An evaluation of the cost-effectiveness of population genetic screening for familial hypercholesterolemia in US patients.

BACKGROUND AND AIMS: Familial hypercholesterolemia is an underdiagnosed genetic metabolic condition limiting the clearance of low-density lipoprotein cholesterol and increasing lifetime risk of cardiovascular disease. Population genetic screening in unselected individuals could quickly identify cases of familial hypercholesterolemia and enable early prevention, but the economic impact of widespread screening on patients has not been studied. METHODS: We assessed the cost-effectiveness of population genetic screening for familial hypercholesterolemia in 20 and 35-year-old adults in the United States from the perspective of patients. We developed a decision tree Markov hybrid model to examine diagnoses, cardiovascular disease, cardiac events, quality of life, and costs under population genetic screening compared to family-based cascade testing. RESULTS: While population genetic screening increased diagnoses and reduced incidence of cardiovascular disease, population genetic screening was not cost-effective compared to cascade testing at current levels of willingness to pay. Lower genetic testing costs, combined screening with other genetic conditions, and support to maintain lipid-lowering therapy use over time could improve the cost-effectiveness of population genetic screening. CONCLUSIONS: Future research is needed to examine how cost-sharing strategies may affect the cost-effectiveness of screening to patients and how families and providers experience the clinical and economic outcomes of population screening.

Measuring Costs of Cardiovascular Disease Prevention for Patients with Familial Hypercholesterolemia in Administrative Claims Data.

INTRODUCTION: Familial hypercholesterolemia is a common genetic condition that significantly increases an individual's risk of cardiovascular events such as heart attack, stroke, and cardiac death and is a candidate for population-wide screening programs. Economic analyses of strategies to identify and treat familial hypercholesterolemia are limited by a lack of real-world cost estimates for screening services and medications for reducing cardiovascular risk in this population. METHODS: We estimated the cost of lipid panel testing in patients with hyperlipidemia and the cost of statins, ezetimibe, and PCKS9 inhibitors in patients with familial hypercholesterolemia from a commercial claims database and report costs and charges per panel and prescription by days' supply. RESULTS: The mean cost for a 90-day supply for statins was $183.33, 2.3 times the mean cost for a 30-day supply at $79.35. PCSK9 inhibitors generated the highest mean costs among medications used by patients with familial hypercholesterolemia. CONCLUSIONS: Lipid testing and lipid-lowering medications for cardiovascular disease prevention generate substantial real-world costs which can be used to improve cost-effectiveness models of familial hypercholesterolemia screening and care management.

Prevalence and management of familial hypercholesterolaemia in patients with chest pain admitted to hospital: a retrospective observational study.

OBJECTIVES: Patients with familial hypercholesterolaemia (FH) are genetically burdened by a lifelong elevation of the low-density lipoprotein cholesterol (LDL-C) level, putting them at a very high risk of premature ischaemic heart disease (IHD). This study aims to assess the prevalence of FH among patients admitted for IHD and the preventive treatment status before admission. DESIGN: Observational, retrospective, register-based study. SETTING: Individuals discharged with a diagnosis of IHD were enrolled consecutively throughout 2012-2016 from the cardiac care units of two hospitals in Copenhagen. PARTICIPANTS: 4223 individuals were discharged during the period. Inclusion criteria for further investigation were the availability of one measurement of LDL-C at the time of admission. In total, 2797 individuals were included for further investigation. There were no exclusion criteria. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary objective has been to determine the prevalence of FH in the population. The secondary objective has been to determine the use of lipid-lowering therapy and to which extend the individuals reach their treatment goal. RESULTS: Among the 2797 consecutive patients evaluated, the prevalence of potential FH was 7.7% (1: 13) and 6.8% (1:15) had probably or definite FH. The prevalence of FH was age-dependent: Among the 680 patients (24.3%) with premature IHD (men <55 years/women <60 years), 136 patients (20.0%) had potential FH and 21 (3.1%) had probable/definite FH. None were diagnosed and almost none attained their treatment goal. CONCLUSIONS: There is still a massive lack of recognition of FH in patients admitted to a cardiac care unit with a diagnosis of IHD. Despite a measured high LDL-C, the diagnosis was not made for any patients not even in patients who were admitted at an early age or had a previous cardiovascular event.

