Outcomes Following a False-Positive Multi-Cancer Early Detection Test: Results from DETECT-A, the First Large, Prospective, Interventional MCED Study.

Guideline recommended standard of care screening is available for four cancer types; most cancer-related deaths are caused by cancers without standard of care screening. DETECT-A is the first prospective interventional trial evaluating a multi-cancer early detection (MCED) blood test (CancerSEEK) in women without a history of cancer, providing the first opportunity to assess the long-term outcomes of individuals with false-positive (FP) MCED results. This prospective analysis of DETECT-A participants with FP results evaluates the performance of an imaging-based diagnostic workflow and examines cancer risk following a FP result. This analysis included all DETECT-A participants with a positive CancerSEEK test and subsequent flourine-18 fluorodeoxyglucose positron emission tomography-IV contrast-enhanced computed tomography (18-F-FDG PET-CT) imaging and clinical workup indicating no evidence of cancer within 1 year of enrollment (n = 98). Medical records, study interactions, and study surveys were used to assess cancer incidence, treatments, and clinical outcomes through August 2023. Ninety-five of 98 participants with a FP result remained cancer-free with a median follow-up of 3.6 years (IQR: 2.5-4.1) from determination of FP status. Three incident cancers were observed over the follow-up period. One bilateral stage IIIC ovarian cancer was diagnosed 1.9 years after determination of FP status; two stage I breast cancers were diagnosed 0.1 and 1.6 years from determination of FP status. The annual incidence rate of cancer during follow-up from FP determination was 1.0% (95% confidence interval, 0.2%-2.8%). Participants with a positive CancerSEEK test who underwent 18-F-FDG PET-CT and clinical workup without cancer findings had low risk for cancer over the following several years. Prevention Relevance: This study provides multiyear clinical outcomes data following a false-positive multi-cancer early detection test for individuals participating in a prospective interventional trial. It provides a preliminary performance assessment of an imaging-based diagnostic workflow following a false-positive multi-cancer early detection test.

Simple Incisionless Temporary Stabilization: An Adjunct to Lower Blepharoplasty.

Background: Lateral canthal tightening is indicated for patients undergoing lower eyelid blepharoplasty who have preexisting lower eyelid laxity or ectropion. A canthoplasty or canthopexy is indicated at the time of lower blepharoplasty to avoid postoperative complications, such as eyelid retraction or ectropion. Various surgical techniques are described to accomplish this goal, including canthopexy procedures, which usually access the lateral canthal tendon through an upper eyelid blepharoplasty or lateral canthal incision. Objectives: To describe an incisionless technique adjunctive to lower blepharoplasty, which stabilizes the lower eyelid in the week following blepharoplasty. Methods: This operative technique description and retrospective case series includes 15 patients who underwent a simple incisionless temporary stabilization (SITS) during lower eyelid blepharoplasty. The procedures were performed at the same outpatient office-based surgery center and were performed by the author surgeons. Patients were followed from 3 to 6 months postoperatively. Results: The SITS procedure during lower eyelid blepharoplasty successfully maintained a desirable functional and aesthetic eyelid position with minimal complications. One patient reported tearing postoperatively which was determined to be unrelated to the SITS and resolved by the 1-month follow-up visit. No patient had any other complications during the follow-up period. Conclusions: The SITS procedure was successfully utilized in patients with mild-to-moderate lower eyelid laxity and/or a negative vector to prevent postoperative ectropion and eyelid retraction. It is a more favorable alternative to temporary tarsorrhaphy, as it does not obstruct vision during healing and better secures the eyelid. It should not be used in patients with significant lower eyelid laxity that would place the patient at significant risk of ectropion and lower eyelid retraction related to swelling and inappropriate eyelid position during the early postoperative course.

Outcomes following a false positive multi-cancer early detection (MCED) test: Results from DETECT-A, the first large, prospective, interventional MCED study.

