
net financial benefit is realized, without even considering DALYs and through healthier
livestock, people’s livelihoods as well as their own health is improved. Controlling sleeping
sickness, a disease of poor and marginalized populations, thus offers a highly cost-effective
opportunity for poverty alleviation.
6 What Lessons can be Drawn for other Diseases?
The global burden of this disease is not so important in absolute terms, however, as HAT is a
very focal disease, it has serious consequences at the local level, disrupting entire communities.
DALY ranking at a global or even national level might lead to misguided priority setting in
such a case.
Secondly, when evaluating the cost effectiveness of interventions in infectious diseases it is
important to realize that control efforts can have an effect on future transmission and thus the
benefits of preventing epidemics or controlling them at an early stage are considerable.
Summary Points
By the year 2000 Human African Trypanosomiasis (HAT), a largely forgotten disease, had
made a frightening comeback.
The burden of the disease in affected individuals is high. Untreated it is always fatal and
estimates of the DALYs lost per premature death range from 25 to 33 years. The morbidity
component is also high.
Due to the inherent difficulties of diagnosing sleeping sickness, under-reporting has always
been problematic. At the start of the present epidemic, it was thought that for every
reported case, ten remained undiagnosed and untreated. Recent research in endemic
rhodesiense areas and in areas where active surveillance for the chronic gambiense form
of the disease occurs indicates that even in active population screening campaigns 40–50%
of patients are not found.
In 1999 the annual global burden was estimated at two million DALYs, based on the
number of reported cases. Now it looks as though, despite the falling number of reported
cases, the figure is likely to range between 0.5 and 1.5 million DALYs, reflecting new
research showing a higher burden per affected individual and depending on the results of
evidence-based estimates of the proportion of unreported cases.
HAT affects above all economically active adults, and patients require a lot of care from the
other adults in the family. Seeking a diagnosis and obtaining treatment is costly and time-
consuming. Thus the burden on households and livelihoods is high – between 1.5 and
10 months’ income, even when diagnostics and HAT drugs are provided for free and
patients have been successfully treated with no long term after-effects from the treatment
or the disease.
Costs ranging from $10 to 17 per DALY averted for case-finding and treatment of chronic
sleeping sickness places the control of HAT firmly in the category of highly cost-effective
health interventions, well below the $25 threshold of “very good value for money.” This
cost estimate would be even lower if the effect in reducing the human reservoir of the
disease, and thus preventing future epidemics, were taken into account.
Appendix
Key Facts for Human African Trypanosomiasis (HAT)

HAT is transmitted by tsetse flies.
There are two forms of the disease. In East Africa HAT presents as an acute syndrome
caused by T.b. rhodesiense, and is maintained by an animal reservoir. West African HAT
is caused by T.b. gambiense, has a much more protracted course than East African HAT and
is transmitted in a man-fly-man cycle. The role of an animal reservoir still needs to be
clarified.
There are two stages of the disease, an early stage (hemolymphatic stage), with few or
aspecific symptoms, and a late (meningo-encephalitic) stage.
Main symptoms of HAT are neuro-psychiatric, including behavioral problems, personality
disorders, sleep disturbances and coma. It almost invariably results in death, if left
untreated.
Treatment of patients in the meningo-encephalitic stage requires more expensive and
toxic drugs. Melarsoprol, still the most commonly used drug for second stage, kills
between 5 and 10% of the patients. The only alternative, eflornithine, is expensive and
difficult to administer.
Ninety percent of HAT cases in the world are caused by T.b. gambiense. T.b. gambiense often
occurs in epidemics. Active case finding conducted by mobile teams has been the corner-
stone of the control of HAT since colonial times.
If treated at a late stage, sequelae, mainly persistence of personality disorders and decreased
mental capacities, are very frequent and pose a huge burden on the community long after
the HAT epidemics are brought under control.
References
Fèvre EM, Odiit M, Coleman PG, Woolhouse ME, Laveissiére C, Grébaut P, Lemasson J. (1994). Les com-
Welburn SC. (2008). BMC Public Health. 8: 96. munautés rurales et la lutte contre la maladie du
Fèvre EM, Picozzi K, Fyfe J, Waiswa C, Odiit M, Coleman sommeil en forêt de Côte-d’Ivoire, WHO/TRY/94.1,
PG, Welburn SC. (2005). Lancet. 366: 745–747. Genève.
Goodwin C, Coleman P, Mills A. (2000). Economic Anal- Lutumba P, Makieya E, Shaw A, Meheus F, Boelaert M.
ysis of Malaria Control in Sub-Saharan Africa. Global (2007a). Emerg Infect Dis. 13: 248–254.
Forum for Health Research, Geneva, Switzerland. Lutumba P, Meheus F, Robays J, Miaka C, Kande V,
Gouteux JP, Bansimba P, Noireau F, Frézil JL (1987). Med Buscher P, Dujardin B, Boelaert M. (2007b). Emerg
Trop. 47: 61–63. Infect Dis. 13: 1484–1490.
Gouteux JP, Sinda D. (1990). Trop Med Parasitol. 41: Lutumba P, Robays J, Miaka mia BC, Mesu VK,
49–55. Molisho D, Declercq J, Van der Veken W,
Lancien J. (1991). Ann Soc Belg Méd Trop. 71 (Suppl. 1): Meheus F, Jannin J, Boelaert M. (2005). Emerg
35–47. Infect Dis. 11: 1382–1389.
Moore A, Richer M. (2001). Trop Med Int Health. 6: Shaw AP. (1989). Ann Soc Belg Med Trop. 69 (Suppl. 1):
342–347. 237–253.
Moore A, Richer M, Enrile M, Losio E, Roberts J, Levy D. Shaw AP, Cattand P. (2001). Med Trop (Mars). 61:
(1999). Am J Trop Med Hyg. 61: 315–318. 412–421.
Odiit M. (2003). The Epidemiology of Trypanosoma Shaw APM. (2004). In: Maudlin I, Holmes PH, Miles MA
brucei rhodesiense in Eastern Uganda. Unpublished (eds.). The Trypanosomiases. CAB International,
PhD thesis, University of Edinburgh, pp. 210. Wallingford, UK, pp. 369–402.
Odiit M, Coleman PG, Liu WC, McDermott JJ, Simarro PP, Sima FO, Mir M, Mateo MJ, Roche J. (1991).
Fèvre EM, Welburn SC, Woolhouse ME. (2005). Bull World Health Organ. 69: 451–457.
Trop Med. Int Health. 10: 840–849. Trowbridge M, McFarland D, Richer M, Adeoye M,
Odiit M, Shaw A, Welburn SC, Fèvre EM, Coleman PG, Moore A. (2001). Am J Trop Med Hyg. 62
McDermott JJ. (2004). Ann Trop Med Parasitol. 98: (3 Suppl.): 312.
339–348. Van Nieuwenhove S, Betu-Ku-Mesu VK, Diabakana PM,
Politi C, Carrin G, Evans D, Kuzoe FA, Cattand PD. Declercq J, Bilengé CM. (2001). Trop Med Int
(1995). Health Econ. 4: 273–287. Health. 6: 335–341.
Priotto G, Pinoges L, Fursa IB, Burke B, Nicolay N, Welburn SC, Fèvre EM, Coleman PG, Odiit M,
Grillet G, Hewison C, Balasegaram M. (2008). Maudlin I. (2001). Trends Parasitol. 17: 19–24.
BMJ. 336: 705–708. WHO. (1998). World Health Organ Tech. Rep. Ser. 881:
Robays J, Bilengue MM, Van der SP, Boelaert M. (2004). I-114.
Trop Med Int Health. 9: 542–550. WHO. (2000) WHO Report on Global Surveillance
Robays J, Raguenaud ME, Josenando T, Boelaert M. of Epidemic-prone Infectious Diseases. WHO
(2008). Trop Med Int Health. Feb; 13(2): 265–271. Department of Communicable Disease Surveillance
Schmid C, Shaw A, Santercole C, Kwete J, Lutumba P, and Response, WHO/CDS/CSR/ISR/2000.1.
Burri C. (2004). In: Schmid C. (2004) 10-Day WHO. (2004) Wkly Epidemiol Rec. 79: 297–300.
Melarsoprol Treatment of Trypanosoma brucei WHO. (2006) Wkly Epidemiol Rec. 81: 71–80.
gambiense Sleeping Sickness. PhD Thesis, University
of Basel. Basler Schnelldruck, Basel.
84 The Economic Burden of
Malaria in Nigeria and
Willingness to Pay
A. Jimoh
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1444
2 Concept of Economic Burden of a Disease and Willingness to Pay . . . . . . . . . . . . . 1445

2.1 Types of Economic Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445
2.2 Three Approaches to Quantifying the Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445
2.3 Production Function Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1446
2.4 Cost-of Illness Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1447
2.5 Willingness to Pay Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1447
3 Extent of Economic Burden of Malaria in Nigeria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1448

3.1 Limitations of Leighton and Foster Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1449
3.2 The Study by Onwujekwe and Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1449
3.3 WHO Funded Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1450
4 Willingness to pay for Malaria Control and Treatment Programs . . . . . . . . . . . . . . 1453

4.1 Onwujekwe’s WTP Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1453
4.2 Onwujekwe and Others’ WTP Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1453
4.3 Jimoh and Others’ WTP Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1454
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1456

1444 84 The Economic Burden of Malaria in Nigeria and Willingness to Pay
Abstract: This chapter reviews available evidence on the size of the economic burden of
> malaria in Nigeria and the citizens’ > willingness to pay (WTP) for malaria control and
treatment programs. It found that the direct and indirect economic burden may be in excess of
13% of the GDP. Furthermore, the review suggests that the average amount that people are
willing to pay for malaria control and treatment programs are below their ruling market prices
and that economic status (wealth and income) is one of the major factors determining
Nigerians’ WTP for the treatment or total elimination of malaria. Consequently, it recom-
mends the promotion of universal access for the treatment of malaria in Nigeria by abolishing
or reducing payment for malaria treatment at the point of need through insurance-based
financing arrangement. It observes that the National Health Insurance Scheme that is current-
ly being put in place is a step in the right direction but that progress has been very slow.
List of Abbreviations: AAAS, American Association for the Advancement Of Science; BWFU,
> binary-with-follow-up; CBN, Central Bank Of Nigeria; COI, > cost of illness; CV, > con-
tingent valuation; DW, Durbin–Watson; FGD, focus group discussion; FMoH, Federal
Ministry of Health, Nigeria; GDP, > gross domestic product; HH, household; HIV/AIDS,
acquired immune deficiency syndrome; ITN, > insecticide-treated net; M, million; N, Naira,
Nigeria local currency; NGOs, non-governmental organizations; PF, > production function
approach; PHCs, primary health care centers; UNICEF, United Nations children’s fund; WHO,
Word Health Organization; WTP, willingness to pay
1 Introduction
Nigeria covers a total area of about 923,770 sq km and a land mass of about 910,770 sq km. It
shares boundaries with Niger Republic and Chad Republic in the north, Benin Republic in the
west and the Cameroon in its east. Its southern border is with the Atlantic Ocean (Federal Office
of Statistics, FOS, 1995, p. 1). Its population was put about 140 million by 2006 Census. On this
account, it is the most populous nation in Africa and the ninth most populous in the world.
Nigeria has a tropical climate with three broad types of vegetation zones, namely, the
forest zones in the southern coastal areas, the savannah zone in the middle areas and the
grass-land zones in the northern-most areas of the country. Corresponding to these vegetation
zones are its three major malaria epidemiological zones, namely, the forest, the savannah
and the grass-land zones.
Like most parts of Africa, malaria is a serious problem in Nigeria which is noted for its high
malaria prevalence rate (AAAS, 1991; Federal Ministry of Health 1992, 2001; Gallup and
Sachs, 2001; Onwujekwe et al., 2000; WHO/UNICEF, 2003; etc.). A number of studies have
quantified the economic burden of malaria in Nigeria (Jimoh, 2004; Jimoh et al., 2007;
Onwujekwe et al., 2000). Similarly, some studies have measured Nigerians willingness to pay
for some components of malaria control programs, malaria treatments and malaria eradica-
tion programs (Onwujekwe, 2001; Onwujekwe et al., 2004; etc.) but all these are scattered in
the literature. It is desirable to bring the results of these studies together to provide a bird-eye
view of the current state of our knowledge of the issues involved as well as to assist policy
makers in understanding these issues and how best to resolve outstanding problems.
Towards these ends, what follows consists of five Sections: Concept of Economic Burden of
a Disease and Willingness to Pay; Extent of Economic Burden of Malaria in Nigeria; Willing-
ness to Pay for Malaria Control and Treatment Programmes; and Policy Implications, Sum-
mary and Conclusions.
The Economic Burden of Malaria in Nigeria and Willingness to Pay 84 1445
2 Concept of Economic Burden of a Disease and

Willingness to Pay
In general, the major effects or end results of an illness may be morbidity or mortality.
In a morbid state, the victim may seek treatment and therefore incur health care > costs.
Beside this, normal economic activities of the victim may cease totally or hours of work are cut
down or productivity is reduced. Furthermore, victims of a disease suffer physical and
psychological pains in the morbid state. Because of these unpleasant consequences, people
under-take preventive expenditures and modify their habits, travel plans, and other economic
and social activities to remain safe from the disease. When an illness results in death –
mortality – the entire human capital investment in the victim is lost as well as the associated
potential future outputs that are foregone. Furthermore, grieving relations under go mental
pains and other knock-down effects, sometimes it may result in the dissolution of the
household.
2.1 Types of Economic Burden
In general, the above mentioned types of burden are classified into three, namely, the direct
cost, the > indirect cost and intangible cost. The direct costs include health care costs (cost of
preventive actions, diagnosis, consultation, drugs, cost of transportation and other incidental
expenses for the victim and the caretaker, etc.). The indirect costs are values of lost output due
to morbidity (for the victim and caretaker) as well as output lost to mortality. This will include
items such as the values of lost time (of victims and caretakers) while seeking care and value of
reduced output in any form it may come. Though intangible burdens also have economic
values because they are difficult to measure, only direct and indirect costs are usually summed
up as the economic burden of the disease in question. These costs are shared among the
households, the firms and public institutions (governments, NGOs, insurance institutions,
etc.) depending on the health financing arrangement that is in place. But in the main,
intangible costs are borne by the individual victims and their households. The nature of the
malaria burden is diagrammatically represented in > Figure 84‐1 In that Figure, the second
line shows the three possible states with regard to malaria that come with costs. Starting with
the first box it shows that before the morbid state, some individuals may undertake malaria
prevention activities and behavior which come with costs. The other two boxes show that
malaria attack may result in morbidity or mortality and these have their costs. In the third line
the cost of illness box collects together all the costs from the three sources and these represent
the burden of the malaria. In the fourth line, the figure shows the three types of malaria
economic burden (costs). In the last line of the figure, the parties that bear the costs
are indicated.
2.2 Three Approaches to Quantifying the Burden
There are three major approaches to quantifying the economic burden of malaria (or any
disease for that matter). These are the Production Function (PF) approach, the Cost-of-Illness
(COI) approach and Willingness-to-Pay (WTP) approach (WHO/AFRO, 2001).
. Figure 84‐1
An overview of the conceptual framework for the COI approach. It is a diagrammatic
representation of the nature of the malaria burden. It shows the three possible health states with
regard to malaria and the corresponding three types of economic burden (costs) as well as the
parties that bear the costs
2.3 Production Function Approach
The PF approach measures a disease burden by determining the effect of the disease on the
output production function. It does this by establishing an empirical statistical relationship
between the output level (as the dependent variable) and a set of explanatory variables (which
usually include the major inputs to the production process and other exogenous shocks). The
inputs to the production process will usually include capital stock, labor, among other factors
of production while the exogenous shocks may be weather, policy variables, and a measure of a
disease prevalence, among others. The production function so specified and estimated is then
calibrated at the historical values of the disease prevalence to determine the impact of the
disease on output levels.
Studies that have employed the PF approach to determine the output effects of malaria
include Audibert (1986), Gallup and Sachs (2001), Jimoh (2004), Wang’ombe and Mwabu
(1993), etc. The major challenge for studies of this variety is getting a measure of the malaria
variable that truly reflects the degree to which malaria has an impact on output (Chima et al.,
2003, p. 14–15).
Audibert et al. (1999) suggest that the extent to which the density of parasitemia in the
blood exceeds a threshold of 500 parasites per micro liter may be a good measure of the
malaria variable that is appropriate for PF study employing cross-sectional data. But even
then, the coexistence of other illnesses with malaria may result in positive bias (over-statement
of) in the estimated output effect of malaria in such studies.
Similarly, Gallup ands Sachs (2001) suggest that an index of malaria prevalence that reflects
the extent of malaria risk – based on historical data on malaria prevalence rates – may be a good
measure of the malaria variable for a PF study using cross-country data. This was confirmed by
Jimoh (2004; 2005) which suggests that an index of malaria prevalence may be a good measure of
the malaria variable in a PF study using time series data. But as with all PF studies on the output
effect of malaria, this does not overcome or reduce the probability that the output-reducing effect
of malaria is over-stated as there is no mechanism for netting out the effects of other diseases that
may coexist with malaria.
2.4 Cost-of Illness Approach
The COI approach measures the economic burden of a disease by measuring and summing up
the total direct cost of treating disease and the indirect costs of lost outputs, resulting from
malaria morbidity (and mortality), value of time lost in the course of obtaining treatment as
well as the cost of protecting oneself against disease.
Studies that have employed the COI approach to measure the economic burden of malaria
are numerous (Ettling and McFarland, 1992; Ettling and Shepard, 1991; Omwujekwe et al.,
2000; Shepard et al., 1991; etc.). These have typically relied on surveys or Focus Group
Discussions (FGD) to determine the average number of malaria episodes per period, the
average cost of treatment per episode, average time lost to morbidity and in the process of
seeking care, average transport cost and other incidental expenses – for the malaria victims and
the caretakers.
The major challenge to this type of studies is obtaining high-quality data. First is the
problem of ensuring that the respondents do not lump together many other illnesses –
especially those that have similar symptoms with malaria – along with true malaria thereby
overstating the number of malaria episodes that they experienced as well as the corresponding
costs of treatment.
Second is the problem of the timing of the survey and its time horizon. To aid memory
recall by respondents, the time horizons do not typically cover more than a maximum of
1 month to the date of interview. But the covered period may not reflect the seasonal
variations in the malaria disease episodes thereby resulting in either under- or over-statement
of average number of malaria episodes. The same can be true of average cost of treatment if the
time covered by the survey data do not reflect seasonal variations in the distribution of
episodes of more complicated and severe malaria that come with higher treatment costs.
Third is the problem associated with valuing time lost by malaria victims (and their
caretakers). Furthermore, there is the likelihood of under-stating the economic burden of
more severe and complicated malaria as the long-term effects are usually not accounted for
e.g., the long-tern effects on the intellectual development of child-victims, on the pregnant
women and the products of such pregnancies, etc. (Chima et al., 2003, p. 9–11).
2.5 Willingness to Pay Approach
The WTP approach to measuring the burden of a disease is a method of contingent valuation
(CV). It measures the burden of a disease by the amount people are ready to pay to avoid being
a victim of the disease. Such individual valuation is expected to reflect both the direct and
indirect costs of the disease to the respondents as well as a valuation of the intangible costs.
Of course there are many other uses of the WTP approach especially in the valuation of
health-care programs. Studies employing the WTP approach to value health outcomes
or health programs include Donaldson (1990), Johannesson et al. (1991), Morrison and
Gyldmark (1992), Onwujekwe et al. (2004), etc. For a more comprehensive list and review
of such studies see Klose (1999). Very recently, Jimoh et al. (2007) employed the values that
respondents stated that they are willing to pay to avoid a disease to estimate the value
they place on the burden of the disease.
However, there are some challenges to the use of this approach in measuring the economic
burden of a disease. First, because WTP involves asking individuals to state the maximum
amount that they would be willing pay to prevent an undesirable health outcome (e.g., illness),
it is desirable that the relevant questions be correctly framed so as to be close to the real life
market pricing situations that the respondents face. In this regard, the issues that are of prime
importance are the > elicitation format, scenario presentation, and the payment methods.
To enhance the validity of the stated WTP values, the questioning format – whether open-
ended, binary-with-follow-up (BWFU) or bidding game, etc. – must be appropriate for the
nature of the problem being studied. For instance, for a typical African market situation where
haggling is the rule, a bidding game may better resemble the pricing situation that respondents
face every day (Onwujekwe, 2001, p. 147). On the contrary, close-ended binary elicitation
format may be more suitable for other markets where price-tagging is the normal mode of
pricing.
Notwithstanding the apparent simplicity of the logic behind the choice of appropriate
elicitation format, the literature on this is less than being conclusive. For instance, Brown et al.
(1996), Frykblom (1997) and Loomis et al. (1997) found that actual outcomes were similar
regardless of the elicitation format adopted. However, there appears to be some agreement that
there could be starting-point bias or range bias with the bidding game and payment card format
respectively (Klose, 1999, p. 100–103).
As regard scenario specification and payment methods, the essential requirement is that
the features and characteristics of the product being offered should be clearly spelt out to the
respondents to enable an informed, valid and consistent response (see Klose, 1999, p. 102–105
for a more detailed discussion of this).
A unique feature of WTP approach to valuing the disease burden is its ability to measure
the intangible costs which none of the other two approaches can measure. It is worth noting
that the COI and WTP approaches are by their very nature implemented through cross-
sectional (micro) studies.
3 Extent of Economic Burden of Malaria in Nigeria
In Nigeria malaria imposes great burden. It is a leading cause of mortality and morbidity
especially among children and pregnant women (Ejezie et al., 1991; FMoH, 2001). Leighton
and Foster (1993) was probably one of the earliest efforts to measure the economic burden of
malaria in Nigeria using a combination of FGD and secondary data. Two possible scenarios –
low and high prevalence regimes – were investigated. They found that the malaria episodes per
adult per year ranges between 1 and 4 and the number of work days missed per adult episode
ranges between 1 and 3. Furthermore, they reported that the number of adult work days
missed per child episode of malaria for caretaking ranges between 1 and 3.
Relying on official statistics on wages by sectors, Leighton and Foster (1993) estimated
average daily wages to be N30.8 per day in the agriculture sector, N23.1 per day in the service
sector and N53.1 per day in the industrial sector. These wage rates were then used to value the
lost work days of malaria victims and their caretakers which was estimated to range between 1
and 5% of the national output (GDP). The value of reduced output (in days of work but with
lower productivity) was similarly estimated to range between 0.1 and 0.4% (Leighton and
Foster, 1993, p. 58–61). This implies that the indirect cost of malaria (i.e., the value of lost
output) in Nigeria in 1991 ranged between 1.1 and 5.4% of the GDP. The study also found that
treatment costs for malaria consumed between 4 and 13% of the households annual incomes
in 1991 (Leighton and Foster, 1993, p. 76).
3.1 Limitations of Leighton and Foster Study
Results from Leighton and Foster (1993) are at best regarded as preliminary. First, because the
study was based on FGD, its estimates of key parameters need to be validated with survey-
based data before its outcome can be accepted as reliable. Second, it is well known that given
the pervasiveness of malaria episodes in Nigeria people undertake various protective actions
which come at some costs. Therefore, the failure of the study to cover protection expenditures
means that the malaria burden was under-stated to that extent. Furthermore, issues could be
raised on the method adopted for the valuation of lost work time. It is most likely that the
official statistics on average would not reflect the marginal wages at the periods of malaria
episodes yet those are the appropriate wage rates to use (Sauerborn et al., 1991).
Also, the study did not cover the mortality costs of malaria. However, this may not be a
major draw back because it is generally accepted that while malaria has some costs associated
with mortality in areas where it is endemic, these are not profound because adults seldom die
of malaria i.e., the indirect costs associated with malaria mortality are likely to be minimal –
unlike a disease like HIV/AIDS (McGregor, 1988).
But given that it is known that mortality rate is however high among Nigerian children
below the age of 5 years (Ejezie et al., 1991; FMoH, 2001), the seemingly low cost of mortality
may become material if the output lost during grieving and bereavement period of victims’
relations and well wishers are accounted for – as relations and well wishers would normally not
engage in economic activities in such periods, resulting in lost outputs. Despite these limita-
tions the study filled in some very important gaps in our knowledge as at 1993 as it invited
further studies.
3.2 The Study by Onwujekwe and Others
Another study that examines the malaria burden in Nigeria is Onwujekwe et al. (2000). The
study conducted a survey of households in five rural communities in an eastern state of
Nigeria (Enugu State) in 1998. It shows that malaria treatment cost per household per month
was N174.35 ($1.84) and that the value of man-days lost was about N121.23 ($1.28) per
household per month giving an average total cost of N295.58 ($3.11) per household per
month (Onwujekwe et al., 2000, p. 152–154). With an average household size of 7.07 persons
reported in the study (p.154), these translated to a per capita treatment cost of N24.66 ($0.26),
indirect cost of N17.15 ($0.18) and a total cost per capita of N41.81 ($0.44) per month. This
amounts to a per capita total cost of N501.72 ($5.28) per annum. If this data were to be
representative of the entire country, with a total estimated population of 108 million in 1998,
this translates to a total cost of N54,186 million for Nigeria which constitutes about 2.0% of the
country’s GDP of N2,708.4 billion in 1998 current prices (see Central Bank of Nigeria (CBN),
1999 for GDP statistics). However, since only rural communities were sampled, these results
cannot be representative of the country because the average treatment costs are much higher in
the urban areas. Similarly, the value of man-hour in the urban areas is likely to be higher.
Like Leighton and Foster (1993) before it, Onwujekwe et al. (2000) did not investigate
protection and mortality costs with the attendant under-statement of the economic burden.
Similarly, the value of lost time was determined using an average wage rate implied by the then
government minimum wage of N3,000. Therefore, most of the issues that could be raised with
Leighton and Foster (1993) apply to that study.
3.3 WHO Funded Study
In 2003, a nationally representative survey was funded by the World Health Organisation
(WHO) with a view to determining the economic burden of malaria in Nigeria. The findings
of the study were reported in Jimoh (2004). The study used a combination of household
survey, health facility survey and official statistics (secondary data) to arrive at its results. The
study employed the three alternative approaches to measuring a disease burden – PF, COI and
WTP approaches. The household survey was conducted in August 2003 covering 1,582
households spread over all the three major malaria epidemiological zones of Nigeria. The
health facility survey was conducted in September 2003 and it covered five primary Health
Centres (PHCs) in Kwara State in the Central Area of Nigeria.
The major findings when the COI approach was applied are that the average number of
malaria episodes is 1.08 per household per month and this translates to average of 13 episodes
per household per year. At an average household size of about 4.4, this translates to about
three malaria episodes per capita per annum. The study suggests that average cost of treating a
malaria episode by self-medication is N45.86 ($1.15), N300.60 ($2.37) by herbalist/spiritualist
and N1551.26 ($12.21) by clinic/hospital. With estimated population of 120 million for
Nigeria in 2003, it was estimated that treatment cost (including cost of transport) was about
N284,992 million ($2,244 million) which constituted about 3.9% of the GDP in 2003 (see
CBN (2003) for 2003 GDP statistics).
The same study found that on the average, 2.64 days are lost by victims per an adult
episode of malaria with a corresponding loss of 2.08 days by caretakers; sick students are
reported to miss on the average 1.67 school days per episode. Projecting this for the entire
country gives a total of N303,910 million ($2,343 million) constituting about 4.1% o the
country’s GDP.
Furthermore, the value of protection expenditure was estimated at N3,208 ($25.26) per
capita per annum. This translated to about N384,965 million ($3,031 million) per annum for
the entire country representing about 5.2% of the GDP. Finally, institutional (or public) cost
was estimated at about 0.27% of the GDP.
> Table 84‐1 presents the main results of Jimoh (2004) along side with the results from two
other similar studies for ease of comparison. The Table shows that Leighton and Foster’s
(1993) estimate of indirect costs of malaria in Nigeria (which is put at between 1.1 and 5.4 per
of the GDP) is similar to that of Jimoh (2004) which is about 4% of the GDP. Similarly, the
estimates of the two studies in respect of the average number of malaria episodes per capita per
annum are similar. However, the table shows that Onwujekwe et al. (2000) estimates – when
. Table 84-1
Estimated indicators of malaria burden by different studies
Leighton and Foster Onwujekwe et al. Jimoh

Description (1993) (2000) (2004)
Average number of adult malaria 1–4 3
episodes
Average missed work days per episode 1–3 4.72
Average treatment cost per household 2,092.20 8,220.94
(N)
Average treatment cost per episode 295.93 634.33
(N)
Average protection cost per – 14,243.52
household (N)
Average protection cost per capita (N) – 3,208.00
Average lost output per household (N) 1,454.76 11,228
Average lost output per capita (N) 205.77 2,529
Institutional cost per episode (N) – 44.40
Total treatment cost for the country 31,960 284,993
(N’m)
Total indirect for the country (N’m) 22,223 303,458
Total Prevention Cost for the Country 384,960
(N’m)
Total institutional cost for the country 19,943
(N’m)
Total cost for the country (N’m) 54,183 993,354
Total treatment cost as % of HH 4–13
income
Total treatment cost as % of GDP 1.18 3.89
Total indirect as % of GDP 1.1–5.4 0.82 4.14
Total prevention cost as % of GDP – 5.25
Total institutional cost as % of GDP – 0.27
Total cost as % of GDP 2.00 13.54
Computed from Leighton and Foster (1993), Onwujekwe et al. (2000) and Jimoh (2004)
It presents major indicators of malaria burden in Nigeria as estimated or derived from three existing studies on that
subject. The first column presents estimates by Leighton and Foster (1993) while the second column presents
estimates derived form Onwujekwe et al. (2000). The third column presents estimates by Jimoh (2004). An increase
in any of these variables implies an increase in the burden of malaria. HH household; GDP gross domestic product;
N Naira; m Million
they are comparable – are generally lower than those of Jimoh (2004) which suggests that the
burden of malaria per capita may be significantly higher in the urban areas than in the rural
areas – from where Onwujekwe (2004) drew its sample.
It seems therefore that Jimoh (2004) provides more comprehensive and representative
estimates of the economic burden of the malaria illness in Nigeria than any of the existing
studies. However, like all other studies on this subject, it does not investigate mortality costs.
> Table 84‐2 presents a summary of such estimates based on the COI approach and this
shows that the economic burden of malaria may be consuming up to 13.5% of Nigeria’s GDP.
But we must caution that this does not translate to 13.5% in lost output because expenditures
on health care (direct treatment cost of a Disease) are expected to stimulate economic
activities and outputs in the healthcare sector and therefore expand the GDP. Similarly,
protection (as well as institutional) expenditures will stimulate economic activities in the
sectors producing the relevant goods and services.
Therefore, whether or not malaria has an overall negative effect on output will depend on
the relative strength of its output-creating effect (which is yet to be estimated by any study that
has come to our knowledge) and its output-reducing effect. One of the ways to determining
the net output effect of malaria is to apply the PF approach.
In terms of the distribution of the economic burden of malaria by types, > Chart 84‐1
shows that private > protection costs take the lion share at about 38.7% of the total costs
which is followed by private indirect costs that account for about 30.6%. Private treatment
costs account for about 28.8% of the burden while > institutional costs about 2%.
. Table 84-2
Estimated economic burden of malaria in Nigeria by types
Description N(million) $(million) % of GDP

Direct treatment cost 284,992 2,244 3.9
Protection cost 384,965 3,031 5.2
Indirect cost (lost output) 303,910 2,393 4.1
Institutional (public lost) 19,943 167 0.3
Total 993,810 7,825 13.5
Source: Jimoh (2004)
> Table 84‐2 presents the value of the economic burden of malaria by four broad types as estimated by Jimoh
(2004). The first column presents these estimates in millions of local currency (Naira) while the second column
presents the same estimates in millions of US dollars. The third column expresses the estimated economic burden
as a percentage of Nigerian GDP. GDP gross domestic product; N Naira; m million
. Chart 84‐1
Nigeria Malaria Burden by Types (Percentages). Chart 1 uses a pie diagram to show the
distribution of the economic burden of malaria by types, namely, private protection costs,
private indirect costs, private treatment costs and institutional costs. The relative sizes of the
components of the chart reflect their relative shares of the burden
The results from the application of the PF approach by Jimoh (2004) to evaluate
the economic burden of malaria in Nigeria puts the negative (net) output effect (indirect
cost) of malaria at about 4% of the GDP and Jimoh (2005, p. 41) suggests that the bulk (75%)
of the output loss is borne by the Nigerian agricultural sector which is the largest employer of
labor and in which peasant farmers are in the majority. Consequently, the economic burden of
the malaria disease seems to fall disproportionately more on the poor in Nigeria.
But it is important to note that even with the application of the PF approach, the
chances are there that the negative output effects that are often attributed to malaria
alone may the combined effects of some other important diseases who impacts are not specifi-
cally provided in the estimated production function. Yet, except the impacts of these other
diseases are truly randomly distributed over time or they are not significant even when put
together, the resulting estimates may overstate the output effect of malaria. Though Gallup and
Sachs (2001) expressed some concern about the large size of the estimated negative output effect
of malaria and concluded that the associated mechanism by which it has such a large effect
remains unclear, it might well be that such effect include the effects of other diseases.
4 Willingness to pay for Malaria Control and Treatment

Programs
There have been a number of studies that have investigated the willingness of Nigerians to
pay for malaria treatment and control programs or some components of such progr-
ams (Jimoh et al., 2007; Onwujekwe, 2001; Onwujekwe et al., 2004, Onwujekwe and
Uzochkwu, 2004).
4.1 Onwujekwe’s WTP Study
Onwujekwe (2001) in an attempt to compare the theoretical and predictive validity of two
alternative elicitation formats – BWFU and bidding game – found, among others, that
over 83% of respondents who were selected from two rural communities in Enugu State
were willing to pay for the large nets for their own use and that the mean slated WTP value was
N242.47 ($2.55) which is below its market of N300 ($3.16) at the period of study.
The implication of this is that ITNs would have to be significantly subsidized for it to be
used by the majority. A similar pattern was observed in respect of respondents’ willingness to
pay for the small-sized ITNs.
Though the study attempted to determine the major determinants of respondents’ WTP
for ITNs, the poor statistical properties of the estimated regression model (adjusted R2 of less
than 0.2 and the statistical insignificance of most of the estimated coefficients) suggest that
little valid inferences could be made from the regression results. Similarly, because the sample
were drawn from two rural communities, the mean stated WTP for ITNs that were reported in
the study are at best indicative estimates of the WTP for ITNS in the entire country.
4.2 Onwujekwe and Others’ WTP Study
Onwujekwe et al. (2004) reported that less than 5% of respondents surveyed were willing to
buy ITNs at the price of N450 ($4.09). It also found that economic status of the respondents
was a significant explanation of whether they own ITNs or not with only 14.9% of the poor
respondents having ITNs in contrast to 21.1% of the rich who had ITNS. The mean stated
WTP for ITNs by the poor was found to be about N105 ($0.95) while the corresponding figure
for the rich is N230 ($2.09). It also found that the demand for ITNs among the poor was more
price sensitive than those of rich. The study concluded that the poorest socio-economic groups
were less likely to purchase ITNs and consequently recommends that a universal or targeted
ITN subsidy program (for the poor and biologically vulnerable groups) would increase the
demand for ITNs in Nigeria.
Onwujekwe and Uzochukwu (2004) found that the mean WTP for ITN for own use
ranged between N179.8 ($1.63) (obtained from open-ended elicitation format) to N188.8
($1.72) (that was obtained from the BWFU elicitation format); the market price then was
N450 ($4.09). This again suggests that subsidy would be required to increase ITN coverage in
Nigeria. Furthermore, it found that some well-to-do households were prepared to pay some
amounts to enable poor households purchase their own ITNs. Mean stated WTP for such
altruistic contributions ranges between N38.8 ($0.35) and N103.7 ($0.94). On the basis of
these findings, they concluded that the potential for well-to-do people to contribute for the
poor to own ITNS actually exists and that malaria control program should explore altruistic
contribution as a mechanism to increase ITN coverage.
The conclusion that can be drawn from these studies is that an ITN subsidy program is
inevitable if ITN coverage is to increase significantly in Nigeria and targeted subsidy programs may
be the way to start. However, all the above mentioned studies have been carried out in Enugu State
and all have virtually been in rural communities which may limit their values for generalization.
4.3 Jimoh and Others’ WTP Study
Jimoh et al. (2007) was directly concerned with obtaining the WTP of Nigerians for malaria
treatment and control. It uses the data obtained from Jimoh (2004) which is nationally
representative. The study investigated four major questions. These are: What households
were willing to pay to be covered if there is a program of medical care which offers free
malaria treatments for members of households that subscribe to it. What they were willing to
pay to be supplied with the number of ITNs that would be sufficient for the needs of all
members of the households. What they are willing to pay to be protected from malaria via area
spraying that would be undertaken twice a year. What they were willing to pay per household
per annum for the total eradication of malaria.
The study found that households were willing to pay an average of N1,112 per month
(USD 9.3) for the treatment of an adult and N1,132 (USD 9.4) for a child. Similarly, house-
holds were willing to pay an average N1,325 (USD 11) per household to be supplied with ITNs
that would be sufficient to meet the needs of all members of the households and would be
willing to pay about N1,068 (USD 8.9) per annum for area spraying. Also, households
were willing to pay N7,324 (USD 61) per household per annum for total eradication of malaria.
Comparing the stated WTP values with relevant households’ actual expenditures (see
> Table 84‐3), the study concluded that the difference between the actual cost of protection,
treatment and indirect cost to the households and what the households are willing to pay for
the eradication of malaria which was about N2,715 (USD 22.6) per month per household
represents the household valuation of the intangible costs. This implies that intangible costs
may be about 12% of the Nigerian GDP. Similar differences in respect of malaria treatment
. Table 84-3
Estimates of what households are willing to pay and their corresponding actual expenditures
Amount they are

Cost items (N) Actual expenditures (N) willing to pay (N) Excess over actual (N)
Treatment – adulta,b 685.19 10 112.10 426.91
0
Treatment – child – 1 131.70 –
Bed nets 10 000.90 10 325.00 324.10
Window/door nets 643.86 –
Area spraying (2/year) – 10 068.00
Room spraying 806.89 –
0 0
Eradication of malaria c
4 609.19 7 324.20 20 715.01
Source: Jimoh et al. (2007)
> Table 84‐3 presents estimates of what Nigerians are willing to pay for various types of malaria interventions and
services as estimated by Jimoh et al. (2007). The first column presents the levels of actual expenditure while the
second column presents stated WTP values. For the first row – treatment cost for adult – the reported actual cost of
treatment is a weighted average of the costs of treatment by self-medication, by herbalist/spiritualist and by clinic/
hospital. The average cost of treatment in clinic/hospital is about N1,340 ($1.17). N Naira
a
Actual is the weighted average cost of obtaining treatment and cure from the three major health-care providers
multiplied by average malaria cases per household (1.08). It is calculated that 0.53, 0.07 and 0.40 of patients are
treated and cured by self-medication, Herbalist/Spiritualist and Clinic/Hospital respectively
b
Treatment cost in Clinic/Hospital not involving admission is used
c
Actual is the sum of protection expenditures, weighted treatment costs and indirect costs – all per household and
per month
and ITNs were interpreted as price for elimination of payment risk (insurance policy) and
payment for the inconvenience involved in self procurement.
At an average household size of 4.4 reported in the study, the reported stated WTP for
ITNs implies a per capita WTP for ITNs of N301.14 ($2.37) which is below its market price of
N450 ($3.54) at the close of 2003. Thus, the study provides further evidence that an ITN
subsidy program would be required to increase ITN coverage in Nigeria.
Similarly, the stated WTP for malaria treatment per capita per month is less than the
average cost of treating an episode of malaria in a clinic/hospital that was reported by Jimoh
(2004) to be about N1,340 ($11.17) for cases that do not involve hospitalization and N1,551
($12.93) for cases that involve hospitalization. This suggest that subsidy would be required if
the utilization rate of modern healthcare facilities for the treatment of malaria is to be
increased significantly.
Another interesting outcome of the study is the identification of the major determinants of
the stated WTP for malaria eradication. The major findings are presented in > Table 84‐4.
These results indicate that the major determinants of households willingness to pay for
malaria eradication and control are their: level of education, income, cost of protection, self
assessment of their status relatively to others in the society and total cost of obtaining
treatment in the hospital with married households ready to pay more than the singles.
Similarly, those currently attending public medical facilities are willing to pay less for
malaria control as well as strangers (i.e., those who have not stayed in the community more
than 1 year). One important implication of these estimates is that, other things held constant,
. Table 84-4
Estimates of the log-linear regression model
Coefficientsa, b
Unstandardized Standardized
coefficients coefficients
Model B Std. error Beta t Sig.
Public medical facilities 0.125 0.069 0.010 1.822 0.069
Log of HH highest level of education 0.408 0.066 0.124 6.203 0.000
Log of HH income 0.408 0.022 0.604 18.466 0.000
Log of cost of spraying 0.224 0.028 0.167 7.877 0.000
Log self-assessment rating 0.578 0.077 0.077 7.460 0.000
Log of total cost of hospital treatmentc 0.210 0.032 0.167 6.652 0.000
Stranger 0.300 0.185 0.005 1.624 0.104
Married household 0.171 0.067 0.019 2.552 0.011
Source: Jimoh et al. (2007)
> Table 84‐4 presents the results of a regression analysis undertaken by Jimoh et al. (2007). The estimated
unstandardized coefficients (B) are the effects of a one percentage change in the corresponding explanatory
variable on the dependent variable (WTP). The last column of the table reports the level at which the explanatory
variable is statistically significant with a value above 0.05 suggesting that variable is not statistically significant at
the conventional 5% level of significance. Dependent Variable: Log of WTP to eradicate malaria; Other Statistics:
R2 = 0.987; DW = 1.522; F = 15341.9
a
Linear regression through the origin
b
Treatment cost in clinic/Hospital not involving admission is used
as the economic status of respondents improves (as indicated by income and wealth levels),
their WTP for malaria treatment and control increases. Consequently, the poor have signifi-
cantly lower WTP than the rich.
Summary Points
Evidence available from existing studies suggests that the burden of malaria illness in
Nigeria may be in excess of 25% of the GDP.
Direct and indirect costs (excluding the costs attributable to mortality) constitute about
13% of the GDP while the value placed on intangible costs comes to about 12% of the GDP.
Of the direct and indirect costs about 98% is borne by the private citizens and the lion
share of this is on protection expenses.
Also, available evidence suggests that that average WTP for malaria treatments is lower
than the average cost of treatment in clinic/hospital and that economic status (wealth and
income) is one of the major factors determining the amount Nigerians are willing to pay
for the treatment or total elimination of malaria.
In a society where most (over 65% of) healthcare expenses are financed through household
out-of-pocket expenditures (Soyibo et al., 2005), majority of the poor who have low WTP
may indeed be unable to pay for the cost of malaria treatment at ruling market rates in
modern clinics/hospitals when the need arises.
Such inability to pay probably explains why self-medication appears to be a popular first-
line of action for the treatment of malaria by the poor as well as explaining why herbal and
spiritual care providers still attract some patronage (Jimoh, 2004, p. 30–32).
There is therefore a need to promote universal access for the treatment of malaria in
Nigeria (and may be for healthcare in general) by abolishing or reducing payment for
malaria treatment (or healthcare) at the point of need.
By abolishing or reducing payment at the point of need, not only are the chances of
catastrophic health expenditures among the poor reduced but by promoting economic
growth via improvement in the health of the poor, it may also be a poverty-alleviation
strategy.
However, this narrows the viable financing options to two, namely, tax-financed free-at-
the-point-of use treatment for malaria or insurance-based financing arrangement for the
same purpose. The latter appears more attractive because it may be more fiscally sustain-
able than the former.
Nigeria is currently putting in place a national health insurance scheme (NHIS) starting
with the formal sector employees but progress has been very slow.
With the informal sector still virtually uncovered by NHIS and the requirement that some
co-payment be made at the point of treatment (NHIS, 2002), it is yet to be seen how the
needs of the very poor will be catered for.
References
American Association for the Advancement of Science Federal Ministry of Health. (1992). The National
(AAAS). (1991). Malaria and Development in Africa: Health Policy of Nigeria. Federal Ministry of Health,
A Cross-Sectoral Approach. AAAS, Washington, DC. Lagos.
Audibert M, Mathonnat J, Nzeyimana I, Henry M. Federal Ministry of Health. (2001). Strategic Plan for
(1999). Revue D’Economie du Development. 4: Rolling Back Malaria in Nigeria 2001–2005.
121–148. FMOH, Abuja.
Audibert M. (1986). J Dev Econ. 24: 275–291. Federal Office of Statistics (FOS). (1995). Annual Ab-
Audibert M, Mathonnat J, Nzeyimana I, Henry M. stract of Statistics. FOS, Lagos.
(1999). Revue D’Economie du Development. 4: National Health Insurance Scheme. (2002). Operational
121–148. Guidelines on NHIS. Abuja.
Brown T, Champ P, Bishop R, McCollum D. (1996). Frykblom P. (1997). J Environ Econ Manage. 34: 275–287.
Land Econ. 72: 152–166. Gallup JL, Sachs JD. (2001). Am J Trop Med Hyg. 64:
Central Bank of Nigeria (CBN). (1999). Statistical Bulle- 85–96.
tin, CBN. Vol. 10, No. 1. Klose T. (1999). Health Policy. 47: 97–123.
Central Bank of Nigeria (CBN). (2003). Annual Reports Jimoh A. (2004). The Economic Burden of Malaria in
and Statement of Accounts, CBN. Nigeria. WHO Final Technical Report.
Chima RI, Goodman CA, Mills A. (2003). Health Policy. Jimoh A. (2005). Agrosearch. 7: 37–46.
63: 17–36. Jimoh A, Sofola O, Petu A, Okorosobo T. (2007). Cost Eff
Donaldson C. (1990). J Health Econ. 9: 103–118. Resour Alloc. 5: 1–17.
Ejezie GC, Ezednachi EN, Usanga EA, Gemade EI, Johannesson M, Jonsson B, Borgquist L. (1991). J Health
Ikpatt NW, Alaribe AA, et al. (1991). Acta Tropica. Econ. 10: 461–473.
48: 17–24. Leighton C, Foster R. (1993). Economic Impacts of
Ettling M, McFarland DA. (1992). Economic Impact of Malaria in Kenya and Nigeria. Health Financing
Malaria in Malawi. Vector Biology Control Project, and Sustainability Project 6, Bethesda, Abt Associ-
Virginia. ates, Maryland.
Ettling MB, Shepard DS. (1991). Trop Med Parasitol. 42: Loomis J, Brown T, Lucero B. (1997). Environ Resour
214–218. Econ. 10: 109–123.
McGregor IA. (1988). In: Wernsdorfer WH, McGregor Shepard DS, Brinkmann U, Ettling M, Sauerborn R.
IA (eds.) Malaria: Principles and Practice of Malariol- (1991). Trop Med Parasitol. 42: 199–203.
ogy. Churchill Livingstone, Edinburgh, pp. 753–767. Soyibo A, Odious O, Ladejobi F, Lawanson AO,
Morrison GC, Gyldmark M. (1992). Health Econ. 1: Oladejo B, Alayande S. (2005). National Health
233–243. Accounts of Nigeria, 1998–2002. Final Report of
Onwujekwe O. (2001). Health Econ. 10: 147–158. World Health Organization (WHO) Sponsored
Onwujekwe O, Chima R, Okonkwo P. (2000). Health Study, Geneva.
Policy. 54: 143–159. Wang’ombe JK, Mwabu GM. (1993). Soc Sci Med. 37:
Onwujekwe O, Hanson K, Fox-Rushby J. (2004). Malaria 275–291.
J. 3: 6. WHO/AFRO. (2001). A Framework for Estimating Eco-
Onwujekwe O, Uzochukwu B. (2004). Health Econ. 13: nomic Burden of Malaria in the African Region.
477–492. WHO, Harare, Zimbabwe.
Sauerborn R, Shepard D, Ettling M, Brinkmann U, WHO/UNICEF. (2003). Africa Malaria Report. WHO/
Nougtera A, Diebfeld H. (1991). Trop Med Parasi- CDS/MAL/2003.1093.
tol. 42: 219–223.
85 Measurement of Adverse
Health Burden Related
to Sexual Behavior
S. H. Ebrahim . M. McKenna
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1460
2 History of Analysis of Sexual Behavior Related Health Burden . . . . . . . . . . . . . . . . . . . 1461
3 Challenges to Assessment: Conceptual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1463
4 Challenges to Assessment: Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1464
5 Estimation of Attributable Fractions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1465
6 DALY-Specific Computations and Adjustments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1465
7 Comment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1466
8 Way Forward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1467
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1468
Disclaimer: The findings and conclusions in this report are those of the authors, and do not necessarily represent the
official position of the U.S. Department of Health and Human Services.