Cost-Effectiveness of Screening Strategies for Familial Hypercholesterolaemia: An Updated Systematic Review.

BACKGROUND: OBJECTIVE: This study aimed to systematically synthesise the cost-effectiveness of screening strategies to detect heterozygous familial hypercholesterolemia (FH). METHODS: We searched seven databases from inception to 2 February , 2023, for eligible cost-effective analysis (CEA) that evaluated screening strategies for FH versus the standard care for FH detection. Independent reviewers performed the screening, data extraction and quality evaluation. Cost results were adapted to 2022 US dollars (US$) to facilitate comparisons between studies using the same screening strategies. Cost-effectiveness thresholds were based on the original study criteria. RESULTS: A total of 21 studies evaluating 62 strategies were included in this review, most of the studies (95%) adopted a healthcare perspective in the base case, and majority were set in high-income countries. Strategies analysed included cascade screening (23 strategies), opportunistic screening (13 strategies), systematic screening (11 strategies) and population-wide screening (15 strategies). Most of the strategies relied on genetic diagnosis for case ascertainment. The most common comparator was no screening, but some studies compared the proposed strategy versus current screening strategies or versus the best next alternative. Six studies evaluated screening in children while the remaining were targeted at adults. From a healthcare perspective, cascade screening was cost-effective in 78% of the studies [cost-adapted incremental cost-effectiveness ratios (ICERs) ranged from dominant to 2022 US$ 104,877], opportunistic screening in 85% (ICERs from US$4959 to US$41,705), systematic screening in 80% (ICERs from US$2763 to US$69,969) and population-wide screening in 60% (ICERs from US$1484 to US$223,240). The most common driver of ICER identified in the sensitivity analysis was the long-term cost of lipid-lowering treatment. CONCLUSIONS: Based on reported willingness to pay thresholds for each setting, most CEA studies concluded that screening for FH compared with no screening was cost-effective, regardless of the screening strategy. Cascade screening resulted in the largest health benefits per person tested.

Health economics of detection and treatment of children with familial hypercholesterolemia: to screen or not to screen is no longer the question.

PURPOSE OF REVIEW: Heterozygous familial hypercholesterolemia (HeFH) is one of the most common monogenic disorders and is safely treatable with lipid-lowering medication. However, most individuals with HeFH remain untreated and undetected, especially in paediatric populations where the potential for long-term therapeutic benefit is higher. Here, we review the recent literature on health economic outcomes for the detection and management of FH in children. RECENT FINDINGS: A targeted literature review identified eight studies evaluating detection and management strategies for paediatric FH populations in the last 25 years. Most studies conducted modelled cost-effectiveness analyses to understand the long-term impact of these strategies on health outcomes and the financial impact on the healthcare system. All studies reported that detection and management of HeFH in paediatric populations was cost-effective, regardless of the age of the children. However, cost-effectiveness varied depending on the method of case ascertainment - targeted screening was generally cheaper overall, but less effective, than whole-of-population screening, although both methods were generally cost-effective. SUMMARY: Detection and management of HeFH in paediatric populations is a cost-effective way to significantly lower the burden of disease later in life for these individuals. These strategies should be implemented across healthcare systems.

A systematic review of cost-effectiveness analysis of different screening strategies for familial hypercholesterolemia.

AIMS: Diagnosis rate of familial hypercholesterolemia (FH) remained less than 10 % globally and the economic evaluation results of different FH screening strategies varied. This study aimed to systematically review the methodology and results of cost effectiveness analysis (CEA) of FH screening, which will provide evidence support for health-related decision-making. METHODS: The Medline/PubMed, Embase, Cochrane Library, Web of science, National Health Service Economic Evaluation Database (NHSEED) and CEA Registry databases were electronically searched to collect full economic evaluation from the establishment of the databases to June 30, 2022. The quality of included studies was evaluated by the Consolidated Health Economic Evaluation Reporting Standards statement 2022 (CHEERS 2022) checklist. RESULTS: Among 232 retrieved studies, 18 economic evaluations were included and all of them are from developed countries, with an average quality score of 0.73. The decision tree model and/or Markov model were constructed by thirteen articles (72 %). Twelve studies (67 %) adopted the healthcare perspective and the lifetime horizon to compare the costs and health outcome of different screening strategies. The results of eight studies indicated that cascade screening was a cost-effective strategy compared with no screening, which was more pronounced in younger adults. Universal screening in young adults aged 16 years or 18-40 years (n=3) and in children aged 1-2 years combined with reverse cascade screening (n=3) are both cost-effective. The probability of being cost-effective for cascade screening (n=6) and universal screening (n=1) of young aged 18-40 years were greater than 95 %. CONCLUSIONS: Our review demonstrated the economic advantages of cascade screening, universal screening of young adults, and universal screening of newborns combined with reverse cascade screening. Further health economic evaluation is needed in children and in low- and middle-income countries.

