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This JAMA Guide to Statistics and Methods explains the construction and utility of case-control studies to find associations between risk factors, including treatments, and patient outcomes.

Associations between patient characteristics or treatments received and clinical outcomes are often first described using observational data, such as data arising through usual clinical care without the experimental assignment of treatments that occurs in a randomized clinical trial (RCT). These data based on usual clinical care are referred to by some as “real-world” data. A key strategy for efficiently finding such associations is to use a case-control study.1 In a recent issue of JAMA Internal Medicine, Wang et al2 assessed the association between cardiovascular disease (CVD) and use of inhaled long-acting β2-agonists (LABAs) or long-acting antimuscarinic antagonists (LAMAs) in chronic obstructive pulmonary disease (COPD), utilizing a nested case-control study.


What Are Case-Control and Nested Case-Control Studies?

A case-control study compares individuals who had the outcome of interest (cases) vs individuals who did not have that outcome (controls) with respect to exposure to a potential risk factor. The goal is to determine if there is an association between the risk factor and the outcome. The risk factor may be a behavior such as tobacco use, a patient characteristic, or a treatment. The idea is to define a population or cohort, identify the cases and controls in the population, and retrospectively determine which patients in each group were exposed to the risk factor; the case-control study works backward from outcome to exposure (Figure 8). A higher proportion of individuals with exposure to the risk factor among cases than among controls suggests that the risk factor is associated with the outcome. The term control refers to an individual who did not have the outcome; in contrast, the same term in a clinical trial refers to a study participant who receives the standard (or placebo) treatment.


Hypothetical Example of a Case-Control Study

Exposure to a risk factor (in this case, new COPD inhaler use) changes the chance of subsequently developing the outcome of interest. However, in conducting a case-control study, the outcome (in this case, a cardiovascular event) is used initially to define cases and controls, and then the distribution of the exposure is assessed.

In a nested case-control study, the cases are identified in a large cohort and, for each case, a specified number of controls matching the case are selected from the cohort. The selected controls should match the cases with respect to characteristics, other than the risk factor, that are likely related to the outcome of interest. Because it is easier to find controls than cases when the outcome is rare, increasing the number of controls beyond the number of cases ...

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