Genetic Testing for Familial Hypercholesterolemia: Health Technology Assessment

Familial hypercholesterolemia (FH) is an inherited disorder characterized by abnormally elevated low-density lipoprotein (LDL) cholesterol serum levels from birth, which increases the risk of premature atherosclerotic cardiovascular disease. Genetic testing is a type of a medical test that looks for changes in genes or chromosome structure to discover genetic differences, anomalies, or mutations that may prove pathological. It is regarded as the gold standard for screening and diagnosing FH. We conducted a health technology assessment on genetic testing for people with FH and their relatives (i.e., cascade screening). The assessment included an evaluation of clinical utility (the ability of a test to improve health outcomes), the diagnostic yield (ability of a test to identify people with FH), cost-effectiveness, the budget impact of publicly funding genetic testing for FH, and patient preferences and values.

We performed a systematic literature search of the clinical evidence. For evaluation of clinical utility, we assessed the risk of bias of each included study using the ROBINS-I tool and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria.We performed a systematic economic literature search and conducted a cost-effectiveness and cost-utility analysis with a lifetime horizon from a public payer perspective. We assessed the cost-effectiveness of using genetic testing both for confirming a FH clinical diagnosis and for cascade screening in relatives of genetically confirmed cases. We evaluated the cost effectiveness of cascade screening strategies with genetic testing, sequential testing, and lipid testing approaches. We also analyzed the budget impact of publicly funding genetic testing in Ontario.

We included 11 studies in the clinical evidence review. Overall, our review found that genetic testing to diagnose FH improves several health outcomes (GRADE: Moderate) compared with clinical evaluation without a genetic test. We also found that genetic cascade screening leads to a high diagnostic yield of FH.According to our primary economic evaluation, genetic testing is a dominant strategy (more effective and less costly) compared with no genetic testing for individuals with a FH clinical diagnosis. It reduced the number of FH diagnoses, led to fewer cardiovascular events, and improved QALYs. For first-degree relatives of genetically confirmed cases, all cascade screening strategies (genetic testing, sequential testing, and lipid testing) were cost-effective when compared with no cascade screening in a pairwise fashion. The ICERs of cascade screening with genetic, sequential, and lipid testing compared with no cascade screening were $58,390, $50,220, and $45,754 per QALY gained, respectively. When comparing all screening strategies together, cascade screening with lipid testing was the most cost-effective strategy. At commonly used willingness-to-pay values of $50,000 and $100,000 per QALY gained, the probability of lipid cascade screening being cost-effective was 53.5% and 71.5%, respectively.The annual budget impact of publicly funding genetic testing for individuals with a clinical FH diagnosis in Ontario ranged from a cost saving of $2 million in year 1 to $64 million in year 5, for a total of $141 million saved over the next 5 years, assuming the cost of genetic testing remains at $490 per person. If only testing-related costs were considered, the budget impact was estimated to be an additional cost of $7 million in year 1, increasing to $20 million in year 5, for a total cost of $64 million over the next 5 years. For relatives of genetically confirmed cases, publicly funding genetic cascade screening would lead to an additional cost of $5 million in year 1, increasing to $27 million in year 5, for a total cost of $73 million over the next 5 years. If only testing-related costs were considered, the budget impact was estimated to be an additional of $66 million.

Genetic testing for FH has a higher clinical utility than clinical evaluation without a genetic test. It also results in a high diagnostic yield of FH through cascade screening. For individuals with a clinical diagnosis of FH, genetic testing would be a cost-saving and more effective diagnostic strategy. For relatives of index cases confirmed through genetic testing, genetic and lipid cascade screening are both cost-effective compared with no screening, but genetic cascade screening is less cost-effective than lipid cascade screening. We estimated that publicly funding genetic testing for individuals with a clinical diagnosis of FH in Ontario would save $141 million, and publicly funding genetic testing in a cascade screening program for relatives would cost an additional $73 million over the next five years.Most people with a positive genetic test perceived the screening, diagnosis, and treatment for FH more positively. The discovery of the condition can lead people to adhere to relevant treatments in an effort to control their cholesterol levels. People we spoke with felt that greater awareness and education would allow for more efficient uptake of cascade screening.