Assessment of ethnic inequalities in diagnostic coding of familial hypercholesterolaemia (FH): A cross-sectional database study in Lambeth, South London.

BACKGROUND AND AIMS: Differences in the perceived prevalence of familial hypercholesterolemia (FH) by ethnicity are unclear. In this study, we aimed to assess the prevalence, determinants and management of diagnostically-coded FH in an ethnically diverse population in South London. METHODS: A cross-sectional analysis of 40 practices in 332,357 adult patients in Lambeth was undertaken. Factors affecting a (clinically coded) diagnosis of FH were investigated by multi-level logistic regression adjusted for socio-demographic and lifestyle factors, co-morbidities, and medications. RESULTS: The age-adjusted FH % prevalence rate (OR, 95%CI) ranged from 0.10 to 1.11, 0.00-1.31. Lower rates of FH coding were associated with age (0.96, 0.96-0.97) and male gender (0.75, 0.65-0.87), p < 0.001. Compared to a White British reference group, a higher likelihood of coded FH was noted in Other Asians (1.33, 1.01-1.76), p = 0.05, with lower rates in Black Africans (0.50, 0.37-0.68), p < 0.001, Indians (0.55, 0.34-0.89) p = 0.02, and in Black Caribbeans (0.60, 0.44-0.81), p = 0.001. The overall prevalence using Simon Broome criteria was 0.1%; we were unable to provide ethnic specific estimates due to low numbers. Lower likelihoods of FH coding (OR, 95%CI) were seen in non-native English speakers (0.66, 0.53-0.81), most deprived income quintile (0.68, 0.52-0.88), smokers (0.68,0.55-0.85), hypertension (0.62, 0.52-0.74), chronic kidney disease (0.64, 0.41-0.99), obesity (0.80, 0.67-0.95), diabetes (0.31, 0.25-0.39) and CVD (0.47, 0.36-0.63). 20% of FH coded patients were not prescribed lipid-lowering medications, p < 0.001. CONCLUSIONS: Inequalities in diagnostic coding of FH patients exist. Lower likelihoods of diagnosed FH were seen in Black African, Black Caribbean and Indian ethnic groups, in contrast to higher diagnoses in White and Other Asian ethnic groups. Hypercholesterolaemia requiring statin therapy was associated with FH diagnosis, however, the presence of cardiovascular disease (CVD) risk factors lowered the diagnosis rate for FH.

Alternative cascade-testing protocols for identifying and managing patients with familial hypercholesterolaemia: systematic reviews, qualitative study and cost-effectiveness analysis.

Background: Cascade testing the relatives of people with familial hypercholesterolaemia is an efficient approach to identifying familial hypercholesterolaemia. The cascade-testing protocol starts with identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective. Objectives: The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers. Design and methods: This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)-Hospital Episode Statistics (HES) linked primary-secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals. Result: Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested [40%, 95% confidence interval (CI) 37% to 42%] than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing (p < 0.01); the CPRD-HES data set indicated that 70% did not achieve target treatment levels, and demonstrated increased cardiovascular disease risk among these individuals, compared with controls (hazard ratio 9.14, 95% CI 8.55 to 9.76). The specialist familial hypercholesterolaemia register confirmed excessive cardiovascular morbidity (standardised morbidity ratio 7.17, 95% CI 6.79 to 7.56). Cost-effectiveness modelling found a net health gain from diagnosis of -0.27 to 2.51 quality-adjusted life-years at the willingness-to-pay threshold of £15,000 per quality-adjusted life-year gained. The cost-effective protocols cascaded from genetically confirmed index cases by contacting first- and second-degree relatives simultaneously and directly. Interviews found a service-led direct-contact approach was more reliable, but combining direct and indirect approaches, guided by index patients and family relationships, may be more acceptable. Limitations: Systematic reviews were not used in the economic analysis, as relevant studies were lacking or of poor quality. As only a proportion of those with primary care-coded familial hypercholesterolaemia are likely to actually have familial hypercholesterolaemia, CPRD analyses are likely to underestimate the true effect. The cost-effectiveness analysis required assumptions related to the long-term cardiovascular disease risk, the effect of treatment on cholesterol and the generalisability of estimates from the data sets. Interview recruitment was limited to white English-speaking participants. Conclusions: Based on limited evidence, most cost-effective cascade-testing protocols, diagnosing most relatives, select index cases by genetic testing, with services directly contacting relatives, and contacting second-degree relatives even if first-degree relatives have not been tested. Combined approaches to contact relatives may be more suitable for some families. Future work: Establish a long-term familial hypercholesterolaemia cohort, measuring cholesterol levels, treatment and cardiovascular outcomes. Conduct a randomised study comparing different approaches to contact relatives. Study registration: This study is registered as PROSPERO CRD42018117445 and CRD42019125775. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 16. See the NIHR Journals Library website for further project information.

