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Competing Interests: Conflict of Interest C.J.Z.-M. is a director of a cytogenomics testing laboratory that offers cancer diagnostic testing. M.A. is a director of a molecular testing laboratory that offers carrier screening. K.B. is a genetic counselor of a molecular testing laboratory that offers carrier screening. F.Q.-R. is a director of a cytogenomics testing laboratory that offers cancer diagnostic testing. M.V. is a director of a molecular testing laboratory that offers carrier screening and sponsored panel testing. All other authors declare no conflicts of interest.

Purpose: Assessing 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., Methods: To 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., Results: GIRAs 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., Conclusion: Return 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., Competing Interests: Conflict of Interest N.S.A.-H. is an employee and equity holder of 23andMe; serves as a scientific advisory board member for Allelica, Inc; received personal fees from Genentech Inc, Allelica Inc, and 23andMe; received research funding from Akcea Therapeutics; and was previously employed by Regeneron Pharmaceuticals. T.W. has grant funding from Gilead Sciences, Inc. L.O. and T.R.-B are founders of a company developing MeTree. T.S., E.D.E., and E.H. are employees and stockholders of Invitae Corporation. E.M.M. has been a consultant for Avidity Bioscience, Amgen Inc, AstraZeneca, Cytokinetics, Invitae Corporation, Janssen Pharmaceuticals, Pfizer Inc, PepGen Inc, Tenaya Therapeutics, and Stealth BioTherapeutics Inc; she is also the founder of Ikaika Therapeutics. E.E.K. received personal fees from Illumina Inc, 23andMe, and Regeneron Pharmaceuticals and serves as a scientific advisory board member for Encompass Bioscience, Foresite Labs, and Galateo Bio. B.K. is an advisory board member and stockholder of Genome Medical. M.S. is a member of the Institutional Review Board of the All of Us Research Program. E.F.P. is a paid consultant for Allecia Inc. J.F.P. is a paid consultant for Natera Inc. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of Interest Funding and support listed in this section did not support the development of this document unless included in the acknowledgments section. M.K.T., M.C., P.R.G., and A.R.S. all serve as directors in clinical laboratories that perform a breadth of genetic and genomic analyses on a fee-for-service basis. D.R.S. is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Rockville, MD, and also performs contract clinical telehealth services for Genome Medical, Inc in accordance with relevant National Cancer Institute ethics policies. All other authors declare no conflicts of interest.

