Research biobank participants attitudes towards genetic exceptionalism and health record confidentiality.

Understanding attitudes towards genetic exceptionalism and confidentiality is important in guiding policies regarding special protections for genetic/genomic information stored in electronic health records (EHR). The goals of this study were to determine biobank participants' attitudes towards genetic exceptionalism and confidentiality and whether those attitudes are related to their preference for return of genetic results. An online questionnaire was distributed to patients with an EHR and email address who had previously enrolled in the BioMe Biobank program. Most participants responded with similar levels of concern in scenarios involving the use of genetic information and other types of health information, suggesting that participants want similar protections for genetic data as other types of sensitive health information, particularly mental health and family history records. Of the 829 respondents, the majority had genetic exceptionalist views when directly asked, even though their concerns about confidentiality were similar for their genetic information and other health information. There were no differences in genetic exceptionalist views between those who had a documented preference to have genetic results returned and those who did not. Notably, for many participants, their recall of preference did not align with their documented preference. The majority of biobank participants were most anxious about the loss of confidentiality for genetic, mental health, and family history information, indicating that certain types of health information are considered more "sensitive" than others. These findings suggest the importance of assuring people participating in biobank research that the confidentiality of their "sensitive" health information is secured.

Return of polygenic risk scores in research: Stakeholders' views on the eMERGE-IV study.

Research on polygenic risk scores (PRSs) for common, genetically complex chronic diseases aims to improve health-related predictions, tailor risk-reducing interventions, and improve health outcomes. Yet, the study and use of PRSs in clinical settings raise equity, clinical, and regulatory challenges that can be greater for individuals from historically marginalized racial, ethnic, and other minoritized communities. As part of the National Human Genome Research Institute-funded Electronic Medical Records and Genomics IV Network, we conducted online focus groups with patients/community members, clinicians, and members of institutional review boards to explore their views on key issues, including PRS research, return of PRS results, clinical translation, and barriers and facilitators to health behavioral changes in response to PRS results. Across stakeholder groups, our findings indicate support for PRS development and a strong interest in having PRS results returned to research participants. However, we also found multi-level barriers and significant differences in stakeholders' views about what is needed and possible for successful implementation. These include researcher-participant interaction formats, health and genomic literacy, and a range of structural barriers, such as financial instability, insurance coverage, and the absence of health-supporting infrastructure and affordable healthy food options in poorer neighborhoods. Our findings highlight the need to revisit and implement measures in PRS studies (e.g., incentives and resources for follow-up care), as well as system-level policies to promote equity in genomic research and health outcomes.

Hope, but never expect? Comparing parents' pre- and post-disclosure attitudes toward return of results from diagnostic exome sequencing for their child.

BACKGROUND: Counseling for whole-exome sequencing (WES) could benefit from aligning parents' pre- and post-disclosure attitudes. A few studies have qualitatively compared parents' pre- and post-disclosure attitudes toward receiving WES results for their child in a diagnostic setting. This study explored these attitudes in the context of children with a developmental delay. METHODS: Semi-structured interviews were conducted with parents (n = 27) of 16 children undergoing diagnostic WES in trio-analysis, both before and after receiving results. RESULTS: Three key insights emerged. First, the distinction between hoping and expecting was relevant for shaping parents' experiences with receiving results related to the primary indication. Second, parents of young children whose development of autonomous capacities was uncertain sometimes found themselves in a situation resembling a Catch-22 when confronted with decisions about unsolicited findings (UFs): an important reason for consenting to WES was to gain a better picture of how the child might develop, but in order to make responsible choices about UFs, some ideas of their child's development is needed. Third, default opt-ins and opt-outs helped parents fathom new kinds of considerations for accepting or declining UFs in different categories, thereby aiding decision-making. CONCLUSION: Results from this study are relevant for counseling and policy development.

Perceptions and beliefs of community gatekeepers about genomic risk information in African cleft research.

BACKGROUND: A fundamental ethical issue in African genomics research is how socio-cultural factors impact perspectives, acceptance, and utility of genomic information, especially in stigmatizing conditions like orofacial clefts (OFCs). Previous research has shown that gatekeepers (e.g., religious, political, family or community leaders) wield considerable influence on the decision-making capabilities of their members, including health issues. Thus, their perspectives can inform the design of engagement strategies and increase exposure to the benefits of genomics testing/research. This is especially important for Africans underrepresented in genomic research. Our study aims to investigate the perspectives of gatekeepers concerning genomic risk information (GRI) in the presence of OFCs in a sub-Saharan African cohort. METHODS: Twenty-five focus group discussions (FGDs) consisting of 214 gatekeepers (religious, community, ethnic leaders, and traditional birth attendants) in Lagos, Nigeria, explored the opinions of participants on genomic risk information (GRI), OFC experience, and the possibility of involvement in collaborative decision-making in Lagos, Nigeria. Transcripts generated from audio recordings were coded and analyzed in NVivo using thematic analysis. RESULTS: Three main themes-knowledge, beliefs, and willingness to act-emerged from exploring the perspective of gatekeepers about GRI in this group. We observed mixed opinions regarding the acceptance of GRI. Many participants believed their role is to guide and support members when they receive results; this is based on the level of trust their members have in them. However, participants felt they would need to be trained by medical experts to do this. Also, religious and cultural beliefs were crucial to determining participants' understanding of OFCs and the acceptance and utilization of GRI. CONCLUSIONS: Incorporating cultural sensitivity into public engagement could help develop appropriate strategies to manage conflicting ideologies surrounding genomic information in African communities. This will allow for more widespread access to the advances in genomics research in underrepresented populations. We also recommend a synergistic relationship between community health specialists/scientists, and community leaders, including spiritual providers to better understand and utilize GRI.

