Machine learning-based phenotyping and risk assessment of hypertrophic cardiomyopathy - linking ECGs, morphology and genotypes

Funding Acknowledgements Type of funding sources: None. Background Integrating clinical data to distinguish hypertrophic cardiomyopathy (HCM) phenotypes is relevant in clinical practice. Machine learning (ML) can help - deep learning (DL) networks can automate detection and segmentation of 12-lead electrocardiograms (ECGs), whereas unsupervised learning can group patients to compare ECG, imaging and genetic characteristics. The aim is to automate ECG morphology analysis from all 12 ECG leads and multiple beats, and relate this to HCM genotypes and imaging phenotypes. Methods The single-center cohort included phenotype- and genotype-positive (G+) HCM patients (n = 104) and their phenotype-negative relatives (n = 50, 42% G+). All patients had a digital 12-lead ECG, echocardiography, and a magnetic resonance (CMR) study performed. The workflow is shown in Fig 1. A U-Net DL network was used for ECG delineation (P, QRS, T onsets/offsets) for all cardiac cycles. Three heartbeats were selected for each patient based on their morphology, with the aim of capturing beat-to-beat variability. An unsupervised representation learning algorithm was used to fuse ECG data and assess inter-patient similarities. Patients were clustered based on similarities of ECG biomarkers, and compared with regards to genotypes, family history of sudden cardiac death (SCD), history of ventricular arrhythmias/syncope/aborted SCD, implanted defibrillators (ICD), left ventricular (LV) obstruction, maximal wall thickness, late gadolinium enhancement (LGE), and HCM risk-SCD score. Results ML based on ECG biomarkers provided a good separation of HCM patients and relatives (Fig 1A), also showing G- and patients with variants of uncertain significance grouping together (Fig 1B). Clustering resulted in 6 ECG phenogroups (C1-6). C1 and 2 were related to less comorbidities, cardiac remodeling, and HCM risk score, capturing the majority of G- patients. C3 and 4 were related to LV obstruction – where C4 consisted of symptomatic patients with high ICD implantation and event rates, high LGE, and impaired systolic function. C5 captured patients with high comorbidities, extremely remodeled hearts, but no obstruction, whereas C6 patients with positive family history and high arrhythmic events (Fig 1C, Table 1). The average ECG morphology is shown side-by-side for C1 and C5 in Fig 1D – negative T waves, increased R/S wave amplitudes, left axis deviation (LAD) and ST elevation can be recognized as macro-biomarkers in C5 (yellow arrows). Conclusion ML can automate the analysis of complex clinical data, simultaneously taking into account the morphology of all ECG components in all 12-leads, throughout multiple beats, compare it with clinical and imaging data, and identify clinically sensible phenogroups as validated by structural and functional findings, as well as with genotypes and clinical information. Automated and comprehensive cardiac data analysis has diagnostic and research potential to help screen populations and phenotype disease etiologies. Abstract Figure 1: analysis pipeline Abstract Table 1: clinical variables