{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:34:44Z","timestamp":1790796884326,"version":"4.1.0"},"reference-count":80,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T00:00:00Z","timestamp":1627862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T00:00:00Z","timestamp":1627862400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T00:00:00Z","timestamp":1627862400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to detect drug-induced toxicity in vitro. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those with potential cardiotoxic liabilities in iPSC-CMs using a single-parameter score based on deep learning. Compounds demonstrating cardiotoxicity in iPSC-CMs included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks that show cardiotoxic signal in iPSC-CMs. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that may protect against diseased phenotypes and deleterious mutations.<\/jats:p>","DOI":"10.7554\/elife.68714","type":"journal-article","created":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T08:01:12Z","timestamp":1627891272000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.68714","source":"Crossref","is-referenced-by-count":72,"title":["Deep learning detects cardiotoxicity in a high-content screen with induced pluripotent stem cell-derived cardiomyocytes"],"prefix":"10.7554","volume":"10","author":[{"given":"Francis","family":"Grafton","sequence":"first","affiliation":[{"name":"Tenaya Therapeutics, South San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaclyn","family":"Ho","sequence":"additional","affiliation":[{"name":"Tenaya Therapeutics, South San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Ranjbarvaziri","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farshad","family":"Farshidfar","sequence":"additional","affiliation":[{"name":"Tenaya Therapeutics, South San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiia","family":"Budan","sequence":"additional","affiliation":[{"name":"Tenaya Therapeutics, South San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Steltzer","sequence":"additional","affiliation":[{"name":"Tenaya Therapeutics, South San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahnaz","family":"Maddah","sequence":"additional","affiliation":[{"name":"Dana Solutions, Palo Alto, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin E","family":"Loewke","sequence":"additional","affiliation":[{"name":"Dana Solutions, Palo Alto, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Green","sequence":"additional","affiliation":[{"name":"Tenaya Therapeutics, South San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Snahel","family":"Patel","sequence":"additional","affiliation":[{"name":"Tenaya Therapeutics, South San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Hoey","sequence":"additional","affiliation":[{"name":"Tenaya Therapeutics, South San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5323-7891","authenticated-orcid":true,"given":"Mohammad Ali","family":"Mandegar","sequence":"additional","affiliation":[{"name":"Tenaya Therapeutics, South San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,8,2]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"7729","DOI":"10.1038\/sj.onc.1209046","article-title":"SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation","volume":"24","author":"Ahuja","year":"2005","journal-title":"Oncogene"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1136\/heart.89.2.150","article-title":"NT-proBNP: a new diagnostic screening tool to differentiate between patients with normal and reduced left ventricular systolic function","volume":"89","author":"Bay","year":"2003","journal-title":"Heart"},{"key":"bib3","volume-title":"Advanced Assay Development Guidelines for Image-Based High Content Screening and Analysis - Assay Guidance Manual","author":"Bray","year":"2017"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1038\/nmeth.2999","article-title":"Chemically defined generation of human cardiomyocytes","volume":"11","author":"Burridge","year":"2014","journal-title":"Nature Methods"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nm.4087","article-title":"Human induced pluripotent stem cell\u2013derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity","volume":"22","author":"Burridge","year":"2016","journal-title":"Nature Medicine"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1161\/01.RES.0000077045.84609.9F","article-title":"NFATc3 and NFATc4 are required for cardiac development and mitochondrial function","volume":"92","author":"Bushdid","year":"2003","journal-title":"Circulation Research"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1177\/1087057113500812","article-title":"Phenotypic screening with human iPS cell-derived cardiomyocytes: hts-compatible assays for interrogating cardiac hypertrophy","volume":"18","author":"Carlson","year":"2013","journal-title":"Journal of Biomolecular Screening"},{"key":"bib8","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000012705","article-title":"Risk of regorafenib-induced cardiovascular events in patients with solid tumors","volume":"97","author":"Chen","year":"2018","journal-title":"Medicine"},{"key":"bib9","article-title":"Anagrelide","author":"Clinic M","year":"2020","unstructured":"Clinic M. 2020. Anagrelide. https:\/\/www.mayoclinic.org\/drugs-supplements\/anagrelide-oral-route\/side-effects\/drg-20061875 [Accessed November 28, 2020]."