Guideline recommended standard of care (SoC) screening is available for four cancer types; most cancer-related deaths are caused by cancers without SoC screening. DETECT-A is the first prospective interventional trial evaluating an MCED blood test (CancerSEEK) in women without a history of cancer, providing the first opportunity to assess the long-term outcomes of individuals with false positive (FP) MCED results. This prospective analysis of DETECT-A participants with FP results evaluates the performance of an imaging-based diagnostic workflow and examines cancer risk following a FP result. This analysis included all DETECT-A participants with a positive CancerSEEK test and subsequent flourine-18 fluorodeoxyglucose positron emission tomography-IV contrast enhanced computed tomography (18-F-FDG PET-CT) imaging and clinical workup indicating no evidence of cancer within one year of enrollment (n=98). Medical records, study interactions, and study surveys were used to assess cancer incidence, treatments, and clinical outcomes through August 2023. Ninety-five of 98 participants with a FP result remained cancer-free with a median follow-up of 3.6 years (IQR: 2.5-4.1) from determination of FP status. Three incident cancers were observed over the follow-up period. One bilateral stage IIIC ovarian cancer was diagnosed 1.9 years after determination of FP status; two stage I breast cancers were diagnosed 0.1 and 1.6 years from determination of FP status. The annual incidence rate of cancer during follow-up from FP determination was 1.0% (95% CI: 0.2%-2.8%). Participants with a positive CancerSEEK test who underwent 18-F-FDG PET-CT and clinical workup without cancer findings had low risk for cancer over the following several years.

Multi-year clinical outcomes of cancers diagnosed following detection by a blood-based multi-cancer early detection (MCED) test.

In the U.S., <20% of cancers are diagnosed by standard-of-care (SoC) screening. Multi-cancer early detection (MCED) tests offer the opportunity to expand cancer screening. Understanding the characteristics and clinical outcomes of MCED-detected cancers is critical to clarifying MCED tests' potential impact. DETECT-A is the first prospective interventional trial of an MCED blood test (CancerSEEK). CancerSEEK, coupled with diagnostic PET-CT, identified cancers including those not detected by SoC screening, the majority of which were localized or regional. We report multi-year outcomes in patients with cancers diagnosed following a positive CancerSEEK test. Nine cancer types were diagnosed in 26 participants whose cancers were first detected by CancerSEEK. Information on cancer diagnoses, treatments, and clinical outcomes was extracted from medical records through November 2022. Data collection occurred a median of 4.4 years (IQR: 4.1-4.6) following study enrollment. Thirteen of 26 (50%) participants were alive and cancer-free [ovarian (4), thyroid (1), uterine (2), breast (1), colorectal (2), and lung (3)]; 7/13 (54%) had cancers without recommended SoC screening modalities. All 8 treated stage I or II participants (8/8, 100%) and 12/14 (86%) surgically-treated participants were alive and cancer-free. Eligibility for surgical treatment was associated with favorable multi-year outcomes (p = 0.0002). Half of participants with MCED-detected cancers were alive and cancer-free after 4.4 years median follow-up. Most were diagnosed with early-stage cancers and were treated surgically. These results suggest that early cancer detection by CancerSEEK may have facilitated curative-intent treatments and associated positive clinical outcomes in some DETECT-A participants.

Real-time evaluation and adaptation to facilitate rapid recruitment in a large, prospective cohort study.

BACKGROUND: Recruiting large cohorts efficiently can speed the translation of findings into care across a range of scientific disciplines and medical specialties. Recruitment can be hampered by factors such as financial barriers, logistical concerns, and lack of resources for patients and clinicians. These and other challenges can lead to underrepresentation in groups such as rural residents and racial and ethnic minorities. Here we discuss the implementation of various recruitment strategies for enrolling participants into a large, prospective cohort study, assessing the need for adaptations and making them in real-time, while maintaining high adherence to the protocol and high participant satisfaction. METHODS: While conducting a large, prospective trial of a multi-cancer early detection blood test at Geisinger, an integrated health system in central Pennsylvania, we monitored recruitment progress, adherence to the protocol, and participants' satisfaction. Tracking mechanisms such as paper records, electronic health records, research databases, dashboards, and electronic files were utilized to measure each outcome. We then reviewed study procedures and timelines to list the implementation strategies that were used to address barriers to recruitment, protocol adherence and participant satisfaction. RESULTS: Adaptations to methods that contributed to achieving the enrollment goal included offering multiple recruitment options, adopting group consenting, improving visit convenience, increasing the use of electronic capture and the tracking of data and source documents, staffing optimization via leveraging resources external to the study team when appropriate, and integrating the disclosure of study results into routine clinical care without adding unfunded work for clinicians. We maintained high protocol adherence and positive participant experience as exhibited by a very low rate of protocol deviations and participant complaints. CONCLUSION: Recruiting rapidly for large studies - and thereby facilitating clinical translation - requires a nimble, creative approach that marshals available resources and changes course according to data. Planning a rigorous assessment of a study's implementation outcomes prior to study recruitment can further ground study adaptations and facilitate translation into practice. This can be accomplished by proactively and continuously assessing and revising implementation strategies.

