Measuring perceived utility of genomic sequencing: Development and validation of the GENEtic Utility (GENE-U) scale for adult screening.

PURPOSE: As population-based screening programs to identify genetic conditions in adults using genomic sequencing (GS) are increasingly available, validated patient-centered outcome measures are needed to understand participants' experience. We aimed to develop and validate an instrument to assess the perceived utility of GS in the context of adult screening. METHODS: Informed by a 5-domain conceptual model, we used a 5-step approach to instrument development and validation: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. Adults undergoing risk-based or population-based GS who had received GS results as part of ongoing research studies participated in structured cognitive interviews and 2 rounds of surveys. After item pool refinement, we conducted an exploratory factor analysis and calculated Pearson correlations with related instruments. RESULTS: We derived the 18-item Adult Screening version of the GENEtic Utility scale (total sum score α = .87). Mirroring the Pediatric Diagnostic version, the instrument has a 2-factor structure, including an Informational Utility subscale (14 items, α = .89) and an Emotional Utility subscale (4 items, α = .75). The Informational Utility subscale was strongly associated with empowerment and personal utility of GS. Correlations of the Emotional Utility subscale with psychosocial impact and anxiety and depression were weak to moderate. CONCLUSION: Initial psychometric testing of the Adult Screening GENEtic Utility scale demonstrates its promise, and additional validation in translational genomics research is warranted.

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.

Implementing evidence-based assertions of clinical actionability in the context of secondary findings: Updates from the ClinGen Actionability Working Group.

PURPOSE: The ClinGen Actionability Working Group (AWG) developed an evidence-based framework to generate actionability reports and scores of gene-condition pairs in the context of secondary findings from genome sequencing. Here we describe the expansion of the framework to include actionability assertions. METHODS: Initial development of the actionability rubric was based on previously scored adult gene-condition pairs and individual expert evaluation. Rubric refinement was iterative and based on evaluation, feedback, and discussion. The final rubric was pragmatically evaluated via integration into actionability assessments for 27 gene-condition pairs. RESULTS: The resulting rubric has a 4-point scale (limited, moderate, strong, and definitive) and uses the highest-scoring outcome-intervention pair of each gene-condition pair to generate a preliminary assertion. During AWG discussions, predefined criteria and factors guide discussion to produce a consensus assertion for a gene-condition pair, which may differ from the preliminary assertion. The AWG has retrospectively generated assertions for all previously scored gene-condition pairs and are prospectively asserting on gene-condition pairs under assessment, having completed over 170 adult and 188 pediatric gene-condition pairs. CONCLUSION: The AWG expanded its framework to provide actionability assertions to enhance the clinical value of their resources and increase their utility as decision aids regarding return of secondary findings.

Multiyear Clinical Outcomes of Cancers Diagnosed Following Detection by a Blood-Based Multicancer Early Detection Test.

In the US, <20% of cancers are diagnosed by standard-of-care (SoC) screening. Multicancer 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 multiyear 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 at 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 eight 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 multiyear 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. Prevention Relevance: This study provides preliminary evidence of the potential of multicancer early detection testing as an effective screening tool for detecting cancers without standard-of-care (SoC) screening modalities and complementing SoC cancer screening.

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.

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.

Defining critical educational components of informed consent for genetic testing: views of US-based genetic counselors and medical geneticists.

The Clinical Genome Resource (ClinGen) Consent and Disclosure Recommendation (CADRe) framework proposes that key components of informed consent for genetic testing can be covered with a targeted discussion for many conditions rather than a time-intensive traditional genetic counseling approach. We surveyed US genetics professionals (medical geneticists and genetic counselors) on their response to scenarios that proposed core informed consent concepts for clinical genetic testing developed in a prior expert consensus process. The anonymous online survey included responses to 3 (of 6 possible) different clinical scenarios that summarized the application of the core concepts. There was a binary (yes/no) question asking respondents whether they agreed the scenarios included the minimum necessary and critical educational concepts to allow an informed decision. Respondents then provided open-ended feedback on what concepts were missing or could be removed. At least one scenario was completed by 238 respondents. For all but one scenario, over 65% of respondents agreed that the identified concepts portrayed were sufficient for an informed decision; the exome scenario had the lowest agreement (58%). Qualitative analysis of the open-ended comments showed no consistently mentioned concepts to add or remove. The level of agreement with the example scenarios suggests that the minimum critical educational components for pre-test informed consent proposed in our prior work is a reasonable starting place for targeted pre-test discussions. This may be helpful in providing consistency to the clinical practice of both genetics and non-genetics providers, meeting patients' informational needs, tailoring consent for psychosocial support, and in future guideline development.