},{"key":"bib10","doi-asserted-by":"publisher","first-page":"D745","DOI":"10.1093\/nar\/gky1113","article-title":"Ensembl 2019","volume":"47","author":"Cunningham","year":"2019","journal-title":"Nucleic Acids Research"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.jhealeco.2016.01.012","article-title":"Innovation in the pharmaceutical industry: new estimates of R&D costs","volume":"47","author":"DiMasi","year":"2016","journal-title":"Journal of Health Economics"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S1470-2045(15)00464-7","article-title":"Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study","volume":"17","author":"Dimopoulos","year":"2016","journal-title":"The Lancet Oncology"},{"key":"bib13","first-page":"1893","article-title":"The role of BNP testing in heart failure","volume":"74","author":"Doust","year":"2006","journal-title":"American Family Physician"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.1038\/nprot.2009.97","article-title":"Mapping identifiers for the integration of genomic datasets with the R\/Bioconductor package biomaRt","volume":"4","author":"Durinck","year":"2009","journal-title":"Nature Protocols"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/nrd4336","article-title":"The discovery of first-in-class drugs: origins and evolution","volume":"13","author":"Eder","year":"2014","journal-title":"Nature Reviews Drug Discovery"},{"key":"bib16","article-title":"Sotalol","author":"FDA.gov","year":"2020","unstructured":"FDA.gov. 2020. Sotalol. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2009\/022306s000lbl.pdf [Accessed November 28, 2020]."},{"key":"bib17","doi-asserted-by":"publisher","first-page":"D766","DOI":"10.1093\/nar\/gky955","article-title":"GENCODE reference annotation for the human and mouse genomes","volume":"47","author":"Frankish","year":"2019","journal-title":"Nucleic Acids Research"},{"key":"bib18","doi-asserted-by":"publisher","DOI":"10.1101\/2020.05.12.091082","article-title":"Androgen regulates SARS-CoV-2 receptor levels and is associated with severe COVID-19 symptoms in men","volume-title":"bioRxiv","author":"Ghazizadeh","year":"2020"},{"key":"bib19","article-title":"SGFT","volume-title":"Software Heritage","author":"Grafton","year":"2021","unstructured":"Grafton F. 2021. SGFT. Software Heritage. swh:1:rev:1413b18726172659dcb9a09e6f91653063ab3361. https:\/\/archive.softwareheritage.org\/swh:1:dir:56e743b5a05fbf175e07bc039f3ef555f1f77aa0;origin=https:\/\/github.com\/maxsalick\/SGFT;visit=swh:1:snp:327b94c95d99adc0bbd0f5d26b180e9b88409146;anchor=swh:1:rev:1413b18726172659dcb9a09e6f91653063ab3361."},{"key":"bib20","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1038\/nrd3577","article-title":"Induced pluripotent stem cells--opportunities for disease modelling and drug discovery","volume":"10","author":"Grskovic","year":"2011","journal-title":"Nature Reviews Drug Discovery"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1093\/toxsci\/kfr158","article-title":"Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes","volume":"123","author":"Guo","year":"2011","journal-title":"Toxicological Sciences"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1093\/eurheartj\/ehu301","article-title":"Atlas of the clinical genetics of human dilated cardiomyopathy","volume":"36","author":"Haas","year":"2015","journal-title":"European Heart Journal"},{"key":"bib23","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.01044","article-title":"Deep Learning-Based Structure-Activity relationship modeling for Multi-Category toxicity classification: a case study of 10K Tox21 chemicals with High-Throughput Cell-Based androgen receptor bioassay data","volume":"10","author":"Idakwo","year":"2019","journal-title":"Frontiers in Physiology"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1016\/j.amjcard.2004.12.032","article-title":"The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study","volume":"95","author":"Januzzi","year":"2005","journal-title":"The American Journal of Cardiology"},{"key":"bib25","doi-asserted-by":"publisher","DOI":"10.1186\/s40537-019-0192-5","article-title":"Survey on deep learning with class imbalance","volume":"6","author":"Johnson","year":"2019","journal-title":"Journal of Big