Journal
COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING
Volume 348, Issue -, Pages 313-333Publisher
ELSEVIER SCIENCE SA
DOI: 10.1016/j.cma.2019.01.033
Keywords
Machine learning; Gaussian process regression; Sensitivity analysis; Uncertainty quantification; Finite element analysis; Drug development
Funding
- Stanford School of Engineering Fellowship (USA)
- Becas ChileFulbright Fellowship (Chile)
- Stanford Bio-X IIP Seed Grant (USA)
- National Institutes of Health (USA) [U01-HL119578]
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Prolonged QT intervals are a major risk factor for ventricular arrhythmias and a leading cause of sudden cardiac death. Various drugs are known to trigger QT interval prolongation and increase the proarrhythmic potential. Yet, how precisely the action of drugs on the cellular level translates into QT interval prolongation on the whole organ level remains insufficiently understood. Here we use machine learning techniques to systematically characterize the effect of 30 common drugs on the QT interval. We combine information from high fidelity three-dimensional human heart simulations with low fidelity one-dimensional cable simulations to build a surrogate model for the QT interval using multi-fidelity Gaussian process regression. Once trained and cross-validated, we apply our surrogate model to perform sensitivity analysis and uncertainty quantification. Our sensitivity analysis suggests that compounds that block the rapid delayed rectifier potassium current I-Kr have the greatest prolonging effect of the QT interval, and that blocking the L-type calcium current I-CaL and late sodium current I-NaL shortens the QT interval. Our uncertainty quantification allows us to propagate the experimental variability from individual block-concentration measurements into the QT interval and reveals that QT interval uncertainty is mainly driven by the variability in I-Kr block. In a final validation study, we demonstrate an excellent agreement between our predicted QT interval changes and the changes observed in a randomized clinical trial for the drugs dofetilide, quinidine, ranolazine, and verapamil. We anticipate that both the machine learning methods and the results of this study will have great potential in the efficient development of safer drugs. (C) 2019 The Authors. Published by Elsevier B.V.
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