Supplementary Material for: Performance of GALAD, GAAD, and ASAP for early HCC detection in chronic liver disease: A systematic review and meta-analysis

Background: Multi-biomarker panels have shown promise to improve hepatocellular carcinoma (HCC) surveillance in patients with chronic liver disease; however, we lack comparative data on their relative performance for early-stage HCC detection. Methods: We conducted a systematic review of PubMed, Ovid MEDLINE and EMBASE databases from January 2010 to November 2024 to identify studies evaluating the performance of three commercially available blood-based biomarker panels (GALAD, GAAD, and ASAP) for HCC surveillance. Pooled estimates were calculated using the DerSimonian and Laird method for a random effects model. Results: Of 44 eligible studies (n=33,100 patients) examining HCC surveillance, 37 studies evaluated GALAD, 12 GAAD, and 11 ASAP. Pooled sensitivities of the biomarker panels for early-stage HCC ranged from 70.1% to 74.1%, with pooled specificities ranging from 83.3% to 87.2%. Among studies directly comparing biomarker panels, sensitivity for early-stage HCC did not significantly differ for GALAD versus GAAD (RR 0.96, 95%CI 0.80 – 1.15) or GALAD versus ASAP (RR 1.12, 95%CI 0.79 – 1.60). The pooled sensitivity of GALAD for early-stage HCC was higher than that of ultrasound among studies directly comparing the two (79.0% (95%CI 62.2 – 89.6) versus 73.3% (95%CI 45.4 – 90.1), respectively); however, this difference was not statistically significant (RR 1.09, 95%CI 0.78 – 1.51). Studies were limited by inclusion of patients with non-cirrhotic liver disease, varying biomarker cut-offs across studies, and high statistical heterogeneity (I2 >50%) for pooled estimates. Conclusion: Multi-biomarker panels including GALAD, GAAD, and ASAP demonstrate promising performance for early-stage HCC detection, supporting their prospective validation for HCC surveillance.