Genetics Visit Uptake Among Individuals Receiving Clinically Actionable Genomic Screening Results.

Importance: 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. Objective: To identify factors associated with postdisclosure genetics visits in a genomic screening cohort. Design, Setting, and Participants: 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. Exposure: Clinically confirmed P/LP result disclosed by phone or letter. Main Outcomes and Measures: Completion of genetics visit in which the result was discussed and variables associated with completion were assessed by electronic health record (EHR) review. Results: 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%]). Conclusions and Relevance: 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.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Testing and Management of Iron Overload After Genetic Screening-Identified Hemochromatosis.

Importance: HFE gene-associated hereditary hemochromatosis type 1 (HH1) is underdiagnosed, resulting in missed opportunities for preventing morbidity and mortality. Objective: To assess whether screening for p.Cys282Tyr homozygosity is associated with recognition and management of asymptomatic iron overload. Design, Setting, and Participants: This cross-sectional study obtained data from the Geisinger MyCode Community Health Initiative, a biobank of biological samples and linked electronic health record data from a rural, integrated health care system. Participants included those who received a p.Cys282Tyr homozygous result via genomic screening (MyCode identified), had previously diagnosed HH1 (clinically identified), and those negative for p.Cys282Tyr homozygosity between 2017 and 2018. Data were analyzed from April 2020 to August 2023. Exposure: Disclosure of a p.Cys282Tyr homozygous result. Main Outcomes and Measures: Postdisclosure management and HFE-associated phenotypes in MyCode-identified participants were analyzed. Rates of HFE-associated phenotypes in MyCode-identified participants were compared with those of clinically identified participants. Relevant laboratory values and rates of laboratory iron overload among participants negative for p.Cys282Tyr homozygosity were compared with those of MyCode-identified participants. Results: A total of 86 601 participants had available exome sequences at the time of analysis, of whom 52 994 (61.4%) were assigned female at birth, and the median (IQR) age was 62.0 (47.0-73.0) years. HFE p.Cys282Tyr homozygosity was disclosed to 201 participants, of whom 57 (28.4%) had a prior clinical HH1 diagnosis, leaving 144 participants who learned of their status through screening. There were 86 300 individuals negative for p.Cys282Tyr homozygosity. After result disclosure, among MyCode-identified participants, 99 (68.8%) had a recommended laboratory test and 36 (69.2%) with laboratory or liver biopsy evidence of iron overload began phlebotomy or chelation. Fifty-three (36.8%) had iron overload; rates of laboratory iron overload were higher in MyCode-identified participants than participants negative for p.Cys282Tyr homozygosity (females: 34.1% vs 2.1%, P < .001; males: 39.0% vs 2.9%, P < .001). Iron overload (females: 34.1% vs 79.3%, P < .001; males: 40.7% vs 67.9%, P = .02) and some liver-associated phenotypes were observed at lower frequencies in MyCode-identified participants compared with clinically identified individuals. Conclusions and Relevance: Results of this cross-sectional study showed the ability of genomic screening to identify undiagnosed iron overload and encourage relevant management, suggesting the potential benefit of population screening for HFE p.Cys282Tyr homozygosity. Further studies are needed to examine the implications of genomic screening for health outcomes and cost-effectiveness.

Low adenoma burden in unselected patients with a pathogenic APC variant.

PURPOSE: Genomic screening can improve clinical outcomes, but presentation of individuals with risk for polyposis identified via genomic screening is unknown. To inform assessment of clinical utility of genomic screening for polyposis risk, clinical presentation of individuals in an unselected health care system cohort with an APC pathogenic or likely pathogenic (P/LP) variant causative of familial adenomatous polyposis are described. METHODS: Electronic health records of individuals with an APC P/LP variant identified via the MyCode program (MyCode APC+) were reviewed to assess adenoma burden and compare it among individuals with a clinical diagnosis of familial adenomatous polyposis and matched variant-negative controls. RESULTS: The prevalence of APC P/LP variants in this health care cohort is estimated to be 1 in 2800. Twenty-four MyCode APC+ individuals were identified during the study period. Median age at result disclosure was 53 years. Rate of clinical polyposis was 8%. Two of six participants with a classic region variant and none of those with an attenuated region variant had polyposis. MyCode APC+ participants did not differ from controls in cumulative adenoma count. CONCLUSION: APC P/LP variant prevalence estimate in the MyCode cohort is higher than prior published prevalence rates. Individuals with APC P/LP variants identified via genomic screening had a low adenoma burden.

