Evaluating the Effect of Longitudinal Dose and INR Data on Maintenance Warfarin Dose Predictions

Warfarin, a commonly prescribed drug to prevent blood clots, has a highly variable individual response. Determining a maintenance warfarin dose that achieves a therapeutic blood clotting time, as measured by the international normalized ratio (INR), is crucial in preventing complications. Machine learning algorithms are increasingly being used for warfarin dosing; usually, an initial dose is predicted with clinical and genotype factors, and this dose is revised after a few days based on previous doses and current INR. Since a sequence of prior doses and INR better capture the variability in individual warfarin response, we hypothesized that longitudinal dose response data will improve maintenance dose predictions. To test this hypothesis, we analyzed a dataset from the COAG warfarin dosing study, which includes clinical data, warfarin doses and INR measurements over the study period, and maintenance dose when therapeutic INR was achieved. Various machine learning regression models to predict maintenance warfarin dose were trained with clinical factors and dosing history and INR data as features. Overall, dose revision algorithms with a single dose and INR achieved comparable performance as the baseline dose revision algorithm. In contrast, dose revision algorithms with longitudinal dose and INR data provided maintenance dose predictions that were statistically significantly much closer to the true maintenance dose. Focusing on the best performing model, gradient boosting (GB), the proportion of ideal estimated dose, i.e., defined as within $pm$20% of the true dose, increased from the baseline (54.92%) to the GB model with the single (63.11%) and longitudinal (75.41%) INR. More accurate maintenance dose predictions with longitudinal dose response data can potentially achieve therapeutic INR faster, reduce drug-related complications and improve patient outcomes with warfarin therapy.