The proposed strategy offers a possible answer to a major question raised by the community of safety pharmacology. By allowing a more automated analysis of the signals, our approach could contribute to promote the technology based on MEA and hiPSC-CMs and, therefore, improve reliability and efficiency of drug screening.

The Micro-Electrode Array (MEA) device enables high-throughput electrophysiology measurements that are less labor-intensive than patch-clamp based techniques. Combined with human-induced pluripotent stem cells cardiomyocytes (hiPSC-CM), it represents a new and promising paradigm for automated and accurate in vitro drug safety evaluation. In this article, the following question is addressed: which features of the MEA signals should be measured to better classify the effects of drugs? A framework for the classification of drugs using MEA measurements is proposed. The classification is based on the ion channels blockades induced by the drugs. It relies on an in silico electrophysiology model of the MEA, a feature selection algorithm and automatic classification tools. An in silico model of the MEA is developed and is used to generate synthetic measurements. An algorithm that extracts MEA measurements features designed to perform well in a classification context is described. These features are called composite biomarkers. A state-of-the-art machine learning program is used to carry out the classification of drugs using experimental MEA measurements. The experiments are carried out using five different drugs: mexiletine, flecainide, diltiazem, moxifloxacin, and dofetilide. We show that the composite biomarkers outperform the classical ones in different classification scenarios. We show that using both synthetic and experimental MEA measurements improves the robustness of the composite biomarkers and that the classification scores are increased.

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Novel studies conducting cardiac safety assessment using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are promising but might be limited by their specificity and predictivity. It is often challenging to correctly classify ion channel blockers or to sufficiently predict the risk for Torsade de Pointes (TdP). In this study, we developed a method combining in vitro and in silico experiments to improve machine learning approaches in delivering fast and reliable prediction of drug-induced ion-channel blockade and proarrhythmic behaviour. The algorithm is based on the construction of a dictionary and a greedy optimization, leading to the definition of optimal classifiers. Finally, we present a numerical tool that can accurately predict compound-induced pro-arrhythmic risk and involvement of sodium, calcium and potassium channels, based on hiPSC-CM field potential data.