157

chemotherapy,
and
autologous
bone marrow
transplantation.
Lancet
1989;
ii: 891-95.
20 Steward WP, Scarffe
JH,
Dirix
LY,
et al.
Granulocyte-macrophage
colony-stimulating
factor
(GM-CSF)
after
high-dose melphalan
in
patients
with advanced colon cancer.
Br J
Cancer
1990;
61: 749-54.
21 Nemunaitis
J,
Rabinowe
SN, Singer JW,
et al. Recombinant
granulocyte-macrophage colony-stimulating
factor after
autologous
bone marrow
transplantation
for
lymphoid
cancer. N
Engl J
Med
1991;
324: 1773-78.
22 Socinski MA,
Cannistra SA,
Elias
A,
Antman
KH, Schnipper L,
Griffin JD. Granulocyte-macrophage colony-stimulating
factor
expands
the
circulating haemopoietic progenitor
cell
compartment
in
man. Lancet 1988;
i: 1194-98.
23 Sheridan WP, Begley CG, Juttner CA,
et al. Effect of
peripheral-blood
progenitor
cells mobilised
by filgrastim (G-CSF)
on
platelet recovery
after
high-dose chemotherapy.
Lancet
1992;
339: 640-44.
24 Hammond WP,
Price
TH, Souza
LM,
Dale DC. Treatment for
cyclic
neutropenia
with
granulocyte colony-stimulating
factor. N
Engl J
Med
1989; 320:
1306-11.
25 Schuster MW,
Liu
ET, Solberg LA,
et al.
Granulocyte-macrophage
colony-stimulating
factor
(GM-CSF)
for
aplastic
anemia
(AA):
preliminary
results of a multi-centre randomised controlled trial. Blood
1990;
76: 47
(abstr).
26 Miles SA, Mitsuyasu RT, Moreno
J,
et al. Combined
therapy
with
recombinant
granulocyte colony-stimulating
factor and
erythropoietin
decreases
hematologic toxicity
from zidovudine. Blood 1991; 77:
2109-17.
27 Pluda
JM,
Yarchoan R,
Smith
PD,
et al. Subcutaneous recombinant
granulocyte-macrophage colony-stimulating
factor used as a
single
agent
and in an
alternating regimen
with
azidothymidine
in
leukopenic
patients
with severe human
immunodefficiency
virus infection. Blood
1990; 76: 463-72.
28 Wodzinski
MA, Hampton KK, Reilly JT.
Differential effects of
G-CSF and GM-CSF in
acquired
chronic
neutropenia. Br J
Haematol
1991;
77: 249-250.
29 Lieschke
GJ,
Cebon
J, Morstyn
G. Characterisation of the clinical
effects after the first dose of
bacterially synthesised
recombinant
human
granulocyte-macrophage colony-stimulating
factor. Blood
1989;
74: 2634-43.
30 Bennett
CL, Greenberg P,
Gulati
SC,
Advani
R,
Bonnem E.
GM-CSF decreased duration of
cytopenia
and
hospitalization,
and
in-hospital
costs in
patients
with
Hodgkins
disease treated with
high-dose chemotherapy
and
autologous
bone marrow transfusion
(ABMT).
Blood
1990;
76: 132
(abstr).
31 Sachs L. The control of
growth
and differentiation in normal and
leukemic blood cells. Cancer
1990;
65: 2196-206.
Making comparisons
Center for Clinical
Epidemiology
and
Biostatistics, University
of
Pennsylvania,
317R
Nursing
Education
Building/6095, Philadelphia,
Pennsylvania, 19104,
USA (Jeane Ann Grisso MD)
When
making
clinical
choices,
we often
rely
on standard
approaches taught
when we trained or are influenced
by
colleagues, experience,
or the latest
reports. Unfortunately,
initial
reports
often mislead because the
study
did not
include a
comparison group
or included an
inappropriate
one. In the 1950s an
accepted
method of
treating angina
involved
ligation
of the internal
mammary artery.
