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Abstract The Comprehensive In-vitro Proarrhythmia Assay (CiPA) initiative aims to refine the assessment of drug-induced torsades de pointes (TdP) risk, utilizing computational models to predict cardiac drug toxicity. Despite advancements in machine learning applications for this purpose, the specific contribution of in-silico biomarkers to toxicity risk levels has yet to be thoroughly elucidated. This study addresses this gap by implementing explainable artificial intelligence (XAI) to illuminate the impact of individual biomarkers in drug toxicity prediction. We employed the Markov chain Monte Carlo method to generate a detailed dataset for 28 drugs, from which twelve in-silico biomarkers of 12 drugs were computed to train various machine learning models, including Artificial Neural Networks (ANN), Support Vector Machines (SVM), Random Forests (RF), XGBoost, K-Nearest Neighbors (KNN), and Radial Basis Function (RBF) networks. Our study’s innovation is leveraging XAI, mainly through the SHAP (SHapley Additive exPlanations) method, to dissect and quantify the contributions of biomarkers across these models. Furthermore, the model performance was evaluated using the test set from 16 drugs. We found that the ANN model coupled with the eleven most influential in-silico biomarkers namely $$\frac{dVm}{dt}_{repol}, \frac{dVm}{dt}_{max}, {APD}_{90}, {APD}_{50}, {APD}_{tri}, {CaD}_{90}, {CaD}_{50}, {Ca}_{tri}, {Ca}_{Diastole}, qInward, and qNet$$ dVm dt repol , dVm dt max , APD 90 , APD 50 , APD tri , CaD 90 , CaD 50 , Ca tri , Ca Diastole , q I n w a r d , a n d q N e t showed the highest classification performance among all classifiers with Area Under the Curve (AUC) scores of 0.92 for predicting high-risk, 0.83 for intermediate-risk, and 0.98 for low-risk drugs. We also found that the optimal in silico biomarkers selected based on SHAP analysis may be different for various classification models. However, we also found that the biomarker selection only sometimes improved the performance; therefore, evaluating various classifiers is still essential to obtain the desired classification performance. Our proposed method could provide a systematic way to assess the best classifier with the optimal in-silico biomarkers for predicting the TdP risk of drugs, thereby advancing the field of cardiac safety evaluations.

Abstract Continuous blood pressure (BP) monitoring is essential for managing cardiovascular disease. However, existing devices often require expert handling, highlighting the need for alternative methods to simplify the process. Researchers have developed various methods using physiological signals to address this issue. Yet, many of these methods either fall short in accuracy according to the BHS, AAMI, and IEEE standards for BP measurement devices or suffer from low computational efficiency due to the complexity of their models. To solve this problem, we developed a BP prediction system that merges extracted features of PPG and ECG from two pulses of both signals using convolutional and LSTM layers, followed by incorporating the R-to-R interval durations as additional features for predicting systolic (SBP) and diastolic (DBP) blood pressure. Our findings indicate that the prediction accuracies for SBP and DBP were 5.306 ± 7.248 mmHg with a 0.877 correlation coefficient and 3.296 ± 4.764 mmHg with a 0.918 correlation coefficient, respectively. We found that our proposed model achieved a robust performance on the MIMIC III dataset with a minimum architectural design and high-level accuracy compared to existing methods. Thus, our method not only meets the passing category for BHS, AAMI, and IEEE guidelines but also stands out as the most rapidly accurate deep-learning-based BP measurement device currently available.

This study proposes a small one-dimensional convolutional neural network (1D-CNN) framework for individual authentication, considering the hypothesis that a single heartbeat as input is sufficient to create a robust system. A short segment between R to R of electrocardiogram (ECG) signals was chosen to generate single heartbeat samples by enforcing a rigid length thresholding procedure combined with an interpolation technique. Additionally, we explored the benefits of the synthetic minority oversampling technique (SMOTE) to tackle the imbalance in sample distribution among individuals. The proposed framework was evaluated individually and in a mixture of four public databases: MIT-BIH Normal Sinus Rhythm (NSRDB), MIT-BIH Arrhythmia (MIT-ARR), ECG-ID, and MIMIC-III which are available in the Physionet repository. The proposed framework demonstrated excellent performance, achieving a perfect score (100%) across all metrics (i.e., accuracy, precision, sensitivity, and F1-score) on individual NSRDB and MIT-ARR databases. Meanwhile, the performance remained high, reaching more than 99.6% on mixed datasets that contain larger populations and more diverse conditions. The impressive performance demonstrated in both small and large subject groups emphasizes the model’s scalability and potential for widespread implementation, particularly in security contexts where timely authentication is crucial. For future research, we need to examine the incorporation of multimodal biometric systems and extend the applicability of the framework to real-time environments and larger populations.

