Title
Population FH Screening in Childhood and Early Adulthood: Effective but Not Cost‑Effective—A Critical Appraisal of a New JAMA Modeling Study
Highlights
- The CVD Policy Model projected that sequential screening (lipid screen then genetic testing) at age 10 or 18 identifies more people with heterozygous familial hypercholesterolemia (FH) and prevents a small number of lifetime cardiovascular events.
- Absolute population benefits are small (<0.1% reduction in total lifetime CVD events); the best screening strategy had an incremental cost‑effectiveness ratio (ICER) of $289,700 per QALY—well above common US thresholds.
- Screening could become cost‑effective only under optimistic assumptions that identification increases lifetime lipid monitoring and lifestyle interventions for many with non‑FH dyslipidemia as well as for those with genetically confirmed FH.
Background
Heterozygous familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by lifelong elevation of low‑density lipoprotein cholesterol (LDL‑C) and markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Population prevalence is commonly cited around 1 in 250, and most affected individuals remain undiagnosed and untreated, presenting an opportunity for earlier detection and intervention to reduce lifetime cardiovascular risk [1,2]. Pediatric and adolescent lipid screening recommendations vary: several pediatric societies endorse selective and universal screening windows (for example, universal lipid screening between ages 9–11 and again in late adolescence) to detect primary lipid disorders including FH [3]. Therapeutic options (statins) are safe and effective at reducing LDL‑C in children with FH and are recommended when indicated [4]. Despite biological plausibility and guideline support for targeted detection, the population health value of systematic childhood or young adult screening—versus opportunistic lipid testing and cascade family screening—remains uncertain.
Study design
The authors used the CVD Policy Model, a validated discrete event simulation of cardiovascular disease risk and outcomes, to simulate lifetime health and economic outcomes in a hypothetical cohort of 4.2 million US 10‑year‑olds. Individual-level inputs were based on National Health and Nutrition Examination Survey (NHANES) data and other national sources. Usual care in the model represented current practice with opportunistic lipid testing and LDL‑C/CVD risk‑guided treatment.
Intervention strategies added sequential screening to usual care: universal LDL‑C testing at age 10 (childhood) or age 18 (early adulthood), with genetic testing for those with elevated LDL‑C using three thresholds (≥130, ≥160, or ≥190 mg/dL) to select candidates for confirmatory genotyping. Outcomes included direct health care costs (2021 USD), quality‑adjusted life years (QALYs), and incremental cost‑effectiveness ratios (ICERs); costs and QALYs were discounted at 3% annually. Strategies with ICERs <$100,000 per QALY were considered cost‑effective in the base case.
Key findings
The model projected large absolute numbers of lifetime ASCVD events under usual care—approximately 3.12 million events for the simulated cohort—of which about 16,182 occurred in individuals with FH. Adding sequential population screening at age 10 could avert 1,385–1,820 ASCVD events over the cohort lifetime depending on LDL‑C thresholds used; screening at age 18 averted 1,154–1,448 events. These reductions translate into a very small population‑level effect (<0.1% reduction in total lifetime CVD events) because FH is relatively uncommon and because many FH‑neutral events will not be prevented by detecting FH alone.
From an economic perspective, none of the evaluated screening strategies met the model’s cost‑effectiveness benchmark. The least costly incremental strategy was screening at age 18 with an LDL‑C threshold ≥190 mg/dL for genetic testing; its ICER versus usual care was $289,700 per QALY gained—nearly three times the $100,000/QALY threshold used in the study. Other strategies had even higher ICERs. In sensitivity analyses, sequential screening could approach cost‑effectiveness only when the screening intervention triggered sustained increases in nonpharmacologic care (lifetime lipid monitoring and lifestyle therapy) for people with elevated LDL‑C even when they lacked genetically confirmed FH—an optimistic behavior change assumption.
Safety and downstream consequences were modeled primarily in terms of costs and QALYs; the analysis did not identify clinical harms from screening itself but highlighted tradeoffs between resource use and modest population health gains.
Interpretation and clinical implications
This modeling study provides several clinically relevant takeaways:
1. Clinical benefit but limited population impact: Identification of FH earlier in life reduces ASCVD events at an individual level, but on a population scale the absolute gains are modest because FH affects a small fraction of people and because not all events are attributable to the monogenic defect.
2. Economics drive policy: Under realistic assumptions about follow‑up care and adherence, universal sequential screening in childhood or early adulthood is unlikely to be a good value for money in the US health care context. Even selective thresholds (LDL‑C ≥190 mg/dL at age 18) produced ICERs far above typical willingness‑to‑pay thresholds.
