title: A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics.
abstract: OBJECTIVE
  This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients.
  
  
  METHODS
  A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals.
  
  
  RESULTS
  The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001). The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias).
  
  
  CONCLUSIONS
  Results supported our rationale to incorporate individual's genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01318057.
authors.affiliation: Pharmaceutical Sciences Department, School of Pharmacy, University of Puerto Rico Medical Sciences Campus (UPR-MSC), San Juan, Puerto Rico, United States of America.
authors.forename: Jorge
authors.initials: J
authors.lastname: Duconge
authors.affiliation: Pharmaceutical Sciences Department, School of Pharmacy, University of Puerto Rico Medical Sciences Campus (UPR-MSC), San Juan, Puerto Rico, United States of America.
authors.forename: Alga S
authors.initials: AS
authors.lastname: Ramos
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, University of Puerto Rico Medical Sciences Campus (UPR-MSC), San Juan, Puerto Rico, United States of America.
authors.forename: Karla
authors.initials: K
authors.lastname: Claudio-Campos
authors.affiliation: Pharmacy Service, VA Caribbean Healthcare Systems (VACHS), San Juan, Puerto Rico, United States of America.
authors.forename: Giselle
authors.initials: G
authors.lastname: Rivera-Miranda
authors.affiliation: Pharmaceutical Sciences Department, School of Pharmacy, University of Puerto Rico Medical Sciences Campus (UPR-MSC), San Juan, Puerto Rico, United States of America.
authors.forename: Luis
authors.initials: L
authors.lastname: Bermúdez-Bosch
authors.affiliation: Molecular Genetics Lab, Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus (UPR-MSC), San Juan, Puerto Rico, United States of America.
authors.forename: Jessicca Y
authors.initials: JY
authors.lastname: Renta
authors.affiliation: Molecular Genetics Lab, Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus (UPR-MSC), San Juan, Puerto Rico, United States of America.
authors.forename: Carmen L
authors.initials: CL
authors.lastname: Cadilla
authors.affiliation: Pharmaceutical Sciences Department, School of Pharmacy, University of Puerto Rico Medical Sciences Campus (UPR-MSC), San Juan, Puerto Rico, United States of America.
authors.forename: Iadelisse
authors.initials: I
authors.lastname: Cruz
authors.affiliation: Pharmacy Service, VA Caribbean Healthcare Systems (VACHS), San Juan, Puerto Rico, United States of America.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Feliu
authors.affiliation: Brownstone Outpatient Clinic, Hartford Hospital, Hartford, CT, United States of America.
authors.forename: Cunegundo
authors.initials: C
authors.lastname: Vergara
authors.affiliation: Genomas Inc., Hartford, CT, United States of America.
authors.forename: Gualberto
authors.initials: G
authors.lastname: Ruaño
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001281:Atrial Fibrillation / Q000188:drug therapy*; D017691:Caribbean Region; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D003710:Demography; D054796:Drug Dosage Calculations; D005260:Female; D005838:Genotype; D006207:Half-Life; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D013927:Thrombosis / Q000188:drug therapy*; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases