Chapter four

Epidemiological Study design

BY:

Nebiyou T (PhD in Public Health )

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• Objectives of the session
• When you have completed this session you will be able to:

1. Describe well all types of epidemiological study designs

2. Explain the uses of the various study designs.

3. Express well the characteristics of descriptive study

designs and how hypothesis is generated.
4. Determine when to proceed with an analytic study for
further test of the hypothesis.

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• Categories of epidemiological studies
1. Descriptive epidemiological studies
Population as study subject
o Correlational /ecological studies
Individual as study subjects
o Case report / Case series
o Cross-sectional surveys
2. Analytic epidemiological studies
2.1. Observational studies
o Case-control study

o Cohort study
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Epidemiological studies

Populations Ecologic

Case-series
Descriptive
Case-report
Individuals
Cross-sectional

Prospective
Cohort
Observational
Retrospective
Case-control
Analytical
Intervention Clinical trials
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 Descriptive study design

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• Descriptive study design
 Describes the general characteristics of the distribution of a
disease in relation to person, place and time.

Who? Where? When?

 It provides valuable information
To allocate resources efficiently
To plan effective prevention or education programs.
It provides the first important clues about possible
determinants of a disease (formulation of hypothesis).
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• Case report:
 It is the study of health profile of a single
individual using a careful and detailed report by
one or more clinicians.
 It is common form that is published in articles
 It is made using
 Simple history,
 Physical examination and
 Lab. / radiologic investigation.

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 Report is usually documented if there is unusual
medical occurrence, thus it may be first clue for
identification of a new disease.
It is useful in constructing a natural history of
individual disease.
E.g
It was a single case report that formulated the
hypothesis of oral contraceptive use increases MI.

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• Case series
 Individual case report can be expanded to a case series,
which describes characteristics of a number of patients
(usually 5-12) with a similar disease.
 Similar to case report, it is usually made on cases having
new and/ or unusual disease (giving interest to clinicians)
 It is often used to detect the emergence of new disease or
an epidemics.

Eg. The first five AIDS cases in USA.

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Example:
• Five young, previously health homosexual men were
diagnosed as having Pneumocystis carinii pneumonia at
Los Angeles hospital during a six month period from 1980
to 1981.
• This form of pneumonia had been seen almost exclusively
among older men and women whose immune systems were
suppressed.
• This unusual circumstance suggested that these individuals
were actually suffering with a previously unknown disease,
subsequently it was called AIDS.
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 Both case report and case series are able to
formulate a hypothesis but are not able to test for
presence of valid association.
Fundamental limitation of case report is presence
of a risk factor that is simply coincidental (by
chance)
It is difficult to test for association because there is
no relevant comparison group
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• Case reports or case series
 Useful for the recognition of new diseases,
 Useful for constructing of the natural history of a
disease,
 Use to formulate a hypothesis and to detect an
epidemic

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• Cross-sectional surveys
 Is generally called study of prevalence
 Survey is conducted in a population, to find
prevalence of a disease and exposure.
 Exposure and disease status are assessed
simultaneously among individuals at the same point in
time .
 Cross-sectional surveys could provide information
about the frequency of a disease by furnishing a
02/17/2024 ‘snapshot’ at a specified
Nebiyou T ( time.
PhD) 13
  Cont…

 May be used first step in cohort or case control studies.

 Data are obtained Only once.

 It can be considered as analytic study, if it assesses

presence of an association.
 Measures of association is made using odds ratio.

 For factors that remain unaltered overtime such as sex,

race, blood group,

It can provide a good evidence.

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• Limitations
Since exposure and disease status is assessed at a
single point in time, temporal relationship between
exposure and disease can not be clearly determined.
Egg and hen phenomena

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• Correlational/ Ecological study
 Uses aggregated data from entire population (as a whole) to

compare disease frequencies. (i.e. it doesn’t need data

from individuals)
 Can be done quickly and inexpensively, often using already
available data.
 The aggregate data could be
 Prevalence of a health event,
 Death rate,
 Incidence of a health related problem
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• Example:

1. Fluoride content of water and dental caries

– Proportion of people with dental caries in villages
Vs
– Fluoride content of water in villages

2. Circum-incision and HIV in Ethiopia

– HIV prevalence of districts in Ethiopia

Vs
– Proportion of male circum-incision in the same districts
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• Rationale for ecological studies
1. Low cost and convenient
2. Measurement limitation (conditions that are difficult to
measure at individual level)

(e.g environmental contact, dietary exposure, fluoride

content) other designs may be unable to measure

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• Limitations
Unable to link an exposure to occurrence of disease in
a single individual.
Lack of the ability to control for effect of
confounders.
Data represent average exposure levels rather than
actual individual values as in ecological “fallacy” or
bias.

