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GALAD Demonstrates High Sensitivity for HCC Surveillance in a Cohort of Patients with Cirrhosis. BACKGROUND: Most patients with hepatocellular carcinoma (HCC) are diagnosed at a late stage, highlighting the need for more accurate surveillance tests. Although biomarkers for HCC early detection have promising data in phase II case-control studies, evaluation in cohort studies is critical prior to adoption in practice. METHODS: We leveraged a prospective cohort of patients with Child Pugh A or B cirrhosis who were followed until incident HCC, liver transplantation, death, or lost to follow-up. We used a prospective specimen-collection, retrospective-blinded-evaluation (PRoBE) design for biomarker evaluation of GALAD, longitudinal GALAD and the HES algorithm -compared to alpha fetoprotein (AFP) - using patient-level sensitivity and screening-level specificity. RESULTS: Of 397 patients with cirrhosis, 42 patients developed HCC (57.1% early-stage) over a median of 2.0 years. Longitudinal GALAD had the highest c-statistic for HCC detection (0.85, 95%CI 0.77 - 0.92), compared to single-timepoint GALAD (0.79, 95%CI 0.71 - 0.87), AFP (0.77, 95%CI 0.69 - 0.85), and HES (0.76, 95%CI 0.67 - 0.83). When specificity was fixed at 90%, the sensitivity for HCC of single-timepoint and longitudinal GALAD was 54.8% and 66.7%, respectively, compared to 40.5% for AFP. Sensitivity for HCC detection was higher when restricted to patients with biomarker assessment within 6 months prior to HCC diagnosis, with the highest sensitivities observed for single-timepoint (72.0%) and longitudinal GALAD (64.0%), respectively. Sensitivity of single-timepoint and longitudinal GALAD for early-stage HCC was 53.8% and 69.2%, respectively. CONCLUSION: GALAD demonstrated high sensitivity for HCC detection in a cohort of patients with cirrhosis. Validation of these results are warranted in large phase III datasets.