Bias due to Within-Subject Exposure Dependency with or without Bias due to Lack of Pairwise Exchangeability when Exposure is Chronic in Case-Crossover and Case-Time-Control Studies: A Simulation Study.

The case-crossover study has been proposed as a suitable design when a brief exposure causes a transient change in risk of an acute-onset disease. In pharmacoepidemiology, the condition of "brief exposure" is rarely satisfied because drug use is often chronic or successive, which may result in bias due to within-subject exposure dependency. We describe a simulation of a case-crossover study conducted within a cohort, where patients successively used a drug for 60 or more days and the rate ratio for the outcome occurrence was 4.0. Standard conditional logistic regression for the analysis produced overestimated odds ratios up to 7.8. This bias due to within-subject exposure dependency from chronic use can be removed by the Mantel-Haenszel method, or by our recently proposed weighting method. We also show that when some patients are censored after switching to another drug, a lack of pairwise exchangeability causes bias which is similar to bias due to an exposure time trend. This bias can be removed by the case-time-control design. We show that bias due to within-subject exposure dependency and lack of pairwise exchangeability occur independently and can occur separately or simultaneously, and how to detect and remove them.