The reckoning: The return of genomic results to 1444 participants across the eMERGE3 Network

PurposeThe goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants.MethodsRoR processes were developed and approved by each eMERGE institution’s internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant’s disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed.ResultsOf the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052).ConclusionThe real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.     

Participant choices for return of genomic results in the eMERGE Network

PurposeSecondary findings are typically offered in an all or none fashion when sequencing is used for clinical purposes. This study aims to describe the process of offering categorical and granular choices for results in a large research consortium.MethodsWithin the third phase of the electronic MEdical Records and GEnomics (eMERGE) Network, several sites implemented studies that allowed participants to choose the type of results they wanted to receive from a multigene sequencing panel. Sites were surveyed to capture the details of the implementation protocols and results of these choices.ResultsAcross the ten eMERGE sites, 4664 participants including adolescents and adults were offered some type of choice. Categories of choices offered and methods for selecting categories varied. Most participants (94.5%) chose to learn all genetic results, while 5.5% chose subsets of results. Several sites allowed participants to change their choices at various time points, and 0.5% of participants made changes.ConclusionOffering choices that include learning some results is important and should be a dynamic process to allow for changes in scientific knowledge, participant age group, and individual preference.     

Returning integrated genomic risk and clinical recommendations: The eMERGE study

PurposeAssessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.MethodsTo enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report and will assess uptake of care recommendations after return of results.ResultsGIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.ConclusionReturn of a novel report for communicating monogenic, polygenic, and family history-based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.     

Impact of returning unsolicited genomic results to nongenetic health care providers in the eMERGE III Network

PurposeAs genomic sequencing becomes more common, medically actionable secondary findings will increasingly be returned to health care providers (HCPs), who will be faced with managing the resulting patient care. These findings are generally unsolicited, ie, unrelated to the sequencing indication and/or ordered by another clinician.MethodsTo understand the impact of receiving unsolicited results, we interviewed HCPs who received genomic results for patients enrolled in the Electronic Medical Records and Genomics (eMERGE) Phase III Network, which returned results on >100 actionable genes to eMERGE participants and HCPs.ResultsIn total, 16 HCPs across 3 eMERGE sites were interviewed about their experience of receiving a positive (likely pathogenic or pathogenic), negative, or variant of uncertain significance result for a patient enrolled in eMERGE Phase III and about managing their patient on the basis of the result. Although unsolicited, HCPs felt responsible for managing the patient’s resulting medical care. HCPs indicated that clinical utility depended on the actionability of results, and whereas comfort levels varied, confidence was improved by the availability of subspecialist consults. HCPs were concerned about patient anxiety, insurability, and missing an actionable result in the electronic health record.ConclusionOur findings help inform best practices for return of unsolicited genomic screening findings in the future.     

Reanalysis of eMERGE phase III sequence variants in 10,500 participants and infrastructure to support the automated return of knowledge updates

PurposeThe clinical genomics knowledgebase is dynamic with variant classifications changing as newly identified cases, additional population data, and other evidence become available. This is a challenge for the clinical laboratory because of limited resource availability for variant reassessment.MethodsThroughout the Electronic Medical Records and Genomics phase III program, clinical sites associated with the Mass General Brigham/Broad sequencing center received automated, real-time notifications when reported variants were reclassified. In this study, we summarized the nature of these reclassifications and described the proactive reassessment framework we used for the Electronic Medical Records and Genomics program data set to identify variants most likely to undergo reclassification.ResultsReanalysis of 1855 variants led to the reclassification of 2% (n = 45) of variants, affecting 0.6% (n = 67) of participants. Of these reclassifications, 78% (n = 35) were high-impact changes affecting reportability, with 8 variants downgraded from likely pathogenic/pathogenic to variants of uncertain significance (VUS) and 27 variants upgraded from VUS to likely pathogenic/pathogenic. Most upgraded variants (67%) were initially classified as VUS–Favor Pathogenic, highlighting the benefit of VUS subcategorization. The most common reason for reclassification was new published case data and/or functional evidence.ConclusionOur results highlight the importance of periodic sequence variant reevaluation and the need for automated approaches to advance routine implementation of variant reevaluations in clinical practice.     

