Estimation of time-dependent rate ratios in case-control studies: comparison of two approaches for exposure...

In pharmacoepidemiology, it is well recognized that the rate of adverse events may vary as a function of the cumulative duration of the drug exposure and/or the time since the end of the exposure. In case-control studies, two different approaches have been used to estimate temporal effects of drug exposure: the time-windows (T-Ws) approach and the duration-specific (D-S) approach. We decided to conduct a simulation study to compare the two approaches when the rate ratios (RRs) vary as a function of the cumulative duration of exposure and/or the time since the end of exposure.

We generated three cohorts of 500,000 individuals in which the rate of the event was varying as a function of the cumulative duration of exposure and the time since the end of exposure. For each cohort, a nested case-control analysis was performed using both the D-S and the T-Ws approaches. In the T-Ws approach, a RR is estimated within specific periods of time prior to the outcome, while a RR is estimated within periods of cumulative duration of exposure and time since the end of exposure in the D-S approach.

We found that the RRs obtained from the D-S approach exactly corresponded to the RRs obtained from the cohort analyses, while the RRs obtained from the T-Ws approach generally not. RRs obtained from the T-Ws approach were difficult to interpret in terms of the effect of the duration and timing of the exposure.

The D-S approach should be used to investigate the duration-related effects of exposure in case-control studies.