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

Importance: Population-based genomic screening can facilitate early detection of medullary thyroid carcinoma (MTC) in patients with pathogenic/likely pathogenic (P/LP) RET variants. Objective: 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. Design, Setting, Participants: 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. Main Outcomes and Measures: The outcomes of interest were preoperative evaluation and treatment-related outcomes. Measures included imaging and laboratory findings, extent of surgery, pathologic diagnosis, and staging. Results: 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. Conclusions and Relevance: 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.

Integrating primary care, shared decision making, and community engagement to facilitate equitable access to multi-cancer early detection clinical trials.

Effective implementation of cancer screening programs can reduce disease-specific incidence and mortality. Screening is currently recommended for breast, cervical, colorectal and lung cancer. However, initial and repeat adherence to screening tests in accordance with current guidelines is sub-optimal, with the lowest rates observed in historically underserved groups. If used in concert with recommended cancer screening tests, new biospecimen-based multi-cancer early detection (MCED) tests could help to identify more cancers that may be amendable to effective treatment. Clinical trials designed to assess the safety and efficacy of MCED tests to assess their potential for reducing cancer mortality are needed and many are underway. In the conduct of MCED test trials, it is crucial that participant recruitment efforts successfully engage participants from diverse populations experiencing cancer disparities. Strategic partnerships involving health systems, clinical practices, and communities can increase the reach of MCED trial recruitment efforts among populations experiencing disparities. This goal can be achieved by developing health system-based learning communities that build understanding of and trust in biomedical research; and by applying innovative methods for identifying eligible trial patients, educating potential participants about research trials, and engaging eligible individuals in shared decision making (SDM) about trial participation. This article describes how a developing consortium of health systems has used this approach to encourage the uptake of cancer screening in a wide range of populations and how such a strategy can facilitate the enrollment of persons from diverse patient and community populations in MCED trials.

Implementation-effectiveness trial of systematic family health history based risk assessment and impact on clinical disease prevention and surveillance activities.

BACKGROUND: Systematically assessing disease risk can improve population health by identifying those eligible for enhanced prevention/screening strategies. This study aims to determine the clinical impact of a systematic risk assessment in diverse primary care populations. METHODS: Hybrid implementation-effectiveness trial of a family health history-based health risk assessment (HRA) tied to risk-based guideline recommendations enrolling from 2014-2017 with 12 months of post-intervention survey data and 24 months of electronic medical record (EMR) data capture. SETTING: 19 primary care clinics at four geographically and culturally diverse U.S. healthcare systems. PARTICIPANTS: any English or Spanish-speaking adult with an upcoming appointment at an enrolling clinic. METHODS: A personal and family health history based HRA with integrated guideline-based clinical decision support (CDS) was completed by each participant prior to their appointment. Risk reports were provided to patients and providers to discuss at their clinical encounter. OUTCOMES: provider and patient discussion and provider uptake (i.e. ordering) and patient uptake (i.e. recommendation completion) of CDS recommendations. MEASURES: patient and provider surveys and EMR data. RESULTS: One thousand eight hundred twenty nine participants (mean age 56.2 [SD13.9], 69.6% female) completed the HRA and had EMR data available for analysis. 762 (41.6%) received a recommendation (29.7% for genetic counseling (GC); 15.2% for enhanced breast/colon cancer screening). Those with recommendations frequently discussed disease risk with their provider (8.7%-38.2% varied by recommendation, p-values ≤ 0.004). In the GC subgroup, provider discussions increased referrals to counseling (44.4% with vs. 5.9% without, P < 0.001). Recommendation uptake was highest for colon cancer screening (provider = 67.9%; patient = 86.8%) and lowest for breast cancer chemoprevention (0%). CONCLUSIONS: Systematic health risk assessment revealed that almost half the population were at increased disease risk based on guidelines. Risk identification resulted in shared discussions between participants and providers but variable clinical action uptake depending upon the recommendation. Understanding the barriers and facilitators to uptake by both patients and providers will be essential for optimizing HRA tools and achieving their promise of improving population health. TRIAL REGISTRATION: Clinicaltrials.gov number NCT01956773 , registered 10/8/2013.

