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Background: An age, sex, and blood gene expression score (ASGES) has been previously validated to detect obstructive coronary artery disease (CAD) in non-diabetic patients presenting with stable chest pain in the outpatient setting. However, the diagnostic performance of this test in ruling out obstructive CAD in patients presenting with acute chest pain (ACP) to the emergency department (ED) is unknown.Methods: In an ongoing study, 371 low-intermediate risk patients with ACP and no prior history of CAD (TIMI risk score ≤ 2, negative troponins and normal/non-diagnostic ECG) underwent coronary CT angiography (CCTA) using institutional protocols. Patients were classified based on severity of stenosis (obstructive CAD, >50%; high grade stenosis, >70%) and ASGES. The ASGES blood test sample was drawn before ED discharge and analyzed in a commercial reference laboratory (Redwood City, CA). We excluded 23 (6%) patients with unreportable ASGES and 47 (13%) diabetics from this primary analysis.Results: 301 (53±10 years, 45% males, 78% Hispanics) non-diabetic ACP patients undergoing CCTA in an ED setting were included in this analysis. No plaque was detected in 183 (60%) patients, and 22 (7%) patients had obstructive CAD. In this population, 51% of patients had scores below the previously defined threshold of ASGES≤ 15. This threshold yielded sensitivity, specificity, NPV, and PPV of 71% (52-86%), 53% (47-59%), 97% (93-98%), and 12% (9-14%) for obstructive CAD. Furthermore, ASGES≤15 yielded a 100% sensitivity and NPV for patients with high grade stenosis (n=7, 2%). In a multivariable analysis including patient demographics and clinical covariates, ASGES ≤15 was significantly associated with obstructive CAD (OR: 0.15, 95% CI: 0.04-0.62). As a continuous variable, increasing ASGES was positively correlated with the presence of obstructive CAD and CCTA-defined plaque burden (p<0.0001).Conclusions: This is the first study validating the use of this blood-based precision medicine test to rule out obstructive CAD among low-intermediate risk non-diabetic patients presenting with ACP in ED setting. 30-day follow-up is underway to evaluate the prognostic implications of these findings.