Familial hypercholesterolaemia is an inherited condition that causes raised cholesterol levels from birth and increases risk of heart disease if left untreated. After someone in a family is found to have familial hypercholesterolaemia (called an index case), their close relatives need to be contacted and checked to see if they have familial hypercholesterolaemia, using genetic or cholesterol testing. This is called 'cascade testing'. We planned to find the most cost-effective and acceptable way to do this. The relatives could be contacted for testing by the index case (indirect approach), by a health-care professional (direct approach) or by a combination of both approaches. We found, based on looking at hospital records, that more relatives were tested if health-care professionals directly contacted relatives. In previous studies, slightly more relatives were tested for familial hypercholesterolaemia with a combination approach. Interviews with patients also suggested that the direct approach was the most effective, but the most acceptable and successful approach depends on family relationships: using one approach for some families and using both for other families. Furthermore, by looking at the health-care records of large numbers of patients, we confirmed that people with a recorded diagnosis of familial hypercholesterolaemia in general practice records have a much higher risk of heart disease than the general population, and this was especially so for those with previous heart disease and/or raised cholesterols levels when diagnosed. However, one-quarter of new patients with familial hypercholesterolaemia recorded in their records were not treated within 2 years, with less than one-third reaching recommended cholesterol levels. We used what we had learned to help us estimate the most cost-effective way to do cascade testing. This showed that if the health service directly contact all relatives simultaneously for further assessment, rather than the current approach whereby close (first-degree) relatives are contacted first, this was cost-effective and good value for money.

Low-Cost High-Throughput Genotyping for Diagnosing Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a common but underdiagnosed genetic disorder characterized by high low-density lipoprotein cholesterol levels and premature cardiovascular disease. Current sequencing methods to diagnose FH are expensive and time-consuming. In this study, we evaluated the accuracy of a low-cost, high-throughput genotyping array for diagnosing FH. METHODS: An Illumina Global Screening Array was customized to include probes for 636 variants, previously classified as FH-causing variants. First, its theoretical coverage was assessed in all FH variant carriers diagnosed through next-generation sequencing between 2016 and 2022 in the Netherlands (n=1772). Next, the performance of the array was validated in another sample of FH variant carriers previously identified in the Dutch FH cascade screening program (n=1268). RESULTS: The theoretical coverage of the array for FH-causing variants was 91.3%. Validation of the array was assessed in a sample of 1268 carriers of whom 1015 carried a variant in LDLR, 250 in APOB, and 3 in PCSK9. The overall sensitivity was 94.7% and increased to 98.2% after excluding participants with variants not included in the array design. Copy number variation analysis yielded a 89.4% sensitivity. In 18 carriers, the array identified a total of 19 additional FH-causing variants. Subsequent DNA analysis confirmed 5 of the additionally identified variants, yielding a false-positive result in 16 subjects (1.3%). CONCLUSIONS: The FH genotyping array is a promising tool for genetically diagnosing FH at low costs and has the potential to greatly increase accessibility to genetic testing for FH. Continuous customization of the array will further improve its performance.

Filling the gap: Genetic risk assessment in hypercholesterolemia using LDL-C and LPA genetic scores.

