pharmacoepidemiology and drug safety 2001; 10: 5±11
DOI: 10.1002/pds.562
INVITED PAPER
The role of cohort studies in medical research
Michael Goldacre*
University of Oxford, UK
Cohort studies have a number of applications in med-
icine, including the study of growth, development,
ageing and the natural history of disease; and, in aetio-
logical epidemiology, the investigation of causes and
risks of disease.1±3 In this paper I mainly cover the
role of prospective cohort studies in studying aetiol-
ogy, causes and risks, using Martin Vessey's Oxford/
Family Planning Association study of contraception
and women's health as the example; and I will brie¯y
discuss retrospective cohort studies.
The cohort study is one of the major investigative
strategies of aetiological epidemiology, so the starting
point is to consider brie¯y the role of aetiological epi-
demiology itself. Aetiological epidemiology is con-
cerned with the identi®cation of factors which cause
disease. Several disciplines, of course, seek to learn
about the causes of disease. The distinctive contribu-
tion of epidemiology is its study of patterns of the dis-
tribution of disease in de®ned populations or groups
of people, combined with study of the distribution
of factors which the investigators consider may be
contributing causes. The concept of cause is funda-
mental; awareness of the possibility of obtaining spur-
ious associations, through bias and confounding, is a
central feature in the design, analysis, and interpreta-
tion of epidemiological studies.
To set epidemiology alongside other branches of
medicine with interests in causation, and at the risk
of over-simpli®cation, epidemiological methods are
aimed at asking questions about whether a factor,
extrinsic to the individual (an environmental or beha-
vioural characteristic), causes the disease of interest
and, if so, by how much. Laboratory sciences, when
applied to causation, tend to be concerned with
mechanisms of how the factor might cause disease.
* Correspondence to: Dr M. Goldacre, Unit of Health Care
Epidemiology, Institute of Health Sciences, Old Road, Headington,
Oxford OX3 7LF, UK.
Copyright # 2001 John Wiley & Sons, Ltd.
COHORT STUDIES IN THE HIERARCHY
OF EPIDEMIOLOGICAL STUDIES
The ®rst clues that a particular factor (e.g. the use of
oral contraceptives) might cause disease (e.g. throm-
boembolism) typically come from clinicians, with
their insights into the personal circumstances of the
individual patients whom they see, or from hypotheses
generated from laboratory science. Typically, the
initial idea is followed by the assembly of a clinical
series of patients to determine whether the proposed
cause and disease do indeed seem to coincide. Next,
routine mortality and morbidity statistics may be used
to seek associations between the proposed cause and
the disease by studying whether (for example) they
tend to change together over time, and whether the
putative cause and disease tend to be found together
in different groups of people de®ned by such chara-
cteristics as area of residence, age, gender, and
occupation.
Ecological studies, like these, using routinely col-
lected data are useful for generating or testing the plau-
sibility of aetiological hypotheses. However,
epidemiologists will usually wish to proceed to case±
control, cohort or experimental studies to test whether
the observations made on populations as a whole can
be con®rmed in groups of people de®ned according to
whether they, as individuals, have experienced the
aetiological factor under study and manifest the disease.
The starting point for a case±control study is the
identi®cation of a group of individuals all of whom
have the illness under study and of an appropriate
`control' group of individuals none of whom have the
illness (Fig. 1). Information about prior exposure to
the suspected cause is then sought. The exposure of
the case and control group to the suspected cause is
compared to determine whether it is any commoner
among the cases than the controls. In a cohort study,
groups of people are identi®ed according to whether
Received 11 July 2000
Accepted 2 November 2000
6 m. goldacre

Case±control
* people de®ned by whether they do (cases) or do not (controls) have the
disease B, with information sought on prior exposure to A
Cohort
* people de®ned by whether they do or do not have exposure A, prior to
development of disease, followed up to determine the subsequent
occurrence of disease B

Figure 1. Design of case±control and cohort studies to address the question: does exposure/environment/behaviour A
cause disease B?

or not they have not been exposed to a factor which is
thought to cause the disease of interest (Fig. 1). These
groups of people, with and without the exposure, are
then observed over a period of time to determine and
compare the frequency of disease between the groups.
Case±control studies involve many fewer subjects
than cohort studies: they are relatively quick, cheap,
and easy to undertake. Cohort studies usually need
observations on large numbers of individuals, with
long periods of follow-up, and are generally slow to
yield answers, expensive, and complex in their execu-
tion. Some of their main characteristics are contrasted
in Fig. 2.
