Comparison of Nine Statistical Model Based Warfarin Pharmacogenetic Dosing Algorithms Using the Racially Diverse International Warfarin Pharmacogenetic Consortium Cohort Database

Objective

Multiple linear regression (MLR) and machine learning techniques in pharmacogenetic algorithm-based warfarin dosing have been reported. However, performances of these algorithms in racially diverse group have never been objectively evaluated and compared. In this literature-based study, we compared the performances of eight machine learning techniques with those of MLR in a large, racially-diverse cohort.

Methods

MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied in warfarin dose algorithms in a cohort from the International Warfarin Pharmacogenetics Consortium database. Covariates obtained by stepwise regression from 80% of randomly selected patients were used to develop algorithms. To compare the performances of these algorithms, the mean percentage of patients whose predicted dose fell within 20% of the actual dose (mean percentage within 20%) and the mean absolute error (MAE) were calculated in the remaining 20% of patients. The performances of these techniques in different races, as well as the dose ranges of therapeutic warfarin were compared. Robust results were obtained after 100 rounds of resampling.

Results

BART, MARS and SVR were statistically indistinguishable and significantly out performed all the other approaches in the whole cohort (MAE: 8.84–8.96 mg/week, mean percentage within 20%: 45.88%–46.35%). In the White population, MARS and BART showed higher mean percentage within 20% and lower mean MAE than those of MLR (all p values < 0.05). In the Asian population, SVR, BART, MARS and LAR performed the same as MLR. MLR and LAR optimally performed among the Black population. When patients were grouped in terms of warfarin dose range, all machine learning techniques except ANN and LAR showed significantly higher mean percentage within 20%, and lower MAE (all p values < 0.05) than MLR in the low- and high- dose ranges.

Conclusion

Overall, machine learning-based techniques, BART, MARS and SVR performed superior than MLR in warfarin pharmacogenetic dosing. Differences of algorithms’ performances exist among the races. Moreover, machine learning-based algorithms tended to perform better in the low- and high- dose ranges than MLR.