A novel computational approach combining simulations of drug effects on ventricular myocyte dynamics with machine learning provided superior risk prediction for drug-induced Torsades de Pointes.
Does a computational approach combining simulations and machine learning improve the prediction of drug-induced Torsades de Pointes?
A novel machine learning and simulation-based computational approach improves the prediction of drug-induced Torsades de Pointes by incorporating action potential and calcium waveform dynamics.
The ventricular arrhythmia Torsades de Pointes (TdP) is a common form of drug-induced cardiotoxicity, but prediction of this arrhythmia remains an unresolved issue in drug development. Current assays to evaluate arrhythmia risk are limited by poor specificity and a lack of mechanistic insight. We addressed this important unresolved issue through a novel computational approach that combined simulations of drug effects on dynamics with statistical analysis and machine-learning. Drugs that blocked multiple ion channels were simulated in ventricular myocyte models, and metrics computed from the action potential and intracellular (Ca(2+) ) waveform were used to construct classifiers that distinguished between arrhythmogenic and nonarrhythmogenic drugs. We found that: (1) these classifiers provide superior risk prediction; (2) drug-induced changes to both the action potential and intracellular (Ca(2+) ) influence risk; and (3) cardiac ion channels not typically assessed may significantly affect risk. Our algorithm demonstrates the value of systematic simulations in predicting pharmacological toxicity.
Lancaster et al. (Mon,) conducted a other in Drug-induced Torsades de Pointes (TdP). Computational simulations and machine learning algorithms vs. Current assays was evaluated on Prediction of arrhythmogenic versus nonarrhythmogenic drugs. A novel computational approach combining simulations of drug effects on ventricular myocyte dynamics with machine learning provided superior risk prediction for drug-induced Torsades de Pointes.
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