Population Genomic Screening Research Articles

Development and Pilot Testing of Evidence-Based Interventions to Improve Adherence after Receiving a Genetic Result.

Previous research indicates that population genomic screening can benefit individuals who act on the genetic results. However, there remains a significant gap between individuals receiving genetic information and acting on current risk management recommendations, prompting exploration of interventions to close this gap. This study aimed to determine the feasibility and acceptability, and conduct a pilot implementation, of existing evidence-based interventions (EBIs) for adherence to disease management for select genetic conditions among individuals ascertained through a population genomic screening program. Surveys of and interviews with individuals who received a genomic screening result were conducted to assess barriers to guideline-recommended care and assess the acceptability of problem solving (PS) and motivational interviewing (MI) EBIs to facilitate adherence to recommendations. A Design Thinking Workshop was conducted with clinicians to co-develop a MI- and PS-based intervention that would fit with current workflows to be piloted. Post-pilot engagement sessions with implementers determined acceptability and feasibility of the MI/PS pilot program for clinical implementation and elicited proposed adaptations for improvement. PS and MI EBIs were reported to be acceptable and feasible to individuals with a result, and barriers to performing recommended management were identified. The pilot program included outreach by genetic counselors to individuals with a result, review of a checklist of barriers, and delivery of PS or MI as appropriate to facilitate care. The protocol as piloted was deemed acceptable and feasible for clinicians to deliver, with adaptations suggested. These results will inform an effectiveness trial to address gaps in adherence in patients who have received actionable genomic results.

Dissecting the Reduced Penetrance of Putative Loss-of-Function Variants in Population-Scale Biobanks.

Loss-of-function variants (LoFs) disrupt the activity of their impacted gene. They are often associated with clinical phenotypes, including autosomal dominant diseases driven by haploinsufficiency. Recent analyses using biobanks have suggested that LoF penetrance for some haploinsufficient disorders may be low, an observation that has important implications for population genomic screening. However, biobanks are also rife with missing data, and the reliability of these findings remains uncertain. Here, we examine the penetrance of putative LoFs (pLoFs) using a cohort of ≈24,000 carriers derived from two population-scale biobanks: the UK Biobank and the All of Us Research Program. We investigate several possible etiologies for reduced pLoF penetrance, including biobank recruitment biases, annotation artifacts, missed diagnoses, and incomplete clinical records. Systematically accounting for these factors increased penetrance, but widespread reduced penetrance remained. Therefore, we hypothesized that other factors must be driving this phenomenon. To test this, we trained machine learning models to identify pLoFs with high penetrance using the genomic features specific to each variant. These models were predictive of penetrance across a range of diseases and ploF types, including those with prior evidence for pathogenicity. This suggests that reduced ploF penetrance is in fact common, and care should be taken when counseling asymptomatic carriers.

Genetics Visit Uptake Among Individuals Receiving Clinically Actionable Genomic Screening Results

