Addressing underrepresentation in genomics research through community engagement.

The vision of the American Society of Human Genetics (ASHG) is that people everywhere will realize the benefits of human genetics and genomics. Implicit in that vision is the importance of ensuring that the benefits of human genetics and genomics research are realized in ways that minimize harms and maximize benefits, a goal that can only be achieved through focused efforts to address health inequities and increase the representation of underrepresented communities in genetics and genomics research. This guidance is intended to advance community engagement as an approach that can be used across the research lifecycle. Community engagement uniquely offers researchers in human genetics and genomics an opportunity to pursue that vision successfully, including by addressing underrepresentation in genomics research.

Developing pathways for community-led research with big data: a content analysis of stakeholder interviews.

BACKGROUND: Big data (BD) informs nearly every aspect of our lives and, in health research, is the foundation for basic discovery and its tailored translation into healthcare. Yet, as new data resources and citizen/patient-led science movements offer sites of innovation, segments of the population with the lowest health status are least likely to engage in BD research either as intentional data contributors or as 'citizen/community scientists'. Progress is being made to include a more diverse spectrum of research participants in datasets and to encourage inclusive and collaborative engagement in research through community-based participatory research approaches, citizen/patient-led research pilots and incremental research policy changes. However, additional evidence-based policies are needed at the organisational, community and national levels to strengthen capacity-building and widespread adoption of these approaches to ensure that the translation of research is effectively used to improve health and health equity. The aims of this study are to capture uses of BD ('use cases') from the perspectives of community leaders and to identify needs and barriers for enabling community-led BD science. METHODS: We conducted a qualitative content analysis of semi-structured key informant interviews with 16 community leaders. RESULTS: Based on our analysis findings, we developed a BD Engagement Model illustrating the pathways and various forces for and against community engagement in BD research. CONCLUSIONS: The goal of our Model is to promote concrete, transparent dialogue between communities and researchers about barriers and facilitators of authentic community-engaged BD research. Findings from this study will inform the subsequent phases of a multi-phased project with the ultimate aims of organising fundable frameworks and identifying policy options to support BD projects within community settings.

Analysis of state laws on informed consent for clinical genetic testing in the era of genomic sequencing.

This article assesses the adequacy of informed consent to clinical genetic testing laws based on an examination of 15 states with institutions that had been involved in a National Institutes of Health-supported Clinical Sequencing Exploratory Research Consortium project. We identified relevant statutory provisions through a legal search engine and included statutes that describe the informed consent requirements for clinical genetic testing and/or the protections for genetic material, information, or data. We found that statutory definitions were often limited in problematic ways, such as focusing only on variants known to be associated with disease or negative health effects or associated with asymptomatic disease. Some statutes required complex levels of detail if applied to genomic technologies and set confusing disclosure standards for current use and future access. Others had exceptions from informed consent requirements for future research use, limited requirements for the destruction of specimens as opposed to derived data, or linked key definitional components to the evolving concept of "identifiability." Further reform and research are needed to ensure that state law protections advance as rapidly as the science they aspire to enable.

Attitudes of genetics professionals toward the return of incidental results from exome and whole-genome sequencing.

Professional recommendations for the return of results from exome and whole-genome sequencing (ES/WGS) have been controversial. The lack of clear guidance about whether and, if so, how to return ES/WGS incidental results limits the extent to which individuals and families might benefit from ES/WGS. The perspectives of genetics professionals, particularly those at the forefront of using ES/WGS in clinics, are largely unknown. Data on stakeholder perspectives could help clarify how to weigh expert positions and recommendations. We conducted an online survey of 9,857 genetics professionals to learn their attitudes on the return of incidental results from ES/WGS and the recent American College of Medical Genetic and Genomics Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. Of the 847 respondents, 760 completed the survey. The overwhelming majority of respondents thought that incidental ES/WGS results should be offered to adult patients (85%), healthy adults (75%), and the parents of a child with a medical condition (74%). The majority thought that incidental results about adult-onset conditions (62%) and carrier status (62%) should be offered to the parents of a child with a medical condition. About half thought that offered results should not be limited to those deemed clinically actionable. The vast majority (81%) thought that individual preferences should guide return. Genetics professionals' perspectives on the return of ES/WGS results differed substantially from current recommendations, underscoring the need to establish clear purpose for recommendations on the return of incidental ES/WGS results as professional societies grapple with developing and updating recommendations.

Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.

