Assessing proarrhythmic potential of environmental chemicals using a high throughput in vitro-in silico model with human induced pluripotent stem cell-derived cardiomyocytes_suppl2

QT prolongation and the potentially fatal arrhythmia Torsades de Pointes are common causes for withdrawing or restricting drugs; however, little is known if environmental chemicals may have similar liabilities. Current in vitro-in silico models for testing proarrhythmic liabilities, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), provide an opportunity to address this data gap. These methods are still low- to medium-throughput and not suitable for testing the tens of thousands of chemicals in commerce. We hypothesized that combining high-throughput population-based in vitro testing in hiPSC-CMs with a fully in silico data analysis workflow can offer sensitive and specific predictions of proarrhythmic potential. We calibrated the model with a published hiPSC-CM dataset of drugs known to be positive or negative for proarrhythmia and tested its performance using internal cross-validation and external validation. Additionally, we used computational down-sampling to examine three study designs for hiPSC-CM data: one replicate of one donor, five replicates of one donor, and one replicate of a population of five donors. We found that the population of five donors had the best performance for predicting proarrhythmic potential. The resulting model was then applied to predict the proarrhythmic potential of environmental chemicals, additionally characterizing risk through margin of exposure (MOE) calculations. Out of over 900 environmental chemicals tested, over 150 were predicted to have proarrhythmic potential, but only seven chemicals have MOE < 1. We conclude that a high throughput in vitro-in silico approach using population-based hiPSC-CM testing provides a reasonable approach to screening environmental chemicals for proarrhythmic potential.