Attitudes of Canadian researchers toward the return to participants of incidental and targeted genomic findings obtained in a pediatric research setting

PurposeThe purpose of this study was to explore the attitudes of genomics researchers in a pediatric setting in the context of regulatory guidance recommending the disclosure of clinically significant research findings.MethodsA validated 32-item questionnaire was sent to 107 researchers with two large-scale projects (the Canadian Pediatric Cancer Genome Consortium and the Finding of Rare Genes Canada Consortium). We examined researchers’ attitudes toward obligations to offer genomic research results (including if the participant was deceased, a relative, or a child), influence of the certainty/severity of the condition on this obligation, and personal experiences.ResultsOf the 107 researchers, 74 (69%) responded. Researchers did not feel a strong responsibility to look for meaningful incidental results in the research genomic data set (n = 27, 37%). However, once identified, they felt participants had a strong right to receive them, irrespective of being incidental (n = 50, 68%) or primary targets (n = 64, 87%). There was a high degree of support for informing siblings of genomic results (n = 46, 62%), especially for treatable conditions (n = 56, 76%). Less than half of the participants indicated that their research ethics board required an offer of results (n = 34, 46%) or provided a detailed process (n = 16, 22%).ConclusionResearchers strongly support the offer of targeted and incidental genomic research results to participants. Greater regulatory guidance is needed for a consistent approach.Genet Med 2013:15(7):558–564     

Offering aggregate results to participants in genomic research: opportunities and challenges

Although issues involved in offering individual results to participants in genomic research have received considerable attention, communication of aggregate results has been the subject of relatively little ethical analysis. Offering participants aggregate results is typically assumed to be a good thing, and studies have found that a significant majority of biobank research participants, when asked about their interest in aggregate results, say that access to such information would be important. Even so, return of aggregate results remains a relatively uncommon practice. In this article, we explore the opportunities involved in communicating aggregate results to participants in genomic research, including affirming the value of research participation, informing participants about research being conducted based on broad consent for future unspecified research, educating participants and the public about the research process, and building trust in the research enterprise. We also explore some of the challenges, including the complex intersection between individual and aggregate results, as well as practical hurdles. We conclude by offering our preliminary recommendations concerning the provision of aggregate results and an agenda for much-needed future research.Genet Med 2012:14(4):490–496     

Increasing genomic literacy among adolescents

PurposeAdolescents increasingly need to be “genomics literate,” and may engage more with video educational formats than traditional written formats. We conducted a pilot study to assess and compare the impact of two modes of education about genome sequencing (GS) on adolescents’ genomic knowledge and genomic-related decisions.MethodsUsing an online survey, 43 adolescents ages 14–17 years were randomly assigned to watch a video or read a pamphlet about GS. Measures included pre- and postintervention assessment of genomic knowledge, perceived utility of these materials for decisions about participating in genetic research, interest in receiving GS results, and overall satisfaction with these materials. Analyses described results for all participants and compared results between intervention groups.ResultsSelf-reported genomic knowledge increased overall (p < 0.001). Postintervention knowledge about GS limitations was higher among video group than pamphlet group participants (p = 0.038). More video group than pamphlet group participants expressed satisfaction with the material’s understandability (45% vs. 29%) and suitability (91% vs. 76%). Interest in receiving personal GS results was significantly associated with being female (p = 0.01) and younger (14–15 years vs. 16–17 years) (p = 0.002).ConclusionA video format may be preferable for increasing genomic literacy among adolescents. Further research with adolescents is needed to better understand how gender and age may impact genomic decisions and preferences.     

Research participants in NGS studies want to know about incidental findings

Following the implementation of high-throughput sequencing legal and ethical issues are discussed intensively. The management of incidental findings (IFs) in a research setting have been investigated but there is a lack of literature concerning research participant''s perspective. The aim of this study was to investigate whether research participants want disclosure of IFs and what kind of IFs they want to know about. One hundred and twenty-seven research participants in a study of gastrointestinal polyps were informed about whole-exome sequencing and the risk of IFs. They were asked to decide whether they (A) wanted disclosure of IFs no matter whether the variants were associated with a non-treatable or non-preventable condition, (B) wanted disclosure of variants associated with treatable or preventable conditions or (C) wanted no disclosure at all. Participants who wanted disclosure of all the IFs (A) accounted for the majority (n=78), 45 of the participants only wanted disclosure of variants, which could lead to surveillance or treatment (B) and 4 participants did not want IFs to be disclosed at all (C). The study showed that almost all research participants wanted disclosure of at least some types of IFs.     

