Within-subject exposure dependency in case-crossover studies

In the case-crossover design, only cases are sampled and the hazard ratio i s estimated from within-subject comparisons of exposures at the event time and in M control periods prior to the event. We consider the effect of with in-subject dependence of exposures in successive time periods. We show that estimates obtained from the conditional logistic model are biased. This bi as disappears if the distribution of exposures in the M + 1 successive time intervals is exchangeable. In contrast, the Mantel-Haenszel estimator for the odds ratio is approximately unbiased provided that exposures are statio nary. Suitable methods of analysis of case-crossover designs using maximum likelihood may be derived from cohort rather than case-control models. Copy right (C) 2001 John Wiley & Sons, Ltd.