Data"},{"key":"bib26","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.94623","article-title":"A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress","volume":"2","author":"Judge","year":"2017","journal-title":"JCI Insight"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4161\/spmg.19885","article-title":"Cell lines","volume":"2","author":"Kaur","year":"2012","journal-title":"Spermatogenesis"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"21.4.1","DOI":"10.1002\/0471142905.hg2104s88","article-title":"Efficient CRISPR\/Cas9\u2010Based genome engineering in human pluripotent stem cells","volume":"88","author":"Kime","year":"2016","journal-title":"Current Protocols in Human Genetics"},{"key":"bib29","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4511","article-title":"Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle","volume":"5","author":"Lamoureux","year":"2014","journal-title":"Nature Communications"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.stem.2012.10.010","article-title":"Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells","volume":"12","author":"Lan","year":"2013","journal-title":"Cell Stem Cell"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1038\/nature14539","article-title":"Deep learning","volume":"521","author":"LeCun","year":"2015","journal-title":"Nature"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1159\/000484889","article-title":"Study of HSPB6: insights into the properties of the multifunctional protective agent","volume":"44","author":"Li","year":"2017","journal-title":"Cellular Physiology and Biochemistry"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"E1848","DOI":"10.1073\/pnas.1200250109","article-title":"Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical wnt signaling","volume":"109","author":"Lian","year":"2012","journal-title":"PNAS"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0","volume":"27","author":"Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"bib35","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2017.00253","article-title":"Culture in Glucose-Depleted medium supplemented with fatty acid and 3,3\u2032,5-Triiodo-l-Thyronine Facilitates Purification and Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes","volume":"8","author":"Lin","year":"2017","journal-title":"Frontiers in Endocrinology"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/nmeth902","article-title":"Feeder-independent culture of human embryonic stem cells","volume":"3","author":"Ludwig","year":"2006","journal-title":"Nature Methods"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.stemcr.2015.02.007","article-title":"A Non-invasive platform for functional characterization of Stem-Cell-Derived cardiomyocytes with applications in Cardiotoxicity testing","volume":"4","author":"Maddah","year":"2015","journal-title":"Stem Cell Reports"},{"key":"bib38","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2020.106895","article-title":"Quantifying drug-induced structural toxicity in hepatocytes and cardiomyocytes derived from hiPSCs using a deep learning method","volume":"105","author":"Maddah","year":"2020","journal-title":"Journal of Pharmacological and Toxicological Methods"},{"key":"bib39","doi-asserted-by":"publisher","DOI":"10.1038\/srep25333","article-title":"Modeling Doxorubicin-Induced cardiotoxicity in human pluripotent stem cell Derived-Cardiomyocytes","volume":"6","author":"Maillet","year":"2016","journal-title":"Scientific Reports"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1016\/j.stem.2016.01.022","article-title":"CRISPR interference efficiently induces specific and reversible gene silencing in human iPSCs","volume":"18","author":"Mandegar","year":"2016","journal-title":"Cell Stem Cell"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1517\/17425255.2015.981523","article-title":"Human induced pluripotent stem cell-derived hepatocytes for toxicology testing","volume":"11","author":"Mann","year":"2015","journal-title":"Expert Opinion on Drug Metabolism & Toxicology"},{"key":"bib42","doi-asserted-by":"publisher","DOI":"10.1186\/scrt375","article-title":"Human induced pluripotent stem cell-based microphysiological tissue models of myocardium and liver for drug development","volume":"4","author":"Mathur","year":"2013","journal-title":"Stem Cell Research & Therapy"},{"key":"bib43","article-title":"Tegaserod","author":"MayoClinic","year":"2020","unstructured":"MayoClinic. 2020. Tegaserod. https:\/\/www.mayoclinic.org\/drugs-supplements\/tegaserod-oral-route\/description\/drg-20066200 [Accessed November 28, 2020]."