When is a Case-Control Study Desirable?

Given the greater efficiency of case-control studies, they are particularly advantageous in the following situations:

  1. When the disease or outcome being studied is rare.
  2. When the disease or outcome has a long induction and latent period (i.e., a long time between exposure and the eventual causal manifestation of disease).
  3. When exposure data is difficult or expensive to obtain.
  4. When the study population is dynamic.
  5. When little is known about the risk factors for the disease, case-control studies provide a way of testing associations with multiple potential risk factors. (This isn't really a unique advantage to case-control studies, however, since cohort studies can also assess multiple exposures.)

Another advantage of their greater efficiency, of course, is that they are less time-consuming and much less costly than prospective cohort studies.

The DES Case-Control Study

A classic example of the efficiency of the case-control approach is the study (Herbst et al.: N. Engl. J. Med. Herbst et al. (1971;284:878-81) that linked in-utero exposure to diethylstilbesterol (DES) with subsequent development of vaginal cancer 15-22 years later. In the late 1960s, physicians at MGH identified a very unusual cancer cluster. Eight young woman between the ages of 15-22 were found to have cancer of the vagina, an uncommon cancer even in elderly women. The cluster of cases in young women was initially reported as a case series, but there were no strong hypotheses about the cause.

In retrospect, the cause was in-utero exposure to DES. After World War II, DES started being prescribed for women who were having troubles with a pregnancy -- if there were signs suggesting the possibility of a miscarriage, DES was frequently prescribed. It has been estimated that between 1945-1950 DES was prescribed for about 20% of all pregnancies in the Boston area. Thus, the unborn fetus was exposed to DES in utero, and in a very small percentage of cases this resulted in development of vaginal cancer when the child was 15-22 years old (a very long latent period). There were several reasons why a case-control study was the only feasible way to identify this association: the disease was extremely rare (even in subjects who had been exposed to DES), there was a very long latent period between exposure and development of disease, and initially they had no idea what was responsible, so there were many possible exposures to consider.

In this situation, a case-control study was the only reasonable approach to identify the causative agent. Given how uncommon the outcome was, even a large prospective study would have been unlikely to have more than one or two cases, even after 15-20 years of follow-up. Similarly, a retrospective cohort study might have been successful in enrolling a large number of subjects, but the outcome of interest was so uncommon that few, if any, subjects would have had it. In contrast, a case-control study was conducted in which eight known cases and 32 age-matched controls provided information on many potential exposures. This strategy ultimately allowed the investigators to identify a highly significant association between the mother's treatment with DES during pregnancy and the eventual development of adenocarcinoma of the vagina in their daughters (in-utero at the time of exposure) 15 to 22 years later.

For more information see the DES Fact Sheet from the National Cancer Institute.

An excellent summary of this landmark study and the long-range effects of DES can be found in a Perspective article in the New England Journal of Medicine. A cohort of both mothers who took DES and their children (daughters and sons) was later formed to look for more common outcomes. Members of the faculty at BUSPH are on the team of investigators that follow this cohort for a variety of outcomes, particularly reproductive consequences and other cancers.