Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study

Claudio‐Campos, Karla; Labastida, Aurora; Ramos, Alga S; Gaedigk, Andrea; Renta-Torres, Jessicca; Padilla, Dariana; Rivera-Miranda, Giselle; Scott, Stuart A.; Ruaño, Gualberto; Cadilla, Carmen L.; Duconge, Jorge

doi:10.3389/fphar.2017.00347

Cited by 17 publications

(22 citation statements)

References 66 publications

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“…For UIC, genetic ancestry was determined using 105 autosomal DNA ancestry informative markers for West African (WA), Native American (NA), and European-American (EA) genetic ancestry, with each patient having a value for WA, NA, and EA ancestry from 0-100%. 26,27 UPR and UAZ provided data on genetic ancestry using DNA ancestry informative markers from the DMET Plus Panel 28 and Illumina Infinium Multi-Ethnic Global BeadChip Array, respectively.…”

Section: Genotypingmentioning

confidence: 99%

Multi‐site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

Rouby

Marcatto

Claudio

et al. 2020

Clinical Translational Sci

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We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (β = −0.29, P < 2.0 × 10 −16 ; β = −0.21, P = 4.7 × 10 −7 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (β = 0.10, P = 2 × 10 −4 ; β = 0.10, P = 0.01, respectively). Associations with VKORC1 (β = −0.14, P = 2.0 × 10 −16), CYP2C9 (β = −0.07, P = 5.6 × 10 −10), and CYP4F2 (β = 0.03, P = 3 × 10 −3), but not NQO1*2 (β = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from the United States and Brazil. Although the use of direct acting oral anticoagulants is increasing, warfarin remains commonly prescribed for prevention and treatment of thromboembolic events. 1,2 Complicating therapy with warfarin is the drug's narrow therapeutic index and high interpatient variability in dose requirements. 3 Latinos are at notably high risk for poor outcomes as a result of nontherapeutic anticoagulation with warfarin. 4-8 Particularly alarming is the increased risk for warfarin-related intracranial hemorrhage in Latinos compared with non-Latino whites. 7 Latinos also have a higher recurrence rate of thrombotic events and worse outcomes from these events compared with whites. 5,

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Section: Genotypingmentioning

confidence: 99%

Multi‐site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

Rouby

Marcatto

Claudio

et al. 2020

Clinical Translational Sci

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“…At the same time, our analysis suggests that health services research, translational medicine, and/or CBPR are types of research that could be further developed within the context of the six health condition areas that were reviewed. Whereas the focus on implementation science and translational research at the NIH has been increasing (92,93), our findings suggest that future research could focus on understudied approaches in Hispanic/Latino health, including, but not limited to, deeper understanding of effectiveness of currently recommended therapies and potential differences among heritage groups (56,(94)(95)(96); participation and/or increased inclusion in genetics/genomic studies (97)(98)(99); innovative strategies to implement recommended guidelines of care, and especially those move beyond the "sideways" approach (100); the intersection (101-103) of social determinants of health other factors on disease risk and the effectiveness of clinical or multi-level interventions (104)(105)(106)(107); design and analysis of multi-level or multi-sectoral (108)(109)(110) interventions; implementation and dissemination studies in real-world settings (92,111); the role of health information technologies on health-care delivery and health outcomes (112)(113)(114)(115)(116)(117)(118); the impact of interventions or policies designed to reduce health and health-care disparities (119)(120)(121)(122)(123)(124)(125)(126); and the effects of national or local policies on healthcare services and health outcomes (e.g., natural experiments) (127,…”

Section: Discussionmentioning

confidence: 92%

Funding of Hispanic/Latino Health-Related Research by the National Institutes of Health: An Analysis of the Portfolio of Research Program Grants on Six Health Topic Areas