Initial
reports (involving
series of treated
patients)
showed sub-
stantial
improvement
in
symptoms. However,
in
1959,
a
study randomising patients
to a "sham"
operation
or to
ligation reported equal improvements
in both
groups2
and
the
procedure
fell into
disrepute.
In the
1960s, coronary
artery bypass surgery (CABG)
was introduced for the
treatment of
coronary artery
disease. Initial
reports (again
based on series of treated
patients)
showed that
angina
symptoms improved significantly
and
mortality
rates were
lower than those in
past groups
of
patients
treated with
drugs. Although subsequent
controlled trials demonstrated
that
mortality
rates were
improved
in
only
a subset of
patients,
the number of CABGs in the US increased more
than sixfold from 1976 to 1986.3,4
Comparisons
are crucial in
reaching
conclusions about what is normal or abnormal or
in
determining
whether a treatment
improves
the course of
the disease.
The
strength
of the
experimental
method lies in the
investigators
control over the selection of treatment
groups,
nature of
interventions,
and
management during
follow-up,
in order to make unbiased
comparisons.
How-
ever, many
clinical
questions
cannot be
ethically
or
logistically
addressed
by experimental
studies. Does
postmenopausal oestrogen therapy
cause breast cancer?
Does
passive smoking
cause
respiratory
illness? To address
these
questions,
observational studies are
designed
in which
the
investigator
does not control the
therapy
or
exposure
but
attempts
to make valid
comparisons
between individ-
uals with or without diseases or between those
"naturally"
Panel:
Advantages
and
disadvantages
of
major
-
epidemiological study designs
Adapted from Strom,$with perm issfon.
158
exposed
or
unexposed
to a factor of interest. The
panel
summarises the
advantages
and
disadvantages
of the
different
experimental
and observational
designs.
Observational studies
In an observational
study,
the
investigator
is not able to
specify
the
exposures
or treatments for
study subjects.
Observational studies are often further divided into
descriptive (case reports,
case
series)
and
analytic (cross-
sectional, case-control,
and
cohort)
studies. Data from
descriptive
studies can be used to
generate hypotheses.
Analytic
studies are
designed specifically
to test
hypotheses
about risk
factors, allowing
more definitive conclusions.
Case
reports
and case series
Case
reports provide
detailed clinical and
laboratory
results
for 1
patient
or a small
group
of
patients
whereas case series
are
descriptions
of
larger
numbers. Patients often come
from a
single hospital
or medical
practice
and thus
may
not
be
typical.
Without a
comparison group,
we cannot be
certain which features in the
description
of the
patients
are
unique
to the
exposure
or disease. For
example,
the
original
case series of what was later identified as AIDS included
small numbers of
young
homosexual men with unusual
disorders,
such as
Kaposis
sarcoma.6 It was not
possible
from these studies to know whether AIDS was associated
with
being young
and homosexual without
comparing
the
rates of disease in other
groups.
Case
reports
and case series
are used to raise
hypotheses
and data from
laboratory
studies
may
contribute to our
understanding
of the
mechanisms of disease.
Cross-sectional studies
In a cross-sectional
study, exposure
to a
possible
risk and
the
presence
of disease at one
point
in time are assessed in a
population group.
Prevalence
(number
of cases of
existing
disease
per population
at
risk)
can be
compared among
those with and without current
exposure
to the factor of
interest. For
instance, comparison
of the estimated
preva-
lence of AIDS for different
population groups thought
to
vary
in risk showed that the
highest
rates were found
among
young single
men in certain
geographical regions
in the US
as well as
among patients
who had received
multiple
blood
transfusions or who had
haemophilia.7
In a cross-sectional
study,
the
timing
of
exposure
and
onset of disease cannot be determined. For
example,
we
might
learn that obese individuals are more
likely
to have
osteoarthritis than non-obese individuals.8
However,
in a
cross-sectional
study
it would not be clear whether
obesity
causes osteoarthritis or whether
people
with osteoarthritis
tend to
get
less exercise and therefore become obese.
Thus,
for these
studies, interpretation
of measures of association
between
exposures
and disease is often limited because of
the uncertain
temporal sequence. Nevertheless, prevalence
studies are useful to describe the extent of the disease and
exposures
in the
population, especially
for chronic diseases.
