7 research outputs found

    A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics.

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    AIM:This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. 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. TRIAL REGISTRATION:ClinicalTrials.gov NCT01318057

    Validation of the admixture-adjusted pharmacogenetic algorithm for dose refinement in Caribbean Hispanics (upper plot A) as compared to two publicly available algorithms (i.e., IWPC-derived [37] and Lenzini <i>et al</i> [36] models, plots B and C, respectively) as well as a clinical non-genetic algorithm (plot D) in an independent sample of 55 Puerto Ricans from the Brownstone Clinic in Hartford, CT.

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    <p>Each filled diamond represents the observed versus predicted dose of each patient. The upper solid line is (predicted + 1 mg/day) of the actual dose, the middle solid line (i.e. 45% degree line) illustrates perfect prediction in this validation cohort, and the lower solid line is (predicted −1 mg/day) of the actual dose. 1 mg/day change in warfarin dose is sufficient to change the INR by 0.5, a clinically meaningful difference.</p

    CONSORT flowchart illustrating an open-label, single-center, population-based, observational, retrospective cohorts study with cross-sectional genotyping analysis.

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    <p>The study uses existing data collected in the past (CPRS) to preliminarily identify eligible participants from the defined study population (i.e., Caribbean Hispanics), determine their stabilization status and retrieve relevant covariates for performing regression analysis and association testing. GNT stands for genotypes. PHT stands for phenotypes (e.g., therapeutic warfarin dose). CPRS stands for computerized patient record system.</p
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