Studies which are observational rather than experi-
mental, including case±control and cohort studies, are
potentially ¯awed. In free-living, non-experimental
populations, associations found between an exposure
and a disease may have explanations which are not
cause and effect but which come about as a conse-
quence of study bias and confounding. The most ef®-
cient way of removing the effects of bias and
confounding±strictly speaking, the only way±is by
the experiment of exposing a randomized group of
individuals to the factor thought to cause disease; pro-
tecting another randomized group from exposure; and
studying the subsequent development of disease in the

Case±control
* 100 cases; 100 controls (or more, e.g. 200 or 300 depending on precise
design)
* disease has occurred
* answer about hypothesis available soon
* biases in study may be hard to eliminate (e.g. recall bias)
* exposures, as they were many years ago, may be hard to quantify
Cohort
* 100 000 people followed to get 100 cases
* disease awaited
* answer in 10±20 years
* less prone to bias; more reliable information about exposure
* gives absolute risk as well as relative risk
* wide range of outcomes of exposure can be studied

Figure 2. Some contrasting features of case±control studies and cohort studies in studying a hypothesis about a disease and
exposure when the incidence of disease is 1 in 1000 people, and latent period from exposure is 10±20 years

Copyright # 2001 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety 2001; 10: 5±11
 cohort studies in medical research
groups. However, a randomized trial of a potentially
harmful exposure is generally not an option. The par-
ticular role of the cohort study is its use when a pro-
spective study is needed to answer an important
epidemiological cause-and-effect and when an experi-
mental intervention study is not possible.
THE OXFORD/FAMILY PLANNING
ASSOCIATION CONTRACEPTIVE
COHORT STUDY
This study followed the typical epidemiological cas-
cade. Clinical speculation that oral contraceptive use
might have caused cases of venous and arterial throm-
boembolism were followed by case±control studies.
The latter included studies described in four papers
by Martin Vessey and colleagues4±7 which, inciden-
tally, are among the 50 most cited British Medical
Journal papers as recorded in the 1945±89 science
citation index.8
It was then decided that a cohort study of oral con-
traception, and of other contraceptive methods, should
be undertaken. The reasons for this included the need
to collect reliable current and prospective inform-
ation about contraception, and about important con-
founders, the need to identify a wide range of
bene®cial and potentially harmful outcomes, and the
need to quantify absolute risk for any harmful out-
comes. The Oxford/FPA study started in 1968.9±11
Its aim was to study the long-term ef®cacy and
safety of a number of contraceptive methods in
women; and, in particular, to provide a balanced view
of the bene®cial and harmful effects of different meth-
ods of contraception. The advent of widely available,
effective contraception±particularly in the past 30
years or so has±been one of the most important devel-
opments in the social history and social evolution of
humankind. Accordingly, the issue of the ef®cacy
and safety of reliable, easy-to-use contraceptive
methods has clearly been one of considerable
importance.
The study recruited 17 000 women from 17 clinics
in different parts of the United Kingdom. It involved
the prospective collection of information about con-
traceptive methods, and about social and behavioural
factors of relevance to choice of contraceptive meth-
ods and to health and disease. It also involved collect-
ing data on changes over time in these factors. Indeed,
one of the most important de®ning features of a pro-
spective cohort study is its role in capturing the
dynamic nature of risk factors, which may change
Copyright # 2001 John Wiley & Sons, Ltd.
7
over time. The study involved both personal follow-
up and ¯agging in the NHS central register. For perso-
nal follow-up, a special form was kept in the clinic
folder of each participant in the study. Entries were
made on this form, by doctors or nurses who were spe-
cially instructed in the use of the forms, each time the
subject returned to the clinic. This provided a contin-
uous record of pregnancies and their outcome, hospi-
tal admissions and outpatient attendances, and all
changes in contraceptive practices together with rea-
sons for the changes. Each follow-up form was
retained in the subject's folder for approximately 1
year, after which it was sent to Oxford and replaced
by another. Subjects who ceased to attend the clinic
were sent a postal version of the follow-up form. If
this was not returned, research assistants contacted
the subject by telephone or visited her at home. Cod-
ing of all diagnostic information was undertaken
throughout the full duration of the study by Martin
Vessey himself. Analyses of the data were undertaken
by Martin Vessey and colleagues in Oxford.