Screening unselected populations for clinically actionable genetic disease risk can improve ascertainment and facilitate risk management. Genetics visits may encourage at-risk individuals to perform recommended management, but little has been reported on genetics visit completion or factors associated with completion in genomic screening programs. To identify factors associated with postdisclosure genetics visits in a genomic screening cohort. This was a cohort study of biobank data in a health care system in central Pennsylvania. Participants' exome sequence data were reviewed for pathogenic or likely pathogenic (P/LP) results in all genes on the American College of Medical Genetics and Genomics Secondary Findings list. Clinically confirmed results were disclosed by phone and letter. Participants included adult MyCode biobank participants who received P/LP results between July 2015 and November 2019. Data were analyzed from May 2021 to March 2022. Clinically confirmed P/LP result disclosed by phone or letter. Completion of genetics visit in which the result was discussed and variables associated with completion were assessed by electronic health record (EHR) review. Among a total of 1160 participants (703 [60.6%] female; median [IQR] age, 57.0 [42.1-68.5] years), fewer than half of participants (551 of 1160 [47.5%]) completed a genetics visit. Younger age (odds ratio [OR] for age 18-40 years, 2.98; 95% CI, 1.40-6.53; OR for age 41-65 years, 2.36; 95% CI, 1.22-4.74; OR for age 66-80 years, 2.60; 95% CI, 1.41-4.98 vs age ≥81 years); female sex (OR, 1.49; 95% CI, 1.14-1.96); being married (OR, 1.74; 95% CI, 1.23-2.47) or divorced (OR, 1.80; 95% CI, 1.11-2.91); lower Charlson comorbidity index (OR for score of 0-2, 1.76; 95% CI, 1.16-2.68; OR for score of 3-4, 1.73; 95% CI, 1.18-2.54 vs score of ≥5); EHR patient portal use (OR, 1.42; 95% CI, 1.06-1.89); living closer to a genetics clinic (OR, 1.64; 95% CI, 1.14-2.36 for <8.9 miles vs >20.1 miles); successful results disclosure (OR for disclosure by genetic counselor, 16.32; 95% CI, 8.16-37.45; OR for disclosure by research assistant, 20.30; 95% CI, 10.25-46.31 vs unsuccessful phone disclosure); and having a hereditary cancer result (OR, 2.13; 95% CI, 1.28-3.58 vs other disease risk) were significantly associated with higher rates of genetics visit completion. Preference to follow up with primary care was the most common reported reason for declining a genetics visit (68 of 152 patients [44.7%]). This cohort study of a biobank-based population genomic screening program suggests that targeted patient engagement, improving multidisciplinary coordination, and reducing barriers to follow-up care may be necessary for enhancing genetics visit uptake.

Combined population genomic screening for three high-risk conditions in Australia: a modelling study

No previous health-economic evaluation has assessed the impact and cost-effectiveness of offering combined adult population genomic screening for mutliple high-risk conditions in a national public healthcare system. This modeling study assessed the impact of offering combined genomic screening for hereditary breast and ovarian cancer, Lynch syndrome and familial hypercholesterolaemia to all young adults in Australia, compared with the current practice of clinical criteria-based testing for each condition separately. The intervention of genomic screening, assumed as an up-front single cost in the first annual model cycle, would detect pathogenic variants in seven high-risk genes. The simulated population was 18-40 year-olds (8,324,242 individuals), modelling per-sample test costs ranging AU$100-$1200 (base-case AU$200) from the year 2023 onwards with testing uptake of 50%. Interventions for identified high-risk variant carriers follow current Australian guidelines, modelling imperfect uptake and adherence. Outcome measures were morbidity and mortality due to cancer (breast, ovarian, colorectal and endometrial) and coronary heart disease (CHD) over a lifetime horizon, from healthcare-system and societal perspectives. Outcomes included quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER), discounted 5% annually (with 3% discounting in scenario analysis). Over the population lifetime (to age 80 years), the model estimated that genomic screening per-100,000 individuals would lead to 747 QALYs gained by preventing 63 cancers, 31 CHD cases and 97 deaths. In the total model population, this would translate to 31,094 QALYs gained by preventing 2612 cancers, 542 non-fatal CHD events and 4047 total deaths. At AU$200 per-test, genomic screening would require an investment of AU$832 million for screening of 50% of the population. Our findings suggest that this intervention would be cost-effective from a healthcare-system perspective, yielding an ICER of AU$23,926 (∼£12,050/€14,110/US$15,345) per QALY gained over the status quo. In scenario analysis with 3% discounting, an ICER of AU$4758/QALY was obtained. Sensitivity analysis for the base case indicated that combined genomic screening would be cost-effective under 70% of simulations, cost-saving under 25% and not cost-effective under 5%. Threshold analysis showed that genomic screening would be cost-effective under the AU$50,000/QALY willingness-to-pay threshold at per-test costs up to AU$325 (∼£164/€192/US$208). Our findings suggest that offering combined genomic screening for high-risk conditions to young adults would be cost-effective in the Australian public healthcare system, at currently realistic testing costs. Other matters, including psychosocial impacts, ethical and societal issues, and implementation challenges, also need consideration. Australian Government, Department of Health, Medical Research Future Fund, Genomics Health Futures Mission (APP2009024). National Heart Foundation Future Leader Fellowship (102604).