Ecological
studies
These studies evaluate correlations or trends based on
information derived from
groups. Usually, routinely
col-
lected information on disease rates is
compared
with
available data on the
general
level of
exposure
for selected
geographical areas-eg,
male circumcision
practices
in
different countries in Africa have been
compared
with the
HIV
seroprevalence
rates in those countries.9
Comparisons
Figure:
Cohort and case-control studies
These studies
provide
similar information but
approach
data from
opposite
directions.
(Reprinted
from Strom,l2 with
permission.)
may
be made across
geographical regions
or over time
(called analyses
of secular trends or time-series
studies).
For
example,
a secular trend
analysis
demonstrated a
correlation between sales over time of
Rely tampons
and the
toxic shock
syndrome epidemic.10
Ecological
studies are most useful in
raising hypotheses.
However,
these studies lack data on individuals and cannot
identify
a factor as a true
cause,
since other factors
may
account for the association.
Inappropriate
conclusions
about associations identified from
ecological
data are often
referred to as the
"ecological fallacy". 11
Case-control studies
The use and
understanding
of case-control studies are
major developments
in
epidemiology.
Case-control studies
compare persons
with a disease with controls without the
disease, looking
for differences in
previous exposures
(figure).
As an
example,
women with
hip
fractures have
been
compared
with controls without
hip fractures,
with
assessment of
previous
use of
postmenopausal oestrogen
therapy.
Such studies have
generally
demonstrated a
strong
protective
association between the use of
oestrogen therapy
and
hip
fractures.13,14 Case-control studies
usually
obtain
information on
exposures retrospectively. Thus,
research-
ers must
rely
on
memory
and the
accuracy
and
complete-
ness of medical records. The
difficulty
of assessment of
exposure,
often termed information
bias,
is a
major
limitation to case-control research.
Another
challenge
is the selection of controls. The
objective
is to choose individuals
representative
of the
theoretical
population
to which the cases
belong.
This is
often defined as the
population
in which its
members,
had
they developed disease,
would have been selected as cases.
Controls should be selected
independently
of the
exposures
of interest. One of the first case-control studies of AIDS
included,
as a control
group,
homosexual men
seeking
care
in a
sexually
transmitted disease
(STD)
clinic.15 The
proportion
who
reported
anal intercourse in the
previous
year
did not differ between cases and controls because the
control
group
was selected on the basis of
being
homosexual
and
sexually
active.
Case-control studies can be
particularly
useful in
studying multiple possible
causes of a
single disease,
because several different
potential
risk factors can be
investigated
with the same cases and controls. This
design
is also useful when
studying
a rare disease because it
guarantees
a sufficient number of cases while
maintaining
smaller
sample
sizes than those needed for cohort studies.
159
Cohort studies
Two or more
groups
who are free of the disease under
study
and differ
according
to
exposure
to a
potential
cause of the
disease are observed over time to
compare
the incidence of
disease in each
group (figure).
Cohort studies can be done
concurrently
or
not, by creating exposure groups
from
past
records and
following
them
up
from that time to the
present.
Persons are recruited disease-free on the basis of
exposure,
and their
subsequent
disease course is then
studied. For
instance,
the Centers for Disease Control and
Prevention has followed health-care workers to assess HIV
infection rates in workers
exposed
to the blood of HIV-
infected
patients.16
Usually
both the
exposed
and
unexposed
cohort mem-
bers come from a similar
subgroup
of the
population.
In
some
studies, however,
an external
comparison group,
such
as the
general population,
is used. General
population
groups
are not ideal in studies
evaluating occupational
exposures,
because workers are
usually
healthier than the
general population (the healthy
worker
effect)-healthier
people
are more
likely
to
get jobs
and continue to work. For
example,
in a
study
of carbon
disulphide exposure
and
coronary
heart
disease, exposed
workers had
higher
mor-
tality
rates from
coronary
heart disease than workers in the
paper industry
in the same
town,
but the rates in the
paper
industry
workers were lower than those in the
general
population. 17
Concurrent cohort studies have fewer
problems
with
information bias than case-control studies because of the
prospective
collection of data. Cohort studies are
particu-
larly
useful to
study multiple possible
outcomes from a
single exposure. Finally, exposure-specific
rates of disease
can be calculated
directly. Unfortunately,
a cohort
design
is
often limited because the incidence of disease is
low,
which
means that a
large
number of
people
must be followed
up
for
a
long
time before results are available.