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.

Observational study of population genomic screening for variants associated with endocrine tumor syndromes in a large, healthcare-based cohort.

BACKGROUND: In current care, patients' personal and self-reported family histories are primarily used to determine whether genetic testing for hereditary endocrine tumor syndromes (ETS) is indicated. Population genomic screening for other conditions has increased ascertainment of individuals with pathogenic/likely pathogenic (P/LP) variants, leading to improved management and earlier diagnoses. It is unknown whether such benefits occur when screening broader populations for P/LP ETS variants. This manuscript assesses clinical utility outcomes of a large, unselected, healthcare-based genomic screening program by describing personal and family history of syndrome-related features, risk management behaviors after result disclosure, and rates of relevant post-disclosure diagnoses in patient-participants with P/LP ETS variants. METHODS: Observational study of individuals informed of a P/LP variant in MEN1, RET, SDHAF2, SDHB, SDHC, SDHD, or VHL through Geisinger's MyCode Community Health Initiative between June 2016 and October 2019. Electronic health records (EHRs) of participants were evaluated for a report of pre-disclosure personal and self-reported family histories and post-disclosure risk management and diagnoses. RESULTS: P/LP variants in genes of interest were identified in 199 of 130,490 (1 in 656) adult Geisinger MyCode patient-participants, 80 of which were disclosed during the study period. Eighty-one percent (n = 65) did not have prior evidence of the result in their EHR and, because they were identified via MyCode, were included in further analyses. Five participants identified via MyCode (8%) had a personal history of syndrome-related features; 16 (25%) had a positive self-reported family history. Time from result disclosure to EHR review was a median of 0.7 years. Post-disclosure, 36 (55.4%) completed a recommended risk management behavior; 11 (17%) were diagnosed with a syndrome-related neoplasm after completing a risk management intervention. CONCLUSIONS: Broader screening for pathogenic/likely pathogenic variants associated with endocrine tumor syndromes enables detection of at-risk individuals, leads to the uptake of risk management, and facilitates relevant diagnoses. Further research will be necessary to continue to determine the clinical utility of screening diverse, unselected populations for such variants.

Clinical validation of genomic functional screen data: Analysis of observed BRCA1 variants in an unselected population cohort.

Functional assessment of genomic variants provides a promising approach to systematically examine the potential pathogenicity of variants independent of associated clinical data. However, making such conclusions requires validation with appropriate clinical findings. To this end, here, we use variant calls from exome data and BRCA1-related cancer diagnoses from electronic health records to demonstrate an association between published laboratory-based functional designations of BRCA1 variants and BRCA1-related cancer diagnoses in an unselected cohort of patient-participants. These findings validate and support further exploration of functional assay data to better understand the pathogenicity of rare variants. This information may be valuable in the context of healthy population genomic screening, where many rare, potentially pathogenic variants may not have sufficient associated clinical data to inform their interpretation directly.

Penetrance of Breast Cancer Susceptibility Genes From the eMERGE III Network.

Background: Unbiased estimates of penetrance are challenging but critically important to make informed choices about strategies for risk management through increased surveillance and risk-reducing interventions. Methods: We studied the penetrance and clinical outcomes of 7 breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, ATM, PALB2, and PTEN) in almost 13 458 participants unselected for personal or family history of breast cancer. We identified 242 female participants with pathogenic or likely pathogenic variants in 1 of the 7 genes for penetrance analyses, and 147 women did not previously know their genetic results. Results: Out of the 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 17.8% to 43.8%, depending on the gene. In clinical-impact analysis, 42.3% (95% confidence interval = 31.3% to 53.3%) of women had taken actions related to their genetic results, and 2 new breast cancer cases were identified within the first 12 months after genetic results disclosure. Conclusions: Our study provides population-based penetrance estimates for the understudied genes CHEK2, ATM, and PALB2 and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve health care through early diagnosis and preventative screening.

Clinical Findings and Diagnostic Yield of Arrhythmogenic Cardiomyopathy Through Genomic Screening of Pathogenic or Likely Pathogenic Desmosome Gene Variants.