Abstract 18260: Association of Physical Activity History With Disease Penetrance in a Disease-Based Cohort Does Not Replicate in a Healthcare-Based Genomic Screening Population

Background: Physical activity (PA) restriction is a recommended intervention for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), due to strong associations of PA history with disease, and the known risk of arrhythmic events in affected patients from tertiary referral centers. However, in patients with secondary findings of genetic risk for ARVC, the association of PA exposure with disease expression is unknown. Hypothesis: Among individuals with incidentally identified pathogenic or likely pathogenic (P/LP) variants in desmosome genes (PKP2, DSP, DSG2, DSC2), clinical evidence of disease will be associated with higher pre-diagnostic PA exposure. Methods: The MyCode (MC) cohort included individuals with P/LP variants in desmosome genes, discovered via population genomic screening of 175,000 individuals; the Johns Hopkins (JH) disease-based cohort included ARVC probands and family members with single P/LP variants enrolled in the JH ARVC Registry. The ARVC task force criteria (TFC) status of each patient was defined based on most recent clinical evaluation. Recreational PA history from age 10 to time of diagnosis (TFC+) or survey (TFC-) was self-reported through structured phone interview and each activity was assigned a metabolic equivalent score. Results: The MC cohort was older, more female-predominant, had a lower proportion of PKP2 variants, and had less disease than the JH cohort (Figure; all p&lt;0.001). As expected, MET-hrs/year of exercise prior to presentation was significantly higher in affected vs. unaffected patients in the JH cohort. In contrast, no association between PA history and disease expression was observed in MC (p=0.42). Conclusions: The MyCode cohort demonstrated both a paucity of clinically evident disease and a lack of obvious association of exercise with disease expression. These findings may be seen as reassuring in the management of patients with secondary ARVC genetic findings, but additional data are needed.

Multiple endocrine neoplasia type 2: towards a risk-based approach integrating molecular and biomarker results

Purpose of review Significant advances have transformed our understanding of the molecular biology and natural history of multiple endocrine neoplasia type 2 (MEN2). This progress enacted a paradigm shift with regard to routine neck dissection for medullary thyroid cancer and total adrenalectomy for pheochromoytoma. The purpose of this review is to summarize key molecular and clinical data underpinning the current risk-based approach to MEN2 that integrates molecular and biomarker results. Recent findings Early identification and biochemical monitoring of rearranged during transfection (RET) carriers yield important lead time. Within these ‘windows of opportunity’, total thyroidectomy alone, avoiding incremental morbidity from node dissection; ‘tissue-sparing’ subtotal adrenalectomy, balancing risks of steroid dependency with pheochromocytoma recurrence in adrenal remnants; and parathyroidectomy of enlarged glands only, weighing risks of postoperative hypoparathyroidism against hyperactive parathyroid glands left behind, are adequate therapies. Summary All that is needed to determine a RET carriers’ risk of medullary thyroid cancer, pheochromocytoma and/or primary hyperparathyroidism in the molecular era is patient age, underlying RET mutation, and biomarker levels. As broader testing begins to penetrate healthcare, the needle on population genomic screening and education needs to be moved forward to complete the transition from symptom-based to preventive healthcare.

Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program.

Malignant hyperthermia (MH) susceptibility is a heritable musculoskeletal disorder that can present as a potentially fatal hypermetabolic response to triggering anesthesia agents. Genomic screening for variants in MH-associated genes RYR1 and CACNA1S provides an opportunity to prevent morbidity and mortality. There are limited outcomes data from disclosing variants in RYR1, the most common MH susceptibility gene, in unselected populations. The authors sought to identify the rate of MH features or fulminant episodes after triggering agent exposure in an unselected population undergoing genomic screening including actionable RYR1 variants. The MyCode Community Health Initiative by Geisinger (USA) is an electronic health record-linked biobank that discloses pathogenic and likely pathogenic variants in clinically actionable genes to patient-participants. Available electronic anesthesia and ambulatory records for participants with actionable RYR1 results returned through December 2020 were evaluated for pertinent findings via double-coded chart reviews and reconciliation. Descriptive statistics for observed phenotypes were calculated. One hundred fifty-two participants had an actionable RYR1 variant disclosed during the study period. None had previous documented genetic testing for MH susceptibility; one had previous contracture testing diagnosing MH susceptibility. Sixty-eight participants (44.7%) had anesthesia records documenting triggering agent exposure during at least one procedure. None received dantrolene treatment or had documented muscle rigidity, myoglobinuria, hyperkalemia, elevated creatine kinase, severe myalgia, or tea-colored urine. Of 120 possibly MH-related findings (postoperative intensive care unit admissions, hyperthermia, arterial blood gas evaluation, hypercapnia, or tachycardia), 112 (93.3%) were deemed unlikely to be MH events; 8 (6.7%) had insufficient records to determine etiology. Results demonstrate a low frequency of classic intraanesthetic hypermetabolic phenotypes in an unselected population with actionable RYR1 variants. Further research on the actionability of screening for MH susceptibility in unselected populations, including economic impact, predictors of MH episodes, and expanded clinical phenotypes, is necessary.

