Machine Learning of Human Pluripotent Stem Cell-Derived Engineered Cardiac Tissue Contractility for Automated Drug Classification

Abstract

Summary: Accurately predicting cardioactive effects of new molecular entities for therapeutics remains a daunting challenge. Immense research effort has been focused toward creating new screening platforms that utilize human pluripotent stem cell (hPSC)-derived cardiomyocytes and three-dimensional engineered cardiac tissue constructs to better recapitulate human heart function and drug responses. As these new platforms become increasingly sophisticated and high throughput, the drug screens result in larger multidimensional datasets. Improved automated analysis methods must therefore be developed in parallel to fully comprehend the cellular response across a multidimensional parameter space. Here, we describe the use of machine learning to comprehensively analyze 17 functional parameters derived from force readouts of hPSC-derived ventricular cardiac tissue strips (hvCTS) electrically paced at a range of frequencies and exposed to a library of compounds. A generated metric is effective for then determining the cardioactivity of a given drug. Furthermore, we demonstrate a classification model that can automatically predict the mechanistic action of an unknown cardioactive drug. : Analysis methods must be improved in parallel with advancements in drug screening platforms. Machine learning principles are used here to analyze multidimensional datasets to determine cardioactivity of unknown drugs. Furthermore, this study describes the use of multiclassification algorithms to classify unknown drugs based on their mechanistic action and compare their potency with related drugs. Keywords: human pluripotent stem cell-derived cardiomyocytes, drug-induced cardiotoxicity, machine learning, human engineered cardiac tissue, drug classification library