Exome sequencing (ES) is rapidly being deployed for use in clinical settings despite limited empirical data about the number and types of incidental results (with potential clinical utility) that could be offered for return to an individual. We analyzed deidentified ES data from 6,517 participants (2,204 African Americans and 4,313 European Americans) from the National Heart, Lung, and Blood Institute Exome Sequencing Project. We characterized the frequencies of pathogenic alleles in genes underlying Mendelian conditions commonly assessed by newborn-screening (NBS, n = 39) programs, genes associated with age-related macular degeneration (ARMD, n = 17), and genes known to influence drug response (PGx, n = 14). From these 70 genes, we identified 10,789 variants and curated them by manual review of OMIM, HGMD, locus-specific databases, or primary literature to a total of 399 validated pathogenic variants. The mean number of risk alleles per individual was 15.3. Every individual had at least five known PGx alleles, 99% of individuals had at least one ARMD risk allele, and 45% of individuals were carriers for at least one pathogenic NBS allele. The carrier burden for severe recessive childhood disorders was 0.57. Our results demonstrate that risk alleles of potential clinical utility for both Mendelian and complex traits are detectable in every individual. These findings highlight the necessity of developing guidelines and policies that consider the return of results to all individuals and underscore the need to develop innovative approaches and tools that enable individuals to exercise their choice about the return of incidental results.

My46: a Web-based tool for self-guided management of genomic test results in research and clinical settings.

A major challenge to implementing precision medicine is the need for an efficient and cost-effective strategy for returning individual genomic test results that is easily scalable and can be incorporated into multiple models of clinical practice. My46 is a Web-based tool for managing the return of genetic results that was designed and developed to support a wide range of approaches to disclosing results, ranging from traditional face-to-face disclosure to self-guided models. My46 has five key functions: set and modify results-return preferences, return results, educate, manage the return of results, and assess the return of results. These key functions are supported by six distinct modules and a suite of features that enhance the user experience, ease site navigation, facilitate knowledge sharing, and enable results-return tracking. My46 is a potentially effective solution for returning results and supports current trends toward shared decision making between patients and providers and patient-driven health management.Genet Med 19 4, 467-475.

Anthropologists' views on race, ancestry, and genetics.

Controversies over race conceptualizations have been ongoing for centuries and have been shaped, in part, by anthropologists. OBJECTIVE: To assess anthropologists' views on race, genetics, and ancestry. METHODS: In 2012 a broad national survey of anthropologists examined prevailing views on race, ancestry, and genetics. RESULTS: Results demonstrate consensus that there are no human biological races and recognition that race exists as lived social experiences that can have important effects on health. DISCUSSION: Racial privilege affects anthropologists' views on race, underscoring the importance that anthropologists be vigilant of biases in the profession and practice. Anthropologists must mitigate racial biases in society wherever they might be lurking and quash any sociopolitical attempts to normalize or promote racist rhetoric, sentiment, and behavior.

Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features.

PURPOSE: The pace of Mendelian gene discovery is slowed by the "n-of-1 problem"-the difficulty of establishing the causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier, but it is often impeded by lack of a convenient or widely available way to share data on candidate variants/genes among families, clinicians, and researchers. METHODS: Social networking among families, clinicians, and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes. RESULTS: De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features. CONCLUSION: Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with nonspecific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP; http://uwcmg.org/#/family). Design and development of MyGene2 (http://www.mygene2.org), a Web-based tool that enables families, clinicians, and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP, is under way.Genet Med 18 8, 788-795.

Use of metaphors about exome and whole genome sequencing.

Clinical and research uses of exome and whole genome sequencing (ES/WGS) are growing rapidly. An enhanced understanding of how individuals conceptualize and communicate about sequencing results is needed to ensure effective, mutual exchange of information between care providers and patients and between researchers and participants. Focus groups and interviews participants were recruited to discuss their attitudes and preferences for receiving hypothetical results from ES/WGS. African Americans were intentionally oversampled. We qualitatively analyzed participants' speech to identify unsolicited metaphorical language pertaining to genes and health, and grouped these occurrences into metaphorical concepts. Participants compared genetic information to physical objects including tools, weapons, contents of boxes, and formal documents or reports. These metaphorical concepts centered on several key themes, including locus of control; containment versus release of information; and desirability, usability, interpretability, and ownership of genetic results. Metaphorical language is often used intentionally or unintentionally in discussions about receiving results from ES/WGS in both clinical and research settings. Awareness of the use of metaphorical language and attention to its varied meanings facilitates effective communication about return of ES/WGS results. In turn, both should foster shared and informed decision-making and improve the translation of genetic information by clinicians and researchers.

"We don't know her history, her background": adoptive parents' perspectives on whole genome sequencing results.

