Eptdemiotogk; Reviews
1
Copyright O 1994 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved
Overview and Historical Perspective
Haroutune K. Armenian1 and David E. Lilienfeld2
A PROBLEM-SOLVING TOOL
The case-control method is an investiga-
tive tool that is being used today in a variety
of applications. These applications go be-
yond etiologic research and may focus on a
number of problem-solving activities within
the practice of public health and medicine.
As a method, it has developed into an effi-
cient approach for investigating outbreaks
and evaluating interventions and programs,
among other uses.
The central feature of a case-control de-
sign is a comparison of two groups, one with
a specific outcome and the other without that
outcome. The frequency of the hypothesized
factor(s) suspected of being related to the
outcome is compared in the two groups. As
with other methods of epidemiologic inves-
tigation, it is necessary to start by identify-
ing and clearly delineating the problem un-
der consideration. The definition of the
problem will dictate the ensuing steps of the
study design, particularly the selection of
the cases and controls. Thus, in a study that
is striving to test an etiologic hypothesis,
case selection will have to follow an ac-
cepted definition of the disease, while a
search for a particular brand of tryptophan
that causes eosinophilia-myalgia syndrome
will lead the authors to use cases and
controls that are all tryptophan users (1).
For most applications of the case-control
method, the definition of a case delineates
the problem that needs to be addressed; the
Received for publication and in final form March 25,
1994.
1
Department of Epidemiology, School of Hygiene
and Public Health, The Johns Hopkins University, Bal-
timore, MD.
2
The EMMES Corporation, Potomac, MD.
Vol. 16, No.
Printed In USA.
choice of controls defines the approach that
is being taken to investigate and analyze the
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problem.
In a problem-solving context, one is con-
cerned with two types of action: the need to
intervene and treat the cases or solve the
problem at hand, and the need to prevent the
future occurrence of cases. The case-control
method helps to provide the information
needed to undertake both of these actions.
As the contributions to this volume illus-
trate, a large number of evaluative studies in
the recent past have used this method to es-
tablish therapeutic interventions and medi-
cal procedures. As a design, the case-control
method is also used extensively in etiologic
investigations that provide useful informa-
tion for the prevention of other cases.
There is a linkage between problem defi-
nition and intervention. The initial step of
describing and defining the problem under
consideration, followed by case definition,
delineates the boundaries of our ability to
generalize from the results of the study and
highlights the group in which an initial in-
tervention based on these same results may
be relevant. By specifying time, place, and
persons for the problem definition and case
definition, we select certain hypotheses or
options for our investigation and exclude
others. If we define our problem as diarrheal
disease among children in Somalia in 1994,
then the hypotheses for investigation of this
particular problem are limited by the current
realities of disease ecology in that country.
By focusing the investigation on Somalian
children in 1994, we also restrict our options
for intervention to that time, place, and
group of persons.
Standard textbooks have listed a number
of advantages and disadvantages of the case-
2 Armenian and Lilienfeld
control method (2,3). Various aspects of the
problems and strengths of case-control stud-
ies will be discussed by authors in this vol-
ume. The main advantages of the method
relate to its efficiency and informativeness.
Efficiency in case-control studies is not lim-
ited to concerns of cost and time. Efficiency
in case-control studies is also expressed by
the ability of the method to deal with rare
outcomes. The case-control study is also
very informative. It can test the effect and
interaction of a large number of factors as
they relate to the outcome selected. The fact
that as a method it may sometimes deal with
almost the entire universe of the outcome, or
a large proportion of the cases, provides the
investigator with the opportunity to assess
the total spectrum of severity of outcomes as
these relate to the suspected determinant(s).
These two strengths of efficiency and in-
formativeness make the case-control design
very attractive within the problem-solving
environment of public health and medicine,
where cost and parsimony are important
considerations for decision-makers.
In addition, in many problem-solving
situations, the case-control method investi-
gates the actual cases that brought the prob-
lem to our attention in the first place; for
example, one of the earliest uses of the case-
control method to analyze disease outbreaks
involved the investigation of the first rec-
ognized cases of Legionella pneumonia (4).
As such, the case-control study may rep-
resent more of an immediate response to
problem-solving than a prospective cohort
study or experimental study.
Over the past few decades, the increas-
ingly extensive use of case-control method-
ology has been manifested by the large num-
ber of case-control studies being conducted
and the varied types of applications. The
contributions in this volume illustrate this
growth.
HISTORICAL PERSPECTIVE
In this section, we do not aim to present
an exhaustive historical review of the de-
velopment of the case-control method. Such
reviews have been attempted in the past and
require more extensive historical research
(5). We will consider the social stimuli for
the development, adoption, and adaptation
of the method as a problem-solving tool,
particularly for acute event investigations.
The origins of the case-control method are
nested in the roots of epidemiology itself.