Avilés-Santa

Hsu

Lam

et al. 2020

Front. Public Health

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Avilés-Santa et al. NIH Funding Hispanic/Latino Health poses opportunities to evaluate knowledge gained and their clinical application, explore new research questions, or to update some methods or instruments. The findings of the present study suggest opportunities to expand research in understudied mechanisms of disease that could explain differences in prevalence of conditions like diabetes and cancer among different heritage groups. In addition, our findings suggest that the impact of interventions or policies designed to reduce health disparities, innovative multi-level interventions, implementation and dissemination studies, the role of health information technology on health outcomes, and the intersectionality of individual, sociocultural, geographic, and other factors on health outcomes, among others, are understudied approaches, which could potentially advance research in Hispanic/Latino health and contribute to the achievement of better health outcomes in this diverse population.

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“…Only 95 warfarin patients from the original cohort (n = 275) had full genetic, ancestry, clinical, and demographic data available to run the corresponding ML methods. Pharmacogenetic variants previously found to be associated with warfarin dose requirements in Puerto Ricans (Ramos et al, 2012;Duconge et al, 2016;Claudio-Campos et al, 2017), individual ancestry proportions, as well as clinical and demographic data from all enrolled patients were considered in the corresponding analyses. The primary cohort, which corresponds to patients on warfarin, included 40 "normal," 38 "sensitive," and 17 "resistant" cases.…”

Section: Dataset Preparationmentioning

confidence: 99%

“…Our group has earlier published three previously developed pharmacogenetic algorithms to predict optimal warfarin dosing in Caribbean Hispanics of mostly Puerto Rican origin, which included ethno-specific alleles and adjustments by admixture measures in the derivation cohort (Ramos et al, 2012;Duconge et al, 2016;Claudio-Campos et al, 2017). All these models were based on multivariate linear regression analyses.…”

Section: Comparison To Previous Algorithms For Dose Predictions In Camentioning

confidence: 99%

Machine Learning Algorithm for Predicting Warfarin Dose in Caribbean Hispanics Using Pharmacogenetic Data

et al. 2020

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Despite some previous examples of successful application to the field of pharmacogenomics, the utility of machine learning (ML) techniques for warfarin dose predictions in Caribbean Hispanic patients has yet to be fully evaluated. This study compares seven ML methods to predict warfarin dosing in Caribbean Hispanics. This is a secondary analysis of genetic and non-genetic clinical data from 190 cardiovascular Hispanic patients. Seven ML algorithms were applied to the data. Data was divided into 80 and 20% to be used as training and test sets. ML algorithms were trained with the training set to obtain the models. Model performance was determined by computing the corresponding mean absolute error (MAE) and % patients whose predicted optimal dose were within ±20% of the actual stabilization dose, and then compared between groups of patients with "normal" (i.e., > 21 but <49 mg/week), low (i.e., ≤21 mg/week, "sensitive"), and high (i.e., ≥49 mg/week, "resistant") dose requirements. Random forest regression (RFR) significantly outperform all other methods, with a MAE of 4.73 mg/week and 80.56% of cases within ±20% of the actual stabilization dose. Among those with "normal" dose requirements, RFR performance is also better than the rest of models (MAE = 2.91 mg/week). In the "sensitive" group, support vector regression (SVR) shows superiority over the others with lower MAE of 4.79 mg/week. Finally, multivariate adaptive splines (MARS) shows the best performance in the resistant group (MAE = 7.22 mg/week) and 66.7% of predictions within ±20%. Models generated by using RFR, MARS, and SVR algorithms showed significantly better predictions of weekly warfarin dosing in the studied cohorts than other algorithms. Better performance of the ML models for patients with "normal," "sensitive," and "resistant" to warfarin were obtained when compared to other populations and previous statistical models.

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Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study

Cited by 17 publications

References 66 publications

Multi‐site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

Multi‐site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

Funding of Hispanic/Latino Health-Related Research by the National Institutes of Health: An Analysis of the Portfolio of Research Program Grants on Six Health Topic Areas

Machine Learning Algorithm for Predicting Warfarin Dose in Caribbean Hispanics Using Pharmacogenetic Data

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