Development of a system to support warfarin dose decisions using deep neural networks

The first aim of this study was to develop a prothrombin time international normalized ratio (PT INR) prediction model. The second aim was to develop a warfarin maintenance dose decision support system as a precise warfarin dosing platform. Data of 19,719 inpatients from three institutions was analyzed. The PT INR prediction algorithm included dense and recurrent neural networks, and was designed to predict the 5th-day PT INR from data of days 1-4. Data from patients in one hospital (n = 22,314) was used to train the algorithm which was tested with the datasets from the other two hospitals (n = 12,673). The performance of 5th-day PT INR prediction was compared with 2000 predictions made by 10 expert physicians. A generator of individualized warfarin dose-PT INR tables which simulated the repeated administration of varying doses of warfarin was developed based on the prediction model. The algorithm outperformed humans with accuracy terms of within ± 0.3 of the actual value (machine learning algorithm: 10,650/12,673 cases (84.0%), expert physicians: 1647/2000 cases (81.9%), P = 0.014). In the individualized warfarin dose-PT INR tables generated by the algorithm, the 8th-day PT INR predictions were within 0.3 of actual value in 450/842 cases (53.4%). An artificial intelligence-based warfarin dosing algorithm using a recurrent neural network outperformed expert physicians in predicting future PT INRs. An individualized warfarin dose-PT INR table generator which was constructed based on this algorithm was acceptable.ope

Warfarin dosing algorithms: A systematic review

AIMS:Numerous algorithms have been developed to guide warfarin dosing and improve clinical outcomes. We reviewed the algorithms available for various populations and the covariates, performances and risk of bias of these algorithms. METHODS:We systematically searched MEDLINE until 20 May 2020 and selected studies describing the development, external validation, or clinical utility of a multivariable warfarin dosing algorithm. Two investigators conducted data extraction and quality assessment. RESULTS:Of 10,035 screened records, 266 articles were included in the review, describing the development of 433 dosing algorithms, 481 external validations and 52 clinical utility assessments. Most developed algorithms were for dose-initiation (86%), developed by multiple linear regression (65%) and mostly applicable to Asians (49%) or Whites (43%). The most common demographic/clinical/environmental covariates were age (included in 401 algorithms), concomitant medications (270 algorithms) and weight (229 algorithms) while CYP2C9 (329 algorithms), VKORC1 (319 algorithms) and CYP4F2 (92 algorithms) variants were the most common genetic covariates. Only 26% and 7% algorithms were externally validated and evaluated for clinical utility, respectively, with less than 2% of algorithm developments and external validations being rated as having a low risk of bias. CONCLUSION:Most warfarin dosing algorithms have been developed in Asians and Whites and may not be applicable to under-served populations. Few algorithms have been externally validated, assessed for clinical utility, and/or have a low risk of bias which makes them unreliable for clinical use. Algorithm development and assessment should follow current methodological recommendations to improve reliability and applicability, and under-represented populations should be prioritized

A New Approach towards Minimizing the Risk of Misdosing Warfarin Initiation Doses

It is a challenge to be able to prescribe the optimal initial dose of warfarin. There have been many studies focused on an efficient strategy to determine the optimal initial dose. Numerous clinical, genetic, and environmental factors affect the warfarin dose response. In practice, it is common that the initial warfarin dose is substantially different from the stable maintenance dose, which may increase the risk of bleeding or thrombosis prior to achieving the stable maintenance dose. In order to minimize the risk of misdosing, despite popular warfarin dose prediction models in the literature which create dose predictions solely based on patients’ attributes, we have taken physicians’ opinions towards the initial dose into consideration. The initial doses selected by clinicians, along with other standard clinical factors, are used to determine an estimate of the difference between the initial dose and estimated maintenance dose using shrinkage methods. The selected shrinkage method was LASSO (Least Absolute Shrinkage and Selection Operator). The estimated maintenance dose was more accurate than the original initial dose, the dose predicted by a linear model without involving the clinicians initial dose, and the values predicted by the most commonly used model in the literature, the Gage clinical model