Aim This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. 0.89 mg/day, 24% mean bias). Conclusions Results supported our rationale to incorporate individuals genotypes and unique admixture metrics into pharmacogenetic refinement models in Cladribine order to increase predictability when expanding them to admixed populations like Caribbean Hispanics. Trial Registration ClinicalTrials.gov “type”:”clinical-trial”,”attrs”:”text”:”NCT01318057″,”term_id”:”NCT01318057″NCT01318057 Introduction Warfarin is an oral anticoagulant used to treat or prevent multiple thromboembolic disorders, including atrial fibrillation, heart valve replacement, recurrent stroke, deep vein thrombosis, pulmonary embolism, acute myocardial infarction and cerebrovascular accidents [1C2]. Although several clinical trials have compared its effectiveness and safety to the new oral anticoagulants (NOACs) , warfarin continues to be the standard of care in oral anticoagulation. According to IMS Health, over 19 million prescriptions of warfarin sodium were dispensed annually in the US by 2012, ranking #18th overall [4C5]. However, it is still in the top 10 drug products by reports of adverse events in outpatients [6C7]. Despite its confirmed clinical benefits and its use for a long time, warfarin therapy is still a challenge due to a wide inter-individual variation in dose requirements, narrow therapeutic range and risk of serious bleeding [1,8]. Pharmacogenetic-guided warfarin dosing algorithms have been developed to explain about 60% of dose variability in various populations, mostly in Caucasians . Nonetheless, their impact on clinical outcomes remains controversial and reimbursement for genotyping is usually debated [9C10]. On the other hand, Hispanics have been largely excluded from the corresponding derivation cohorts [11C13]. Accordingly, these algorithms are limited to account for the effect of multi-hybrid admixtures and the unique stratification observed in Hispanics, which increase dramatically the disparities in translating benefits from pharmacogenomics to this medically underserved, minority populace. We believe that a better approach for global pharmacogenetics (PGt) is usually to guide warfarin dosing by using a pharmacogenetic-based algorithm that also accounts for the effect of admixture or ancestry proportions. Fostered by an urgent need to eliminate potential ethnic disparities in health care while implementing the personalized medicine paradigm, this study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to predict individual maintenance doses of warfarin, after the fourth day of therapy (refinement model), in Caribbean Hispanic patients receiving anticoagulation therapy at the Veterans Affairs Caribbean Healthcare System (VACHS). We also compare the predictability of the developed algorithm in Caribbean Hispanics versus a clinical non-genetic algorithm and two other previously established pharmacogenetic-guided warfarin dosing models. Methods Study Design and Patient Cohort All research activities involving human participants in this study were properly approved by the Institutional Review Boards (IRBs) at both VACHS (#00558) Cladribine and UPR-MSC (A4070109) in November 2010 (S1 Text). All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained from each single participant of the study prior to enrollment (S2 Text and S3 Text). This is an open-label, single-center, population-based, observational, retrospective cohort study (ClinicalTrial.gov Identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT01318057″,”term_id”:”NCT01318057″NCT01318057) as depicted in Fig 1. Four hundred and twenty one (N = 421) warfarin-treated outpatients from the VACHS anticoagulation clinics in San Juan, Puerto Rico, were assessed for eligibility between February 2011 and March 2014. A total of 275 eligible patients who Kdr met inclusion criteria were approached regarding participation in this trial. Two patients declined to participate in the study, resulting in 273 subjects enrolled between March 22 and April 7, 2011. To be in compliance with the Ethical Principles for Medical Research Involving Human Subjects, Cladribine the first participant was recruited 5 days after the study registration date in ClinicalTrials.gov (March 17, 2011). Another eighteen (18) patients were excluded from further analysis due to lack of complete clinical data from the CPRS and incomplete genotype information (e.g., poor call rates) or admixture estimates. This resulted in 255 patients available to include their clinical, demographic and genomic data for full analysis. Because this study required a blood sample at enrollment followed by a retrospective CPRS medical record review, no patients were withdrawn or lost to follow-up. The study completion date was July 2014. The authors confirm that all ongoing and related trials for this drug/intervention are registered..