Routine genetic testing in hypercholesterolemia patients reveals a causative monogenic variant in less than 50% of affected individuals. Incomplete genetic characterization is partly due to polygenic factors influencing low-density-lipoprotein-cholesterol (LDL-C). Additionally, functional variants in the LPA gene affect lipoprotein(a)-associated cholesterol concentrations but are difficult to determine due to the complex structure of the LPA gene. In this study we examined whether complementing standard sequencing with the analysis of genetic scores associated with LDL-C and Lp(a) concentrations improves the diagnostic output in hypercholesterolemia patients. 1.020 individuals including 252 clinically diagnosed hypercholesterolemia patients from the FH Register Austria were analyzed by massive-parallel-sequencing of candidate genes combined with array genotyping, identifying nine novel variants in LDLR. For each individual, validated genetic scores associated with elevated LDL-C and Lp(a) were calculated based on imputed genotypes. Integrating these scores especially the score for Lp(a) increased the proportion of individuals with a clearly defined disease etiology to 68.8% compared to 46.6% in standard genetic testing. The study highlights the major role of Lp(a) in disease etiology in clinically diagnosed hypercholesterolemia patients, of which parts are misclassified. Screening for monogenic causes of hypercholesterolemia and genetic scores for LDL-C and Lp(a) permits more precise diagnosis, allowing individualized treatment.

In vitro assessment of the pathogenicity of the LDLR c.2160delC variant in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an inherited disorder with markedly elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. Although many mutations have been reported in FH, only a few have been identified as pathogenic mutations. This study aimed to confirm the pathogenicity of the LDL receptor (LDLR) c.2160delC variant in FH. METHODS: In this study, the proband and her family members were systematically investigated, and a pedigree map was drawn. High-throughput whole-exome sequencing was used to explore the variants in this family. Next, quantitative polymerase chain reaction (qPCR), western blot (WB) assays, and flow cytometry were conducted to detect the effect of the LDLR c.2160delC variant on its expression. The LDL uptake capacity and cell localization of LDLR variants were analyzed by confocal microscopy. RESULTS: According to Dutch Lipid Clinic Network (DLCN) diagnostic criteria, three FH patients were identified with the LDLR c.2160delC variant in this family. An in-silico analysis suggested that the deletion mutation at the 2160 site of LDLR causes a termination mutation. The results of qPCR and WB verified that the LDLR c.2160delC variant led to early termination of LDLR gene transcription. Furthermore, the LDLR c.2160delC variant caused LDLR to accumulate in the endoplasmic reticulum, preventing it from reaching the cell surface and internalizing LDL. CONCLUSIONS: The LDLR c.2160delC variant is a terminating mutation that plays a pathogenic role in FH.

Cost-effectiveness and Return on Investment of a Nationwide Case-Finding Program for Familial Hypercholesterolemia in Children in the Netherlands.

Importance: The Netherlands is one of the few countries that has a long-term history of active screening for familial hypercholesterolemia (FH), enabling health-economic analyses. Objective: To investigate cost-effectiveness and the return on investment (ROI) of a nationwide cascade case-finding and preventive treatment program starting with identification of FH in children and treatment, from both a societal and health care perspective. Design, Setting, and Participants: Cascade case-finding and early preventive treatment were modeled to simulate the progression of disease and costs of 10-year-olds suspected of having heterozygous FH over a lifetime. The model consisted of 3 health states: alive without coronary heart disease (CHD), alive with CHD, and deceased. Mendelian randomization analysis was used to quantify the risk of a first CHD event as a function of age and total lifetime exposure to low-density lipoprotein cholesterol. Cost-effectiveness was defined as €20 000 ($21 800) per QALYs (quality-adjusted life-years) gained, using incremental cost-effectiveness ratios (ICERs). All future benefits and costs were discounted annually by 1.5% and 4%, respectively. Interventions: The study compared 2 strategies: (1) cascade screening and initiation of treatment with statins in children (mean age, 10 years) and (2) no screening, later detection, and treatment. Main Outcomes and Measures: Outcome of interest included cost, detection, and successful treatment of FH in terms of life-years gained and QALYs. The clinical and cost outputs for each model in the 2 scenarios (early detection and treatment and later detection and treatment) were totaled to determine the overall cost-effectiveness and ROI attributed to implementation of the Dutch FH program. Results: In this model constructed to simulate the progression of FH in 1000 hypothetical 10-year-olds, from a health care perspective, the program would gain 2.53 QALYs per person, at an additional cost of €23 365 ($25 468) (both discounted). These equated to an ICER of €9220 ($10 050) per QALY gained. From the societal perspective, the detection and treatment program were cost saving over a lifetime compared with no cascade screening for FH. The ROI for the detection and treatment program for FH in children was €8.37 ($9.12). Conclusions and Relevance: The findings of this study suggest that the early detection and treatment program for FH in children may offer a good value for investment, being both health and cost saving. The findings and interpretations are conditional on assumptions inherent in the health economic model.

