A greedy classifier optimization strategy to assess ion channel blocking activity and pro-arrhythmia in hiPSC-cardiomyocytes

by Fabien Raphel, Tessa De Korte, Damiano Lombardi, Stefan Braam, Jean-Frederic Gerbeau

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.