Artificial Intelligence–enabled Electrocardiogram for Mortality and Cardiovascular Risk Estimation: an Actionable, Explainable and Biologically Plausible Platform

Background and Aims Artificial intelligence-enhanced electrocardiograms (AI-ECG) can be used to predict risk of future disease and mortality but has not yet been adopted into clinical practice. Existing model predictions lack actionability at an individual patient level, explainability and biological plausibility. We sought to address these limitations of previous AI-ECG approaches by developing the AI-ECG risk estimator (AIRE) platform. Methods and Results The AIRE platform was developed in a secondary care dataset of 1,163,401 ECGs from 189,539 patients, using deep learning with a discrete-time survival model to create a subject-specific survival curve using a single ECG. Therefore, AIRE predicts not only risk of mortality, but time-to-mortality . AIRE was validated in five diverse, transnational cohorts from the USA, Brazil and the UK, including volunteers, primary care and secondary care subjects. AIRE accurately predicts risk of all-cause mortality (C-index 0.775 (0.773-0.776)), cardiovascular (CV) death 0.832 (0.831-0.834), non-CV death (0.749 (0.747-0.751)), future ventricular arrhythmia (0.760 (0.756-0.763)), future atherosclerotic cardiovascular disease (0.696 (0.694-0.698)) and future heart failure (0.787 (0.785-0.889))). Through phenome- and genome-wide association studies, we identified candidate biological pathways for the prediction of increased risk, including changes in cardiac structure and function, and genes associated with cardiac structure, biological aging and metabolic syndrome. Conclusion AIRE is an actionable, explainable and biologically plausible AI-ECG risk estimation platform that has the potential for use worldwide across a wide range of clinical contexts for short- and long-term risk estimation. ![Figure][1] ### Competing Interest Statement JWW was previously on the advisory board for Heartcor solutions LLC, the remaining authors have no conflicts to declare ### Funding Statement AS is funded by a British Heart Foundation (BHF) clinical research training fellowship (FS/CRTF/21/24183). FSN and NSP are supported by the BHF (RG/F/22/110078 and RE/18/4/34215). KAM is support by a BHF fellowship (FS/IPBSRF/22/27059). FSN is supported by the National Institute for Health Research Imperial Biomedical Research Centre. ES is supported by a EJP RD Research Mobility Fellowship (European Reference Networks). DO'R is supported by the Medical Research Council (MC\_UP\_1605/13); National Institute for Health Research (NIHR) Imperial College Biomedical Research Centre; and the British Heart Foundation (RG/19/6/34387, RE/18/4/34215). For the purpose of open access, the authors have applied a creative commons attribution (CC BY) licence to any author accepted manuscript version arising. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: For the Beth Israel Deaconess Medical Center (BIDMC) cohort ethics review and approval was provided by the Beth Israel Deaconess Medical Center Committee on Clinical Investigations, IRB protocol # 2023P000042. The Sao Paulo-Minas Gerais Tropical Medicine Research Center (SaMi-Trop) study was approved by the Brazilian National Institutional Review Board (CONEP), No. 179.685/2012. The Clinical Outcomes in Digital Electrocardiography (CODE) study was approved by the Research Ethics Committee of the Universidade Federal de Minas Gerais, protocol 49368496317.7.0000.5149. The Longitudinal Study of Adult Health (ELSA-Brasil) was approved by the Research Ethics Committees of the participating institutions and by the National Committee for Research Ethics (CONEP 976/2006) of the Ministry of Health. The UK Biobank has approval from the North West Multi-Centre Research Ethics Committee as a Research Tissue Bank (application IDs 48666, 40616 and 47602). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes SaMi-Trop cohort was made openly available (). The CODE-15% cohort was also made openly available (). Restrictions apply to additional clinical information on the CODE-15% and SaMi-Trop cohorts; to the full CODE cohort, the ELSA-Brasil cohort. UK Biobank data are available upon application (). The BIDMC dataset is restricted due to ethical limitations. Researchers affiliated to educational, or research institutions may make requests to access the datasets. Requests should be made to the corresponding author of this paper. They will be forwarded to the relevant steering committee. [1]: pending:yes