},{"key":"bib44","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1161\/CIRCRESAHA.117.310945","article-title":"An unbiased High-Throughput screen to identify novel effectors that impact on cardiomyocyte aggregate levels","volume":"121","author":"McLendon","year":"2017","journal-title":"Circulation Research"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"S21","DOI":"10.1517\/14740338.2011.589834","article-title":"Anthracycline cardiotoxicity","volume":"11","author":"Menna","year":"2012","journal-title":"Expert Opinion on Drug Safety"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"1166","DOI":"10.1016\/j.cub.2012.05.016","article-title":"Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration","volume":"22","author":"Miyaoka","year":"2012","journal-title":"Current Biology"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1038\/s41592-019-0403-1","article-title":"Deep learning for cellular image analysis","volume":"16","author":"Moen","year":"2019","journal-title":"Nature Methods"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/nrd4366","article-title":"Phenotypic screening in Cancer drug discovery - past, present and future","volume":"13","author":"Moffat","year":"2014","journal-title":"Nature Reviews Drug Discovery"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/nrd.2017.111","article-title":"Opportunities and challenges in phenotypic drug discovery: an industry perspective","volume":"16","author":"Moffat","year":"2017","journal-title":"Nature Reviews Drug Discovery"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1056\/NEJMra1100265","article-title":"Cardiovascular toxic effects of targeted Cancer therapies","volume":"375","author":"Moslehi","year":"2016","journal-title":"New England Journal of Medicine"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"2457","DOI":"10.1056\/NEJMoa072761","article-title":"Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes","volume":"356","author":"Nissen","year":"2007","journal-title":"New England Journal of Medicine"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nmeth.4197","article-title":"Salmon provides fast and bias-aware quantification of transcript expression","volume":"14","author":"Patro","year":"2017","journal-title":"Nature Methods"},{"key":"bib53","doi-asserted-by":"publisher","DOI":"10.1101\/2020.08.25.265561","article-title":"SARS-CoV-2 infection of human iPSC-derived cardiac cells predicts novel cytopathic features in hearts of COVID-19 patients","volume-title":"bioRxiv","author":"P\u00e9rez-Bermejo","year":"2020"},{"key":"bib54","article-title":"Solifenacin","author":"Plus M","year":"2020","unstructured":"Plus M. 2020. Solifenacin. https:\/\/medlineplus.gov\/druginfo\/meds\/a605019.html [Accessed November 28, 2020]."},{"key":"bib55","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/j.bj.2019.05.005","article-title":"Characterization of human telomerase reverse transcriptase immortalized anterior cruciate ligament cell lines","volume":"42","author":"Prager","year":"2019","journal-title":"Biomedical Journal"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1093\/toxsci\/kfs233","article-title":"Characterization of human-induced pluripotent stem cell-derived cardiomyocytes: bioenergetics and utilization in safety screening","volume":"130","author":"Rana","year":"2012","journal-title":"Toxicological Sciences"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1161\/CIRCRESAHA.116.310363","article-title":"Multi-Imaging method to assay the contractile mechanical output of micropatterned human iPSC-Derived cardiac myocytes","volume":"120","author":"Ribeiro","year":"2017","journal-title":"Circulation Research"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"2609","DOI":"10.1056\/NEJMoa030288","article-title":"A phase 2 study of bortezomib in relapsed, refractory myeloma","volume":"348","author":"Richardson","year":"2003","journal-title":"New England Journal of Medicine"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/nature10761","article-title":"The promise of induced pluripotent stem cells in research and therapy","volume":"481","author":"Robinton","year":"2012","journal-title":"Nature"},{"key":"bib60","article-title":"Adrucil","author":"RxList","year":"2020","unstructured":"RxList. 2020. Adrucil. https:\/\/www.rxlist.com\/adrucil-drug.htm [Accessed November 28, 2020]."},{"key":"bib61","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8122195","article-title":"Metabolic alterations in inherited cardiomyopathies","volume":"8","author":"Sacchetto","year":"2019","journal-title":"Journal of Clinical Medicine"},{"key":"bib62","doi-asserted-by":"publisher","DOI":"10.1063\/1.5129347","article-title":"The scanning gradient fourier transform (SGFT) method for assessing sarcomere organization and alignment","volume":"127","author":"Salick","year":"2020","journal-title":"Journal of Applied Physics"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.pcad.2010.06.007","article-title":"Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection?","volume":"53","author":"Sawyer","year":"2010","journal-title":"Progress