1460 85 Measurement of Adverse Health Burden Related to Sexual Behavior
Abstract: As part of an analysis of the burden of disease and injury in the United States, we
established a method to identify and quantify the incidence of adverse health events, deaths,
and disability adjusted life years (DALY) attributed to unprotected sexual behavior (USB).
Estimates for the incidence, morbidity and mortality from sexually transmitted diseases (STD)
were derived from vital statistics, notifiable disease surveillance system, national surveys,
outpatient and hospital discharge summaries, prevalence data from individuals attending
health care services, the published literature, and expert opinion. Because many conditions
for which USB is implicated as a cause have multifactorial causes, a major challenge is
developing estimates for the attributable fraction of disease that is exclusively related to
USB. For conditions with risk factors other than sexual behavior (e.g., HIV), or etiology
(e.g., liver disease), sexual behavior-attributable fraction was estimated based on the literature
or through expert consultations. Maternal and infant conditions related to unintended preg-
nancy and all voluntary abortions were considered as adverse outcomes of sexual behavior.
A comprehensive estimation including morbidity, mortality, and summary measures such as
DALYs can identify a larger burden related to sexual behavior and more profound disparities by
gender than that can be captured by traditional measurement of mortality or morbidity alone.
However, because epidemiology of health events related to sexual behavior varies by countries
or regions, statistics such as attributable fractions should be developed based on these geo-
graphic units. Further, summary measures involve the synthesis of parameters considered
objective and science-driven with culture-specific and value oriented inputs. Many countries
have limited information regarding either of these topics and must develop estimates in this
context. This chapter provides only a roadmap for such estimation.
List of Abbreviations: DALY, disability adjusted life years; HIV, human immunodeficiency
virus;; ICD, international classification of diseases; STD, sexually transmitted diseases; USB,
unprotected sexual behavior
1 Introduction
Health systems and health policies are increasingly being challenged by increasing demand for
health care, rapid epidemiologic transition, exploding costs associated with the delivery of
medical services and greater accountability for effective use of resources. The evidence base for
health policy decisions can only as sophisticated as the comprehensiveness and relevance of the
information provided to those individuals responsible for these decisions. The past four decades
experienced significant changes in how we measure health and prioritize health challenges.
Improvements in epidemiology and biomedical sciences have heralded conceptual changes in
our understanding of the depth and scope of health service needs, prevention opportunities and
research. Many factors the interconnectedness among diseases in terms of causation, the
potential opportunities of a bundled approach to their combined prevention, and a life-span
approach to evaluating the impact of public health measures have helped move health initiatives
from a disease and end stage oriented approach to more of an ‘‘upstream,’’ health determinants
approach. Such an approach is epidemiologically sound, rational, and potentially cost-effective.
Health determinants that have generally received the most attention include sexual
behavior, smoking, alcohol consumption, caloric over consumption inadequate fruit and
vegetable intake, the built environment, and poverty. The influence of sexual behavior on
reproductive health and sexually transmitted diseases (STDs) is obviously one of the strongest
Measurement of Adverse Health Burden Related to Sexual Behavior 85 1461
relationships. For the purposes of this review USB is defined as sexual activities that result in
outcomes considered undesirable from a societal perspective regardless of the intent of the
participants at the time of the sexual encounter. This includes encounters where contraceptives
and barrier methods were used incorrectly, or ineffectively – as well as sexual encounters
resulting in unintended pregnancies. An important clarification about the DALYs attributed to
unintended pregnancies is that only the negative health outcomes associated with these
pregnancies (e.g. infection, hemorrhage, infant mortality) were denominated. There are no
valuations based on the negative, or positive, emotional relationships, or productivity out-
comes that develop as a result of the pregnancies being unintended. Similarly, the DALYs
attributed to elective abortions only include the direct, negative health outcomes (e.g. infec-
tion, hemorrhage, post-surgical complications) which may result from such procedures. The
epidemiologic focus of this approach calls for programmatic interventions aimed at promot-
ing healthy sexual behavior. Because the adverse outcomes of sexual behavior usually affect
younger individuals than many other major diseases such as cancer or heart disease, relative
assessments of the impact of these various conditions that only count deaths or incident cases
of disease alone are inadequate for a proper understanding of the dimensions of the issue.
Some adverse effects of prevalent disease (for example Chlamydia trachomatis infection in
women who may remain asymptomatic and untreated) affect individuals prior to and even
during some of their most potentially productive years. In addition, some of these conditions
will have long term effects that diminish the quality of life of the affected for many years (for
example infertility related to sexually transmitted infections).
This chapter builds upon past efforts to quantify the burden attributable to sexual
behavior and presents a comprehensive approach to assess the public health burden related
to USB. This paper presents a roadmap for the estimation of summary statistics on adverse
health burden from sexual behavior including the incidence of adverse health events (morbid-
ity and their sequelae), mortality; and disability-adjusted life- years. DALY is a time-based,
composite indicator of the burden of disease that adds loss of life-years due to premature
death and loss of healthy life due to morbidity and associated disability.
2 History of Analysis of Sexual Behavior Related Health

Burden
Composite examination of the burden from sexual behavior was not considered until
the1980s during which the emergence of HIV and related expansion in research lead to
broadening of the spectrum of disorders associated with USB. Until then, diseases related to
sexual behavior were subsumed under the umbrella of reproductive health. To our knowledge
the first attempt to focus attention on comprehensive burden assessment was an analysis by
Grimes of the U.S. Centers for Disease Control in 1986, who studied STD-related mortality in
the United States for the years 1955, 1965, and 1975, expanding the concept of reproductive
mortality to include deaths related to sexually transmitted diseases. Under this new classifica-
tion which counted both infectious and other conditions related to reproductive health within
the framework of USB, STDs caused 32% of reproductive mortality in 1965. As the debate on
the causation of cervical cancer was not conclusive at that time, Grimes excluded cervical
cancer from this analysis. However, Grimes underscored that if cervical cancer was included,
then cervical cancer deaths alone would alone outnumber all other reproductive causes
combined. Cervical cancer deaths have declined substantially in the U.S. and other developed
countries and its contribution to the burden of USB will continue to decline in developed
countries. However, the burden form cervical cancer remains significant in developing countries.
Globally, the 1994 International Conference on Population and Development expanded
the reproductive health concept to include ‘‘sexual and reproductive health.’’ The recognition
of cervical cancer as being related to USB, the emergence of sexually transmitted cases of HIV,
recognition of and improvements in laboratory diagnosis of Chlamydia trachomatis, better
understanding regarding the transmission dynamics of hepatitis viruses in the 1980s
prompted the reexamination of the concept of USB as a major root cause of ill health. In
1993, McGinnes and Foege developed a crude estimate of deaths by causative factors and
identified USB as a rapidly increasing factor. This estimate was not based on International
Classification of Diseases (ICD) codes of individual case records; rather they attributed deaths
from specific causes based on the role of of sexual behavior on the total number of deaths. In
1997, Ebrahim and colleagues at the U.S. Centers of Disease Control refined the earlier
methodologies and published a revised analysis of deaths attributable to USB in the U.S. for
the 20 year period from 1973 through 1992. They used ICD-coded actual data reported on
death certificates of individuals. Due to various challenges in attribution of a cause-disease
link and limitation of data, they categorized the quality of their findings as ‘‘hard’’ data
indicating verifiable statistics, and ‘‘soft’’ data that indicates best estimates based on various
assumptions. The analysis categorized diseases related to USB into three categories; those
conditions that are always sexually transmitted (e.g., gonorrhea), conditions that are not
always transmitted sexually (e.g., hepatitis viruses) for which attribution was based on
epidemiological estimates, and HIV infections acquired sexually based on patient information
provided from case reports on HIV infected individuals. Although Chlamydia was recognized
as STD pathogen by this time, it was not included in the ICD eighth revision. Therefore, it was
not possible to identify persons who had the diagnosis of Chlamydia in that analysis. Given the
burden of Chlamydia infections in women and its relevance to infertility, the inability to
include an estimate Chlamydia burden in that analysis was a major limitation.
By the late 1990s a new concept for the measurement of ill health was being articulated by
the Global Burden of Disease (GBD) study. A metric called the disability-adjusted life year
(DALY) was developed which attempted to capture both fatal and non-fatal health outcomes,
separately and in combination. The GBD provided comprehensive data on sexual and
reproductive health related DALYs worldwide. Using this methodology, Ebrahim et al.
(2005), published a detailed account of all measurable health effects attributable to USB in
the U.S. Their findings indicated that DALYs were able to elucidate previously unrecognized
burdens from the non-fatal losses in health associated with the adverse effects of USB. Overall,
in the United States, in 1998, mortality estimates attributed 1.3% of U.S. deaths to USB,
whereas DALY estimates put the proportion of the health burden associated with USB at 6.2%
of the total. Some disparity was seen by gender between mortality and DALYs; females suffered
the majority of incident USB-related adverse health events (62%) and DALYs (57%), whereas
males suffered the majority of deaths (66%). If HIV-related mortality were excluded, more
than 80% of USB-related mortality would be those among women. Among females, more than
half of the incident events and DALYs were contributed by curable infections and their sequale.
However, deaths from curable STDs were rare; the majority of USB deaths are from viral
infections and their sequelae (men 99.5%; women 96.8%). Cervical cancer and HIV were the
leading causes of such mortality among females, whereas HIV was by far the single leading
cause among males. Also, viral diseases caused the majority of health burden attributed to USB
among males. This chapter summarizes that methodology.
3 Challenges to Assessment: Conceptual
A major conceptual challenge in defining USB related health burden is the overlap between
reproductive health and USB-related health. Current definition of USB-related health burden
includes all conditions or aspect of health condition for which USB is epidemiologically
significant. Therefore, the list of conditions includes sexually transmitted diseases, medical
complications of pregnancy and child birth, and some reproductive outcomes (> Table 85-1).
A comprehensive approach to calculate burden from root causes such as USB is challeng-
ing from a measurement perspective. The health metrics that are in use today by most health
systems are not comprehensive enough to capture the full dimensions of adverse effects of root
causes of diseases. This is because of both the challenges in quantifying certain behaviors and
because the adverse effects of behaviors or root causes cuts across the lines along which
diseases have traditionally been measured. Public health and medical practice is dominated
by vertical disease-focused programs that yield separate and poorly coordinated data collec-
tion efforts. Measurement of burden of chronic diseases that is attributable to USB is much
. Table 85-1
Attributable fractions used for estimation of sexual behavior-related adverse health burden in
the United States
Attributable to sex (%)

Female
Curable diseases and their sequelae
Chlamydia 100
Gonorrhea 100
Trichomoniasis 100
Syphilis 100
Other curable STDs 100
PID 65
Infertility 10
Viral diseases and their sequelae
Genital herpes 100
HPV 100
-Cervical cancer 100
Hepatitis B Virus 33b,58c
Hepatitis C Virus 9b,20c
HIV 57d
Pregnancy-related
e
Pregnancy outcome’
Elective abortions’ 94f
Male
Curable diseases and their sequelae
Chlamydia 100
1464 85
Measurement of Adverse Health Burden Related to Sexual Behavior
Attributable to sex (%)

Gonorrhea 100
Trichomoniasis 100
Syphilis 100
Other curable STDs 100
Urethral stricture –h
Epididymitis –h
Infertility –h
Viral diseases and their sequelae
Genital herpes 100
HPV 100
Hepatitis B Virus 33b,58c
Hepatitis C Virus 9b,20c
HIV 72d
These conditions include events attributed to adverse effects of unprotected sex and not necessarily attributed to
sexually transmitted infections or their sequelae. All other conditions are attributed to infections and their
sequelae
a
Not included in the number of women with HPV
b
Chronic liver disease and hepatocellular carcinoma
c
Acute conditions
d
McGinnis and Foege (1993)
e
Based on age-specific rates of unintendeness of pregnancy (Henshaw 1998) and includes effects on both mother
and child
f
Abortions performed for medically not indicated reasons are attributed as adverse effects of sexual behavior
g
Allocated to pregnancy outcome
h
Based on natural history of gonorrhea and chlamydia (Murray 1998)
i
Parameters are inadequate to compute DALYs
more challenging than infectious diseases that have a clear causal pathogen, more defined
incubation period and pathological process. Also, mixing burden from chronic disease causes
based on events that occurred several decades ago with current statistics from acute conditions
presents a challenge to policy assessment when considering the time frame for events. For
example, USB that results in papilloma virus infections and subsequent cervical cancers occurs
one or two decades ago, prior to the diagnosis of the neoplasm, whereas pregnancy-related
health events result within less than one year of the occurrence of the USB. Therefore, overall
DALY measurements of current morbidity and mortality associated with USB may not capture
all of the relevant changes in such behaviors in recent years.
4 Challenges to Assessment: Data
Statistics needed for estimation of sexual behavior-related burden may come from
(1) reportable infections (such as syphilis, gonorrhea, Chlamydia) which may vary by
countries (2) diagnosis made during outpatient or inpatient visits to medical facilities
(3) national surveys of representative population samples, and (4) data from mathematical
models of STD epidemiology based on knowledge about the natural history of these diseases.
A simple comprehensive approach for attributing adverse health outcomes to specific root
causes such as USB is not available. USB plays a role in many adverse health outcomes that
have a multifactorial etiology. USB leads to a variety of harmful consequences, ranging from
unintended pregnancy, social stigma, infections and chronic psychological or pathological
sequelae including cancers. The consequences are considered not because all adverse effects are
classical diseases or pathological process that can be easily defined but because they affect the
quality of life of the affected individual. The current scheme for the classification of diseases
ICD is based on diseases and this is inadequate to assess disease burden from a root cause. For
example, only a proportion of hepatitis B virus is transmitted sexually, and only a proportion
of liver cancer is caused by hepatitis B virus. Sorting out the relative contribution of sexual
behavior for some conditions and quantification of such conditions require disparate
approaches and varying data sources. Similarly, calculation of DALY’s for a given condition
require information on the natural history of that condition including incidence and duration
of illness, the extent of disability, and the number of deaths, some of which are not readily
available.
5 Estimation of Attributable Fractions
The analytic methodology presented here adapted and updated the methodology used in the
global burden of disease study—initiated by the World Bank and the World Health Organiza-
tion, and all other attempts to assess various components of USB- related health burden. Data
were reviewed from published estimates of incidence of STD and reproductive morbidity and
mortality, national vital statistics, notifiable disease surveillance system, national surveys,
outpatient and hospital discharge summaries, prevalence data from individuals attending
health care services, and expert opinion.
We included 100% of all major sexually transmitted infections. For conditions with risk
factors other than USB (e.g., HIV), or etiology (e.g., liver disease), we identified the sexual
behavior-attributable fraction from the literature (> Table 85-1). Consistent with assumptions
in the report of the World Health Organization, maternal and infant conditions related to
unintended pregnancy and all voluntary abortions were considered as adverse outcomes of sexual
behavior. Sexual behavior-related conditions with insufficient data on attributable fractions (e.g.,
bacterial vaginosis, rape-associated violence and post-traumatic stress disorders) were generally
excluded. For conditions that are not always attributable to sexual transmission, data shown in
> Table 85-1 are prepared for the United States based on various epidemiological parameters.
These numbers need to be reassessed for other countries based on regional or local epidemiologic
patterns of respective conditions. When adequate epidemiologic data is not available, expert
opinion may be used to come up with most appropriate estimates.
6 DALY-Specific Computations and Adjustments
Comprehensive measures that attempt to combine the impact of non-fatal as well as fatal
health conditions are known as summary health measures. The DALY is one example of such a
summary measure. The methodologic and ethical complexities as well as long-standing
controversies associated with the computation of these measures, and especially the DALY,
have been reviewed in greater detail elsewhere and are beyond the scope of this chapter (Field
and Gold, 1998; Murray et al., 2002, 2006). Briefly, the DALY is a time-based measure that
attempts to enumerate the years lost to premature death (years of life lost-YLLs), and the years
of healthy life ‘‘lost’’ to living in a state of less-than-perfect health (yeast lost to disability-
YLDs). In order to calculate cause-specific YLLs the number of years each person was expected
to live at each age of death was summed across a common set of conditions listed as the
underlying cause of death on the decedent’s death certificate. The life-expectancy is calculated
separately for men and women and is based on the longest observed life-expectancy in the
world (i.e., Japanese women). The YLDs were estimated by multiplying incident, non-fatal
health conditions by the estimated, average duration of disability associated with each type of
condition. The impact of the non-fatal conditions on lost health was obtained by multiplying
these durations by disability weights that range between 0 (perfect health) and 1 (severity
equivalent to death). These valuations were developed for the Global Burden of Disease study
and were validated for the United States as part of the overall U.S. Burden of Disease and
Injury project.
Various adjustments are needed when developing epidemiologic estimates for DALY-based
epidemiologic studies to assure that plausible figures result. For example, because cardiovas-
cular diseases are such a major source of disease burden in these analyses, and there is
tremendous variation between, and within, countries in the attribution of deaths to these
conditions, various statistical techniques are required to standardize the crude numbers for
ischemic heart disease mortality. In addition to modifications of the epidemiologic measure-
ments, because DALYs are time-based, they are usually adjusted for time preference, or
discounting in accordance with widely accepted standards. Finally, many Burden of Disease
analyses, also incorporates weights that provide differential value for years of life at specific
ages according to the following equation:
" Cxe-Bx
where C and B are constants equal to 0.1658 and 0.04, respectively, and x is the value for a
particular year of age. This calculation is not the same as assuming a death at a younger
age imposes a greater burden because of the longer expectation of life associated with youth.
The DALYage-weights adjust for the fact that young and middle-age adults are generally the care-
takers of children and the elderly within societies. Therefore, the loss of those years of life
represents a greater threat to the stability and productivity of the society than years lived in the
more dependent stages of life. Given the controversy surrounding this component of the DALY
measure, many investigators do not execute this adjustment. In the original Global Burden of
Disease Study, age-weighted and non-age-weighted DALYs were provided.
7 Comment
Assessment of USB as a composite measure (DALY) helps magnify its burden on the health
care system and the population more than that achieved by mortality measurements or
morbidity measurements. This analysis framework is the most comprehensive account of
USB burden to date and included more USB‐related conditions than were considered in
previous analyses for the United States (such as hepatitis, infertility, reproductive sequelae
in men, maternal conditions and abortions). Even so, these estimates likely reflect the lower
bound of the USB-related public health burden and call for reassessing the attributable burden
for each geographical location and year of calculation. For instance, for HIV infection, we
included only the percentage attributable to sexual transmission alone, and not in combina-
tion with other risk factors such as intravenous drug use. These factors change over time.
Therefore, the attributable proportions listed in this paper should be revised to match the
epidemiology of sexual transmission of HIV in target populations. Furthermore, USB attrib-
uted DALYs, particularly those attributed to HIV/AIDS, may vary slightly for more recent
years due to the declines in HIV/AIDS deaths, increases in the number of people living with
HIV/AIDS, and the resurgence of bacterial STDs and unsafe sex among some population
groups. DALYs may not capture the full social and economic dimensions of reproductive
morbidity and those arising from some prevalent viral infections such as genital herpes human
papilloma virus infections.
Of note, attributable fractions provided in this chapter used epidemiological data relevant
to the U.S. and are not universal. Therefore, other geographical regions or countries
interested in developing such estimates need to adjust the data according to the regional
epidemiology.
8 Way Forward
Crude analyses of the data from the current public health information system cannot provide a
comprehensive picture of the disease burden from underlying causes of health outcomes in
order to effectively guide health planning. Health policies will be more effective if they are
guided by reliable information on levels, patterns, and causes of ill health and suffering and
how they change over time. Estimation of health burden with respect to a underlying causes
(such as USB) is limited by the conceptual difficulties in defining the link between exposure
and health event, deficiencies in the primary databases, and to the variable approaches used in
various studies to derive attributable fractions. It is generally acknowledged that the field of
sexual and reproductive health should not only address the key adverse outcomes but pay
attention to positive, life enhancing aspects such as ‘‘safe and satisfying sex life’’ and ‘‘the
enhancements of life and personal relations.’’ Methods to estimate such benefits and, more so,
how to translate such findings to action for programs remain unclear. In the meantime, the
quantification attempts, such as this one which focused on the adverse outcomes, compel us to
further refine the methodology. The findings offer a mandate that help us focus public health
policy on fundamental factors that affect a wide variety of diseases. Despite the many criticisms
of the DALY as a measurement unit, it represents a major conceptual advance to assess public
health burden providing a common metric for fatal and no-fatal outcomes.
Both the assessment of burden and assessment of sexual-behavior attributable compo-
nent of a given condition are evolving disciplines and hence subject to change based on
methodologic enhancements and greater availability of data. Therefore, attempts to use
the methodology at the national or public health level should consider the following
recommendations.
The need for full delineation of the natural history of USB related conditions and
associated death, disability and mortality.
Country level case studies are needed to identify, evaluate and utilize more existing and
prospective data sources. For the estimation of attributable fractions such data should be
subject to secondary analysis and expert panel discussions.
Long term research strategies may be needed to determine the incidence and
sequeale of some conditions with long incubation periods and complex, extended natural
histories.
Summary Points
Unprotected sexual behavior (USB) is defined as sexual activities that result in outcomes
considered undesirable from a health or societal perspective.
The list of USB-related conditions expanded in recent decades to include emerging or
newly recognized infections, unintended pregnancy, the acute or chronic complications or
sequelae arising from such outcomes including cancers, and efforts to minimize some
outcomes such as medical termination of pregnancy.
Continues assessment and monitoring of the health burden from USB is critical to
evidence-based health policy because USB is among the top 10 causes of disease burden
globally including in many developing countries and the U.S.
Measurement of USB is challenging due to the conceptual difficulties in delineating the
link between exposure and a health event, the multifactorial etiology of some outcomes
that necessitate computation of geographically appropriate attributable fractions, and
deficiencies in primary databases.
Use of summary measures (DALY) that capture both fatal and non-fatal outcomes can
demonstrate the full extent of the USB-related burden and profound disparities by gender
than that measured by mortality and morbidity statistics.
Summary measures of USB helps to capture the epidemiologic transition in USB; declines
in burden from bacterial causes and increases in burden attributable to virally mediated
conditions.
All USB-related health events are preventable through sexual behavioral change.
Further Reading
AbouZahr C, Vaughan JP. (2000). Bull World Health Centers for Disease Control and Prevention. (1998).
Org. 78: 655–665. Recommendations for prevention and control of
Barendregt JJ, Bonneux L, Maas PJ Van der. (1996). Bull hepatitis C virus (HCV) infection and HCV-related
World Health Organ. 74(4): 439–443. chronic disease. MMWR. 47: 1–39.
Cates W Jr. (1999). Sex Transm Dis. 26(4): S2–S7. Ebrahim SH, Peterman TA, Zaidi AA, Kamb ML. (1997).
Centers for Disease Control and Prevention. (2001). Am J Public Health. 87: 938–944.
Pregnancy-related deaths among Hispanic, Asian/ Ebrahim SH, MCkenna MT, Marks JS. (2005). Sex
Pacific Islander, and American Indian/Alaska Transm Infect. 81: 38–40.
Native women-United States, 1991–1997. MMWR. Field M, Gold MR. (1998). Summarizing Population
50: 361–364. Health: Directions for the Development and
Application of Population Metrics. National Acade- sexually transmitted diseases, HIV, maternal condi-
my, Washington DC. tions, perinatal disorders, and congenital anomalies.
Grimes DA. (1986). JAMA. 255: 1727–1729. World Health Organization, Geneva.
Gold MR, Siegel J, Russell L, Weinstein MC (ed.). (1996). Murray CJL, Salomon JA, Mathers CD, Lopez AD (ed.).
Cost-effectiveness in Health and Medicine. Oxford (2002). Summary Measures of Population Health:
University Press, New York. Concepts, Ethics, Measurement and Applications.
Henshaw SK. (1998). Fam Plann Perspect. 30: 24–29. World Health Organization, Geneva.
Koran JM, Fleming PL, Steketee RW, De Cock KM. Rein DB, Kassler WJ, Irwin KL, Rabiee L. (2000). Obstet
(2001). Am J Public Health. 91: 1060–1068. Gynecol. 95: 397–402.
McGinnis J, Foege WH. (1993). JAMA 270: 2207–2217. Torres A, Forrest JD. (1988). Fam Plann Perspect. 20:
Michaud CM, Murray CJL, Bloom BR. (2001). JAMA. 169–176.
285: 535–539. Williams A. (1999). Health Economics. 8: 1–8.
Murray CJ, Kulkarni SC, Ezzati M. (2006). Circulation. Wilcox LS, Mosher WD. (1993). Obstet Gynecol. 82:
113(17): 2071–2081. 122–127.
Murry CJL, Lopez AD (ed.). (1998). Health dimensions
of sex and reproduction: the global burden of
Impacts
2.6 Psychosocial, Social,
Behavioural, Psychiatric,
Neurological and Addictions
86 Global Burden of Mental
Health
M. Kastrup
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1474
2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475
3 Main Diagnostic Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475

3.1 Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475
3.2 Affective Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1477
3.3 Nervous Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1478
3.4 Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1479
3.5 Suicide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1479
4 Factors Related to Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1480

4.1 Migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1480
4.2 Poverty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1481
4.3 Comorbidity with Other Health Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1481
4.4 Gender Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1481
5 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1482
6 Consequences of Globalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1482

6.1 Cultural Competence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1483
7 Health Economics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1483
8 Therapeutic Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1485
9 Primary Health Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1485
10 Treatment Gap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1485
11 Ethical Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1487
12 Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1488
13 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1489
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1489

1474 86 Global Burden of Mental Health
Abstract: Mental disorders contribute significantly to the Global Burden of Disease, as

four out of the ten diseases with the highest burden are psychiatric. About 25% of all develop
one or more psychiatric and behavioral disorders during their lifetime. Unipolar depression
ranges as the leading mental disorder with respect to disability adjusted life years. The major
psychiatric disorders like schizophrenia and depression are found in all cultures and result in
significant disability. The cost of mental disorders worldwide needs receiving increasing
recognition.
Mental disorders are highly associated with other health problems and increase the
risk for both communicable and non-communicable diseases as well as for both intentional
and unintentional injuries. Vice versa, many physical disorders increase the risk for the
development of mental disorders.
A large proportion of mental health problems go unnoticed and the recognition hereof
is close related to social and cultural factors. Similarly, the treatment gap is closely associated
with economic, social and cultural background, and access to adequate care in many settings
a rarity.
Awareness of mental health issues should be an integrated and significant part of any
health and social policy both at international as well as national level. The WHO Health for
all targets focusing on disparities in health and strategies to overcome them is still pertinent.
List of Abbreviations: DALY, disability adjusted life years; DOSMED, determinants of
outcome of severe mental disorders; GBD, global burden of disease; IPSS, international pilot
study of schizophrenia; OCD, obsessional compulsive disorder; PTSD, post traumatic stress
disorder; US, United States; WHO, World Health Association; YLD, years of life lived with
disability
1 Introduction
Until the middle of the twentieth century, it was a commonly held belief that mental disorders
were less frequent in developing countries compared to industrialized countries. But since
then it has been documented that mental disorders are frequently found worldwide and that
stress factors precipitating mental distress may occur irrespective of developmental level
(Sartorius, 2000a).
The global burden of mental illness has been further documented in e.g., the three
international reports: World Mental Health (World Bank, 1993), Institution of Medicine
(Murray and Lopez, 1996) and World Health Report (WHO, 2001). These comprehensive
reports have been accompanied with regional and national reports where the report from the
European Ministerial Conference in 2005 deserves particular mentioning as it was signed by
all Ministers of Health in the WHO European Region (WHO, 2005a).
But mental health problems reach further than the mere mental health, they have an
impact on the physical health, and the general mortality of those afflicted. Further, the
existence of mental health problems are linked with poverty, stigmatization, marginalization
in most areas of the world (Lancet Global, 2007). And the impact is not only affecting the
mentally ill, but also their families and surroundings.
The large epidemiological studies initiated by WHO on schizophrenia and depression
(Jablensky et al., 1992; Sartorius et al., 1983) indicate the similarities in frequency across
culture. Socio-cultural factors on the other hand have a significant impact on the incidence
of minor mental disorders and culture specific disorders.
Global Burden of Mental Health 86 1475
Despite geographical differences in the occurrence of mental disorders, these disorders are
characterized by generally having an early onset compared to many other severe long-lasting
diseases, thereby having a great impact on the life of those affected (WHO, 2001).
2 Epidemiology
Mental disorders contribute significantly to the global burden of disease, and currently it is
estimated that about 450 million people worldwide suffer at a certain point of a neurological,
psychiatric or behavior related disease (WHO, 2001).
The lifetime risk for the worlds population of developing at a certain moment of their life a
psychiatric or behavioral disorder is estimated to be around 25% (WHO, 2001).
Lifetime prevalence rates for any kind of psychological disorder are higher than previously
thought, the disorders are increasing in recent cohorts and affect nearly half the population.
And yet, the true burden of disease is likely to be far greater, as there is a large proportion of
mental problems that go unnoticed, and there is a widespread lack of recognition of the link
between mental disorders and other health conditions.
Despite being common, mental illness is under diagnosed by doctors, and less than half of
those who meet diagnostic criteria for psychological disorders are identified by doctors
(WHO, 2008a).
Patients, too, appear reluctant to seek professional help. Only 2 in every 5 people
experiencing a mood, anxiety or substance use disorder, seek assistance in the year of the
onset of the disorder.
It is noteworthy that in low and middle income countries mental problems are frequently
given low priority and communicable diseases, maternity and child health are among condi-
tions that are ranked higher (Prince et al., 2007). And yet 85% of the worlds population lies in
countries that according to the World bank criteria are classified as low-income or middle-
income countries (Jacob et al., 2007).
Mental disorders contribute to severe morbidity, to long-term disability, and to mortality.
According to WHO (2005a) neuropsychiatric disorders contribute to 31.7% of all years lived
with disability (DALY), with unipolar depression ranking the highest (11.8%), followed by
alcohol related conditions (3.3%), and schizophrenia with (2.8%). Among the ten most
important diseases measured by YLD (Years of Life lived with Disability) psychiatric condi-
tions comprise four, namely uni-polar depression, alcohol abuse, schizophrenia and bipolar
disorder (WHO, 2001).
The burden of neuropsychiatric disease is greater in upper middle-income countries
than lower middle-income countries that for their part is higher than in low-income
countries (Jacob et al., 2007), and in the European Union, psychiatric conditions constitute
25% of the total burden of disease (Andlin-Sobocki et al., 2005) (> Tables 86-1 and 86-2).
3 Main Diagnostic Groups
3.1 Schizophrenia
Schizophrenia is the most disabling and serious psychiatric disorder and is found in all
cultures. Today, it is estimated that schizophrenia comprises 1.1% of the global burden of
disease and 2.8% of YLD.
. Table 86-1
Leading causes of disability-adjusted life years (DALYs) 15–44 years old, estimates for 2000
Males 15–44 years % total Females 15–44 years % total

3. Unipolar depressive disorders 6.7 2. Unipolar depressive disorders 10.6
4. Alcohol use disorders 5.1 5. Schizophrenia 2.8
7. Self-inflicted injury 3.0 7. Bipolar affective disorders 2.5
8. Schizophrenia 2.5 9. Self-inflicted injury 2.4
9. Bipolar affective disorders 2.4 14. Panic disorder 1.6
16. Drug use disorders 1.6
The table shows how the mental disorders are to be found among the leading causes of life years adjusted for
disability in both sexes with unipolar depression being the top cause in both sexes. Source: WHO (2001)
. Table 86-2
Leading causes of years lived with disability (YLD) in males and females, estimates for year 2000
Males all ages % total Females all ages % total

1. Unipolar depressive disorders 9.7 1. Unipolar depressive disorders 14.0
2. Alcohol abuse disorders 5.5 6. Schizophrenia 2.7
7. Schizophrenia 3.0 7. Bipolar affective disorders 2.4
9. Bipolar affective disorders 2.6 9. Dementias & Alzheimer 2.3
16. Dementias & Alzheimer 1.8 20. Panic disorder 1.6
20. Drug abuse disorders 1.6
The table show how the mental disorders contribute as leading causes of years lived with disability in both sexes
Again unipolar depression stands at the top. Source: WHO (2001)
One of the largest epidemiological studies of mental health disorders is the World Health
Organization investigation carried out in the 1960s in which the incidence and course of
schizophrenia were compared in ten different countries (the IPSS project and DOSMED
project) (Jablensky et al., 1992). This investigation demonstrated similarities in the presenta-
tion form and incidences of schizophrenia across cultures using a narrow delineation of
schizophrenia, but the differences of these variables increased significantly when using a
wider delineation of schizophrenia from 4.2 per 100,000 in Chandigarh, India to 1.6 per
100,000 in Århus (Jablensky et al., 1992).
In the European region it is estimated that 3.7% million persons suffer from schizophrenia
(Olesen et al., 2006).
In the WHO Outcome study, the outcome of schizophrenia was found more favorable in
developing countries compared to highly industrialized countries (Jablensky et al., 1992), and
the differences in outcome were interpreted as due to genetic factors as well as specific
environmental conditions. This more favorable prognosis in developing countries has recently
been challenged.
Later it has been reported that also countries as Japan and Singapore report a more
favorable outcome of schizophrenia which could be attributed to their ability to adhere to a
traditional culture despite high technological development (Jilek, 2001).
Considerable interest has also been paid to the high preponderance of schizophrenia
among Afro-caribian immigrants to UK (Bhugra, 2004). No simple explanation has been
found for this phenomenon, but issues like misdiagnosis, migratory stress and increased
tendency of substance abuse have been mentioned. The preponderance is however likely to
be linked to an interaction of biological and sociocultural factors as well as increased stress.
The preponderance of schizophrenia in migrants have also been reported in a Danish
register study in particular among young male descendants of migrants (Helweg-Larsen
et al., 2007).
Brief psychotic episodes are reported worldwide, but with a tendency to increase in
frequency, the less technologically developed the society, and the psychotic episodes are
frequently found to be related to sociocultural factors.
3.2 Affective Disorders
Affective disorders comprise a group of disorders characterized by significant mood distur-

bances.
The burden of depression depends upon region having a relatively smaller burden
in poorer regions. The prevalence of two of the major disorders of the group: major
depression and bipolar disorders amounts to 21 million persons in the European region
(Olesen et al., 2006). For example depression amounts to 1.2% of the total burden in
Africa to 8.9% in high-income countries, but depression in the developing countries is
predicted to become a leading cause of disease burden in these regions as well (Murray
and Lopez, 1997).
Uni-polar depression has a point prevalence amounting to 1.9% for males and 3.2% for
females; and 5.8% of males and 9.5% of females are likely to develop a depressive episode
within a 12-month period. Every year 5–8% of the adult population gets a depression (Andlin-
Sobocki et al., 2005). It is estimated that the lifetime risk for a severe depression amounts to
12–16%.
The frequency of depression may be measured in the community using well-defined
diagnostic categories and reliable operational criteria. WHO carried out a study on mental
illness in general health care comprising 14 countries around the world. A main finding
was that the prevalence of current depression ranged from 2.6% in Nagasaki, 4.0% in Shanghai
to 16.9% in Manchester and 29.5% in Santiago (Goldberg and Lecrubier, 1995). Four possible
explanations were given as contributing to this finding: namely that there indeed are
true differences in depression; that the concept of disease may differ according to culture;
that there are differences in help-seeking behavior; and finally that the demographic
characteristics of the studied populations differ (Goldberg and Lecrubier, 1995).
Symptoms like lowered mood, lack of joy, anxiety, lack of energy and interest in surround-
ings are reported in most cultures, and depressive disorders occur at different levels of
frequency in all known cultures (Jablensky et al., 1992).
WHO reports of quite similar symptomatology in different cultural contexts, but consid-
erable variation in prevalence, and the question is whether these differences are due to
differences in social or cultural conditions, and the cultural context may have a pathoplastic
effect on the manifestations of the depression (Tseng, 2001).
One should keep in mind that in many cultures, depressive traits may be interpreted as a
natural reaction following losses or other severe life events. Also severe pathological grief reactions
can be seen as a sign of genuine grief more than as a pathological phenomenon, which may lead to
the situation that persons suffering from major depressive episodes may not receive adequate
treatment. Also depressive traits in old age may be interpreted as a condition not requiring any
therapeutic intervention. Thus, it is important to recognize the interaction between culture and
depression whenever interviewing a patient suspect of a depressive episode.
The measures of disability may differ but persons with depressive disorders demonstrate
impaired physical health, impaired level of functioning, increased work impairment and high
utilization of health services (Lecrubier, 2001).
Race or ethnicity do not significantly influence the rate of occurrence of depression.
Socioeconomic or educational differences may contribute to some differences observed
between ethnic groups, but on statistical correction of these factors, there is no variation in
risk by ethnic groups (WHO, 2008b).
WHOs investigation of depression in five countries showed that signs of tristesse, lack of
joy anxiety and tension were central in all settings. In Switzerland guilt feelings were common
in contrast to Iran whereas somatic complaints were more common in Iran compared to
Canada. It appears that guilt feelings are more common among persons of Jewish-Christian
faith (Sartorius et al., 1983).
The variation in prevalence was not easily explained, but women had generally a higher
prevalence Lifetime prevalence varied between 1.5% in Taiwan to 19% in Beirut (Wittchen
et al., 1999).
3.3 Nervous Disorders
Anxiety disorders are a major group of the nervous disorders. Anxiety problems comprise
panic disorder, generalized anxiety, phobic disorders, OCD and PTSD.
Anxiety disorders comprise the largest group of persons with mental distress worldwide.
About one third of absenteeism due to sickness is due to anxiety disorders. In the large US
Epidemiological Catchment Area study (Tseng, 2001) general anxiety was reported in 2.7% of
Afro-Americans and in 1.6% of Anglosaxon-American (1 year prevalence). In the European
region the anxiety disorders including OCD comprise approximately 41 million persons and
the 1-year prevalence amounts to 12% of the population (Olesen et al., 2006). In China it is
reported that 4 out of 1,000 men and 39 out of 1,000 women suffer from anxiety (Tseng, 2001).
Anxiety problems are frequently found in general practice – ranging from 22% in Rio de
Janeiro to 1% in Ankara.
Particular interest has been paid to the frequency of Post traumatic stress disorders (PTSD)
in recognition of that an increasing proportion of war related deaths and war-casualties
are civilians, and women are in particular risk. It is estimated that 80% of the 50 million
people affected by violent conflicts, civil wars, disasters, and displacement are women
and children. Lifetime prevalence rate of violence against women ranges from 16 to 50%
(WHO, 2008a).
The symptomatology of PTSD shows clear communalities across culture, but over the
years the delineation and overall existence of the diagnosis have been the subject of repeated
discussion. The need for treatment is also closely linked to the cultural background, coping
strategies, political/religious conviction and existence of social network.
The prevalence of PTSD following traumatic events vary considerably but is generally
reported between 9 and 37% (Ekblad and Jaranson, 2004). In the general population PTSD
point prevalence amounts to 0.4% and the life-time prevalence to 10.4% in women and 5% in
men (Ekblad and Jaranson, 2004).
3.4 Abuse
Abuse is a pattern of symptoms linked to the use of the substance with impaired capacity to
control the abuse, a tolerance of withdrawal from preoccupation with substance and
continuing use of the harmful substances.
Alcohol abuse is estimated on a worldwide basis to comprise about 76 million people and
the point prevalence is deemed to be 1.7% globally, 2.8% in men and 0.5% in women. The life-
time prevalence shows similar gender ratio with reported prevalences as 31 and 7% respec-
tively in males and females in Canada and 43% compared to 3% in South Korea. The
preponderance of males is reported in general and across cultures, both with respect of
consumption as well as physical and social consequences (WHO, 2001). Gender differences
however seem to diminish in some regions with womens’ increasing educational background.
Regional differences in the accepted behavior and attitudes to the abuse of ethanol are
significant which has a heavy impact on help-seeking behavior and the socio-cultural context
plays a great role in the overall consequences of the abuse (Tseng, 2001).
The prevalence in Europe amounts to 9 million people abusing alcohol and illicit sub-
stances (Olesen et al., 2006). Increase in alcohol consumption is often seen following societal
disintegration and destabilization as seen in the former Soviet Union. But alcohol abuse is
growing rapidly in low-income and middle-income countries – in particular among males –
and in these regions many may avoid to seek help either because of shame or because of
ignorance about treatment facilities (Patel et al., 2007). Thus, we see large ranges in the
frequency of alcohol abuse revealed in consultations to general practitioners, in a study of
general practice we saw approximately 10% of patients from large cities like Paris, Seattle or
Berlin compared to 2% in Ankara (Kastrup and Baez, 2007).
Alcohol abuse is in the global burden of disease project estimated as the cause of
about 1.5% of all deaths. Alcohol ranks high in the burden of disease with 3.5% of all
DALY’s (WHO, 2001).
3.5 Suicide
About 877,000 people die by suicide every year, and suicide is the 13th leading cause of death
globally (WHO 2005), the median suicide rate being 6.55 per 100,000 population (Jacob et al.,
2007). WHO (2001) have reported age-standardized rates of suicide in 24.0 males per 100,000
and 6.8 females per 100,000. Suicide is globally on the increase and we know that suicide is
linked to psychosocial stressors, family structure and abuse. Certain groups run a particular
risk due to e.g., migration, stay in prison or due to a feeling of lack of coherence with the
sociocultural group. In fact, sociocultural factors as well as biological and psychological ones
all contribute to suicidal behavior.
It is also well known that there is a close link between suicide and the existence of mental
disorders and about 15% of those suffering from depression is estimated to commit suicide at
a certain point (WHO, 2008b). This has also been demonstrated among others in studies using
case registers (Helweg-Larsen, 2006). Suicide trends has varied considerably over time. Thus
whereas we see a steady decline in recent decades in many Western countries, clear increases
are reported in other parts of the world, e.g. India, Mexico and the former Soviet Union
(Helweg-Larsen, 2006; WHO, 2001). In many low-income and middle-income countries
suicide is now one of the leading causes of death among the young, and in the European
region among those aged 15–44 years, suicide is the second most frequent cause of death.
Presently suicide rates for males are above 35 per 100,000 in Belarus, Kazakhstan, Lithuania,
Russia and Ukraine (Jacob et al., 2007).
Regional variation is also reported when it comes to suicide attempts that are frequently
seen in younger women and in persons marked by lack of stability or poverty. The experience
of alienation faced with a new culture or torn between the demands of two cultures may
explain the tendency to suicide attempts documented in certain ethnic groups and also among
young internationally adopted (Helweg-Larsen et al., 2007).
4 Factors Related to Mental Disorders

A number of factors are associated with the presence, the kind and the course of mental and
behavioral disorders and include e.g., migration, poverty, gender, conflicts and catastrophs,
concomitant severe physical disorders, urbanization and family history (> Table 86-3).
. Table 86-3
Presence of mental health programs for special populations in the world
Mental health programs for special populations Countries %

Minority groups 16.5
Refugees 26.2
Disaster affected populations 37.7
Indigenous people 14.8
Elderly persons 50.5
Children 62.4
This table shows that only a small proportion of countries worldwide have developed mental health programs
focusing on special populations that frequently are more vulnerable, such as refugees. Source: WHO (2005b)
4.1 Migration
Among these factors the role of migration on mental health deserves particular attention.
Migration is influenced by an interaction of several different interactive factors (Bhugra
and Becker, 2005). On a pre-migratory level, factors such as psychological, social and
biological vulnerability, political conditions in home country, education etc all are contribu-
tory. The time after the migration may often be marked by several losses (e.g., identity, family,
language, values, social network), insecurity, social, work or economic problems, language
isolation or adjustment to the new life circumstances. Migration implies a feeling of alienation
and despair and it may imply an increased risk to develop depressive disorders.
It has been brought forward that those who migrate are the particularly gifted, robust
individuals, who are rich in initiatives. This could explain why the morbidity is frequently
low particularly immediately following the migration. Migration research that has been broad
in its approach has hitherto primarily related to the emergence of psychotic disorders in
particular schizophrenia (e.g., Cantor-Graa et al., 2003) The importance of the interaction
between migration for the development of a depression is not evident (Bhugra, 2003) and
investigations and findings that relate to other mental disorders are far less clear, and they
often relate to restricted populations. It has been demonstrated that limited social contact is a
main contributory factor for the increased frequency of depression among migrants compared
to native Norwegians and investigations have reported a relation between lack of a sense of
coherence and the depression in young refugees (Roth and Ekblad, 2006).
A factor, that may be contributing is that persons who migrate from collectivistic, socio-
centriske societies to egocentric societies may experience alienation and worries, that makes
adjustment to new societies difficult (Bhugra and Becker, 2005).
There is increasing evidence that not only migrants are exposed to stress also their
descendants run an increased risk of mental disorders (Helweg-Larsen et al., 2007). Similarly
international adoptees have been found to have an increased prevalence of mental disorders
(e.g., Helweg-Larsen et al., 2007).
4.2 Poverty
It has been demonstrated persons that with low education and low income had a particular
vulnerability to common mental disorders, no matter what society we deal with. Results from
low-and middle-income countries in Latin America had shown a relationship between high
rate of mental illness and poor education (Saxena et al., 2007).
4.3 Comorbidity with Other Health Conditions
Approximately 15% of patients seen in primary care exhibit medically unexplained somatic
conditions linked with psychological distress (Prince et al., 2007), and somatization is seen to
increase significantly health care costs. Furthermore, adding to the burden and disability is the
fact that persons with mental disorders have a high degree of co-morbidity with both physical and
mental disorders.
4.4 Gender Issues
It has again and again been documented that gender is a major determinant of mental health
and mental illness, and that depression, anxiety, psychological distress, violence occurs more
frequently in women across countries.
Gender has decisive impact on social position, status, opportunities, and in some areas
female gender per se prevents access e.g., adequate mental heath care.
With respect to depression, women have on a global level a 1.5–2 times higher risk of
getting a depression compared to men. In all countries of the Cross National Collaborative
Group women had a higher prevalence ranging from a ratio female: male of 3.1 in West
Germany to 1.6 in Beirut and Lebanon (Weissman et al., 1996).Women are under pressure
due to their many roles and obligations, their risk of violence and sexual abuse and the
discrimination encountered in many countries (WHO, 2008a). The increased risk among
women to develop PTSD is repeatedly reported and yet findings of gender differences in the
prevalence of PTSD among non-Western adults exposed to political violence are inconsistent.
There is little gender difference in the prevalence of schizophrenia, but it manifests earlier
in males.
It is also documented that males have an about two times higher life-time prevalence rates
of alcohol dependence, and men are more likely to be diagnosed with antisocial personality
disorder.
Gender also has a critical input on compliance to treatment, social adjustment and long-
term outcome.
In case of war, disaster or exile, women fulfill the role of nurturers and providers of
emotional support, and they have usually the main responsibility for care giving in the family.
Women’s capacity to cope may be overloaded, as preoccupation with the needs of the
family may lead to that they are not able to consider their own needs. On the other hand
the care giving role may have a protective function as women contrary to their partners
have a natural role and identity in the new environment.
5 Prevention
Despite the fact that severe mental disorder take an increasing toll also in low-income and
middle-income countries, preventive trials focusing on how to prevent the psychotic disorders
have not been carried out in these regions (Patel et al., 2007). In the preventive research emphasis
should be placed on interventions that focus on the need of the low-income and middle-income
countries. Combining medication, psycho-education and support to the family the relapse rate of
psychotic manifestations can be reduced from about 50% to less than 10% after a year which
could be seen as a very cost-effective intervention (WHO, 2001).
6 Consequences of Globalization
We live in a world that undergoes drastic changes, and it is essential to avoid that walls are built
between modern societies and traditional cultures, whereby certain cultural groups are
excluded from participating in the societal development (Brundtland, 1999). As Brundtland
points out globalization is a challenge that some may take up more than others. Those that
come from less developed regions may face a future that is so different from the world in which
they grew up, that most of the skills they have taken over from previous generations are of no
use to cope with the tasks of a globalized world.
In the age of globalization, one definition of culture deserves attention, namely that it is an
ever-changing construct that emerges from interactions between individuals, communities
and institutional practices (Kirmayer, 2001). In that context culture plays an important role on
the symptoms and manifestation of mental problems, the explanation models used, the coping
mechanisms and help seeking behavior, and the social response to mental distress and
disability (Kirmayer, 2001).
The question is frequently asked whether we are ready for this global culture. For certain
groups globalization will have as a consequence that they cannot cope with the changes
and thereby their mental health will be influenced. The demands for change and adjusting to
the consequences of globalization are particularly pronounced among the populations of the
developing world. On a global level, such groups run an increased risk of developing
stress related mental problems, both in their home country and in relation to migration.
This is an issue that in the light of the global burden deserves further attention.
6.1 Cultural Competence
As a consequence of globalization mental health professionals are increasingly confronted with

multicultural patient populations. A certain proportion of them may have had contact with
alternative approaches of treatment or indigenous healers partly because this approach to
treatment may reflect their belief systems and explanatory models better, and partly because
they may have experienced limited access to mental health services. Today, the majority of
mental health professionals working in urban settings will encounter such patients in their
daily clinical life (Kastrup, 2008).
It is important that mental health care staff possesses competencies to deal with this
diversity of patients. The question remains whether the training about appreciation of cultural
aspects will enter medical curricula and whether those who provide the training will consider
this sufficiently medically relevant (Fox, 2005).
Few have outlined the aspects of cultural competence better than Tseng (2003) who
has presented some of the needed ingredients including the need to focus on cultural sensitivity
and acknowledge the existence of different lifestyles and attitudes, and accept them without
prejudice; the acquisition of cultural knowledge; the need for cultural empathy and under-
standing the patients own perspective; the recognition of culturally relevant relations and
interactions with consideration of cultural background; and cultural impact on help-seeking,
Mental health professionals in Western societies face a doctor-patient relationship that has
undergone a considerable transition. Previously, the patient accepted the authority of the
doctor, and an asymmetrical position characterized the relationship. Today, the relationship
between therapist and patient is strongly focused on informed consent with the aim to
promote patient autonomy and permit the individual patient to make rational decisions.
The responsibility for the treatment is in some way shared, and it may be described as a kind of
contract where the two agents negotiate conditions and come to an agreement (Kastrup,
2008). The outcome of disorder is mainly described as self-determined and the patient is
encouraged to take an active part. In contrast to this we see the traditional approach that is
often acknowledging dependence on God (or other agents outside the individual) regarding
health and illness and stress the spiritual/divine role for the outcome (Okasha, 2000).
Communication with female patients may in some traditional settings be very authoritar-
ian, thereby making it difficult for women to tell about their emotional distress. Distress may
be interpreted as a critique of her husband or male members of the family which may result in
that these women are either under- over over-treated.
7 Health Economics
Since the World Bank and WHO in the 1990s carried out their analyses of the Global Burden
of Disease (GBD) the attention to the health economic consequences of mental disorders
has increased. Low-income countries spend significantly less of their Gross Domestic Product
on health than middle-income countries and they in turn spend significantly less than
high-income countries. The proportion of the health budget allocated to mental health varies
in the WHO regions from 0.76% in the African, over 2% in the Western Pacific and the Eastern
Mediterranean region, to 6.3% in the European region, or when distributed according to
income level from 1% in low-income over 2.15% in lower-middle income, to 3% in upper-
middle income, and 6.8% in high-income countries (Jakob et al., 2007).
Availability of mental health beds differ similarly with 0.24 per 10,000 in the low-income
countries over 1.59 in lower-middle income to 7.7 in upper-middle and 7.5 per 10,000 in high-
income countries (Jakob et al., 2007) (> Table 86-4).
. Table 86-4
Income group and psychiatric beds, proportion in mental hospitals and number of psychiatrists
Median no
Income group Median no psychiatric Proportion psychiatric psychiatrists per
of countries beds per 10,000 pop beds in mental hospitals 100,000 pop
Low 0.24 74.4 0.05
Lower middle 1.59 82.7 1.05
Higher middle 7.70 78.8 2.70
High 7.50 55.0 10.50
This table shows how the number of psychiatric beds, and how many of them are placed in mental hospitals differ
in the different income group of countries. Similarly with the number of psychiatrists in the different income group
of countries. Source: WHO (2005b)
The European Brain Council too has recently published an overview of the impact of
mental disorders on the European health economy. Projections towards 2020 show that the
neuropsychiatric disorders will increase in proportion from the present 10.5% of the total
burden of disease in 1990 to 15% in 2020. As a consequence, these disorders have achieved a
high ranking on the international health political and economic agenda.
Most middle-income and low-income countries devote less than 1% of their health
expenditure to mental health, and many also lack mental health policy and legislation
(Jakob et al., 2007).
Till now the vast majority of research on effectiveness of mental health services are carried
out in high-income countries and it is not necessarily so that results may be extrapolated to
low-income countries (Saxena et al., 2007). But even within the same income level, compo-
nents of mental health care differ greatly (Jakob et al., 2007).
But the increased focus has not been guaranteeing that persons with mental disorders in
the developing world will have a more fortunate destiny, and there is still a significant distance
between the size and amount of the illnesses and the possibility for adequate treatment hereof,
not the least in the non-industrialized countries where access of psychiatrically trained staff
is very limited.
8 Therapeutic Issues
According to the survey of Patel et al. (2007) who identified 11,501 trials globally focusing on
the assessment of therapeutic or preventive interventions for mental health problems, the
majority of the evidence stems from high-income countries. Less than 1% were carried out
in low-income countries.
Breaking the studies according to diagnostic groups it is characteristic that about 3 out of 4
trials in low-income or middle-income countries were dealing with the treatment of schizo-
phrenia and about 1 out if 4 with depression, whereas other disorders were hardly focused
upon (Patel et al., 2007).
And yet examples do exist of effective community-based interventions for psychotic and
depressive disorders, programs that are feasible and affordable in such settings. Patel el al.
(2007) in their survey emphasize as examples hereof primary care depression program in Chile
and community-based program for rehabilitation of chronic schizophrenics in rural India.
But we also have limited experience with the integration of treatment programs developed in
high-income countries, in low-income or middle-income countries with different organiza-
tion and availability of services.
As regards treatment of depression, group psychological interventions were reported to be
efficacious in some trials in low-income and middle-income countries, and this finding was
related to the fact that this kind of intervention may resemble traditional social mechanisms
such as support through collective action (Patel et al., 2007).
9 Primary Health Care
About 20% of all patients who consult the primary health sector have a psychiatric disorder,
but a considerable part of them are never diagnosed or treated properly (WHO, 2001).
To overcome the treatment gap one strategy is to train, assist and supervise primary care
physicians to identify and treat mental illness (Saxena et al., 2007). This training need to be
followed by regular supervision in order to provide mental care in low-income countries.
10 Treatment Gap
Since the publication of the three reports on global mental health (World Bank, 1993, Murray
and Lopez 1996, WHO, 2001) the economic and social consequences of mental illnesses has
been increasingly recognized.
Worldwide there is a vast treatment gap between those needing care and those receiving
adequate care for their mental disorders. This gap differs according to region and whereas it is
estimated to 35–50% in developed countries, it is 76–85% in low-and middle-income countries
(WHO, 2004). Even in the US it is estimated that 2/3 of those with mental disorders are not
treated (Kessler et al., 2005). In Europe up to 74% of those suffering from mental disorder
are not treated (Wittchen and Jacobi, 2005). According to the European Ministerial Report
(WHO, 2005a) the treatment gap in Western Europe is estimated to 17.8% for schizophrenia,
45.4% for severe depression, and 62.3% for generalized anxiety (> Table 86-5).
In low-income and middle-income countries we may see that even among those treated,
only a small proportion are adequately treated (Lancet Global, 2007). Thus, the increased
. Table 86-5
Median percentage treatment gap for selected psychiatric disorders based on community based
surveys
Psychiatric disorder Median rate untreated

