ECG-Guided Pre-Screening of Family Members for Hypertrophic Cardiomyopathy
Background: Current clinical guidelines recommend serial ECG and echocardiographic surveillance for first-degree relatives of probands with Hypertrophic Cardiomyopathy (HCM). Objectives: To evaluate the accuracy and validity of ECG alone as a pre-screening tool for the diagnosis of HCM and to develop a random forest (RF) model for HCM phenotype prediction. Method: Pediatric relatives of primary HCM probands attending the cardiomyopathy screening program at The Hospital for Sick Children were included from 1993 to 2025. Subjects were followed until the last follow-up, censored at phenotype conversion. ECGs were classified as normal or abnormal based on predefined parameters. Associations between binary ECG variables and HCM phenotype were assessed using Phi ({varphi}) coefficient. A Random Forest classifier was developed using significant ECG variables (70:30 training: test split) and evaluated using precision, recall, specificity, negative predictive value, F1 score and AUROC. Feature importance was assessed using SHAP analysis. Variables with an impact of >5% were included in a simplified model, which was evaluated by repeating performance metrics and externally validated in a healthy cohort. Results: 350 screened relatives (44% female, mean follow-up 6.8 +- 4.8 years) were included. At baseline, 13% (46350) were phenotype-positive for HCM. 9 subjects converted during the surveillance. Thirteen ECG variables were significantly associated with phenotype-positive HCM and were included in the full random forest model. Four variables had >5% impact (Left ventricular hypertrophy, right ventricular hypertrophy, T-wave inversion and ST-segment depression) and were included in a simplified model, which maintained high specificity (93% vs 97%), negative predictive value (97% vs 93%) and AUROC (90% vs 96%). The simplified model classified 83% subjects as phenotype-negative, with eight being false-negative, all of whom developed an abnormal ECG in a mean of 1 year, and none had an interim adverse cardiac event. The simplified model was evaluated in an independent healthy cohort of 153 school-age subjects and correctly identified 98% as phenotype-negative with 100% NPV. Conclusion: ECG abnormalities were strongly associated with phenotype-positive status. A simplified ECG-based random forest model using four ECG variables demonstrated high specificity and negative predictive value for identifying phenotype-negative subjects. If prospectively validated, this could reduce the need for concurrent echocardiographic screening by up to 83% per encounter, lowering screening burden and cost.