Clinical presentation of MEN 2A in index vs. non-index patients.

Differences in syndromic manifestations of multiple endocrine neoplasia 2 A (MEN2A) between index and non-index patients are ill-defined. Cross-sectional analysis of 602 REarranged during Transfection (RET) carriers (156 index and 446 non-index patients) who underwent thyroidectomy, adrenalectomy, and/or parathyroidectomy between 1985 and 2022, stratified by mutational risk. Index patients were 5.8-13.9 years older at thyroidectomy than non-index patients, at which point they had developed 10.6-14.4 mm larger medullary thyroid cancers. Correlations between index status and primary tumor size (ρ = 0.489-0.544) were stronger than correlations between index status and age at thyroidectomy (ρ = 0.359-0.438). For pheochromocytoma and primary hyperparathyroidism, no significant differences were noted. When stratified by time of surgery before vs. in the new millennium, age at thyroidectomy fell significantly only for non-index patients in the new millennium: from 28.6 to 21.2 years (moderate-high risk mutations; P = 0.049) and from 23.1 to 12.3 years (high-risk mutations; P < 0.001). All other inter-millennium comparisons did not reach statistical significance. These findings imply that differences between index and non-index patients impact the first syndromic manifestation without extending to subsequent syndromic manifestations. Because they exhibited similar age and tumor characteristics for the secondary and tertiary manifestations of MEN2A, screening for these syndromic components remains an integral element of MEN2A management in index and non-index patients alike. Wider use of population genomic screening may work to diminish the observed disparities between index and non-index patients going forward.

Medical and psychosocial outcomes of state-funded population genomic screening.

As the uptake of population screening expands, assessment of medical and psychosocial outcomes is needed. Through the Alabama Genomic Health Initiative (AGHI), a state-funded genomic research program, individuals received screening for pathogenic or likely pathogenic variants in 59 actionable genes via genotyping. Of the 3874 eligible participants that received screening results, 858 (22%) responded to an outcomes survey. The most commonly reported motivation for seeking testing through AGHI was contribution to genetic research (64%). Participants with positive results reported a higher median number of planned actions (median = 5) due to AGHI results as compared to negative results (median = 3). Interviews were conducted with survey participants with positive screening results. As determined by certified genetic counselors, 50% of interviewees took appropriate medical action based on their result. There were no negative or harmful actions taken. These findings indicate population genomic screening of an unselected adult population is feasible, is not harmful, and may have positive outcomes on participants now and in the future; however, further research is needed in order to assess clinical utility.

Summary for Patients: Population Genomic Screening for Three Common Hereditary Conditions

Summary for Patients: Population Genomic Screening for Three Common Hereditary Conditions

How Clinicians Conceptualize "Actionability" in Genomic Screening.