Schizophrenia and non-affective psychotic disorders 32.2
Major depression 56.3
Bipolar disorders 50.2
General anxiety disorders 57.5
Alcohol abuse 78.1
This table shows how large a proportion of persons with a particular disorder are left untreated. Source: Kohn et al.
(2004)
focus on the burden of mental health has not ensured better conditions for the mentally ill in
the low-income and lower-middle income countries (Kastrup and Baez, 2007).
Community based services vary considerably from region to region. Thus provision of
community based care ranges from 97% in high-income countries to 52% in low-income
countries (Saxena et al., 2007). Saxena et al. (2007) further point out that middle income
countries that have invested in the creation of large mental hospitals may have little incentive
in establishing community health care (> Table 86-6).
. Table 86-6
Presence of community mental care in the WHO regions, income group and the world
WHO regions Countries %

Low-income countries 51.7
Lower middle-income countries 51.9
Higher middle-income countries 90.9
High income countries 97.4
This table shows to what extent community care is available in the different income group of countries. Source:
WHO (2005b)
Many countries do not have a mental health budget, and in African and South Asian
countries less than 1% of the health budget is allocated to mental health (World Mental Health
Atlas, 2005b). But also in the European region we see a relatively small proportion of the health
budget allocated to mental health, thus among 24 European countries 5.8% of their Gross
National Product is allocated to mental health, even though the disorders comprise 20% of the
burden of disease (WHO, 2005a).
Many low-income countries prioritize inadequately the development of mental health
policies despite the fact that the consequences of mental disorders show an increasing
proportion of the burden of disease.
The human resources allocated to mental health are unevenly distributed at a global
level. According to the WHO Mental Health Atlas (2005b) the amount of psychiatrists
in low-income countries are 0.05 per 100,000 population to 1.05 in lower-middle to 10.5 in
high-income countries. Within a given country, the tendency is that psychiatrists and other
mental health professionals live in larger urban areas which result in low access to care in the
rural population.
In settings with inavailability of mental health professionals one should bear in mind that
specialist mental health staff in such settings preferably could concentrate on supervising less
specialized staff instead of acting as clinicians, and that non-professionals need to be part of
the mental health programming of the communities (Saraceno et al., 2007). Non-formal
community interventions are needed and community members should be mobilized if we
are to overcome the treatment gap in low-income countries. Furthermore, it needs mentioning
that the shortage of trained mental health professionals also prevent many countries to
introduce psychosocial interventions, psychotherapy, etc.
Low-income countries are faced with another obstacle as the cost of the necessary
drugs are relatively more expensive in these countries. According to Saxena et al. (2007)
1 year supply of one of the least expensive antidepressants only costs twice as much in
high-income compared to low-income countries despite a 12.5 time difference in the
Gross National Product.
Prescribing antipsychotic medication for the treatment of schizophrenia is a key compo-
nent of treatment of the disorder, but in low-income and middle-income countries, the
treatment gap for schizophrenia is large and resources for medication low (Patel et al.,
2007). Consequently in such countries it may be difficult to provide sufficient and adequate
medication, and the long-term outcome of chronic psychoses may be less favorable.
11 Ethical Concerns
As a consequence of the increased globalization the debate is ongoing whether there should be
a universal set of ethical guidelines or whether ethical guidelines rather should reflect a given
cultural context and vary accordingly (Sartorius, 2000b). Should e.g., the guiding principles of
the Declaration of Madrid be interpreted according to the setting in which they are applied? Or
according to the cultural background of the mentally ill patient in front of us?
The danger of having a culture relativistic approach in psychiatry is that it implies that all
cultures and values could be seen as equally good, and that there is no such thing as absolute
global moral values.
Global mental health is to a large extent a question of political and economic welfare. But
to what degree is mental health a fundamental human right? Access to psychiatric help is a
close function of economic differences inter as well as intra nationally, and access to adequate
psychiatric service is still inaccessible in larger parts of the world. And we should not forget
that most psychiatrists are treating patients who belong to a different social and educational
background than that of their psychiatrists.
The economic disparities both between and within nations are reflected in the availability
of adequate mental health care but the moral need for an equitable allocation as stressed in the
Declaration of Madrid moves further away if indefinite progress in certain regions is given
priority over the implementation of limited achievable goals globally.
If we want to see to that the intentions of the Declaration of Madrid in their entirety are
fulfilled on a worldwide basis, we should formulate mental health policy goals that to a greater
extent pay attention to the problems of the poor, and use goals that are expressed in terms
of enhancement of equity than what is seen today.
We are confronted with a difficult balance how to adhere to the universal standards and at
the same time not disregard local values of our target population. And, on the other hand, that
ensuring respect for the local culture should not become a pretext for bypassing or ignoring
ethical guidelines. We have to weigh the different values and consider the diverse views in the
modern multicultural world (Okasha, 2002). Judgments on values of the past cannot stand
alone, and we take the challenge facing us and reconstruct the world and create perspectives
we can live with (Okasha, 2002).
12 Perspectives
Changes in demographic distribution have consequences for the future projection of the
burden of mental disorders. Thus the ageing of certain Western populations like the European
one implies that it is likely that we shall see an increasing proportion of mental disorders. In
Europe neuropsychiatric diseases are estimated in 2020 to increase to 15% of the total burden
and amount to 40% of all chronic diseases (WHO, 2005a).The Global Burden of Disease study
estimates that major depression would rank second among the leading ten causes of DALY
in 2020 (Murray and Lopez, 1997).
Most mental health programs have primarily targeted local populations and may
succeed locally but till now we only have few that have undergone systematic assess-
ments of their effectiveness in large scale populations (Patel et al., 2007). Most of the evidence
for interventions unfortunately has little relevance for settings in low-income and
middle-income countries. Here it is needed to focus on interventions that are relying
on low-technology and mental health workers who are not specialists as such interventions
may be as efficient in such contexts (McKenzie et al., 2004). In low-and middle-income
countries we however still see that approximately 80% of mental beds are found in large
mental hospitals (Jacob et al., 2007) and that despite recommendations for deinstitutionalized
care there are large obstacles preventing this development. Some of them are found
among mental health staff themselves, and there is in many settings still a culture of paternal-
ism and a lack of belief in the ability of the mentally ill to make proper decisions (Saraceno
et al., 2007).
Saraceno and co-workers (2007) outlined several obstacles to the development of services.
The public health agenda need to prioritize mental health, and the move away from centralized
mental health hospitals towards community-based services. Further, primary care needs to
integrate mental health care and the lack of human resources, clinically as well as organiza-
tionally, is pertinent.
In a survey on mental health priorities on a global level (Prince et al., 2007) respondents
identified a number of reasons why mental health is low on the public agenda. These included
that advocating on mental health may not easily be understood by non-mental health practi-
tioners, but also that persons suffering from mental health problems and their families are
often hidden and not outspoken. Further, that the indicators for mental health may be weak
and that the general public’s interest in the life and well-being of mentally disordered limited
(Saraceno et al., 2007).
Surveys of recent research on mental health consistently document that almost all
research in this field takes place in high-income countries (Patel and Sumathipala, 2007).
13 Conclusion
A dialogue with all stakeholders involved in global mental health is needed in recognition of
that worldwide health systems are confronted with great tasks if they are to provide adequate
mental health care and ensure the protection of the human rights of the mentally ill (Lancet
global, 2007).
In the three high-profiled international reports on the burden of mental health
(Murray and Lopez, 1996; WHO, 2001; World Bank, 1993) it is recommended that avail-
ability of mental care be increased. Furthermore, that provision of better and increased
mental health be provided through the development of human resources and mental health
policies.
But despite such reports, the Lancet series on global mental health have pointed out that
scaling-up of initiatives to improve mental health services have been slow (Saraceno et al.,
2007).Unfortunately, mental health is almost absent from the international agenda for public
health and mental health lobbyists may either work against one another as they focus on
different mental health problems each needing different solutions or they may offer different
views on the type of intervention needed (Saraceno et al., 2007).
If we want that persons living in low-income and middle-income countries should get
access and receive help for their mental health problems, a help that is sufficient, affordable,
accessible and acceptable heavy tasks lie ahead and the health resources have to be prioritized
differently. As pointed out by the Lancet Global Mental Health Group, change in public health
only comes about if three core elements are present: a knowledge base, strategies to implement
what we know, and the political will to act.
Summary Points
Mental health problems are linked with poverty, stigmatization, with impact on physical
health and general mortality of those afflicted and their families.
Mental disorders have early onset compared to many other long-lasting diseases and
contribute significantly to global burden of disease. Approximately 450 millions have at
a certain point a neurological, or psychiatric disease.
Neuropsychiatric disorders contribute to 31.7% of years lived with disability. Unipolar
depression, alcohol abuse, schizophrenia and bipolar disorder belong to the top ten
diseases measured by years lived with disability.
The burden is greater in upper middle-income countries and lowest in low-income
countries.
Schizophrenia comprises 1.1% of the global burden of disease.
Depression amounts to 1.2% of the total burden in Africa, 8.9% in high-income countries.
Suicide is the 13th leading cause of death globally with 877,000 annually.
Migrants and their descendants run an increased risk of mental disorders.
Depression, and anxiety are more common in women, alcohol dependence, antisocial
personality disorder more common in men.
Culture plays an important role on manifestation of mental problems; explanatory mod-
els; coping mechanisms and help seeking behavior.
The proportion of the health budget allocated to mental health varies from 1% in low-
income to 6.8% in high-income countries.
Mental health beds ranges from 0.24 per 10,000 in the low-income, 1.59 in lower-middle
income, 7.7 in upper-middle and 7.5 in high-income countries.
The treatment gap differs from 35–50% in developed, to 76–85% in low-and middle-
income countries.
References
Andlin-Sobocki P, Jönsson B, Wittchen H-U, et al. Kirmaye LJ. (2001). J Clin Psychiatr. 62(suppl 13):
(2005). Eur J Neurol. 12(suppl 1). 1–27. 22–28.
Bhugra D. (2003). Acta Psychiatr Scand 108: 67–72. Kohn R, Saxena S, Levav I, Saraceno B. (2004). Bull
Bhugra D. (2004). Acta Psychiatr Scand. 109: 243–258. WHO. 82: 858–866.
Bhugra D, Becker M. (2005). World Psychiatr. 4: 18–24. Lancet Global mental Health Group. (2007). Lancet. 370:
Brundtland GH. (1999). International consultation on 2241–2252.
the health of indigenous peoples. Speech at Sweet Lecrubier Y. (2001). J Clin Psychiatr. 62(Suppl 8): 4–9.
Briar College. McKenzie K, Patel V, Araya R. (2004). BMJ. 329:
Cantor-Graae E, Pedersen CB, McNeil TF, Mortensen PB. 1138–1140.
(2003). Br J Psychiatr. 182: 117–122. Murray CJ, Lopez AD. (1996). The Global Burden of
Ekblad S, Jaranson J. (2004). In: Wilson J, Drozdek B Disease: A Comprehensive Assessment of Mortality
(eds.) Broken Spirits. Brunner & Routledge, New and Disability from Diseases, Injuries, and Risk Fac-
York. tors in 1990 and Projected to 2020. Harvard School
Fox RC. (2005). New Engl J Med. 353: 1316–1319. of Public Health, Cambridge.
Goldberg D, Lecrubier Y. (1995). In: Ûstuü TB, Murray CJ, Lopez AD. (1997). Lancet. 349: 1498–1504.
Sartorius N (eds.) Mental Illness in General Okasha A. (2000). In: Okasha, et al. (eds.) Ethics Culture
Health Care. Wiley, Chichester. and Psychiatry. APA Press, Washington.
Helweg-Larsen K. (2006). In: Danish (ed.) Suicide in Okasha A. (2002) In: Sartorius N, et al. (eds.) Psychiatry
Denmark. Significant Decrease in Suicide, But In- in Society. Wiley, Chichester.
creasing Number of Suicide Attempts, Why? The Olesen J, Baker M, Freund T, di Luca M, Mendlewicz I,
National Institute of Public Health, Copenhagen. Ragan Westphal M. (2006). J Neurol Neurosurg
Helweg-Larsen K, Kastrup M, Baez A, Flachs E. (2007). Psychiatr. 77(Suppl 1): 1–49.
Etniske forskelle i kontaktmønstret til psykiatrisk Patel V, Sumathipala A. (2007). Br J Psychiatr. 190:
behandling. Et registerbaseret studie (Ethnic differ- 77–78.
ences in contact patterns A register based Patel V, Araya R, Chatterjee S, Chrisholm D, Cohen A, De
study). Videnscenter for Transkulturel Psykiatri, Silva M, Hosman C, McGuire H, Rojas G, van
Copenhagen. Ommeren M. (2007). Lancet. 370: 991–1005.
Jablensky A, Sartorius N, Ehrenberg G, Anker M, Prince M, Patel V, Saxena S, Maj M, Maselko J, Phillips
Corten A, Cooper JE, Day R, Bertelsen A. (1992). M, Rahman A. (2007). Lancet. 370: 859–877.
Psychol Med Monogr Suppl. 20: 1–97. Roth G, Ekblad S. (2006). J Nerv Ment Dis. 194: 378–381.
Jacob KS, Sharan P, Mirzo I, Garrido-Cumbrega M, Saraceno B, van Ommeren M, Batniji R, Cohen A, Gureje
Seedat S, Mari JJ, Screenivas V, Saxena S. (2007). O, Mahoney J, Sridhar D, Underhill C. (2007).
Lancet. 370: 1061–1077. Lancet. 370: 1164–1174.
Jilek W. (2001). Cultural Factors in Psychiatric Disorders. Sartorius N. (2000a). In: Helmchen H, et al. (eds.)
Paper 26th Congress of World Federation of Mental Psychiatrie der Gegenwart. Band 3: Psychiatrie
Health. Available at: http://www.mentalhealth.com/ spezieller Lebenssituationen. 4. Auflage. Springer,
mag1/wolfgang.html/april 2002. Berlin/Heidelberg/New York, pp. 425–446.
Kastrup M, Baez A. (2007). Dan Med Bull. 54: 42–43. Sartorius N. (2000b). In: Okasha A, et al. (eds.) Culture,
Kastrup M. (2008). Eur Psychiatr 23(Suppl 1): 59–68. Ethics and Psychiatry. APA Press, Washington.
Kessler R, Demler O, Frank RG, et al. (2005). New Engl J Sartorius N, Davidian H, Ehrenberg G, Fenton FR, Jujii I,
Med. 353: 2515–2523. Gastpar M, Guibinat W, Jablensky A, Kielholz P,
Lehmann HE, Naraghi M, Shimizu M, Shinfuku N, Ministerial Conference. WHO Regional Office,
Takahashi R. (1983). Depressive Disorders in Differ- Copenhagen.
ent Cultures: Report on the WHO-Collaborative- WHO. (2005b). World Mental Health Atlas. WHO,
Study on Standardized Assessment of Depressive Geneva.
Disorders. World Health Organization, Geneva. WHO. (2008a). http://www.who.int/mental_health/pre-
Saxena S, Thornicroft G, Knapp M, Whiteford H. (2007). vention/genderwomen/en/ 2.2.2008.
Lancet. 370: 878–889. WHO. (2008b). http://www.searo.who.int/en/Section1174/
Tseng W-S. (2001). Handbook of Cultural Psychiatry. Section1199/Section1567/Section1826_8101.htm) 8.1.
Academic Press, San Diego. 2008.
Tseng WS. (2003). Clinician’s guide to cultural psychia- Wittchen HU, Lieb R, Wunderlich U, Schuster P. (1999).
try. Academic Press, San Diego. Clin Psychiatr. 60(Suppl 7): 29–36.
Weismann MM, Bland RC, Canino GJ, et al. (1996). Wittchen HU, Jacobi F. (2005). Eur Neur psych pharma-
JAMA. 276: 293–299. col. 15: 357–376.
WHO. (2001). World Health Report. WHO, Geneva. World Bank. (1993). World Development Report 1993:
WHO. (2004). JAMA. 291: 2581–2590. Investing in Health. Oxford University Press,
WHO. (2005a). Mental Health: Facing the Challenges, New York.
Building Solutions. Report from WHO European
87 Disease Burden and
Due to Schizophrenia and
Psychotic Disorders
A. Theodoridou . W. Rössler
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1494
1.1 Schizophrenia, Schizophrenia Spectrum Disorders and Other Psychotic
Disorders with a More Benign, Short-Lived Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1495
2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1499
3 The Link Between Physical and Mental Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1499
4 Treatment Possibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1501
5 Stigma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1501
6 Burden and the Role of Unmet Need . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1501
7 Family Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1502
8 Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1503
9 The Economic Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1505
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1506

1494 87 Disease Burden and DALY Due to Schizophrenia and Psychotic Disorders
Abstract: > Schizophrenia usually starts in young adulthood. The cumulative lifetime risk for
men and women is similar, although it is higher for men in the age group younger than
40 years. A common categorization of severe mental illness includes the schizophrenic and
delusional disorders listed under e.g. categories F20–29 of the WHO International Classifica-
tion of Diseases (ICD). Characteristic for the schizophrenic disorder is a distortion of thinking
and perception and affects that are inappropriate or blunted. > Hallucinations, delusional
perceptions and > delusion of controls are psychopathological phenomena that appear in
schizophrenia. Diagnosis and treatment of schizophrenia are often delayed. Schizophrenia is
one of the most burdensome and costly illnesses worldwide, because of onset, course and rate
of disabilities. Family relationships suffer, if the burden of care is shifted to families. According
to the Global Burden of Disease Study, schizophrenia causes a high degree of disability, which
accounts for 1.1% of the total > DALYs (disability-adjusted life years) and 2.8% of YLDs
(years lived with disability). Schizophrenia is listed as the eighth leading cause of DALYs
worldwide in the age group 15–44 years, according to the WHO World Health Report: new
understanding, new hope, 2001, Geneva. The risk of suicide is very high, 10–13% of people
with schizophrenia commit suicide. Comorbid somatic conditions in people with schizophre-
nia can also lead to premature death. Optimizing the general health needs attention.
List of Abbreviations: BPRS, brief psychiatric rating scale; DALY, disability-adjusted life year;
DSM, diagnostic and statistical manual of mental disorders; GAF, global assessment of
functioning; GBD, global burden of disease; ICD, international classification of diseases;
MSQOL, > modular system for Quality of Life; > PANSS, positive and negative syndrome
scale; QOL, quality of life; QUALY, quality-adjusted life year; > SF-36, Short-Form 36; WHO,
world health organization; YLD, years lived with disability; YLL, years of lost life
1 Introduction
‘‘Schizophrenia and psychotic disorders’’ are a heterogeneous category. Emil Kraepelin

(1896) first described an entity in using the term ‘‘dementia praecox,’’ which was later called
schizophrenic. With this expression he described clinical symptoms like hallucinations and
delusions (Jaspers, 1913/1963) within a long-term course. A few years later Eugen Bleuler
(1911) implemented the term schizophrenia. Symptoms can be e.g. disturbances in thinking,
perception and emotions. As recommended by Kane it is possible to split schizophrenic
symptoms into two categories, i.e. positive and > negative symptoms. > Positive symptoms
comprise hallucinations (e.g. internal voices discussing or commenting), delusions (e.g. of
being controlled or persecuted) and thought disorders like incoherence. Negative symptoms
reflecting a diminution or loss of normal function include poverty of speech, inappropriate or
flattening affect, apathy and anhedonia. These symptoms can appear together or alternate.
Crow proposed a new typology for schizophrenia in 1980, dividing the disorder into type I
(among others characterized by predominantly positive symptoms, good response to treat-
ment) and type II (characterized mainly by negative symptoms, insidious onset and tendency
to drug resistance). Negative symptoms are supposed to be more stable than positive symp-
toms. However, the measurement of negative symptoms can be confounded by various factors
like neuroleptic side-effects, depression or environmental understimulation. The term > psy-
chosis was introduced by Ernst Feuchtersleben and has been in use since 1845, initially to
differentiate from neuroses. Commonly, psychosis means to be impaired in reality testing with
hallucinations or delusions occurring. In broader definitions, psychosis can also include
Disease Burden and DALY Due to Schizophrenia and Psychotic Disorders 87 1495
disorganized speech or other positive symptoms of schizophrenia. The illness not only affects the
patient, but also his or her family and the society. Due to stigma and other factors schizophrenia
has been a misunderstood condition to patients, their families and to many in the medical field.
1.1 Schizophrenia, Schizophrenia Spectrum Disorders and Other

Psychotic Disorders with a More Benign, Short-Lived Course
Schizophrenia and Psychotic Disorders are classified in the chapter F2 (see > Table 87-1) of the
International Classification of Diseases (WHO) and analogous in the Diagnostic and Statisti-
cal Manual of Mental Disorders (> DSM IV-TR) (APA). Nevertheless these two classification
systems differ regarding definition, duration and subtypes of schizophrenia. > ICD-10 e.g.
avoids criteria based on social and occupational dysfunction because of the difficulties to equate
these criteria between different cultures. Regarding the longitudinal course and the subtypes
both classification systems are broadly similar. Schizophrenia functions as the main item in this
group, the remaining categories are related to schizophrenia. Characteristic for the schizophrenic
disorder is a distortion of thinking and perception and affects that are inappropriate or blunted.
The core psychopathological phenomena of Schizophrenia includes thought echo, thought
insertion or withdrawal, thought broadcasting, delusional perception and delusions of control
(for further details see Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 8th edition).
Depressive symptoms are often among the earliest signs of schizophrenia onset (Yung and
McGorry, 1996). Impairments in attention and information processing, which can often occur
in schizophrenia, are associated with social and vocational impairments.
In the further course depressive symptoms can appear as a sign of an imminent relapse
(Gaebel et al., 2000). They can also appear in a psychotic episode or following a psychotic
episode.
The course of schizophrenic disorders can be either continuous or episodic with progres-
sive or stable deficits. One or more episodes can occur with complete or incomplete remission.
A better course of the illness has been observed in women, in patients who had an acute, stress-
related onset of their illness, low levels of negative symptoms, higher social class, better
premorbid social development and no cannabis use (Kelly et al., 2001).
Onset usually occurs in late adolescence or early adulthood. Often a prodromal period
appears several years before the diagnosis can be made. The initial phase of schizophrenia,
with the prodromal stage and the psychotic prephase, varies greatly in type and length (see
> Figure 87-1). In the ‘‘ABC Study,’’ a retrospective epidemiological study called the
Mannheim Age – Beginning – Course Study, it was shown that the impairments often already
occur in the early preclinical course of the disease and the duration of untreated psychosis
(DUP) had a mean of 1.1 years in this study (Häfner et al., 1995). The DUP is seen as a
predictor of an unfavorable illness course (Häfner et al., 2002). The longer the DUP, the more
of persisting symptoms and the longer the inpatient treatment. Although this association is
not seen consistently in all groups, early detection and early intervention could be helpful in
reducing the pronounced social consequences of the disorder.
With regard to the mental health of young people we have to realize that mental disorders
in young people have a substantial effect on economic and social outcome, since most young
people take first steps regarding their career, job, friendships and relationships during this
period of their life. The functional impairment, exposure to stigma and discrimination can
persist into adulthood and have an impact on public health (Patel et al., 2007).
. Table 87-1
Block of ICD-10 categories relating to schizophrenia, schizotypal and delusional disorders
Schizophrenia, schizotypal and delusional disorders

F 20 Schizophrenia
F 20.0 Paranoid schizophrenia
F 20.1 Hebephrenic schizophenia
F 20.2 Catatonic schizophrenia
F 20.3 Undifferentiated schizophenia
F 20.4 Post-schizophrenic depression
F 20.5 Residual schizophrenia
F 20.6 Simple schizophrenia
F 20.8 Other schizophrenia
F 20.9 Unspecified schizophrenia
F 21 Schizotypal disorder
F 22 Persistent delusional disorders
F 22.0 Delusional disorder
F 22.8 Other persistent delusional disorders
F 22.9 Persistent delusional disorder, unspeciefied
F 23 Acute and transient psychotic disorders
F 23.0 Acute polymorphic psychotic disorder without symptoms of schizophrenia
F 23.1 Acute polymorphic psychotic disorder with symptoms of schizophrenia
F 23.2 Acute schizophrenia-like psychotic disorder
F 23.3 Other acute predominantly delusional psychotic disorders
F 23.8 Other acute transient psychotic disorders
F 23.9 Acute and transient psychotic disorders unspecified
F 24 Induced delusional disorder
F 25 Schizoaffective disorders
F 25.0 Schizoaffective disorder, manic type
F 25.1 Schizoaffective disorder, depressive type
F 25.2 Schizoaffective disorder, mixed type
F 25.8 Other schizoaffective disorders
F 25.9 Schizoaffective disorder, unspecified
F 28 Other nonorganic psychotic disorders
F 29 Unspecified nonorganic psychosis
Course: continuous/episodic(with progressive deficit, stable deficit, remittent)/incomplete
remission/complete remission/other
This is an excerpt from ICD-10 Classification of Mental and Behavioral Disorders (1992) (Data source: ICD-10;
Clinical Descriptions and Diagnostic Guidelines, pp. 84–85, WHO Geneva. Reprinted with permission from World
Health Organization)
The prephases of schizophrenia

. Figure 87-1
The prephases of schizophrenia from the first sign of mental disorder, the first positive
symptom to first admission. On average 5 years before the first positive symptoms occur
patients reported unspecific symptoms (N = 232) (Data source: Search for the Causes of
Schizophrenia, vol III (1995), pp. 43–56, (ed: Häfner H, Gattaz H) Onset and early course of
schizophrenia. Häfner H, Maurer K, Löffler W, Bustamante S, an der Heiden W, Riecher-
Rössler A, Nowotny B. (p. 53, > Figure 87-5) With kind permission of Springer Science and
Business Media.)
Diagnosis and treatment of schizophrenia are often delayed. Patients can show symptoms
like delusions or hallucinations for years before the disorder is diagnosed and treatment is
initiated. This duration of untreated psychosis (DUP, see > Figure 87-2) seemed to be
associated with impaired quality of life and poor outcome (Browne et al., 2000) and higher
risk of depression and suicide (Addington et al., 1998). Treatment during the prodromal
period is hoped to prevent psychosis or at least reduce its severity. In the past years a lot of
efforts have been made to understand symptoms of the schizophrenia prodrome. McGorry
and his colleagues developed a set of criteria for identifying a prodrome. Other groups in
Europe and USA developed different assessments, e.g. the Instrument for the Retrospective
Assessment of the Onset of Schizophrenia (IRAOS) (Häfner et al., 1992) or the Structured
Interview for Prodromal Symptoms (SIPS) and Scale of Prodromal Symptoms (SOPS) (Miller
et al., 1999).
Multiple interactions between genes and environment are involved in the etiology of
schizophrenia. Triggering factors and environmental influences, e.g. like birth complications,
. Figure 87-2
Early course of schizophrenia – phases and definitions. DUP duration of untreated psychosis; DUI
duration of untreated illness. Phases and their definitions pointing out the different stages of
schizophrenia (Data source: modified from McGlashan and Johannessen (1996), with permission
from Oxford University Press.)
drug abuse or urban background have been identified. Further knowledge about possible
genotype-environment interactions is required in order to develop and improve strategies for
the prevention and early treatment of schizophrenia (van Os and Marcelis, 1998). Beside the
role genetic predisposition plays in the etiology of schizophrenia, strong evidence exists for a
number of co-factors that influence manifestation and course of the illness (> Figure 87-3)
(Ehrenreich et al., 2002).
2 Epidemiology
Schizophrenia has been observed worldwide in all societies. In most psychiatric textbooks the
incidence and lifetime prevalence rates are defined as equal worldwide. Lifetime prevalence of
schizophrenia can be estimated at 1%. McGrath and colleagues point out in their systematic
review from 2004, that the median incidence rate was 15.2 per 100,000, with many studies
reporting rates in the upper range (10–90% quantiles = 7.7–43.0). They describe higher
incidence rates in men compared to women, higher rates in urban sites compared to mixed
urban/rural sites and higher rates in migrants compared to native-born individuals (McGrath
et al., 2004). Due to the sometimes chronic course the patients can be ill over a long period of
time, although the life expectancy for a person with schizophrenia is 20% shorter than for the
general population. The incidence or prevalence of schizoaffective disorder, schizophreniform
disorder and brief psychotic disorder is not yet clear today because of the change in diagnosis
over time. Due to differing observation times, methodology and true differences, the preva-
lence rates show more than a 50-fold variation (Wittchen and Jacobi, 2005). In a WHO study
the determinants of outcome of severe mental disorders (DOS) were obtained with a cohort
size of 1,379 incidence, based on service contacts and clinical information on the diagnosis
(Jablensky et al., 1992). The incidence ranged between 0.016 and 0.042% per year with a
tendency toward earlier onset in males for a broadly defined diagnosis of schizophrenia.
Wittchen et al. identified 27 eligible studies with quite variable designs and methods including
over 150,000 subjects from 16 European countries. Only 26% of all cases had had any
consultation with professional health care services, a finding suggesting a considerable degree
of unmet need. Severity, disability and comorbidity are necessary information for determining
the degree of met and unmet needs. These needs are most pronounced for the new EU member
states as well as more generally for adolescent and older populations (Wittchen and Jacobi,
2005). Nearly 30% of patients diagnosed with schizophrenia had attempted suicide at least once
during their lifetime (Radomsky et al., 1999) and about 10% of the patients commit suicide
(Caldwell and Gottesmann, 1990).
3 The Link Between Physical and Mental Problems
There are great variations in life expectancy worldwide. Compared to the general population
life expectancy of people with severe mental illness is reduced. In a systematic review of
mortality in schizophrenia Saha et al. conclude that people with schizophrenia have a twofold
to threefold increased mortality risk. Both sexes are equally affected (Saha et al., 2007). People
with severe mental illness suffer an increased risk of having e.g. diabetes and hypertension.
They have a ten times a greater risk of cardiovascular disease (STAKES, 2003).
According to published data the greatest cause of death among persons with schizophrenia
is cardiovascular disease followed by suicides (Brown, 1997). Caldwell and Gottesmann
1500
. Figure 87-3
Etiology and pathogenesis of schizophrenic psychosis. Co-factors that influence manifestation and course of schizophrenia (Data source, modified
from: Risk and Protective Factors in Schizophrenia (2002, p. 259), Neuroprotection in Schizophrenia – What does it mean? – What means do we have?
87
Ehrenreich H, Siren A-L, > Figure 87-1. With kind permission of Springer Science and Business Media.)
Disease Burden and DALY Due to Schizophrenia and Psychotic Disorders
showed in their review that 10–13% of people with schizophrenia committed suicides. In
comparison to the specific-cause standardized mortality ratios, suicide was estimated 12 times
greater than expected in the general population (Saha et al., 2007). The risk of suicide
increased with e.g., depressive symptoms, alcohol and drug dependency and socioeconomic
difficulties.
4 Treatment Possibilities
Today psychosocial interventions and medication are the most common treatment
approaches. They include, tailored to each individual, medication, psychotherapy, family
counseling and community-based service. Although a number of promising interventions
seem to be efficient for different domains, the fragmented care can often represent a barrier to
access care. An integrated approach to treatment may be helpful in trying to optimize recovery
and outcome for individuals. Another area of intense interest is the attempt to identify
premorbid symptoms early and intervene before the illness reaches full manifestation.
Evaluation of the use of low-dosage antipsychotic treatment in high-risk individuals is
under way.
5 Stigma
Patients, their families and the society can be affected through negative attitudes and stereo-
types. They can also internalize false beliefs like being defective and undeserving. It is well-
known that negative attitudes towards the mentally ill still exist, especially towards persons
with schizophrenia (Stuart and Arboleda-Florez, 2001). This creates a vicious cycle of dis-
crimination leading to social isolation, unemployment, drug abuse, long-lasting institutional-
ization or even homelessness, which further decreases the chances of recovery and
reintegration into normal life. Several strategies were developed to fight the stigma and
discrimination because of schizophrenia, e.g. the global anti-stigma program from the
World Psychiatric Association.
6 Burden and the Role of Unmet Need
With the Global Burden of Disease Study (GBD) a new metric called disability-adjusted life
year (DALY) was introduced to quantify the burden of diseases. In a standardized approach to
epidemiological assessment DALY should aid comparisons. DALY combines information on
the impact of mortality (years of life lost because of premature death = YLL) and disability
(years lived with disability = YLD). One DALY can be thought as one lost year of ‘‘healthy’’ life.
According to the Global Burden of Disease Study (Murray and Lopez, 1996, 1997), schizo-
phrenia causes a high degree of disability that accounts for 1.1% of the total DALYs and 2.8%
of YLDs. In the World Health Report (2001) schizophrenia is listed as the eighth leading cause
of disability-adjusted life years worldwide in the age group 15–44 (Rössler et al., 2005).
In further studies (Harwood et al., 2004; Üstün et al., 1999) active psychosis ranked higher
than paraplegia and blindness in the general population and ranked in the highest disability
class, requiring daily care.
Maybe Policy makers and public health experts are interested in tools for estimating the
burden of disease in the context of evaluation and priority setting for health disorders. Though
DALYs and QALYs (quality-adjusted life years, the complement to DALY, a measure for the
impact of a disease in terms of duration and quality of life) are common measures, we have to
take the values (not only monetary) into account which play a critical role in decision making
(Frohberg and Kane, 1989). Another limitation is the fact that basic parameters for mental
health epidemiology like incidence, duration and change in parameters over time and treat-
ment effectiveness depend on the based classification system and can change, and we also have
to take the fact into account that up to now these do not exist in many developing countries.
It is possible to distinguish between the total and the ‘‘avoidable’’ burden. ‘‘Avoidable’’ in
the sense of Hollinghurst et al. (2000) means the element of the total burden that ought to be
amenable to prevention and treatment. The authors distinguish between incidence-based
DALYs and prevalence-based DALYs. The first are appropriate where prevention should be
able to reduce the burden of disease. The prevalence-based DALYs are appropriate when a
disease cannot be prevented but effective treatment is available. Several assumptions have to be
made, while keeping in mind that there are still considerable gaps in knowledge about the
natural history of schizophrenia. Hollinghurst et al. consider that ‘‘avoidable’’ DALYs are
relevant in deciding which health care to pay for, and total DALYs offer useful information to
indicate how research funds ought to be spent. Both kinds of DALYs can be useful in providing
information about monitoring the health of populations.
7 Family Burden
The burden of care has often shifted to families. Family relationships suffer. They sustain a
substantial amount of the burden due to the schizophrenic illness. Examples of this kind
of burden are emotional reactions to the illness, the stress of coping with disturbed behavior,
the disruption of household routine, the stigma they too are confronted with, the restriction of
social activities and economic difficulties. The most important predictor of burden on
relatives according to Lauber et al. (2003) was the distress and changes in the relationship
between the caregiver and the affected individual that occur during acute illness. Recent
research has studied burden in relatives of persons with schizophrenia (Jungbauer et al.,
2004; Schulze et al., 2005; Thornicroft et al., 2004). In a qualitative study Jungbauer et al.
investigate the effect of care giving in spouses of people with schizophrenia, they discuss
partnership difficulties and resources and compare burden between spouses and parents.
Thornicroft et al. investigated the personal impact of schizophrenia in a multi-centre study.
The authors compared caregiver burden across five European countries. They found caregiver
burden in schizophrenia to be almost identical across five countries. Scores were higher when
patients lived with their family and in regions with fewer psychiatric beds. For the practical
and psychological burden experienced by relatives of patients with schizophrenia see
> Table 87-2 (Magliano et al., 2002). In another study with a representative sample the authors
compared burden and social networks in families of patients with schizophrenia or a long-
term physical disease, and found higher subjective burden as well as dramatically
lower social support and help in emergencies concerning the patient with schizophrenia
(Magliano et al., 2005).
. Table 87-2
Practical and psychological burden experienced by relatives of patients with schizophrenia
(N = 709)
Always-
often/yes Sometimes Never/
Variables (%) (%) no(%)
Practical problems
I have had to wake up during the night 22 34 44
I have had to neglect my hobbies and things I like doing in my 45 28 27
free time
I have had difficulty in going on Sunday outings 38 29 33
I found it difficult to have fiends at home 31 24 45
I found it difficult to meet my friends and people I like to 33 29 38
spend my leisure time
I found it difficult to carry out my usual work or household 22 33 45
activities or I had to stay at home from work or school
I had to neglect other family members 21 30 49
I had difficulty in going on holiday 47 21 32
Psychological problems
I felt that I would not be able to bear this situation much 38 37 25
longer
I cried or felt depressed 45 38 17
I worry for the future of other family members 40 33 27
When I went to a public place with my ill relative, I felt that 21 31 48
everyone was watching us
I feel guilty because I believe that I or my spouse may have 9 18 73
passed on the illness to our relative
I think that if our relative didn’t have this problem, everything 62 23 15
would be all right in our family
When I think of how our ill relative was beforehand and how 83 14 3
he/ she is now, I feel disappointed
Practical and psychological problems experienced by relatives of patients with schizophrenia (Data source:
Magliano et al. (2002), with permission from Blackwell Publishing, Oxford)
8 Quality of Life
Quality of life (QOL) not only depends on the disorder but also on the individual, economic
and sociocultural conditions that the patients live in. It is a complex multidimensional
construct that consists of various domains including physical health, psychological health
and general health perceptions of the individual, social functioning and role functioning
(Wilson and Cleary, 1995). Subjective QOL can be measured reliably and reflect clinically
relevant changes responsively by the MSQOL and the SF-36, although discriminant validity
with regard to depression and current mood is questionable (Pukrop et al., 2003).
Individuals with first episode spectrum disorders (schizophrenia, schizoaffective and

schizophreniform disorders show a negative correlation between the QOL and negative
symptomatology on the PANSS (Ho et al., 1998; Sim et al., 2004).
In a study published 1999, Rössler et al. assessed the Quality of life (QOL) of 96
schizophrenic patients in different treatment settings (community mental health care vs.
long-term hospital care) with the > Munich Quality of Life Dimensions List (MLDL, Heinisch
et al., 1991) and searched for the factors which influenced their QOL. The patients in
community care reported a better QOL than those in long-term hospital care. They showed
a greater satisfaction with life. The dimensions with which the patients were most satisfied and
more dissatisfied were not significantly different for the two groups. The most dissatisfying
domains were marriage/partnership, sex life, financial situation and job situation, and the
patients were most satisfied with their medical treatment and leisure time (see > Figure 87-4).
Regression analysis showed that, when other factors influencing QOL (like age, gender, marital
status, level of education, professional training, current paid employment, duration of illness,
number of previous inpatient stays, first contact with psychiatric services when under 25 years
of age, total number of supporting individuals) were included, the place of treatment was no
longer significant, but rather the social support, the severity of the illness, educational level
and certain illness concepts.
Salokangas et al. (2006) interviewed a national sample of 2,221 persons with schizophrenia
in Finland 3 years after discharge. Subjective life satisfaction was measured. They conclude that
being female and having a good psychosocial functioning, confidants, good physical health,
. Figure 87-4
Quality of life in community-care patients (dark line) vs. long-term hospital-care patients.
*Significant differences in QOL domains ( 50: least satisfied, 50: most satisfied) (Data source:
modified from Rössler et al. (1999), with permission from Blackwell Publishing, Oxford)
. Figure 87-5
Service cost comparison for schizophrenic patients in five European countries. Average direct
cost of mental health care per annum and patient (in English pounds, for the year 1998). Costs
were adjusted for center, gender, marital status, ethnicity, language, employment, age,
education, GAF and BPRS (Data source: The EPSILON Study, Knapp et al. (2002), with permission
from Blackwell Publishing, Oxford)
and living arrangements in the community that offer support are important factors of life
satisfaction (> Figure 87-5).
9 The Economic Perspective
Schizophrenia is found to be a worldwide public health problem that causes enormous

economic costs. It begins early in life and can cause long-lasting impairments.
Direct and indirect costs due to schizophrenia have been examined in different studies. It is
estimated that indirect costs (expressed in financial terms) are five times higher than the direct
costs of treatment and care. Schizophrenia has financial consequences for the patients, their
relatives and the national economy (Rössler et al., 1998). In Germany in the year 2002 the health
expenditure for schizophrenia patients came to an estimated 1.3% (Statistisches Bundesamt,
2004). In the EPSILON Study the authors compared patterns and costs of schizophrenia care in
five European countries and found differences in the annual cost of care per patient between
different countries (see > Figure 87-5) (Knapp et al., 2002). With regard to the relatively high
prevalence and the fact, that schizophrenia often leads to mental and social disability,
the illness is one of the most burdensome and costly illnesses worldwide (Rössler et al.,
2005). In a cost-effectiveness study of current and optimal treatments for mental disorders and
the proportion of burden avertable by each, Andrews et al. compared data (cost, burden averted,
efficiency of current and optimal treatment) for affective disorders, anxiety disorders, alcohol use
disorders and schizophrenia. They conclude that the efficiency of treatment varied more than
tenfold across disorders. Treatment of schizophrenia was ten times the average per case in this
investigation. Optimal treatment of everyone with a mental disorder would still leave 60% of the
burden unaverted (Andrews et al., 2004). In another modeling study of the same group, they
conclude that optimal, evidence-based care for people with schizophrenia would not cost more
but would increase the health gain by two-thirds (Andrews et al., 2003). Schizophrenia has a high
burden. Knowledge of optimal intervention today allows an improvement, but more work has to
be done to better understand the mechanisms and to provide prevention strategies.
Summary Points
Schizophrenia usually starts in young adulthood. The initial phase shows variations in type
and length with an estimated lifetime prevalence of 1%.
Diagnosis and treatment of schizophrenia are often delayed with a long duration of
untreated psychosis (DUP).
The etiology of schizophrenia seems to be multifactorial based on interactions between
genes and environment.
Schizophrenia is listed as the eighth leading cause of disability-adjusted life years (DALYs).
Values in decision making and changes in the based classification system have to be taken
into account as limitations regarding the effort to optimize the estimation of the burden of
disease.
Burden of care often falls to families.
Indirect costs (expressed in financial terms) are five times higher than the direct costs of
treatment and care in schizophrenia.
References
Addington D, Addington J, Patten S. (1998). Br J Psychi- Ehrenreich H, Sirén AL. (2002). In: Häfner H (ed.) Risk
atry 172/Suppl. 33: 90–92. and Protective Factors in Schizophrenia. Steinkopff
American Psychiatric Association. (2000). Diagnostic Verlag Darmstadt, pp. 257–262.
and Statistical Manual of Mental Disorders, Fourth Frohberg DG, Kane RL. (1989). J Clin Epidemiol. 42(4):
Ed., Text Revision. American Psychiatric Associa- 345–354.
tion, Washington, DC. Gaebel W, Jänner M, Frommann N, Pietzcker A,
Andrews G, Sanderson K, Corry J, Issakidis C, Lapsley H. Köpke W, Linden M, Müller P, Müller-Spahn F.
(2003). Br J Psychiatry. 183: 427–435. (2000). Compr Psychiatry. 41: 76–85.
Andrews G, Issakidis C, Sanderson K, Corry J, Lapsley H. Harwood RH, Sayer AA, Hirschfeld M. (2004). Bull
(2004). Br J Psychiatry. 184: 526–533. World Health Organ. 82(4): 251–258.
Bleuler E. (1911). Dementia praecox oder Gruppe der Häfner H, Maurer K, Löffler W, an der Heiden W,
Schizophrenien. Deutike, Leipzig-Wien. Könnecke R, Hambrecht M. (2002). In: Häfner H
Brown S. (1997). Br J Psychiatry. 171: 502–508. (ed.) Risk and Protective Factors in Schizophrenia.
Browne S, Clarke M, Gervin M, Waddington JL, Steinkopff Verlag Darmstadt, pp. 207–228.
Larkin C, O’Callaghan E. (2000). Br J Psychiatry. Häfner H, Nowotny B, Löffler W, Heiden an der W,
176: 173–176. Maurer K. (1995). Eur Arch Psychiatry Clin Neu-
Caldwell CB, Gottesman II. (1990). Schizophr Bull. 16 rosci. 246(1): 17–28.
(4): 571–589.
Häfner H, Riecher-Rössler A, Hambrecht M, Maurer K, Mortality and Disability from Diseases, Injuries
Meissner S, Schmidtke A, Faktenheuer B, Löffler W, and Risk Factors in 1990 and Projected to 2020.
an der Heiden W. (1992). Schizophr Res. 6: 209–223. Global Burden of Disease and Injury Series, Vol. 1.
Heinisch M, Ludwig M, Bullinger M. (1991). Bullinger Harvard School of Public Mental Health, Cam-
M, Ludwig M, von Steinbüchel N (ed.) Lebensqua- bridge, MA.
lität bei Kardiovaskulären Erkrankungen. Grundla- Murray CJL, Lopez AD. (1997). Lancet 349(9064):
gen, Messverfahren und Ergebnisse. Göttingen, 1498–1504.
Hogrefe, pp. 73–90. Patel V, Flisher AJ, Hetrick S, McGorry PM. (2007).
Ho BC, Nopoulos P, Flaum M, Arndt S, Andreasen NC. Lancet. 369: 1302–1313.
(1998). Am J Psychiatry. 155: 1196–1201. Pukrop R, Schlaak V, Möller-Leimkühler AM, Albus M,
Hollinghurst S, Bevan G, Bowie C. (2000). Health Care Czernik A, Klosterkötter J, Möller HJ. (2003). Psy-
Manag Sci. 3: 9–21. chiatry Res. 119: 63–79.
Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Radomsky ED, Haas GL, Mann JJ, Sweeny JA. (1999).
Cooper JE, Day R, Bertelsen A. (1992). Schizophre- Am J Psychiatry. 156(10): 1590–1595.
nia: Manifestations, Incidence and Course in Differ- Rössler W, Salize HJ, Cucchiaro G, Reinhard I,
ent Cultures. Cambridge University Press. Kernig C. (1999). Acta Psychiatr Scand. 100:
Jaspers K. (1913/1963). General Psychopathology. Man- 142–148.
chester University Press (orig.: Allgemeine Psycho- Rössler W, Salize HJ, Knapp M. (1998). Fortschr Neurol
pathologie, Springer Verlag, Berlin). Psychiattr. 66(11): 496–504.
Jungbauer J, Wittmund B, Dietrich S, Angermeyer MC. Rössler W, Salize HJ, van Os J, Riecher-Rössler A. (2005).
(2004). Schizophr Bull. 30(3): 665–675. Eur Neuropsychopharmacol. 15: 399–409.
Kaplan & Sadock’s Comprehensive Textbook of Psy- Saha S, Chant D, McGrath J. (2007). Arch Gen Psychitry.
chiatry, 8th ed., Lippincott Williams & Wilkins, 64(10): 1123–1131.
pp. 1096–1232. Salokangas RK, Honkonen T, Stengard E, Koivisto AM.
Knapp M, Chisholm D, Leese M, Amaddeo F, Tansella M, (2006). Psychiatr Serv. 57(3): 373–381.
Schene A, Thornicroft G, Vasquez-Barquero JL, Schulze B, Rössler W. (2005). Curr Opin Psychiatry. 18:
Knudson HC, Becker T. (2002). Acta Psychiatr 684–691.
Scand. 105(1): 42–54. Sim K, Mahendran R, Siris SG, Heckers S, Chong SA.
Kelly J, Murray RM, van Os J. (2001). The outcome of (2004). Psychiatry Res. 129: 141–147.
psychotic illness. In: Lieberman J, Murray RM (ed.). Statistisches Bundesamt. (2004). Krankheitskosten 2002.
The Comprehensive Care of Schizophrenia. Dunitz, Wiesbaden.
London, pp. 1531–1539. Stuart H, Arboleda-Florez J. (2001). Can J Psychiatry.
Kraepelin E. (1896). Psichiatrie, 5th ed. Barth, Leipzig. 46(3): 245–252.
Lauber C, Eichenberger A, Luginbuhl P, Keller C, The ICD-10 Classification of Mental and Behavioural Dis-
Rössler W. (2003). Eur Psychiatry. 18(6): 285–289. orders. (1992). World Health Organization, Geneva.
McGlashan TH, Johannessen JO. (1996). Schizophr Bull. The WHO World Health Report: New Understanding,
22(2): 201–222. New Hope. Geneva, 2001.
McGrath J, Sukanta S, Welham J, El Saadi O, Thornicroft G, Tansella M, Becker T, Knapp M, Leese M,
MacCauley C, Chant D. (2004). BMC Med. 2: 13. Schene A. (2004). Schizophr Res. 69(2–3): 125–132.
Magliano L, Fiorillo A, De Rosa C, Malangone C, Maj M. Üstün TB, Rehm J, Chatterji S, Saxena S, Trotter R,
(2005). Soc Sci Med. 61(2): 313–322. Room R, Bickenbach J. (1999). Lancet. 354(9173):
Magliano L, Marasco C, Fiorillo A, Malangone C, 111–115.
Guameri M, Maj M. (2002). Acta Psychiatr Scand. Van Os J, Marcelis M. (1998). Schizophr Res. 32:
106: 291–298. 127–135.
Miller TJ, McGlashan TH, Woods SW, Stein K, Wilson IB, Cleary PD. (1995). JAMA. 273: 59–65.
Driesen N, Corcoran CM, Hoffman R, Davidson L. Wittchen HU, Jacobi F. (2005). Eur Neuropsychophar-
(1999). Psychiatr Q. 70: 273–287. macol. 15: 357–376.
Murray CJL, Lopez AD. (1996). The Global Burden Yung AR, McGorry PD. (1996). Schizophr Bull. 22:
of Disease: A Comprehensive Assessment of 353–370.
88 The Societal Costs of Anxiety
and Mood Disorders: An
Epidemiological Perspective
R. C. Kessler . P. S. Wang . H.-U. Wittchen
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1510
2 Methods of Assessing Anxiety and Mood Disorders in