Population Genomic Screening for Three Common Hereditary Conditions : A Cost-Effectiveness Analysis.

BACKGROUND: The cost-effectiveness of screening the U.S. population for Centers for Disease Control and Prevention (CDC) Tier 1 genomic conditions is unknown. OBJECTIVE: To estimate the cost-effectiveness of simultaneous genomic screening for Lynch syndrome (LS), hereditary breast and ovarian cancer syndrome (HBOC), and familial hypercholesterolemia (FH). DESIGN: Decision analytic Markov model. DATA SOURCES: Published literature. TARGET POPULATION: Separate age-based cohorts (ages 20 to 60 years at time of screening) of racially and ethnically representative U.S. adults. TIME HORIZON: Lifetime. PERSPECTIVE: U.S. health care payer. INTERVENTION: Population genomic screening using clinical sequencing with a restricted panel of high-evidence genes, cascade testing of first-degree relatives, and recommended preventive interventions for identified probands. OUTCOME MEASURES: Incident breast, ovarian, and colorectal cancer cases; incident cardiovascular events; quality-adjusted survival; and costs. RESULTS OF BASE-CASE ANALYSIS: Screening 100 000 unselected 30-year-olds resulted in 101 (95% uncertainty interval [UI], 77 to 127) fewer overall cancer cases and 15 (95% UI, 4 to 28) fewer cardiovascular events and an increase of 495 quality-adjusted life-years (QALYs) (95% UI, 401 to 757) at an incremental cost of $33.9 million (95% UI, $27.0 million to $41.1 million). The incremental cost-effectiveness ratio was $68 600 per QALY gained (95% UI, $41 800 to $88 900). RESULTS OF SENSITIVITY ANALYSIS: Screening 30-, 40-, and 50-year-old cohorts was cost-effective in 99%, 88%, and 19% of probabilistic simulations, respectively, at a $100 000-per-QALY threshold. The test costs at which screening 30-, 40-, and 50-year-olds reached the $100 000-per-QALY threshold were $413, $290, and $166, respectively. Variant prevalence and adherence to preventive interventions were also highly influential parameters. LIMITATIONS: Population averages for model inputs, which were derived predominantly from European populations, vary across ancestries and health care environments. CONCLUSION: Population genomic screening with a restricted panel of high-evidence genes associated with 3 CDC Tier 1 conditions is likely to be cost-effective in U.S. adults younger than 40 years if the testing cost is relatively low and probands have access to preventive interventions. PRIMARY FUNDING SOURCE: National Human Genome Research Institute.

Enhancing the Detection and Care of Heterozygous Familial Hypercholesterolemia in Primary Care: Cost-Effectiveness and Return on Investment.

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is under-detected and undertreated. A general practitioner-led screening and care program for HeFH effectively identified and managed patients with HeFH. We evaluated the cost-effectiveness and the return on investment of an enhanced-care strategy for HeFH in primary care in Australia. METHODS: We developed a multistate Markov model to estimate the outcomes and costs of a general practitioner-led detection and management strategy for HeFH in primary care compared with the standard of care in Australia. The population comprised individuals aged 50 to 80 years, of which 44% had prior cardiovascular disease. Cardiovascular risk, HeFH prevalence, treatment effects, and acute and chronic health care costs were derived from published sources. The study involved screening for HeFH using a validated data-extraction tool (TARB-Ex), followed by a consultation to improve care. The detection rate of HeFH was 16%, and 74% of the patients achieved target LDL-C (low-density lipoprotein cholesterol). Quality-adjusted life years, health care costs, productivity losses, incremental cost-effectiveness ratio, and return on investment ratio were evaluated, outcomes discounted by 5% annually, adopting a health care and a societal perspective. RESULTS: Over the lifetime horizon, the model estimated a gain of 870 years of life lived and 1033 quality-adjusted life years when the general practitioner-led program was employed compared with standard of care. This resulted in an incremental cost-effectiveness ratio of AU$14 664/quality-adjusted life year gained from a health care perspective. From a societal perspective, this strategy, compared with standard of care was cost-saving, with a return on investment of AU$5.64 per dollar invested. CONCLUSIONS: An enhanced general practitioner-led model of care for HeFH is likely to be cost-effective.