Experimental
studies
In an
experiment
the
investigator assigns
the
exposure
to
the
subject.
Thus ethical constraints limit
experimental
studies to evaluation of
therapeutic
or
preventive
interven-
tions. There are two forms
of epidemiological experiments.
Clinical trials
Individuals in the
experimental
or treated
group
are
exposed
to the intervention and individuals in the control or
comparison groups
are not. The clinical course of both
groups
is observed and
any
differences in outcome are
attributed to the intervention. Numerous
strategies
have
been used to assemble
comparison groups. Subjects may
serve as their own
comparators
before intervention.
Comparison groups may
be selected from another
geo-
graphical
location or time
(historical controls).
These
approaches
are limited
by
the fact that location and time are
almost
always
related to
outcomes, making
it difficult to
disentangle
the true effect of the intervention. Sacks et al18
reviewed clinical trials to see if the use of concurrent as
opposed
to historical controls
produced
different results.
Only 20%
of trials with a
concurrent,
randomised control
group
found the
experimental
treatment to be
better,
compared
with
79%
of trials with historical controls. In
general, choosing
concurrent controls from a similar setting
reduces this
problem
to a minimum. To evaluate the
unique
effects of a clinical intervention without
bias,
the best
way
to
assemble a
comparison group
is to
assign subjects randomly
to either the treatment or control
group.
Randomised
controlled trials can
occasionally
be used to
study
the cause
of disease. For
example,
to answer the
question
of whether
STDs enhance the transmission of HIV
infection,
some
investigators
advocate randomised trials to assess whether
intervention
against
STDs reduces the transmission of
HIV.19
Randomised clinical
trials, however,
are
expensive
and
artificial: often
only
a select
subgroup
of
patients
is
included. Common exclusion criteria are
atypical disease,
the
presence
of other
diseases,
an
unusually poor prognosis,
and contra-indications to one of the treatments .20 Because
the
group
of
patients
is
restricted, generalising
from the
results to other
patients
is limited. Randomisation
may not,
by
chance
alone,
result in similar
groups.
Differences
arising
after randomisation
(such
as in
drop-out rates,
participants receiving
other interventions
unequally,
and in
adherence)
can also bias
study
results.
Community
trials
These involve an intervention on a
community-wide
rather
than an individual basis and are
necessary
when the
intervention cannot be
easily implemented separately
for
individuals.
Examples
include interventions
involving
the
media,
or the use of water fluoridation to
prevent
dental
caries.
Community
trials are often
designed
to
prevent
disease occurrence and thus can be
large
and
expensive.
The main
problem
is
assignment
of the intervention to
ensure
similarity
of the
groups.
Conclusions
In
general,
we
proceed
from case
reports
and case
series,
which
suggest
an
association,
to case-control
studies,
which
explore
the association. If a
question
warrants the
delay,
cohorts can be studied.
Finally,
clinical trials can be used to
answer
questions
about
therapeutic
or
preventive efficacy.
For
instance,
as the AIDS
epidemic unfolded,
the first
published reports
were of clinical observations of small
numbers
(case series).
These were followed
by descriptive
epidemiological analyses
of the
prevalence
of the disease in
different
population groups
and in different
geographical
areas
(cross-sectional
and
ecological studies). Next,
case-
control and cohort studies were
designed
to
identify
risk
factors and
prognostic
factors.
Now,
trials are
being
done to
evaluate treatment and
preventive
measures.
Although
each
design
has an
appropriate
role in contri-
buting
to our
understanding
of health and
disease,
clini-
cians should be aware of the limitations of each
type
of
study.
