Plasmode simulation for the evaluation of pharmacoepidemiologic methods in complex healthcare databases.

Longitudinal healthcare claims databases are frequently used for studying the comparative safety and effectiveness of medications, but results from these studies may be biased due to residual confounding. It is unclear whether methods for confounding adjustment that have been shown to perform well in small, simple nonrandomized studies are applicable to the large, complex pharmacoepidemiologic studies created from secondary healthcare data. Ordinary simulation approaches for evaluating the performance of statistical methods do not capture important features of healthcare claims. A statistical framework for creating replicated simulation datasets from an empirical cohort study in electronic healthcare claims data is developed and validated. The approach relies on resampling from the observed covariate and exposure data without modification in all simulated datasets to preserve the associations among these variables. Repeated outcomes are simulated using a true treatment effect of the investigator's choice and the baseline hazard function estimated from the empirical data. As an example, this framework is applied to a study of high versus low-intensity statin use and cardiovascular outcomes. Simulated data is based on real data drawn from Medicare Parts A and B linked with a prescription drug insurance claims database maintained by Caremark. Properties of the data simulated using this framework are compared with the empirical data on which the simulations were based. In addition, the simulated datasets are used to compare variable selection strategies for confounder adjustmentvia the propensity score, including high-dimensional approaches that could not be evaluated with ordinary simulation methods. The simulated datasets are found to closely resemble the observed complex data structure but have the advantage of an investigator-specified exposure effect.