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Existing methodologies, particularly those reliant on a single biomarker derived from CiPA O'Hara\u2010Rudy (CiPAORdv1.0) ventricular cell model without the hERG dynamic as input to the individual machine learning model, have limitations in capturing the complexity inherent in the comprehensive range of factors influencing drug\u2010induced TdP risk. This study aims to overcome these limitations by proposing a stacking ensemble machine learning approach by integrating multiple in silico biomarkers derived from the CiPAORdv1.0 with hERG dynamic characteristics. The ensemble machine learning model consisted of three artificial neural network (ANN) models as baseline model and support vector machine (SVM), logistic regression (LR), random forest (RF), and extreme gradient boosting (XGBoost) models as meta\u2010classifier. The highest AUC score of 1.00 (0.90\u20131.00) for high risk, 0.97 (0.84\u20131.00) for intermediate risk, and 1.00 (0.87\u20131.00) for low risk were obtained using seven biomarkers derived from the CiPAORdv1.0 with hERG dynamic characteristics. Furthering our investigation, we explored the model's robustness by incorporating interindividual variability into the generation of in silico biomarkers from a population of human ventricular cell models. This study also enabled an analysis of TdP risk classification under high clinical exposure and therapeutic scenarios for several drugs. Additionally, from a sensitivity analysis, we revealed four important ion channels, namely, CaL, NaL, Na, and Kr channels that affect significantly the important biomarkers for TdP risk prediction.<\/jats:p>","DOI":"10.1002\/psp4.13229","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T11:40:27Z","timestamp":1724672427000},"page":"2159-2170","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A stacking ensemble machine learning model for evaluating cardiac toxicity of drugs based on in silico biomarkers"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4285-4824","authenticated-orcid":false,"given":"Yunendah Nur","family":"Fuadah","sequence":"first","affiliation":[{"name":"Computational Medicine Lab, Department of IT Convergence Engineering Kumoh National Institute of Technology  Gumi Korea"},{"name":"School of Electrical Engineering Telkom University  Bandung Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4507-3812","authenticated-orcid":false,"given":"Ali Ikhsanul","family":"Qauli","sequence":"additional","affiliation":[{"name":"Computational Medicine Lab, Department of IT Convergence Engineering Kumoh National Institute of Technology  Gumi Korea"},{"name":"Department of Engineering, Faculty of Advanced Technology and Multidiscipline Universitas Airlangga  Surabaya Jawa Timur Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5944-2784","authenticated-orcid":false,"given":"Muhammad Adnan","family":"Pramudito","sequence":"additional","affiliation":[{"name":"Computational Medicine Lab, Department of IT Convergence Engineering Kumoh National Institute of Technology  Gumi Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8273-6152","authenticated-orcid":false,"given":"Aroli","family":"Marcellinus","sequence":"additional","affiliation":[{"name":"Computational Medicine Lab, Department of IT Convergence Engineering Kumoh National Institute of Technology  Gumi Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9129-8951","authenticated-orcid":false,"given":"Ulfa Latifa","family":"Hanum","sequence":"additional","affiliation":[{"name":"Computational Medicine Lab, Department of IT Convergence Engineering Kumoh National Institute of Technology  Gumi Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6729-8129","authenticated-orcid":false,"given":"Ki Moo","family":"Lim","sequence":"additional","affiliation":[{"name":"Computational Medicine Lab, Department of IT Convergence Engineering Kumoh National Institute of Technology  Gumi Korea"},{"name":"Computational Medicine Lab, Department of Medical IT Convergence Engineering Kumoh National Institute of Technology  Gumi Korea"},{"name":"Meta Heart Co., Ltd.  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