How does cholesterol burden change the case for investing in familial hypercholesterolaemia? A cost-effectiveness analysis.

BACKGROUND AND AIMS: This study aimed to ascertain how the long-term benefits and costs of diagnosis and treatment of familial hypercholesterolaemia (FH) vary by prognostic factors and 'cholesterol burden', which is the effect of long-term exposure to low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) risk. METHODS: A new cost-effectiveness model was developed from the perspective of the UK National Health Service (NHS), informed by routine data from individuals with FH. The primary outcome was net health gain (i.e., health benefits net of the losses due to costs), expressed in quality-adjusted life years (QALYs) at the £15,000/QALY threshold. Prognostic factors included pre-treatment LDL-C, age, gender, and CVD history. RESULTS: If cholesterol burden is considered, diagnosis resulted in positive net health gain (i.e., it is cost-effective) in all individuals with pre-treatment LDL-C ≥ 4 mmol/L, and in those with pre-treatment LDL-C ≥ 2 mmol/L aged ≥50 years or who have CVD history. If cholesterol burden is not considered, diagnosis resulted in lower net health gain, but still positive in children aged 10 years with pre-treatment LDL-C ≥ 6 mmol/L and adults aged 30 years with pre-treatment LDL-C ≥ 4 mmol/L. CONCLUSIONS: Diagnosis and treatment of most people with FH results in large net health gains, particularly in those with higher pre-treatment LDL-C. Economic evaluations of FH interventions should consider the sensitivity of the study conclusions to cholesterol burden, particularly where interventions target younger patients, and explicitly consider prognostic factors such as pre-treatment LDL-C, age, and CVD history.

Cost-Effectiveness of Pediatric Universal Screening for Familial Hypercholesterolemia in Argentina.

OBJECTIVE: Our study aimed to evaluate the expected cost-effectiveness of pediatric universal screening for the early diagnosis of familial hypercholesterolemia in Argentina using a probabilistic model. METHODS: Two different healthcare technologies were compared: (1) Universal screening of hypercholesterolemia at 6 years of age and (2) previous diagnostic situation (comparator). The perspective of the public Argentine healthcare system funded by the National Ministry of Health was used, considering only direct costs. Effectiveness was evaluated in terms of the number of life-years gained (LYG) and quality-adjusted life-years (QALYs) obtained by identifying familial hypercholesterolemia through each of the screening strategies. Only direct costs of screening and treatment of each strategy were evaluated. The time horizon was extended to 60 years. Future avoided costs of prevented coronary events were also included. Cost-effectiveness was measured in terms of the incremental cost-effectiveness ratio (ICER) per LYG and QALYs. Different scenarios were evaluated: (1) only index case, (2) index case and first-degree relatives, and (3) index case and first-degree relatives measuring QALYs. Sensitivity studies were conducted. RESULTS: Each identified child complying with follow-up visits and treatment gains 8.14 life-years. The ICER values obtained were 1465.35 USD/LYG and 1726.50 USD/LYG when applying a discount rate of 5%. The ICER was 10%-17% of the gross domestic product per capita in Argentina (mean 2010-2019: 12 446 USD) and did not exceed the minimum annual retirement income. CONCLUSION: Pediatric universal screening for familial hypercholesterolemia could be considered a cost-effective health technology in Argentina.

The Assessment of Carotid Atherosclerotic Plaque among Young Patients with Familial Hypercholesterolemia.