Over the last decade, the concept of actionability has become a primary framework for assessing whether genetic data is useful and appropriate to return to patients. Despite the popularity of this concept, there is little consensus about what should count as "actionable" information. This is particularly true in population genomic screening, where there is considerable disagreement about what counts as good evidence and which clinical actions are appropriate for which patients. The pathway from scientific evidence to clinical action is not straightforward-it is as much social and political as it is scientific. This research explores the social dynamics shaping the integration of "actionable" genomic data into primary care settings. Based on semi-structured interviews with 35 genetics experts and primary care providers, we find that clinicians vary in how they define and operationalize "actionable" information. There are two main sources of disagreement. First, clinicians differ on the levels and types of evidence required for a result to be actionable, such as when we can be confident that genomic data provides accurate information. Second, there are disagreements about the clinical actions that must be available so that patients can benefit from that information. By highlighting the underlying values and assumptions embedded in discussions of actionability for genomic screening, we provide an empirical basis for building more nuanced policies regarding the actionability of genomic data in terms of population screening in primary care settings.

Thyroidectomy Outcomes in Patients Identified With RET Pathogenic Variants Through a Population Genomic Screening Program

Population-based genomic screening can facilitate early detection of medullary thyroid carcinoma (MTC) in patients with pathogenic/likely pathogenic (P/LP) RET variants. To evaluate the clinical treatment and patient outcomes after identification of P/LP RET proto-oncogene variants associated with the risk of MTC via a population genomic screening program. This retrospective cross-sectional study was completed between June 1, 2016, and May 31, 2022, for a mean follow-up period of 22.4 months (range, 2-76 months). The study included patients who were identified as having P/LP RET variants through a population genomic screening program at a rural tertiary care center and who underwent thyroidectomy after results disclosure. The outcomes of interest were preoperative evaluation and treatment-related outcomes. Measures included imaging and laboratory findings, extent of surgery, pathologic diagnosis, and staging. Seventy-five patients were identified as having P/LP RET variants exclusively through genomic screening. Twenty of these patients (27%; 11 women [55%] and 9 men [45%]; median age, 48 years [range, 22-73 years]) underwent total thyroidectomy; 13 of these patients (65%) also had a central neck dissection. No patients had clinically apparent disease at the time of surgery. Pathologic findings indicated MTC for 12 patients and papillary thyroid carcinoma in 2. Of patients with MTC, 10 had stage I disease, 1 had stage II disease, 1 had stage III disease, and none had stage IV disease. Based on postoperative surveillance imaging and laboratory results, no patient had evidence of recalcitrant disease. In this cross-sectional study, all malignant neoplasms identified on surgical pathology were clinically occult, with surgical intervention based solely on the identification of the P/LP RET variant via population genomic screening. This finding suggests that genomic screening may provide opportunities for early detection and treatment of MTC, with the potential for improved patient outcomes.

P493: Disease burden of DCM genes newly added to ACMG secondary findings via population genomic screening: Impact of TTN and FLNC

P493: Disease burden of DCM genes newly added to ACMG secondary findings via population genomic screening: Impact of TTN and FLNC

P120: Prevalence of malignant hyperthermia symptoms in patients receiving RYR1 results through a population genomic screening program

P120: Prevalence of malignant hyperthermia symptoms in patients receiving RYR1 results through a population genomic screening program

EE217 Population Genomic Screening for Tier 1 Genomic Applications: A Cost-Effectiveness Analysis

To assess the impact and cost-effectiveness of offering population genomic screening to all young adults in Australia to detect heterozygous familial hypercholesterolemia (FH), hereditarian breast and ovarian cancer and Lynch Syndrome.

Investigating Psychological Impact after Receiving Genetic Risk Results-A Survey of Participants in a Population Genomic Screening Program.

Genomic screening programs have potential to benefit individuals who may not be clinically ascertained, but little is known about the psychological impact of receiving genetic results in this setting. The current study sought to further the understanding of individuals' psychological response to receiving an actionable genetic test result from genomic screening. Telephone surveys were conducted with patient-participants at 6 weeks and 6 months post genetic result disclosure between September 2019 and May 2021 and assessed emotional response to receiving results via the FACToR, PANAS, and decision regret scales. Overall, 354 (29.4%) study participants completed both surveys. Participants reported moderate positive emotions and low levels of negative emotions, uncertainty, privacy concern, and decision regret over time. There were significant decreases in negative emotions (p = 0.0004) and uncertainty (p = 0.0126) between time points on the FACToR scale. "Interested" was the highest scoring discrete emotion (T1 3.6, T2 3.3, scale 0-5) but was significantly lower at 6 months (&lt;0.0001). Coupled with other benefits of genomic screening, these results of modest psychological impact waning over time adds support to clinical utility of population genomic screening programs. However, questions remain regarding how to elicit an emotional response that motivates behavior change without causing psychological harm.

