Objective: To test whether a frequently used cohort-nested case-control study design exaggerated exposure-response relationships because of unrecognized study design bias. Our aim was to evaluate empirically the performance of this complex study design.
Methods: We applied the design from one such study to a closely related cohort using randomly selected probands as cases. Values for average exposures were assigned to probands equal to, greater than, and less than those assigned to controls (matches).
Results: Under certain lag scenarios, the nested study design produced higher average exposure in probands compared with their matches, even when this was clearly not the case.
Conclusions: Empirical evaluation demonstrated that the study design produced a biased case-control lagged exposure difference under the null hypothesis and could not distinguish qualitatively between null and alternate hypotheses. Empirical evaluation provided a useful check on results generated from a complex study design. It gave useful insight into the behavior of the index study design that was not otherwise readily deducible.