Confounding and exposure trends in case-crossover and case-time-control designs.

As with ordinary studies, both case-crossover and case-time-control studies can suffer from confounding, including confounding by indication. In a case-crossover analysis, confounding by fixed (constant) characteristics is eliminated by pairing of cases to themselves, at the possible cost of introducing bias due to time trends in exposure. A case-time-control analysis can correct case-crossover results only for bias due to such time trends. If an uncontrolled confounder (such as disease severity) is present, the use of time controls can introduce new confounding, and the case-time-control results may end up either more or less confounded than the ordinary and case-crossover results. The relative confounding in the different approaches depends on details of the relations among the unmeasured confounder, the study exposure, the study disease, and any trend in these variables or their effects. Like an ordinary study, a case-time-control study must assume absence of unmeasured confounders, whether fixed or time-varying. Like a case-crossover study, it must also assume absence of carryover effects and can be more prone to misclassification bias than an ordinary study.