A Nonparametric Bayesian Local-Global Model for Enhanced Adverse Event Signal Detection in Spontaneous Reporting System Data

Abstract

Spontaneous reporting system databases are key resources for post-marketing surveillance, providing real-world evidence (RWE) on the adverse events (AEs) of regulated drugs or other medical products. Various statistical methods have been proposed for AE signal detection in these databases, flagging drug-specific AEs with disproportionately high observed counts compared to expected counts under independence. However, signal detection remains challenging for rare AEs or newer drugs, which receive small observed and expected counts and thus suffer from reduced statistical power. Principled information sharing on signal strengths across drugs/AEs is crucial in such cases to enhance signal detection. However, existing methods typically ignore complex between-drug associations on AE signal strengths, limiting their ability to detect signals. We propose novel local-global mixture Dirichlet process (DP) prior-based nonparametric Bayesian models to capture these associations, enabling principled information sharing between drugs while balancing flexibility and shrinkage for each drug, thereby enhancing statistical power. We develop efficient Markov chain Monte Carlo algorithms for implementation and employ a false discovery rate (FDR)-controlled, false negative rate (FNR)-optimized hypothesis testing framework for AE signal detection. Extensive simulations demonstrate our methods' superior sensitivity -- often surpassing existing approaches by a twofold or greater margin -- while strictly controlling the FDR. An application to FDA FAERS data on statin drugs further highlights our methods' effectiveness in real-world AE signal detection. Software implementing our methods is provided as supplementary material.