@article{03b87b3a8efb4e83821c5dae13317cbf,
title = "Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the CiPA Initiative",
abstract = "The International Council on Harmonization (ICH) S7B and E14 regulatory guidelines are sensitive but not specific for predicting which drugs are pro-arrhythmic. In response, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) was proposed that integrates multi-ion channel pharmacology data in vitro into a human cardiomyocyte model in silico for proarrhythmia risk assessment. Previously, we reported the model optimization and proarrhythmia metric selection based on CiPA training drugs. In this study, we report the application of the prespecified model and metric to independent CiPA validation drugs. Over two validation datasets, the CiPA model performance meets all pre-specified measures for ranking and classifying validation drugs, and outperforms alternatives, despite some in vitro data differences between the two datasets due to different experimental conditions and quality control procedures. This suggests that the current CiPA model/metric may be fit for regulatory use, and standardization of experimental protocols and quality control criteria could increase the model prediction accuracy even further.",
author = "Zhihua Li and Ridder, {Bradley J.} and Xiaomei Han and Wu, {Wendy W.} and Jiansong Sheng and Tran, {Phu N.} and Min Wu and Aaron Randolph and Johnstone, {Ross H.} and Mirams, {Gary R.} and Yuri Kuryshev and James Kramer and Caiyun Wu and Crumb, {William J.} and Strauss, {David G.}",
note = "Funding Information: This work was supported by the Wellcome Trust (grant number 101222/Z/13/Z) and by the Engineering and Physical Sciences Research Council (grant number EP/G037280/1). The Wellcome Trust grant jointly with The Royal Society through a Sir Henry Dale Fellowship awarded to G.R.M. R.H.J. was supported by a Systems Approaches to Biomedical Science Industrial Doctorate Centre studentship by the UK EPSRC and F. Hoffmann-La Roche AG. This project was supported by the Research Participation Program at CDER, administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. The authors thank members of the CiPA Steering Committee, especially Drs. Thomas Colatsky, Derek Leishman, Gary Gintant, and Norman Stockbridge, and members of the CiPA ion channel working group, especially Drs. Adam Hill, Jamie Vandenberg, and Najah Abi-Gerges, for discussions about the Validation Strategy. Special thanks to former In Silico Team members Drs. Sara Dutta, Kelly Chang, and Kylie Beattie for their contribution to model building and training. We would also like to thank Drs. Christine Garnett, Lars Johannesen, and Jose Vicente for insightful suggestions about data analysis, and the HESI Cardiac Safety High-Throughput Systems Subteam for their data contributions to this study. Funding Information: This work was supported by the Wellcome Trust (grant number 101222/Z/13/Z) and by the Engineering and Physical Sciences Research Council (grant number EP/G037280/1). The Wellcome Trust grant jointly with The Royal Society through a Sir Henry Dale Fellowship awarded to G.R.M. R.H.J. was supported by a Systems Approaches to Biomedical Science Industrial Doctorate Centre studentship by the UK EPSRC and F. Hoffmann-La Roche AG. This project was supported by the Research Participation Program at CDER, administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. Publisher Copyright: {\textcopyright} 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.",
year = "2019",
month = feb,
doi = "10.1002/cpt.1184",
language = "English (US)",
volume = "105",
pages = "466--475",
journal = "Clinical pharmacology and therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "2",
}