Linking MedDRA registered -Coded Clinical Phenotypes to Biological Mechanisms by the Ontology of Adverse Events: A Pilot Study on Tyrosine Kinase Inhibitors

A translational bioinformatics challenge exists in connecting population and individual clinical phenotypes in various formats to biological mechanisms. The Medical Dictionary for Regulatory Activities (MedDRA) is the default dictionary for adverse event (AE) reporting in the US Food and Drug Administration Adverse Event Reporting System (FAERS). The ontology of adverse events (OAE) represents AEs as pathological processes occurring after drug exposures. The aim of this work was to establish a semantic framework to link biological mechanisms to phenotypes of AEs by combining OAE with MedDRA in FAERS data analysis. The authors investigated the AEs associated with tyrosine kinase inhibitors (TKI) and monoclonal antibodies (mAbs) targeting tyrosine kinases. The five selected TKIs/mAbs (i.e., dasatinib, imatinib, lapatinib, cetuximab, and trastuzumab) are known to induce impaired ventricular function (non-QT) cardiotoxicity. Statistical analysis of FAERS data identified 1053 distinct MedDRA terms significantly associated with TKIs/mAbs, where 884 did not have corresponding OAE terms. They manually annotated these terms, added them to OAE by the standard OAE development strategy, and mapped them to MedDRA.