Epidemiological Surveys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1511
3 Lifetime and 12-Month Prevalence of Anxiety and Mood Disorders . . . . . . . . . . . . . . 1512
4 Age-of-Onset Distributions of Anxiety and Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . 1515
5 The Course of Anxiety and Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1518
6 Comorbidity Among Anxiety and Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1519
7 The Adverse Effects of Anxiety and Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1520
8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1522
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1522

1510 88 The Societal Costs of Anxiety and Mood Disorders: An Epidemiological Perspective
Abstract: This chapter reviews the epidemiological literature on the prevalence and adverse
societal consequences of anxiety and mood disorders. A special emphasis is put on the
recently collected data from the completed World Health Organization (WHO) World
Mental Health (WMH) Surveys (Kessler and Üstün, 2008). The first section of the chapter
discusses the methods used in community epidemiological surveys to estimate
the prevalence and correlates of mental disorders. The next section reviews the recent
worldwide epidemiological literature on the general population prevalence of anxiety
and mood disorders. This is followed by reviews of recent epidemiological evidence on
age-of-onset distributions, illness course, and comorbidity among the anxiety and mood
disorders. The last section reviews the recent epidemiological literature on the adverse
effects of anxiety and mood disorders. The evidence presented in these sections documents
clearly that anxiety and mood disorders are commonly occurring, that many of them start
at an early age and have a chronic-recurrent course, and that they have a number of
adverse effects that make them among the most costly of all health problems from a
societal perspective.
List of Abbreviations: AOO, Age-Of-Onset; BPD, Bipolar Disorder; CDS, The National
Institute of Mental Health Collaborative Depression Study; CIDI, The Composite Interna-
tional Diagnostic Interview; DIS, The Diagnostic Interview Schedule; DSM, The American
Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders; GAD,
Generalized Anxiety Disorder; HARP, The Harvard/Brown Anxiety Disorders Research
Program; ICD, The World Health Organization International Classification of Diseases;
ICPE, The World Health Organization International Consortium of Psychiatric Epidemiology;
IQR, Inter-Quartile Range; MDD, Major Depressive Disorder; NCS-R, The National
Comorbidity Survey Replication; NIMH, The National Institute of Mental Health; OCD,
Obsessive-Compulsive Disorder; PTSD, Post-Traumatic Stress Disorder; SAD, Separation
Anxiety Disorder; WHO, World Health Organization; WMH Surveys, The World Mental
Health Surveys
1 Introduction
This chapter reviews the epidemiological literature on the societal costs of anxiety and mood
disorders. Interest in the costs of illness – not only direct treatment costs, but the human costs
as well – has increased dramatically over the past decade as part of the larger movement to
rationalize the allocation of treatment resources and maximize benefit in relation to cost.
Much of the current interest in anxiety and mood disorders among health policy makers is
based on the fact that these disorders have consistently been found in cost-of-illness studies to
be among the most costly health problems in the population (e.g., Ormel et al., 2008). A
number of factors account for these results and have important implications for the design of
treatment programs for anxiety and mood disorders: that anxiety and mood disorders are
commonly occurring, often begin at an early age, often are quite persistent throughout the
life course, and often have substantial adverse effects on functioning. This chapter reviews
the epidemiological evidence regarding these points, with a special emphasis on data from
the recently completed World Health Organization (WHO) World Mental Health (WMH)
Surveys (Kessler and Üstün, 2008).
The Societal Costs of Anxiety and Mood Disorders: An Epidemiological Perspective 88 1511
2 Methods of Assessing Anxiety and Mood Disorders in

Epidemiological Surveys
Information about the epidemiology of anxiety and mood disorders has proliferated over the
past two decades. The reason for this can be traced to modifications in the criteria for
diagnoses of mental disorders in the DSM system beginning with DSM-III that made it
much easier than previously to operationalize diagnostic criteria. Fully structured research
diagnostic interviews appropriate for use by trained lay interviewers were subsequently
developed for this purpose. The first of these interviews was the Diagnostic Interview Schedule
(DIS; Robins et al., 1981), an instrument developed for use in a large community epidemio-
logical survey in the US (Robins and Regier, 1991) and subsequently used in a number of
similar surveys in other parts of the world (e.g., Horwath and Weissman, 2000).
The WHO subsequently developed the Composite International Diagnostic Interview
(CIDI; Robins et al., 1988), which was based on the DIS, in order to have an instrument
that could be used to generate diagnoses according to the definitions of both the DSM and
ICD systems and that could be used reliably in many different cultures throughout the world
(Wittchen, 1994). As general population surveys were carried out in a number of countries
with the first version of CIDI, WHO developed a cross-national research consortium to carry
out systematic comparisons of CIDI survey results (WHO International Consortium in
Psychiatric Epidemiology, 2000).
Results based on these comparisons led to the expansion and refinement of the CIDI and
to a new generation of cross-national CIDI surveys in the WHO World Mental Health (WMH)
Survey Initiative. The latter is an initiative aimed at carrying out and analyzing the results of
parallel CIDI surveys in countries throughout the world. Twenty-eight countries have com-
pleted WMH surveys as of the time this chapter is being written and close to 200 country-
specific reports have been published from these surveys (www.hcp.med.harvard.edu/wmh).
Although only a small number of cross-national comparative WMH reports have been
published so far (e.g., Nock et al., 2008; Ormel et al., 2008; Wang et al., 2007), the first volume
in a new series of WMH books was recently completed that provides very useful comparative
data on disorder prevalence and treatment (Kessler and Üstün, 2008). We draw heavily on
these data in this chapter.
As the CIDI has become so predominant in psychiatric epidemiological surveys, a few
words need to be said about the extent to which diagnoses based on the CIDI are consistent
with diagnoses based on independent clinician-administered research diagnostic interviews.
Clinical reappraisal studies of the original version of CIDI were quite mixed in this regard,
some showing concordance of anxiety and mood disorder diagnoses with clinical diagnoses to
be low and others moderate to good. Concordance has been considerably better for more
recent versions of CIDI in clinical reappraisal studies carried out in Western countries (Haro
et al., 2006). Both individual-level diagnostic concordance and consistency of CIDI anxiety
disorder prevalence estimates with prevalence estimates based on clinical interviews have been
good in these studies.
Much less is known about the clinical relevance of diagnoses based on fully-structured
diagnostic interviews in developing countries. Prevalence estimates in epidemiological surveys
in some developing countries seem implausibly low, raising concerns either that research
diagnostic interviews are not valid in countries where there is no tradition of public opinion
research or that the Western diagnostic constructs embedded in existing interviews have low
relevance to some developing countries. Methodological studies are underway to investigate

these possibilities. Caution is needed in interpreting results of epidemiological studies carried
out in developing countries until methodological investigations have reached a conclusion.
3 Lifetime and 12-Month Prevalence of Anxiety and

Mood Disorders
With these cautions as a backdrop, we consider the prevalence estimates of anxiety and mood
disorders reported in published community epidemiological surveys. Several recent literature
reviews have presented detailed summary tables of prevalence estimates for individual anxiety
and mood disorders across a number of epidemiological surveys (Somers et al., 2006; Waraich
et al., 2004; Wittchen and Jacobi, 2005). A number of patterns are consistent in these reviews.
One is that anxiety disorders have consistently been found to be the most prevalent class of
mental disorders in the general population. The estimated lifetime prevalence of any anxiety
disorder averages approximately 16% and that of 12-month prevalence approximately 11% in
community surveys. The estimated lifetime prevalence of any mood disorder, in comparison,
averages approximately 12% and that of 12-month prevalence approximately 6%. There is
wide variation around these averages, though, with prevalence estimates generally higher in
Western developed countries than in developing countries. This can be seen clearly by examining
the range of lifetime and 12-month prevalence estimates of anxiety disorders (> Table 88-1) and
mood disorders (> Table 88-2) in the WMH surveys. As shown there, the median lifetime
prevalence estimate is somewhat higher for anxiety disorders than in the larger literature –
14.3%, with an inter-quartile range (QR; 25th–75th percentiles) of 9.9–16.7%. The Median
WMH lifetime prevalence estimate for any mood disorder, in comparison, is somewhat lower
than the average in the larger literature – 10.6% with an IQR of 7.6–17.9%. Twelve-month
prevalence estimates (with IQR in parentheses) in the WMH surveys average 8.3% (6.5–12.1)
for any anxiety disorder and 5.1% (3.4–6.8) for any mood disorder.
Focusing on individual disorders, specific phobia is generally found to be the most
prevalent anxiety or mood disorder in community epidemiological surveys, with lifetime
prevalence estimates usually in the 6–12% range and 12-month prevalence estimates in the
4–8% range (Silverman and Moreno, 2005). Major depressive disorder (MDD) is generally
found to be the next most prevalent lifetime anxiety or mood disorder, with lifetime preva-
lence estimates usually in the 4–10% range and 12-month prevalence estimates in the 3–6%
range (Judd and Akiskal, 2000). Social phobia is generally found to be the next most prevalent
anxiety or mood disorder, with prevalence estimates sometimes approaching those of MDD
(Furmark, 2002). At the other extreme, Bipolar I disorder is usually found to be the least
prevalent anxiety or mood disorder, with lifetime prevalence estimates averaging approxi-
mately 1% and 12-month prevalence averaging 0.6% (Benazzi, 2007). Obsessive compulsive
disorder (OCD) is usually found to be the least common anxiety disorder, with lifetime
prevalence typically less than 2% and 12-month prevalence of approximately 1% (Fontenelle
et al., 2006). Prevalence estimates for the other anxiety and mood disorders are higher than
these, but lower than those for specific phobia, MDD, and social phobia. The WMH estimates
are generally quite consistent with these more general estimates (Kessler et al., 2008).
Controversy exists regarding the appropriate diagnostic thresholds for some anxiety and
mood disorders, such as post-traumatic stress disorder (PTSD; Mylle and Maes, 2004) and
generalized anxiety disorder (GAD; Ruscio et al., 2007). In both these cases, good evidence
. Table 88-1
Lifetime and 12-month prevalence estimates of DSM-IV anxiety disorders in the WMH surveysa
Lifetime 12-month
% (SE) % (SE)
I. WHO Region: Pan American Health Organization (PAHO)
Colombia 25.3 (1.4) 14.4 (1.0)
Mexico 14.3 (0.9) 8.4 (0.6)
US 31.0 (1.0) 19.0 (0.7)
II. WHO Region: African Regional Office (AFRO)
Nigeria 6.5 (0.9) 4.2 (0.5)
South Africab,c 15.8 (0.8) 8.2 (0.6)
III. WHO Region: Eastern Mediterranean Regional Office (EMRO)
Lebanon 16.7 (1.6) 12.2 (1.2)
IV. WHO Region: European Regional Office (EURO)
Belgium 13.1 (1.9) 8.4 (1.4)
France 22.3 (1.4) 13.7 (1.1)
Germany 14.6 (1.5) 8.3 (1.1)
Israeld,b,c 5.2 (0.3) 3.6 (0.3)
Italy 11.0 (0.9) 6.5 (0.6)
Netherlands 15.9 (1.1) 8.9 (1.0)
Spain 9.9 (1.1) 6.6 (0.9)
Ukraineb,c 10.9 (0.8) 6.8 (0.7)
V. WHO Region: Western Pacific Regional Office (WPRO)
PRCe 4.8 (0.7) 3.0 (0.5)
Japanc 6.9 (0.6) 4.2 (0.6)
c
New Zealand 24.6 (0.7) 15.0 (0.5)
a
Anxiety disorders include Agoraphobia without a history of panic disorder, adult and childhood separation
anxiety disorder, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, social phobia, and
specific phobia. Organic exclusions were made as specified in the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition
b
Specific phobia was not assessed
c
Adult and childhood separation anxiety disorder not assessed
d
Social phobia was not assessed
e
People’s Republic of China
exists from epidemiological surveys that one or more particular diagnostic criteria define a
much more restrictive set of cases than the other criteria, calling into question the wisdom of
including the restrictive criteria. In the case of GAD, for example, the original diagnostic
criteria in DSM-III required a minimum duration of 1 month that was changed in the DSM-
III-R and DSM-IV to 6 months in an effort to reduce the high comorbidity found in clinical
samples (but not, as it was subsequently discovered, in community samples) between GAD
and MDD. The ICD-10 criteria for practice split this difference by requiring a minimum
. Table 88-2
Lifetime and 12-month prevalence estimates of DSM-IV mood disorders in the WMH surveysa
Lifetime 12-month
% (SE) % (SE)
I. WHO Region: Pan American Health Organization (PAHO)
Colombia 14.6 (0.7) 7.0 (0.5)
Mexico 9.2 (0.5) 4.7 (0.3)
US 21.4 (0.6) 9.7 (0.4)
II. WHO Region: African Regional Office (AFRO)
Nigeria 3.3 (0.3) 1.1 (0.2)
South Africab 9.8 (0.7) 4.9 (0.4)
III. WHO Region: Eastern Mediterranean Regional Office (EMRO)
Lebanon 12.6 (0.9) 6.8 (0.7)
IV. WHO Region: European Regional Office (EURO)
Belgiumb,c 14.1 (1.0) 5.4 (0.5)
Franceb,c 21.0 (1.1) 6.5 (0.6)
b,c
Germany 9.9 (0.6) 3.3 (0.3)
Israel 10.7 (0.5) 6.4 (0.4)
Italyb,c 9.9 (0.5) 3.4 (0.3)
b,c
Netherlands 17.9 (1.0) 5.1 (0.5)
Spainb,c 10.6 (0.5) 4.4 (0.3)
Ukraineb 15.8 (0.8) 9.0 (0.6)
V. WHO Region: Western Pacific Regional Office (WPRO)
PRCd 3.6 (0.4) 1.9 (0.3)
Japan 7.6 (0.5) 2.5 (0.4)
New Zealand 20.4 (0.5) 8.0 (0.4)
a
Mood disorders include bipolar disorders, dysthymic disorder, and major depressive disorder. Organic exclusions
were made as specified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
b
Bipolar disorders were not assessed
c
Dysthymia was not included
d
People’s Republic of China
duration of ‘‘several’’ months. Considerable epidemiological research has now shown, though,
that the original 1-month requirement makes more sense from an epidemiological perspective
than the more strict duration requirements in that the predictors of lifetime GAD (e.g.,
childhood adversity, family history of anxiety disorder, primary comorbid disorders) and
the clinical correlates of GAD (e.g., age-of-onset, course, role impairment, suicidality) are all
very similar for cases with 1-month durations versus 6-month durations. Many of the people
with episodes of GAD that do not last as long as 6 months report having many episodes in
their lifetimes, suggesting that this is a chronic-recurrent episodic disorder characterized by
extreme stress reactivity that triggers episodes of excessive worry that remit (in less than
6 months) and then recur repeatedly over time. The 6-month duration requirements results
in these people failing to be defined as clinically meaningful cases. If these diagnostic
controversies were resolved in the direction of broadening the criteria for PTSD and GAD,
prevalence estimates would increase substantially: as much as 50% in the case of PTSD and as
much as 150% in the case of GAD.
A related issue is that considerable evidence exists for the existence of clinically significant
sub-threshold manifestations of many anxiety and mood disorders that are much more
prevalent than the disorders themselves. Unlike the situations with PTSD and GAD noted in
the previous paragraph, the more general issue is that many anxiety and mood disorders
appear to be extremes on underlying dimensions rather than categorical manifestations that
are qualitatively distinct from these distributions (Brown and Barlow, 2005). For example,
even though OCD is almost always estimated to be fairly rare in general population surveys,
sub-threshold manifestations of OCD, some of them appearing to be clinically significant, are
fairly common (Matsunaga and Seedat, 2007). The same is true for bipolar spectrum disorder,
where even though the lifetime prevalence of BP-I is estimated to be only about 0.8–1.5%, the
combined prevalence of BP-I, BP-II, and clinically significant sub-threshold BPD is likely in
the range 4–6% (Skeppar and Adolfsson, 2006). However, as community epidemiological
surveys have for the most part not explored these sub-threshold manifestations systematically,
we do not currently have good estimates of the proportion of the population that would meet
criteria for one or more anxiety and mood spectrum disorders.
4 Age-of-Onset Distributions of Anxiety and Mood Disorders
While the results reviewed in the last section document that anxiety and mood disorders are
highly prevalent, it is also important to examine age-of-onset (AOO) distributions (the
distribution of when the disorder first occurred across people with a lifetime history of a
disorder) for three reasons. The first reason is that commonly occurring lifetime disorders
might have much less effect on the overall lives of the people who experience them if they only
occur late in life. All else equal, earlier-onset disorders are more burdensome. Second, and
related, AOO information allows us to distinguish between lifetime prevalence (the propor-
tion of the population who had a disorder at some time in their life up to their age at
interview) and projected lifetime risk (the estimated proportion of the population who will
have the disorder by the end of their life). The estimates reported above were for lifetime
prevalence rather than for lifetime risk. Lifetime risk cannot be estimated directly from commu-
nity surveys because respondents differ in age and, therefore, number of years at risk. Projections
of estimated future risk can be made from AOO distributions, though, using standard statistical
methods. Third, an understanding of AOO is important for targeting research on prevention
of mental disorders, early intervention with prodromal or incipient mental disorders, and
primary prevention of secondary disorders. In the absence of AOO information, we would
have no way to know the appropriate age range to target these interventions.
Although AOO is routinely assessed retrospectively in community surveys, only a few
reports have been published over the years that describe AOO distributions based on these
data. These studies are reviewed elsewhere (Kessler et al., 2007). Recently, though, compre-
hensive AOO data were published from the WMH surveys (Kessler et al., 2008). These data are
remarkably consistent across countries as well as consistent with the AOO data reported in
previous studies in showing that some anxiety disorders, most notably the phobias and
separation anxiety disorder (SAD), have very early AOO distributions. In the WMH data,
these disorders had a median AOO in the range 7–14 and an IQR between 4 and 20 years.
Inspection of the country-specific AOO curves (> Figure 88-1) shows striking consistency. No
significant associations were observed between the position of the curve in the swarm and
either prevalence of the disorders in the country or the county’s level of economic develop-
ment. The other common anxiety disorders (panic disorder, generalized anxiety disorder, and
post-traumatic stress disorder), in comparison, have considerably later AOO distributions
(> Figure 88-2). In addition, the cross-national variation in both median AOO in the WMH
surveys (ages 25–53) and in IQR (15–75 years) is considerably wider than for the phobias or
SAD. As with the earlier-onset disorders, no significant associations were observed between
the position of the curve in the swarm and either prevalence of the disorders in the country or
the country’s level of economic development. The mood disorder AOO distributions in the
WMH surveys are quite similar to those for the later-onset anxiety disorders (> Figure 88-3).
Mood disorder AOO curves show consistently low prevalence until the early teens followed by
a roughly linear increase through late middle age and a declining increase thereafter. The
median AOO of mood disorders has a very wide range across countries (ages 25–45) and an
even wider IQR (17–65 years) but again without any consistent association between the shape
of the curve and either prevalence of the disorders in the country or the county’s level of
economic development. A note of caution is needed in interpreting these results, as they are
based on retrospective lifetime recall and thus are subject to bias. Indeed, somewhat earlier
AOO estimates are generally found in prospective-longitudinal studies than in the analysis of
retrospective AOO reports (Wittchen et al., 1999). Nonetheless, these prospective data are
generally quite consistent with the AOO distributions seen in the retrospective WMH data.
. Figure 88-1
Standardized age-of-onset distributions of DSM-IV phobias and separation anxiety disorder in
the WMH surveys (no significant association was found between the position of the curve and
either the prevalence of the disorders in the country or the level of economic development of the
country. See > Tables 88-1–> 88-3 for a list of the countries included in the figure)
. Figure 88-2
Standardized age-of-onset distributions of DSM-IV generalized anxiety disorder, panic disorder,
and post-traumatic stress disorder in the WMH surveys (no significant association was found
between the position of the curve and either the prevalence of the disorders in the country or
the level of economic development of the country. See > Tables 88-1–> 88-3 for a list of the
countries included in the figure)
We noted above that AOO distributions can be used to generate projections of lifetime
risk: the proportion of the population that will experience a given disorder at some time in
their life. These estimates will necessarily be higher than estimates of lifetime prevalence, as
they include not only all lifetime-to-date cases but also some number of anticipated future
onsets. The issue of interest is the size of this projected number of future onsets. Estimates of
projected lifetime risk of any DSM-IV disorder in the WMH data are roughly one-third higher
(IQR 28–44%) than the estimates of lifetime prevalence-to-date (Kessler et al., 2008). This
means that 3–4 people in the populations of these countries are likely to develop a first mental
disorder at some time in the future for every ten people who already had a disorder. The
highest risk-to-prevalence ratios (57–69%) were found in countries exposed to sectarian
violence (Israel, Nigeria, South Africa). Excluding these three, no strong difference in risk-
to-prevalence ratios were found of less developed countries (28–41%) versus developed
countries (17–49%). Not surprisingly, the highest class-specific proportional increase in
projected lifetime risk versus prevalence was associated with mood disorders (IQR 61–98%).
This is because of the comparatively late onset of mood disorders compared to most other
mental disorders. The proportional increases were comparable for GAD and PTSD, but very
low for the other anxiety disorder, again reflecting the typically later ages of onset of the
former than the latter.
It is noteworthy that most anxiety disorders have considerably earlier AOO distributions
than mood disorders or substance use disorders. There are three noteworthy exceptions,
though. First, the AOO distribution of GAD looks more like that of major depression than
. Figure 88-3
Standardized age-of-onset distributions of DSM-IV mood disorders in the WMH surveys (no
significant association was found between the position of the curve and either the prevalence of
the disorders in the country or the level of economic development of the country. See
> Tables 88-1–> 88-3 for a list of the countries included in the figure)
other anxiety disorders. Second, the AOO distribution of panic disorder, while similar to that
of GAD in being later than most other anxiety disorders, has a more complex shape than GAD
and appears in some studies to differ by gender. Third, the AOO distribution of PTSD is most
variable due to the fact that traumatic events can occur at any time in the life course. Despite
these differences, though, the results in > Figure 88-1 show that the retrospectively reported
AOO distribution of any anxiety disorder is remarkably consistent across countries. This early
onset, coupled with the fact that significant associations exist between early-onset anxiety
disorders and the subsequent first onset of other mental and substance use disorders (Bittner
et al., 2004; Zimmermann et al., 2003), has led some commentators to suggest that aggressive
treatment of child-adolescent anxiety disorders might be effective in preventing the onset of
the secondary mental and substance disorders that are associated with the vast majority of
people with serious mental illness (Kendall and Kessler, 2002). It is noteworthy in this regard
that despite their generally early ages of onset, epidemiological data show that first treatment
of anxiety disorders usually does not occur until adulthood, often more than a decade after
onset of the disorder (Christiana et al., 2000).
5 The Course of Anxiety and Mood Disorders
Course of illness, like AOO, has been much less well studied in epidemiological surveys of
anxiety and mood disorders than has prevalence. Indeed, few direct questions about course
of illness were included in most community epidemiological surveys of mental disorders prior
to the WMH surveys. However, the fact that anxiety and mood disorders are seen as often
being quite persistent adds to the judgment that they have such adverse effects. Objective
assessment of this persistence can be obtained by comparing estimates of recent prevalence
(variously reported for the year, 6 months, or 1 month before interview) with estimates of
lifetime prevalence. The 12-month to lifetime prevalence ratios for anxiety and mood dis-
orders are typically in the range .4–.6, with the ratio always somewhat higher for anxiety
disorders than mood disorders. This pattern can be seen by comparing the 12-month and
lifetime prevalence estimates reported above for any anxiety disorder and any mood disorder.
The highest disorder-specific ratios in these surveys are usually found for specific phobia and the
lowest for PTSD, and MDD (Bijl et al., 1998; Kringlen et al., 2001). Ratios as high as these
strongly imply that anxiety and mood disorders are highly persistent throughout the life course.
More detailed analyses of these ratios could be carried out by breaking them down
separately for sub-samples defined by age at interview or by time since first onset, but we
are unaware of any published research that has reported such analyses. Our own preliminary
analyses of this sort in the WMH data suggest, though, that although 12-month to lifetime
prevalence ratios decline with increasing age, this decline is fairly modest, suggesting that
anxiety and mood disorders are often quite persistent over the entire life course. The few long-
term longitudinal studies that exist in representative samples of people with anxiety and mood
disorders yield results consistent with this and suggest that this persistence is due to a
recurrent-intermittent course that often features waxing and waning of episodes of different
comorbid anxiety and mood disorders (Angst and Vollrath, 1991; Bruce et al., 2005).
The most detailed information currently available on the course of anxiety disorders
comes from the Harvard/Brown Anxiety Disorders Research Program (HARP), a prospective,
naturalistic multi-center study of patients who were originally treated for anxiety disorders as
adults and were subsequently followed for over a decade to chart the course of their illness
(Bruce et al., 2005). Comparable data for mood disorders come from the NIMH Collaborative
Depression Study (CDS), a study similar to HARP but for people with depression that has
been going on for over two decades (Leon et al., 2003). The HARP and CDS respondents are
not representative of all people with anxiety or mood disorders, as they were treated in tertiary
care settings and consequently over-represent seriously impaired refractive cases. Nonetheless,
the long-term results of these studies are quite consistent with those of community surveys in
finding that anxiety and mood disorders have a typically chronic-recurrent course.
6 Comorbidity Among Anxiety and Mood Disorders
Comorbidity among anxiety and mood disorders is quite common, with up to half of people
with any lifetime anxiety or mood disorder meeting criteria for two or more such disorders
(Kessler, 1995). Factor analytic studies of diagnostic comorbidity consistently document
separate internalizing and externalizing factors in which anxiety and mood disorders have
high factor loadings on the internalizing dimension (Kendler et al., 2003). The internalizing
dimension, furthermore, has secondary dimensions that distinguish between fear disorders
(panic, phobia) and distress disorders (depression, dysthymia, GAD) (Watson, 2005). The
locations of OCD, PTSD, and BPD in this two-dimensional space are less distinct, as the former
appears to be more related to the fear dimension (Watson, 2005), the second more related to the
distress dimension (Cox et al., 2002), and the third not strongly related to either dimension
(Watson, 2005). Social phobia, furthermore, appears to be somewhat more strongly related
to the distress dimension than are the other phobias. Separation anxiety disorder has not been
included in factor analytic studies to date.
These results have recently been used by Watson (2005) to call into question the codifica-
tion of anxiety disorders as a distinct class of disorders in the DSM and ICD systems and to
suggest that a more useful organizing scheme in the upcoming DSM-V and ICD-11 revisions
would be one that distinguished between fear disorders and distress disorders, with the latter
including not only GAD and possibly PTSD but also unipolar depression and dysthymia. The
argument for a class of fear disorders has the stronger support of the two in neurobiological
research based on extensive investigation of fear brain circuitry (Knight et al., 2005). The
possibility also exists that future research might lead to OCD being distinguished from either
fear disorders or distress disorders as part of a spectrum of impulse-control disorders based
both on evidence of differential comorbidity and differences in brain circuitry (Whiteside
et al., 2004).
7 The Adverse Effects of Anxiety and Mood Disorders
Early-onset anxiety and mood disorders are significant predictors of the subsequent onset and
persistence of other mental and substance use disorders as well as of a wide range of physical
disorders (He et al., 2008; Ormel et al., 2007). It is important to note that these predictive
associations are part of a larger pattern of associations that has been documented between
anxiety-mood disorders and a much wider array of adverse life course outcomes that might be
conceptualized as societal costs of these disorders, including reduced educational attainment,
early marriage, marital instability, and low occupational and financial status (Kessler et al.,
1995, 1997, 1998). It is unclear if these associations are causal; that is, if interventions to treat
early-onset anxiety and mood disorders would prevent the subsequent onset of the adverse
outcomes with which they are associated. As a result, it is not possible to state unequivocally
that these outcomes are consequences of anxiety and mood disorders. It would be very
valuable, though, from a public health perspective to have long-term evidence to evaluate
this issue from experimental treatment effectiveness studies.
A considerable amount of research has been carried out to quantify the magnitude of the
short-term societal costs of anxiety and mood disorders in terms of healthcare expenditures,
impaired functioning, and reduced longevity, but most of this work has been done in the US
(Greenberg and Birnbaum, 2005; Greenberg et al., 1999). The magnitude of the cost estimates
in these studies is staggering. For example, Greenberg et al. (1999) estimated that the annual
total societal costs of active anxiety disorders in the US over the decade of the 1990s exceeded
$42 billion. This estimate excludes the indirect costs of early-onset anxiety disorders through
adverse life course outcomes (e.g., the documented effects of child-adolescent anxiety dis-
orders in predicting low educational attainment and consequent long-term effects on lower
income) and through increased risk of other disorders (e.g., anxiety disorders predicting the
subsequent onset of cardiovascular disorder).
Although comparable studies of the societal costs of anxiety and mood disorders have been
carried out in few other countries, a recent study of the comparative impairments in role
functioning caused by mental disorders and commonly occurring chronic physical disorders
in the WMH surveys documented that anxiety and mood disorders have substantial adverse
effects on functioning in many countries around the world (Ormel et al., 2008). This analysis
made use of the fact that physical disorders were assessed in the WMH surveys with a standard
chronic disorders checklist. Respondents with the ten most commonly reported such disorders
were asked to report the extent to which each such disorder interfered with their ability to
carry out their daily activities in both productive roles (i.e., job, school, housework) and social
roles (i.e., social and personal life). The same questions about disorder-specific role impair-
ments were also asked of respondents with each of the mental disorders assessed in the surveys,
the ten most commonly occurring of which were compared to the ten physical disorders.
Of the 100 logically possible pair-wise disorder-specific mental-physical comparisons,
mean impairment ratings were higher for the mental than physical disorder in 91 comparisons
in developed and also for 91 comparisons in developing countries. Nearly all of these
. Table 88-3
Disorder-specific impairment ratings in the WHO World Mental Health surveysa
Proportion rated severely impaired

Developed Developing
nb % (SE) nb % (SE) xb
I. Physical disorders
Arthritis 526 23.3 (1.5) 127 22.8 (3.0) 0.1
Asthma 119 8.2c (1.4) 44 26.9 (5.4) 9.0c
Back/neck 912 34.6c (1.5) 305 22.7 (1.8) 27.0c
Cancer 60 16.6 (3.2) 8 23.9 (10.3) 0.0
Chronic pain 296 40.9c (3.6) 109 24.8 (3.8) 12.9c
Diabetes 49 13.6 (3.4) 39 23.7 (6.1) 1.4
Headaches 751 42.1c (1.9) 401 28.1 (2.1) 15.7c
Heart disease 83 26.5 (3.9) 63 27.8 (5.2) 0.3
c
High blood pressure 91 5.3 (0.9) 144 23.8 (2.6) 50.0c
Ulcer 31 15.3 (3.9) 59 18.3 (3.6) 0.1
II. Mental disorders
ADHD 87 37.6 (3.6) 14 24.3 (7.4) 0.8
Bipolar 419 68.3c (2.6) 87 52.1 (4.9) 7.9c
Depression 1028 65.8c (1.6) 622 52.0 (1.8) 30.4c
c
GAD 576 56.3 (1.9) 127 42.0 (4.2) 7.9c
IED 136 36.3 (2.8) 106 27.8 (3.6) 2.0
ODD 29 34.2 (6.0) 12 41.3 (10.3) 1.2
Panic disorder 317 48.4c (2.6) 67 38.8 (4.7) 4.3c
c
PTSD 329 54.8 (2.8) 53 41.2 (7.3) 4.2c
Social phobia 593 35.1 (1.4) 164 41.4 (3.6) 2.6
Specific phobia 537 18.6 (1.1) 144 16.2 (1.6) 1.9
a
See > Tables 88-1 and > 88-2 for the list of countries included in the analyses. Colombia, Lebanon, Mexico,
Nigeria, PRC, South Africa, and Ukraine were classified developing. All other countries were classified developed
b
Number of respondents rated severely impaired
c
Significant difference between developed and developing at the .05 level, two-sided test
higher mental-than-physical impairment ratings were statistically significant at the .05 level
and held in within-person comparisons (i.e., comparing the reported impairments associated
with a particular mental-physical disorder pair in the sub-sample of respondents who had
both disorders). Comparable results were obtained for severe disability ratings (> Table 88-3).
Furthermore, a similar pattern held when treated physical disorders were compared with all
(i.e., treated or not) mental disorders to address the concern that the more superficial
assessment of physical than mental disorders might have led to the inclusion of sub-threshold
cases of physical disorders that might have low disability. It is noteworthy that seven of the ten
mental disorders in this analyses were anxiety or mood disorders.
8 Conclusions
The epidemiological data reviewed here document that anxiety and mood disorders are
commonly occurring in the general population, often have an early age of onset and a
persistent course, and are often associated with significant adverse societal costs. We also
reviewed evidence to suggest that the current definitions of anxiety and mood disorders might
under-estimate the proportion of the population with a clinically significant anxiety or mood
syndrome, in which case the societal costs of these disorders would be even greater than
estimated here. Based on these results, we can safely conclude that anxiety and mood disorders
are common and consequential problems. As early-onset conditions, anxiety disorders are of
special importance, as they typically begin prior to the vast majority of the other problems
with which they are subsequently associated. Yet young people with early-onset anxiety
disorders seldom receive treatment. This is a situation that has to change if we are to be
effective in addressing the enormous public health burden created by early-onset anxiety
disorders. To do this will require a level of political will that has heretofore been lacking in even
the most progressive countries.
Summary Points
DSM-IV anxiety disorders are usually found to be the most common class of mental
disorders in community epidemiological surveys. Lifetime prevalence estimates of any
anxiety disorder are typically in the range 10–17%, while 12-month prevalence estimates
are typically in the range 6–12%.
DSM-IV mood disorders are usually found to be somewhat less common than anxiety
disorders in community epidemiological surveys. Lifetime prevalence estimates of any
mood disorder are typically in the range 8–18%, while 12-month prevalence estimates are
typically in the range 3–7%.
Some DSM-IV anxiety disorders, most notably the phobias and separation anxiety disor-
der, have retrospectively reported median ages-of-onset in late childhood or early adoles-
cence (ages 7–14).The vast majority of the lifetime cases of these disorders begin within a
relatively narrow age band spanning only about a decade.
DSM-IV mood disorders and other anxiety disorders have considerably later retrospec-
tively reported median ages-of-onset (ages 25–45) as well as a much wider age range when
these disorders typically begin.
Although DSM-IV anxiety disorders are typically more persistent than mood disorders,
both classes of disorders often have a chronic-recurrent course.
Early-onset anxiety and mood disorders are associated with reduced educational attain-
ment, early marriage, marital instability, and low occupational and financial status.
The short-term societal costs of anxiety and mood disorders are substantial in terms of
effects on healthcare expenditures and impaired functioning. Comparative analyses show
that the adverse effects of anxiety and mood disorders on role functioning are generally
greater than the effects of commonly occurring chronic physical disorders.
Acknowledgments
Preparation of this chapter was supported, in part, by grants The National Comorbidity
Survey Replication (NCS-R) is supported by NIMH (U01-MH60220) with supplemental
support from the National Institute on Drug Abuse (NIDA), the Substance Abuse and Mental
Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF;
Grant 044780), and the John W. Alden Trust. Collaborating NCS-R investigators include
Ronald C. Kessler (Principal Investigator, Harvard Medical School), Kathleen Merikangas
(Co-Principal Investigator, NIMH), James Anthony (Michigan State University), William
Eaton (The Johns Hopkins University), Meyer Glantz (NIDA), Doreen Koretz (Harvard
University), Jane McLeod (Indiana University), Mark Olfson (New York State Psychiatric
Institute, College of Physicians and Surgeons of Columbia University), Harold Pincus (Uni-
versity of Pittsburgh), Greg Simon (Group Health Cooperative), Michael Von Korff (Group
Health Cooperative), Philip Wang (Harvard Medical School), Kenneth Wells (UCLA), Elaine
Wethington (Cornell University), and Hans-Ulrich Wittchen (Max Planck Institute of Psychi-
atry; Technical University of Dresden). The views and opinions expressed in this report are
those of the authors and should not be construed to represent the views of any of the
sponsoring organizations, agencies, or U.S. Government. A complete list of NCS publications
and the full text of all NCS-R instruments can be found at http://www.hcp.med.harvard.edu/
ncs. Send correspondence to ncs@hcp.med.harvard.edu.
The NCS-R is carried out in conjunction with the World Health Organization World Mental
Health (WMH) Survey Initiative. We thank the staff of the WMH Data Collection and Data
Analysis Coordination Centres for assistance with instrumentation, fieldwork, and consultation
on data analysis. These activities were supported by the National Institute of Mental Health (R01
MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the US
Public Health Service (R13-MH066849, R01-MH069864, and R01 DA016558), the Fogarty
International Center (FIRCA R03-TW006481), the Pan American Health Organization, Eli Lilly
and Company, Ortho-McNeil Pharmaceutical, Inc., GlaxoSmithKline, and Bristol-Myers Squibb.
A complete list of WMH publications can be found at http://www.hcp.med.harvard.edu/wmh/.
Portions of this chapter appeared previously in Kessler, R.C., Ruscio, A.M., Shear, K.,
Wittchen, H.-U. (in press). The epidemiology of anxiety disorders. In M.M. Antony and M.B.
Stein (Eds.), Handbook of Anxiety and the Anxiety Disorders. New York: Oxford University
Press Oxford University Press; Wang, P.S., Kessler, R.C. (2005). Global burden of mood
disorders. In D. Stein, D. Kupfer and A. Schatzberg (Eds.), Textbook of Mood Disorders
(pp. 55–67). Washington DC: American Psychiatric Publishing, Inc. American Psychiatric
Publishing, Inc. 2005; Kessler, R.C. (2007). The global burden of anxiety and mood disorders:
Putting the European Study of the Epidemiology of Mental Disorders (ESEMeD) findings into
perspective. Journal of Clinical Psychiatry 68 (suppl. 2), 10–19, Physicians Postgraduate Press,
Inc. 2007. All used with permission.
References
Angst J, Vollrath M. (1991). Acta Psychiatr Scand. 84: Oakley-Browne MA, Pennell B, Petukhova M,
446–452. Posada-Villa J, Ruscio R, Stein DJ, Tsang CHA,
Benazzi F. (2007). CNS Drugs. 21: 727–740. Üstün TB (2008). In: Kessler RC, Üstün TB (eds.)
Bijl RV, van Zessen G, Ravelli A, de Rijk C, Langendoen Y. The WHO World Mental Health Surveys: Global
(1998). Soc Psychiatry Psychiatr Epidemiol. 33: Perspectives on the Epidemiology of Mental Disor-
581–586. ders. Cambridge University Press, New York, NY,
Bittner A, Goodwin RD, Wittchen HU, Beesdo K, Hofler pp. 511–521.
M, Lieb R. (2004). J Clin Psychiatry. 65: 618–626; Kessler RC, Amminger GP, Aguilar-Gaxiola S, Alonso J,
quiz 730. Lee S, Üstün TB. (2007). Curr Opin Psychiatry. 20:
Brown TA, Barlow DH. (2005). J Abnorm Psychol. 114: 359–364.
551–556. Kessler RC, Berglund PA, Foster CL, Saunders WB, Stang
Bruce SE, Yonkers KA, Otto MW, Eisen JL, Weisberg RB, PE, Walters EE. (1997). Am J Psychiatry. 154:
Pagano M, Shea MT, Keller MB. (2005). Am J Psy- 1405–1411.
chiatry. 162: 1179–1187. Kessler RC, Foster CL, Saunders WB, Stang PE. (1995).
Christiana JM, Gilman SE, Guardino M, Kessler RC, Am J Psychiatry. 152: 1026–1032.
Mickelson K, Morselli PL, Olfson M. (2000). Kessler RC, Üstün TB (eds.) (2008). The WHO World
Psychol Med. 30: 693–703. Mental Health Surveys: Global Perspectives on the
Cox BJ, Clara IP, Enns MW. (2002). Depress Anxiety. 15: Epidemiology of Mental Disorders. Cambridge Uni-
168–171. versity Press, New York, NY.
Fontenelle LF, Mendlowicz MV, Versiani M. (2006). Prog Kessler RC, Walters EE, Forthofer MS. (1998). Am J
Neuropsychopharmacol Biol Psychiatry. 30: 327–337. Psychiatry. 155: 1092–1096.
Furmark T. (2002). Acta Psychiatr Scand. 105: 84–93. Knight DC, Nguyen HT, Bandettini PA. (2005). Neuro-
Greenberg PE, Birnbaum HG. (2005). Expert Opin Phar- image. 26: 1193–1200.
macother. 6: 369–376. Kringlen E, Torgersen S, Cramer V. (2001). Am J Psychi-
Greenberg PE, Sisitsky T, Kessler RC, Finkelstein SN, atry. 158: 1091–1098.
Berndt ER, Davidson JR, Ballenger JC, Fyer AJ. Leon AC, Solomon DA, Mueller TI, Endicott J, Rice JP,
(1999). J Clin Psychiatry. 60: 427–435. Maser JD, Coryell W, Keller MB. (2003). Am J Psy-
Haro JM, Arbabzadeh-Bouchez S, Brugha TS, de Giro- chiatry. 160: 727–733.
lamo G, Guyer ME, Jin R, Lepine JP, Mazzi F, Ren- Matsunaga H, Seedat S. (2007). CNS Spectr. 12: 392–400.
eses B, Vilagut G, Sampson NA, Kessler RC. (2006). Mylle J, Maes M. (2004). J Affect Disord. 78: 37–48.
Int J Methods Psychiatr Res. 15: 167–180. Nock MK, Borges G, Bromet EJ, Alonso J, Angermeyer M,
He Y, Zhang M, Lin EH, Bruffaerts R, Posada-Villa J, Beautrais A, Bruffaerts R, Chiu WT, de Girolamo G,
Angermeyer MC, Levinson D, de Girolamo G, Uda Gluzman S, de Graaf R, Gureje O, Haro JM,
H, Mneimneh Z, Benjet C, Graaf RD, Scott KM, Huang Y, Karam E, Kessler RC, Lepine JP, Levinson
Gureje O, Seedat S, Haro JM, Bromet EJ, Alonso J, D, Medina-Mora ME, Ono Y, Posada-Villa J,
von Korff M, Kessler R. (2008). Psychol Med. 1–12. Williams D. (2008). Br J Psychiatry. 192: 98–105.
Horwath E, Weissman MM. (2000). Psychiatr Clin North Ormel J, Petukhova M, Chatterji S, Aguilar-Gaxiola S,
Am. 23: 493–507. Alonso J, Angermeyer MC, Bromet EJ, Burger H,
Judd LL, Akiskal HS. (2000). Pharmacopsychiatry. 33: Demyttenaere K, de Girolamo G, Haro JM,
3–7. Hwang I, Karam E, Kawakami N, Lepine JP,
Kendall PC, Kessler RC. (2002). J Consult Clin Psychol. Medina-Mora ME, Posada-Villa J, Sampson N,
70: 1303–1306. Scott K, Üstun TB, Von Korff M, Williams D,
Kendler KS, Prescott CA, Myers J, Neale MC. (2003). Zhang M, Kessler RC (2008) Br J Psychiatry. 192:
Arch Gen Psychiatry. 60: 929–937. 368–375.
Kessler RC. (1995). In: Tsuang MT, Tohen M, Zahner Ormel J, Von Korff M, Burger H, Scott K, Demyttenaere K,
GEP (eds.) Textbook in Psychiatric Epidemiology. Huang YQ, Posada-Villa J, Lepine JP, Angermeyer MC,
Wiley, New York, pp. 179–197. Levinson D, de Girolamo G, Kawakami N, Karam E,
Kessler RC, Aguilar-Gaxiola S, Alonso J, Angermeyer MC, Medina-Mora ME, Gureje O, Williams D, Haro JM,
Anthony JC, Berglund P, Chatterji S, de Girolamo G, Bromet EJ, Alonso J, Kessler RC. (2007). Gen Hosp
de Graaf R, Demyttenaere K, Gasquet I, Gluzman S, Psychiatry. 29: 325–334.
Gruber MJ, Gureje O, Haro JM, Heeringa S, Karam A, Robins LN, Helzer JE, Croughan JL, Ratcliff KS. (1981).
Kawakami N, Lee S, Levinson D, Medina-Mora ME, Arch Gen Psychiatry. 38: 381–389.
Robins LN, Regier A. (1991). Psychiatric Disorders in Waraich P, Goldner EM, Somers JM, Hsu L. (2004). Can
America: The Epidemiologic Catchment Area J Psychiatry. 49: 124–138.
Study. The Free Press, New York. Watson D. (2005). J Abnorm Psychol. 114: 522–536.
Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Whiteside SP, Port JD, Abramowitz JS. (2004). Psychiatry
Burke J, Farmer A, Jablenski A, Pickens R, Regier DA. Res. 132: 69–79.
(1988). Arch Gen Psychiatry. 45: 1069–1077. WHO International Consortium in Psychiatric Epide-
Ruscio AM, Chiu WT, Roy-Byrne P, Stang PE, Stein DJ, miology. (2000). Bull World Health Organ. 78:
Wittchen HU, Kessler RC. (2007). J Anxiety Disord. 413–426.
21: 662–676. Wittchen HU, Lieb R, Schuster P, Oldehinkel T. (1999).
Silverman WK, Moreno J. (2005). Child Adolesc Psy- In: Rapoport JL (ed.) Childhood Onset of ‘‘Adult’’
chiatr Clin N Am. 14: 819–843; ix–x. Psychopathology: Clinical and Research Advances.
Skeppar P, Adolfsson R. (2006). Nord J Psychiatry. 60: American Psychiatric Press, Washington, DC,
7–26. pp. 259–302.
Somers JM, Goldner EM, Waraich P, Hsu L. (2006). Can Wittchen HU. (1994). J Psychiatr Res. 28: 57–84.
J Psychiatry. 51: 100–113. Wittchen HU, Jacobi F. (2005). Eur Neuropsychophar-
Wang PS, Aguilar-Gaxiola S, Alonso J, Angermeyer MC, macol. 15: 357–376.
Borges G, Bromet EJ, Bruffaerts R, de Girolamo G, Zimmermann P, Wittchen HU, Hofler M, Pfister H,
de Graaf R, Gureje O, Haro JM, Karam EG, Kessler RC, Lieb R. (2003). Psychol Med. 33:
Kessler RC, Kovess V, Lane MC, Lee S, Levinson D, 1211–1222.
Ono Y, Petukhova M, Posada-Villa J, Seedat S,
Wells JE. (2007). Lancet. 370: 841–850.
89 Estimating the Disease
Burden of Combat-Related
Posttraumatic Stress Disorder
in United States Veterans and
Military Service Members
M. C. Freed . R. K. Goldberg . K. L. Gore . C. C. Engel
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1528
2 What is PTSD? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1529
3 Prevalence in Military and VA Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1531
4 Course of Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1535
5 Impact on Patients and the Healthcare System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1536
6 Measuring Disease Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1537
7 Efficacy of Primary Prevention and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1543
8 Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1544
9 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1545
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1545

1528 89 Estimating the Disease Burden of Combat-Related Posttraumatic Stress Disorder
Abstract: > Posttraumatic stress disorder (PTSD) is chronic, disabling, but treatable and
potentially preventable anxiety disorder characterized by re-experiencing, avoidance, and hyper-
arousal symptoms following a traumatic event. The World Health Organization (WHO) char-
acterized disease burden in the general population and listed PTSD among the top 20 most
‘‘burdensome’’ diseases. The WHO Global Burden of Disease study estimated a > disability weights
for PTSD of 0.11 (0 = perfect health; 1 = dead), but other studies have estimated weights up to
0.66, a figure closer to estimates for severe major depression. Limited research exists on the
disease burden of PTSD, and to date, no literature estimated the disease burden of combat-
related PTSD in the US military and Veterans Affairs (VA) healthcare systems. Extant PTSD
literature is arguably sufficient in scope and content needed to calculate reasonable estimates
of disease burden of PTSD in these populations. We review five key components to estimating
the disease burden of PTSD in the US military and VA: disorder > prevalence; course of illness;
disability weights; impact on the healthcare system; and prevention and treatment efficacy.
Current PTSD prevalence estimates vary, but range from 4.2 to 24.5% in > servicemembers
returning from Operation Iraqi and Enduring Freedom, depending on the subpopulation and
assessment method. PTSD often develops months to years after traumatic exposure, and 40% of
Vietnam veterans with PTSD reported symptom chronicity over 20 years. PTSD is associated with
low quality of life, high rates of medical service utilization, interpersonal conflict, co-morbidity,
and work impairment compared to persons without PTSD.
PTSD is a chronic, disabling, but treatable and perhaps preventable condition. Disease
burden estimates of PTSD could be used to better determine the need for and utility of
therapeutic interventions designed to alleviate symptoms of PTSD and associated impairment.
List of Abbreviations: CS, cross sectional; DALY, disability adjusted life year; DI, diagnostic
interview; DoD, department of defense; DSM, diagnostic and statistics manual; GBD, global
burden of disease; IOM, Institute of Medicine; L, longitudinal; MOS SF, 36 medical outcome
survey short form-36; MRR, medical record review; NRC, National Research Council; OEF,
operation enduring freedom; OIF, operation Iraqi freedom; OR, odds ratio; P, Probability;
PC-PTSD, primary care- posttraumatic stress disorder (screen); PCL, posttraumatic stress
disorder check list; PDHA, post-deployment health assessment; PDHRA, post-deployment
health re-assessment; PTO, > person tradeoff; PTSD, posttraumatic stress disorder; QALY,
> quality adjusted life year; SF-6D, short form-6 dimensional health state classification;
SRS, self-report screen; SUD, substance used disorder; US, United States; VA, veterans affairs;
VHA, veterans health administration; WHO, World Health Organization; YLD, year of life
with disability; YLL, years of life lost
1 Introduction
In the United States (US), the World Health Organization (WHO) estimated that posttrau-
matic stress disorder (PTSD) ranked within the top 20 diseases in terms of population disease
burden in the general population (Michaud et al., 2006). When ranked in women with an
outcome that combines morbidity (i.e., health-related quality of life) and mortality (death),
PTSD ranked 17th under diseases like ischemic heart disease (ranked first) and breast
cancer (ranked sixth) and above HIV (ranked 18th). When ranked with an outcome that
measures only, PTSD falls in the top 20 of most burdensome diseases, when race and sex are
collapsed.
Estimating the Disease Burden of Combat-Related Posttraumatic Stress Disorder 89 1529
There has been an increase in the > incidence of PTSD in the US military, since the
beginning of the wars in Iraq and Afghanistan (Army Medical Surveillance Activity, 2004,
accessed 2 February 2008). Currently, disease burden estimates of PTSD are broad based
(Murray and Lopez, 1996), without consideration of combat or other specific traumatic
stressors. PTSD and depression are believed to be the two most burdensome psychological
disorders (McFarlane, 2004). Extant PTSD literature is sufficient in scope and content to
provide the information needed to calculate reasonable estimates of disease burden of PTSD.
We review five key components to estimating the disease burden of PTSD in the US military
and Veterans Affairs (VA): disorder prevalence; course of illness; disability weights; impact on
the healthcare system; and prevention and treatment efficacy. Future researchers can then use
this information to estimate the disease burden of combat-related PTSD.
In this chapter, we present current prevalence estimates derived from large samples in VA
and US military Department of Defense (DoD) settings, with an emphasis on combat-related
PTSD from the wars in Iraq and Afghanistan. We focus on current findings because (1) there
have been changes in diagnostic criteria from DSM-III (APA, 1980) to DSM-IV-TR (APA,
2000); (2) DoD and VA have recently given increased attention to PTSD; and c) data from the
conflicts in Iraq and Afghanistan and related health policy concerns are relevant to both DoD
and VA, while > veterans from prior wars are typically only seen in VA medical centers.
However, we recognize that other traumas are important issues within both VA and DoD (e.g.,
15.9% women and 0.8% men screen positive for military sexual trauma within the Veterans
Health Administration; Kimerling et al., 2007) and combat trauma from other eras still afflict
many veterans (Magruder et al., 2005) to include 15% current prevalence of PTSD in Vietnam
era veterans (Kulka et al., 1990). Although the focus of this chapter is to identify necessary
components for disease burden estimates for PTSD resulting from Conflicts in Iraq and
Afghanistan, when published data from these datas are lacking, we offer data from non
combat PTSD or other era combat PTSD to serve as a proxy.
2 What is PTSD?
PTSD is an anxiety disorder with symptoms divided into three categories: re-experiencing
(Criterion B), avoidance (Criterion C), and hyperarousal (Criterion D; DSM-IV-TR; APA,
2000). Symptoms occur following a traumatic event in which ‘‘an individual experienced,
witnessed, or was confronted with an event or events that involved actual or threatened death
or serious injury, or a threat to the physical integrity of self or others’’ (Criterion A1). And, the
individual’s emotional response to the traumatic event involved ‘‘intense fear, helplessness, or
horror.’’ (Criterion A2). In order to be diagnosed with PTSD, symptoms must be present for at
least 1 month (Criterion E) and be clinically significant (Criterion F). See > Table 89‐1 for a
summary of current DSM-IV TR diagnostic criteria for PTSD.
PTSD was first introduced as a formal psychiatric disorder in the Diagnostic and Statistical
Manual of Mental Disorders, Third Edition (DSM-III; APA, 1980). The Vietnam War was
instrumental in the development of PTSD as a formal diagnosis. Veterans of the war were
returning with debilitating trauma reactions, and some prominent psychiatrists, who opposed
the war, felt that formalizing a diagnoses of PTSD would provided further justification for
ending the war (Jones and Wessely, 2007). Thus, PTSD was forged, in part, out of political
policy. However, post war difficulties have long been recognized in soldiers following combat,
dating back thousands of years to Homer’s, The Illiad (reported in Jones and Wessely, 2007).
. Table 89‐1
Summary of DSM-IV-TR (APA, 2000) criteria for PTSD in adults (Blake et al., 1995)
A. Defining traumatic exposure (need both)