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 Analytical epidemiological
study design

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• Application of Case-Control studies
• It is good to do for rare diseases or outcomes
• Persons with the disease are compared with
controls free of disease, for presence of the factor
under investigation
• Cases are compared to controls with respect to
exposure frequency
• It may be possible to explore a wide range of
potential exposures for a single outcome
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 • Application…

• If all the cases of the disease have been diagnosed

at the time the investigator initiates the study, it is a
Retrospective case control
• If the study is begun and all new cases that are
diagnosed within the next period of time are
included, the study is a Prospective case control
• Will you include incident(newly diagnosed) or
Prevalent(existing at a point in time) cases.
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 Incident Vs Prevalent cases

• Prevalent Cases • Incident cases

– Increase sample size – Helpful to establish

available for rare disease temporal relationship

between exposure and
– Difficult to establish
outcome
temporal sequence
– Records are easily
between exposure and
obtainable and recall bias
outcome reverse
minimized.
causation.
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• Cases
♦ It is the outcome of interest
♦ It can be
• A disease

Eg. HIV status, Malaria

• A behavior

Eg. Alcohol drinking habit, Cigarette smoking

• Occurrence of an event

Eg. migration

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• Selection of cases
• Define ‘disease’ and how it will be ascertained
• Selecting the source population
• Sources of cases are commonly
– All persons with the disease in a population during a
specific time of period
– All persons with the disease seen at a particular facility (
e.g a hospital) in a specific time period

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 Source population

Exposed
Unexposed

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 Source population

Exposed
Cases
Unexposed

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• Sources of cases
• Hospital or medical care facility
• This approach is referred to as hospital-based case
control study
• It is more common because it is relatively easy &
inexpensive to conduct

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• General population
• Referred as population-based case control study
• Involves locating and obtaining data from all affected
individuals or a random sample from a defined population
• It avoids bias arising from whatever selection factors lead
affected individual to utilize a particular health care facility
or physician
• Allows the description of the entire picture of the disease in
that population
• Are not routinely used because of the logistic and cost
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considerations
• Control
• It is the comparison group
• It should be free of the disease of interest
• It should be as similar as the cases in all aspects
except for the disease of interest
• Controls must have the same opportunity of getting
exposure as cases and should be subjected to the
same inclusion and exclusion criteria.

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• Principles of Control Selection
• Controls should be selected from the same study
base (target population) as cases
• Should be selected independently of their exposure
status.
• If they had developed illness, they should be
excluded or should be considered as cases
• Comparable information should be obtained from
controls as it is from cases
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• Sources of controls
• Hospital controls: Are patients who have been admitted for
conditions other than the disease being studied
• Advantages: Easily identified and readily available in
sufficient numbers
• Minimal cost and effort involved in their assembly
• They are more aware of antecedent exposures or events
• More likely to be willing to cooperate than healthy
individuals, thus minimizing bias due to non-response
• They have same intangible selection factors that influenced
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the cases to come to this particular physician or hospital
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• Disadvantages:
• They are ill and therefore differ from healthy
individuals
• Thus, the experience of these other patients may
not accurately represent the exposure distribution
in the population from which the cases derived

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• General population controls
• When the cases have been chosen from a hospitalized
population but the use of hospitalized controls is not
scientifically desirable or feasible, the comparison group
may be selected from the general population.
• Should also be utilized when the cases have been selected
to represent affected individuals in a defined general
population
• The use of general population controls assures the greatest
level of comparability

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• Limitations of general population controls
• More costly and time consuming

• Population lists are not always available

• It is difficult to contact healthy people with busy work

and leisure activity schedules
• May not recall exposures with the same level of
accuracy as those who have developed the disease
• Tend to be less motivated to participate

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• Special controls
• Consists of special groups such as friends,
neighbour, relatives, or spouses of cases
• Advantage: They are healthy
• More likely to be cooperative
• Offer a degree of control of important confounding
factors related to ethnic background, socioeconomic
status