The development of an epidemiologic ap-
proach to disease etiology and natural his-
tory by P. C. A. Louis in Paris in the 1830s
and the expansion of that approach in Vic-
torian England laid the foundations for fu-
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ture epidemiologic endeavors, including
case-control studies (5).
It is not surprising that the investigation of
disease outbreaks in the 19th century was
key to the establishment of epidemiology
as a field of inquiry. In Victorian London,
the London Epidemiological Society was
formed, in part, as a response to the cholera
and smallpox epidemics that were periodi-
cally visited upon the city (6, 7). Typically,
these investigations consisted of a descrip-
tion of the disease of interest, a discus-
sion of the known cases, the chronology
of the outbreak, and any investigations un-
dertaken, whether epidemiologic or labora-
tory-based. A few epidemiologic inquiries
calculated rates and compared them in
population subgroups; John Snow provided
one of these exceptions. In addition to cal-
culating rates of cholera among various
subgroups of interest, he used information
from a vast array of cholera cases to support
his inferences. He also individually ascer-
tained the exposure status of his cases dur-
ing his investigation of the epidemic of
1854 (8).
The development of epidemiology during
the second half of the 19th century was
dominated by the bacteriologic revolution.
The earlier paradigm which had considered
the important role of social factors in disease
was replaced by the germ theory (9). If bac-
teria were agents of disease, it was thought,
then an epidemiologist need only trace the
"point-contact spread" of infection to deter-
mine the source of an outbreak or the eti-
ology of a disease (10, 11). Epidemiologic
expertise could be trained on disease control

by knowledge of the etiologic agent. The
population focus of epidemiologic en-
deavor, an essential aspect of epidemiologic
investigation into disease etiology and a
characteristic of Victorian epidemiology,
waned.
A number of developments in the first half
of the 20th century contributed to the evo-
lution of the case-control method. These in-
cluded the development of field methods in
sociology, the clinical concern of elucidat-
ing disease etiology by studying large series
of cases, and the formulation of appropriate
statistical methods of analysis. Using newly
developed methods, sociologists started
tackling major health problems as social is-
sues (3). In addition to field survey tech-
niques, these methods included research that
started at the level of the outcome and tried
to elucidate etiology (ex post facto). Within
the medical community, the clinical case
series became a standard approach for in-
vestigating disease. It is interesting to note
that a number of these case series obtained
information from noncases in order to have
a reference for comparison regarding vari-
ous exposures. Thus, Broders compared the
smoking habits of 537 patients with squa-
mous cell epithelioma of the lip to those of
500 controls (12); Lane-Claypon reported a
case-control comparison of the role of re-
productive experience in the etiology of
breast cancer (13); and Gregg compared the
frequency of a history of rubella in his cases
of congenital cataract with the frequency in
100 other patients attending his clinic (14).
The involvement of statisticians in public
health markedly changed the epidemiologic
firmament. Edgar Sydenstricker, Harold
Dorn, and A. Bradford Hill revitalized epi-
demiology with their interest in and concen-
tration on the occurrence of disease in the
population (3). The establishment of biosta-
tistics as a core discipline in schools of pub-
lic health was another focus for the close
interaction between epidemiologists and
statisticians (15). The impact of the work of
these statisticians on the subsequent devel-
opment of epidemiology would be difficult
to overstate.
Overview and Historical Perspective 3
In the United States, Dorn stimulated
much of the thinking that took place during
the 1950s, when the case-control method
was first scrutinized. Indeed, Dorn himself
was cautious in advocating the use of the
case-control approach, partly because of
concern regarding the representativeness of
case and control groups to be studied in
comparison with the general population.
Under Dora's direction, some of the major
statistical innovations that facilitated the
widespread use of the case-control study
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were developed. An example is Cornfield's
suggestion of using the odds ratio to esti-
mate a relative risk in a case-control inves-
tigation (16). In the United Kingdom, it was
Hill who led in the development and use of
the case-control method. Of particular note
was the 1950 study by Hill and his student,
Doll, relating cigarette smoking to lung can-
cer (17)one of the first such reports.
Interestingly, it was the appearance of two
reports on case-control studies of cigarette
smoking and lung cancer in the United
States in 1950 that established the technique
as a viable research tool. Two groups of re-
searchers, Levin et al. (18) and Wynder and
Graham (19), had independently conducted
case-control studies into the association of
cigarette smoking with lung cancer. Levin,
a student of Wade Hampton Frost at the
Johns Hopkins University School of Hy-
giene and Public Health in the mid-1930s,
had been trained as an infectious disease
epidemiologist, with a particular interest in
tuberculosis. He had been recruited to the
Roswell Park Memorial Institute in Buffalo,
New York, to investigate the etiology of
cancer. Frost encouraged Levin to undertake
such investigations, because he (Frost)
thought that the cancer-causing agents were
infectious ones, specifically viruses. Early
in his career as an epidemiologist at Roswell
Park, Levin was asked to revise the standard
admission questionnaire that was used to
collect data from all patients. As part of this
revision, he introduced cigarette smoking as
a new item on the questionnaire (M. L.
