Cost-effectiveness of cascade genetic testing for familial hypercholesterolemia in the United States: A simulation analysis

Abstract

Objective There is no coordinated cascade testing program for familial hypercholesterolemia (FH) in the U.S. We evaluated the contemporary cost-effectiveness of cascade genetic testing relatives of FH probands with a pathogenic variant. Methods A simulation model was created to simulate multiple family trees starting with progenitor individuals carrying a pathogenic variant for FH who were followed through several generations. This approach allowed us to examine a family tree that had grown sufficiently to have large numbers of relatives across multiple degrees of relatedness. The model estimated costs and life years gained (LYG) when cascade genetic testing was implemented for relatives of FH probands identified through standard care who were at or older than designated age thresholds (5, 10, 15, 20, 25, 30, 35, 40). Costs were valued in 2018 U.S. dollars. Future costs and LYG projected by the model were discounted at an annual rate of 3%. Results For 1st degree relatives, cascade testing at every age threshold resulted in a positive number of average LYG per person, though this number decreased as testing was started at higher age thresholds. Testing was not cost-effective if initiated at an age threshold of 40 and older but was cost-effective at younger age thresholds, with a discounted cost per LYG per person of less than $50,000. For 2nd degree relatives, testing was cost-effective with a screening age threshold of 10 but no longer cost-effective at a threshold of 15 or higher. In more distant relatives, cascade genetic testing was not beneficial or cost-effective. Conclusions Based on our simulation model, cascade genetic testing for FH in the U.S. is cost-effective if started before age 40 in 1st degree relatives and before age 15 in 2nd degree relatives.

Familial Hypercholesterolemia and Elevated Lipoprotein(a): Cascade Testing and Other Implications for Contextual Models of Care

“…The Center for Disease Control and Prevention recommends cascade testing for FH (the leading and actionable Tier condition), because early diagnosis can be aided by genetic testing, and implementation of ASCVD prevention measures can have a significant public health impact. Cascade testing for FH has been shown to be highly cost-effective in multiple populations ( Marang-van de Mheen et al, 2002 ; Ademi et al, 2013 ; Kerr et al, 2017 ; Knowles et al, 2017 ; Lázaro et al, 2017 ), including children ( Wald et al, 2016 ; Ademi et al, 2020 ; Jackson et al, 2021 ). A related approach is child-parent testing, following the detection of a child at immunization at 2 years old ( Wald et al, 2016 ).…”

Familial hypercholesterolemia. Perspectives on FH registry systems

“…3 In The increased prevalence of the disease confirms the need to find patients to reduce the risk of death from cardiovascular events, which is its first silent manifestation at a young age. 14,26…”

“…13 A systematic review of financial evaluations for the detection and treatment of familial hypercholesterolemia has shown that screening of relatives with suspected FH is highly costeffective. 14 The current European high levels of undiagnosed people with FH and associated morbidity and mortality mean that the adoption of ongoing services will bring significant benefits to quality of life and survival.…”

“…15 Other research on the same topic regarding genetic testing for FH in the US has shown that it is more effective if started before the age of 40 in first-degree relatives and before the age of 15 in second-degree relatives. 14 Researches on familial hypercholesterolemia conclude that potentially millions of children and adults worldwide are unaware that they are ill. Respectively, in Greece the true prevalence of FH is unknown.…”

A machine learning model to aid detection of familial hypercholesterolaemia

“…(3) There is currently no systematic way of identifying new index FH cases in the general population, although cascade testing in families of affected individuals has been shown to be highly cost-effective in many countries. (5)(6)(7)(8) showed that measurement of LDL-C alone at age 9 may be insufficiently accurate in reliably distinguishing FH-variant carriers from those with an elevated cholesterol as a consequence diet and lifestyle factors, or carriage of a high burden of common cholesterol-raising alleles, and suggested adding a confirmatory targeted-sequencing step to reduce the number of false positive cases detected. (10) The increased availability of routine health checks in adults either through work-place schemes or local healthcare providers offers an opportunity to systematically identify adult carriers of FH-causing variants.…”