In the United States, approximately 1 in every 212 people are affected by familial hypercholesterolemia (FH), a hereditary metabolic condition preventing the clearance of low-density lipoprotein cholesterol from the blood [1], [2]. Cholesterol elevation begins early in life putting individuals with FH at an increased risk of early atherosclerosis, heart attack, stroke, and cardiac death. Prior studies of cardiovascular risk in patients with FH have found untreated men have a 50% risk of a cardiac event by age 50 while untreated women have a 30% risk of a cardiac event by age 60 [1], [3].

The current gold standard for FH diagnosis is genetic testing for pathogenic variants in the LDLR, APOB, and PCSK9 genes due to the increased sensitivity and specificity of genetic tests compared to phenotypic criteria.[1] Early diagnosis with FH is essential to providing lipid-lowering therapies such as statins, ezetimibe, and PCSK9 inhibitors to reduce cardiovascular disease risk in this population [3]. Cascade testing, the systematic testing in relatives of individuals diagnosed with FH, is recommended by the Centers for Disease Control and Prevention Office of Public Health Genomics as a screening strategy to diagnose individuals early in life [4, p. 1]. Nevertheless, most individuals with FH remain undiagnosed in the US due to low uptake of cascade testing [5]. Population screening for FH in unselected individuals without personal and family risk factors for FH is an alternate approach to enable early diagnosis of FH. In addition to facilitating early prevention for cardiovascular disease, population screening could also support further cascade testing among the pool of newly diagnosed patients, or probands.

To date, only two studies have examined the cost-effectiveness of population screening for FH among adults in the US, and these take the perspective of the healthcare sector and payers [6], [7]. Few economic evaluations of healthcare examine the cost-effectiveness of interventions to patients and no studies have evaluated the economic and clinical impact of population screening to patients directly despite representing a key party in the implementation of FH testing and cardiovascular risk prevention. Full consideration of the benefits and costs of early diagnosis and disease management to patients using a behavioral approach in modeling is necessary to understand their interest and participation in FH population screening. The objective of this study is to analyze the cost-effectiveness of population genetic screening for FH compared to family-based cascade testing from a patient-centered perspective of young adults in the US.