Objective Few data exist regarding when atherosclerotic changes occur among patients with familial hypercholesterolemia (FH). Carotid ultrasonography is a non-invasive method of evaluating this issue. The present study (1) compared the clinical utilities of carotid intima-media thickness (cIMT) and carotid plaque score (cPS) and (2) estimated the onset and progression of carotid atherosclerosis among patients with heterozygous FH (HeFH). Methods We retrospectively analyzed 511 patients under 30 years old who underwent carotid ultrasonography at our hospital from 2006 to 2019. We classified them into the HeFH group (n=78, 21.4±5.9 years old) and non-FH group (n=433, 23.4±6.0 years old) based on the clinical diagnosis and compared their cIMT and cPS values. In addition, we estimated the onset and progression of carotid atherosclerosis among young HeFH patients. Results There was no significant difference in the cIMT between the HeFH and non-FH groups (0.44 mm vs. 0.42 mm, p=0.25). In contrast, the cPS was significantly higher in the HeFH group than in the non-FH group (1.11 vs. 0.26, p=0.002). The regression equation for cPS of HeFH group was Y=-2.05+0.15X (r=0.37, p<0.001). Conclusion An assessment based on the cPS rather than the cIMT appears to be better to capture the progress of carotid atherosclerosis among young HeFH patients. Carotid atherosclerosis may start to develop at 14 years old in patients with HeFH.

Genetic Testing for Familial Hypercholesterolemia: Health Technology Assessment.

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Cost-effectiveness of population-wide genomic screening for familial hypercholesterolemia in the United States.

BACKGROUND: Population genomic screening for familial hypercholesterolemia (FH) in unselected individuals can prevent premature cardiovascular disease. OBJECTIVE: To estimate the clinical and economic outcomes of population-wide FH genomic screening versus no genomic screening. METHODS: We developed a decision tree plus 10-state Markov model evaluating the identification of patients with an FH variant, statin treatment status, LDL-C levels, MI, and stroke to compare the costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness of population-wide FH genomic screening. FH variant prevalence (0.4%) was estimated from the Geisinger MyCode Community Health Initiative (MyCode). Genomic test costs were assumed to be $200. Age and sex-based estimates of MI, recurrent MI, stroke, and recurrent stroke were obtained from Framingham risk equations. Additional outcomes independently associated with FH variants were derived from a retrospective analysis of 26,025 participants screened for FH. Sensitivity and threshold analyses were conducted to evaluate model assumptions and uncertainty. RESULTS: FH screening was most effective at younger ages; screening unselected 20-year-olds lead to 111 QALYs gained per 100,000 individuals screened at an incremental cost of $20 M. The incremental cost-effectiveness ratio (ICER) for 20-year-olds was $181,000 per QALY, and there was a 38% probability of cost-effectiveness at a $100,000 per QALY willingness-to-pay threshold. If genomic testing cost falls to $100, the ICER would be $91,000 per QALY. CONCLUSION: Population FH screening is not cost-effective at current willingness to pay thresholds. However, reducing test costs, testing at younger ages, or including FH within broader multiplex screening panels may improve clinical and economic value.

Familial hypercholesterolemia: A systematic review of modeling studies on screening interventions.

BACKGROUND AND AIMS: FH is still underdiagnosed. Cost-effectiveness results of preventive screening strategies vary. We aimed at systematically assessing the benefits, harms and cost effectiveness of screening for familial hypercholesterolemia (FH) and at providing an overview of the main characteristics and methodological approaches of applied decision-analytic models. METHODS: A systematic literature search was conducted in MEDLINE, EconLit, CRD-databases and the CEA-registry for FH screening starting 2012. Earlier studies were included from a published systematic review. Results were reported in standardized semi-quantitative evidence tables. Costs were converted to current euros. Incremental cost-effectiveness ratios (ICERs) were recalculated according to economic guidelines. RESULTS: Out of our 211 retrieved studies, eight were included in the review in addition to six studies from an earlier review. Studies were conducted in Europe (UK, The Netherlands, Spain, Poland), USA and Australia evaluating cascade (CS), opportunistic (OS), universal screening (UniS), or combinations using genetic testing, clinical criteria or combinations. Studies evaluating only CS identified strategies with an ICER of up to 37,100 EUR/quality-adjusted life-year (QALY) but some strategies were dominated depending on test combinations. UniS of newborns in combination with CS had an ICER≤15,000 EUR/QALY for sequential cholesterol-genetic screening. In other studies, UniS was dominated by OS/CS. CONCLUSIONS: Our systematic review demonstrates the values of FH screening and provides an overview of potentially relevant screening strategies to be tested using a decision-analytic model for the respective country or region. Future research is needed on the transferability of results to other countries and modeling spillover effects to newborns.