Medication class enrichment analysis: a novel algorithm to analyze multiple pharmacologic exposures simultaneously using electronic health record data.

Objective: Observational studies analyzing multiple exposures simultaneously have been limited by difficulty distinguishing relevant results from chance associations due to poor specificity. Set-based methods have been successfully used in genomics to improve signal-to-noise ratio. We present and demonstrate medication class enrichment analysis (MCEA), a signal-to-noise enhancement algorithm for observational data inspired by set-based methods. Materials and Methods: We used The Health Improvement Network database to study medications associated with Clostridium difficile infection (CDI). We performed case-control studies for each medication in The Health Improvement Network to obtain odds ratios (ORs) for association with CDI. We then calculated the association of each pharmacologic class with CDI using logistic regression and MCEA. We also performed simulation studies in which we assessed the sensitivity and specificity of logistic regression compared to MCEA for ORs 0.1-2.0. Results: When analyzing pharmacologic classes using logistic regression, 47 of 110 pharmacologic classes were identified as associated with CDI. When analyzing pharmacologic classes using MCEA, only fluoroquinolones, a class of antibiotics with biologically confirmed causation, and heparin products were associated with CDI. In simulation, MCEA had superior specificity compared to logistic regression across all tested effect sizes and equal or better sensitivity for all effect sizes besides those close to null. Discussion: Although these results demonstrate the promise of MCEA, additional studies that include inpatient administered medications are necessary for validation of the algorithm. Conclusions: In clinical and simulation studies, MCEA demonstrated superior sensitivity and specificity for identifying pharmacologic classes associated with CDI compared to logistic regression.