Case-Time-Control Design

A case-crossover study uses only cases, each serving as their own control across hazard and reference windows, which removes time-invariant confounding but is biased by any secular trend in exposure. The case-time-control design adds a separate control series analyzed the same way to estimate that trend, then divides the case-crossover odds ratio by the control odds ratio to remove it. Equivalently, it is the case-by-exposure interaction in a conditional logistic model. The result is a trend-adjusted effect estimate, valid under stronger assumptions than the case-crossover alone.

Greenland's 1996 paper showed that the time-control correction is valid only if the controls share the same exposure trend as the cases and there is no within-subject (time-varying) confounder. If a time-varying confounder such as worsening disease severity drives both the exposure change and the event — classic confounding by indication — the control series does not capture it, and adjusting by the controls can introduce new bias. So the design fixes secular trends but cannot fix severity-driven confounding, and using it blindly in that situation can degrade the estimate.

Both are self-controlled designs that use within-person comparisons to eliminate fixed confounders, and both target transient effects of intermittent exposures. The case-time-control design extends the case-crossover by borrowing an external control series to net out exposure time trends, whereas the self-controlled case series models the within-person rate of events across exposed and unexposed time using only cases and an explicit time-trend term. When time trends are the concern, both can address them; the SCCS handles trends through its model specification, while the case-time-control handles them through the added control group.