Managing incidental genomic findings: legal obligations of clinicians

PurposeClinical whole-exome and whole-genome sequencing will result in a broad range of incidental findings, but clinicians’ obligations to identify and disclose such findings are a matter of debate. We sought legal cases that could offer insights into clinicians’ legal liability.MethodsWe searched for cases in which incidental findings were related to the cause of action, using the search engines WestLaw, WestLaw Next, Lexis, and Lexis Advance.ResultsWe found no case law related to incidental findings from genetic testing but identified eight cases involving incidental findings in medical imaging. These cases suggest that clinicians may face liability for failing to disclose incidental findings that would have offered an opportunity for interventions to improve health outcome, if under the applicable standard of care, they fail to identify or appreciate the significance of the incidental finding or they negligently fail to notify other clinicians and/or the patient of the identified incidental finding. Other cases support liability for failure to refer appropriately to a clinician with greater expertise.ConclusionsClinicians may face liability if they fail to disclose incidental information that could inform interventions to improve health outcome; information lacking clinical actionability is likely to have less import.Genet Med 2013:15(8):624–629     

Actionable exomic incidental findings in 6503 participants: challenges of variant classification

Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.Whole genome and exome tests are increasingly applied in clinical medicine. The American College of Medical Genetics and Genomics (ACMG) has recommended identification and return of incidental findings (IFs) from a minimum set of 56 actionable genes when a genomic test is performed (Green et al. 2013), unless patients opt out (American College of Medical Genetics and Genomics 2014). Some clinical laboratories return a broader set of IFs. However, there are limited data on frequency of such actionable pathogenic variants, and a standardized level of evidence for determining the pathogenicity of these variants has not been identified. We previously reviewed the primary literature for possible actionable, high penetrance pathogenic single-nucleotide variants (SNVs) in 114 genes in 500 European- and 500 African-ancestry participants randomly selected from the NHLBI Exome Sequencing Project (ESP) and posted on the exome variant server (EVS; http://evs.gs.washington.edu/EVS/) (Dorschner et al. 2013). We now extend these analyses to the 5503 additional participants in the ESP and revise from 114 to 112 genes associated with medically actionable genetic disorders that may remain undiagnosed in adults. These data give a more precise estimate of the frequency of such actionable findings in individuals of European or African ancestry. Such an estimate will allow a better understanding of the implications, including cost, of recommendations to return IFs from genomic tests.Lack of consensus criteria for pathogenicity classification of variants is an ongoing issue in genomic medicine. It is common for clinicians to disagree with classifications from clinical laboratories. Therefore, we compare the results of our variant classification system to the classification of these variants by different clinical and research laboratories. A goal of these analyses is to investigate consistency in variant classification using criteria from different classification systems and to understand the features of these approaches that lead to discrepant pathogenicity assignments.     

Genomic sequencing identifies secondary findings in a cohort of parent study participants

PurposeClinically relevant secondary variants were identified in parents enrolled with a child with developmental delay and intellectual disability.MethodsExome/genome sequencing and analysis of 789 “unaffected” parents was performed.ResultsPathogenic/likely pathogenic variants were identified in 21 genes within 25 individuals (3.2%), with 11 (1.4%) participants harboring variation in a gene defined as clinically actionable by the American College of Medical Genetics and Genomics. These 25 individuals self-reported either relevant clinical diagnoses (5); relevant family history or symptoms (13); or no relevant family history, symptoms, or clinical diagnoses (7). A limited carrier screen was performed yielding 15 variants in 48 (6.1%) parents. Parents were also analyzed as mate pairs (n = 365) to identify cases in which both parents were carriers for the same recessive disease, yielding three such cases (0.8%), two of which had children with the relevant recessive disease. Four participants had two findings (one carrier and one noncarrier variant). In total, 71 of the 789 enrolled parents (9.0%) received secondary findings.ConclusionWe provide an overview of the rates and types of clinically relevant secondary findings, which may be useful in the design and implementation of research and clinical sequencing efforts to identify such findings.     

