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

Jorge Duconge, Alga S Ramos, Karla Claudio-Campos, Giselle Rivera-Miranda, Luis Bermúdez-Bosch, Jessicca Y Renta, Carmen L Cadilla, Iadelisse Cruz, Juan F Feliu, Cunegundo Vergara, Gualberto Ruaño, Jorge Duconge, Alga S Ramos, Karla Claudio-Campos, Giselle Rivera-Miranda, Luis Bermúdez-Bosch, Jessicca Y Renta, Carmen L Cadilla, Iadelisse Cruz, Juan F Feliu, Cunegundo Vergara, Gualberto Ruaño

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02345356.

Conflict of interest statement

Competing Interests: The authors have the following interests: The contents of this publication are solely the responsibility of the authors and do not represent the official views of the VA Caribbean Healthcare System, the Department of Veterans Affairs, the NIH or the United States Government. Dr. Gualberto Ruaño is founder and President of Genomas Inc. Dr. Jorge Duconge, Ms. Alga S. Ramos, Ms. Karla Claudio-Campos and Mr. Luis Bermudez-Bosch also held a without compensation (WOC) employment status with the Pharmacy Service, VA Caribbean Healthcare Systems (VACHS), in San Juan, Puerto Rico, at the time of conducting the study. The authors have no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or conflicts of interest with the subject matter or materials discussed in the article that need to be disclosed. No writing assistance was utilized in the production of this manuscript. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials as detailed online in the guide for authors.

Figures

Fig 1. CONSORT flowchart illustrating an open-label,…
Fig 1. CONSORT flowchart illustrating an open-label, single-center, population-based, observational, retrospective cohorts study with cross-sectional genotyping analysis.
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.
Fig 2. Admixture-adjusted pharmacogenetic warfarin dose refinement…
Fig 2. Admixture-adjusted pharmacogenetic warfarin dose refinement algorithm in Caribbean Hispanic patients, developed by using a multiple regression analysis in a derivation cohort of 255 individuals.
The solid “identity” line illustrates perfect prediction. MAE and MSE stand for the mean absolute error and the mean standard error of estimate, respectively.
Fig 3. Validation of the admixture-adjusted pharmacogenetic…
Fig 3. 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 et al [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.
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.
Fig 4. Association between the degree of…
Fig 4. Association between the degree of Amerindian ancestry and low dose requirements.
ID codes depicted for those requiring

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