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• Limitation of special controls
• If the study factor itself is one for which family
members and friends are likely to be similar to the
cases, an underestimate of the true effect of the
exposure of interest may result

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• How many control groups?
• Ideally a single control group
• If you think one comparison group is not
appropriate – Consider more than one
• The use of multiple control groups is also indicated
when there is concern that one selected group has a
specific deficiency that could be overcome by the
inclusion of another control group

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 • How many control groups?
• When the number of available cases and controls is
large and the cost of obtaining information from
both groups is comparable, the optimal control-to-
case ratio is 1:1
• When the sample size of cases is limited, or when
the cost of obtaining information is greater for cases
or controls, the control-to-case ratio can be altered
to achieve the desired sample size
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• As the number of controls per case increases, the
power of the study also increases.
• Not generally recommended that this ratio
increase beyond 4:1

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• Sources of information for disease status:
• Review of death certificates, case registries
• That maintain on-going surveillance
• Office records of physicians
• Hospital admission or discharge records
• Pathology department log books

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• Matched Case Control study
♦ A way of making the cases and controls as similar as
possible for some risk factors other than the exposure
♦ It is through controlling for confounding effect of
other risk factors.
♦ A confounder is unevenly distributed risk factor in the
two groups resulting in distortion of the findings.
♦ When matching is made, the possible confounder is
made distributed equally in each groups.
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• Matching may be done at
• Individual level (each control is matched to its
case)
» Eg: If sex is thought as a confounder
• when a male case is selected, then a male
control will be selected,
• By stratum (balancing overall distribution of cases
and controls)

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• Advantages
♦ Controls confounding effect of the variables on
which it is matched
♦ Improves power to detect effects within strata of
matching variable

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• Disadvantages
♦ May be difficult logistically
♦ May make data difficult to present
♦ Controlling for unmatched confounders difficult
♦ May lead to ‘overmatching’- when matching is
performed on variable which is not a true
confounder (eg related to exposure, or
intermediate in pathway – leads to loss of power to
detect real effect).
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• Analysis
• Compare between cases and controls with respect to
the frequency of an exposure
• This comparison is made primarily by estimating the
RR as computed by the OR
• If the case control study is population based, or if
estimates of disease incidence are available from an
outside source, rates of disease for those exposed and
non-exposed can be computed and compared directly
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• Analysis of matched case-control study

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 • Analysis…
• Evaluate the role of chance by testing the
significance of this measure of association and
calculating confidence intervals
• Cases and controls must also be compared to ensure
similarity with respect to other baseline differences
that could be associated with the risk of developing
the outcome under study

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• Advantages of Case-control Studies

• Assesses well for rare diseases

• It can assess several exposures (determinants) of a

single outcome
• It can be completed within short time (Rapid)

• It can be performed with very cheap or Low cost

• A small sample size may be needed

• It can also be done from available data

• Not needing detailed

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ethical problem/ issues
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• Disadvantages of Case-control Studies

• No direct calculation of rates and risks

• Not suitable for rare exposures

• Problems with bias

– Selection of controls

– Recall

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• Basic elements
• “Disease” free at entry

• Selected by exposure status rather than outcome

• Follow up is needed to determine the incidence of

the outcome in each exposure group
» For non communicable chronic diseases this may
take years

• Compares incidence rates among exposed against

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• Exposure status
• Study subjects should be disease free
• Define study subjects using inclusion and exclusion
criteria on the basis of exposure status
– Environmental factors: smoking, air pollution, pesticides

• Criteria can be specified by amount of exposure

– Eg. Cigarette Smocking (# of cigarette per day)

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• Sources of exposure information
• Pre-existing records: In some circumstances, this
may be the only way to obtain such data accurately.
• Advantages: Such information is usually available
for a high proportion of the cohort & is relatively
inexpensive to obtain.
• Allow objective and unbiased classification of
exposure status

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 • Pre-existing records:
• Disadvantages: The level of detail present in such
records may be insufficient to address specific
research question adequately.
• Such records frequently do not contain data on
potential confounding variables.

