Background: Cascade screening (CS) for familial hypercholesterolemia (FH) is cost-effective in many countries. However, most existing economic evaluation studies (i) ignored or overstated first-degree relative (FDR) participation rate (as 60-100%), (ii) did not consider novel and expensive therapies, e.g. PCSK9 inhibitors (PCSK9i), (iii) were conducted outside of Asia. In Singapore, FDR participation rate is about 25% among probands who have known pathogenic variants. Aims: To evaluate and identify drivers of cost-effectiveness of CS protocols for FH Methods: Four CS protocols, which vary in the application of genetic testing, were examined using a hybrid decision tree-Markov model. Sensitivity analysis and scenario analyses were conducted to identify drivers of cost-effectiveness. Results: All CS protocols are likely to be cost-effective (probabilities of being cost-effective: 85%-95% when no access to PCSK9i; 73%-99% when PCSK9i are provided). The most cost-effective protocol differs depending on whether PCSK9i are provided. Cascade acceptance rates are key drivers of cost-effectiveness. Other drivers include timeliness of starting treatment post-screening, age of proband, health-related quality of life loss with cardiovascular disease, prevalence of FH mutation among probands, conventional treatment effect and cost of PCSK9i. Conclusion: CS for FH is cost-effective across most scenarios and assumptions. For better cost-effectiveness, health systems need to look for ways to improve proband's willingness to share contact of their relatives and relatives' willingness to be screened. Other ways to improve cost-effectiveness include to select age groups for proband screening, raise diagnostic yields among probands, and start timely treatment post-screening. Keywords: familial hypercholesterolemia, cascade screening, cascade acceptance rates, PCSK9 inhibitor

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf. Hwee-Lin WEE declares funding for research and symposium sponsorships from organizations including A*STAR, Ipsos, Pfizer, GlaxoSmithKline, MSD, Roche, and AstraZeneca; payments for presentations or expert inputs from Takeda Pharmaceuticals, Ipsos, and Galen Center for Health and Social Policy; and travel support from Takeda Pharmaceuticals for ISPOR Europe Conference presentations. Khung-Keong YEO declares research funding from Amgen, AstraZeneca, Abbott Vascular, Bayer, Boston Scientific, Shockwave Medical, and Novartis (via institution); consulting fees from Abbott Vascular, Medtronic, Novartis, and Peijia Medical; honoraria for lectures or presentations from Novartis, Abbott Medical, Shockwave Medical, Boston Scientific, Medtronic, and others; six patents related to cardiac valve repairs and diagnostic methods; and is a co-founder with equity ownership in TriSail, which has investments from Orbus Neich. The remaining authors declare no competing interests.

This study was funded by research grant from the Precision Medicine Coordination Office, Ministry of Health, Singapore and Agency for Science, Technology and Research (A*STAR) Precision Medicine Office to W.H.L. Additional funding support includes: (1) research grants from Alexandra Health Fund to S.T., (2) Clinical Implementation Pilot (CIP) Grant from Precision Health Research, Singapore (PRECISE), to S.T. and W.H.L., (3) National Precision Medicine Programme (NPM) PHASE II FUNDING (MOH-000588) to W.K.L. The funding bodies had no role in the interpretation of the data and the formulation of this report.

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