1. Traumatic event: The event must involve actual or threatened death, serious injury, or a
threat to the physical integrity of oneself or another person. A person must personally
experience, witness, or learn about the event.
2. The emotional reaction: Emotional response to the event is intense fear, helplessness, or
horror.
B. Re-experiencing of traumatic event (need one or more)
1. Intrusive thoughts, images, or perceptions. These are unwanted memories, which are
difficult to dismiss.
2. Recurring nightmares. That have thematic similarity to the trauma and cause distress (e.g.,
cause waking, with difficulty returning back to sleep).
3. Acting or feeling as if the experience was occurring again. May include other sensory
experiences (e.g., sights, sounds, or smells), and may include some dissociation and a loss of
awareness of one’s surroundings.
4. Intense psychological distress (e.g., crying) following reminders of the traumatic event. The
psychological distress causes some impairment in functioning.
5. Intense physiological reactivity (e.g., increased heart rate, sweating, or shaking) following
reminders of the traumatic event. The physiological reactivity causes some impairment in
functioning.
C. Avoidant behaviors (need three or more symptoms that were not present prior to the trauma)
1. Avoiding thoughts, feelings, or talking to others about the trauma. Doing so requires
significant effort or interferes with one’s life.
2. Avoiding activities, places, or people that serve as reminders about the trauma. Doing so
requires significant effort or interferes with one’s life.
3. Difficulty remembering important parts of the traumatic event. The difficulty is not due to
the passage of time, a traumatic brain injury, or pharmacological substances.
4. Significant loss of interest, pleasure, or desire to participate in important or pleasurable
activities.
5. Feeling distant, cut off, detached, or disconnected from others. These feelings cause
impairments in social functioning.
6. Feeling emotionally numb (e.g., unable to feel love or happiness, and similarly, difficulty
feeling sadness or grief).
7. Sense that one’s future will be shortened in some way. This symptom differs from suicidal
ideation, in that the foreshortened future will not be due to self injury or harm. Rather, one
believes he/she may die prematurely from another cause, like an illness.
D. Increased arousal (Need two or more symptoms that were not present prior to the trauma)
1. Difficulty with sleep onset or maintenance.
2. Irritability or angry outbursts.
3. Concentration difficulties.
4. Increased watchfulness or alertness for oneself, family, or home (i.e., hypervigilance) even
when there is no need to be.
5. Increased startle response, where one is jumpy.
E. Symptoms must persist for more a than 1 month
Estimating the Disease Burden of Combat-Related Posttraumatic Stress Disorder

89 1531
F. Symptoms must cause significant distress, disturbance, or impairment to domains of life to other
life areas (i.e., social or occupational)
Specifiers
Acute: symptoms less than 3 months
Delayed Onset: symptoms appear after 6 months
Chronic: symptoms duration 3 months or more
This table describes the diagnostic criteria for PTSD. Language is paraphrased from the DSM-IV-TR (APA, 2000), and
the Clinician Administered PTSD Scale (CAPS; Blake et al., 1995), considered the ‘‘gold standard’’ of PTSD
assessment. PTSD posttraumatic stress disorder
Exposure to a war zone may well satisfy the DSM-IV-TR Criterion A1, but Criterion A2, the
emotional response to the exposure, is necessary for a PTSD diagnosis. Breslau and Kessler (2001)
reported the conditional probability of endorsing A2 after experiencing military combat is 33.8%,
which is relatively low compared to other A1 events. For example, rape or a potentially life-
threatening car accident results in a conditional probability of 93.3% and 73.2% respectively. As
discussed in Gore et al. (2006) and Adler et al. (2008), soldiers may experience numbness or intense
anger in response to A1 events, emotions not covered by A2, although they may endorse Criteria B
through D symptoms. Thus, if future versions of DSM expand the A2 list of emotional reactions,
the rates of PTSD diagnosed following exposure to a war zone are likely to be even higher.
The inclusion of the precipitating event (i.e., etiology) in the diagnostic criteria is unique to
PTSD and adjustment disorders, whereas other mental disorders require only symptom presence
to meet diagnostic criteria. The Criterion A definition of a traumatic event has changed consider-
ably with each DSM revision. In DSM-III, a traumatic event was defined as, ‘‘existence of a
recognizable stressor that would evoke significant symptoms of distress in almost anyone’’ (APA,
1980). In DSM-III-R, Criterion A1 defined the trauma as, ‘‘an event that is outside the range of
usual human experience and that would be markedly distressing to almost anyone’’ (APA, 1987).
Here, a distinction was drawn between the event and the emotional reaction to the event. Defining
criterion A and developing a universal standard has been difficult. One of the main problems with
Criterion A is defining what a usual or unusual human experience is (Davidson and Foa, 1991).
For example, how unusual is combat for a soldier in a volunteer Army? In its current form,
Criterion A is comprised of two parts, one subjective and one objective. This alleviates the
challenge of determining what constitutes an ‘‘unusual human experience’’ and places the
importance on the person’s emotional response to that experience (Weathers and Keane, 2007).
3 Prevalence in Military and VA Populations
Rates of PTSD can vary considerably, depending on the sample surveyed and the data
collection methods. For example, PTSD can be determined through self-report, diagnostic
interview, or by record review. Moreover, patients seen in VA and DoD clinics can include
spouses, and family members of those who served in the armed forces, and veterans
and active duty servicemembers may or may not have been deployed to a combat zone. See
> Table 89‐2 for a summary of these findings.
In a study designed to test the operating characteristics of a single item PTSD screening
measure, > Gore et al. (2008) screened 3,234 servicemembers, retirees, and family members
for PTSD in three National Capital Area military primary care clinics. They then interviewed a
. Table 89‐2
Prevalence of PTSD in VA and DoD
Data
collection
Source Sample Method period Prevalence
Gore et al. 3,234 active duty, retired, CS; DI 2005–2006 9%
2008 and beneficiary (e.g.,
family members)
screened, 213
interviewed, all in a
primay care setting
Grieger et al. 613 (not including L; SRS 2003–2004 1-month: 4.2%; 4-months:
(2006) attrition) soldiers 12.2%; and 7-months:
hospitalized due to battle 12.0%
injuries
Hoge et al. 2,350 soldiers pre-Iraq CS; SRS; 2003 Post-deployment (OR
(2004) deployment and 3,671 liberal compared to
soldiers and marines post- criterion pre-deployed); Army
Iraq or Afghanistan Afghanistan: 11.5% (1.25);
deployment Army Iraq: 18.0% (2.13);
Marine Iraq: 19.9 (2.4)
Hoge et al. 2,350 soldiers pre-Iraq CS; SRS; 2003 Post-deployment (OR
(2004) deployment and 3,671 conservative compared to
soldiers and marines post- criterion pre-deployed); Army
Iraq or Afghanistan Afghanistan: 6.2% (1.26);
deployment Army Iraq: 12.9% (2.84);
Marine Iraq: 12.2% (2.66)
Hoge et al. 2,863 soldiers 1-year post- CS; SRS Not 16.6%
(2007) Iraq reported
Hoge et al. 2,714 soldiers who CS; SRS 2006 14%
(2008) returned from Iraq
Hoge et al. 222,620 returnees from CS; SRS 2003–3004 OIF: 9.8%; OEF: 4.7%;
(2006) OIF, 16,318 from OEF, and Other: 2.1%
64,967 from other locations
Magruder 746 veterans receiving CS; DI 1999 11.5% Total; 4.4% No war
et al. (2005) primary care services zone exposure; 19% War
zone exposure
Magruder 746 veterans receiving CS; MRR 1999 8.4%
et al. (2005) primary care services
Milliken et al. 56,356 active duty army L; SRS; Liberal 2005–2006 Active: PDHA 11.8, PDHRA
(2007) and 31,885 army national Criterion 16.7; Reserve: PDHA 12.7,
guard and reserve PDHRA 24.5
Milliken et al. 56,356 active duty army L; SRS; 2005–2006 Active: PDHA 6.2, PDHRA
(2007) and 31,885 army national Conservative 9.1; Reserve: PDHA 6.6,
guard and reserve criterion PDHRA 14.3
Seal et al. 103,788 OEF/OIF veterans CS; MRR 2001–2005 13%
(2007) who separated from the
military
Data
collection
Source Sample Method period Prevalence
Smith et al. 50,128 servicemembers L; SRS 2001–2003 New Onset within 2.7
(2008) (average) year period;
Deployed w/combat
exposure 7.6–8.7%;
Deployed w/o combat
exposure 1.4–2.1%; non
deployed 2.3–3.0%;
variability reflects
screening method
This table presents current prevalence estimates, dates of data collection, and broad assessment method, of
combat PTSD in DoD and VA settings, focusing on the conflicts in Iraq and Afghanistan, when possible. CS cross
sectional; L longitudinal; SRS self-report screen; DI diagnostic interview; MRR medical record review; OR odds ratio;
VA veterans affairs; DoD department of defense; PTSD posttraumatic stress disorder; OEF/OIF operation enduring
freedom/operation Iraqi freedom
selected sample of 213 patients with a structured diagnostic interview. Based on the demo-
graphics of the larger sample, the estimated prevalence of PTSD was 9%. Preliminary unpub-
lished findings from this dataset suggest that the prevalence of PTSD in servicemembers is
approximately 10%, and 39% of servicemembers with PTSD report combat as the index
trauma. At the time of this chapter, prevalence stratified by military status was not available.
Grieger et al. (2006) assessed PTSD in 613 soldiers hospitalized after medical evacuation
from the theater of operations for serious combat injuries at 1- (n = 613), 4- (n = 395), and
7-(n = 301) months following hospitalizations they found that the PTSD prevalence was 4.2%,
12.2%, and 12.0%, respectively. They used the PTSD Checklist (PCL; Blanchard et al., 1996)
a 17-item self-report scale. To meet case criteria, respondents needed to endorse one reexper-
iencing, three avoidance, and two hyperarrousal symptoms of at least moderate distress (a three
or more on a 1–5 likert scale), and the sum score of the measure needed to be at least 50.
In a landmark study, Hoge et al. (2004) used a serial cross-section research design and
anonymously screened Army combat soldiers prior to an Iraq deployment (n = 2,530), Army
combat soldiers three-months after Iraq (n = 894) or Afghanistan (n = 1,962) deployment,
and combat Marines (n = 815) three-months after Iraq deployment. The researchers used two
scoring criteria for PCL (Blanchard et al., 1996). In the pre-deployment group, PTSD
prevalence was 5.0 and 9.4%, depending on whether a strict (PCL score 50) or liberal
(PCL score 30) criteria was used. In the post-deployment groups, prevalence ranged from
6.2% in soldiers who returned from Afghanistan when a conservative method was used to
19.9%, in marines who returned from Iraq, when a liberal method was employed. The pre-
deployment results were compared with each of the post-deployment groups. The odds of
PTSD were 1.26 (95% CI = 0.97–1.64) times greater in the post- than the pre-deployed group,
when the prevalence was 6.2%, and the odds of PTSD were 2.40 (95% CI = 1.92–2.99) times
greater in the post- than the pre-deployed group when the prevalence was 19.9%.
In a similar study, Hoge et al. (2007) evaluated 2,863 soldiers 1-year following their return
from Iraq. They reported a prevalence of 16.6% using the same PCL scoring methodology as
Grieger et al. (2006; discussed above).
Hoge et al. (2008) assessed 2,714 active duty and national guard/reserve soldiers 4 months
following their return from Iraq for a history of head injury and a history of mental health
problems. They administered the PCL and determined PTSD caseness if a soldier both met
DSM symptom criteria of PTSD (one intrusion symptom, three avoidance symptoms, and two
hyperarousal symptoms) and reported distress to total at least 50 (out of 85; the conservative
method in Hoge et al., 2004). Fourteen percent of their sample met criteria for PTSD. It is
unclear the extent that these three studies (Hoge et al., 2004; Hoge et al., 2007; Hoge et al., 2008)
rely on independent versus overlapping study samples.
Magruder et al. (2005) estimated the prevalence of PTSD to be 11.5% in a random sample
of 746 veterans from four hospital-based VA primary care clinics, who were administered a
gold standard research diagnostic interview. War zone exposed veterans had a significantly
higher prevalence of PTSD (19%) than non-war zone exposed veterans (4.4%). Of note, only
46.5% of veterans with a research diagnosis of PTSD had PTSD documented in their medical
record, and 3.4% of veterans who did not receive a research diagnosis of PTSD nonetheless had
a medical record diagnosis of PTSD.
Milliken et al. (2007) analyzed data from the US military’s population-based post-
deployment screening programs to assess the longitudinal mental health of Army soldiers
returning from Iraq. The Post-Deployment Health Assessment (PDHA) is administered to all
uniformed military personnel upon their return from deployment, and the Post-Deployment
Health Re-Assessment (PDHRA) is administered approximately 3 to 6 months later. The
PDHRA and PDHA employ a 4-item primary care PTSD screen (PC-PTSD; Prins et al., 2003).
Milliken et al. (2007) used these program data to examine the longitudinal course of PTSD
screening results in 56,350 Active Component and 31,885 Guard/Reserve Component soldiers.
The porportion of soldiers screening positive for PTSD (2 or more on the 4-question screen)
increased from 11.8% at baseline to 16.7%, a median of 6-months later in active component
soldiers. The increase among national guard and reserve soldiers was even greater, rising from
12.7% to 24.5%. Using PDHA screening results as a baseline, Hoge et al. (2006) prospectively
examined data from 222,620 OIF returnees, 13,318 OEF returnees, and 64,967 returnees from
other deployment locations for one year. The baseline proportion of returning troops screen-
ing positive for PTSD was 9.8%, 4.7%, and 2.1%, repectively. Of note, automated military
health sysem utilization data found that 22% of troops accessed mental health service use
during the follow-up year, and 35% of returnees from the Iraq War accessed services in the
year after return from deployment. However, only about 10% of post-Iraq mental health visits
occurred in those who were initially PDHA screen positive.
Seal et al. (2007) performed a record review among 103,788 OEF/OIF veterans who
separated from the military and received care at VA medical centers. In their sample, 13,205
veterans (13%) received a chart diagnosis of PTSD. Of those 13,205 veterans, 5,844 (44%) were
first diagnosed with PTSD by a non-behavioral health provider, like a primary care provider.
Of the 5,844 veterans first diagnosed with PTSD by a non-behavioral health provider, 4,198
(72%) veterans followed-up with a behavioral health provider. And, 3925 (94%) of those
veterans received a chart diagnoses of PTSD by the behavioral health provider. This high
concordance rate may be inflated, as it does not include the 66% of the 13,205 veterans not
first diagnosed with PTSD by a behavioral health provider. It is unknown whether those
veterans saw a behavioral health provider first, who subsequently made the PTSD diagnosis, or
saw a non-behavioral health provider first, who missed the PTSD diagnosis. Thus, if one
considers a PTSD from a behavioral health specialist to be more valid than from a primary care
provider, the overall 13% prevalence may be an overestimate.
Smith et al. (2008) calculated a threefold increase in new onset PTSD among deployed
servicemembers (i.e., soldiers, sailors, marines, and airmen) who report combat exposures. In
this longitudinal study, data from the first panel of 50,128 servicemembers who participated
in the millennium cohort study were used. Participants were evaluated pre- and post-deployment
(on average, assessments were 2.7 years apart, SD = 0.5 years) and the researchers used the
PTSD Checklist, a 17-item self report questionnaire which assess each of the 17 criterion B, C,
and D symptoms of PTSD on a 1–5 Likert scale. Researchers employed two criteria to
determine PTSD status: (1) PCL score of 50 or greater, a recommended cutscore or (2)
endorsement of at least one reexperiencing, three avoidance, and two hypervigilance symptoms
of at least moderate distress (item score of at least three) to match the DSM criteria for PTSD.
When using the more conservative cutscore method, they found new onset PTSD in 7.6% of
deployed servicemembers who reported combat exposures, 1.4% of servicemembers who were
deployed without combat, and 2.3% of servicemembers who were not deployed. The DSM
criteria method yielded new onset in 8.7% of deployed servicemembers with combat exposure,
2.1% of deployed without combat exposure, and 3.0% of non deployed servicemembers.
Participants with the following characteristics had the highest rates of new onset PTSD:
deployed, female, divorced, enlisted, current smoker or problematic drinking at baseline.
These prevalence findings demonstrate that PTSD is an increasingly common problem
that presents at multiple levels (e.g., primary care and in-patient) of the VA and DoD
healthcare system. However a condition can be prevalent without being burdensome.
4 Course of Illness
Exposure to trauma and the development of PTSD. Exposure to traumatic events does not
necessarily lead to the development of PTSD symptoms. Rates of traumatic exposure in the
general population are quite common and as reported in Hidalgo and Davidson (2000),
range from 39% (Breslau et al., 1991) or lower (28%, Hepp et al., 2006) to 90% (Breslau
et al., 1998). Of those exposed, relatively few develop PTSD. For example, only 6% of men
and 11.3% of women met criteria in Breslau et al. (1991). When stratified by type of trauma
(reported in Kessler, 2000), the conditional probability of developing PTSD from combat
exposure was 38.8% (in men). Rape had the highest conditional probability (65% men and
45.9% women), and the event with the conditional probability most similar to combat was
sexual assault other than rape (12.2% in men and 26.5% in women). More recently,
Magruder et al. (2005) reported that the odds of PTSD from serving in a war zone were
9-times greater (unadjusted OR; 19% prevalence) than for those veterans who did not serve
in a war zone (4.4% prevalence). Hoge et al. (2006) reported that exposure to combat was
correlated with a positive PTSD screen among OIF veterans. For example, compared with
95,894 (47.8%) of OIF returnees who screened negative for PTSD, of the 21,822 (9.8% of
OIF sample) veterans who screened positive for PTSD (score of two or more on the 4-item
screen; Prins et al., 2003), 79.6% reported ‘‘witnessing persons being wounded or killed or
engaging in direct combat during which they discharged their weapon’’ (Hoge et al., 2006, pg
1028).
Delayed onset. Of persons who develop PTSD, many experience delayed onset of symptoms
(i.e., symptom onset occurs at least 6 months or later following exposure to traumatic event;
APA, 2000). In a sample of Vietnam veterans (Schnurr et al., 2003), symptom onset occurred
1.34 years after entry into Vietnam, with 40% of their sample reporting that symptoms first
occurred 2 or more years after entering Vietnam. McFarlane (2004) discusses delayed onset
PTSD and presents findings from several studies using civilian and veteran populations. Most
striking is that some people experience latency periods of decades. More recently, Grieger et al.
(2006) reported that the majority (78.8%) of injured soldiers who reported PTSD and
depression symptoms at 7 months post hospitalization reported no symptoms at 1 month.
Chronicity of symptoms. PTSD is chronic for many veterans, with symptoms lasting more
than 50 years (Magruder et al., 2005). In Vietnam veterans, average symptom duration was
18.5 years, with 92.5% of veterans experiencing symptoms for more than 5 years, and 40.2% of
veterans reporting a duration of 20 or more years (Schnurr et al., 2003). Kessler et al. (1995)
found that 60% of patients with PTSD reached spontaneous remission in 72 months, but type
of trauma affected time to remission. In a personal communication with Kessler, McFarlane
(2004) reported that time to remission from combat was 85 months (7 years). Even with
treatment, approximately 1/3 of respondents did not remit at 120 months (Kessler et al., 1995),
suggesting that these treatment refractory people will experience symptoms for their lifetime.
In the US burden of disease study (Michaud et al., 2006), researchers estimated PTSD to last
4 years for males and 5 years for females. These estimates did not distinguish combat PTSD
from noncombat PTSD. Researchers argue that risk and resilience factors such as social
support, intensity, frequency, and duration of trauma, family history of mental illness,
ethnicity, and sex can mediate the development and chronicity of PTSD (Friedman, 2006;
Hoge et al., 2004; IOM, 2006; Kessler, 2000).
Section summary. Although most people exposed to a traumatic event will not develop
PTSD, a significant minority will. Of those that develop PTSD, many cases of PTSD will be
chronic, and arguably, chronic for the patient’s lifetime. Still, a disease may be chronic and
prevalent without being burdensome. Thus, we now examine the psychosocial impact of
PTSD on patients and the associated strain on the healthcare system.
5 Impact on Patients and the Healthcare System
PTSD is associated with significant decrements in quality of life. In a sample of Vietnam

veterans with chronic PTSD, baseline scores on a health-related quality of life measure (MOS
SF-36; Ware and Sherbourne, 1992) were 1–2 standard deviations below the US general
population, where lower scores indicate poorer functioning (Schnurr et al., 2006). Magruder
et al. (2005) compared SF-36 scores of veterans with and without PTSD, and veterans with
PTSD had significantly lower scores than veterans without PTSD. The differences remained
even after the researchers controlled for age, race, study site, education, and co-occurring
mental disorders. In a review, Seedat et al. (2006) reported that patients with PTSD have more
impairments in quality of life than the general public and patients with other chronic physical
conditions (e.g., diabetes, multiple sclerosis) and anxiety disorders. They report that PTSD is
second only to depression in terms of the quality of life decrements associated with mental
disorders. PTSD is also associated with educational failure, work impairment (an estimated
$3 billion loss in productivity in the US), unemployment, and marital instability (Kessler,
2000). For example, OEF/OIF returnees reported a 4-fold increase in concerns about interper-
sonal conflict (Milliken et al., 2007), and have higher rates of attrition from the military (Hoge
et al., 2006). OEF/OIF returnees with PTSD were associated with more sick call visits, greater
somatic complaints, lower ratings of general health, more physical symptoms, and more
missed workdays (Hoge et al., 2007). Most recently, Hoge et al. (2008) concluded that
PTSD, and not mild traumatic brain injury, accounted for poor general health, missed work-
days, medical visits, and a high number of somatic and post-concussive symptoms (except
headache) in a sample of returnees.
PTSD is associated with a significant use of healthcare resources. As reviewed by Hidalgo
and Davidson (2000) and Kessler (2000), PTSD patients use more medical services than
patients without PTSD, and veterans with PTSD were more likely to have dermatologic,
gastrointestinal, ophthalmologic, endocrinologic, gynecologic, and cardiovascular problems.
PTSD patients seek medical care more often than mental health care. Kessler (2000) summar-
ized reasons why medical services were used more often than mental health services in those
with PTSD in a large community study. Males (66.2%) and females (60.0%) believed their
problems did not warrant treatment. Males (66.2%) and females (40.4%) believed treatment
would be ineffective. Males (42.4%) and females (66.5%) thought the problem would resolve
on its own. However, the symptoms resolved in only 4% of males and 32.6% of females. Hoge
et al. (2004) reported 86% of returnees who screened positive for a depression, PTSD, or
generalized anxiety disorder acknowledged having a problem, but only 45% of those respondents
were interested in receiving help, and approximately half of those interested actually received
help. Moreover PTSD frequently goes undetected (Hidalgo and Davidson, 2000; Magruder
et al., 2005), and therefore untreated, which may contribute to ongoing problems and
continued seeking of medical services.
War veterans are also eligible to receive disability compensation, called a service-connection,
if they meet criteria for PTSD resulting from combat exposure. These benefits are unique to
the military and VA healthcare systems, and they pose various assessment, treatment, and
health policy challenges because benefits can be denied, reduced, or increased depending on
PTSD diagnosis and symptom severity (IOM and NRC, 2007). The number of beneficiaries
from fiscal years 1999 to 2004 grew by 79.5%, from 120,265 to 215,871 beneficiaries, and the
amount of payment increased 148.8% to $4.28 billion (reported in IOM and NRC, 2007).
Veterans can receive over $3,000 per month, depending on their family situation, plus free
health care and other benefits. Although there is debate about how compensation for a service-
connected disability may serve as an incentive for veterans to remain symptomatic (e.g., to
improve might mean the loss of substantial benefits; IOM and NRC, 2007), effectively
identifying and treating war veterans with PTSD may prevent the need for such lifetime
compensation and thereby reduce some of the financial burden to DoD and VA.
6 Measuring Disease Burden
Introducing disease burden and the concept of ‘‘preference.’’ The true burden of a disorder may
be defined as ‘‘the burden in the absence of treatment, that is calculated from the burden
observed in the population under study plus the burden presently averted by current popula-
tion coverage and mix of interventions’’ (Andrews et al., 2004, pg. 526). The burden of disease
in a population in a given year is the sum of a) years of life lost due to premature deaths (YLL)
and b) estimate of the future years of life with disability (YLD) for new cases of disease or
injury, weighted for severity (Vos et al., 2001). Disease burden is the confluence of two
measurements: morbidity and mortality. Mortality is rarely attributed to mental disorders
(Andrews et al., 2004). However, persons with PTSD do attempt suicide at rates of up to
8.2 times of the general population, even after controlling for other disorders, like
depression (reported in McFarlane, 2004). Put more simply, disease burden measures
pervasiveness (e.g., incidence or prevalence as the number of cases, not the percentage),
persistence (that is, course or duration of illness), and impact (that is, death and/or decrement
in preference-weighted health status associated with the disease at any given time) in one unit
of measurement.
Morbidity of a disease is basically measured using one of two scales (both ranging from
zero to one), anchored by perfect health and death. The number between 0 and 1 is considered
a preference-weight for a particular disease or health state. To estimate the disease burden, the
> preference weight is multiplied by a) the amount of time spent in that health state and b)
the disease incidence. Preference weights differ from other measures of severity, in that
preference-weighted metrics incorporate how a population determines the value or worth of
a health condition. For example, Kiberd and Lawson (2000) measured the preference of a
Type-I diabetes mellitus (DM) with comorbid blindness and end stage renal disease (ESRD;
requiring dialysis) health state from patients with DM and ESRD. In a separate study, Revicki
and Wood (1998) measured the preference of a severe depression health state from patients
being pharmacologically treated for depression. Preference was measured in units called health
utilities (discussed below) by both sets of researchers. Health utilities (and other units of
preference) are valued by having a group of raters read a brief vignette describing the health
states (depression or DM with ESRD in this example). Raters are administered one or more of
econometric instruments (e.g., the person tradeoff; PTO; or > standard gamble; both methods
described below) designed to elicit preference. In these two examples, average preference
for the severe depression health state was less desirable than was average preference for DM
with comorbidities. Thus, a health state like DM with comorbidities, which requires frequent
life-saving medical treatment, is more desirable than severe depression, which is theoretically
treatable with mediation and/or psychotherapy. Depression is life-threatening only if a patient
attempts or completes suicide, unlike DM with ESRD. This example demonstrates that non
preference based measures of health status and clinical symptom focused measures are
predominantly clinician tools, not health policy tools per se (Bennett and Torrance, 1996;
Berzon et al., 1996; Garza and Wyrwich, 2003; Tsevat, 2000).
Disability weights associated with PTSD. The Global Burden of Disease study (GBD;
Murray and Lopez, 1996) assessed disease burden using the disability adjusted life year
(DALY), which equals YLL plus YLD. Here, zero represents perfect health and one represents
death, such that a year in perfect health is worth 0 DALYs. DALYs are considered an interval scale,
such that they can be summed across individuals and over time. ‘‘The DALY measures the gap
between the actual health of a population and a hypothetical norm, namely a life expectancy of
82.5 years for women and 80 years for men. DALYs for a disease or health condition are calculated
as the sum of the years of life lost due to premature mortality in the population and the years of
life lost due to disability’’ (Michaud et al., 2001, pg. 535). DALYs can also include life expectancy,
and adjust for age, such that a young adult is considered to be ‘‘worth’’ more than someone at the
beginning or end of the life cycle.
A component of YLD is a value called a disability weight, where 0 equals perfect health and
1 equals death. In the GBD study and other studies which assessed DALYs (e.g., Kruijshaar
et al., 2005), disability weights for DALYs were obtained for 22 ‘‘indicator conditions,’’
including depression, by administering a series of ‘‘person tradeoff ’’ (PTO) vignettes to a
sample of clinicians. Two variants were used. First, clinicians were given a choice between
trading quantity of life for healthy individuals and disabled individuals. In the second, they are
asked to tradeoff quantity of life for healthy individuals versus improved quality of life for a
group of disabled individuals’’ (Murray and Lopez, 1996, pg. 91). As an example, a disability
. Figure 89‐1
Person tradeoff method used in Murray and Lopez (1996) and Sanderson and Andrews (2001):
‘‘trading quantity of life for healthy and disabled individuals’’ (pg. 670). This is one variant of
the person tradeoff (PTO), a method designed to determine preference and ‘‘worth’’ for a
particular disease state. Respondents indicate their preference by valuing quantity of life in
a hypothetical sample of healthy and disabled individuals. A low disability weight (close to 0)
indicates that the disease is considered less disabling, and conversely, a high disability weight
(close to 1) indicates that the disease is considered more disabling
weight would equal 0.5, if a respondent considered 2,000 people with depression to represent
the same amount of health as 1,000 people without depression (Sanderson and Andrews,
2001). See > Figures 89‐1 and > 89‐2 for a graphical representation of the PTO.
The GBD study valued hundreds of conditions. Because it was not feasible to administer
the PTO for each condition, a short-cut estimation procedure was developed. The 22 indicator
conditions were used to define seven disability categories. PTSD was one of the conditions
valued using this short-cut procedure. In a replication study Sanderson and Andrews (2001)
administered the PTO to a panel of physicians for 20 vignettes capturing mental
disorders, including PTSD. They also used a rating scale method, on which PTSD is valued
from 0 to 100. The differing methodologies led to very different disability weights for PTSD
(see > Table 89‐3). Not only is method variance an important concern for the health
economics field, but these findings suggest the GBD study grossly underestimated the burden
of PTSD. Perhaps, as Kessler (2000) suggests, the burden of PTSD is akin to that of depression,
which is projected to rank second (Murray and Lopez, 1996). The GBD study did not evaluate
treated versus untreated PTSD, as it did for depression. Andrews et al. (2004) found that
treatment of PTSD can account for between 11 and 32% of the disease burden, depending on
gross categories of treatment coverage and treatment type.
. Figure 89‐2
Second variant of the PTO used in Murray and Lopez (1996) and Sanderson and Andrews (2001):
‘‘trading quantity of life for healthy individuals versus improved quality of life for disabled
individuals’’ (pg 670). This is another variant of the person tradeoff (PTO), a method designed to
determine preference and ‘‘worth’’ for a particular disease state. Respondents indicate their
preference by valuing quantity and quality of life in a hypothetical sample of healthy and
disabled individuals. A low disability weight (close to 0) indicates that the disease is considered
less disabling, and conversely, a high disability weight (close to 1) indicates that the disease is
considered more disabling
Health utilities associated with PTSD. A similar metric is called a quality adjusted life year
(QALY). Here, a year in perfect health equals one QALY and death equals zero, the reverse
of the aforementioned DALYs. Like DALYs, the number representing disease preference in
QALYs is weighted by time spent in a given disease state and by the number of persons with the
disease. Unlike DALYs, the number is not adjusted for age. The number is called a > health
utility (versus a disability weight). We recognize that the nomenclature used to describe the
preference weight needed to calculate a QALY differs according to the method. To minimize
jargon, we use the term health utility, independent of method, when referencing the preference -
based unit of measurement associated with a QALY. Of note, numerous methods can be used to
obtain a health utility (e.g., interpolation from a generic health-related quality of life scale or
direct valuation of a health state vignette from a community sample). And, as discussed by
Sherbourne et al. (2001), each method can produce a wide range of health utilities. Health
utilities may or may not be sensitive enough to detect changes in symptom severity, and are
therefore questionable indicators of treatment outcomes (Sherbourne et al., 2001). Nevertheless,
health utilities (and the eventual calculation of QALYs) are the recommended outcome in cost-
effectiveness analyses (Gold et al., 1996).
. Table 89‐3
Existing disability weights for PTSD and depressive disorders
Disability
Source Method Disease weight
Michaud et al. (2006); Murray Short-cut PTSD 0.11
and Lopez, (1996) estimation
Sanderson and Andrews, (2001) PTO PTSD 0.66
(SD = 0.25)
Sanderson and Andrews, (2001) Rating scale PTSD 0.57
(SD = 0.22)
Murray and Lopez, (1996) PTO Comparator: unipolar depression/ 0.6/0.30
treated depression
Sanderson and Andrews, (2001) PTO Comparator: mild/moderate/ 0.09/0.34/
severe depression 0.70
This table presents existing disability weights for PTSD and the methods utilized. It also presents a selected sample
of utility weights used to calculate the disease burden of depression. PTO person tradeoff; PTSD posttraumatic
stress disorder; SD standard deviation
The standard gamble (> Figure 89‐3) is the classic method of eliciting health utilities.
Here, respondents choose between (1) a health state with certainty or, (2) a gamble,
where treatment could lead to perfect health with some probability of death. The point of
indifference is called the health utility. In this paradigm, the health state can be a vignette
describing symptoms and disability associated with a specific disease (e.g., depression;
Revicki and Wood, 1998). Or, a health state can be a description of generic health-related
quality of life impairments (Brazier et al., 2002). Respondents are then administered the
standard gamble multiple times, where the researchers vary the value of probability (p),
until the respondent is indifferent between Choices 1 and 2. The procedure is repeated
for multiple health states within a specific disease (e.g., severe depression, moderate depres-
sion, mild depression) or by for multiple severity levels of the domains of health–related
quality of life.
To our knowledge, the first health utilities for PTSD were only recently calculated
(Freed et al., 2007). Here, our team of scientists estimated health utilities by stratifying a
sample of veterans based on diagnosis and examining their responses to a preference-weighted
measure of health status, the Short-Form 6-dimensional health state classification (SF-6D),
an abbreviated version of the Medical Outcome Survey Short-Form-36 (MOS SF-36; Brazier
et al., 2002; Ware and Sherbourne, 1992). Magruder et al. (2005) administered questions
of the MOS SF-36 (Ware and Sherbourne, 1992) to a large, multi-site primary care sample of
veterans. We applied Brazier et al.’s (2002) health utility formula to the SF-36 responses in
Magruder et al. (2005). Brazier et al. previously determined the health utilities of SF-6D-defined
health states by administering the standard gamble to a community sample. Brazier et al. then
intended for these health utilities to be mapped onto the raw scores of an SF-36 dataset without
having to re-administer the standard gamble. We then explored the relationship among PTSD,
other anxiety disorders, and mood and substance use disorders on health utilities. Mental health
disorders were diagnosed using well-validated diagnostic interviews. > Figure 89‐4 presents the
. Figure 89‐3
The standard gamble paradigm for calculating a health utility for a particular health state (figure
adapted from Freed and Engel, 2006). An example of the standard gamble, a method designed to
determine preference and ‘‘worth’’ for a particular disease state. Respondents value a disease by
indicating their willingness to accept a risky but disease-curing intervention versus living with
the disease. A low health utility (close to 0) indicates that the disease is considered very
undesirable, and conversely, a high health utility (close to 1) indicates that the disease is not
considered undesirable
mean health utilities and standard error associated with veterans diagnosed with (PTSD+) and
without (PTSD-) PTSD and with and without one co-occurring mood, anxiety, and substance
use disorder (SUD).
The authors concluded that PTSD contributes to decrements in health status, with greater
decrements associated with the presence of more than one co-occurring disorder. Further-
more, the health utilities of PTSD were comparable to those for mood, anxiety, and SUD
alone. The findings were limited in two important ways. First, the SF-6D preferences were
obtained from a British community sample (Brazier et al., 2002), as opposed to veterans or
active duty servicemembers. And second, the Magruder et al. (2005) data was collected from
veterans before the conflicts in Iraq and Afghanistan, which potentially calls into question the
generalizability of these findings to returnees from OEF/OIF.
Section summary. Both the disability weights in DALYs and the health utilities in QALYs,
are preference-based. Preference-based measures differ form other symptom severity or
health-related quality of life measures. Non preference-based measures describe functioning
while preference-based measures include a value component, which assesses the relative worth
of diseases or health states. Gold et al. (2002) and Sassi (2006) provide detailed discussions of
the similarities and differences between QALYs and DALYs.
. Figure 89‐4
Estimated mean health utilities with standard error bars for PTSD and co-occurring mental health
conditions from Freed et al. (2007). SUD: diagnosed with a substance use disorder; PTSD+:
diagnosed with posttraumatic stress disorder; PTSD-: not diagnosed with posttraumatic stress
disorder; Mood: diagnosed with one mood disorder; Anxiety: diagnosed with one anxiety
disorder. This figure presents the mean estimated health utilities with standard error bars for
several combinations of diagnostic groups. PTSD+ veterans had significantly lower health utility
scores (indicating greater dysfunction) than veteran without a diagnosed mood, anxiety, or
substance use disorder. PTSD+ veterans diagnosed with greater than one co-occurring disorder
(e.g., a mood and substance use disorder) had significantly lower health utilities than
PTSD-veterans with greater than one co-occurring disorder
7 Efficacy of Primary Prevention and Treatment
The VA/DoD clinical practice guidelines for the management of posttraumatic stress (VHA/
DoD, 2004) suggest that primary prevention strategies should be considered. The US military
arguably provides months to years of training in efforts to prepare soldiers for the challenges
they may face in combat situations. This training can be seen as primary prevention, and
a paucity of research exists which details how these strategies affect a military population.
More recently, the military implemented pre- and post-deployment training modules called
‘‘Battlemind’’ (Adler et al., 2007; http://www.battlemind.org/), which can be administered,
to soldiers, healthcare professionals, leaders, and family members. The training provides mental
health education about the reality of combat situations and readjustment issues upon return.
Results of this training have lead to lower PTSD, lower depression, less anger, and less perceived
stigma about receiving treatment (Adler et al., 2007). More research needs is needed to determine
whether this particular intervention can reduce the incidence of PTSD following combat exposure.
In contrast to prevention, much research exists on the efficacy of PTSD treatment. A full review
of the efficacy literature is beyond the scope of this chapter, but several recent reviews determined
psychotherapeutic (Bisson et al., 2007; Bradley et al., 2005) and pharmacologic (Davidson, 2006;
Ipser et al., 2006) interventions for PTSD can be effective. The effectiveness of varying types of
therapy or drug treatments depend on the type of intervention and samples studied. In general,
treatments were less effective for combat-trauma (Bisson et al., 2007; Bradley et al., 2005; Ipser
et al., 2006) relative to non-combat trauma, but the patients in the combat-trauma studies were
veterans of other wars (namely Vietnam) and not OEF/OIF. Friedman (2006) discusses specific
treatments options for OEF/OIF returnees with PTSD. However, existing barriers to seeking
care limit the potential for servicemembers to reap the benefits of treatment.
8 Other Considerations
Clearly, the foundation of estimating the disease burden of PTSD rests on multiple factors. So far
we have reviewed current prevalence estimates, course of illness, disability weights, and treatment
efficacy. In this section, we discuss two more variables that contribute to the estimation of disease
burden: techniques used to determine disease prevalence and the consideration of comorbidities.
PTSD assessment methods. The VA/DoD clinical practice guidelines (2004) call for a
thorough evaluation to accurately diagnose PTSD. It is often impractical to include lengthy,
clinician-administered diagnostic evaluations in large epidemiological studies, and therefore
self-report measures are used in place of a clinical interview. Although useful and efficient,
screening measures such as the 17-item PCL (Blanchard et al., 1996) and the 4-item PC-PTSD
(Prins et al., 2003) do not assess Criterion A. For example, Prins et al. (2003); corrigendum
(2004) compared the two measures in relation to a structured diagnostic clinician administered
PTSD interview. At a cutscore of 3 on the PC-PTSD, sensitivity (proportion of people with
PTSD who screen positive) was 0.78 and specificity (proportion of people without PTSD who
screen negative) was 0.78. At a cutscore of 48 on the PCL, sensitivity was 0.84 and specificity was
0.90. The cutscores used to indicate presumptive PTSD diagnosis may differ depending on the
sample in question, which has a significant impact on the reported prevalence of PTSD across
research studies. Since disease prevalence is a component of disease burden, considerations of
assessment methods used to derive prevalence estimates are important.
Dealing with comorbidities. Disease co-morbidities must also be considered when estimat-
ing disease burden. For example, of the veterans diagnosed with PTSD, Magruder et al. (2005)
found that 68.6% met criteria for major depression, 73.3% met criteria for another anxiety
disorder, and 10.5% met criteria for a substance use disorder, and thus 87.2% of veterans
diagnosed with PTSD also met criteria for another mental disorder. In an injured servicemember
population (Grieger et al., 2006), the prevalence of PTSD co-occurring with depression was 46%
at 1-month, 63% at 4-months, and 53% at 7-months. Smith et al. (2008) found that the odds of
new onset PTSD were greater for servicemembers who smoked and who met criteria for
problem drinking, although these problems were reported as risk factors, rather than co-morbid
conditions. In other reviews (Kessler, 2000), the evidence suggests that co-occurring disorders
appear after PTSD, and are due to PTSD and not an underlying vulnerability.
Not surprisingly, comorbidity impacts estimates of disease burden, especially when dis-
ability weights and health utilities are calculated from disease specific vignettes that do not
include the co-occurring condition. Here, one must ask what the impact is of the co-occurring
condition on the preference weight. Is the impact additive, for example, such that the
preference weight of one disorder is added to the weight of a second disorder for a person’s
comorbidity? Comorbidity is a problem in both DALY and QALY calculations, but it has not
been thoroughly addressed in disability weighing. Melse et al. (2000) briefly summarize the
issue, and state that summing the weights of comorbid conditions is an acceptable solution
because the inclusion of comorbidity insignificantly changes disease burden calculations.
Using this summing approach, however, permits a person to have a disability weight of greater
than one. Thus, if that person is diagnosed with multiple conditions, thereby creating a
disability weight greater than one, then theoretically, his disability is worse than death.
Freed et al.’s findings (2007; > Figure 89-4) suggest the recommendations of Melse et al.
(2000) may not be an acceptable solution because the impact of a second or third co-occurring
disorder is not cumulative. Vos et al. (2001) split the number of prevalent cases of co-
occurring disorders equally across their sample, thereby allowing for the fact that people
with multiple diagnoses would be likely to have more severe disease weightings than those
with only one diagnosis.
One solution is to create vignettes based on generic health status, establish preference weights
for those generic vignettes, and then assess patients with the generic health status measure. Then,
it is possible to apply the existing preference weights to the patient responses and examine
the relationship between generic health status and specific diseases (e.g., PTSD).
9 Conclusions
Despite an increasing incidence, chronic nature, drain on the healthcare system, and a
significant decrement in health status associated with combat PTSD, the major burden
of disease is largely unrecognized at a policy level (McFarlane, 2004). To date, Freed et al.
(2007) are the only researchers who attempted to estimate health utilities (a morbidity
outcome) associated with PTSD in a veteran sample, a morbidity. Freed et al. did not calculate
QALYs associated with PTSD, nor did they weight the health utilities by disease prevalence or
incidence in the primary care sample. Thus, disease burden estimates from Freed et al. alone
are not possible. The other preference-based estimates (> Table 89‐3) did not distinguish
combat from noncombat PTSD.
The primary method to estimate the disease burden of PTSD is to calculate the years
lived YLD. Here, incidence of disease (that is, the number of new cases in one year) is multiplied
by the average time spent in the disease state, and the product is then multiplied by the disability
weight (Murray and Lopez, 1996). The incidence of PTSD is not widely studied, but the
prevalence can be also be used instead of incidence. Melse et al. (2000) multiplied disease
prevalence (that is, the number of new cases in one year) by disability weight. If disability weights
change over time (e.g., disease worsens with age), then researchers can average the weights
and use that average. The choice to use prevalence- or incidence-based estimates is often
dependent on the goal of the study (Melse et al., 2000). Incidence-based calculations are more
appropriate for disease prevention programs while prevalence-based calculations are present-
centered. Other choices in disease burden estimates include what discounting rate to use and
whether to use age weightings. For example, ‘‘discounting is applied because people value their
current health more than future health, and age-weighting is applied because most societies
would choose to save young to middle-aged adults over the young or very old’’ (Andrews et al.,
1998, pg. 123).
Ultimately, disease burden estimates are just that, estimates of population health. The
estimates are used for comparison purposes to better assist policy and decision makers to
reduce that burden and prioritize valuable healthcare resources to better treat and prevent
illness. PTSD is a chronic, recurring, but treatable disorder affecting a high percentage of
military servicemembers and veterans. Although no disease burden estimates exist to date
specific to this population, the breadth of current literature can provide researchers with
enough information to reasonably estimate the disease burden of PTSD.
Summary Points
PTSD is an anxiety disorder characterized by re-experiencing, avoidance, and hyperarousal

symptoms following a traumatic event.
Although the WHO characterized the burden to be among the top 20 most burdensome
diseases in the US, others have argued that PTSD is as burdensome as depression, which
the WHO predicts will be the second most burdensome disease worldwide.
Extant disease burden estimates do not distinguish combat-related from noncombat-related
PTSD. Combat exposure is a risk factor for PTSD, and people with combat-related PTSD
may respond as well to treatment.
PTSD prevalence estimates from OEF/OIF returnees range from 4.2 to 24.5%, depending
on the specific subpopulation and assessment method.
We review the literature for several key components to estimating the disease burden of
combat PTSD in US active duty servicemembers and veteran populations prevalence;
course of illness; impact on the healthcare system; preference weights; and intervention
effectiveness.
PTSD is associated with low quality of life, high rates of medical service utilization,
interpersonal conflict, co-morbidity, somatic complaints, lower general health ratings,
and work impairment compared to military servicemembers without PTSD.
PTSD is chronic, with symptoms lasting over 50 years in some veterans.
Disease burden is the confluence of two measurements, morbidity and mortality, although
mortality is not typically included when assessing the disease burden of mental health
conditions.
Unlike symptom severity or generic quality of life, morbidity (measured by a preference-
weighted metric) accounts for the value or worth that society places on a particular disease
state, relative to other disease states and anchored by perfect health and death.
Once calculated, disease burden for combat PTSD can assist in medical decision making
and in determining priorities for interventions.
References
Adler AB, Wright KM, Bliese PD, Eckford R, Hoge CW. Army Medical Surveillance Activity. (2004). Defense
(2008). J Trauma. 21: 301–308. Medical Epidemiology Database (DMED 3.7) [com-
Adler AB, Castro CA, McGurk D. (2007). US Army puter software]. Available at: http://amsa.army.mil/
Medical Research Unit-Europe Research Report AMSA/amsa_home.htm.
2007–001. USAMRU-E, Heidelberg, Germany. Bennett KJ, Torrance GW. (1996). Measuring health state
American Psychiatric Association. (1980). Diagnostic preferences and utilities: rating scale, time trade-off,
and Statistical Manual of Mental Disorders, 3rd and standard gamble techniques. In Spiker B. (ed.),
ed. American Psychiatric Association, Washington, Quality of Life and Pharacoeconomics in Clinical
DC. Trials, 2nd ed. Lippincott-Raven Publishers,
American Psychiatric Association. (1987). Diagnostic Philadelphia, PA.
and Statistical Manual of Mental Disorders, 3rd ed, Berzon RA, Mauskoph JA, Simeon GP. (1996). Choos-
(text revision). American Psychiatric Association, ing a health profile (descriptive) and/or a patient-
Washington, DC. preference (utility) measure for a clinical trial. In
American Psychiatric Association. (2000). Diagnostic B. Spiker (ed), Quality of Life and Pharacoeco-
and Statistical Manual of Mental Disorders, 4th ed, nomics in Clinical Trials, 2nd ed. Lippincott-Raven
(text revision). American Psychiatric Association, Publishers, Philadelphia, PA.
Washington, DC. Bisson JI, Ehlers A, Matthews R, Pilling S, Richards D,
Andrews G, Issakidis C, Sanderson K, Corry J, Lapsley H. Turner S. (2007). Br J Psychiatry. 190: 97–104.
(2004). Br J Psychiatry. 184: 526–533. Blake DD, Weathers FW, Nagy LM, Kaloupek DG,
Andrews G, Sanderson K, Beard J. (1998). Br J. Psychia- Gusman FD, CharneyDS, Keane TM. (1995).
try. 173: 123–131. J Trauma Stress. 8: 75–90.
Blanchard EB, Jones-Alexander J, Buckley TC, Forneris Institute of Medicine (IOM), National Research Council
CA. (1996). Behav Res Ther. 34: 669–673. (NRC), Committee on Veterans Compensation for
Bradley R, Greene J, Russ E, Dutra L, Westen D. (2005). Posttraumatic Stress Disorder. (2007). PTSD Com-
Am J Psychiatry. 162: 214–227. pensation and Military Service. National Academies
Brazier J, Roberts J, Deverill M. (2002). J Health Econ. 21: Press, Washington, DC. Available at: http://www.
271–292. nap.edu/catalog/11870.html.
Breslau N, Davis GC, Andreski P, Peterson E. (1991). Institute of Medicine (IOM), Subcommittee on Posttrau-
Arch Gen Psychiatry. 48: 216–222. matic Stress Disorder of the Committee of Gulf War
Breslau N, Kessler RC. (2001). Biol Psychiatry. 50: and Health. (2006). Posttraumatic Stress Disorder:
699–704. Diagnosis and Assessment. National Academies
Breslau N, Kessler RC, Chilcoat HD, Schultz LR, Davis Press, Washington, DC. Available at: www.nap.edu/
GC, Andreski P. (1998). Arch Gen Psychiatry. 55: catalog/11674.html.
626–632. Ipser J, Seedat S, Stein DJ. (2006). S Afr Med J. 96:
Davidson JR. (2006). J Clin Psychiatry. 67: 34–39. 1088–1096.
Davidson JRT, Foa EB. (1991). J Abnorm Psychology. Jones E, Wessely S. (2007). J Anxiety Disord. 21: 164–175.
100: 346–355. Kessler RC. (2000). J Clin Psychiatry. 61: 4–12.
Freed MC, Engel CC. (2006). Behavioral Health Track at Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB.
the U.S. Army Center for Health Promotion and (1995). Arch Gen Psychiatry. 52: 1048–1060.
Preventive Medicine-hosted Force Health Protec- Kiberd BA, Lawson T. (2000). Transplantation. 70(7):
tion Conference, Albuquerque, NM. 1121–1127.
Freed MC, Yeager D, Liu X, Gore KL, Engel CC, Kimerling R, Gima K, Smith MW, Street A, Frayne S.
Magruder KM. (2007). Behavioral Health Track at (2007). Am J Public Health. 97: 2160–2166.
the U.S. Army Center for Health Promotion and Kruijshaar ME, Hoeymans N, Spijker J, Stouthard ME,
Preventive Medicine-hosted Force Health Protec- Essink-Bot ML. (2005). Bull World Health Organ.
tion Conference, Louisville, KY. 83: 443–448.
Friedman MJ. (2006). Am J Psychiatry. 163: 586–593. Kulka RA, Schlenger WE, Fairbank JA, Hough RL,
Garza AG, Wyrwich KW. (2003). Acad Emerg Med. 10 Jordan BK, Marmar CR, Weiss DS. (1990). Trauma
(4): 360–363. and the Vietnam War Generation: Report of Find-
Gold MR, Siegel JE, Russell LB, Weinstein MC. (1996). ings from the National Vietnam Veterans Readjust-
Cost-Effectiveness in Health and Medicine. Oxford ment Study. Brunner/Mazel, New York.
University Press, New York. Magruder KM, Frueh BC, Knapp RG, Davis L, Hamner
Gold MR, Stevenson D, Fryback DG. (2002). Annu Rev MB, Martin RH, Gold PB, Arana GW. (2005). Gen
Public Health. 23: 115–134. Hosp Psychiatry. 27: 169–179.
Gore KG, Engel CC, Freed MF, Liu XL, Armstrong DW. McFarlane A. (2004). Soc Psychiatry Psychiatr Epide-
(2008). Gen Hosp Psychiatry. 30: 391–397. miol. 39: 874–882.
Gore KG, Freed MC, Messer SC, Engel CC. (2006). Melse JM, Essink-Bot ML, Kramers PG, Hoeymans N.
Behavioral Health Track at the U.S. Army Center (2000). Am J Public Health. 90: 1241–1247.
for Health Promotion and Preventive Medicine- Michaud CM, McKenna MT, Begg S, Tomijima N,
hosted Force Health Protection Conference, Albu- Majmudar M, Bulzacchelli MT, Ebrahim S, Ezzati M,
querque, NM. Salomon JA, Kreiser JC, Hogan M, Murray CJ.
Grieger TA, Cozza SJ, Ursano RJ, Hoge C, Martinez PE, (2006). Popul Health Metr. 4:11.
Engel CC, Wain HJ. (2006). Am J Psychiatry. 163: Michaud CM, Murray C, Bloom B. (2001). JAMA. 285:
1777–1783. 535–539.
Hepp U, Gamma A, Milos G, Eich E, Adjacic-Gross V, Milliken CS, Auchterlonie JL, Hoge CW. (2007). JAMA.
Rossler W, Angst J, Schnyder U. (2006). Eur Arch 298: 2141–2148.
Psychiatry Clin Neurosci. 256: 151–158. Murray CJL, Lopez AD (eds). (1996). The Global Burden
Hidalgo RB, Davidson JR. (2000). J Clin Psychiatry. 61: of Disease: A Comprehensive Assessment of Mortality
5–13. and Disability from Diseases, Injuries, and Risk Fac-
Hoge CW, Auchterlonie JL, Miliken CS. (2006). JAMA. tors in 1990 Projected to 2020. Harvard School of
295: 1023–1032. Public Health, Cambridge, MA.
Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Prins A, Ouimette P, Kimerling R, Cameron RP,
Koffman RL. (2004). N Engl J Med. 351: 13–22. Hugeishofer DS, Shaw-Hegwer J, Thraikill A,
Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Gusman FD, Sheikh JI. (2003). Primary Care Psy-
Castro CA. (2008). N Engl J Med. 358: 453–463. chiaty. 9: 9–14; Corrigendum (2004) Primary Care
Hoge CW, Terhakopian A, Castro CA, Messer SC, Engel Psychiatry. 9(4): 151.
CC. (2007). Am J Psychiatry. 164(1): 150–153. Revicki DA, Wood M. (1998). J Affect Disord. 48: 25–36.
Sanderson K, Andrews G. (2001). Aust N Z J Psychiatry. Smith TC, Ryan MA, Wingard DL, Slymen DJ, Sallis JF,
35: 668–676. Kritz-Silverstein D. (2008). BMJ. 336: 366–371.
Sassi F. (2006). Health Policy Plan. 21: 402–408. Tsevat J. (2000). Med Care. 38(9) II160–II164.
Schnurr PP, Hayes AF, Lunney CA, McFall M, Uddo M. Veterans Health Administration (VHA), Department of
(2006). J Consult Clin Psychol. 74: 707–713. Defense (DoD). (2004). VA/DoD0 Clinical Practice
Schnurr PP, Lunney CA, Sengupta A, Waelde LC. (2003). Guideline for the Management of Post-Traumatic
J Trauma Stress. 16: 545–553. Stress. Veterans Health Administration, Department
Seal KH, Bertenthal D, Miner CR, Sen S, Marmar C. of Defense, Washington, DC.
(2007). Arch Intern Med. 167(5): 476–482. Vos T, Mathers C, Herrman H, Harvey C, Gureje O, Bui
Seedat S, Lochner C, Vythilingum B, Stein DJ. (2006). D, Watson N, Begg S. (2001). Soc Psychiatry Psy-
Pharmacoeconomics. 24: 989–998. chiatr Epidemiol. 36: 53–62.
Sherbourne C, Unutzer J, Schoenbaum M, Duan N, Ware JE, Sherbourne CD. (1992). Med Care. 30: 473–483.
Lenert LA, Sturm R, Wells KB. (2001). Med Care. Weathers FW, Keane TM. (2007). J Trauma Stress. 20:
39: 1246–1259. 107–121.
90 Estimating the Disease
Burden of Seasonal
Affective Disorder
M. C. Freed . R. L. Osborn . K. J. Rohan
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1550
2 What Is SAD? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1551

2.1 Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1553
2.2 Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1554
2.3 Measuring Disease Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1556
2.4 Course of Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1560
2.5 Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1564
2.6 Bringing It All Together . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565
Disclaimer: The opinions and assertions expressed herein are those of the authors and are not to be construed as
expressing the views or policies of the Deployment Health Clinical Center, United States Army, Uniformed Services
University of the Health Sciences, Department of Defense, United States Government, or The University of Vermont.