BACKGROUND: Genomic screening holds great promise for presymptomatic identification of hidden disease, and prevention of dramatic events, including sudden cardiac death associated with arrhythmogenic cardiomyopathy (ACM). Herein, we present findings from clinical follow-up of carriers of ACM-associated pathogenic/likely pathogenic desmosome variants ascertained through genomic screening. METHODS: Of 64 548 eligible participants in Geisinger MyCode Genomic Screening and Counseling program (2015-present), 92 individuals (0.14%) identified with pathogenic/likely pathogenic desmosome variants by clinical laboratory testing were referred for evaluation. We reviewed preresult medical history, patient-reported family history, and diagnostic testing results to assess both arrhythmogenic right ventricular cardiomyopathy and left-dominant ACM. RESULTS: One carrier had a prior diagnosis of dilated cardiomyopathy with arrhythmia; no other related diagnoses or diagnostic family history criteria were reported. Fifty-nine carriers (64%) had diagnostic testing in follow-up. Excluding the variant, 21/59 carriers satisfied at least one arrhythmogenic right ventricular cardiomyopathy task force criterion, 11 (52%) of whom harbored DSP variants, but only 5 exhibited multiple criteria. Six (10%) carriers demonstrated evidence of left-dominant ACM, including high rates of atypical late gadolinium enhancement by magnetic resonance imaging and nonsustained ventricular tachycardia. Two individuals received new cardiomyopathy diagnoses and received defibrillators for primary prevention. CONCLUSIONS: Genomic screening for pathogenic/likely pathogenic variants in desmosome genes can uncover both left- and right-dominant ACM. Findings of overt cardiomyopathy were limited but were most common in DSP-variant carriers and notably absent in PKP2-variant carriers. Consideration of the pathogenic/likely pathogenic variant as a major criterion for diagnosis is inappropriate in the setting of genomic screening.

Developing and Optimizing Innovative Tools to Address Familial Hypercholesterolemia Underdiagnosis: Identification Methods, Patient Activation, and Cascade Testing for Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is the most common cardiovascular genetic disorder and, if left untreated, is associated with increased risk of premature atherosclerotic cardiovascular disease, the leading cause of preventable death in the United States. Although FH is common, fatal, and treatable, it is underdiagnosed and undertreated due to a lack of systematic methods to identify individuals with FH and limited uptake of cascade testing. METHODS AND RESULTS: This mixed-method, multi-stage study will optimize, test, and implement innovative approaches for both FH identification and cascade testing in 3 aims. To improve identification of individuals with FH, in Aim 1, we will compare and refine automated phenotype-based and genomic approaches to identify individuals likely to have FH. To improve cascade testing uptake for at-risk individuals, in Aim 2, we will use a patient-centered design thinking process to optimize and develop novel, active family communication methods. Using a prospective, observational pragmatic trial, we will assess uptake and effectiveness of each family communication method on cascade testing. Guided by an implementation science framework, in Aim 3, we will develop a comprehensive guide to identify individuals with FH. Using the Conceptual Model for Implementation Research, we will evaluate implementation outcomes including feasibility, acceptability, and perceived sustainability as well as health outcomes related to the optimized methods and tools developed in Aims 1 and 2. CONCLUSIONS: Data generated from this study will address barriers and gaps in care related to underdiagnosis of FH by developing and optimizing tools to improve FH identification and cascade testing.

Uncertainty management for individuals with Lynch Syndrome: Identifying and responding to healthcare barriers.

OBJECTIVE: Examine the uncertainty management process of individuals with Lynch syndrome (LS). METHODS: 19 phone interviews were conducted with individuals with LS. The interview guide included questions on family communication, risk perceptions, and uncertainty management. Data were analyzed using the constant comparison method to code for emergent themes. RESULTS: Qualitative analysis found individuals with LS tried to manage their uncertainty through preventive care, but were often confounded by healthcare barriers. Healthcare barriers included cost and insurance issues, absence of coordinated care, insufficient provider knowledge, and lack of patient-centered communication. Participants reported increased uncertainty and anxiety due to these barriers and used alternative uncertainty management strategies such as advocating for themselves with providers, seeking information online, and communicating with family for emotional support. CONCLUSION: Healthcare barriers identified in this study exacerbated uncertainty and anxiety for individuals with LS and challenged their ability to engage in preventive care. In response, participants used alternative uncertainty management strategies to reduce their uncertainty, which may have unintended negative consequences. PRACTICE IMPLICATIONS: Findings support the need for providers to partner with specialists in genetics and/or LS to better care for individuals with LS. Findings highlight opportunities for interventions in healthcare to better support individuals with LS.