PROJECT SUMMARY / ABSTRACT Hepatocellular carcinoma (HCC)-related mortality in the U.S. is rapidly rising. Given the association between early detection and improved survival, screening using ultrasound +/- a serum biomarker, alpha fetoprotein (AFP), is recommended in at-risk individuals, including all patients with cirrhosis. However, most HCC patients are diagnosed at a late stage due to limitations in this strategy. Specifically, the strategy of ultrasound and AFP in all cirrhosis patients is inadequate because it ignores: 1) heterogeneity in risk between patients; 2) the poor accuracy of screening tests; and 3) the poor reliability of screening test performance between patients. The current “one-size-fits-all” approach to HCC screening leads to over-screening of low-risk cirrhosis patients and under-screening of high-risk patients, diluting the overall value of HCC screening. Our proposal's goal is to develop and evaluate a precision screening strategy for early stage HCC in patients with cirrhosis that matches the best screening tests to individual risk and screening test performance. We will leverage five patient populations (4 prospective cohorts and one case-control dataset) with a total of >6000 cirrhosis patients to evaluate and compare biomarker- and imaging-based models for HCC risk stratification and early detection. Specifically, we propose to: Aim 1: Validate and compare the performance of two risk stratification models to stratify cirrhosis patients with low-, intermediate- and high-risk of developing HCC Aim 2: Evaluate the performance of an abbreviated MRI protocol +/- serum biomarkers (including AFP, AFP- L3, and DCP) vs. ultrasound +/- serum biomarkers for early HCC detection in patients with cirrhosis Aim 3: Compare the cost effectiveness, using micro-simulation modeling, of a tailored screening strategy based on individual HCC risk and expected screening test performance to the current standard strategy of ultrasound and AFP in all patients with cirrhosis Our proposal leverages 5 distinct patient populations with >6000 cirrhosis patients, to compare biomarker- and imaging-based models for HCC risk stratification and early detection. We use these data to compare the effectiveness of a tailored screening strategy to the current strategy of ultrasound and AFP for all patients using micro-simulation modeling. Tailoring HCC screening efforts to individual risk and screening test performance moves beyond the current “one-size-fits-all” strategy and aligns HCC screening with the principles of precision medicine. Our proposed HCC screening strategy would maximize screening benefits and minimize screening harms for each patient, thereby optimizing overall HCC screening value in the United States. 2

PUBLIC HEALTH NARRATIVE The current “one-size-fits-all” strategy for hepatocellular carcinoma (HCC) screening using abdominal ultrasound +/- a serum biomarker, alpha fetoprotein (AFP), in all patients with cirrhosis ignores heterogeneity in HCC risk among patients with cirrhosis and the suboptimal accuracy of current screening tests, leading to over-screening of low-risk patients and under-screening of high-risk patients. Our proposal leverages five patient populations (4 prospective cohorts and one case-control dataset) with a total of >6000 cirrhosis patients to compare biomarker- and imaging-based strategies for HCC risk stratification and early detection as well as compare the cost-effectiveness of a tailored screening strategy to the current standard of ultrasound and AFP in all cirrhosis patients using micro-simulation modeling. These data would transform HCC screening in the U.S. to align with the principles of precision screening, thereby optimizing the value of HCC screening in patients with cirrhosis. 1