Case-Time-Control Design

The case-time-control design is a pharmacoepidemiologic study design that repairs a specific weakness of the case-crossover study: bias from a secular trend in exposure. In a case-crossover analysis each case acts as their own control, comparing exposure in a short hazard window just before the event to exposure in earlier reference windows, which automatically removes all fixed, time-invariant confounders. But if the prevalence of exposure is rising or falling over calendar time for reasons unrelated to the outcome, this within-person comparison is biased. Samy Suissa's 1995 design adds a separate control series, analyzed the same way, to estimate that pure time trend; dividing the case-crossover odds ratio by the control odds ratio cancels the trend and leaves the exposure effect. Sander Greenland's 1996 analysis clarified the assumptions: the correction works only if the controls share the same exposure trend and there is no within-subject confounder, and it can introduce new bias if those conditions fail.