ABSTRACT
Introduction: Predicting ventricular arrhythmia Torsade de Pointes (TdP) caused by drug-induced cardiotoxicity is essential in drug development. Several studies used single biomarkers such as qNet and Repolarization Abnormality (RA) in a single cardiac cell model to evaluate TdP risk. However, a single biomarker may not encompass the full range of factors contributing to TdP risk, leading to divergent TdP risk prediction outcomes, mainly when evaluated using unseen data. We addressed this issue by utilizing multi-in silico features from a population of human ventricular cell models that could capture a representation of the underlying mechanisms contributing to TdP risk to provide a more reliable assessment of drug-induced cardiotoxicity. Method: We generated a virtual population of human ventricular cell models using a modified O'Hara-Rudy model, allowing inter-individual variation. IC50 and Hill coefficients from 67 drugs were used as input to simulate drug effects on cardiac cells. Fourteen features (dVmdtrepol, dVmdtmax, Vmpeak, Vmresting, APDtri, APD90, APD50, Capeak, Cadiastole, Catri, CaD90, CaD50, qNet, qInward) could be generated from the simulation and used as input to several machine learning models, including k-nearest neighbor (KNN), Random Forest (RF), XGBoost, and Artificial Neural Networks (ANN). Optimization of the machine learning model was performed using a grid search to select the best parameter of the proposed model. We applied five-fold cross-validation while training the model with 42 drugs and evaluated the model's performance with test data from 25 drugs. Result: The proposed ANN model showed the highest performance in predicting the TdP risk of drugs by providing an accuracy of 0.923 (0.908-0.937), sensitivity of 0.926 (0.909-0.942), specificity of 0.921 (0.906-0.935), and AUC score of 0.964 (0.954-0.975). Discussion and conclusion: According to the performance results, combining the electrophysiological model including inter-individual variation and optimization of machine learning showed good generalization ability when evaluated using the unseen dataset and produced a reliable drug-induced TdP risk prediction system.
ABSTRACT
Heart-sound auscultation is one of the most widely used approaches for detecting cardiovascular disorders. Diagnosing abnormalities of heart sound using a stethoscope depends on the physician's skill and judgment. Several studies have shown promising results in automatically detecting cardiovascular disorders based on heart-sound signals. However, the accuracy performance needs to be enhanced as automated heart-sound classification aids in the early detection and prevention of the dangerous effects of cardiovascular problems. In this study, an optimal heart-sound classification method based on machine learning technologies for cardiovascular disease prediction is performed. It consists of three steps: pre-processing that sets the 5 s duration of the PhysioNet Challenge 2016 and 2022 datasets, feature extraction using Mel frequency cepstrum coefficients (MFCC), and classification using grid search for hyperparameter tuning of several classifier algorithms including k-nearest neighbor (K-NN), random forest (RF), artificial neural network (ANN), and support vector machine (SVM). The five-fold cross-validation was used to evaluate the performance of the proposed method. The best model obtained classification accuracy of 95.78% and 76.31%, which was assessed using PhysioNet Challenge 2016 and 2022, respectively. The findings demonstrate that the suggested approach obtained excellent classification results using PhysioNet Challenge 2016 and showed promising results using PhysioNet Challenge 2022. Therefore, the proposed method has been potentially developed as an additional tool to facilitate the medical practitioner in diagnosing the abnormality of the heart sound.