Informed consent for return of incidental findings in genomic research

PurposeResearchers face the dilemma of how to obtain consent for return of incidental findings from genomic research. We surveyed and interviewed investigators and study participants, with the goal of providing suggestions for how to shape the consent process.MethodsWe performed an online survey of 254 US genetic researchers identified through the NIH RePORTER database, abstracts from the 2011 American Society of Human Genetics meeting, and qualitative semi-structured interviews with 28 genomic researchers and 20 research participants.ResultsMost researchers and participants endorsed disclosure of a wide range of information about return of incidental findings, including risks, benefits, impact on family members, data security, and procedures, for return of results in the event of death or incapacity and for recontact. However, most researchers were willing to devote 30 min or less to this process and expressed concerns that disclosed information would overwhelm participants, a concern shared by many participants themselves.ConclusionThere is a disjunction between the views of investigators and participants about the amount of information that should be disclosed and the practical realities of the research setting, including the time available for consent discussions. This strongly suggests the need for innovative approaches to the informed consent process.     

The rate of secondary genomic findings in the Saudi population

Secondary findings (SF) are defined as genetic conditions discovered unintentionally during an evaluation of raw data for another disease. We aimed to identify the rate of secondary genetic findings in the Saudi population in the 59 genes of the American College of Medical Genetics and Genomics (ACMG) list. In our study, the raw data of 1254 individuals, generated from exome sequencing for clinical purposes, were studied. Variants detected in the 59 genes on the ACMG list of secondary findings were investigated. Pathogenicity classifications were assigned to those variants based on the ACMG scoring system. We identified 2409 variants in the 59 gene list, 45 variants were classified as pathogenic/likely pathogenic variants according to the ACMG classification. The LDLR gene had the greatest number of pathogenic/likely pathogenic variants 12%. Cardiovascular genetic diseases had the highest frequency of disorders detected as secondary findings. In this study, the overall rate of positive cases identified with secondary findings in the Saudi population was 8%. The different in our current study and the previous studies in Saudi Arabia can be explained by the differences between the sequencing method, the criteria used for variant classification, the availability of newer evidence at the time of the publication, and the fact that we identified Saudi novel variants never reported in other populations.     

The cost-effectiveness of returning incidental findings from next-generation genomic sequencing

PurposeThe American College of Medical Genetics and Genomics (ACMG) recommended that clinical laboratories performing next-generation sequencing analyze and return pathogenic variants for 56 specific genes it considered medically actionable. Our objective was to evaluate the clinical and economic impact of returning these results.MethodsWe developed a decision-analytic policy model to project the quality-adjusted life-years and lifetime costs associated with returning ACMG-recommended incidental findings in three hypothetical cohorts of 10,000 patients.ResultsReturning incidental findings to cardiomyopathy patients, colorectal cancer patients, or healthy individuals would increase costs by $896,000, $2.9 million, and $3.9 million, respectively, and would increase quality-adjusted life-years by 20, 25.4, and 67 years, respectively, for incremental cost-effectiveness ratios of $44,800, $115,020, and $58,600, respectively. In probabilistic analyses, returning incidental findings cost less than $100,000/quality-adjusted life-year gained in 85, 28, and 91%, respectively, of simulations. Assuming next-generation sequencing costs $500, the incremental cost-effectiveness ratio for primary screening of healthy individuals was $133,400 (<$100,000/quality-adjusted life-year gained in 10% of simulations). Results were sensitive to the cohort age and assumptions about gene penetrance.ConclusionReturning incidental findings is likely cost-effective for certain patient populations. Screening of generally healthy individuals is likely not cost-effective based on current data, unless next-generation sequencing costs less than $500.Genet Med 17 7, 587–595.     

Exploring differential attrition rates among system of care evaluation participants

The purpose of the present study is to investigate differential attrition rates in terms of both demographic characteristics and initial levels of child functioning of participants in North Carolina's system of care evaluation. Participants included 303 families (78 dropped out of the study, a 26% attrition rate). Families dropped out of the evaluation for three main reasons: refusal to participate, moving, or inability to contact the family. The majority of families who dropped out of the study did so after completing only the baseline interview. Differential attrition did not exist in terms of demographic characteristics, but there was some support for possible differential attrition indicated by initial levels of child functioning in some cases. Additionally, higher parental education level predicted longer participation in longitudinal evaluation. Recommendations and implications for applied research are offered. © 2004 Wiley Periodicals, Inc. J Comm Psychol 32: 167–176, 2004.     

Making sense of genetic risk: A qualitative focus-group study of healthy participants in genomic research

Objective

It is well known that research participants want to receive genetic risk information that is about high risks, serious diseases and potential preventive measures. The aim of this study was to explore, by qualitative means, something less well known: how do healthy research participants themselves make sense of genetic risk information?