PROJECT SUMMARY Over 30 million people worldwide remain undiagnosed for a common cardiovascular genetic disorder, familial hypercholesteremia (FH). Individuals with FH can significantly reduce their high risk of premature atherosclerotic cardiovascular disease (ASCVD) if they are identified early in life and initiate lipid lowering treatment promptly. Suboptimal implementation and understanding of costs to implement screening programs has resulted in fewer individuals with FH being identified, resulting in a substantial population living with unmanaged risk for ASCVD. In this renewal application, we will address questions regarding generalizability, costs, and sustainability of initial findings from IMPACT-FH. Implementation strategies for cascade testing reported in the initial IMPACT-FH study were evaluated in specialty care settings (genetic) at Geisinger; they need to be tested and adapted for primary care settings and institutions beyond Geisinger. Implementation costs are important to consider when health systems make decisions about when a prevention program is feasible and whether it can be deployed with a high level of success. Sustainability should be built into care strategies and include cost analyses. Currently, FH screening programs exist all over the world in varying forms of maturity in middle- and high-income countries but little is known about factors that promote or hinder sustainability or promoters to improve existing programs. The main objective of this renewal application to the IMPACT-FH study is to decrease the FH-associated burden of ASCVD by testing the applicability of our cascade testing strategies in the primary care setting, estimating, and comparing the implementation costs and performance of FH screening strategies, and measuring the sustainability of the FH screening programs in real-world contexts. Our specific aims are to: 1) optimize and compare FH cascade testing uptake (adoption) among FH patients offered one of the cascade testing implementation strategies with their relatives versus those who do not use a strategy, 2) calculate and compare implementation costs, efficiency, and performance FH screening strategies, 3) explore sustainability of FH screening programs.