1550 90 Estimating the Disease Burden of Seasonal Affective Disorder
Abstract: > Seasonal Affective Disorder (SAD) is defined as a recurrent pattern of Major
Depressive Episodes with a temporal relationship between the episodes and time of year (e.g.,
onset during fall/winter with remission during spring/summer) that affects 10–20% of major
depression cases. Because SAD is a subtype of recurrent major depression and shares many
symptoms, it also presumably shares the same disability during symptomatic months. In an
alarming trend, the WHO predicts that by 2020, unipolar depression will rank second only to
ischemic heart disease in disease burden. Although no SAD disease burden estimates exist to
date, extant SAD literature is sufficient in scope and content to provide the information
needed to estimate the disease burden, using the major depression literature as a proxy if
necessary. We summarize and present literature that addresses key components to estimating
disease burden: > prevalence; treatment efficacy, existing > preference weights, and course of
illness.
Current SAD prevalence estimates vary between 0.4 and 16% in the general adult popula-
tion, depending on latitude, age, gender, and measurement method. Longitudinal data suggest
that SAD remits in up to 27% of patients, becomes more complicated in presentation in up to
44% of patients, and remains in 42% of patients. Efficacy data suggests that treatment can lead
to remission in up to 83% of patients, depending on treatment type. We present preference
weights from the major depression literature, because they do not exist for SAD. > Disability
weights range from 0.09 (minor depression) to 0.83 (severe depression). Similarly, health
utilities range from 0.83 (mild depression) to 0.15 (severe depression).
SAD is a chronic, disabling, but treatable condition. Disease burden estimates of SAD
could be used to better determine the need for and utility of therapeutic interventions
designed to alleviate symptoms of SAD and associated impairment.
List of Abbreviations: APA, American Psychiatric Association; CBT, > cognitive behavioral
therapy; CI, confidence interval; DALY, disability adjusted life year; DSM IV-TR, diagnostic
and statistical manual of mental disorders IV – text revision; GBD, global burden of disease;
ICD-10, international classification of disease-10; LT, > light therapy; NDA, no data available;
QALY, > quality adjusted life year; SAD, seasonal affective disorder; SHQ, Seasonal Health
Questionnaire; SIGH-SAD, structured interview guide for the Hamilton depression rating
scale-seasonal affective disorder version; SPAQ, seasonal pattern assessment questionnaire;
SSRIs, selective serotonin reuptake inhibitors; WHO, World Health Organization; YLD, years
of life with disability; YLL, years of life lost
1 Introduction
As of 2000, the World Health Organization (WHO) estimated that unipolar (major) depres-
sive disorders were the fourth most common cause global disease burden in women and the
seventh in men (Ustün et al., 2004). In an alarming trend, the WHO predicts that by 2020,
unipolar depression will rank second only to ischemic heart disease in disease burden
(Michaud et al., 2001). This rank was supported by new GBD data and remains constant in
2,030 projections (Mathers and Loncar, 2006). Because seasonal affective disorder (SAD) is a
subtype of recurrent major depression and shares many symptoms (APA, 2000), it also
presumably shares the same disability during symptomatic months (Freed et al., 2007).
Despite these symptom-based and possibly functional commonalities, SAD prevalence
Estimating the Disease Burden of Seasonal Affective Disorder 90 1551
(Magnusson, 2000), course (APA, 2000), etiology (Sohn and Lam, 2005), and treatment choice
and efficacy (Westrin and Lam, 2007b) differ from that of nonseasonal major depression.
No SAD disease burden estimates exist to date, and the disease burden estimates for major
depression may not generalize to SAD. That said, extant SAD literature is arguably sufficient in
scope and content to provide the information needed to calculate reasonable estimates of
disease burden of SAD. We review four key components to estimating the disease burden of
SAD: disorder prevalence to include demographic and environmental influences and mea-
surement variance; disease burden measurement techniques; course of illness; and treatment
efficacy.
2 What Is SAD?
SAD, as defined by DSM IV-TR (APA, 2000), is a recurrent pattern of Major Depressive
Episodes with a temporal relationship between the episodes and time of year (e.g., onset
during fall and winter with remission during spring and summer). SAD affects 10–20% of
recurrent depression cases (Magnusson, 2000). Individuals diagnosed with SAD frequently
endorse ‘‘atypical’’ symptoms of depression, including carbohydrate cravings, hypersomnia,
fatigue, and weight gain. However, cognitive symptoms are often similar to nonseasonal
depression (Sullivan and Payne, 2007), and may include feelings of worthlessness, excessive
or inappropriate guilt, indecisiveness, diminished ability to concentrate, and/or thoughts
of death. Left untreated, SAD episodes often recur annually (Sakamoto et al., 1995).
See > Table 90-1 for the diagnostic criteria and associated features of SAD.
Etiological models of SAD propose biological mechanisms to link light availability to SAD
onset, based on the observation that SAD prevalence increases with latitude in the United
States (Mersch et al., 1999). Given that photoperiod (i.e., day length) is completely determined
by latitude and day of the year, light availability may be implicated in SAD etiology through a
number of mechanisms: a) phase-delayed circadian rhythms with respect to objective time or
to the timing of sleep, b) a dose of light (photons) to the retina that falls below a critical
threshold, c) an abnormally prolonged duration of nocturnal melatonin release during winter,
and d) reduced serotonergic activity (Magnusson and Boivin, 2003).
The aforementioned hypothesized light availability-based models do not necessarily hold
true for summer-type SAD (i.e., depressive episodes which begin in spring and remit in the fall
and winter; Schwartz and Schwartz, 1993). DSM IV-TR (APA, 2000) does not distinguish
between summer- and winter-type SAD. Summer SAD appears much less common than
winter SAD (Magnusson, 2000) and includes the ‘‘typical’’ depressive symptoms common in
nonseasonal depression such as weight loss, insomnia, agitation, and loss of appetite
(Schwartz and Schwartz, 1993). Some persons diagnosed with summer SAD, especially in
tropical climates, find relief in the dark or in air conditioned spaces (Schwartz and Schwartz,
1993). These observations suggest that temperature, and not necessarily light availability,
mediates SAD symptoms. Because the DSM-IV-TR and ICD-10 classification systems do
not distinguish between summer- and winter-type SAD, we report findings from both the
summer and winter SAD literature; but unless explicitly named, SAD will refer to winter-type
SAD in this chapter.
Young (1999) and Young et al. (1991, 1997) were the first to suggest that there may be a
‘‘dual’’ vulnerability to SAD, consisting of a physiological vulnerability and a psychological
. Table 90-1
Diagnostic criteria and associated features or SAD (APA, 2000)
Must meet criteria for a major depressive episode as part of major depressive disorder,
recurrent; bipolar I disorder; or bipolar II disorder
In adults, a major depressive episode is characterized by these clinically significant symptoms
a) Depressed mood or loss of interest in activities and
b) Four or more of these symptoms
5% unintentional change in weight or significant change in appetite
Daily and significant increased or decreased sleep
Observable and significant restlessness or slowing
Fatigue or loss of energy
Daily and significant feelings of worthlessness or guilt, which is considered excessive or
inappropriate
Difficulty thinking, concentrating, or making decisions
Recurrent thoughts of death or dying (not just fear of dying) with or without a plan for
suicide or a suicide attempt
Here, symptoms for a major depressive episode cannot be due to events such as bereavement or a
medical condition
SAD is a specifier, not a stand-alone disorder, and is characterized by the following
Regular temporal relationship between onset of episode and time of year for at least 2 years
(with no nonseasonal episodes in that timeframe)
Full remission or change to mania/hypomania has a regular temporal relationship
Seasonal episodes occur more frequently than nonseasonal episodes over a patient’s lifetime
Persons diagnosed with SAD episodes are often report these ‘‘atypical’’ symptoms of depression.
However, these symptoms are not required for a SAD diagnosis
Prominent anergy
Increased sleep
Overeating
Weight gain and
Carbohydrate cravings
This table summarizes the diagnostic criteria and associated features of SAD as reported in the DSM-IV-TR (APA, 2000)
vulnerability. In an expansion of the concept of a dual-vulnerability to SAD, Rohan et al. (2003,

2004a) specified content for the psychological component of SAD vulnerability; specifically, the
psychological component to the etiology of SAD is hypothesized to involve activation of
negative cognitions (e.g., maladaptive schemas, attitudes, and automatic thoughts) and behav-
ioral disengagement from potential sources of positive reinforcement during the winter
months. Rohan et al. further proposed that the psychological vulnerability interacts with the
physiological vulnerability (consisting of the factors mentioned above) in a maintaining cycle.
Rohan’s model is termed the integrative, cognitive-behavioral model. Rohan’s cognitive-behav-
ioral factors might also interact with an underlying physiological vulnerability to explain onset
of SAD symptoms during the debilitating summer heat in tropical climates.
2.1 Prevalence
We discuss several factors affecting prevalence of SAD: latitude, age, gender, and measurement
method. Although evidence suggests that one or more of these factors is related to prevalence
of SAD, reported prevalence rates vary widely across geographic regions and have been
estimated to range from 0.4 to 16% in the general adult population (Blazer et al., 1998;
Booker et al., 1991; Magnusson, 2000).
As previously discussed, length of photoperiod (i.e., the light/dark cycle) is thought to be
related to winter SAD onset (Mersch et al., 1999; Young et al., 1997) through one or more
proposed mechanisms. Prevalence may be higher, and severity may be greater at northern
latitudes, where sunlight is reduced (Lurie et al., 2006). Rosen et al. (1990) reported a nearly
linear relationship between latitude within the United States and prevalence of SAD. Specifically,
they reported SAD prevalence of just over 1% in Florida compared to 9.7% in New Hampshire.
Mersch et al. (1999) investigated the relationship between the prevalence of seasonal affective
disorder and latitude and found the mean prevalence of SAD to be two times higher in North
America compared to Europe. Moreover, a significant positive correlation was found between
prevalence and latitude in North America. However, the correlation was low, calling into
question the clinical utility of such information. Haggerty et al.’s (2001) meta-analysis of the
literature also reported significant correlations between latitude and SAD, although similar to
Mersch et al. (1999), the predictive power of such correlations was extremely low.
Importantly, Magnusson has reminded us that ‘‘latitude is only an indirect measure of how
much light people receive in winter’’ (Magnusson, 2000, pg. 177). Sakamoto et al. (1993)
reported prevalence of SAD at different latitudes in Japan, but it was total hours of sunshine
that appeared to be related to prevalence, not latitude. Still others report no relationship
between SAD onset and hours of sunshine (Young et al., 1997). Because SAD is thought to be
primarily caused by lack of light in winter (Magnusson, 2000), this factor and others (e.g.,
climate, genetics, and socio-cultural factors) may be expected to play a role in seasonal
depression as researchers continue to delineate these relationships. In conclusion, a review
of the literature reveals a small to moderate correlation between latitude and SAD; but these
results should be considered with caution until a more systematic method of evaluating this
relationship is established.
Age has repeatedly been described as a factor related to prevalence of SAD. Rosenthal et al.
(1984) reported that there may be a developmental component to SAD, such that children and
adolescents may develop SAD and may respond to light treatment (Giedd et al., 1998; for a
discussion of treatments, see below). As described in Magnusson’s (2000) review, Carskadon
and Acebo (1993) estimated that 4.2% of children ages 9–12 met their criteria for SAD, with
lower rates among the younger children. Using a self-report questionnaire, Sonis (1989)
reported 6.9% of adolescents aged 14–18 years had high seasonal variation in depressive
symptoms. Swedo et al. (1995) reported estimates of 1.7–5.5% of students from an American
sample were identified as probable SAD cases. Rastad et al. (2006) reported that among
Swedish students of similar ages (17–18 years), 20% self-reported depressed mood during
the winter season. However, these data are not descriptive of diagnosed SAD but rather of self-
reported seasonal variation in mood.
Rohan and Sigmon (2000) reported that prevalence of SAD among college students in
Maine, United States, was similar to that of an adult sample from nearby latitudes. They
reported that over half of the participants reported a winter mood pattern, but only 5% met
criteria for SAD, suggesting that studies only reporting seasonal patterns of mood should not
be taken as a reliable estimate of true SAD cases. In fact, Soriano et al. (2007) reported no
relationship between age and SAD among a sample of postgraduate students (medical
students) in Romania with an average age of 23.2 years. Mersch et al. (1999) measured SAD
in a large sample of the general population in The Netherlands and found that young women
were more sensitive to seasonal variation than older women and that this sensitivity decreased
with age for both men and women. Overall, it seems that younger people may be at equal, or
nominally higher, risk for SAD than older individuals (Mangusson, 2000), however the
problems plaguing prevalence rate estimations (discussed later) limit the generalizability of
the current findings.
Finally, women have generally been reported to represent a larger proportion of SAD cases
than men (Chotai et al., 2004; Magnusson, 2000; Rastad et al., 2005), which may be a reflection
of the gender difference in depressive disorders in general. Kasper (1989) found a 3.5:1
(women: men) sex ratio of seasonal mood patterns in the general population. However, others
report no particular relationship between gender and SAD. For example, Lucht and Kasper
(1999) reported no differences on the Seasonal Pattern Assessment Questionnaire (SPAQ)
between men and women, but indicated that more women than men referred themselves to
the outpatient clinic, highlighting the importance of considering bias when drawing conclu-
sions. As with other mental health conditions, data on differences between men and women
may be influenced by several factors, including response bias, symptom report differences, or
other factors; and, therefore, readers are encouraged to consider such factors when drawing
conclusions. Although current data seem to suggest that SAD may be less common among
men overall, Goel et al. (2002) reported that men and women with SAD did not differ in the
overall severity of the depression.
Problematic for the studies reviewed here and other places (e.g., Magnusson, 2000) is
the fact that many epidemiological reports rely on widely varying methodologies when
reporting SAD prevalence. Many have reported prevalence of SAD assessed by the SPAQ
(e.g., Soriano et al., 2007; Srisurapanont and Intaprasert, 1999; Tonetti et al., 2007). However,
others have used a modified version of the SPAQ (e.g., Rastad et al. 2005), the Structured
Interview Guide for the Hamilton Depression Rating Scale – Seasonal Affective Disorder
version (SIGH-SAD; e.g., Goel et al., 2002; Williams et al., 1992), the Seasonal Health
Questionnaire (SHQ; e.g., Thompson et al., 2004), or DSM criteria (Blazer et al., 1998) to
name a few. Studies using self-report questionnaires to assess seasonality may or may not give
accurate rates of seasonal depression meeting diagnostic criteria for SAD. Larger scale com-
munity samples using clinical, diagnostic interviews to determine DSM criteria have reported
lower prevalence (e.g., Blazer et al., 1998), suggesting that the SPAQ may tend to overestimate
true prevalence of the disorder. In fact, Thompson and Cowan (2001) suggest that the SPAQ
should not be used to determine prevalence of SAD as it ‘‘gives misleadingly high estimates
of prevalence.’’ Interestingly, the Blazer et al. (1998) study reported no relationship between
latitude and prevalence of SAD when using DSM criteria, supporting the questions we
have raised previously.
2.2 Treatment Options
Broadly, three treatment options exist for SAD: (1) light therapy (LT), considered the gold-
standard; (2) pharmacotherapy; and (3) behavioral interventions. Rosenthal et al. (1984)
were the first researchers to demonstrate that bright artificial light had an antidepressant
effect. In a recent summary, Westrin and Lam (2007b) describe LT as the most widely used and
preferred treatment for SAD. It includes daily exposure to 10,000 lux of cool-white or full-
spectrum fluorescent lamps with ultraviolet rays filtered out, for at least 30-min during
symptomatic months. The light sources must be positioned at the appropriate distance
from the patient to ensure that the full 10,000 lux reaches the retina, as lux exponentially
decreases as distance from light source increases. Indoor evening room light is 100 lux, and a
brightly lit office is 500 lux. Outdoor light ranges from 4,000 lux (cloudy grey winter day) to
100,000 lux (bright sunny day). Side effects are considered mild and transient and can include
headache, nausea, eyestrain, insomnia, agitation, and mania. Variants of LT exist, but we focus
on the more traditional light box in this chapter. For example, dawn simulators (i.e., a light
that gradually brightens as patients wake) and portable head-mounted light therapy devices
are available.
Golden et al. (2005) reviewed eight light therapy trials that met their selection criteria
(i.e., inclusion of an adequate placebo control group and SAD diagnosis according to
established criteria). The combined effect size was 0.84 with a 95% CI of 0.60–1.08. Six
of the eight studies reported individual effect sizes where the lower end of the CI around
the effect size was greater than 0. Golden et al. also reported an odds ratio for remission of
2.9 (95% = 1.6–5.4) at the end of a trial of light therapy from the four studies where the
number of remitted subjects was known. In an older review, where study inclusion was less
restrictive than Golden et al. (2005), Terman et al. (1989) concluded that LT is most likely to
lead to remission if patients begin with mild SAD symptoms. Broken down by light dosing
schedule, Terman et al. reported remission rates of 51%, 53%, 32%, and 38% in patients who
received morning plus evening light, morning light alone, midday light alone, and evening
light alone, respectively. Thus, up to 53% of individuals with SAD, and an even smaller
percentage (43%) of individuals with moderate to severe SAD showed clinically significant
improvement with LT (Terman et al. 1989). In contrast, he reported remission rates of 31%
for brief exposure to light (a control condition) and 11% for dim light exposure (a control
condition).
Fewer trials have evaluated the efficacy of medication in the treatment of SAD. Lam et al.
(2006) summarized the main findings of two key medication trials. To date, selective serotonin
reuptake inhibitors (SSRIs) have demonstrated the best treatment efficacy. Relative to placebo,
patients taking fluoxetine and sertraline (in two different studies) demonstrated improvement
in symptom severity. However, improvement from baseline was not statistically significant in
the fluoxetine trial, and percentages of score reduction (50% was considered a clinically
significant response though not necessarily indicative of full remission) between the active
treatment and placebo were strikingly similar: 59% (fluoxetine) versus 34% (placebo) and
63% (sertraline) versus 46% (placebo). Lam et al. state that these clinical response rates are
similar to trials for nonseasonal depression. Westrin and Lam (2007a) summarized other
findings that bupropion was helpful to prevent a SAD episode recurrence when initiated
before symptoms began (16% bupropion versus 28% placebo); but the rate of recurrence
overall was remarkably low, even in the placebo condition. Less rigorous examinations of other
medications have been completed and suggest potentially promising acute treatments that
require further research.
Lam et al. (2006) state that both antidepressants and LT are considered first-line SAD
treatments. In head-to-head comparisons of LT and medication, current findings are equivo-
cal, with descriptive evidence suggesting superiority for LT. The findings from Lam et al., who
compared fluoxetine and LT in longest and largest trial to date (8-weeks; N = 96), supported
this conclusion. Specifically, the reported a 50% remission for LT compared to 54% for
fluoxetine, and remission rates were similar in patients with more severe symptoms (48%
for LT and 50% for fluoxetine).
As an alternative to LT, Rohan et al. (2004b) developed a group cognitive-behavioral
therapy (CBT) for SAD. Preliminary data suggest that Rohan’s SAD-tailored CBT may be
comparably efficacious to the ‘‘best available’’ treatment (i.e., LT) in the acute treatment phase
and substantially more effective than LT in symptom severity and relapse rates 1-year later
(Rohan et al., 2004b). The initial study, a feasibility randomized clinical trial (N = 23)
compared Rohan’s 6-week SAD-tailored group CBT, LT, and the combination of SAD-tailored
group CBT + LT. Participants were evaluated at pre-treatment, post-treatment, and a 1-year
follow-up. Although all treatment groups were associated with significant improvement in
SAD symptoms from pre- to post-treatment on both measures, CBT demonstrated superior
treatment durability at 1-year follow-up (i.e., the winter following treatment completion). No
participant who received CBT (either alone or in conjunction with LT) experienced a full
episode recurrence at the 1-year follow-up. However, 62.5% of participants who received LT
alone endorsed severity of symptoms sufficient to qualify for a full-blown SAD episode
recurrence. Moreover, at the 1-year follow-up, participants in the CBT alone and CBT + LT
conditions reported significantly lower SAD symptoms. 1-year remission rates are as follows
(variations reflect differences in remission criteria): (1) 43–57% for CBT (2) 25–38% for LT,
67–83% for CBT + LT.
In a larger sample (N = 61), Rohan et al. (2007) generally replicated her follow-up findings
from the pilot study (1-year data is not yet published). In the intent-to-treat sample, remission
rates at post treatment were as follows (again, variations reflect differences in remission
criteria): (1) 44–50% for LT, (2) 40–47% for CBT, (3) 53–73% for CBT + LT, and (4) 7–20%
for a minimal contact delayed treatment control group.
2.3 Measuring Disease Burden
The true burden of a disorder may be defined as ‘‘the burden in the absence of treatment, that
is calculated from the burden observed in the population under study plus the burden
presently averted by current population coverage and mix of interventions’’ (Andrews et al.,
2004, pg. 526). The burden of disease in a population in a given year is the sum of (1) years of
life lost due to premature deaths (YLL) and (2) an estimate of the future years of life with
disability (YLD) for new cases of disease or injury, weighted for severity (Vos et al., 2001).
Disease burden allows disease pervasiveness (measured by incidence or prevalence), persistence
(that is, length of time someone has the disease), and morbidity to be combined onto one scale.
In the Global Burden of Disease study (Murray and Lopez, 1996), depression was ranked fourth
in disease burden and expected to rank second by 2020. In ages 14–44, unipolar depression was
ranked between first and third in disability, depending on sex and country development.
Disease burden is the confluence of two measurements: morbidity and mortality. However,
mortality is rarely attributed to mental disorders (Andrews et al., 2004), and persons with SAD
experience less suicidal ideation than in nonseasonal depression (reported in Magnusson and
Partonen, 2005). However, mortality is associated with depression (Kinder et al., 2008).
Although patients with SAD rarely commit suicide, researchers have considered mortality
associated with depression to be negligible (Melse et al., 2000; Stouthard et al., 2000). We
focus on morbidity in this chapter.
Morbidity of a disease is basically measured using one of two scales (both ranging from
zero to one) and anchored by perfect health and death. The number between 0 and 1 is
considered a preference weight for a particular disease or health state. To estimate the disease
burden, the preference weight is multiplied by (1) the amount of time spent in that health state
and (2) the disease prevalence. Preference weights differ from other measures of severity, in
that preference-weighted metrics incorporate how a health condition is valued by a given
population. For example, Kiberd and Lawson (2000) measured the preference of a Type-I
diabetes mellitus (DM) with comorbid blindness and end stage renal disease (ESRD; requiring
dialysis) health state from patients with DM and ESRD. In a separate study, Revicki and Wood
(1998) measured the preference of a severe depression health state from patients being
pharmacologically treated for depression. Preference was measured in units called health
utilities (discussed below) by both sets of researchers. Health utilities (and other units of
preference) are valued by having a group of raters read a brief vignette describing the health
states (depression or DM with ESRD in this example). Raters are administered one or more of
econometric instruments (e.g., the person trade-off; PTO, described below) designed to elicit
preference. In these two examples, average preference for the severe depression health state was
less desirable than was average preference for DM with comorbidities. Thus, a health state like
DM with comorbidities, which requires frequent life-saving medical treatment, is more
desirable than severe depression, which is theoretically treatable with medication and/or
psychotherapy. Depression is life-threatening only if a patient chooses to attempt suicide,
unlike DM with ESRD. This example demonstrates that non preference-based measures of
health status and clinical symptom focused measures are predominantly clinician tools, not
health policy tools per se (Bennett and Torrance, 1996; Berzon et al., 1996; Garza and
Wyrwich, 2003; Tsevat, 2000).
The GBD study (Murray and Lopez, 1996) assessed disease burden with the disability
adjusted life year (DALY), which equals YLL plus YLD. Here, 0 represents perfect health and 1
represents death, such that a year in perfect health is worth 0 DALYs. DALYs are considered an
interval scale, such that they can be summed across individuals and over time. ‘‘The DALY
measures the gap between the actual health of a population and a hypothetical norm, namely a
life expectancy of 82.5 years for women and 80 years for men. DALYs for a disease or health
condition are calculated as the sum of the years of life lost due to premature mortality in the
population and the years of life lost due to disability’’ (Michaud et al., 2001, pg. 535). DALYs
also include life expectancy, and can adjust the weighting based on age, such that a young adult
is ‘‘worth’’ more than someone at the beginning or end of the life cycle.
A component of YLD is a value called a disability weight, where 0 equals perfect health and
1 equals death. In the GBD study and other studies which assessed DALYs (e.g., Kruijshaar
et al., 2005; Sanderson and Andrews, 2001), disability weights for DALYs were obtained for
specific diseases by administering a series of ‘‘> person tradeoff ’’ (PTO) vignettes to a sample
of clinicians. Two variants were used. First, clinicians were given a choice between trading
‘‘quantity of life for healthy individuals and disabled individuals.’’ In the second, they are asked
to tradeoff ‘‘quantity of life for healthy individuals versus improved quality of life for a group
of disabled individuals’’ (Murray and Lopez, 1996, pg. 91). As an example, a disability weight
would equal 0.5, if a respondent considered 2,000 people with depression to represent the
same amount of health as 1,000 people without depression (Sanderson and Andrews, 2001).
See > Figures 90-1 and > 90-2 for graphical representation of the PTO.
A similar metric is called a quality adjusted life year (QALY). Here, a year in perfect health
equals one QALY and death equals zero, the reverse of the aforementioned DALY. Like DALYs,
. Figure 90-1
Person tradeoff method used in Murray and Lopez (1996) and Sanderson and Andrews (2001):
‘‘trading quantity of life for healthy and disabled individuals’’ (pg. 670). This is one variant of the
PTO, a method designed to determine preference and ‘‘worth’’ for a particular disease state.
Respondents indicate their preference by valuing quantity of life in a hypothetical sample of
healthy and disabled individuals. A low disability weight (close to 0) indicates that the disease is
considered less disabling, and conversely, a high disability weight (close to 1) indicates that the
disease is considered more disabling
the number representing disease preference in QALYs is weighted by time spent in a given
disease state and disease prevalence. Unlike DALYs, the number is not adjusted for age. The
number is called a > health utility (versus a disability weight). We recognize that the nomen-
clature used to describe the preference weight needed to calculate a QALY differs according to
the method. To minimize jargon, we use the term health utility in this chapter, independent
of method. Of note, numerous methods can be used to obtain a health utility (e.g., interpola-
tion from a generic health-related quality of life scale or direct valuation of a health state
vignette from a community sample). And, as discussed by Donald Sherbourne et al. (2001),
each method can produce a wide range of health utilities. Health utilities may or may not be
sensitive enough to detect changes in symptom severity, and are therefore questionable
indicators of treatment outcomes. Nevertheless, health utilities (and the eventual calculation
of QALYs) are the recommended outcome in cost-effectiveness analyses Gold et al. (1996).
The > standard gamble (> Figure 90-3) is the classic method to elicit health utilities. Here,
respondents choose between (1) a health state with certainty or (2) a gamble, where treatment
could lead to perfect health with some probability of death. The point of indifference is called
the health utility. In this paradigm, the health state can be a vignette describing symptoms and
. Figure 90-2
Second variant of the PTO used in Murray and Lopez (1996) and Sanderson and Andrews (2001):
‘‘trading quantity of life for healthy individuals versus improved quality of life for disabled
individuals’’ (pg. 670). This is another variant of the PTO, a method designed to determine
preference and ‘‘worth’’ for a particular disease state. Respondents indicate their preference by
valuing quantity and quality of life in a hypothetical sample of healthy and disabled individuals.
A low disability weight (close to 0) indicates that the disease is considered less disabling, and
conversely, a high disability weight (close to 1) indicates that the disease is considered more
disabling
disability associated with a specific disease (e.g., depression; Revicki and Wood, 1998).
Respondents are then administered the standard gamble multiple times, where the researchers
vary the value of p, until the respondent is indifferent between Choices 1 and 2. The procedure
is repeated for multiple health states within a specific disease (e.g., severe depression, moderate
depression, mild depression). Freed et al. (2007) successfully assessed the only published study
that reported health utilities in the SAD literature.
Both the disability weight in DALYs and the health utility in QALYs are preference-based.
Preference-based measures differ form other symptom severity or health-related quality of life
measures. Where as non preference-based measures describe functioning, preference-based
measures include a value component, which assess the relative worth of diseases or health
states. Gold et al. (2002) and Sassi (2006) provide detailed discussions of the similarities and
differences between QALYs and DALYs. In > Tables 90-2 and > 90-3, we report the disability
weights and health utilities associated with non seasonal depression.
Preference-based assessments of SAD do not yet exist in the literature. As such, preferences
for non seasonal depression can serve as a proxy for SAD, as was argued and demonstrated in
Freed et al. (2007). Here, the researchers estimated QALYs of SAD patients who received one of
. Figure 90-3
The standard gamble paradigm for calculating a health utility for a particular health state (figure
adapted from Freed et al., 2006). An example of the standard gamble, a method designed to
determine preference and ‘‘worth’’ for a particular disease state. Respondents value a disease by
indicating their willingness to accept a risky but disease-curing intervention versus living with
the disease. A low health utility (close to 0) indicates that the disease is considered very
undesirable, and conversely, a high health utility (close to 1) indicates that the disease is not
considered undesirable
three treatments: light therapy, group cognitive-behavioral therapy, a combination of light and
group cognitive-behavioral therapies. The researchers coarsely accounted for seasonality by
assuming all patients would spontaneously remit in the spring and summer months. Because
of this recurring seasonal remission, an episode of SAD would be less burdensome than an
episode of nonseasonal depression, if symptom severity during the episode was equal.
2.4 Course of Illness
As reported in Magnusson and Partonen (2005) and Tonetti et al. (2007), the average age of
SAD onset is between 20 and 30 years old, and the average patient age is 40. Schwartz et al.
(1996) reported age of onset between 35.9 and 38.6 years (SD ranges 8.0–9.9) and Sakamoto
et al. (1995) reported 31.5 years (SD = 13.3). SAD onset has been reported in childhood and
adolescence. Tonetti et al. (2007) surveyed age groups in Italy: 10–17 years old (n = 1,709) and
18–25 years (n = 1,867). As reported above in this chapter, the younger group had a lower
prevalence (9.52% females and 7.95% males) than the older sample (12.74% females and 8.93%
males; results of significance tests between the older and younger groups were not reported).
. Table 90-2
Existing disability weights for nonseasonal depression
Source Method Depression disability weights

Kruijshaar Extrapolation from a preference- Mild: 0.19 (95% CI = 0.16–0.22) Moderate
et al. (2005) weighted self-report health-related to severe: 0.51 (95% CI = 0.46–0.55)
quality of life measure Severe w/psychotic features: 0.84
(95% CI = 0.80–0.88)
Murray and Person trade-off Overall: 0.6 Treated: 0.3
Lopez (1996)
Sanderson Person trade-off Mild: 0.09 (SD = 0.07) Moderate: 0.34
and Andrews (SD = 0.21) Severe: 0.70 (SD = 0.26)
(2001) Overall: 0.42
Sanderson Rating scale Mild: 0.19, SD = (0.11) Moderate: 0.32,
and Andrews SD = (0.15) Severe: 0.61, SD = (0.17)
(2001)
Schwarzinger Visual analog scale Severe: 0.78 (SD = 0.17)
et al. (2003)
Schwarzinger Person trade-off Severe: 0.34 (SD = 0.40)
et al. (2003)
Schwarzinger Time trade-off Severe: 0.67 (SD = 0.26)
et al. (2003)
Stouthard Person trade-off Mild: 0.14 (95% CI = 0.09–0.19) Moderate:
et al. (2000) 0.36 (95% CI = 0.27–0.42) Severe: 0.76
(95% CI = 0.56–0.97) Severe w/psychotic
features: 0.83 (95% CI = 0.75–0.92) Overall
males: 0.41 Overall females: 0.37
Because no disability weights for SAD exist, we report the disability weights for nonseasonal depression. Different
measures exist for determining disability weights. There is a relationship between depression severity and the
disability weighting, such that more severe depression is considered more disabling
The 10-year differential between SAD onset and average patient age suggests that persons
with SAD either are misdiagnosed or cope with SAD symptoms for many years before seeking
treatment. We argue that the former is more likely because of the high use of health care services
by undiagnosed persons with SAD. Eagles et al. (2002) screened primary care patients for SAD
and examined health care usage over a 5-year period. They identified 145 previously diagnosed
SAD suffers, matched them to 246 non-SAD controls, and compared the two groups along a
variety of health services variables. On average (median) SAD patients had 43% more primary
care consultations, 50% more tests/investigations, 56% more prescriptions, and 200%
more specialist referrals than the non-SAD controls over the 5-year period. Moreover, SAD
patients presented with a greater diversity of both psychiatric and nonpsychiatric symptoms.
The authors suggest that SAD possibly goes undiagnosed and untreated because patients present
with other symptoms, many of which are further assessed and treated with limited success.
Magnusson and Partonen (2005) summarize the very limited long-term and aggregated
follow-up data, which suggests that 22–42% of persons with SAD still experience symptoms
. Table 90-3
Existing health utilities for nonseasonal depression
Source Method Depression health utilities

Hatziandreu Direct General practitioners and Treatment with SSRI: 0.72 Treatment
et al. (1994) psychiatrists administered the standard with TCA: 0.69 Remission, with SSRI
gamble maintenance: 0.93 Remission, off drug
therapy: 0.95
Kamlet et al. Indirect Determined utilities from a Overall: 0.45 Worst Case: 0.3
(1995) previously preference-weighted self- Best Case = 0.7
report health-related quality of life
measure administered to research
participants
Revicki et al. Direct valuation from patients using the Overall w/pharmacotherapy: 0.67–0.82
(1997) standard gamble Overall no treatment: 0.31
Revicki and Direct valuation from patients using the Mild (with pharmacotherapy): 0.64–0.73,
Wood (1998) standard gamble (SD = 0.20–0.21) Moderate: (with
pharmacotherapy): 0.55–0.63 (SD = 0.03–
0.23) Severe (no medication): 0.30
(SD = 0.28)
Sapin et al. Indirect Determined utilities from a Slight to Moderate: 0.45 (SD = 0.22)
(2004) previously preference-weighted self- Marked: 0.33 (SD = 0.24) Serious: 0.15
report health-related quality of life (SD = 0.21)
participants
Sobocki Indirect Determined utilities from a Mild: 0.60 (95% CI = 0.54–0.65) Moderate:
et al. (2007) previously preference-weighted self- 0.46 (95% CI = 0.30–0.48) Severe: 0.27
report health-related quality of life (95% CI = 0.21–0.34)
participants
Donald Various Methods Indirect from Symptoms (no diagnosis): 0.56–0.94
Sherbourne preference-weighted health-related Lifetime: 0.47–0.92 Current: 0.44–0.90
et al. (2001) quality of life measures; direct valuation Double depression: 0.38–0.88
with time-tradeoff and standard gamble
Because no health utilities for SAD exist, we report the health utilities for nonseasonal depression. Different
measures exist for determining health utilities. There is a relationship between depression severity and the health
utility, such that more severe depression is considered more disabling. SSRI selective serotonin reuptake inhibitor;
TCA tricyclic antidepressant
5–11 years later. In that same timeframe, 33–44% of persons with SAD developed a
non-seasonal pattern in subsequent episodes; approximately 6% of persons experienced
sub-syndromal SAD, and SAD resolved in only 14–18% of patients. The authors state that
the data may be artificial, and not reflect the natural course of SAD because the data were
obtained from patients who sought treatment for SAD. Course of SAD from several published
studies is presented in > Table 90-4. These studies report that SAD is often characterized by
chronic SAD and often complicated with other affective symptoms, even with treatment.
. Table 90-4
Course of SAD reported in long-term follow-up studies
Develop
complicated SAD Remain with Sub-clinical Reported Mean follow-up Data collection
Study N Remission (%) (%) pure SAD (%) SAD (%) treatment usea period (years) method
Leonhardt 26 27 38 31 NDA 54% (LT) 19% 4 Interview
et al. (1994) (Antidepressants)
Magnussson NDA 14–18 33–44 22–42 6 NDA 5–11 Literature
and Partonen reviewb
(2005)
Sakamoto et al. 41 NDA 42 22 NDA NDA 10.4 (SD = 4.8) Case record and
(1995) interview
Schwartz et al. 59 14 44 42 NDA 42% (LT) 58% 8.8 (SD = 1.3) Case record and
(1996) (Antidepressants) interview
Thompson 93 18 37 38 11 NDA 5–8 Interview
et al. (1995)
This table reports on the course of SAD in patients who participated in long-term follow-up studies. Over many years, SAD can remit, become more complicated (e.g., significant
depression symptoms or episodes occur during what were asymptomatic months), not develop into complicated SAD, or improve (but not to remission). NDA no data available
a
Not mutually exclusive
Estimating the Disease Burden of Seasonal Affective Disorder
b
Review article summarized existing literature
90
1563
2.5 Other Considerations
Clearly, the foundation of estimating the disease burden of SAD rests on an accurate and
consistent diagnosis. However, method variance exists in three arenas: diagnostic criteria,
measures used, and the inclusion of co-occurring disorders.
SAD is accurately diagnosed when all criteria are met according to DSM-IV-TR (APA,
2000). To prospectively assess SAD, researchers rely on self-report screening and/or
structured diagnostic interviews. A structured interview is preferred, but this type of
assessment is time consuming and may not be practical for larger epidemiological studies.
When assessing the efficacy of SAD treatment from a clinical trial, interviews are frequently
used, the most common of which is SIGH-SAD (Williams et al., 1992). The most widely
used screening tool is the SPAQ (Rosenthal et al., 1987). As discussed in Magnusson (2001)
and Lurie et al. (2006), the SPAQ overestimates prevalence of SAD. For example, of the 274
identified as SAD positive on the SPAQ, only 127 (46%) met DSM-IV criteria for SAD, when
interviewed (Eagles et al., 2002). SAD screening instruments are not recommended for
routine use in clinical practice because they are not sensitive enough (Lurie et al, 2006).
Co-occurring conditions (i.e., comorbidities), common in clinical settings, can compro-
mise the identification and treatment of SAD (Magnusson and Partonen, 2005). Common co-
occurring conditions are similar to those of nonseasonal depression and include bulimia
nervosa, panic disorder, posttraumatic stress disorder, attention deficit hyperactivity disorder,
generalized anxiety disorder, other depressive disorders (e.g., bipolar II and premenstrual
depressive disorder) adjustment disorder, alcohol use disorders, and Axis II disorders, as
reviewed in Lurie et al. (2006), Magnusson (2000), Magnusson and Partonen (2005), and
Westrin and Lam (2007b).
Not surprisingly, co-morbidity clouds estimates of disease burden, especially when dis-
ability weights and health utilities are calculated from disease specific vignettes that do not
include the co-occurring condition. Here, one must ask what the impact is of the co-occurring
condition on the preference weight? Is the impact additive, for example, such that the
preference weight of one disorder is added to the weight of a second disorder for a person’s
comorbidity? A solution is to create vignettes based on generic health status, value those
generic vignettes, and then assess patients with a generic measure that includes domains in
the vignettes. But researchers then must partial out what disorder is driving the decrements
in health status, an arduous task when there is a paucity of literature which assesses the quality
of life in patients with SAD (Michalak et al., 2005; Michalak et al., 2007). Also, researchers
may not have the resources to assess co-occurring conditions in large epidemiological studies
of SAD.
Comorbidity is a problem in both DALY and QALY calculations, but it has not been
thoroughly addressed in disability weighing. Melse et al. (2000) briefly summarize the issue,
and state that summing the weights of comorbid conditions is an acceptable solution because
the inclusion of comorbidity insignificantly changes disease burden calculations. Using this
summing approach, however, permits a person to have a disability weight of greater than 1.
Thus, if that person is diagnosed with multiple conditions creating a disability weight greater
than 1, then theoretically, his disability is worse than death. Vos et al. (2001) split the number
or prevalent cases of co-occurring disorders equally across their sample, thereby allowing for
the fact that people with multiple diagnoses would be likely to have more severe disease
weightings than those with only one diagnosis.
2.6 Bringing It All Together
To date, Freed et al. (2007) is the only published article that attempted to synthesize current
literature and estimate the QALYs gained from SAD treatment. Their research combined
health utilities derived from patients with nonseasonal depression (Revicki and Wood, 1998),
and participant responses from a small pilot study (Rohan et al., 2004b). Freed et al. (2007) did
not include any estimates of disease prevalence, and the participants were heavily screened
before they were enrolled in the study (e.g., participants with another Axis I disorder were
excluded). Their time horizon was 1-year, and they rationally but arbitrarily and simplistically
decided when SAD symptoms would remit for the spring and summer months. Although
arguably sufficient enough in scope to incorporate treatment costs and publish a paper on the
cost-effectiveness of SAD treatments, Freed et al.’s article is not sufficient enough to estimate
the disease burden of SAD.
The primary method to estimate the disease burden of SAD is to calculate the years lived with
disability (YLD). Here, > incidence of disease is multiplied by the average time spent in the
disease state, and the product is then weighted by the disability weight (Murray and Lopez,
1996). The incidence of SAD is not widely studied, but the prevalence can be also be used
instead of incidence. Melse et al. (2000) multiplied disease prevalence by disability weight. If
disability weights changed over time (e.g., disease worsens with age), then researchers can
average the weights and use that average. The choice to use prevalence- or incidence-based
estimates is often dependent on the goal of the study (Melse et al., 2000). Incidence-based
calculations are more appropriate for disease prevention programs while prevalence-based
calculations are present-centered. Other choices in disease burden estimates include what
discounting rate to use and whether to use age weightings. For example, ‘‘discounting is
applied because people value their current health more than future health, and age-weight-
ing is applied because most societies would choose to save young to middle-aged adults over
the young or very old’’ (Andrews et al., 1998, pg. 123).
Ultimately, disease burden estimates are just that, estimates. The estimates are used for
comparison purposes to better assist policy and decision makers to reduce that burden and
prioritize valuable healthcare resources to better treat and prevent illness. SAD is a chronic,
recurring, but treatable subtype of major depression affecting people worldwide. Although no
disease burden estimates exist to date, the breadth of current literature can provide researchers
with enough information to reasonably estimate the disease burden of SAD worldwide, and
across strata of age, gender, and latitude.
Summary Points
SAD is a subtype of major depression that recurs annually and may be related to available
light, negative cognitions, or the combination.
SAD prevalence estimates vary from 0.4 to 16% depending on latitude, age, gender, and
measurement method.
SAD is a chronic and disabling condition that includes symptoms such as fatigue,
weight gain, feelings of guilt, and loss of concentration with average age of onset
20–30 years.
Treatment for SAD, such as light therapy, cognitive-behavioral therapy, medication, or