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.

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 (<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.

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.

A RE-AIM Framework Analysis of DNA-Based Population Screening: Using Implementation Science to Translate Research Into Practice in a Healthcare System.

Introduction: DNA-based population screening has been proposed as a public health solution to identify individuals at risk for serious health conditions who otherwise may not present for medical care. The clinical utility and public health impact of DNA-based population screening is a subject of active investigation. Geisinger, an integrated healthcare delivery system, was one of the first healthcare systems to implement DNA screening programs (MyCode Community Health Initiative (MyCode) and clinical DNA screening pilot) that leverage exome data to identify individuals at risk for developing conditions with potential clinical actionability. Here, we demonstrate the use of an implementation science framework, RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance), to conduct a post-hoc evaluation and report outcomes from these two programs to inform the potential impact of DNA-based population screening. Methods: Reach and Effectiveness outcomes were determined from the MyCode research program, while Adoption and Implementation outcomes were measured using the clinical DNA screening pilot. Reach was defined as the number of patients who were offered and consented to participate in MyCode. Effectiveness of DNA screening was measured by reviewing MyCode program publications and synthesizing findings from themes. Adoption was measured by the total number of DNA screening tests ordered by clinicians at the clinical pilot sites. Implementation was assessed by interviewing a subset of clinical pilot clinicians about the deployment of and recommended adaptations to the pilot that could inform future program dissemination. Results: Reach: As of August 2020, 68% (215,078/316,612) of individuals approached to participate in the MyCode program consented. Effectiveness: Published evidence reported from MyCode demonstrates that DNA screening identifies at-risk individuals more comprehensively than clinical ascertainment based on phenotypes or personal/family history. Adoption: From July 2018 to June 2021, a total of 1,026 clinical DNA screening tests were ordered by 60 clinicians across the three pilot clinic sites. Implementation: Interviews with 14 clinicians practicing at the pilot clinic sites revealed motivation to provide patients with DNA screening results and yielded future implementation strategies. Conclusion: The RE-AIM framework offers a pragmatic solution to organize, analyze, and report outcomes across differently resourced and designed precision health programs that include genomic sequencing and return of clinically actionable genomic information.

Establishing the Medical Actionability of Genomic Variants.

Actionability is an important concept in medicine that does not have a well-accepted standard definition, nor is there a general consensus on how to establish it. Medical actionability is often conflated with clinical utility, a related but distinct concept. This lack of clarity contributes to practice variation and inconsistent coverage decisions in genomic medicine, leading to the potential for systematic bias in the use of evidence-based interventions. We clarify how medical actionability and clinical utility are distinct and then discuss the spectrum of actionability, including benefits for the person, the family, and society. We also describe applications across the life course, including prediction, diagnosis, and treatment. Current challenges in assessing the medical actionability of identified genomic variants include gaps in the evidence, limited contexts with practice guidelines, and subjective aspects of medical actionability. A standardized and authoritative assessment of medical actionability is critical to implementing genomic medicine in a fashion that improves population health outcomes and reduces health disparities.

ClinGen's Pediatric Actionability Working Group: Clinical actionability of secondary findings from genome-scale sequencing in children and adolescents.

PURPOSE: Synthesis and curation of evidence regarding the clinical actionability of secondary findings (SFs) from genome-scale sequencing are needed to support decision-making on reporting of these findings. To assess actionability of SFs in children and adolescents, the Clinical Genome Resource established the Pediatric Actionability Working Group (AWG). METHODS: The Pediatric AWG modified the framework of the existing Adult AWG, which included production of summary reports of actionability for genes and associated conditions and consensus actionability scores for specific outcome-intervention pairs. Modification of the adult framework for the pediatric setting included accounting for special considerations for reporting presymptomatic or predictive genetic findings in the pediatric context, such as maintaining future autonomy by not disclosing conditions not actionable until adulthood. The Pediatric AWG then applied this new framework to genes and associated conditions with putative actionability. RESULTS: As of September 2021, the Pediatric AWG applied the new framework to 70 actionability topics representing 143 genes. Reports and scores are publicly available at www.clinicalgenome.org. CONCLUSION: The Pediatric AWG continues to curate gene-condition topics and build an evidence-based resource, supporting clinical communities and decision-makers with policy development on the return of SFs in pediatric populations.