Objective: We currently rely on probands to communicate genetic testing results and health risks within a family to stimulate preventive behaviors, such as cascade testing. Rates of guidelines-based cascade testing are low, possibly due to low frequency or non-urgent communication of risk among family members. Understanding what is being communicated and why may help improve interventions that increase communication and rates of cascade testing., Methods: Participants (n = 189) who were to receive both positive and negative colorectal cancer (CRC) sequencing results completed surveys on family communication, family functioning, impact of cancer in the family, and future communication of risk and were participants in eMERGE3. Questions were taken from existing surveys and administered electronically using email and a web driven tool., Results: Common family member targets of CRC risk communication, before results were received, were mothers and fathers, then sisters and grandchildren and finally, children and brothers. A communication impact score of 0.66 (sd = 0.83) indicated low-to-moderate communication impact. Age and education were significantly associated with frequency of familial communication, but not on the cancer-related impact of familial communication., Conclusions: There is infrequent communication about cancer risk from probands to family members., Practice Implications: These results demonstrate an opportunity to help families improve communication., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Clinical exome sequencing (CES) provides the advantage of assessing genetic variation across the human exome compared to a traditional stepwise diagnostic approach or multi-gene panels. Comparative effectiveness research methods offer an approach to better understand the patient-centered and economic outcomes of CES., Purpose: To evaluate CES compared to usual care (UC) in the diagnostic work-up of inherited colorectal cancer/polyposis (CRCP) in a randomized controlled trial (RCT)., Methods: The primary outcome was clinical sensitivity for the diagnosis of inherited CRCP; secondary outcomes included psychosocial outcomes, family communication, and healthcare resource utilization. Participants were surveyed 2 and 4 weeks after results return and at 3-month intervals up to 1 year., Results: Evolving outcome measures and standard of care presented critical challenges. The majority of participants in the UC arm received multi-gene panels [94.73%]. Rates of genetic findings supporting the diagnosis of hereditary CRCP were 7.5% [7/93] vs. 5.4% [5/93] in the CES and UC arms, respectively (P = 0.28). Differences in privacy concerns after receiving CRCP results were identified (0.88 in UC vs 0.38 in CES, P = 0.05); however, healthcare resource utilization, family communication and psychosocial outcomes were similar between the two arms. More participants with positive results (17.7%) intended to change their life insurance 1  month after the first return visit compared to participants returned a variant of uncertain significance (9.1%) or negative result (4.8%) (P = 0.09)., Conclusion: Our results suggest that CES provides similar clinical benefits to multi-gene panels in the diagnosis of hereditary CRCP., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Laboratory-generated genomic test reports are used to convey complex, and frequently multivariant or uncertain, information about disease risk to medical genetics professionals as well as to nonspecialist clinicians, patients, and family members. However, few guidelines exist to guide the content and format of genomic test reports, and little is known about variation in current reporting practices., Methods: We conducted a structured content analysis of hereditary cancer gene panel test reports obtained from 16 United States-based CLIA-certified laboratories, including reports describing a variant of uncertain significance (VUS) only and reports with both a VUS and pathogenic or likely pathogenic (P/LP) test result., Results: Report content and format varied widely across laboratories and between VUS and VUS + P/LP reports from the same laboratory, with regard to the inclusion and visual prominence of key content as well as in terms of overall length and readability., Conclusion: Test report heterogeneity is likely to reflect both the lack of comprehensive reporting guidelines and disagreements between laboratories about the salience of specific types of information to test interpretation and use. Future research should explore the impact of reporting differences on clinician interpretation and shared decision making.

Purpose: Concerns about patient safety and the potential for medical error are largely unexplored for genetic testing, despite the expansion of test use. In this preliminary qualitative study, we sought the views of genetics professionals about error and patient safety concerns in genomic medicine and factors that might mitigate them., Methods: Twelve semistructured interviews with experienced genetics professionals were conducted. Transcripts were analyzed using selective coding for issues related to error definition, mitigation, and communication. Additional thematic analysis captured themes across content categories., Results: Key informants suggested that the potential for adverse events exists in all phases of genetic testing, from ordering to analysis, interpretation, and follow-up. A perceived contributor was lack of physician knowledge about genetics, resulting in errors in test ordering and interpretation. The limitations and uncertainty inherent to rapidly evolving technology were also seen as contributing factors. Strategies to prevent errors included physician education, availability of genetic experts for consultation, and enhanced communication such as improved test reports and electronic decision support., Conclusion: Genetic testing poses concerns for patient safety due to errors and the limitations of current tests. As genomic tests are integrated into medical care, anticipating and addressing patient safety concerns identified by these key informants will be crucial.Genet Med 18 11, 1136-1142., Competing Interests: The authors declare no other conflicts of interest.