The study has been an impressive and formidable
undertaking. It has yielded results of considerable
importance and in¯uence. Its ®ndings have included
information of the ef®cacy of contraceptive methods
and on the return to fertility after their cessation.12±
21
It helped to con®rm the fact that vascular risk was
associated with high dose oral contraceptives and, no
doubt, helped in¯uence manufacturers to seek safer
formulations. In addition to cardiovascular and cere-
brovascular disease, publications have included stu-
dies of oral contraceptives and ovarian cancer, breast
cancer, gall bladder disease, and a wide range of other
conditions.22±55 It has also yielded much important
information about disease in relation to other contra-
ceptive methods.56±63
One of the major advantages of a cohort study is
that, unlike a case±control study, it yields measures
of absolute risk as well as relative risk. Table 1 shows
the important ®nding, from one of the early papers
from the study, that the risk of thromboembolism
was considerably higher in pill-users than in non-
users. As a point estimate, the relative risk was about
7 times higher. The measure of relative risk is very
important, because it shows the strength of association
between the pill (of its generation) and the disease. It
is not, however, a suf®cient measure on which to
assess the full clinical and public health importance
of the risk. The study also provided the context of
how common the condition actually is±the risk is
expressed here per 1000 woman-years. The measure
of `woman-years at risk' is calculated by summing
the total number of years over which, collectively,
Pharmacoepidemiology and Drug Safety 2001; 10: 5±11
8 m. goldacre
Table 1. Absolute risk ± Incidence rate of certain or probable deep vein thrombosis (DVT) or pulmonary embolism (PE) per 1000 woman-
years at risk (and numbers of women with DVT/PE)
Cohort Incidence per 1000 woman-years
Current oral contraceptive
Never/past oral contraceptive users
Chi-square 1 df ˆ 22.4, p < 0.001.
(From: Vessey et al., BMJ 1986; 292: 52632)
Table 2. Identi®cation of different outcomes related to use of oral
contraceptives: death rates per 100 000 woman-years (and number
of deaths) by cohort and cause
Cohort Oral contraceptive Others
users
Circulatory diseases 16.0 (25) 10.4 (12)
Ovarian cancer 3.6 (5) 9.1 (12)
(From: Vessey et al., BMJ 1989; 299: 1487±149140)
the women used oral contraceptives (and, for never/
past users, the number of years over which they were
studied without such use). The data show, in abso-
lute terms, the frequency of occurrence of venous
thromboemobolism in current pill-users and in
never/past users.
Another major advantage of the cohort approach,
compared with the case±control approach, is the fact
that a cohort study enables the investigator to study a
wide range of possible outcomes. The two disease out-
comes shown in Table 2, from the Oxford/FPA study,
go in opposite directions. The data show the now well-
established risk of circulatory disease, at least with
high dose oral contraceptives, and the now well-estab-
lished protection against ovarian cancer. Considering
these two conditions, at least at the time of publication
of these results, the risks and bene®ts are evenly
balanced.
Generally, in case±control studies, controls have
no more meaning than simply being controls. Some-
times, in cohort studies, the comparison groups have
meaning in their own right. The cohorts in the Oxford/
FPA study included women using different methods of
contraception. This provided the means to look at ben-
e®ts and risks associated with other contraceptive
methods in addition to the pill. The importance of this
is that, where the alternative to the pill is the use of
other methods, the safety and risks of the other meth-
ods themselves need to come into the balance sheet.
Table 3 shows the risk of pelvic in¯ammatory disease
Copyright # 2001 John Wiley & Sons, Ltd.
(n)
0.43 (23)
0.06 (6)
Table 3. Incidence rates per 1000 woman-years (and numbers of
women) related to use of intrauterine device: acute pelvic
in¯ammatory disease
Cohort Incidence rate (n)
Current users of an IUD 1.51 (31)
Ex-users of an IUD 0.48 (2)
Non-users 0.14 (9)
Current users versus non-users, chi-square 1 df ˆ 60.3, p < 0.001.
(From: Vessey et al., BMJ 1981; 282: 855±85759)
in current users, ex-users and never users of intra-uter-
ine devices; and it shows a striking gradient of risk in
association with use.
