RS-ADR: A Reference Standard for Adverse Drug Reaction Signal Assessment by Integrating Real-World Evidence and Controlled Vocabularies (Preprint)

BACKGROUND Pharmacovigilance using real-world data (RWD), such as multicenter electronic health records (EHRs), yields massively parallel adverse drug reaction (ADR) signals. However, proper validation of computationally detected ADR signals is not possible due to the lack of a reference standard for positive and negative associations. OBJECTIVE To develop a reference standard for ADR (RS-ADR) to streamline the systematic detection, assessment, and understanding of almost all drug-ADR associations suggested by RWD analyses. METHODS We integrated well-known reference sets for drug-ADR pairs, including Side Effect Resource (SIDER), Observational Medical Outcomes Partnership, and EU-ADR. We created a pharmacovigilance dictionary using controlled vocabularies and systematically annotated EHR data. Drug-ADR associations computed from MetaLAB and MetaNurse analyses of multicenter EHRs and extracted from the FDA Adverse Event Reporting System (FAERS) were integrated as ‘empirically determined’ positive and negative reference sets by means of cross-validation between institutions. RESULTS The RS-ADR consisted of 1,344 drugs, 4,485 ADRs, and 6,027,840 drug-ADR pairs with positive and negative consensus votes as pharmacovigilance reference sets. After curation of the initial version of RS-ADR, novel ADR signals such as ‘famotidine’-‘hepatic function abnormal’ were detected and reasonably validated by RS-ADR. While the validation of the entire reference standard is challenging, especially with this initial version, the reference standard will improve as more RWD participate in the consensus voting with advanced pharmacovigilance dictionaries and analytic algorithms. One can check if a drug-ADR pair has been reported by our web-based search interface for RS-ADRs available at https://bioemr2.snubi.org:19108/. CONCLUSIONS RS-ADRs enriched with the pharmacovigilance dictionary, ADR knowledge, and real-world evidence from EHRs may streamline the systematic detection, evaluation, and causality assessment of computationally detected ADR signals.