Before searching for cases, the study defines the diagnostic and epidemiologic criteria by which cases will be identified. These criteria are called the case definition. The case definition is then uniformly applied to screen for cases. At times it may be advantageous to establish several different case definitions to allow for separate examinations by the different criteria (see Chapter 16).

Cases ascertainment may be limited to incident cases or prevalent cases. Incident cases commenced during the study period. Prevalent cases may have onset at any time either before or during the study period. Incident cases are generally preferred because the survival of prevalent cases may depend on factors that are separate from their cause. In addition, use of prevalent cases may make it difficult to differentiate between past events that are causally related to the disease and events that have occurred consequent to disease onset.

There are times, however, when it is possible only to study prevalent cases. For example, when studying birth defects, the causes occur en utero, before birth. Since many birth defects are associated with high fetal death rates and both spontaneous and induced abortions, birth defects detected after birth represent cases that have survived until delivery (i.e., prevalent cases). Note that use of prevalent cases will not bias the results of a case–control comparison if survival is independent of the cause you are studying and the timing of the exposure in relation to disease onset can be accurately ascertained.

Valid selection of controls is crucial when conducting case–control studies. The valid selection is best understood in terms of their function, which is to represent the exposure experience of the population that gave rise to the cases. In this regard, it is important to clearly define the underlying source population (study base) that gave rise to the cases. As disease events arise in the study base, they are identified as cases. For each case, one or more controls are selected from the same study base.

The study base for a case–control study can be an opened or closed population (see Chapter 3). Cases for the study in Illustrative Example 8.1 (esophageal cancer and alcohol consumption), for example, came from hospitals in the open population of the Ille-et-Vilaine region (France). The catchment area served by these hospitals comprised the source population or study base. Therefore, controls were selected from this catchment area.

Case–control studies that use closed populations (cohorts) as their source population are called nested case–control studies (“case–control studies nested in a cohort”). As an example, a nested case–control study was carried out in a retrospective cohort of 223 292 men employed by three electric utility companies in France and Canada from 1970 to 1989 (Theriault et al., 1994). During this time, 4151 incident cancer cases were identified. For each incident cancer case, between one and four controls were selected from the underlying cohort. Exposure to electromagnetic field radiation for cases and controls was measured by dosimetry. Based on these data, workers who had more than the median cumulative exposure to magnetic fields had an increased risk of acute nonlymphoid leukemia ( = 2.4), acute myeloid leukemia ( = 3.2), and brain cancer ( = 2.0). No elevation in risk was observed for any of the other 29 cancers that were studied. These data strengthen the belief in the hypothesis that occupational exposures to 60 Hz electromagnetic fields increase the risk of certain types of cancer.

When cases came from a restricted source—say for example from a particular clinic—then the controls should be drawn from the same restricted source population. Here is an example in which an HMO population served as the source population for cases and controls.

In conducting case–control studies, the investigator must decide on the number of controls to select per case. When large numbers of cases are available and the cost and difficulty of collecting information for cases and controls is equal, maximum statistical efficiency is gained by studying an equivalent number of cases and controls. This control-to-case sampling ratio of 1:1 will maximize the statistical efficiency of the study for a given total sample size.

However, when the number of cases in the source population is limited, or the collection of information from cases is relatively expensive, an increase in the precision of the study can be achieved by increasing the control-to-case ratio sampling to 4:1. Increasing the control-to-case sampling ratio above 4:1, however, produces negligible increases in statistical power and precision (Gail et al., 1976).

The sample size requirements of case–control studies depends on the following factors: (a) the alpha level of the study, (b) the desired confidence interval length expressed on a logarithmic scale (or desired statistical power of the significance test), (c) the control-to-cases sampling ratio, (d) the expected proportion of controls that are classified as exposed, and (e) the expected odds ratio one is trying to detect.

Information about exposure to potential risks in cases-control studies can be derived by interviewing study subjects or their surrogates (e.g., family members), from the review of health care records, from vital statistics sources (e.g., death certificates), from employment records, from environmental records, and from biological specimens. Whatever the source, information should be obtained in a uniform and accurate way. For example, when deriving information by questionnaire, cases and controls should be questioned in identical manners to obtain information of comparable accuracy and completeness.

The induction time between exposure to a risk factor and its effects can be substantial for chronic diseases. In the meantime, cases may have altered their exposure habits since developing disease, making current exposure status irrelevant. For example, cases with chronic lung disease may have stopped smoking after the damage had already been done. Therefore, it is important to focus on exposure histories from the relevant past.