Exome sequencing and whole genome sequencing (ES/WGS) can provide parents with a wide range of genetic information about their children, and adoptive parents may have unique issues to consider regarding possible access to this information. The few papers published on adoption and genetics have focused on targeted genetic testing of children in the pre-adoption context. There are no data on adoptive parents' perspectives about pediatric ES/WGS, including their preferences about different kinds of results, and the potential benefits and risks of receiving results. To explore these issues, we conducted four exploratory focus groups with adoptive parents (N = 26). The majority lacked information about their children's biological family health history and ancestry, and many viewed WGS results as a way to fill in these gaps in knowledge. Some expressed concerns about protecting their children's future privacy and autonomy, but at the same time stated that WGS results could possibly help them be proactive about their children's health. A few parents expressed concerns about the risks of WGS in a pre-adoption context, specifically about decreasing a child's chance of adoption. These results suggest that issues surrounding genetic information in the post-adoption and ES/WGS contexts need to be considered, as well as concerns about risks in the pre-adoption context. A critical challenge for ES/WGS in the context of adoption will be balancing the right to know different kinds of genetic information with the right not to know. Specific guidance for geneticists and genetic counselors may be needed to maximize benefits of WGS while minimizing harms and prohibiting misuse of the information in the adoption process.

Attitudes of non-African American focus group participants toward return of results from exome and whole genome sequencing.

Exome sequencing and whole genome sequencing (ES/WGS) present individuals with the opportunity to benefit from a broad scope of genetic results of clinical and personal utility. Yet, it is unclear which genetic results people want to receive (i.e., what type of genetic information they want to learn about themselves) or conversely not receive, and how they want to receive or manage results over time. Very little is known about whether and how attitudes toward receiving individual results from ES/WGS vary among racial/ethnic populations. We conducted 13 focus groups with a racially and ethnically diverse parent population (n = 76) to investigate attitudes toward return of individual results from WGS. We report on our findings for non-African American (non-AA) participants. Non-AA participants were primarily interested in genetic results on which they could act or "do something about." They defined "actionability" broadly to include individual medical treatment and disease prevention. The ability to plan for the future was both a motivation for and an expected benefit of receiving results. Their concerns focused on the meaning of results, specifically the potential inaccuracy and uncertainty of results. Non-AA participants expected healthcare providers to be involved in results management by helping them interpret results in the context of their own health and by providing counseling support. We compare and contrast these themes with those we previously reported from our analysis of African American (AA) perspectives to highlight the importance of varying preferences for results, characterize the central role of temporal orientation in framing expectations about the possibility of receiving ES/WGS results, and identify potential avenues by which genomic healthcare disparities may be inadvertently perpetuated.

Self-guided management of exome and whole-genome sequencing results: changing the results return model.

Researchers and clinicians face the practical and ethical challenge of if and how to offer for return the wide and varied scope of results available from individual exome sequencing and whole-genome sequencing. We argue that rather than viewing individual exome sequencing and whole-genome sequencing as a test for which results need to be "returned," that the technology should instead be framed as a dynamic resource of information from which results should be "managed" over the lifetime of an individual. We further suggest that individual exome sequencing and whole-genome sequencing results management is optimized using a self-guided approach that enables individuals to self-select among results offered for return in a convenient, confidential, personalized context that is responsive to their value system. This approach respects autonomy, allows individuals to maximize potential benefits of genomic information (beneficence) and minimize potential harms (nonmaleficence), and also preserves their right to an open future to the extent they desire or think is appropriate. We describe key challenges and advantages of such a self-guided management system and offer guidance on implementation using an information systems approach.

Attitudes of African Americans toward return of results from exome and whole genome sequencing.

Exome sequencing and whole genome sequencing (ES/WGS) present patients and research participants with the opportunity to benefit from a broad scope of genetic results of clinical and personal utility. Yet, this potential for benefit also risks disenfranchising populations such as African Americans (AAs) that are already underrepresented in genetic research and utilize genetic tests at lower rates than other populations. Understanding a diverse range of perspectives on consenting for ES/WGS and receiving ES/WGS results is necessary to ensure parity in genomic health care and research. We conducted a series of 13 focus groups (n = 76) to investigate if and how attitudes toward participation in ES/WGS research and return of results from ES/WGS differ between self-described AAs and non-AAs. The majority of both AAs and non-AAs were willing to participate in WGS studies and receive individual genetic results, but the fraction not interested in either was higher in AAs. This is due in part to different expectations of health benefits from ES/WGS and how results should be managed. Our results underscore the need to develop and test culturally tailored strategies for returning ES/WGS results to AAs.

Practices and policies of clinical exome sequencing providers: analysis and implications.