some combination thereof is efficacious to varying degrees, and under optimal conditions,
can lead to remission in 83% of patients.
Despite the chronicity, worldwide prevalence, and disability, no disease burden estimates
exist for SAD to date. However, extant literature is sufficient in scope and practice to
reasonably estimate the disease burden of SAD, borrowing from the major depression
literature, when necessary.
Disease burden is the confluence of two measurements, morbidity and mortality, although
mortality is not typically included when assessing the disease burden of mental health
conditions.
Unlike symptom severity or generic quality of life, morbidity (measured by a preference-
weighted metric) accounts for the value or worth that society places on a particular disease
state, relative to other disease states and anchored by perfect health and death.
Once calculated, disease burden estimates for SAD can assist in medical decision making
and in determining priorities for interventions.
The present chapter reviews the key components necessary to estimate the disease burden
of SAD: prevalence, course of illness, morbidity, and treatment efficacy.
References
American Psychiatric Association. (2000). Diagnostic Donald Sherbourne C, Unützer J, Schoenbaum M, Duan
and Statistical Manual of Mental Disorders, 4th ed, N, Lenert LA, Sturm R, Wells KB. (2001). Med Care.
Text Revision. > American Psychiatric Association, 39(11): 1246–1259.
Washington, DC. Eagles JM, Howie FL, Cameron IM, Wileman SM,
Andrews G, Issakidis C, Sanderson K, Corry J, Lapsley H. Andrew JE, Robertson C, Naji SA. (2002). Br J
(2004). Br J Psychiatry. 184: 526–533. Psychiatry. 180: 449–454.
Andrews G, Sanderson K, Beard J. (1998). Br J Psychiatry. Freed MC, Rohan KJ, Yates BT. (2007). J Affect Disord.
173: 123–131. 100(1–3): 83–89.
Bennett KJ, Torrance GW. (1996) Measuring health Garza AG, Wyrwich KW. (2003). Acad Emerg Med. 10
state preferences and utilities: rating scale, time (4): 360–363.
trade-off, and standard gamble techniques. In: Giedd JN, Swedo SE, Lowe CH, Rosenthal NE.
Spiker B (ed.) Quality of Life and Pharacoecono- (1998). J Am Acad Child Adolesc Psychiatry. 37(2):
mics in Clinical Trials, 2nd ed. Lippincott-Raven 218–220.
Publishers, Philadelphia, PA. Goel N, Terman M, Terman JS. (2002). Depress Anxiety.
Berzon RA, Mauskoph JA, Simeon GP. (1996). Choos- 15(1): 34–41.
ing a health profile (descriptive) and/or a patient- Gold MR, Siegel JE, Russell, LB, Weinstein MC. (1996).
preference (utility) measure for a clinical trial. In: Cost-Effectiveness in Health and Medicine. Oxford
Spiker B (ed.) Quality of Life and Pharacoecono- University Press, New York.
mics in Clinical Trials, 2nd ed. Lippincott-Raven Gold MR, Stevenson D, Fryback DG. (2002). Annu Rev
Publishers, Philadelphia, PA. Public Health. 23: 115–134.
Blazer DG, Kessler RC, Swartz MS. (1998). Br J Psychia- Golden RN, Gaynes BN, Ekstrom RD, Hamer RM,
try. 172: 164–167. Jacobsen FM, Suppes T, Wisner KL, Nemeroff CB.
Booker JM, Hellekson CJ, Putilov AA, Danilenko KV. (2005). Am J Psychiatry. 162: 656–662.
(1991). Arctic Med Res. Suppl: 281–284. Haggerty J, Hons B, Cernovsky Z, Husni M. (2001). J
Carskadon MA, Acebo C. (1993). J Am Acad Child Nerv Ment Dis. 189(7): 482–484.
Adolesc Psychiatry. 32: 264–269. Hatziandreu EJ, Brown RE, Revicki DA, Turner R, Mar-
Chotai J, Smedh K, Johansson C, Nilsson LG, Adolfsson tindale J, Levine S, Siegel JE. (1994). PharmacoEcon.
R. (2004). Nord J Psychiatry. 58(6): 429–437. 5(3): 249–268
Kamlet MS, Paul N, Greenhouse J, Kupfer D, Frank E, Rohan KJ, Sigmon ST. (2000). J Affect Disorders. 59:
Wade M. (1995). Control Clin Trials. 16: 17–40. 85–96.
Kasper S, Wehr TA, Bartko JJ, Gaist PA, Rosenthal NE. Rohan KJ, Sigmon ST, Dorhofer DM. (2003). J Consult
(1989). Arch Gen Psychiatry. 46(9): 823–833. Clin Psychol. 71: 22–30.
Kiberd BA, Lawson T. (2000). Transplantation. 70(7): Rohan KJ, Sigmon ST, Dorhofer DM, Boulard NE.
1121–1127. (2004a). Cognit Ther Res. 28(1): 39–56.
Kinder LS, Bradley KA, Katon WJ, Ludman E, McDonell Rohan KJ, Tierney Lindsey K, Roecklein KA, Lacy TJ.
MB, Bryson CL. (2008). Psychosom Med. 70(1): (2004b). J Affect Disorders. 80: 273–283.
20–26. Rosen LN, Targum SD, Terman M, Bryant MJ. (1990).
Kruijshaar ME, Hoeymans N, Spijker J, Stouthard MEA, Psychiat Res. 31(2): 131–144.
Essink-Bot ML. (2005). Bull World Health Organ. Rosenthal NE, Genhart M, Sack FM, Skewerer RG, Wehr
83(6): 443–448. TA. (1987). In Hudson and Pope (eds) The Psy-
Lam RW, Levitt AJ, Levitan RD, Enns MW, Morehouse R, chobiology of Bulimia. American psychiatric Press,
Michalak EE, Tam EM. (2006). Am J Psychiatry. Washington, DC.
163(5): 805–812. Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK,
Leonhardt G, Wirz-Justice A, Kraeuchi K, Graw P, Davenport Y, Mueller PS, Newsome DA, Wehr TA.
Wunder D, Haug H-J. (1994). Compr Psychiatry. (1984). Arch Gen Psychiatry. 41:72–80.
35: 457–464. Sakamoto K, Nakadaira S, Kamo K, Kamo T,
Lucht MJ, Kasper S. (1999). Women Ment Health. 2(2): Takahashi K. (1995). Am J Psychiatry. 152(6):
83–89. 862–868.
Lurie S, Gawinski B, Pierce D, Rouseeau SJ. (2006). Am Sakamoto K, Kamo T, Nakadaira S, Tamura A,
Fam Physician. 74: 1521–1524. Takahashi K. (1993). Acta Psychiatr Scand. 87:
Magnusson A. (2000). Acta Psychiatr Scand. 101(3): 258–265.
176–184. Sanderson K, Andrews G. (2001). Aust N Z J Psychiatry.
Magnusson A, Boivin, D. (2003). Chronobiol Int. 20: 35: 668–676.
189–207. Sapin C, Fantino B, Nowicki ML, Kind P. (2004). Health
Magnusson A, Partonen T. (2005). CNS Spectr. 10: Qual Life Outcomes. 2: 20.
625–634. Sassi F. (2006). Health Policy Plan. 21(5): 402–408.
Mathers CD, Loncar D. (2006). PLoS Med. 3(11): e442. Schwartz OJ, Brown C, Wehr TA, Rosenthal NE. (1996).
Melse JM, Essink-Bot ML, Kramers PG, Hoeymans N. Am J Psychiatry. 153: 1028–1036.
(2000). Am J Public Health. 90(8): 1241–1247. Schwartz A, Schwartz RM. (1993). Depression Theories
Mersch PPA, Middendorp HM, Bouhuys AL, Beersma and Treatments: Psychological, Biological and
DGM, Van Den Hoofdakker FH. (1999). J Affective Social Perspectives. Columbia University Press,
Disord. 53: 35–48. New York.
Michalak EE, Murray J, Levitt AJ, Levitan RD, Enns MW, Schwarzinger M, Stouthard ME, Burström K, Nord E.
Morehouse R, Tam EM, Cheung A, Lam RW. (2003). Popul Health Metr. 1(1): 9.
(2007). Psychol Med. 37: 727–736. Sobocki P, Ekman M, Agren H, Krakau I, Runeson B,
Michalak EE, Tam EM, Manjunath, Levitt AJ, Levitan Mårtensson B, Jonsson B. (2007). Value Health. 10
RD, Lam RW. (2005). Can J Psychiatry. 50(5): (2): 153–160.
292–295. Sohn C-H, Lam RW. (2005). CNS Spectr. 10: 635–646.
Michaud CM, Murray C, Bloom B. (2001). JAMA. 285: Sonis WA. (1989). Rosenthal NE, Blehar MC (eds.)
535–539. Seasonal affective disorders and phototherapy. The
Murray CJL, Lopez AD. (1996). The global burden of Guilford Press, New York/London.
disease. Harvard University Press Cambridge, MA. Soriano JJ, Ciupagea C, Rohan KJ, Neculai DB, Yousufi
Rastad C, Sjoden PO, Ulfberg J. (2005). Psychiatry Clin SM, Guzman A, Postolache TT. (2007). Scientific
Neurosci. 59: 666–675. World Journal. 7: 870–879.
Rastad C, Ulfberg J, Sjödén PO. (2006). J Am Acad Child Srisurapanont M, Intaprasert S. (1999). J Affect Dis. 54:
Adolesc Psychiatry. 45(2): 231–238. 97–99.
Revicki DA, Brown RE, Keller MB, Gonzales J, Stouthard MEA, Essink-Bot M-L, Bonsel GJ. (2000). Eur
Culpepper L, Hales RE. (1997). J Clin Psychiatry. J Pub Health. 10: 24–30.
58(2): 47–58. Sullivan B, Payne TW. (2007). Am J Psychiatry. 164(11):
Revicki DA, Wood M. (1998). J Affect Disorders. 48: 1663–1667.
25–36. Swedo SE, Pleeter JD, Richter DM, Hoffman CL, Allen
Rohan KJ, Roecklein KA, Tierney Lindsey K, Johnson LG, AJ, Hamberger SD, Turner EH, Yamada EM,
Lippy RD, Lacy TJ, Barton FB. (2007). J Consult Rosenthal NE. (1995). Am J Psychiatry. 152:
Clin Psychol. 75(3): 489–500. 1016–1019.
Terman M, Terman JS, Quitkin FM, McGrath PJ, Stewart Westrin A, Lam RW. (2007a). CNS Drugs. 21(11):
JW, Rafferty B. (1989). Neuropsychopharmacology 901–909.
2: 1–22. Westrin A, Lam RW. (2007b). Ann Clin Psychiatry. 19(4):
Thompson C, Cowan A. (2001). J Affect Disorders. 64 239–246.
(1): 89–98. Williams JBW, Link MJ, Rosenthal NE, Amira L, Terman
Thompson C, Raheja SJ, King E. (1995). Br J Psychiatry. M. (1992). Structured Interview Guide for the
167: 380–384. Hamilton Depression Rating Scale—Seasonal Affec-
Thompson C, Thompson S, Smith R. (2004). J Affect tive Disorder Version (SIGH-SAD). New York State
Disord. 78: 219–226. Psychiatric Institute, New York.
Tonetti L, Barbato G, Fabbri M, Adan A, Natale V. Young MA. (1999). Biol Rhythms Bull. 1: 4–6.
(2007). J Affect Disorders. 97(1–3): 155–160. Young MA, Meaden PM, Fogg LF, Cherin EA, Eastman
Tsevat J. (2000). Med Care. 38(9) Suppl II:II160–II164. CI. (1997). J Abnorm Psychol. 106(4): 554–562.
Ustün TB, Ayuso-Mateos JL, Chatterji S, Mathers C, Young MA, Watel LG, Lahmeyer HW, Eastman CI.
Murray CJ. (2004). Br J Psychiatry. 184: 386–392. (1991). J Affect Disord. 22(4): 191–197.
Vos T, Mathers C, Herrman H, Harvey C, Gureje O, Bui
D, Watson N, Begg S. (2001). Soc Psychiatry Psy-
chiatr Epidemiol. 36(2): 53–62.
91 The Disease Burden of
Suicide: Conceptual
Challenges and
Measurement Standards
C. A. Claassen . R. M. Bossarte . S. M. Stewart . E. Guzman . P. S. F. Yip
1 Conceptual Challenges and Measurement Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1570
2 Population-Based Health Summary Measures: The Quality-Adjusted Life Year

(QALY) and the Disability-Adjusted Life Year (DALY) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1571
3 Is the Burden Associated with Suicidal States Acute Only, Episodic, Progressive,
Injury-Related, or Disease-Based? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1577
4 Methods and Measurement Standards for Calculating the Burden of Suicidal

Acts via the DALY: Step One – Years of Life Lost to Suicide . . . . . . . . . . . . . . . . . . . . . . 1580
5 Step Two – Estimating the Years of Life Lived with Disability Due to Nonfatal
Suicidal Behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1582
6 The Importance of Suicide Burden Calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1587
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1588

1570 91 The Disease Burden of Suicide: Conceptual Challenges and Measurement Standards
Abstract: Suicide was among the first public health issues to be studied at a population level,
and the field has a research tradition that now spans 110 years. Yet, despite 8 decades
of research documenting their inherent error, suicide rates remain the most widely used
population-based suicide metric today. Health expectancy and > health gap measures have
begun to replace disease rates in population health studies, but a number of conceptual and
methodological challenges still need to be addressed when adapting these new tools to suicide
research. A prerequisite to the use of any suicide measure is the need to define clearly what is
being measured. The International Classification of Disease Manuals categorize suicidal acts as
one type of injury event, suggesting that, like other injuries, these events are most often singular,
largely unpredictable events. However, suicidal behavior is often preceded by functional decline
and often follows a chronic, recurrent course – bearing more resemblance to a disease process
than to an injury event. Next, both case definitions and procedures to correct for the error
inherent in suicide data vary widely, highlighting the need to establish measurement stan-
dards. Because any burden study is only as valid as the disease concepts and measurement
approaches upon which it is based, refinement of methodology will be necessary in order to
achieve maximal benefit when applying the newer population summary statistics to suicide.
List of Abbreviations: CDC, Centers for Disease Control and Prevention; COPD, Chronic
obstructive pulmonary disease; DALY, Disability-Adjusted Life Years; DHHS, Department of
Health and Human Services; DISMOD, Disease Modeling software program; E-codes, External
Cause of Injury Codes from the ICD Manuals (see below); ED, Emergency Department; GBD,
Global Burden of Disease; GDP, Gross Domestic Product; GBD1990, Global Burden of Disease
Study for 1990; GBD2000, Global Burden of Disease Study for 2000; GBD2002, Global Burden
of Disease Study for 2002; GBD2005, Global Burden of Disease Study for 2005; HIV/AIDS,
Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome; ICD, Interna-
tional Classification of Disease Manual; ICD-9, International Classification of Disease Manual,
9th Version; ICD-10, International Classification of Disease Manual, 10th Version; ICE,
International Collaborative Effort for Injury Statistics; MMWR, Morbidity and Mortality
Weekly Review; NEISS-AIP, National Electronic Injury Surveillance System – All Injury
Program; NHAMCS, National Hospital Ambulatory Medical Care Survey; QALY, Quality-
Adjusted Life Years; US, United States; WHO, World Health Organization; YLD, Years of Life
Lived with Disability; YLL, Years of Life Lost
1 Conceptual Challenges and Measurement Standards

" ‘‘It is both extraordinary and unfortunate that, at the end of the twentieth century, the international
public health community does not routinely quantify or project the health problems of populations.
There are no standardized compilations of information on the extent of morbidity, disability and
death in different populations of the world. Information at a global or regional level on behaviors
and exposures that are important risk factors for death and disability is also extremely limited.
Although the demographic community routinely publishes projections of fertility and population,
future trends have been projected for only a very limited number of causes of death. . ..’’
–Murray & Lopez, 1996
The development of population-level health descriptors has not kept pace with the need for
such measures, and suicide measures are no exception. Suicide was among the first health
problems to be studied at a population level (Durkheim, 1951; 1897), and the field has a
The Disease Burden of Suicide: Conceptual Challenges and Measurement Standards 91 1571
research tradition that now spans 110 years. A century ago, the first population-based studies
compared national suicide rates, but – despite eight decades of research documenting their
inherent error (Zilborg, 1935; Mohler and Earls, 2001) – suicide rates remain the most widely
used population-based suicide measure in use today. National suicide rates are not designed to
monitor shifts in suicidal behavior found in particular subgroups (e.g., adolescents, females, or
ethnic minorities – Gunnell and Middleton, 2003; Yip et al., 2005), nor do they incorporate
information on nonfatal suicidal behavior – despite the significant public health burden repre-
sented by this class of self harming behaviors (Corso et al., 2007). A more meaningful indicator
might include a description of additional types of suicide phenomena, rather than just report the
number of suicides occurring annually within a nation.
In lieu of disease rates, two important population > health summary measures are being
used with increasing frequency in health impact studies. Health expectancy measurement tools
monitor progress toward improved health status, while health gap measurement tools estimate
and compare the burdens imposed by > disease states and injury conditions. (Murray and
Lopez, 1996) In light of the World Health Organization’s (WHO) 1948 definition of health as a
‘‘state of complete physical, mental and social well-being, and not merely the absence of
disease or infirmity,’’ the emergence of these new measures signals movement toward adoption
of a global public health agenda that addresses not only the length, but also the quality of life.
The application of these new approaches to population-level suicide phenomena poses both
conceptual dilemmas and methodological challenges. A prerequisite to modeling suicide sum-
mary indicators is the need to define clearly what is to be measured – are suicidal acts really best
understood as injury events or as part of a > suicidal process? Next, measurement approaches
for suicide-related phenomena across studies varies widely, both in terms of case definitions
and of the methods used to estimate and correct for error. Given the substantial issues associated
with the measurement of suicide burden, this chapter first describes currently published
applications of health expectancy and gap summary measures to suicide phenomena. The
implications of defining suicide as an injury event rather than a disease process are examined,
and the technical standards for calculation of the primary suicide burden metric, called the
Disability Adjusted Life Year (DALY), are reviewed. A schematic placing various suicide
indicators within an established public health framework is presented within this discussion.
2 Population-Based Health Summary Measures: The

Quality-Adjusted Life Year (QALY) and the
Disability-Adjusted Life Year (DALY)
The newer classes of population-based health summary measures were introduced when, in
1968, a health expectancy measure was used to evaluate treatments for renal failure. Health gap
measures were developed later, and represent a further development of the health expectancy
measure methodology (Salomon and Lopez, 2002). The conceptual relationship between
health expectancy and health gap measures is illustrated in > Figure 91-1. Both classes of
indicators address the decline in health associated with a disease state or injury condition (A).
However, health expectancy measures demonstrate the potential gain toward > ‘‘full’’ health
status that would occur with the development of new treatment and/or prevention methods
(B). In contrast, health gap measures illustrate the difference between ‘‘full’’ health status (C)
and > actual health status (A) as it stands after adjustment for lives lost and disability
sustained as a result of a disease process or injury condition.
. Figure 91-1
Relationship between health expectancy and health gap summary measures Formulas: Health
Expectancy = A + ƒ(B) Health Gap = C + g(B) Notes: Health expectancies measure the potential
gain in health ƒ(B) resulting from the reduction of disability for a given condition over present
status (A), while health gap measures illustrate the difference between ‘‘full’’ health status (C)
and actual health status after adjustment for lives lost and disability sustained g(B) due to a
given condition. The health expectancy increase over baseline identified above as f(B) is often
expressed in terms of cost per QALY gained from a new treatment or prevention strategy. For
any given health condition, the health gap ‘‘burden,’’ expressed as actual versus ‘‘full’’
population health status [identified above as g(B)] is often measured in terms of DALY rate per
100,000 people. (Adapted with permission from: Mathers CD, Lopez AD, Murray CLJ, 2006. ‘‘The
burden of disease and mortality by condition: Data, methods and results for 2001’’)
Health expectancy measures are used in cost utilization analyses to evaluate specific
treatments or interventions, while health gap measures are used to compare the relative
‘‘burden’’ placed on a population by the presence of one or more disease or injury conditions
(Garcia-Altes, 2006). Health expectancy measure increase over baseline is often expressed
in terms of cost per quality-adjusted life year (QALY) gained from a new treatment or
prevention strategy. For any given health condition, the health gap ‘‘burden’’ metric, expressed
as actual versus ‘‘full’’ population health status, is often measured in terms of the rate of
disability-adjusted life year per 100,000 people. A further comparison of the health expectancy
measure known as the ‘‘Quality Adjusted Life Year’’ (QALY), and the DALY is found in
> Table 91-1.
To date, the QALY has been used in a variety of cost utility studies, while the DALY has
been used primarily in global burden of disease and injury (GBD) studies. Both the QALY
and the DALY metrics are constructed on a ratio scale where the health decrement associated
with ill health is on a continuum, between ‘‘perfect’’ or ‘‘full’’ health and death (Mathers et al.,
2006). Using suicide as an example, calculation of both measures begins by establishing the
. Table 91-1
Summary measures of population health that integrate information
Name of
Measure Definitions and Data Source Type of Weighting Primary Applications
Quality- Definitions: A QALY is a year of life adjusted for its A year in perfect health is considered The primary use of QALYs is within the
Adjusted “quality” or its value. equal to 1.0 QALY. framework of cost-effectiveness analysis, to
Life-Year It is a composite health expectancy indicator The value of a year in ill health is assess the improvement in quality-adjusted life
(QALY) of the relative improvement in quality and quantity discounted. For example, a year expectancy obtained through a specific health
of life associated with a specific treatment of a bedridden might have a value equal to intervention relative to a situation in which
particular disease or injury condition. It addresses 0.5 QALY. either no intervention or a standard alternative
condition-specific mortality; mortality, prevalence, intervention is provided.
incidence, duration of disability; degree to which QALYs can therefore provide an indication of
health status is affected the benefits gained from a variety of medical
procedures in terms of quality and life and
survival for the patient.
Disability- A DALY is a year of life adjusted for the average level of A year in perfect health is considered DALYS provide a straightforward partitioning
Adjusted disability associated with a particular condition. It is a equal to 0 DALYs. of total burden by an exhaustive set of disease
Life Years composite health gap measure of the relative burden The value of a year in a disabled and injury categories, and are additive across
(DALY) placed on a population by the presence of a particular condition is discounted according to disease categories
disease or injury condition for the year under study. It weights established via a multi-method Burden methodologies also lend themselves to
addresses condition-specific mortality; mortality, surveillance system. comparison of the public health impact of a
prevalence, incidence, duration of disability; degree to large number of conditions, and to cross-
which health status is affected The relative value of less- cultural comparisons, attributable risk, cost
than-perfect nonfatal health states was originally effectiveness, and forecasting analyses.
The Disease Burden of Suicide: Conceptual Challenges and Measurement Standards
established through expert panel or population-based

survey, using methods similar to those described
above. The “burden” of nonfatal health states are
generally expressed on a numerical scale ranging from
0 to 1, in which 0 represents no burden/ “full” health,
and 1 the burden of death due to the condition under
study.
91
1573
levels of mortality and disability (morbidity) associated with suicidal acts within a given
population. Both health expectancy and gap measures establish level of disability as a
function of: (1) the total estimated time the population spent in this state during the
index year, and (2) the level of discomfort created by living in this disabled state relative
to other disabling states (e.g., motor vehicle accident, cancer, blindness, etc.) For QALYs
the degree of ‘‘gain’’ in health at the population level associated with a specific treatment
or prevention strategy is then estimated and the ‘‘cost utility’’ of the proposed treatment
relative to baseline is established. For the DALY, mortality and disability totals
are added together to get a population-based measure of burden associated with suicidal
behavior.
Although neither the DALY nor the QALY has been used extensively in suicide research
to date, a few such analyses have been conducted. For instance, QALYs were used to
retrospectively establish the cost effectiveness of an area-based suicide prevention
program (primarily a form of > ‘‘gatekeeper’’ training – see definitions) conducted within
the Western Athabaskan Native American Tribe living in New Mexico (in Platt et al., 2006).
The study estimated that the value of suicides prevented at $1.7 million, at a cost per Quality
Adjusted Life Year gained of $419. The cost effectiveness of a brief cognitive behavioral
intervention for reducing repeated suicide attempts among urban patients with high levels
of comorbid depression and substance use was also evaluated with the QALY (Rothbard and
Koizumi, 2006). The results of that analysis showed an incremental cost effectiveness of
$14,126 per QALY at 18 month follow-up, which was regarded as ‘‘within the acceptable
range’’ of economic costs, compared to other mental health interventions. In contrast to the
QALY, the DALY has primarily been used to assess the national, regional and global burden of
suicide. > Table 91-2 ranks countries with the highest suicide DALYS as calculated for the 2002
Global Burden of Disease and Injury (GBD) Update.
Case Definitions and Data Sources: No globally accepted, operationalized definition of
the term ‘‘suicide’’ or ‘‘suicide attempt’’ exists, and the case definition adopted by a given
study is often derived from whatever data source is available to address the question
under study. In public health studies, suicide data are most commonly taken from vital
registration (mortality) and medical (morbidity) records. By 2003, the diagnostic framework
used with both of these data types in 116 nations was some version of the World
Health Organization’s (WHO) International Classification of Disease and Injury Manual
(ICD – WHO, 1992). Under the ninth revision coding system, suicidal behaviors are among
those acts classified as ‘‘intentional self injuries,’’ a classification that falls within the
external cause of injury (E-codes) coding matrix in ICD-9. To facilitate standardized ICD-
based analyses, the International Collaborative Effort for Injury (ICE) External Cause
Committee has published a recommended list of ICD diagnostic codes that should be included
in ICD-based suicide case definitions (Fingerhut, 2004). A comprehensive list of
these ICE-recommended suicide codes can be found in > Table 91-3 by mechanism and
ICD version.
It is important to note that ICD-based case definitions of suicidal acts do not actually
distinguish between self injurious behaviors in which the intent was to kill oneself via the
act, and those in which this ‘‘suicidal intent’’ was absent. Therefore, the nonfatal condition
identified by these codes more closely resembles the European category of ‘‘deliberate
self harm’’ (also called ‘‘self-harm’’ or ‘‘self-injury’’ in this chapter) than a condition that
could be exclusively labeled as ‘‘suicidal.’’ Despite this important caveat, these are the codes
. Table 91-2
Highest thirty-five country-level suicide DALYs in 2002
Level of evidence
Suicides per DALY rate Age-standardized Total
100,000 per 100,000 DALY per 100,000 mortality♦ YLD♦
Russian Federation 41.0 900 855 Level I or II Level III
Kazakhstan 37.1 892 869 Level I or II Level III
Lithuania 45.5 885 854 Level I or II Level III
Belarus 38.2 787 746 Level I or II Level III
Sri Lanka 31.9 734 694 Level III
Ukraine 35.8 694 658 Level I or II Level III
Lao People’s 21.2 645 692 Level IV
Democratic
Republic
Latvia 30.5 572 544 Level I or II Level III
Estonia 28.7 571 560 Level I or II Level III
Guyana 20.4 559 524 Level III
Slovenia 29.5 527 476 Level I or II Level III
India 17.4 512 504 Level III
Suriname 18.1 508 462 Level III
Finland 23.4 487 488 Level I or II Level III
Hungary 28.2 485 446 Level I or II Level III
China 20.9 429 403 Level III
Japan 24.6 427 399 Level I or II Level III
Jordan 17.2 413 464 Level III
Belgium 20.9 409 407 Level I or II Level III
Bhutan 13.5 405 433 Level IV
Bangladesh 12.2 387 384 Level IV
Kyrgyzstan 14.8 383 388 Level I or II Level III
Nicaragua 11.9 379 372 Level I or II Level III
Republic of 18.3 378 358 Level I or II Level III
Moldova
Trinidad and 14.8 357 334 Level I or II Level III
Tobago
Turkmenistan 12.5 357 360 Level I or II Level III
Poland 17.3 356 333 Level I or II Level III
Republic of Korea 18.2 351 315 Level I or II Level III
Nepal 10.3 349 355 Level IV
Papua New Guinea 10.0 347 350 Level IV
Myanmar 10.6 344 326 Level IV
Croatia 19.9 339 317 Level I or II Level III
Mongolia 12.3 323 330 Level I or II Level III
Level of evidence
Suicides per DALY rate Age-standardized Total
100,000 per 100,000 DALY per 100,000 mortality♦ YLD♦
Austria 18.2 323 303 Level I or II Level III
Mauritius 11.9 317 300 Level I or II Level III
Level of Evidence Code: (1) (Mortality Levels I & II) and (YLD Level III) = Death registration data, complete, or
incomplete, containing useable information on causes of death is available and used to adjust regional YLD
distributions for causes with significant case fatality. Partial country-specific information on incidence or preva-
lence of nonfatal causes available. (2) (Mortality Level III; Missing YLD) = Other forms of information on child and
adult mortality or causes of death (e.g., verbal autopsy) available. Country-specific information on mortality for
specific causes available. Partial country-specific information on incidence or prevalence of nonfatal causes
available. (3) (Mortality Level IV; Missing YLD) = Country information on level of adult mortality not available
and it was predicted from child mortality level OR cause of death information for most causes not available, and
cause pattern predicted using cause-of-death models. Partial country-specific information on incidence or preva-
lence of nonfatal causes available
Legend: DALYs – Disabilty Adjusted Life Years
(World Health Organization, 2002 Global Burden of Disease and Injury Study. Available at: www.who.int/entity/
healthinfo/statistics/bodgbddeathdalyestimates/, Reprinted with permission)
used in most studies of suicide epidemiology. One of the only studies to date to assess the
prevalence of suicidal acts among injuries diagnosed with these codes has estimated that
between 60% and 70% of all medically-diagnosed nonfatal intentional self-harm events are
suicide attempts (Ikeda and Mahendra, 2002).
Definitions of Inputs for Suicide Summary Measures: A number of epidemiological
parameters are required to calculate both QALY and DALY suicide summary measures.
> Figure 91-2 depicts a version of the natural history of suicidal states showing the
relationships between ten public health parameters that are important to the calculation of
suicide health summary measures. While all ten parameters are important to the complete
characterization of health-threatening suicidal experiences within a given population, for
calculation of DALYs the most important parameters are:
1. Population size by age group,
2. Incidence of intentional self-harm and age of onset,
3. Lifetime attempt rate by age group,
4. Case fatality ratios (counts of suicides within the population), and
5. Case complication ratios (disability incidence, duration, and distribution by severity class
and age group (Michaud and McKenna, 2006),
6. Suicide rate.
From these inputs, other GBD variables can also be derived. GBD researchers have developed
a software program, called the DISMOD software program, which uses the expected
causal relationships inherent in disease incidence – prevalence – mortality relationships
to create a mathematical model that can impute missing values and correct error in event-
based datasets (Kruijshaar and Barendregt, 2002). The program establishes consistent
matches between estimates of prevalence, duration, remission, and mortality for any given
health condition, and it is these estimates that are used to calculate GBD for specific
conditions.
. Table 91-3
ICE External Cause of Injury Case Definitions for Suicide and Injuries of Undetermined Intent:
ICD-9 and ICD-10 Equivalent Codes
Mechanism/Cause ICD-9 ICD-103

Self-
Self-inflicted Undetermined inflicted Undetermined
Cut/pierce E956 E986 X78 Y28
Drowning/submersion E954 E984 X71 Y21
Fall E957.0-.9 E987.0-.9 X80 Y30
Fire/burn E958.1,.2,.7 E988.1,.2,.7 X76–X77 Y26–Y27
Fire/flame E958.1 E988.1 X76 Y26
Hot object/substance E958.2,.7 E988.2,.7 X77 Y27
Firearm E955.0–.4 E985.0–.4 X72–X74 Y22–Y24
All Transporta E958.5–6 E988.5–6 X82 Y32
Poisoning E950.0–E952.9 E980.0–E982.9 X60–X69 Y10–Y19
Suffocation E953.0–.9 E983.0–.9 X70 Y20
Other specified and E955.5,.6,.7,.9 E985.5,.6,.7 X75, X81, Y25, Y31
classifiableb,c,d E958.0,.4 E988.0,.4 *
U03.0
Other specified, not elsewhere E958.8, E959 E988.8, E989 X83, Y87.0 Y33, Y87.2
classifiable
Unspecified E958.9 E988.9 X84, *U03.9 Y34, Y89.9
All injury E950–E959 E980–E989 X60–X84, Y10–Y34, Y87.2,
Y87.0 *U03 Y89.9
a
Three 4th-digit codes (.4[occupant of streetcar], .5 [rider of animal], .8[other specified person]) are not presented
separately because of small numbers.
b
Codes in bold are for morbidity coding only, and do not apply to mortality
c
Drowning is the one external cause that has been redefined in this matrix. Codes for water transportation-related
drowning, V90 and V92, are included in the transportation codes rather than with the drowning codes. In the ICD-9
version of the matrix, the comparable codes, E830 and E832, were included with drowning. This change was made
to be consistent with other mechanisms involved with water transport-related injuries.
d
This table contains the new ICD-10 codes for terrorism. The codes are preceded with***
Legend: ICE – International Collaborative Effort for Injury Statistics
ICD – 9 International Classification of Diseases and Injuries, 9th Edition
ICD – 10 International Classification of Diseases and Injuries, 10th Edition
Source: (Fingerhut, 2004) Reprinted with permission
3 Is the Burden Associated with Suicidal States Acute Only,

Episodic, Progressive, Injury-Related, or Disease-Based?
Assumptions about the nature and course of the suicidal state underlies any method used to
analyze and calculate its associated burden. Because the datasets used to calculate suicide burden
are most often mortality or medical data coded according to some version of the ICD diagnostic
system (Begg and Tomijima, 2000), the suicidal state described in burden methodologies is
defined by assumptions associated with the ICD diagnostic system. The ICD regards suicidal acts
as one type of injury event. Even intentional injuries are traditionally understood to be
. Figure 91-2
Definitions of common suicide-related public health indicators Legend: ICD-9 International
Classification of Diseases and Injuries, 9th Edition (Adapted from the template ‘‘Diagram of
Dynamic Disease Model’’ in Mathers, Sabate, and Lopez 2001Template used and adapted with
permission)
predictable only in the ‘‘epidemiologic sense’’ (Institute of Medicine, 1999), and are regarded
as occurring at an identifiable point in time and producing some measure of post-event
disability in a portion of the affected population. Stated another way, those who sustain injury
events are assumed to be in a state approximating full health until the point at which the event
occurs. The fact that the overwhelming majority of suicides are the result of sudden traumatic
insult related to blunt force, suffocation, or firearm reinforces this view, as does the absence of
uniform, identifiable symptoms signaling the presence of an increasingly serious suicidal state
(Rudd et al., 2006). However, suicidal states are often preceded by declines in cognitive and
behavioral functioning (i.e., disability – Kaplan et al., 2007), which are not commonly
associated with injury events.
The other class of medical events included in the ICD lexicon is the disease state, and this type
of ill-health experience can include symptoms that emerge across the course of the illness
episode – some of which may be present before diagnosis. Kashner et al. (2000) suggest that,
while suicidal behaviors do not represent a disease entity, they are ‘‘the most serious natural
end point of a disabling mood or alcohol-related neuropsychiatric disease process.’’ The
fact that a high proportion of self-harming individuals are diagnosed with a psychiatric
disorder suggests that these disorders are indeed among the most salient of risk factors for
suicidal behavior. However, multiple, biologically diverse, neuropsychiatric disease processes
are known to precede suicidal acts (Harris and Barraclough, 1997), and a significant percent-
age of these acts are preceded by no identifiable disorder at all (Yang and Phillips, 2005) –
highlighting the incomplete nature of existing evidence in support of the notion that all
suicidal phenomena represent sequelae of neuropsychiatric disease processes.
On death certificates, ICD nosologists have historically ‘‘resolved’’ problems created by the
discrepant clinical presentations associated with suicidal behavior through the use of a set of coding
rules where suicidal acts can be listed as either an injury event or a symptom of a neuropsychia-
tric disease state. If, for instance, a psychiatric disorder is prominent in the time period
preceding a suicide and the death certifier believes that treatment of this disorder would
have averted the suicide, until 2003, ICD nosologists ‘‘coded’’ the ‘‘underlying cause’’ of the act
as that psychiatric disorder. This is one reason that depression or other psychiatric disorders
were sometimes found among cause-of-death listings for suicide. However, where no pre-
injury psychiatric disorder could be identified, the suicidal act itself became the underlying
cause of death. Classification of suicidal events as injuries has profound implications for the
calculation of suicide burden. When coded in this manner, measurement of the burden
associated with nonfatal self injury involves only disability occurring from the point of the
injury forward in time. Pre-injury burden is assumed to be either absent or not causative.
While the ICD coding conventions partially resolve problems related to diverse suicidal
ICD coding, they do not produce a coherent understanding of the suicidal state. Once a
serious suicidal state emerges, its course is often more like a chronic disease process with
intermittent ‘‘illness episodes’’ than like an injury ‘‘event.’’ For one thing, the experience of
nonfatal suicidal behavior itself generates a lifetime vulnerability to additional self-harming
episodes. The 13-country, 5-year WHO/EURO multicenter study on Suicidal Behavior found
that over 50% of self-injurers experienced more than one self harm-related injury, with nearly
20% of second episodes occurring within 12 months of the first (Schmidtke et al., 1996).
Presumably, some portion of these events can be understood as part of the ‘‘illness episode’’
signaled by the first event. A British cohort of over 11,000 intentional self-injurers followed for
over a decade likewise demonstrated a 39% lifetime recurrence rate (Hawton et al., 2006). In
short, as is the case for many diseases, the evidence suggests the existence of a suicidal process
that varies both in course and outcome, but that can carry substantial within-episode pre- and
post-disability, as well as a marked vulnerability for recurrence. If defined as a process,
however, separation of pre-injury suicide burden-related disability from common psychiatric
and medical disorder sequelae will require substantial additional study.
4 Methods and Measurement Standards for Calculating the

Burden of Suicidal Acts via the DALY: Step One – Years of
Life Lost to Suicide
As above, the DALY is a population-based, cross-sectional, health gap indicator that incor-
porates both fatal and nonfatal outcomes, taking into account the severity and duration of
common disabling sequelae (Murray and Lopez, 1997). It has been used in a series of WHO-
sponsored global burden studies, including the 1990 study calculating global disease rates
(GBD1990), the subsequent update, and comparative risk assessment studies (GBD2000,
GBD2002), the currently underway 2005 methods revision and update study (GBD2005),
and over 30 national and local burden studies.
Applied to intentional self-harm, the DALY is calculated as the sum of all life-years lost
(YLL) plus the sum of all life years lived in a disabled state (YLD) as a result of an episode of
nonfatal intentional self-harm:
DALY ¼ YLL þ YLD
Calculation of the mortality portion of the suicide DALY (years of life lost to suicide) is
fairly straightforward. The difference between life expectancy and age at suicide is summed for
each suicide, represented as:
X
YLL ¼ dx ðL xÞ
where:
L_x is the population-based life expectancy at a given age at which suicide occurs – L_x
is available from WHO in the life tables for each respective country.
dx is the number of suicides occurring in the population at each age x
Depending on the research question under study, this formula can be adjusted to account
for population growth, unstable age structure, and change in death rates over time (Gunnell
and Middleton, 2003).
‘‘Full’’ life expectancy is an upper limit age, based on convenience or appropriateness
to a given research question. GBD1990 set the standardized life expectancy at 82.5 years
for females, and the corresponding GBD male life expectancy at 80 years, to account
for ‘‘probable biological differences’’ in longevity (Murray and Lopez, 1996). However, consider-
able debate exists about how to establish this presumed ‘‘full’’ life expectancy (MMWR, 1986). In
light of recent advances in the understanding of gender-based risk factors for premature death,
GBD2005 is likely to drop gender differences in full life expectancy (Murray, 2008).
The answers to two related questions are important in the development of YLL measures:
1. (Age weighting) whether there are some age groups for which premature death is regarded
as more ‘‘tragic’’ than for others and therefore should be weighted more heavily in
calculating a population’s YLL (i.e., when the individual dies in the ‘‘prime’’ of life).
2. (Time Discounting) whether a nation’s citizens are more willing to expend public health
dollars on symptom alleviation now or on research that may cure the disease or injury
condition in 30 years (e.g., ‘‘health now’’ vs. ‘‘health later’’).
The GBD age weighting paradigm gives more weight to deaths occurring in adolescence
and early adulthood over those occurring during other life states, using methods that
approximate the values illustrated in > Figure 91-3. For GBD2005, age weighting, but not
. Figure 91-3
Approximate relative age weighting applied to GBD YLL calculations across the age span
Legend: GBD – Global Burden of Disease and Injury Studies YLL – Years of Life Lost
discounting, is likely to be applied to baseline burden calculations (Murray, 2008). Because the
frequency of suicide is highest at the ages weighted more heavily in the GBD age weighting
paradigm in most parts of the world, suicide consistently ranks as one of the most burdensome
of all conditions analyzed in GBD studies. (Methods for calculating GBD age weights are
found in Murray, 1996.)
Once these calculations are completed – or a decision is made not to apply age weighting
or discounting to suicide data – a life table can be constructed, and the relative contributions
to the YLL posed by each suicide occurring within the population for the year under study can
be calculated and summed together.
Challenges and Issues when Using Suicide Data to Calculate YLLs: Suicide data are the
end product of a reporting chain that includes new potential sources of error at each level
(Claassen Yip et al., in press). During cause of death determination, factors such as death
circumstance, occupation, and training of the death investigator, death office caseload, and
social stigma contribute to underreporting of suicides. In addition, completion of the death
certificate is frequently inaccurate, and the stringency of the follow-back procedures used by
the mortality reporting agency to correct obvious certificate errors affects data completeness
and reliability. Among the annual mortality datasets provided to the WHO for 107 countries
in the world, evidence of at least some degree of poor death reporting practice is identifiable
(Mathers and Ma Fat, 2005).
To correct for some mortality classification/death certificate coding errors, GBD researchers
have developed specific algorithms that redistribute poorly-coded or obviously miscoded deaths
to other cause of death categories (Michaud and McKenna, 2006). ‘‘Proportional reallocation’’ of
deaths to new cause codes is done within morality ‘‘envelopes,’’ created by breaking mortality data
into 5-year age groups, where the total number of deaths after reallocation is required to equal the
number prior to this process. For example, the approximately 4,500 injury deaths of undeter-
mined intent occurring in the US annually (CDC, 2008) are proportionally reclassified to other
injury-related causes within > age-based mortality envelopes, with about 50% of these deaths
reassigned as suicides (Michaud and McKenna, 2006).
Ill-Defined Cause Deaths: Under current GBD procedures, deaths classified as ‘‘Signs,
Symptoms and Ill-Defined Cause’’ are reallocated among candidate disease states but not to
injury conditions (e.g., none of these deaths gets reassigned as a suicide) (Michaud and
McKenna, 2006). However, in countries where a death certificate has to be filled out before
burial, the ill-defined cause category is often used as a ‘‘placeholder’’ cause on death certificates
until an investigation can be concluded. If cause-of-death is not routinely updated in mortality
datasets at the conclusion of investigation, this placeholder becomes the final underlying cause
used for official reporting purposes. Hawton et al., 2006 examination of all-cause mortality
among 11,000 prior suicide attempters found 3.9 times more ill-defined cause deaths than
would have been expected based on all-cause proportions (Hawton et al., 2006), and a case
review study in France found that 25% of all ill-defined cause deaths were probable suicides
(Jougla and Pequignot, 2002).
Intentional Deaths among Infants and Young Children: One additional common source of
error in suicide death classification occurs as a result of coding suicide as the cause of death
among the very young. The capacity to understand the consequences of deliberate, serious self
injury is believed by many child development experts to be beyond the cognitive abilities of
infants and young children (Grollman, 1967). Therefore, intentional self-injury is never
identified as the cause of death in children under the age of five in the death registries of
many countries (Miller et al., 2004), and a number of researchers refuse to list suicide as the
cause of death for any individual under the age of 10.
5 Step Two – Estimating the Years of Life Lived with Disability

Due to Nonfatal Suicidal Behaviors
Estimating the years lived with a disability (YLD) is regarded as the more complex step in burden
calculations, requiring systematic assessment of available evidence on incidence, prevalence,
duration and severity of disability for the condition under study (Murray and Lopez, 1997).
For some aspects of this process, adequate population-based data is not often available. Com-
plicating the process further is the range of possible future disability scenarios for each condition
studied, which varies both by severity and length of time lived in the disabled state. The basic
approach to establishing YLD levels involves calculating, for each incident, the degree of disability
times the duration of the disability as follows (Murray and Lopez, 1996):
YLD ¼ x:D:L
where:
x is the number of incident cases
D is the disability ‘‘weight’’ for the condition (0 = perfect health; 1 = dead)
L is the average duration of disability in years
This approach quantifies, for each disabling condition, the relative distance between a
state of ‘‘absolute’’ or ‘‘full’’ health and the state of reduced health due to nonfatal disability,
represented as the severity and duration of the injury episode. Ratings for each disabling
condition are developed as relatively constant, homogeneous experiences, symbolizing the
total health loss associated with the injury event in the absence of any comorbid condition
(Begg and Tomijima, 2000; Murray and Lopez, 1996).
The data needed to calculate the suicide-related YLD for each 5-year age group include:
The incidence of suicide attempts with nonfatal outcomes by mechanism and nature
of injury;
The duration of injury-related sequelae, classified by severity level; and

Age at onset of the disability for each event occurring in the population for the year under
study.
Case Definitions: Nonfatal injury events included in GBD calculations are injury episodes
severe enough to require either emergency care or hospitalization (Begg and Tomijima, 2000),
regardless of whether appropriate care is accessible. To understand the DALY’s notion of non-
fatal suicide burden, it is necessary to distinguish between condition-associated impairment,
disability, and handicap (> Figure 91-4). For instance, a serious intentional overdose in which
the agent is an analgesic such as paracetamol (acetaminophen) might result in hepatotoxicity
(impairment), followed by liver failure (disability), and unemployment due to the need for
ongoing medical care (handicap). It is the disability associated with injury conditions that is
measured in the YLD portion of the DALY, rather than either the impairment or the handicap.
The rationale for this approach is that disability is the focus of those rehabilitation services
designed to minimize functional limitations, which vary widely as a result of any given condition.
Disability Weights: YLD disability weights range from 0 (ideal health) to 1 (death), and are
intended to be a clear measure of relative health decrement (Bickenback, 2008). These weights
reflect preferences for living in one state of reduced health versus another one, and are quantified
according to the ‘‘severity’’ of disability associated with different disease states and injury condi-
tions. The original disability weightings were developed for GBD 1990 by an expert panel for
twenty-two different disability conditions, using a method called the Person-Trade-Off exercise
(Michaud et al., 2006). After these weights were developed, the same group of experts used a
modified Delphi approach to weight over 400 other health states, using these twenty-two
indicator conditions as benchmarks (Murray and Lopez, 1996). The range of disability weights
established during GBD1990 included the following: severe sore throat/anemia 0.021–0.120,
radius fracture in a stiff case/angina 0.12–0.240, below-knee amputation/deafness 0.241–0.360,
rectrovaginal fistula/mental retardation/Downs’ syndrome 0.361–0.500, unipolar depression/
blinness/paraplegia 0.5010–00.700, and active psychosis/dementia (with memory impairment,
aphasia, apraxia)/quadriplegia 0.7010–01.000 (Murray and Lopez, 1997). Subsequent work
suggested that a reasonably high level of agreement on disability weights across condition was
present across a number of countries (Schwarzinger and Stouthard, 2003).
Nature of Injury versus External Cause: An important element in the process of estab-
lishing disability weights is defining the nature of the injury. In contrast to the external cause
of injury (i.e., codes for unintentional injury, suicide, homicide, undetermined intent inju-
ries), ICD coding rules define the nature of the injury according to the actual bodily harm
sustained. Severity of injury and duration of disability are more easily established using
classifications based on nature of injury than on external cause of injury, although they
. Figure 91-4
Relationship between impairment, disability, and handicap (From Murray & Lopez, 1996)
Legend: (Murray and Lopez, 1996. Reprinted with permission)
are then attributed back to cause-specific injury classes. These codes are broken down
into 33 categories for GBD analyses (> Table 91-4). Using nature of injury codes, external
cause conditions are classified by expected severity and expected duration of disability
(both short- and long-term), whether treated or untreated. Some nature of injury categories
involve only short-term disability (e.g., open wounds, fractured arm) and others involve only
cases of permanent disability (e.g., amputations, spinal cord lesions). A few categories,
however, contain both short- and long-term disability (e.g., head injuries). Sensitivity analyses
conducted as part of GBD1990 revealed that short-term injuries had little impact on overall
YLD calculations, so essentially only long-term disability significantly adds to the YLD for a
given injury class (Begg and Tomijima, 2000; Murray and Lopez, 1996).
. Table 91-4
GBD nature of injury case definitions
Nature of injury ICD-9 CODE ICD-10 CODE

FRACTURES
Skull – short-term 800–801 S02.0/1/7/9, T90.2
Skull – long-term 800–801 S02.0/1/7/9, T90.2
Face bones 802 S02.2/6/8
Vertebral column 805 S12, S22.0/1, S32.0/7, T91.1
Rib or sternum 807 S22.2–9
Pelvis 808 S32.1–5/8, T91.2
Clavicle, scapula, or humerus 810–812 S42, S49.7
Radius or ulna 813 S52, S59.7, T10, T92.1
Hand bones 814–817 S62, S69.7, T92.2
Femur – short-term 820–821 S72, S79.7
Femur – long-term 820–821 S72, S79.7
Patella, tibia, or fibula 822–823 S82.0–4, S82.7/9, S89.7, T12
Ankle 824 S82.5–6/8
Foot bones 825–826 S92, S99.7
INJURED SPINAL CORD 806, 952 S14, S24, S34, T06.0–1, T08, T91.3
DISLOCATIONS S43, S73
Shoulder, elbow, or hip 831, 832, 835 S03.0–3, S13, S23, S33, S53, S63.0–1,
S83.1–3, S93.1–3, T03, T11.2, T13.2, T14.3,
T92.3, T93.3
Other dislocation 830, 833–834, S03.0–3, S13, S23, S33, S53, S63.0/1, S83.1–3,
836–839 S93.1–3, T03, T11.2, T13.2, T14.6, T92.5,
T93.5
SPRAINS 840–848 S0.34/5, S16, S29.0, S39.0, S46, S56, S63.5–7,
S66, S76, S83.4/7, S86, S93.4/6, S96, TY06.4,
T11.5, T13.5, T14.6, T92.5, T93.5
INTRACRANIAL INJURIES
Short-term 850–854 S06, T90.5
Long-term 850–854 S06, T90.5
The Disease Burden of Suicide: Conceptual Challenges and Measurement Standards