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 • Sources of exposure information
• Information supplied by the study subjects themselves
• Particularly useful for collecting information on
exposures that are not routinely recorded.
• A potential for bias always exists in the use of such data
since it cannot be obtained as objectively as from pre-
existing records.
• Stigma associated with certain exposures may influence a
respondents answer

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 • Sources of exposure information
• Direct physical examination or testing
• For some exposures or characteristics direct
physical examination and/or blood testing may be
necessary.
• Provide an objective and unbiased means of
classifying study subjects with respect to exposure

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• Sources of outcome data
• Depend on the specific resources available as well
as the particular disease under investigation
– Death certificates
– Records
– Directly from the study participants
– For those who report an event of interest, additional
information such as hospital records can be obtained to
confirm the diagnosis
– Periodic direct medical examinations
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 • Possible outcomes in cohort
• No disease
• Disease
• Lost to follow up

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• Features of cohort study
• It shows temporal sequence

Exposure Disease

• Good to assess effect of rare exposures

• Could assess multiple effects of a single
exposure

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• Types of cohort studies

• Two forms of cohort study

• The major difference is on the basis of
• Initiation of study and the occurrence of disease.

• The two forms are similar, because selection of

study subjects is made on the basis of their
exposure status.

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• Classical (Prospective) cohort
• The exposure may or may not have occurred at the
time when the study begin, but the outcome has
certainly not yet occurred.

• Historical (Retrospective) Cohort

• Both the exposure and outcome have already
occurred when the study is initiated.

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• Prospective cohort
• Exposure status determined Past Present Future
at present
Exposure Disease
• Study groups followed up outcome
and disease outcome will be
ascertained in the future

• Retrospective cohort
Disease
• Exposure determined in the
Exposure outcome
past from records
• Disease outcome ascertained
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Timing of case-control, prospective and retrospective cohort
study in relation to exposure and outcome.
1. Case control
Exposure Disease
?
?

2. Prospective Cohort
Exposure Disease
?
?

3. Retrospective Cohort
Exposure Disease
?
?

? To be determined Exposure, (+) or (-)

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• Steps in a prospective cohort study
• Define the population at risk (=cohort)

• Determine exposure status to a factor of interest of all

subjects in the cohort

• Make sure that study subjects are free of the disease of

interest at time of enrolment

• Follow exposed and non-exposed forward in time to

ascertain whether they develop the outcome of interest

• Compare the outcomes in the exposed and the

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unexposed group with each other
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• Analysis
• Calculation of incidence rates of the outcome
among the cohorts
• Using these rates, both relative and absolute
measures of association can be calculated and
tested.
• Groups must also be compared to ensure similarity

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Summary
Strength
Is of particular value when the exposure is rare.
Can examine multiple effects of a single exposure.
Can elucidate temporal relationship between exposure and
disease.
Allows direct measurement of incidence of disease in the
exposed and non exposed.

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Summary
Limitations
Is inefficient for the evaluation of rare diseases,
If prospective, can be extremely expensive and time consuming.
If retrospective, it requires the availability of adequate records.
Validity of results can be seriously affected by losses to follow
up.
Loss to follow up is the major source of bias in cohort studies.
Members of cohort may be lost to follow up, if this proportion is
large, > 20- 25 %, it becomes difficult to validate.

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• Types of intervention studies

• Generally considered either therapeutic or preventive

• Therapeutic (secondary prevention) trial: conducted among
patients with a particular disease to determine the ability of an
agent or procedure to diminish symptoms, prevent recurrence, or
decrease risk of death from that disease.

• Preventive (primary prevention) trial: It involves the evaluation

of whether an agent or procedure reduces the risk of developing
disease among those free from that condition at enrolment It can
be studied among either individuals (Field trial) or entire
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• Clinical Trials:-
• Unit of intervention is a patient, site of intervention is a
health care facility.
• Intervention is not a primary preventive measure because
subjects are already diseased.
• Usually intervention is a form of treatment.

• Subjects are diagnosed with health outcome of interest and

selected to either treatment options.
• Groups are comparable because selection into groups is
unbiased (randomization or matching)
• Longitudinal
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• Example - Insulin Therapy and Diabetes
• Two treatment groups : Intensive insulin and
standard insulin therapy
• Subjects randomized into groups
• Subjects followed-up in time and evaluation of
presence or absence of retinopathy is done.

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• Field Trials:-
• Unit of intervention is healthy individuals

• Site of intervention is the community.

• Priori hypothesis about effect of intervention is

assessed
• Because probability of disease is small, a large number
of subjects are needed
• Individuals are randomly selected to intervention
groups
• Subjects are measured
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 • Community Interventions:- unit of
randomization may be a family or
community (‘cluster’).

