title: Linking MedDRA(®)-Coded Clinical Phenotypes to Biological Mechanisms by the Ontology of Adverse Events: A Pilot Study on Tyrosine Kinase Inhibitors.
abstract: 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. We investigated the AEs associated with tyrosine kinase inhibitors (TKIs) 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. We manually annotated these terms, added them to OAE by the standard OAE development strategy, and mapped them to MedDRA(®). The data integration to provide insights into molecular mechanisms of drug-associated AEs was performed by including linkages in OAE for all related AE terms to MedDRA(®) and the existing ontologies, including the human phenotype ontology (HP), Uber anatomy ontology (UBERON), and gene ontology (GO). Sixteen AEs were shared by all five TKIs/mAbs, and each of 17 cardiotoxicity AEs was associated with at least one TKI/mAb. As an example, we analyzed "cardiac failure" using the relations established in OAE with other ontologies and demonstrated that one of the biological processes associated with cardiac failure maps to the genes associated with heart contraction.
  
  
  
  By expanding the existing OAE ontological design, our TKI use case demonstrated that the combination of OAE and MedDRA(®) provides a semantic framework to link clinical phenotypes of adverse drug events to biological mechanisms.
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. siiraa@umich.edu.|Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA. siiraa@umich.edu.
authors.forename: Sirarat
authors.identifier: 0000-0002-2548-641X
authors.initials: S
authors.lastname: Sarntivijai
authors.affiliation: College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Shelley
authors.initials: S
authors.lastname: Zhang
authors.affiliation: College of Engineering, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Desikan G
authors.initials: DG
authors.lastname: Jagannathan
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Shadia
authors.initials: S
authors.lastname: Zaman
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Keith K
authors.initials: KK
authors.lastname: Burkhart
authors.affiliation: Department of Internal Medicine and Human Genetics and School of Public Health, University of Michigan, Ann Arbor, MI, USA.|Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Gilbert S
authors.initials: GS
authors.lastname: Omenn
authors.affiliation: Unit of Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA.|Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.|Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Yongqun
authors.initials: Y
authors.lastname: He
authors.affiliation: Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.|Psychiatry Department, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Athey
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Abernethy
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D006801:Humans; D010865:Pilot Projects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000911:Antibodies, Monoclonal; D047428:Protein Kinase Inhibitors