Whole exome and whole genome sequencing are applications of next generation sequencing transforming clinical care, but there is little evidence whether these tests improve patient outcomes or if they are cost effective compared to current standard of care. These gaps in knowledge can be addressed by comparative effectiveness and patient-centered outcomes research. We designed a randomized controlled trial that incorporates these research methods to evaluate whole exome sequencing compared to usual care in patients being evaluated for hereditary colorectal cancer and polyposis syndromes. Approximately 220 patients will be randomized and followed for 12 months after return of genomic findings. Patients will receive findings associated with colorectal cancer in a first return of results visit, and findings not associated with colorectal cancer (incidental findings) during a second return of results visit. The primary outcome is efficacy to detect mutations associated with these syndromes; secondary outcomes include psychosocial impact, cost-effectiveness and comparative costs. The secondary outcomes will be obtained via surveys before and after each return visit. The expected challenges in conducting this randomized controlled trial include the relatively low prevalence of genetic disease, difficult interpretation of some genetic variants, and uncertainty about which incidental findings should be returned to patients. The approaches utilized in this study may help guide other investigators in clinical genomics to identify useful outcome measures and strategies to address comparative effectiveness questions about the clinical implementation of genomic sequencing in clinical care., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Little is known about the factors that influence patients' preferences for the return of incidental findings from genome sequencing. This study identified attributes of incidental findings that were important to patients and developed a discrete-choice experiment instrument to quantify patient preferences., Methods: An initial set of key attributes and attribute levels was developed from a literature review and in consultation with experts. The attributes' salience and communication were refined using focus group methodology (n = 12) and cognitive interviews (n = 6) with patients who had received conventional genetic testing for familial colorectal cancer or polyposis syndromes. The attributes and levels used in the hypothetical choices presented to participants were identified using validated experimental design techniques., Results: The final discrete-choice experiment instrument incorporates the following attributes and levels: lifetime risk of disease (5, 40, 70%); disease treatability (medical, lifestyle, none); disease severity (mild, moderate, severe); carrier status (yes, no); drug response likelihood (high, moderate, none); and test cost ($250, $425, $1,000, $1,900)., Conclusion: Patient preferences for incidental genomic findings are likely influenced by a complex set of diverse attributes. Quantification of patient preferences can inform patient-provider communication by highlighting the attributes of incidental findings that matter most to patients and warrant further discussion.

Integrating genomic information into clinical care and the electronic health record can facilitate personalized medicine through genetically guided clinical decision support. Stakeholder involvement is critical to the success of these implementation efforts. Prior work on implementation of clinical information systems provides broad guidance to inform effective engagement strategies. We add to this evidence-based recommendations that are specific to issues at the intersection of genomics and the electronic health record. We describe stakeholder engagement strategies employed by the Electronic Medical Records and Genomics Network, a national consortium of US research institutions funded by the National Human Genome Research Institute to develop, disseminate, and apply approaches that combine genomic and electronic health record data. Through select examples drawn from sites of the Electronic Medical Records and Genomics Network, we illustrate a continuum of engagement strategies to inform genomic integration into commercial and homegrown electronic health records across a range of health-care settings. We frame engagement as activities to consult, involve, and partner with key stakeholder groups throughout specific phases of health information technology implementation. Our aim is to provide insights into engagement strategies to guide genomic integration based on our unique network experiences and lessons learned within the broader context of implementation research in biomedical informatics. On the basis of our collective experience, we describe key stakeholder practices, challenges, and considerations for successful genomic integration to support personalized medicine.

Purpose: Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors., Methods: The Electronic Medical Records and Genomics (eMERGE) Network, which includes five biorepositories conducting genome-wide association studies, convened a return of results oversight committee to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision making., Results: Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The return of results oversight committee identified two sex chromosomal anomalies, Klinefelter syndrome and Turner syndrome, as well as homozygosity for factor V Leiden, as findings that could warrant reporting. Views about returning findings of HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of electronic medical records suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site)., Conclusion: The eMERGE experience reveals the complexity of return of results decision making and provides a potential deliberative model for adoption in other collaborative contexts.

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.

Purpose: Sharing study data within the research community generates tension between two important goods: promoting scientific goals and protecting the privacy interests of study participants. This study was designed to explore the perceptions, beliefs, and attitudes of research participants and possible future participants regarding genome-wide association studies and repository-based research., Methods: Focus group sessions with (1) current research participants, (2) surrogate decision-makers, and (3) three age-defined cohorts (18-34 years, 35-50, >50)., Results: Participants expressed a variety of opinions about the acceptability of wide sharing of genetic and phenotypic information for research purposes through large, publicly accessible data repositories. Most believed that making de-identified study data available to the research community is a social good that should be pursued. Privacy and confidentiality concerns were common, although they would not necessarily preclude participation. Many participants voiced reservations about sharing data with for-profit organizations., Conclusions: Trust is central in participants' views regarding data sharing. Further research is needed to develop governance models that enact the values of stewardship.