Torsades de pointes (TdP) is a type of ventricular arrhythmia that can lead to sudden cardiac death. Drug-induced TdP has been an important concern for researchers and international regulatory boards. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative was proposed that integrates in vitro testing and computational models of cardiac ion channels and human cardiomyocyte cells to evaluate the proarrhythmic risk of drugs. The TdP risk classification performance using only a single TdP metric may require some improvements because of information limitations and the instability of generalizing results. This study evaluates the performance of TdP metrics from the in silico simulations of the Tomek–O'Hara Rudy (ToR–ORd) ventricular cell model for classifying the TdP risk of drugs. We utilized these metrics as an input to an artificial neural network (ANN)-based classifier. The ANN model was optimized through hyperparameter tuning using the grid search (GS) method to find the optimal model. The study outcomes show an area under the curve (AUC) value of 0.979 for the high-risk category, 0.791 for the intermediate-risk category, and 0.937 for the low-risk category. Therefore, this study successfully demonstrates the capability of the ToR–ORd ventricular cell model in classifying the TdP risk into three risk categories, providing new insights into TdP risk prediction methods.

Safety pharmacology examines the potential for new drugs to have unusual, rare side effects such as torsade de pointes (TdP). Recently, as a part of the Comprehensive in vitro Proarrhythmia Assay (CiPA) project, techniques for predicting the development of druginduced TdP through computer simulations have been proposed and verified. However, CiPA assessment generally does not consider the effect of cardiac cell inter-individual variability, especially related to metabolic status. The study aimed to explore whether rare proarrhythmic effects may be linked to the inter-individual variability of cardiac cells and whether incorporating this variability into computational models could alter the prediction of drugs' TdP risks. This study evaluated the contribution of two biological characteristics to the proarrhythmic effects. The first was spermine concentration, which varies with metabolic status; the second was L-type calcium permeability that could occur due to mutations. Twenty-eight drugs were examined throughout this study, and qNet was analyzed as an essential feature. Even though there were some discrepancies of TdP risk predictions from the baseline model, we found that considering the inter-individual variability might change the TdP risk of drugs. Several drugs in the high-risk drugs group were predicted to affect as intermediate and low-risk drugs in some individuals and vice versa. Also, most intermediaterisk drugs were expected to act as low-risk drugs. When compared, the effects of interindividual variability of L-type calcium were more significant than spermine in altering the TdP risk of compounds. These results emphasize the importance of considering interindividual variability to assess drugs. [ABSTRACT FROM AUTHOR]

Torsades de pointes (TdP) is a type of ventricular arrhythmia that can lead to sudden cardiac death. Drug-induced TdP has been an important concern for researchers and international regulatory boards. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative was proposed that integrates in vitro testing and computational models of cardiac ion channels and human cardiomyocyte cells to evaluate the proarrhythmic risk of drugs. The TdP risk classification performance using only a single TdP metric may require some improvements because of information limitations and the instability of generalizing results. This study evaluates the performance of TdP metrics from the in silico simulations of the Tomek-O'Hara Rudy (ToR-ORd) ventricular cell model for classifying the TdP risk of drugs. We utilized these metrics as an input to an artificial neural network (ANN)-based classifier. The ANN model was optimized through hyperparameter tuning using the grid search (GS) method to find the optimal model. The study outcomes show an area under the curve (AUC) value of 0.979 for the high-risk category, 0.791 for the intermediate-risk category, and 0.937 for the low-risk category. Therefore, this study successfully demonstrates the capability of the ToR-ORd ventricular cell model in classifying the TdP risk into three risk categories, providing new insights into TdP risk prediction methods. [ABSTRACT FROM AUTHOR]