91 1585
Nature of injury ICD-9 CODE ICD-10 CODE

INTERNAL INJURIES 860–869 S25-S27, S35-S37, S39.6, T06.4, T91.4/5
OPEN WOUND 870, 872–884, S01, S08, S11, S15, S21, S31, S41, S45, S51,
890–894 S55, S61, S65, S71, S75, S81, S85, S91, S95,
T01, T11.1/4, T13.5, T14.6, T90.1, T92.5, T93.5
INJURY TO EYES
Short-term 871, 950 S05, T90.4
Long-term 871, 950 S05, T90.4
AMPUTATIONS
Thumb 885 S680
Finger 886 S68.1/2
Arm 887 S48, S58, S68.3–9, T05.0/2, T11.6
Toe 895 S98.1/2
Foot 896, 897.0–1 S98.0/3/4, T05.3
Leg 897.2–3 S78, S88, T05.4/6, T13.6
CRUSHING 925–929 S07, S17, S28, S38, S47, S57, S67, S77, S87,
S97, T04, T14.7, T92.6, T93.6
BURNS
Less than 20% – short-term 940–947, 948.0–1 T31.0/1
Less than 20% – Long-term 940–947, 948.0–1 T31.0/1
20 – 60% – short-term 948.2–5 T331.2/5
20 – 60% – long-term 948.2–5 T331.2/5
Greater than 60% – short-term 948.6–9 T31.6/9
Greater than 60% – long-term 948.6–9 T31.6/9
INJURED NERVES
Short-term 951, 953–957 S04, S44, S54, S64, S74, S84, S94, T06.2,
T11.3, T13.3, T14.4
Long-term 951, 953–957 S04, S44, S54, S64, S74, S84, S94, T06.2,
T11.3, T13.3, T14.4
POISONING 960–979, 980–989 T36–T65, T96–T97
Legend: GBD – Global Burden of Disease and Injury Studies
ICD-9 International Classification of Diseases and Injuries, 9th Edition
ICD-10 International Classification of Diseases and Injuries, 10th Edition
((Murray and Lopez, 1996) Reprinted with permission)
Establishing Expected Severity and Weights for Disability Classes: Data from
epidemiological reviews, expert panels and population-based surveys are used to estimate the
proportion of injuries in each class that result in long-term, severe disability, as well as the severity
of the disability. The process of establishing initial YLD estimates for self-injuries, therefore,
involves estimating the percentage of these injuries falling into each severity cell by mechanism
within age-based mortality envelopes. To date, similar disability weights have been applied to
injuries within the same nature of injury cell, regardless of external cause (Begg and Tomijima,
2000), although some preliminary evidence suggests that intentional self harm events with the
same injury severity scores result in greater disability (David et al., 2007).
Challenges and Issues when using Intentional Self-Harm Data to Calculate YLDs:
Where population-based morbidity data are available, data source profoundly affects the
rate of nonfatal suicidal behavior found. There tends to be a stable, significant difference in
the incidence of self-reported nonfatal ‘‘suicide attempt’’ found via > population-based surveil-
lance and that identified within a medical registry. In the US, Kessler et al., 1990–1992 National
Comorbidity Study and its 2001–2003 replication suggested a stable, population-based
12-month incidence of suicidal behavior of 0.6–0.9% within the US population (600–900/
100,000 – Kessler et al., 2005). In contrast, while no national medical registry of suicidal events
exists for the US, the National Electronic Injury Surveillance System – All Injury Program’s
annual, estimated incidence of nonfatal intentional self-harm events treated in US emergency
departments (EDs) between 2001 and 2003 was 122.2/100,000 US population (CDC, 2008). It
is assumed that the definition of suicidal behavior as used in the general population varies
widely by individual, and that definitions of self-reported suicidal act are equally as variable.
Presumably, the medical diagnosis of intentional self-harm involves uniform training in the
use of standardized diagnostic criteria (ICD codes) and standardized application of diagnoses
across cases and treatment providers. Medical records, therefore, are believed to provide more
reliable information on incidence of nonfatal suicidal behavior.
Emergency department-based counts of new cases of injuries – where they represent all
cases treated within a given geographic area – serve as a primary source of data for GBD
YLD injury calculations. In de-identified medical registries, the incidence of nonfatal
intentional self-harm events is often mistakenly equated with the number of ED visits.
However, at least some patients likely make more than one visit to a medical facility for
treatment of the same injury. A brief comparison of two surveillance systems currently
operating in the US provides some information about the number of self-harm episodes treated
more than once in US EDs. The National Hospital Ambulatory Medical Care Survey
(NCHAMCS) estimates the number of visits to US emergency departments, counting each
visit, regardless of whether the injury being treated has also been treated during a prior visit
(McCaig, 2004). In contrast, the National Electronic Injury Surveillance System – All Injury
Program estimates the number of first visits to US emergency departments for treatment of a
new injury condition (CDC, 2008). Assuming that both systems provide reasonably accurate
estimates of US emergency department visit frequency, the 2004–2005 average annual number
of intentional self-injury events occurring within the country as estimated by the NHAMCS
was 161.83 visits per 100,000 person years (McCaig and Nawar, 2006; Nawar and Niska, 2007).
The corresponding 2004–2005 NEISS-AIP first-visit estimate was 135.28 per 100,000 person
years (CDC, 2008), suggesting that approximately 16.4% of all ED intentional self harm visits
for those 2 years were made for follow-up care of a previously-treated nonfatal intentional
self-harm event.
Mathers et al. (2006) reports that when the 2000–2002 GBD studies attempted to locate
datasets from which to estimate YLD for 107 disease and injury conditions, nearly 6,600 were
found to inform estimates of disability due to disease states, while only 18 adequate datasets
world-wide were located to inform YLD estimates of long-term injury sequelae. Among these
18 datasets, one quarter involved populations in sub-Saharan Africa, and one-fifth were from
high-income countries, requiring disability estimates to be imputed for most of the world.
Because of the paucity of data on nonfatal injury, the incidence of disabling events is frequently
imputed in GBD studies from age-specific case fatality ratios, under the assumption that
incident-to-death ratios for many injury events are relatively constant across time and geogra-
phy after taking into account available emergency medical care (Begg and Tomijima, 2000;
Murray and Lopez, 1996). Standardized GBD estimating models use mortality rates and
per capita gross domestic product (GDP) as rough proxies for access to health care in
these models.
This practice is somewhat less relevant to suicide analyses because the majority of
nonfatal suicidal acts are self-poisonings which do not result in inpatient treatment or long-
term physical disability (Fleishmann and Bertolote, 2005). Therefore in countries with rea-
sonable access to emergency care, suicide ‘‘burden,’’ becomes largely a function of the years of
life lost to suicide, while the impact of nonfatal suicidal acts on health status, contributes little
to overall suicide burden (Begg and Tomijima, 2000). However, without sap access, nonfatal
burden contributes more substantially to overall burden.
Applications to Other Conditions: The misclassification of deaths is a common problem
among a handful of injury death categories besides suicide (e.g., certain falls, single-vehicle
accidents, certain poisonings). For these injury categories, many of the same burden-relates
issues arise as for suicides.
6 The Importance of Suicide Burden Calculations
As the time this chapter was written, suicide metrics were being selected for a number of high-
profile local, national, and global public health projects. For instance, suicide measurement
tools were being developed to accompany the suicide prevention goals in national public
health agendas for the decade beginning in 2010 (DHHS, 2008). In addition, mentioned
earlier, GBD2005 – which involves over 800 public health researchers worldwide – is currently
developing comparative estimates of the health burdens associated with 175 different disease
states and injury conditions across 21 regions of the world.
Knowledge of the suicidal process is far from complete, and appropriate data, error
correction methods, and measurement strategies are limited. While this deficit should not
stop attempt to the measure population-based leveis of suicided behavior, it is imperative that
the best, most current knowledge available be employed during each successive iteration of
these measurement processes. In the case of suicide burden, this will require ongoing devel-
opmental the metrics used to measure it.
> Table 91-5 shows GBD2002 projected rankings for the disease states and injury condi-
tions with the greatest global burdens. These DALY-based projections suggest that, the global
burden of suicide will rise from 17th to 14th by the year 2030 (Mathers and Loncar, 2006).
However, the GBD2005 decision to drop gender differences in full life expectancy (Murray,
2008) means that the number of YLLs lost to suicide will increase comparatively for
approximately three out of every four suicides worldwide, thereby increasing the overall
estimated suicide burden substantially. Population analysts, advocacy groups, and policy
makers at all levels will need to acquire the knowledge base necessary to interpret such changes
in burden methodologies, and understand the strengths and limitations of the summary
health measures used to inform decision-making about investment of public health resources.
Such literacy is likely to become increasingly important as methods are refined and measures
change over the years to come.
. Table 91-5
2002 ranked burden as measured in DALYs of selected conditions, and projected change for the
year 2030
2030 Projected Change in

Category Condition 2002 Rank Rank Rank
Within top 15 Perinatal conditions 1 5 4
Lower respiratory infections 2 8 6
HIV/AIDS 3 1 +2
Unipolar depressive 4 2 +2
disorders
Diarrheal diseases 5 12 7
Ischemic heart disease 6 3 +3
Cerebrovascular disease 7 6 +1
Road traffic accidents 8 4 +4
Malaria 9 15 6
Tuberculosis 10 25 15
COPD 11 7 +4
Congenital anomalies 12 20 8
Hearing loss, adult onset 13 9 +4
Cataracts 14 10 +4
Violence 15 13 +2
Outside top 15 Self-inflicted injuries 17 14 +3
Diabetes 20 11 +9
Legend: DALYs – Disability Adjusted Life Years
HIV/AIDS – Human Immunodeficiency Virus/ Acquired Immune Deficiency Syndrome
COPD – Chronic Obstructive Pulmonary Disease
(Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PloS Med 3
(11): 3442. doi:10.1271/journal.ped.0030442 Reprinted with permission)
Summary Points
Despite 8 decades of research documenting their inherent error, suicide rates remain the
most widely used population-based suicide metric today.
Suicidal behavior is classified as an injury event for the purposes of burden analysis;
however, it is often preceded by a decline in functioning and often follows a chronic,
recurrent course – bearing more resemblance to a disease process than to an injury event.
No globally accepted, operationalized definition of the term ‘‘suicide’’ or ‘‘suicide attempt’’
exists, and the case definition adopted by a given study is often derived from whatever data
source is available to address the question under study.
Although no death classified as ‘‘Signs, Symptoms and Ill-Defined Cause’’ is reassigned as a
suicide under current burden methods, recent evidence suggests that a significant number
of these deaths may in fact be suicides.
In countries with reasonable access to emergency care, the majority of nonfatal suicidal
acts do not result in long-term physical disability, so suicide ‘‘burden’’ is largely a function
of mortality-related years of life lost.
The recent GBD2005 decision to drop gender differences in full life expectancy calculations
means that the level associated with number of years of life lost to suicide will likely rise
beyond the currently projected suicide ranking of 14th most burdensome condition by the
year 2020.
It is imperative that the best, most current knowledge available be employed during each
successive iteration of the burden measurement process. In the case of suicide, this will
require ongoing conceptual and method logizal retirements.
References
Begg S, Tomijima N. (1986). MMWR. 25: 1–11. Garcia-Altes A. (2006). CAHTA Newsletter. Barcelona, Spain,
Begg S, Tomijima N. (2000). In: Global Program on Catalan Agency for Health Technology Assessment 38.
Evidence for Health Policy. Global Burden of Dis- Grollman E. (1967). Explaining Death to Children.
ease 2000. World Health Organization, Geneva. Beacon Press, Boston.
Begg S, Tomijima N. (2008). In: Public Health Agency of Gunnell D, Middleton N. (2003). Lancet. 362: 961–962.
Canada Initiatives [online] Accessed 2008 Jan 15. Harris EC, Barraclough B. (1997). Brit J Psychol. 170:
Available at: http://www.phac-aspc.gc.ca/ph-sp/phdd/ 205–228.
initiative/index.html Hawton K, Harriss L, Zahl D. (2006). Psychol Med. 36:
Bickenback J. (2008). In: Ethical Issues in the Measure- 397–405.
ment of Health, Boston, MA, Harvard University Ikeda R, Mahendra R. (2002). MMWR, 51: 436–438.
[online] Accessed 2008 May 1. Available at: peh. Institute of Medicine. (1999). Reducing the Burden of
harvard.edu/events/2008/global_burden_disease/ Injury: Advancing Prevention and Treatment.
CDC. (2008). In: Web-based Injury Statistics Query and National Academy Press, Washington, DC.
Reporting System (WISQARS). [Online Database]. Jougla EF, Pequignot E. (2002). Rev Epidemiol Sante. 50:
National Center for Injury Prevention and Control. 49–62.
Accessed 2008 1 Jan. Available at: www.cdc.gov/ Kaplan MS, McFarland BH, Huguet N, Newsom, JT.
ncipc/wisqars (2007). Am J Orthopsychiat. 77: 56–60.
Claassen CA, Yip SFP, Bossarte RM, Corcoran P in press, Kashner MT, Shoaf T, Rush AJ. (2000). Econ of Neurosci.
Suicide and L.h-Threatening Behavior 2: 44–48.
Corso PS, Mercy JA, Simon TR, Finkelstein EA, Kessler RC, Berglund P, Borges G, Nock M, Wang P.
Miller TR. (2007). Am J Prev Med. 32: 474–482. (2005). JAMA, 293: 2487–2495.
David JS, Gelas-Dore B, Inaba K, Levrat A, Riou B, Kruijshaar M, Barendregt J. (2002). Bull World Health
Gueugniaud PY, Schott AM. (2007). J Trauma. 62: Organ. 80: 622–628.
1495–1500. Mathers CD, Loncar D. (2006). Plos Med. 3: 3442.
DHHS. (2008). In: Office of Disease Prevention and Mathers C, Lopez A, Murray CJL. (2006). In: Lopez A,
Health Promotion. Department of Health and Mathers C, Ezzati M, Murray C, and Jamison D
Human Services [online] Accessed 2008 Feb 15. (ed.) Global Burden of Disease and Risk Factors,
Available at: www.healthypeople.gov Oxford University Press, New York.
Durkheim E. (1951 [1897]). Suicide. Free Press. Mathers C, Ma Fat D. (2005). Bull World Health Organ.
New York, 83: 171–177.
Fingerhut L. (2004). WHO Family of International McCaig L. (2004). 2004 User’s Data Conference [online]
Classifications Network Meeting. Reykajavik, Accessed 2004 September 27, 2004. Available at: http://
Iceland, pp. 1–5. www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm.
Fleischmann A, Bertolote JM, De Leo D, Botega N, McCaig L, Nawar E. (2006). National Hospital Ambula-
Phillips M, Sisask M, Vijayakumar L, Malakouti K, tory Medical Care Survey: 2004 Emergency Depart-
Schlebusch L, De Silva D, Nguyen VT, Wasserman D. ment Summary. Adv Data, No. 372 Hyattsville, MD,
(2005). Psychol Med. 35: 1467–1474. National Center for Health Statistics.
Michaud CM, McKenna MT. (2006). Popul Health Metr. Ministers, Edinburgh. [online] Accessed 2008 Jan 15.
4: 1–49. Available at: http://www.scotland.gov.uk/Publica-
Miller M, Azrael D, Hemenway, D. (2004). Ann Emerg tions/2006/09/06094756/1.
Med. 43: 723–730. Rothbard A, Koizumi N. (2006). Public Health and
Mohler B, Earls F. (2001). Am J Public Health. 91: Human Rights. American Public Health Associa-
150–153. tion, Boston, MA.
Murray CJL. (2008). In: Harvard University Program in Rudd MD, Berman AL, Joiner TE Jr, Nock MK,
Ethics and Health [online] Accessed 2008 May 10. Silverman MM, Mandrusiak M, VanOrden K,
Available at: http://peh.harvard.edu/events/2008/ Witte T. (2006). Suicide Life-Threat. 36: 255–262.
global_burden_disease/day2.html. Salomon JD, Lopez AD. (2002). Summary Measures of
Murray CJL, Lopez AD. (1996). Science. 274: 740–743. Population Health: Concepts, Ethics, Measurement
Murray CJL, Lopez AD. (1996). The Global Burden of and Application. World Health Organization,
Disease: A Comprehensive Assessment of Mortality Geneva.
and Disability from Diseases, Injuries and Risk Schmidtke A, Bille-Brahe U, DeLeo D, Kerkhof A. (1996).
Factors in 1990 and Projected to 2020. Harvard Acta Psychiat Scand. 93: 327–338.
University Press, Cambridge, MA. Schwarzinger M, Stouthard M. (2003). Popul Health
Murray CJL, Lopez AD. (1997). Lancet, 349: 1347–52. Metr. 1: 15.
Murray CJL, Lopez AD. (1997). Bull World Health WHO. (1948). World Health Organization Constitution.
Organ. 75: 377–381. World Health Organization, Geneva.
Murray CJL, Lopez AD. (2000). Health Econ. 9: 69–82. WHO. (1992). International Statistical Classification of
Nawar E, Niska R. (2007). Adv Data, No. 386. Hyattsville, Diseases and Related Health Problems, 10th rev.
MD, National Center for Health Statistics. Geneva, Switzerland, World Health Organization.
Platt S, McLean J, McCollam A, Blamey A, Mackenzie M, Yang G, Phillips MR. (2005). Biomed Environ Sci. 18:
McDavid D, Maxwell M, Halliday E, Woodhous A. 379–89.
(2006). Evaluation of the First Phase of Choose Yip PSF, Liu KY, Law CK, Law YW. (2005). Crisis. 26:
Life: The National Strategy and Action Plan to 156–159.
Prevent Suicide in Scotland. Department of Scottish Zilborg G. (1935). Am J Psychol. 92: 34–52.
92 The Disease Burden Due to
Epilepsy in Rural China
D. Ding . W. Z. Wang . Z. Hong
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1592
2 Study Areas and Target Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1593
3 Prevalence and Treatment Gap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1593
4 Disease Burden by DALY Measure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1595
5 Applications of the Model to Other Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1597
6 Premature Mortality in People with Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1598
7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1600
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1600

1592 92 The Disease Burden Due to Epilepsy in Rural China
Abstract: The World Health Organization (WHO), in cooperation with the International
League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) launched the
Global Campaign Against Epilepsy (GCAE) in an attempt to bring epilepsy “out of the
shadows” and to improve the acceptability, treatment, services and prevention of epilepsy
world-wide. As part of this campaign and under the auspices of the WHO and the Ministry of
Health of China, a demonstration project was implemented in rural areas in six non-contiguous
provinces of the People’s Republic of China (PRC). In the sample areas, the lifetime prevalence
and prevalence of > active epilepsy in rural China were 6.0–7.0/1,000 and 3.8–4.6/1,000
respectively. Sixty-three percent of people with active epilepsy had not received antiepileptic
medication in the week before the survey (i.e., the > treatment gap was 63%). The disease
burden of epilepsy was measured as 2.08 Disability Adjusted Life Years (> DALYs) lost per
1,000 population. The > standardized mortality ratio (SMR) of people with epilepsy was 3.9
indicating that people with epilepsy are three to four times more likely to die prematurely than
those in the general Chinese population. The risk in young people with epilepsy aged 15–29
years in China is particularly high.
List of Abbreviations: AED, anti-epileptic drug; CFR, > case fatality rate; DALY, disability
adjusted life year; EMPHL, epilepsy management at primary health level; GBD, global burden
of disease; GCAE, global campaign against epilepsy; IBE, International Bureau for Epilepsy;
ICBERG, International community-based epilepsy research group; ILAE, International League
Against Epilepsy; PMR, > proportional mortality rate; PRC, People’s Republic of China; SMR,
standardized mortality ratio; WHO, World Health Organization; YLD, years lived with
disability; YLL, years of life lost
1 Introduction
Epilepsy is one of the most common serious neurological disorders, affecting approximately
50 million people worldwide; approximately 2 million people develop epilepsy each year. With
the correct diagnosis and treatment, many people with epilepsy will have a significant
reduction in seizure frequency or be seizure free. In resource-poor countries, 60–90% of
people with epilepsy receive no treatment or are inadequately treated due to deficiencies in
health-care resources and delivery, and to social stigma (Meinardi et al., 2001; Scott et al.,
2001; World Health Organization, 2000).
Prior to 2000 there were few studies to investigate the prevalence of epilepsy in the People’s
Republic of China (PRC) and those that were conducted showed widely divergent values for
the prevalence and incidence of epilepsy (Ding et al., 2006). The differences may be due to
differing study objectives and methodologies or to different economic levels or causes of
epilepsy. The > lifetime prevalence of epilepsy is between three and five per 1,000 population,
and the incidence of epilepsy is between 30 and 40 per 100,000 population per year and
epilepsy-related mortality is between 3 and 7.9 per 100,000 population (Ding et al., 2006). In
1990, the Global Burden of Disease (GBD) study estimated the DALYs lost due to epilepsy as
0.81 per 1,000 population (Murray and Lopez, 1996).
Large numbers of people with epilepsy are at risk of morbidity and mortality, mainly
because of difficulties with the treatment infrastructure and the availability of suitable drugs
(Scott et al., 2001). In rural China about half of patients have not been treated with standard
antiepileptic treatment (Kleinman et al., 1995). Some patients have no treatment at all for their
The Disease Burden Due to Epilepsy in Rural China 92 1593
condition, whereas others are treated inappropriately with high-cost technologies that incur
unnecessarily high expenses.
Mortality associated with a specific disease is assessed with particular parameters: mortality
rate, case fatality rate (CFR), proportional mortality rate (PMR), and standardized mortal-
ity ratio (SMR). In China, only a few studies have described mortality rates of epilepsy in the
general population, providing a range of 3.0–7.9 per 100,000 people per year. The CFR
estimated from national health statistics is 0.7% of in-patient cases (Ding et al., 2006).
In 1997, the World Health Organization (WHO), in cooperation with the International
League against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) launched the
Global Campaign Against Epilepsy in an attempt to bring epilepsy “out of the shadows” and to
improve the treatment of people with epilepsy in resource-poor countries (Kale, 1997).
Demonstration projects were set up aiming to reduce the treatment gap and morbidity of
people with epilepsy using community level interventions, train and educate health profes-
sionals, dispel stigma, identify potential for prevention and develop models of integration of
epilepsy control into the health systems of participating countries (Li, 1989). One such
demonstration project, “Epilepsy Management at Primary Health Level” (EMPHL), under
the auspices of the WHO and the Ministry of Health of China, was implemented in rural areas
in six non-contiguous provinces of the PRC.
2 Study Areas and Target Population
The demonstration project was implemented in rural areas in six non-contiguous provinces of
the PRC, with a total population of over three million people. These areas represented
different scenarios within PRC. The study sites were: Mulin and Dongning counties in
Heilongjiang province; Wuzhong and Qingtongxia counties in the Ningxia Hui Autonomous
Region; Wuxhi county in Henan Province; Zezhou county in Shanxi province; Hanjiang
county in Jiangsu province; and Jinshan county in Shanghai Municipality (> Figure 92-1).
The study areas were representative not only of the different geographical areas but also of the
different economic levels in China.
3 Prevalence and Treatment Gap
The prevalence of epilepsy and the treatment gap were estimated among 66,000 of the total
population of 70,000 in the six areas. 66,393 of the total population of 70,462 (94%) in these
six rural areas were surveyed (Ding et al., 2004; Wang et al., 2002; Wang et al., 2003). The
screening questionnaire was based on the WHO screening questionnaires previously used in
PRC and on the ICBERG screening instrument (Wang et al., 2003) and validated at the Beijing
Neurological Institute for specificity (78.5%) and sensitivity (100%). Participating physicians
and health workers were trained to conduct the questionnaire with a standardized technique.
After the questionnaire had been completed, each person who had a positive response to any
of the questions was examined by a neurologist to determine the diagnosis.
The minimum lifetime prevalence of epilepsy, based on the number of people identified
as having a definitive history of epilepsy, was 6.8/1,000. The prevalence of active epilepsy was
4.5/1,000 (> Table 92-1). Thus, the number of people with epilepsy in PRC was estimated
as almost nine million, and approximately six million people in PRC have active epilepsy.
. Figure 92-1
Map of China, showing the intervention sites
. Table 92-1
Prevalence of epilepsy in six study areas in rural China
Life-time epilepsy Active epilepsy

Province Cases identified Prevalence (%) Cases identified Prevalence (%)
Heilongjiang 82 8.1 49 4.8
Henan 59 4.7 43 3.5
Jiangsu 87 7.8 53 4.8
Ningxia 99 8.5 78 6.7
Shanghai 65 6.0 41 3.8
Shanxi 60 5.8 34 3.3
Total 452 6.8 298 4.5
This table demonstrated the prevalence of life-time epilepsy and active epilepsy in different study areas in China.
The highest prevalence of epilepsy is in Ningxia
The prevalence of epilepsy is presented by sex, age group, and study area in > Table 92-2.
The prevalence of epilepsy ranged from 3.5 (Shanxi) to 6.4 (Ningxia) per 1,000 population
within six areas. Except in Shanxi, the prevalence of epilepsy was higher for females than for
males. The age-specific epilepsy prevalence was different in six areas. In Jiangsu and Ningxia,
the highest prevalence of both sexes was in the “0–4” year (11.49/1,000) and “5–14” year (8.64/
1,000) age groups respectively. In other three areas, however, the peaks of prevalence of both
sexes were in the “45–59” or “60–69” year age groups.
Two fifths of people had not received any treatment for epilepsy, one third had received
irregular treatment, and only a quarter had received reasonable, regular doses of AEDs in the
week before the survey. Of those with active epilepsy, two thirds did not receive reasonable
treatment in the week before the survey (> Table 92-3). The reason for the treatment gap is
unclear, but it may be the result of the perceptions of epilepsy in PRC. If epilepsy is not viewed
as a manageable condition, it is instead stigmatized, and people are unlikely to admit that they
have epilepsy or to know that treatment exists. This situation has been seen across many
different cultures and is probably also evident in PRC (Scott et al., 2001).
4 Disease Burden by DALY Measure
The Disability Adjusted life year (DALY) is an indicator of the time lived with a disability
(Years Lived with Disability, YLD) plus the time lost due to premature mortality (Years of Life
lost, YLL). The general formula and corresponding parameters of the GBD study were used to
calculate the number of YLDs and YLLs lost by one individual (Murray and Lopez, 1996). YLD
was calculated based on the prevalence data from the epidemiological survey. The average
mortality of 6 per 100,000 population reported by Chinese literature was used for the
calculation of YLLs due to epilepsy according to sex and age group in each of the study
areas. The population of China in 2000 was used to adjust for the sex and age structures of the
population of each study area (Ding et al., 2006).
> Table 92-4 shows that epilepsy caused 1.31–1.52 YLLs per 1,000 population in the six study
areas in 2000. The YLDs caused by epilepsy ranged from 0.46 to 1.01 per 1,000 population. There
were 1.83 and 2.48 DALYs per 1,000 population caused by epilepsy in Henan and Ningxia, which
had the lowest and highest DALY lost respectively in six areas. Overall, the YLLs lost for males were
higher than those for females, while the YLDs lost for males were lower than those for females
except in Shanxi province. By adjusting to sex and age structures of the population of China in
2000, epilepsy caused 1.41 YLLs and 0.67 YLDs per 1,000 population, thus the DALYs due to
epilepsy was 2.07 per 1,000 population, representing the epilepsy disease burden in rural China.
The distribution of disease burden within age groups is shown in > Table 92-5. The YLLs
lost per 1,000 population varied from 0.03 (“0–4” year age group) to 2.53 (“15–29” year age
group), whereas the YLDs lost per 1,000 population varied from 0.16 (“70+” year age group)
to 0.91 (“45–59” year age group). Over 3.2 DALYs lost per 1,000 population in people with
15–44 years old, indicating that epilepsy caused large disease burden especially in young
population with physical labor.
In the classification of the WHO sub-regions, China belongs to the sub-region of WPRO B.
The DALY lost due to epilepsy in rural China, based on the combined data of six study areas,
was 2.08 per 1,000 population, which is 2.89 times higher than that of the WPRO B sub-region
(0.72/1,000) and 1.73 times higher than the worldwide burden (1.20/1,000) as assessed by the
GBD study (GBD, 2000).
1596
92
. Table 92-2
The prevalence (cases per 1,000 population) due to epilepsy in six study areas in China, 2000
Males in age group (years) Females in age group (years)

Areas 0–4 5–14 15–29 30–44 45–59 60–69 70+ All ages 0–4 5–14 15–29 30–44 45–59 60–69 70+ All ages Both sexes
Heilongjiang 0.00 1.21 2.22 6.06 5.54 12.55 0.00 4.02 0.00 5.36 6.92 5.78 12.09 4.03 4.57 6.69 5.32
Henan 0.00 0.65 2.75 2.93 4.00 0.00 3.40 2.16 6.12 4.15 2.30 6.18 9.39 3.27 2.47 5.03 3.65
Jiangsu 23.26 2.84 2.25 5.36 4.69 5.99 2.68 4.51 0.00 3.03 5.04 4.88 10.53 8.00 1.76 5.91 5.22
Ningxia 4.32 8.89 8.75 5.80 0.00 3.56 0.00 6.34 5.41 8.34 5.36 9.27 9.86 0.00 5.56 7.10 6.40
Shanghai 0.00 2.29 2.07 3.07 4.56 2.11 4.77 3.15 6.85 2.44 4.90 3.87 6.77 9.29 3.35 5.20 3.84
Shanxi 2.56 3.15 1.53 1.83 9.10 10.68 0.00 3.77 2.66 2.07 2.30 2.49 5.73 10.27 0.00 3.25 3.50
The Disease Burden Due to Epilepsy in Rural China
This table lists the age- and sex-specific prevalence of epilepsy in different study areas in China. This data is used to calculate the YLD due to epilepsy
. Table 92-3
Treatment gap in active epilepsy in six study areas in China, 2000
No. of No. of patients receiving AEDs in previous Treatment gap

Province patients week (%) (%)
Heilongjiang 49 26(53.1) 46.9
Henan 43 16(37.2) 62.8
Jiangsu 53 12(22.6) 77.4
Ningxia 78 29(37.2) 62.8
Shanghai 41 12(29.3) 70.7
Shanxi 34 13(38.2) 61.8
Total 298 108(36.2) 63.8
This table lists the percentage of AED-treated epilepsy patients and treatment gap in active epilepsy in six study
areas in China
. Table 92-4
YLL, YLD and DALY lost per 1,000 population by sex due to epilepsy in six study areas in China
YLL/1,000 YLD/1,000 DALY/1,000

Areas Male Female Total Male Female Total Male Female Total
Heilongjiang 1.64 1.38 1.52 0.60 1.03 0.81 2.24 2.41 2.33
Henan 1.39 1.22 1.31 0.31 0.74 0.52 1.70 1.96 1.83
Jiangsu 1.51 1.19 1.35 0.61 0.96 0.79 2.12 2.15 2.14
Ningxia 1.53 1.42 1.47 1.00 1.01 1.01 2.53 2.43 2.48
Shanghai 1.57 1.22 1.39 0.42 0.71 0.57 1.99 1.93 1.96
Shanxi 1.49 1.29 1.39 0.49 0.44 0.46 1.98 1.73 1.85
Totala 1.52 1.30 1.41 0.55 0.81 0.67 2.07 2.11 2.08
This table lists the sex-specific YLL, YLD, and DALY lost per 1,000 population due to epilepsy in six study areas in
China. Henan and Ningxia have the lowest and highest DALY lost respectively in six areas
a
Sum of six study areas adjusted by the sex and age structure of China population in 2000
5 Applications of the Model to Other Diseases

For the complete assessment of the epilepsy disease burden, DALY measurements should be
acquired not only for neurological diseases, but also for all the diseases in different areas of
China. Unfortunately, this has not been done. Compared to the disease burden due to
neurologic diseases in WPRO B sub-region provided by GBD study, however, the result of
2.08 DALYs lost per 1,000 population is lower than that of Cerebrovascular disease (9.86
DALYs lost per 1,000 population), and higher than that of Alzheimer disease and other
dementia (1.76 DALYs lost per 1,000 population) or Pakinson’s disease (0.21 DALYs lost per
1,000 population) (GBD, 2000).
. Table 92-5
YLL, YLD and DALY lost per 1,000 population by age group due to epilepsy in the entire
population of the six study areas in China
YLL/1,000 YLD/1,000 DALY/1,000

Age group (years) Male Female Total Male Female Total Male Female Total
0–4 0 0.06 0.03 0.24 0.12 0.18 0.24 0.18 0.21
5–14 0.57 0.33 0.46 0.40 0.57 0.48 0.98 0.90 0.94
15–29 2.42 2.64 2.53 0.59 0.82 0.70 3.01 3.46 3.23
30–44 2.88 1.93 2.40 0.70 0.93 0.82 3.58 2.86 3.22
45–59 0.67 0.60 0.64 0.60 1.24 0.91 1.27 1.84 1.55
60–69 0.17 0.29 0.23 0.62 0.69 0.66 0.80 0.99 0.89
70+ 0.12 0.34 0.24 0.10 0.21 0.16 0.21 0.55 0.41
a
Total 1.52 1.30 1.41 0.55 0.81 0.67 2.07 2.11 2.08
This table lists the adjusted YLL, YLD, and DALY lost per 1,000 population due to epilepsy. Epilepsy caused large
disease burden in young population
a
Sum of six study areas adjusted by the sex and age structure of china population in 2000
6 Premature Mortality in People with Epilepsy
People with epilepsy have increased risk of premature death compared with the general
population (Gaitatzis and Sander, 2004). However, the extent and nature of this risk has not
been sufficiently examined, especially in resource-poor countries where there is often a large
treatment gap with many patients not being treated (Cockerell et al., 1994). The EMPHL
protocol used strict follow-up and management procedures, and so it was possible for us to
calculate PMRs and SMRs to assess mortality in people with epilepsy.
During the 1-year follow-up to 2,455 epilepsy patients, local primary-care physicians
recorded demographic data and putative cause of death of any patient who died. Cause of
death was attributed on clinical grounds and verbal autopsy. Specialists and the principal
investigators in each study area gathered information about cause of death through interviews
with relatives or local village physicians. Death certificates were also used for confirmation of
the cause of death (Ding et al., 2006).
There were 35 deaths among 2,455 people with epilepsy during follow-up. The main cause
of death was accidental or as a result of injury (self-inflicted or otherwise); 13 (37%) patients
died of drowning (n = 6), suicide (n = 4), poisoning (n = 2), or a road traffic accident (n = 1).
In 11 (31%) patients, death was attributed to hemorrhagic or ischemic stroke, whereas in two
(6%), death was attributed to pneumonia. The age-adjusted PMRs for injury (30%), stroke
(30%), pneumonia (5%), and myocardial infarction (6%) were higher for the trial partici-
pants than for the 2004 Chinese population (8, 19, 2, and 3%, respectively). The adjusted PMR
for neoplasm (15%) was lower in the study population than in the general population
(> Figure 92-2).
The SMR for people with epilepsy was 3.9 (95% CI 3.8–3.9) and was higher in women (4.1;
3.9–4.4) than in men (3.5; 3.4–3.6). > Figure 92-2 shows that in patients aged at least 15 years,
and with the exception of those aged 70–74 years, the SMR was raised. SMRs were especially
high in patients ages 15–19 years (23.3; 15.9–43.9), 20–24 years (40.2; 32.4–52.8), and 25–29
. Figure 92-2
Age-adjusted cause-specific PMRs in people with epilepsy compared with the general Chinese
population, 2004
. Figure 92-3
Age-specific SMRs of epilepsy in the study population in rural China, adjusted for the Chinese
population, 2004. Bars represents 95% CIs
years (33.3; 28.0–41.1). The SMRs for patients aged 30–49 years were in the range 2.3–8.1, and
for people with epilepsy aged older than 49 years the SMRs were lower than for the 30–49 year
age-group (> Figure 92-3). Cause-specific SMRs of the epilepsy population were calculated
for: pneumonia (21.3; 14.5–40.0), injury (12.2; 11.4–13.0), myocardial infarction (10.7;
5.6–95.3), stroke (7.0; 6.5–7.6), and neoplasm (1.6; 1.5–1.8). Suicide (3.8; 3.2–4.6) and
drowning (5.6; 4.7–6.5) were the major causes of death in those classified as dying of injury.
7 Conclusion
According to our measurement, there was an overall size of burden of 1,681,410 DALYs lost in
rural China based on the rural population of 808,370,000 in 2000. There is an increased risk of
premature mortality in people with epilepsy in rural China, especially among the young. The
increase in mortality in young adults is higher than seen in developed countries. The
information of disease burden can help policy planners to allocate resources and identify
strategies and interventions for the reduction of the burden of epilepsy in China.
Summary Points
The minimum lifetime prevalence of epilepsy was 6.8/1,000, and the prevalence of active
epilepsy was 4.5/1,000. Thus, the number of people with epilepsy in PRC was estimated as
almost nine million, and approximately six million people in PRC have active epilepsy.
Two fifths of people had not received any treatment for epilepsy, one third had received
irregular treatment, and only a quarter had received reasonable, regular doses of AEDs in
the week before the survey. Of those with active epilepsy, two thirds did not receive
reasonable treatment in the week before the survey.
Epilepsy caused 1.41 YLLs and 0.67 YLDs per 1,000 population, thus the DALYs due to
epilepsy was 2.08 per 1,000 population, representing the epilepsy disease burden in rural
China. This is almost three times higher than that of the WPRO B sub-region and twice
that of the worldwide burden as assessed by the GBD study.
The main cause of death of epilepsy patients was accidental or as a result of injury. SMRs
were especially high in patients ages 15–19 years (23.3), 20–24 years (40.2), and 25–29
years (33.3). There is an increased risk of premature mortality in young people with
epilepsy in rural China.
References
Cockerell OC, Johnson AL, Sander JW, Hart YM, Gaitatzis A, Sander JW. (2004). Epileptic Disord. 6: 3–13.
Goodridge DM, Shorvon SD. (1994). Lancet. 344: GBD 2000 (2000). Available from: URL: http://www3.
918–921. who.int/whosis Accessed 2004.
Ding D, Hong Z, Wang WZ, Wu JZ, de Boer HM, Kale R. (1997). BMJ. 315: 2–3.
Prilipko L, Sander JW. (2006). Epilepsia. 47: Kleinman A, Wang WZ, Li SC, Cheng XM, Dai XY, Li KT,
2032–2037. Kleinman J. (1995). Soc Sci Med. 40: 1319–1330.
Ding D, Lu GY, Huang MS, Zhou B, Hou GQ, Zeng J, Jin Li SC. (1989). Chin J Nerv Ment Dis. 22: 144 (Chinese).
MH, Zhu GX, Wang JY, Fu JH, Meng HJ, Zhao QH, Meinardi H, Scott RA, Reis R, Sander JW. (2001).
Hong Z. (2004). Chin J Neurosci. 12: 122–124 Epilepsia. 42: 136–149.
(Chinese). Murray CJL, Lopez AD. (1996). Global Burden of Disease
Ding D, Wang WZ, Wu JZ, Ma GY, Dai XY, Yang B, Wang and Injury Series. World Health Organization, Geneva.
TP, Yuan CL, Hong Z, de Boer HM, Prilipko L, Scott RA, Lhatoo SD, Sander JW. (2001). Bull World
Sander JW. (2006). Lancet Neurol. 5: 823–827. Health Organ. 79: 344–351.
Wang WZ, Wu JZ, Wang DS, Chen GS, Wang TP, Yuan World Health Organization. (2000). The Global Cam-
CL, Yang B, Zhao DH. (2002). Natl Med J China. 82: paign Against Epilepsy – Out of the Shadows. WHO,
449–452 (Chinese). Geneva.
Wang WZ, Wu JZ, Wang DS, Dai XY, Yang B, Wang TP,
Yuan CL, Scott RA, Prilipko L, de Boer HM, Sander
JW. (2003). Neurology. 60: 1544–1545.
93 Alcohol Consumption and
Burden of Disease: Germany
and Switzerland
M. Roerecke . J. Rehm . J. Patra
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1604
2 Data Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1605
3 Exposure Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1606
4 Risk Relations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1606
5 Health Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1607
6 Population Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1607
7 Calculation of Attributable Fractions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1608
8 Alcohol Consumption in Germany and Switzerland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1608
9 Alcohol-Attributable Deaths in Germany and Switzerland . . . . . . . . . . . . . . . . . . . . . . . 1609
10 Alcohol-Attributable Years of Life Lost in Germany and Switzerland . . . . . . . . . . . . 1609
11 Alcohol-Attributable Disability Adjusted Life Years in Germany

and Switzerland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1609
12 Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1613
13 Burden of Disease in Germany and Switzerland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1613
14 Implications for Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1614
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1616

1604 93 Alcohol Consumption and Burden of Disease: Germany and Switzerland
Abstract: We estimated the burden of disease attributable to alcohol in Germany and

Switzerland for the year 2002. We calculated disease-specific attributable fractions for diseases
and conditions based on relative risk estimates from meta-analyzes, prevalence of exposure
from the Global Alcohol Database and large, representative surveys, and obtained > mortality
and burden of disease data from the World Health Organization. Comparatively high alcohol
consumption in Switzerland caused substantial burden, in particular among Swiss women.
Although alcohol consumption was high among women in Germany and Europe as well, the
burden among women was much less compared to Switzerland. For men in both countries
comparable burden of disease was estimated. Both detrimental and beneficial effects of
alcohol consumption were considered in this analysis. Because effective and cost-effective
interventions are available, the burden of disease due to alcohol should be a focus of public
health policy development. Specific measures are discussed.
List of Abbreviations: > DALYs, disability-adjusted life years, a health gap measure combining
years of life lost and years lived with a disability, therefore taking into account mortality and
morbidity; > YLL, years of life lost, a health gap measure taking into account the time of deaths
relative to the normative life expectancy; Mortality, number of deaths; CRA 2000, comparative
risk analysis study for the year 2000, conducted as part of the global burden of disease study by
the World Health Organization; > AF, attributable fraction, the fraction of disease outcome,
for example, that is caused by a specific risk factor, in this case alcohol; > WHO, World Health
Organization; > GBD, global burden of disease study conducted by the World Health Organiza-
tion describing the effect of 26 risk factors on burden of disease around the world; > GAD, global
alcohol database, maintained by the WHO. Alcohol consumption indicators are updated
annually for each member state based on data from multiple sources; Europe A, WHO
subregion defined by very low child and very low adult mortality; APC, estimated adult
(15 years and above) per capita alcohol consumption (in liters of pure alcohol consumed
within one year); HDL, high density lipoprotein
1 Introduction
Alcohol is a cause for substantial burden of disease worldwide, ranking fifth of 26 risk factors
examined by the World Health Organization (WHO) in 2000 (Ezzati et al., 2002). Four
percent of the global burden of disease in 2000 was estimated to be caused by alcohol
consumption; in developed countries, the contribution of alcohol is even higher with 9.2%
of all disease burden attributed to alcohol, just behind tobacco and high blood pressure.
However, the burden varies greatly by region and country with poorer countries and regions
showing less burden attributable to alcohol than developed countries. In Europe in 2002, due
to comparatively high consumption (11.9 liters per adult capita, compared to 6.2 liters
worldwide) the burden is significantly higher with considerable heterogeneity across countries
(Rehm et al., 2006b). For example, an East West gradient within Europe has been described
recently (Popova et al., 2007; Rehm et al., 2007a,b). On a global level, most people abstain
from alcohol and most recent estimates showed strong sex differences with 6.1% of all deaths
worldwide attributable to alcohol among men and 1.1% among women in 2002. Among the
population 60 years and older 5% of all deaths were attributable to alcohol consumption
(Rehm et al., 2006b).
Alcohol Consumption and Burden of Disease: Germany and Switzerland 93 1605
The relationship between alcohol and disease and conditions is complex and several
dimensions of consumption have to be considered. We will concentrate here on direct health
effects (burden of disease) and not consider social and indirect effects on families and com-
munities. Overall, the net costs attributable to alcohol (including indirect health care costs, law
enforcement and social harm job loss, marginalization, etc.) outweigh any benefits because of
the strong impact of social costs. For most diseases the effect is detrimental with few exceptions,
such as coronary heart disease or diabetes when average consumption is low to moderate. Most
researchers to date agree on a cardioprotective effect of regular low to moderate average alcohol
consumption in comparison to heavy drinkers and abstainers (Rehm et al., 2003). Rimm and
colleagues investigated biological mechanisms and summarized the evidence from animal
and experimental studies regarding mediating pathways. Most of the mediating beneficial
effect of regular low alcohol consumption is caused by an increase in high density lipoproteins
(HDL), in addition to inhibiting platelet activation, lower levels of fibrinogen, and anti-
inflammatory effects (Rimm et al., 1999; Rimm and Moats, 2007). It has been estimated that
a risk reduction of 20–30% can be assumed for low to moderate average consumption (Corrao
et al., 2000). In some developed countries the beneficial effect of alcohol on cardiovascular
diseases can be substantial and, mostly among women, result in a net beneficial effect.
Some diseases are caused by alcohol by definition, such as alcohol dependence or alcoholic
liver cirrhosis. These conditions have by definition an attributable fraction of 100%. While
measurement error in disease classification cannot be ruled out, the contribution of alcohol
does not need to be estimated. For chronic diseases, such as cancer or cardiovascular diseases,
alcohol is a contributory cause rather than a sufficient cause. While this presents difficulties
in treatment and causal inference for an individual case, on a population level, a certain
fraction of cancer cases can be attributed to alcohol by calculating attributable fractions (AF)
derived from prevalence estimates of alcohol exposure and relative risk estimates from large
scale epidemiological studies quantifying risk relations for diseases where alcohol has been
found to be a causal factor in disease etiology.
This chapter will compare alcohol consumption and attributable burden in Germany
and Switzerland for the year 2002 using a standardized methodology developed for the
Comparative Risk Analysis 2000 (CRA 2000) within the Global Burden of Disease study
conducted by the WHO (Rehm et al., 2004). The CRA 2000 and recent updates were under-
taken in an effort to compare among other risk factors alcohol consumption and resulting
burden of disease across regions and countries using the same standardized methodology.
2 Data Sources
In order to calculate the burden of disease attributable to a specific risk factor, several data
sources need to be evaluated: disease specific relative risk estimates usually derived
from comprehensive meta-analyzes, data for prevalence of exposure from official sources in
addition to survey data, and an estimate of the total number of deaths, years of life lost (YLL)
and disability adjusted life years (DALYs) per disease condition in the respective population.
Preferably, these estimates should be sex- and age specific. A disease specific approach is
necessary because the burden of disease caused by alcohol depends on the distribution of
consumption and deaths in the population (for a detailed description of the methodology,
please see Rehm et al., 2004; Rehm et al., 2007a,b).
1606 93 Alcohol Consumption and Burden of Disease: Germany and Switzerland
3 Exposure Measurement
Information of exposure to alcohol for a population is not readily available and several data
sources have to be considered, such as official sales statistics, tax revenue statistics, production
data, and survey data. Alcohol consumption of the population 15 and over is usually used to
determine the overall consumption of a population because alcohol consumption typically
takes place in adulthood and the proportion of people under the age of 15 varies by country,
therefore using per capita consumption estimates (total population) would result in biased
consumption estimates for the actual consuming population. We took adult per capita
consumption for Germany and Switzerland from the WHO Global Alcohol Database
(WHO, 2006). Although these data represent the most valid estimates for overall consumption
in a population (Gmel and Rehm, 2004), they have to be combined with survey data in order
to derive sex- and age-specific estimates of the distribution of alcohol consumption in each
country. Unrecorded consumption, i.e., consumption not recorded by official sales statistics,
such as home production, illegal import or production, is commonly low in Germany and
Switzerland (1 L or less). Information on the distribution of alcohol consumption was taken
from the Swiss Health Survey [Schweizerische Gesundheitsbefragung], a random telephone
survey of the Swiss population 15 years and older living in Switzerland. Response rate for the
third instalment of the Swiss survey, conducted in 2002 was 64% at the household level
(Bundesamt für Statistik, 2004). Data for Germany were taken from the 2003 Epidemiological
Survey of Substance Abuse [Epidemiologischer Suchtsurvey 2003], a two-stage random
survey of about 8,000 residents of Germany between 18–59 years. Response rate for the self-
administered questionnaire was 55% (Augustin and Kraus, 2005). We classified drinking levels
into categories based on English et al. (1995) a classification widely used in meta-analyzes
examining the effect of alcohol consumption (> Table 93-1). Both countries were assigned a
. Table 93-1
Definition of drinking categories based on English et al. (1995)
Abstainer or very light Drinking Drinking category Drinking category

drinker (g/day) category I (g/day) II (g/day) III (g/day)
Men 0 – < 2.5 2.5 – < 40 40 – < 60 60+
Women 0 – < 2.5 2.5 – < 20 20 – < 40 40+
Tthe limits of these categories are stated in grams of pure alcohol per day. For reference, a bottle of table wine
contains about 70 g of ethanol; 2.5 g/day corresponds to somewhat more than one bottle of wine per month
pattern score of one, the least detrimental score (range 1–4). The score for pattern of drinking is
composed of indicators for hazardous drinking, such as drinking outside of meals, frequency
of drinking in public places, and frequency of heavy drinking occasions (Rehm et al., 2004).
Pattern scores were available only on the country level.
4 Risk Relations
More than 60 diseases and conditions have been found to be causally related to alcohol,
including cirrhosis of the liver, several types of cancer (mouth and oropharynx, esophagus,
Alcohol Consumption and Burden of Disease: Germany and Switzerland 93 1607
liver, breast in women, colorectal, and others), hypertension, ischaemic heart disease, ischae-
mic and hemorrhagic stroke, diabetes, and intentional and unintentional injuries (Boffetta
and Hashibe, 2006; Cho et al., Corrao et al., 2000; Corrao et al., 2004; English et al., 1995;
Gutjahr et al., 2001, 2004; Reynolds et al., 2003). These conditions have been identified in
several meta-analyzes based on epidemiological criteria (Hill, 1965; Rothman and Greenland,
1998) with an emphasis on epidemiological criteria to determine causality, such as consistency
across studies, temporal order, plausible biological mechanisms, strength of the effect, and
dose-response relationships. Beneficial and detrimental effects were assessed using the same
criteria. For acute outcomes, such as injuries, attributable fractions were taken directly from
the CRA 2000 study. The most recent addition to alcohol attributable diseases is colorectal
cancer for both sexes (Cho et al., 2004). T

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Part 1

1 Instruments and Methodological

3 Implementation of the ICF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

4 ICF-based Classification and Measurement of Functioning . . . . . . . . . . . . . . . . . . . . . . 18

# Springer Science+Business Media LLC 2010 (USA)

2.1 The ICF in the Historical Perspective

2.2 The ICF in the WHO and the UN Perspective

2.3 Development of the ICF

2.4 Up-Date and Revision Process

2.5 The Structure of the ICF

2.6 Validity of the ICF

2.6.1 Exhaustiveness or Width

Codea and title, definition, inclusions and exclusions

Musculoskeletal Grill et al., Scheuringer Boldt et al., Grill et al.,

2.6.2 Precision or Depth

2.6.3 ICF Framework

Context Health condition Reference Measurements/instruments

et al., Algofunctional Indices

Context Health condition Reference Measurements/instruments

3 Implementation of the ICF

4 ICF-based Classification and Measurement of Functioning

4.1 ICF Categories: Building Blocks and Reference Units

4.2.1 ICF Checklist

4.2.2 ICF Core Sets

4.2.2.1 The ICF Core Set Project

4.2.2.2 Conceptual Approach

4.2.2.4 ICF Core Sets for Chronic Conditions

4.2.2.5 Generic ICF Core Set

4.2.2.6 Development Process

4.3 Mapping the World of Measures to the ICF

4.3.2 Linkage Methodology

4.3.3.1 Step one, Identification of Concepts

4.3.3.2 Step Two, Linking of Concepts to the ICF

4.4 ICF-based Measurement of Functioning

4.4.1 Measuring a Single ICF Category

Transcription divided according to meaning Identified

ICF Qualifiera Percentage of problem

4.4.4.2 Transformation of Information Obtained with a Clinical Test or a Patient-oriented

b130: Energy and drive functions

4.5 Measuring Across ICF Categories

4.5.1 Self-reported ICF-based Measurement Instruments

4.5.2 ICF-based Clinical Measurement Instruments

2 Developing a Conceptual Model of Participation Restriction . . . . . . . . . . . . . . . . . . . . 39

3 Developing an Instrument and Measurement Model to

5 Pre-Testing Interview Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

6 Further Development of Instrument . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

7 Pilot Questionnaire Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

# Springer Science+Business Media LLC 2010 (USA)

8 Overview of Psychometric Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

2 Developing a Conceptual Model of Participation Restriction

The WHO defines participation restriction as ‘‘problems an individual may experience in

ICF Domain Activity limitation Participation restriction

v. Participation restriction across multiple domains is summative with restriction in more

3 Developing an Instrument and Measurement Model to

3.1 Item Development

3.2 Number of Items

3.3 Scoring of Each Item

3.4 Instrument Score

ICF domains KAP items

Estimates of prevalence can be produced for:

To examine the ability of the Keele Assessment of Participation to measure person-perceived

5 Pre-Testing Interview Stage

> content validity and > responder burden.

5.1 Cognitive Interviews

Participation restriction is an appealing concept for those interested in older populations

Participation restriction is a performance-based, context-dependent, phenomenon, most