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.
Table 1.
Descriptive clinical (non-genetic) and demographic characteristics of the derivation cohort (N = 255 warfarin-treated patients from VACHS) and the independent sample of 55 warfarin-treated Puerto Ricans from the Brownstone Clinic in Hartford, CT (validation cohort).
Table 2.
Allele and genotype frequency distributions of CYP2C9, CYP4F2, NQO1 and VKORC1 polymorphisms in Hispanic patients treated with warfarin at the VACHS-San Juan, PR (n = 255).
Data expressed as percent (Wald-adjusted 95% Confidence Interval, CI). χ2 <3.84 meet HWE for genotypes, one degree of freedom, p<0.05.
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.
Table 3.
Summary of attributes of the pharmacogenetic equation for warfarin dosing refinement in Caribbean Hispanics.
Derivation cohort (n = 255 patients from the VACHS).
Table 4.
Warfarin daily dose predictability of the admixture-adjusted pharmacogenetic refinement model developed in Caribbean Hispanics (CH), the Lenzini et al. pharmacogenetic refinement model [36], the IWPC pharmacogenetic initiation algorithm [37] and the clinical algorithma as compared with the actual doses of warfarin for the therapeutic effect in patients requiring low (≤3 mg/day), intermediate (>3 and <7 mg/day) or high (≥7 mg/day) exposure.
Study cohort of 255 warfarin patients at the VACHS anticoagulation clinic.
Table 5.
Predictions of ideal doses by using the admixture-adjusted pharmacogenetic refinement model developed in Caribbean Hispanics (CH), the Lenzini et al. pharmacogenetic refinement model [36], the IWPC pharmacogenetic initiation algorithm [37] and the clinical algorithmb in patients requiring low (≤3 mg/day), intermediate (>3 and <7 mg/day) or high (≥7 mg/day) exposure.
Ideal dose is defined as within 20% of the actual warfarin dose at stabilization.
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 Amerindian ancestry and low dose requirements.
ID codes depicted for those requiring <3mg/day.