BackgroundSince myocardial work (MW) and left atrial strain are valuable for screening coronary artery disease (CAD), this study aimed to develop a novel CAD screening approach based on machine learning-enhanced echocardiography.MethodsThis prospective study used data from patients undergoing coronary angiography, in which the novel echocardiography features were extracted by a machine learning algorithm. A total of 818 patients were enrolled and randomly divided into training (80%) and testing (20%) groups. An additional 115 patients were also enrolled in the validation group.ResultsThe superior diagnosis model of CAD was optimized using 59 echocardiographic features in a gradient-boosting classifier. This model showed that the value of the receiver operating characteristic area under the curve (AUC) was 0.852 in the test group and 0.834 in the validation group, with high sensitivity (0.952) and low specificity (0.691), suggesting that this model is very sensitive for detecting CAD, but its low specificity may increase the high false-positive rate. We also determined that the false-positive cases were more susceptible to suffering cardiac events than the true-negative cases.ConclusionsMachine learning-enhanced echocardiography can improve CAD detection based on the MW and left atrial strain features. Our developed model is valuable for estimating the pre-test probability of CAD and screening CAD patients in clinical practice.Trial registration: Registered as NCT03905200 at ClinicalTrials.gov. Registered on 5 April 2019.