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Background: An accurate test to differentiate large artery stroke patients from those with cardioembolic stroke would be of significant utility. Using the Biomarkers of Acute Stroke Etiology (BASE) trial (NCT02014896) dataset, our purpose was to determine if blood gene expression signatures accurately differentiate large artery stroke patients from those with cardioembolic stroke.Methods: The BASE trial enrolled suspected stroke patients presenting to 10 hospitals within 8 hours of symptom onset. Gold standard diagnosis was per local neurologist adjudication blinded to RNA testing. The final gold standard diagnosis was determined by an adjudication committee blinded to RNA test results. Whole blood, obtained in PAX tubes, was frozen at -20C within 72 hours and analyzed at a core lab (Ischemia Care, LLC, Blue Ash, OH) using Affymetrix HTA micro arrays. Significantly differentially expressed genes (p<0.005) were identified by calculating an empirical Bayes moderated t-statistic contrasting expression in large artery and cardioembolic stroke patients. Differentially expressed genes were used as input to a multi-layer perceptron neural network to derive a 66-gene diagnostic signature.Results: Overall, 32 patients were enrolled, 8 (25%) with large artery stroke and 24 (75%) with cardioembolic stroke; 50% were male, and median (IQR) age was 68.6 (47,88). Median (IQR) time from symptoms to presentation was 102.5 (14, 450) minutes. Coexistent pathology at presentation was atrial fibrillation in 13 (41%), heart failure 7 (22%), prior stroke 7 (22%), and coronary artery disease 8 (25%). The resulting gene signature distinguished large artery stroke from cardioembolic stroke; C-statistic 0.99 (0.94-1.0, 95% CI), sensitivity 0.91 (0.56-1.0, 95% CI), at a fixed specificity of 0.95, as observed in 5-fold cross validation of the training data.Conclusion: RNA expression differentiates large artery stroke patients from those with cardioembolic stroke, and may have therapeutic and outcome implications.