In
any one study,
a
reported
association
may
have
occurred
by chance,
and even a true association
may
not
apply
to all
population groups. Findings
should therefore
be evaluated
critically
and in the context of
existing
knowledge.
References
1 McGoon DC.
Prologue:
from whence? Cardiovasc Clin
1987;
17:
xvii-xv.
2 Cobb LA,
Thomas
GI,
Dillard DH,
Merendino
KA, Bruce RA. An
evaluation of
internal-mammary-artery ligation by
a double-blind
technic.
N Engl J Med 1959; 260: 1115-18.
3
Lytle BW, Gosgrove D, Loop
FD. Future
implications
of current
trends in
bypass surgery.
Cardiovasc Clin
1991;
21: 265-78.
4
Murphy ML, Hultgren HKN,
Detre
K,
et al. A
preliminary report
of
survival data of the randomised Veterans Administration
Cooperation
Study.
N
Engl J
Med
1977;
297: 621-27.
5 Strom BL.
Pharmacoepidemiology.
New York: Churchill
Livingstone,
1989: 13-26.
6
Anonymous. Kaposis
sarcoma and
pneumocystis pneumonia among
homosexual men-New York
City
and California. MMWR 1981;
30
(July 3):
305.
160
7
Hardy AM, AllenJR, Morgan WM, Curran
JW.
The incidence rate of
acquired immunodeficiency syndrome
in selected
populations. JAMA
1985;
253: 215-20.
8
Kelsey J, Thompson WD,
Evans AS. Methods in observational
epidemiology.
Oxford:
OUP, 1986: 3.
9
Bongaarts J, Reining P, Way P,
Conant F. The
relationship
between
male circumcision and HIV infection in African
populations.
AIDS
1989;
3: 373-77.
10
Anonymous.
Toxic-shock
syndrome—United States,
1970-1980.
MMWR 1981; 30: 25-28.
11 Michael M
III, Boyce WT,
Wilcox
AJ.
Biomedical
bestiary:
an
epidemiology guide
to flaws and fallacies in the medical literature.
Boston: Little,
Brown and
Co,
1984.
12 Strom BL. Medical databases in
postmarketing drug
surveillance.
Trends Pharmacol Sci
1986; 7: 377.
13 Williams
AR,
Weiss
NS,
Ure
CL,
et al. Effect of
weight, smoking,
and
estrogen
use on the risk of
hip
and forearm fractures in
postmenopausal
women. Obstet
Gynecol 1982; 60: 695-99.
14
Kreiger N, Kelsey JL,
Holford TR,
OConnor T. An
epidemiologic
study
of
hip
fracture in
postmenopausal
women.
Am J Epidemiol 1982;
116: 141-48.
15
Jaffe HW, Choi
KW,
Thomas
PA,
et al. National case-control
study
of
Kaposis
sarcoma and
Pneumocystis
carinii
pneumonia
in homosexual
men:
part I, epidemiological
results. Ann Intern Med 1983;
99:
145-51.
16 Henderson
DK, Fahey BJ, Willy M,
et al. Risk for
occupational
transmission of human
immunodeficiency
virus
type
1
(HIV-1)
associated with clinical
exposure:
a
prospective study.
Ann Intern Med
1990;
113: 740-46.
17 Wen CP, Tsai
SP,
Gibson RL.
Anatomy
of the
healthy
worker effect: a
critical
review. J Occup
Med
1983;
25: 283-89.
18 Sacks
H,
Chalmer
TC,
Smith H
Jr.
Randomized versus historical
controls for clinical trials. Am
J Med 1982; 72: 233-40.
19 Mertens
TE, Hayes RJ,
Smith PG.
Epidemiological
methods to
study
the interaction between HIV infection and other
sexually
transmitted
diseases. AIDS
1990;
4: 57-65.
20 Fletcher
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Fletcher
SW, Wagner
EH. Clinical
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essentials. 2nd ed. Baltimore: Williams &
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Viewpoint
What have teachers learnt?