From the patient to the population: Use of genomics for population screening.

Genomic medicine is expanding from a focus on diagnosis at the patient level to prevention at the population level given the ongoing under-ascertainment of high-risk and actionable genetic conditions using current strategies, particularly hereditary breast and ovarian cancer (HBOC), Lynch Syndrome (LS) and familial hypercholesterolemia (FH). The availability of large-scale next-generation sequencing strategies and preventive options for these conditions makes it increasingly feasible to screen pre-symptomatic individuals through public health-based approaches, rather than restricting testing to high-risk groups. This raises anew, and with urgency, questions about the limits of screening as well as the moral authority and capacity to screen for genetic conditions at a population level. We aimed to answer some of these critical questions by using the WHO Wilson and Jungner criteria to guide a synthesis of current evidence on population genomic screening for HBOC, LS, and FH.

Population genomic screening: Ethical considerations to guide age at implementation.

Currently, most genetic testing involves next generation sequencing or panel testing, indicating future population-based screening will involve simultaneous testing for multiple disease risks (called here “panel testing”). Genomic screening typically focuses on single or groups of related disorders, with little utilization of panel testing. Furthermore, the optimal age for test ordering is rarely addressed in terms of whether it should coincide with the age of majority (18 years old) or after the age of majority (26 years old). We conducted an ethical analysis utilizing a hypothetical “narrow” panel test comprised of the CDC Tier 1 Genomic Applications: Familial Hypercholesterolemia (FH), increases individuals’ cardiovascular risk due to elevated low-density lipoprotein (LDL) cholesterol levels; Hereditary Breast and Ovarian Cancer (HBOC), increases lifetime risk of developing cancer; and Lynch Syndrome (LS), increases lifetime risk of developing colorectal cancer. We conducted a utilitarian analysis, on the assumption that health systems seek to maximize utility for patients. Screening at the “age of majority” is preferred for FH due to lowering FH patients’ cholesterol levels via statins providing high lifetime benefits and low risks. Screening “after the age of majority” is preferred for HBOC and LS due to availability of effective surveillance, the recommendation for screening activities to begin at age 26, and prophylactic interventions connected to surveillance. We also utilized a supplemental principlist-based approach that identified relevant concerns and trade-offs. Consideration of clinical, non-clinical, and family planning implications suggests narrow panel testing would be best deployed after 26 (rather than at 18) years of age.

Understanding the Patient Experience of Receiving Clinically Actionable Genetic Results from the MyCode Community Health Initiative, a Population-Based Genomic Screening Initiative.

Understanding unselected individuals’ experiences receiving genetic results through population genomic screening is critical to advancing clinical utility and improving population health. We conducted qualitative interviews with individuals who received clinically actionable genetic results via the MyCode© Genomic Screening and Counseling program. We purposively sampled cohorts to seek diversity in result-related disease risk (e.g., cancer or cardiovascular) and in personal or family history of related diseases. Transcripts were analyzed using a two-step inductive coding process of broad thematic analysis followed by in-depth coding of each theme. Four thematic domains identified across all cohorts were examined: process assessment, psychosocial response, behavioral change due to the genetic result, and family communication. Coding of 63 interviews among 60 participants revealed that participants were satisfied with the results disclosure process, initially experienced a range of positive, neutral, and negative psychological reactions to results, adjusted positively to results over time, undertook clinically indicated actions in response to results, and communicated results with relatives to whom they felt emotionally close. Our findings of generally favorable responses to receiving clinically actionable genetic results via a genomic screening program may assuage fear of patient distress in such programs and guide additional biobanks, genomic screening programs, and research studies.

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

Population genomic screening for familial hypercholesterolemia (FH) in unselected individuals can prevent premature cardiovascular disease. To estimate the clinical and economic outcomes of population-wide FH genomic screening versus no genomic screening. 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. 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. 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.