TY  - JOUR
AU  - Lee, Suehyun
AU  - Lee, Jeong Hoon
AU  - Kim, Grace Juyun
AU  - Kim, Jong-Yeup
AU  - Shin, Hyunah
AU  - Ko, Inseok
AU  - Choe, Seon
AU  - Kim, Ju Han
PY  - 2022
DA  - 2022/10/6
TI  - A Data-Driven Reference Standard for Adverse Drug Reaction (RS-ADR) Signal Assessment: Development and Validation
JO  - J Med Internet Res
SP  - e35464
VL  - 24
IS  - 10
KW  - adverse drug reaction
KW  - ADR
KW  - real-world data
KW  - RWD
KW  - real-world evidence
KW  - RWE
KW  - pharmacovigilance
KW  - PV
KW  - reference standard
KW  - pharmacology
KW  - drug reaction
AB  - 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: This study aimed 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, 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 Food and Drug Administration Adverse Event Reporting System were integrated as “empirically determined” positive and negative reference sets by means of cross-validation between institutions. Results: The RS-ADR consisted of 1344 drugs, 4485 ADRs, and 6,027,840 drug-ADR pairs with positive and negative consensus votes as pharmacovigilance reference sets. After the 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. Although 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. 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. 
SN  - 1438-8871
UR  - https://www.jmir.org/2022/10/e35464
UR  - https://doi.org/10.2196/35464
UR  - http://www.ncbi.nlm.nih.gov/pubmed/36201386
DO  - 10.2196/35464
ID  - info:doi/10.2196/35464
ER  -