Levin, The Johns Hopkins University, per-
sonal communication, 1987). Subsequently,
4 Armenian and L'lienfeld
Levin and his colleagues began a case-
control study into the etiology of lung can-
cer, stimulated by Pearl's report (20) that it
was inversely associated with tuberculosis.
Analysis of the questionnaire data from the
cases of lung cancer and three other control
groups revealed the association with ciga-
rette smoking.
Levin et al. submitted their paper for pub-
lication to the Journal of the American
Medical Association. The journal was hesi-
tant to publish the report because the Editor
was not certain of the scientific value of the
research approach used. However, shortly
after the receipt of the Levin et al. paper,
Wynder and Graham submitted a paper to
the same journal reporting essentially the
same results from a case-control study! The
second author, Evarts Graham, was a sur-
geon with an international reputation as an
innovator. It was therefore difficult for the
Editor to dismiss the Wynder and Graham
paper. Hence, both papers were published in
the same issue of the Journal of the Ameri-
can Medical Association.
The subsequent development of the case-
control method was a result of the contri-
butions of many epidemiologists, statisti-
cians, and sociologists. This development
was not a smooth one, however. Although
the use of the method in etiologic investi-
gations of chronic diseases was firmly es-
tablished for more than three decades, it was
only about 20 years ago that the case-control
approach began to be used as a problem-
solving tool in outbreak investigations (21).
To understand why the method was not
adopted more readily, we need to under-
stand the environment in which practicing
epidemiologists operated.
Since the 1930s, practitioners of epide-
miology in federal, state, and local health
departments, instilled with the demographic
perspective brought to modern epidemiol-
ogy by Sydenstricker, Dorn, Frost, and oth-
ers, had viewed epidemiologic investiga-
tions in terms of a cohort approach. For this
method, it is necessary initially to determine
the population of interest and calculate the
incidence of disease in the various sub-
groups of exposure. These exposure groups
were defined on the basis of previous knowl-
edge about the etiology of the disease from
laboratory and clinical investigations. The
important role of the cohort approach could
be the topic of another review. However, in
more recent years, the need to deal with epi-
demics of diseases of unknown etiology,
such as legionellosis, brought the case-
control design into prominence as a versatile
tool for acute problem investigations, par-
ticularly when they were not being guided
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by any dominant hypothesis.
Another factor in the adoption of the case-
control approach was the expansion of the
public health community by the entry of a
new generation of epidemiologists. During
the 1950s and 1960s, in recognition of the
need for more epidemiologists to address the
chronic disease challenges of an aging, in-
dustrialized society, the US government
funded several epidemiology training pro-
grams. The students in these programs re-
ceived specific formal training in epidemio-
logic study design, particularly the use of
case-control studies. The experience gained
through the conduct of these studies had pro-
vided academic departments of epidemiol-
ogy with the basis for formal instruction in
conducting such investigations. Given their
training, it is not surprising that this new
generation of epidemiologists approached
field situations with hypotheses that they
tested by means of case-control studies.
The evolution of the case-control method
as a problem-solving tool over the past four
decades has been greatly enhanced by the
availability of appropriate statistical meth-
ods of analysis, the development of better
methods of dealing with various sources of
bias, and the creation of large information
systems, including registries and surveil-
lance systems.
THE PRESENT VOLUME
This volume addresses the needs of the
practicing epidemiologist at various levels.
It provides a forum for discussion and iden-
tifies some of the methodological problems
that need to be addressed. We first present
 Overview and Historical Perspective 5

six contributions that review general meth-
odological issues associated with the case-
control design. We then present reviews of
seven specific applications of the case-
control method. While a number of other
9.
applications could have been chosen, we se-
lected those that were of general interest and
that also addressed specific methodological
issues. Some of their unique aspects may be
10.
suitable for other applications of the case-
control method.
11.
We believe that Epidemiologic Reviews
era. In: Snow on cholera: being a reprint of two
papers by John Snow, M.D., together with a bio-
graphical memoir by B. W. Richardson, M.D.,
and an introduction by Wade Hampton Frost,
M.D. New York, NY: The Commonwealth Fund,
1936.
Susser M. Falsification, verification and causal
inference in epidemiology: reconsiderations in
the light of Sir Karl Popper's philosophy. In:
Rothman KJ, ed. Causal inference. Chestnut Hill,
MA: Epidemiology Resources, Inc, 1988.
Eyler JM. The epidemiology of milk-borne scar-
let fever: the case of Edwardian Brighton. Am J
Public Health 1986;76:573-84.
Eyler JM. Poverty, disease, and responsibility:
Arthur Newsholme and the public health dilem-

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should continue to address the current meth-
odological and substantive issues facing the
practice of epidemiology in its broadest con-
text. We hope that this volume is in line with
such an objective.
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