Propensity score-adjusted three-component mixture model for drug-drug interaction data mining in FDA Adverse Event Reporting System

With increasing trend of polypharmacy, drug-drug interaction (DDI)-induced adverse drug events (ADEs) are considered as a major challenge for clinical practice. As premarketing clinical trials usually have stringent inclusion/exclusion criteria, limited comedication data capture and often times small sample size have limited values in study DDIs. On the other hand, ADE reports collected by spontaneous reporting system (SRS) become an important source for DDI studies. There are two major challenges in detecting DDI signals from SRS: confounding bias and false positive rate. In this article, we propose a novel approach, propensity score-adjusted three-component mixture model (PS-3CMM). This model can simultaneously adjust for confounding bias and estimate false discovery rate for all drug-drug-ADE combinations in FDA Adverse Event Reporting System (FAERS), which is a preeminent SRS database. In simulation studies, PS-3CMM performs better in detecting true DDIs comparing to the existing approach. It is more sensitive in selecting the DDI signals that have nonpositive individual drug relative ADE risk (NPIRR). The application of PS-3CMM is illustrated in analyzing the FAERS database. Compared to the existing approaches, PS-3CMM prioritizes DDI signals differently. PS-3CMM gives high priorities to DDI signals that have NPIRR. Both simulation studies and FAERS data analysis conclude that our new PS-3CMM is a new method that is complement to the existing DDI signal detection methods.