Exome and whole genome sequencing (ES/WGS) offer potential advantages over traditional approaches to diagnostic genetic testing. Consequently, use of ES/WGS in clinical settings is rapidly becoming commonplace. Yet there are myriad moral, ethical, and perhaps legal implications attached to the use of ES and health care professionals and institutions will need to consider these implications in the context of the varied practices and policies of ES service providers. We developed "core elements" of content and procedures for informed consent, data sharing, and results management and a quantitative scale to assess the extent to which research protocols met the standards established by these core elements. We then used these tools to evaluate the practices and policies of each of the 6 U.S. CLIA-certified labs offering clinical ES. Approaches toward informed consent, data sharing, and results return vary widely among ES providers as do the overall potential merits and disadvantages of each, and more importantly, the balance between the two.

Translational Research and Communities.

Impactful translational research requires new approaches to computational analysis and bioethics, both of which have been advanced by adoption of community-engagement strategies. Community knowledge and experience will hone data collection, research, and insights and accelerate the impact of derived translational applications to improve individual health, medical decision-making, and public health policy. In the context of translational research with big health data, meaningful community-researcher engagement will require developing and deploying coengagement tools across the research life cycle and developing approaches for novel coproduction.

Guidelines for genetic ancestry inference created through roundtable discussions.

The use of genetic and genomic technology to infer ancestry is commonplace in a variety of contexts, particularly in biomedical research and for direct-to-consumer genetic testing. In 2013 and 2015, two roundtables engaged a diverse group of stakeholders toward the development of guidelines for inferring genetic ancestry in academia and industry. This report shares the stakeholder groups' work and provides an analysis of, commentary on, and views from the groundbreaking and sustained dialogue. We describe the engagement processes and the stakeholder groups' resulting statements and proposed guidelines. The guidelines focus on five key areas: application of genetic ancestry inference, assumptions and confidence/laboratory and statistical methods, terminology and population identifiers, impact on individuals and groups, and communication or translation of genetic ancestry inferences. We delineate the terms and limitations of the guidelines and discuss their critical role in advancing the development and implementation of best practices for inferring genetic ancestry and reporting the results. These efforts should inform both governmental regulation and self-regulation.

Informed consent for whole genome sequencing: a qualitative analysis of participant expectations and perceptions of risks, benefits, and harms.

Scientific evidence on the extent to which ethical concerns about privacy, confidentiality, and return of results for whole genome sequencing (WGS) are effectively conveyed by informed consent (IC) is lacking. The aim of this study was to learn, via qualitative interviews, about participant expectations and perceptions of risks, benefits, and harms of WGS. Participants in two families with Miller syndrome consented for WGS were interviewed about their experiences of the IC process and their perceptions of risks, benefits, and harms of WGS. Interviews were transcribed and analyzed for common themes. IC documents are included in the Supplementary Materials. Participants expressed minimal concerns about privacy and confidentiality with regard to both their participation and sharing of their WGS data in restricted access databases. Participants expressed strong preferences about how results should be returned, requesting both flexibility of the results return process and options for the types of results to be returned. Participant concerns about risks to privacy and confidentiality from broad sharing of WGS data are likely to be strongly influenced by social and medical context. In these families with a rare Mendelian syndrome, the perceived benefits of participation strongly trumped concerns about risks. Individual preferences, for results return, even within a family, varied widely. This underscores the need to develop a framework for results return that allows explicitly for participant preferences and enables modifications to preferences over time. Web-based tools that facilitate participant management of their individual research results could accommodate such a framework.

Assessing Vietnamese American patient perspectives on population genetic testing in primary care: A community-engaged approach.

Achieving health equity in precision medicine remains a critical challenge because of the continued underrepresentation of non-white populations in research and barriers to genetic services. The goal of this study was to explore Vietnamese American (VA) participant views toward incorporating genetics in routine healthcare to better serve the local VA community within an integrated health system offering primary care-based population genetic testing to adults for conditions that could be prevented or mitigated when detected early. We conducted semi-structured interviews from August-September 2021, with 22 individuals receiving primary care who self-identified as Vietnamese or VA, and employed rapid qualitative analysis (RQA) to identify key concepts. Community research team members participated in study design, data collection, RQA, and reporting. Findings from the interviews revealed that several participant perceived challenges to genetic testing, which included lack of information, fear of results impact, cost, and privacy concerns. Participants suggested various ways to overcome some of these barriers, such as decreasing the cost of testing, receiving information from a trusted physician, using preferred education strategies in the community, and having convenient access to testing. Study participants also shared a variety of trusted sources they would seek out for advice on genetic testing. This study with VAs identified barriers, facilitators, and messengers to offering genetic testing in a local healthcare context and demonstrated how community-engaged research coupled with RQA is a promising approach for healthcare institutions as they identify needs and tailor strategies for implementing population genetic screening programs in local ethnic communities.