3. The role of downstream care patterns: The study underscores that screening is not an isolated act—its value depends critically on what follows. If detection leads to lifelong adherence to lipid‑lowering therapy and consistent monitoring (in both genetically confirmed FH and non‑FH dyslipidemia identified at screening), the balance of benefits and costs can change meaningfully. However, achieving and sustaining such system‑level changes is challenging in practice and requires investment beyond one‑time testing.
4. Alternatives remain important: Cascade screening of relatives of known FH probands, opportunistic testing in high‑risk clinical encounters, and targeted screening in families with early ASCVD remain efficient approaches to find affected people. The study did not replace the need for cascade approaches, which have demonstrated high diagnostic yield and favorable cost‑effectiveness in prior analyses.
Expert commentary and limitations
Strengths of this analysis include use of a validated disease simulation model, nationally representative inputs, exploration of multiple thresholds and ages, and probabilistic sensitivity analyses. The authors transparently report that under baseline assumptions screening strategies do not achieve conventional cost‑effectiveness thresholds.
Limitations deserve emphasis for clinicians and policymakers:
– Model assumptions about long‑term adherence to statins and the effect of early LDL‑C lowering on lifetime ASCVD risk rely on extrapolation from surrogate and intermediate biomarker data. Direct randomized evidence showing reductions in hard clinical end points from childhood statin initiation is limited.
– The effectiveness of cascade and clinician‑driven testing pathways in routine US practice can vary; local systems with robust cascade programs might find different cost‑effectiveness results.
– Behavioral responses to a clinical diagnosis—both for patients and clinicians—are uncertain. The sensitivity analyses demonstrate that generous assumptions about improved monitoring and lifestyle changes drive more favorable estimates; whether these are achievable at scale is unclear.
– The analysis takes a health care sector perspective and does not include wider societal benefits (e.g., productivity gains) that could shift ICERs modestly.
– Finally, cost inputs (genetic testing price, statin costs, clinic visit costs) and thresholds for action (LDL‑C cutoffs) may change over time; declining costs of sequencing and better-targeted genetic panels could alter future value assessments.
How should clinicians and policymakers act on these results?
– Continue to follow guideline recommendations for pediatric lipid screening and management of identified FH (for example, initiating statin therapy when clinically indicated), and emphasize cascade screening for family members of known FH probands.
– Prioritize systems-level interventions that ensure identification is followed by sustained lipid monitoring, medication adherence support, and lifestyle counseling—because the value of screening is tightly linked to what follows.
– Consider targeted strategies (cascade testing, focused screening in families with early ASCVD) that remain high‑yield and more likely cost‑effective than population screening at current costs and practices.
– Monitor trends in the costs of genetic testing and implementation science around adherence interventions; periodic reappraisal of cost‑effectiveness is warranted as practice patterns and prices change.
Conclusion
The JAMA modeling study demonstrates that sequential population screening for FH in childhood or early adulthood identifies affected individuals and prevents some lifetime ASCVD events, but under current real‑world assumptions it is not cost‑effective compared with usual care. The findings emphasize that screening without reliable, sustained downstream care is unlikely to deliver good value at a population level. Investment in cascade programs, adherence support, and systems that translate diagnoses into long‑term risk reduction may be more efficient routes to reducing the clinical burden of FH.
Funding and trial registration
The primary article lists funding sources and disclosures; readers should consult the original JAMA publication for detailed funding and conflict of interest statements [5]. This modeling study does not report a clinical trial registration.
References
1. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J. 2013;34(45):3478–3490a. PubMed PMID: 23801872.
2. Bellows BK, Zhang Y, Ruiz-Negrón N, et al. Familial Hypercholesterolemia Screening in Childhood and Early Adulthood: A Cost-Effectiveness Study. JAMA. 2025 Nov 9. doi:10.1001/jama.2025.20648. Epub ahead of print. PubMed PMID: 41206967.
3. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. 2011 Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics. 2011;128(Suppl 5):S213–S256. PubMed PMID: 22084329.
4. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia. N Engl J Med. 2004;350(21): 2118–2127. PubMed PMID: 15116035.
5. 2018 AHA/ACC Guideline on the Management of Blood Cholesterol: Grundy SM, Stone NJ, Bailey AL, et al. 2019;139:e1082–e1143. Circulation. PubMed PMID: 30586774.
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