Social and Behavioral Sciences
Branch,
Technical
Support Division,
International Health
Program Office,
Centers for Disease Control
and Prevention, F-03,
Clifton
Road, Atlanta, Georgia 30333,
USA
(J Bryce EdD,
J F Naimoli
MPH); London School of
Hygiene
and
Tropical
Medicine (F Cutts
MD);
and Save the Children
Fund, London,
UK
(F Cutts, M
Beesley)
Correspondence
to: Dr Jennifer
Bryce
"No-one doubts the contribution that
training
can make to
development
of all kinds.
Training
is
essential, obviously
so.
The doubt comes over its contribution in
practice.
Complaints
are
growing
about its effectiveness and waste...
Yet
training
continues to be in fashion. No
self-respecting
country
does without it."
Rolf
P
Lynton,
Udai
Pareek,
19671
25
years
after
they
were
written,
these words are still
relevant.
Why?
Have we learnt
nothing,
or are we unable to
apply
what we have learnt? We raise a series of
questions
that we
hope
will stimulate assessment and
improvement
of
training programmes
for health workers in
developing
countries.
Is
training
the
only
solution?
A common
response
to difficulties with
delivery
of health
services is to initiate or
expand
an in-service
training
programme.
In-service
training
can
improve
health
workers
knowledge
and
skills,2.3
but does not
guarantee
that
they
will
provide adequate
services.4-6 In studies in
Cote dlvoire and
Niger State, Nigeria
trained health
workers knew how to treat children with fever and
diarrhoea
correctly,
but could not do so because of
shortages
of oral
rehydration
salts in
Nigeria
and
antimalarial
drugs
in Cote dlvoire.
Similarly,
in Zambezia
province, Mozambique,
over
50%
of difficulties identified
during supervision
were attributable to
inadequate logistic
support.
For
training
to
improve services,
new skills must
be
complemented by
available commodities and other
essential resources.4
Workshops:
the
magic
wand
Workshops
are attractive.
They
are
discrete,
time-limited
activities;
funds can be disbursed
quickly;
and trainees can
be counted
easily.
The ultimate measure of effective
training, however,
is
improvement
on the
job.l
In
Nigeria,
for
example,
an observational
study (Continuing
Education
Unit, Ministry
of
Health, Niger State, Nigeria,
un-
published)
assessed health worker
performance
in demon-
strating
the
preparation
of oral
rehydration
solution to
parents
of children with diarrhoea.
82%
of
parents
who
consulted trained and
supervised
health workers received a
demonstration, compared
with 33
%
of those who consulted
untrained and
unsupervised
workers. To
improve
on-the-
job performance, workshops
must be
part
of a continuous
process
of
training
and
supervision.
Planners must assess
the
learning
needs of
trainees, develop
curricula to meet
these
needs, provide
various
opportunities
for
learning,
and
monitor and follow
up participants.
Standard curricula:
penny-wise
and
pound-foolish?
Train
large
numbers of
people
and train them
quickly!
International
agencies
have
developed
and disseminated
standard curricula to attain these
goals.
The
potential
advantages
are clear. Standard curricula can be
targeted
to different tiers in the health
delivery system
and
adapted
to local situations
by
trained "facilitators".
They
can be
incorporated quickly
into
training pro-
grammes
at low cost to ministries of health and used to
promote procedures
consistent with international health
standards.
However, prepackaged
materials have limitations. Their
predetermined content, format,
and instructions to trainers
may
not be
appropriate
for the skill levels of trainees. Some
target-setting
manuals have
seriously
overestimated the
quantitative
skills of
peripheral
health workers.4
Manage-
ment
training
materials do not
always recognise
the limited
background, skills,
and
decision-making powers
of district
personnel.8
8
Training
materials should
respond
to
changing public
health needs and
priorities,
which
vary widely among
countries.
Although
there are
increasing
efforts to
support
local
adaptation
of standard
materials,
successful training
will
require
that national
capacity
in
designing
instructional
programmes
and materials be built
Up.1.9,10
For
example,
capacity
for curriculum
development
was
expanded among
Ministry
of Health
personnel
in the Central African
Republic through
the
development
of
training
in immunis-