in Cardiovascular Diseases"},{"key":"bib64","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147215","article-title":"When quality beats quantity: decision theory, drug discovery, and the reproducibility crisis","volume":"11","author":"Scannell","year":"2016","journal-title":"PLOS ONE"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nature Protocols"},{"key":"bib66","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf2584","article-title":"High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells","volume":"9","author":"Sharma","year":"2017","journal-title":"Science Translational Medicine"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"256","DOI":"10.21037\/atm.2018.06.21","article-title":"Mitochondria and cardiovascular diseases-from pathophysiology to treatment","volume":"6","author":"Siasos","year":"2018","journal-title":"Annals of Translational Medicine"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.taap.2017.02.020","article-title":"In vitro cardiotoxicity assessment of environmental chemicals using an organotypic human induced pluripotent stem cell-derived model","volume":"322","author":"Sirenko","year":"2017","journal-title":"Toxicology and Applied Pharmacology"},{"key":"bib69","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.7563.1","article-title":"Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences","volume":"4","author":"Soneson","year":"2015","journal-title":"F1000Research"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1136\/hrt.2003.020180","article-title":"Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study","volume":"90","author":"Souverein","year":"2004","journal-title":"Heart"},{"key":"bib71","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"PNAS"},{"key":"bib72","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003552","article-title":"Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy","volume":"4","author":"Sun","year":"2012","journal-title":"Science Translational Medicine"},{"key":"bib73","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0176061","article-title":"A screen for protective drugs against delayed hypoxic injury","volume":"12","author":"Sun","year":"2017","journal-title":"PLOS ONE"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1089\/ten.tec.2017.0247","article-title":"Development of In Vitro Drug-Induced Cardiotoxicity Assay by Using Three-Dimensional Cardiac Tissues Derived from Human Induced Pluripotent Stem Cells","volume":"24","author":"Takeda","year":"2018","journal-title":"Tissue Engineering Part C: Methods"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1016\/j.bbamcr.2010.09.006","article-title":"Bioenergetics of the failing heart","volume":"1813","author":"Ventura-Clapier","year":"2011","journal-title":"Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1038\/nbt1310","article-title":"A ROCK inhibitor permits survival of dissociated human embryonic stem cells","volume":"25","author":"Watanabe","year":"2007","journal-title":"Nature Biotechnology"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1093\/toxsci\/kfy270","article-title":"Today's Challenges to De-Risk and Predict Drug Safety in Human \"Mind-the-Gap\"","volume":"167","author":"Weaver","year":"2019","journal-title":"Toxicological Sciences"},{"key":"bib79","article-title":"Chlorpromazine HCL","author":"WebMD","year":"2020","unstructured":"WebMD. 2020. Chlorpromazine HCL. https:\/\/www.webmd.com\/drugs\/2\/drug-1444\/chlorpromazine-oral\/details [Accessed November 28, 2020]."},{"key":"bib80","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1177\/108705719900400206","article-title":"A simple statistical parameter for use in evaluation and validation of high throughput screening assays","volume":"4","author":"Zhang","year":"1999","journal-title":"Journal of Biomolecular Screening"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/68714\/elife-68714-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/68714\/elife-68714-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/68714","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:16:48Z","timestamp":1697059008000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/68714"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,2]]},"references-count":80,"alternative-id":["10.7554\/eLife.68714"],"URL":"https:\/\/doi.org\/10.7554\/elife.68714","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.03.23.436666","asserted-by":"subject"},{"id-type":"doi","id":"10.1101\/2021.03.23.436666","asserted-by":"object"}],"is-supplemented-by":[{"id-type":"accession","id":"GSE172181","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.68714.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.68714.sa1","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,2]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"e68714"}}