title: STRATEGIES FOR EQUITABLE PHARMACOGENOMIC-GUIDED WARFARIN DOSING AMONG EUROPEAN AND AFRICAN AMERICAN INDIVIDUALS IN A CLINICAL POPULATION.
abstract: The blood thinner warfarin has a narrow therapeutic range and high inter- and intra-patient variability in therapeutic doses. Several studies have shown that pharmacogenomic variants help predict stable warfarin dosing. However, retrospective and randomized controlled trials that employ dosing algorithms incorporating pharmacogenomic variants under perform in African Americans. This study sought to determine if: 1) including additional variants associated with warfarin dose in African Americans, 2) predicting within single ancestry groups rather than a combined population, or 3) using percentage African ancestry rather than observed race, would improve warfarin dosing algorithms in African Americans. Using BioVU, the Vanderbilt University Medical Center biobank linked to electronic medical records, we compared 25 modeling strategies to existing algorithms using a cohort of 2,181 warfarin users (1,928 whites, 253 blacks). We found that approaches incorporating additional variants increased model accuracy, but not in clinically significant ways. Race stratification increased model fidelity for African Americans, but the improvement was small and not likely to be clinically significant. Use of percent African ancestry improved model fit in the context of race misclassification.
authors.affiliation: Div. of Biomedical Informatics and Personalized Med., University of Colorado, 13001 E. 17th Pl. MS F-563 Aurora, CO 80045, USA, laura.wiley@ucdenver.edu.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Wiley
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Vanhouten
authors.forename: David C
authors.initials: DC
authors.lastname: Samuels
authors.forename: Melinda C
authors.initials: MC
authors.lastname: Aldrich
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Josh F
authors.initials: JF
authors.lastname: Peterson
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D001741:Black or African American; D015331:Cohort Studies; D019295:Computational Biology; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D005787:Gene Frequency; D008957:Models, Genetic; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics; D000095223:White
chemical_list: D000925:Anticoagulants; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D064417:Vitamin K Epoxide Reductases; C578523:VKORC1 protein, human; D014859:Warfarin