RETROSPECTIVE COHORT STUDY DESIGN
Sometimes, when historical records have been kept, it
is possible to undertake a cohort study±de®ning the
cohorts by their exposure to the factor of interest prior
to the development of disease±when not only the
exposures but also the outcomes of interest have
already occurred. The example I will use, taken from
a study in which Martin was a co-investigator, is that
of the safety of vasectomy. Vasectomy is now a widely
used method of permanent contraception, but con-
cerns have been expressed from time to time about
whether it might have any long-term risks. Among
other conditions, increases in the incidence of cardio-
vascular disease and of testicular cancer have been
postulated. Using pre-existing data, held in the Oxford
record linkage study, we identi®ed records of thou-
sands of men who had been vasectomized in previous
years.64 We then sought records of subsequent disease
in the men, and compared their experience of diseases
with that of men in comparison cohorts. Table 4 shows
some results: it shows the relative risk for myocardial
infarction in vasectomized men, compared with the
comparison cohorts; and it shows a relative risk of
Pharmacoepidemiology and Drug Safety 2001; 10: 5±11
 cohort studies in medical research
Table 4. Relative risk (RR, with 95% con®dence interval) of
disease in vasectomized men compared with comparison cohort
Disease (no. of men) RR (95% CI)
Myocardial infarction (97) 1.00 (0.8±1.3)
Testicular cancer (4) 0.43 (0.1±1.4)
(From: Nienhuis et al., BMJ 1992; 304: 743±74664)
1. Numbers of men with testicular cancer were small
but the data show no evidence of elevation of risk.
THE FUTURE: LARGE DATABASES
I mention the vasectomy study as an example because,
as we look to the future, we can expect to see the
increasing use by epidemiologists of large routinely
collected databases, capitalizing on the increasing
power, diminishing cost and increasing ubiquity of
automated data processing. Examples include record
linkage databases like the Oxford record linkage study
and Scottish record linkage, linkable disease registers
in a number of Scandinavian countries, and, particu-
larly for pharmacoepidemiology, the UK General
Practice Research Database derived from the VAMP
computer systems in general practice.65±67 The tech-
nical relationship between cohort design and nested
case±control design is rather more blurred in the use
of such datasets than it is in patient-contact-based stu-
dies. Some of the standard textbook considerations in
deciding between case±control or cohort studies cease
to apply.
THE FUTURE: GENETIC SUSCEPTIBILITY
TO RISK
It is important to note that the risk of not contracting a
disease, in relation to an exposure known to cause the
disease, is almost always far higher than the risk of
contracting it.
Table 5 shows the annual odds of not having a
thromboembolic event in pill-users. Even in situations
of very high relative risk, like heavy smoking and lung
cancer, as Table 5 shows, people who do not contract
the condition far outnumber those who do. That
remains the case even if we multiply the annual risk
of 3.5 per thousand by (say) 40 to give an approxi-
mate, cumulative life-time risk. Clearly, there are
other major factors at play in determining who does
and who does not develop disease. These may include
competing causes of death (if you die of one condition
Copyright # 2001 John Wiley & Sons, Ltd.
9
Table 5. Annual odds in each cohort of oral contraceptive users
and heavy smokers
(a) Oral contraceptive users
Not having CVT/PE 999.57 per 1000 women
Having DVT/PE 0.43 per 1000 women
(b) Heavy smokers
Not dying from lung cancer: 996.45 per 1000 men
Dying from lung cancer 3.55 per 1000 men
(a) Risk of DVT/PE in non-users 0.06 per 1000 p.a.; relative risk in
users compared with non-users ˆ 7; from Vessey et al.32
(b) Risk of death in non-smokers 0.14 per 1000 p.a.; relative risk in
heavy smokers compared with non-smokers ˆ 25; from Doll et al.68
you are not at risk of getting another) and, in particu-
lar, they include other personal and environmental risk
factors which interact with, predispose to, or protect
from the risk factor. To date, epidemiology has had
many important successes in identifying group risk.
Within that, however, there is still a long way to go
in identifying other determinants of individual risk.
Clearly, one of the most important other determinants
of susceptibility and protection is genetic make-up;
and in the next few years we will see a considerable
convergence of genetics and epidemiology.69 We
can be sure that cohort studies of the future, big and
small, will increasingly include the means to incorpo-
rate a genetic component. There will be interest, too,
in the possibility of collecting genetic samples from
subjects in cohort studies which are already estab-
lished, such as the Oxford/FPA study, in which there
are already many years of meticulously collected his-
torical exposure data.
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