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• Other ways of classifying intervention studies

• Uncontrolled trial
• No control group

• Control will be past experience (history)

• Non-randomized controlled trial

• There is control group
• Allocation to either group is not randomized

• Randomized controlled trial (RCT)

• There is control group there is random allocation of subjects
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 • Other ways of classifying
• Phase I: trial on small subjects to test a new drug with small
dosage to determine the toxic effect.
• Phase II: trial on small group to determine the therapeutic
effect
• Phase III: Study on large population, Usually randomized
controlled trial
• Phase IV trials: -marketing long term monitoring for
adverse effects.

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• Main steps in an RCT
• Identify new drug/intervention/prevention
• Identify comparison group e.g standard treatment versus placebo

• Define eligible patient population/ exclusions (i.e the sampling

frame)
• Define the outcomes and how to assess them
• Write the protocol

• Obtain research ethics committee approval

• Recruit & consent required sample of patients

• Randomise to treatment, then treat

• Follow-up & compare/analyse outcome data

• Publish/disseminate findings
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• Considerations for Selection of study population
• Must be sufficiently large to achieve the required sample
size for the trial
• Likelihood of obtaining complete and accurate follow-up
information for the period of trial.
• Must produce sufficient number of endpoints
• Subjects must be invited to participate after being fully
informed
• Those willing to participate must then be screened for
eligibility according to predetermined criteria
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 • Considerations for Selection…
• Those who are eventually determined to be both
willing and eligible to enrol in the trial compose the
actual study population
• Obtain baseline data for subjects who are eligible
but unwilling to participate
• This will aid in the judgment of whether the results
among trial participants are generalizable to the
reference population.
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• Allocation of study regimens
• Assignment to a study group should be at random
• Random assignment implies that each individual
has the same chance of receiving each of the
possible treatments

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• Advantages of Randomization
• The potential for bias in allocation to study groups
is removed
• Study subjects will tend to be comparable with
respect to all variables except for the interventions
being studied.
• When the sample size is sufficiently large, both
known and unknown confounding factors are
distributed equally among treatment groups.
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• Ascertainment of outcome
• Need for uniform ascertainment of outcome
• Maintain a high level of follow-up
– Reduce the proportion of outcomes that are not
ascertained to the minimum and comparable between the
two groups

• Use of placebo and blinding to prevent bias in

identification and reporting of event of interest.

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 • Ascertainment of outcome…
• Knowledge participants treatment status might
influence the identification of or reporting of
relevant events
• The likelihood of such bias is directly related to the
subjectivity of the outcome under study
• Keep the study participants and/or the investigators
blinded

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• Blinding
• Blinding prevents biases related to assignment,
assessment, or compliance.
• Eliminates the potential for observation bias:
– In reporting of side effects
– In assessing outcome

• Eliminates differential compliance or loss to

follow-up.

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 • Ascertainment of outcome…
• The use of a placebo will ensure that all aspects of the
program offered to participants are identical except for the
actual experimental treatment.
• One problem in the evaluation of such end points is the
tendency for individuals to report a favourable response to
any therapy regardless of the physiologic efficacy of what
they receive ( placebo effect).
• This is due to the psychological effect than any true
physiologic benefits.
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• "Run-in or Wash out" period
• Strategy to increase compliance
• All participants receive either the active treatment
or the placebo for a number of weeks or months
before formal randomization to a treatment group.
• Subjects failing to comply with the study
procedures are eliminated before actual
randomization

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• Feasibility/ Practical Issues

• Subject recruitment
• Getting adequate individuals to enrol into a difficult study is not
easy.

• Field trials particularly require greater number of subjects since

the risk of contracting a given disease for the first time is small.

• Loss to follow-up
• Select population who are both interested and reliable.

• Arrange frequent contacts with individuals

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• Use incentives, such as providing medical information
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• The quality of "gold standard" in intervention
studies
• Randomization

• Use of placebo

• Blinding

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• Analysis
• Similar to cohort studies

• Compare the rates of the outcome of interest in the treated

group(s) and the corresponding rates in the comparison
group(s).
• The roles of chance, bias, and confounding must be evaluated

• Compare the relevant characteristics of the randomized

treatment and comparison groups to assess balance is achieved.

• This comparison should always be presented as one of the first

tables in the report of the study findings
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• Limitation
• Ethical considerations
 Substances already known to be harmful should
not be used in this study.
• Feasibility/ practical issues
• Cost - experimental studies are often very
expensive because of the long follow-up period.

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