Machine learning derived ECG risk score improves cardiovascular risk assessment in conjunction with coronary artery calcium scoring

Background: Precision estimation of cardiovascular risk remains the cornerstone of atherosclerotic cardiovascular disease (ASCVD) prevention. While coronary artery calcium (CAC) scoring is the best available non-invasive quantitative modality to evaluate risk of ASCVD, it excludes risk related to prior myocardial infarction, cardiomyopathy, and arrhythmia which are implicated in ASCVD. The high-dimensional and inter-correlated nature of ECG data makes it a good candidate for analysis using machine learning techniques and may provide additional prognostic information not captured by CAC. In this study, we aimed to develop a quantitative ECG risk score (eRiS) to predict major adverse cardiovascular events (MACE) alone, or when added to CAC. Further, we aimed to construct and validate a novel nomogram incorporating ECG, CAC and clinical factors for ASCVD. Methods: We analyzed 5,864 patients with at least 1 cardiovascular risk factor who underwent CAC scoring and a standard ECG as part of the CLARIFY study (ClinicalTrials.gov Identifier: NCT04075162). Events were defined as myocardial infarction, coronary revascularization, stroke or death. A total of 649 ECG features, consisting of measurements such as amplitude and interval measurements from all deflections in the ECG waveform (53 per lead and 13 overall) were automatically extracted using a clinical software (GE Muse™ Cardiology Information System, GE Healthcare). The data was split into 4 training (S_tr) and internal validation (S_v) sets [S_tr (1): S_v (1): 50:50; S_tr (2): S_v (2): 60:40; S_tr (3): S_v (3): 70:30; S_tr (4): S_v (4): 80:20], and the results were compared across all the subsets. We used the ECG features derived from S_tr to develop eRiS. A least absolute shrinkage and selection operator-Cox (LASSO-Cox) regularization model was used for data dimension reduction, feature selection, and eRiS construction. A Cox-proportional hazards model was used to assess the benefit of using an eRiS alone (M_ecg), CAC alone (M_cac) and a combination of eRiS and CAC (M_ecg+cac) for MACE prediction. A nomogram (M_nom) was further constructed by integrating eRiS with CAC and demographics (age and sex). The primary endpoint of the study was the assessment of the performance of M_ecg, M_cac, M_ecg+cac and M_nom in predicting CV disease-free survival in ASCVD. Findings: Over a median follow-up of 14 months, 494 patients had MACE. The feature selection strategy preserved only about 18% of the features that were consistent across the various strata (S_tr). The M_ecg model, comprising of eRiS alone was found to be significantly associated with MACE and had good discrimination of MACE (C-Index: 0.7, p = <2e-16). eRiS could predict time-to MACE (C-Index: 0.6, p = <2e-16 across all S_v). The M_ecg+cac model was associated with MACE (C-index: 0.71). Model comparison showed that M_ecg+cac was superior to M_ecg (p = 1.8e-10) or M_cac (p < 2.2e-16) alone. The M_nom, comprising of eRiS, CAC, age and sex was associated with MACE (C-index 0.71). eRiS had the most significant contribution, followed by CAC score and other clinical variables. Further, M_nom was able to identify unique patient risk-groups based on eRiS, CAC and clinical variables. Conclusion: The use of ECG features in conjunction with CAC may allow for improved prognostication and identification of populations at risk. Future directions will involve prospective validation of the risk score and the nomogram across diverse populations with a heterogeneity of treatment effects.