Preparing for the unexpected: Recommendations for returning secondary findings in late-stage cancer care.

PURPOSE: We conducted qualitative interviews with patients with cancer and providers to identify gaps in clinical care and highlight care delivery solutions for the return of secondary germline findings. METHODS: Twelve patients and 19 cancer providers from the United States were interviewed between January 2019 and May 2021. Interviews elicited feedback about patient information needs, emotional responses to secondary findings, and recommendations for improving pre-test education. RESULTS: Patients' responses ranged from gratitude to regret, depending on how much pre-test counseling they received before tumor testing. Providers cited insufficient clinic time as a major barrier to pretest education, favoring online support tools and standardized pre-test education models. Providers had differing perspectives on how pre-test education should be integrated into clinical workflows but agreed that it should include the differences between somatic and germline testing, the likelihood of medically actionable findings, and the possibility of being referred to a genetics provider. CONCLUSION: The spectrum of participants' responses to their secondary findings underscores the importance of adequate pre-test discussions before somatic sequencing. Although educational interventions could address patients' information needs and augment traditional pre-test counseling, health care systems, labs, and genetic providers may be called on to play greater roles in pre-test education.

Researchers' Perspectives Regarding Ethical Issues of Biobank Research in the Arab Region.

Background: The recent expansion of genomic biobank research in the Arab region in the Middle East North Africa has raised complex ethical and regulatory issues. However, there is a lack of studies regarding the views of Arab researchers involved in such research. We aimed to assess the perceptions and attitudes of Arab researchers regarding these issues in biobank research. Methods: We developed a questionnaire to assess the perceptions and attitudes regarding genetic research of researchers from Egypt, Sudan, Morocco, and Jordan. The questionnaire requested demographic data, perceptions, and attitudes regarding the collection, storage, and use of biospecimens and data, the use of broad consent, data security, data sharing, and community engagement. We used multiple linear regressions to identify predictors of perceptions and attitudes. Results: We recruited 383 researchers. Researchers favored equally the use of broad and tiered consent (44.1% and 39.1%, respectively). Most respondents agreed with the importance of confidentiality protections to ensure data security (91.8%). However, lower percentages were seen regarding the importance of community engagement (64.5%), data sharing with national colleagues and international partners (60.9% and 41.1%, respectively), and biospecimen sharing with national colleagues and international partners (59.9% and 36.2%, respectively). Investigators were evenly split on whether the return of individual research results should depend on the availability or not of a medical intervention that can be offered to address the genetic anomaly (47.5% and 46.4%, respectively). Predictors of attitudes toward biospecimen research included serving on Research Ethics Committees, prior research ethics training, and affiliation with nonacademic institutions. Conclusions: We recommend further exploratory research with researchers regarding the importance of community engagement and to address their concerns about data sharing, with researchers within and outside their countries.

Views of adults living with sickle cell disease on the theoretical return of secondary genomic findings.

PURPOSE: Although the body of research investigating research participants' opinions on the return of actionable secondary genomic findings grows, there has been limited study of individuals with genetic conditions, such as sickle cell disease (SCD). It is imperative that the views of diverse research participants on return of results (RoR) be investigated and rooted in the context of advancing health equity in genomics research. METHODS: We conducted qualitative, semi-structured interviews with 30 adults living with SCD with differing insurance coverages and utilized a directed content analysis to derive themes. RESULTS: Study findings show that living with SCD is a key influence on views of RoR. Participants were in favor of RoR while expressing concern regarding the burden RoR would place on their SCD management. Respondents also expressed an expectation for researchers to devote resources toward seeking ancillary care downstream and discussed how barriers faced when navigating SCD would inform their access to ancillary care. CONCLUSION: Research participants living with chronic genetic conditions such as SCD are generally in favor of RoR but anticipate experiencing barriers to care similar to those faced navigating their SCD. Understanding the views of diverse cohorts on RoR will help researchers better understand downstream barriers participants may face.

Returning personalized, genetic health test results to individuals of African descent or ancestry in precision medicine research.

Today, many epidemiological studies and biobanks are offering to disclose individual genetic results to their participants, including the National Institutes of Health's All of Us Research Program. Returning hereditary disease risks and pharmacogenetic test results to study participants from racial/ethnic groups that are historically underrepresented in biomedical research poses specific challenges to those participants and the health system writ large. For example, individuals of African descent are underrepresented in research about drug-gene interactions and have a relatively higher proportion of variants of unknown significance, affecting their ability to take clinical action following return of results. In this brief report, we summarize studies published to date concerning the perspectives and/or attitudes of African Americans engaged in genetic research programs to anticipate factors in disclosure protocols that would minimize risks and maximize benefits. A thematic analysis of studies identified (n = 6) lends to themes centered on motivations to engage or disengage in the return of results and integrating research and care. Actionable strategies determined in reaction to these themes center on ensuring adequate system and health education support for participants and personalizing the process for participants engaging in return of results. Overall, we offer these themes and actionable strategies as early guidance to research programs, and provide recommendations to policy makers focused on fair and equitable return of genetic research results to underrepresented research participants.

Interrogating the Value of Return of Results for Diverse Populations: Perspectives from Precision Medicine Researchers.

BACKGROUND: Over the last decade, the return of results (ROR) in precision medicine research (PMR) has become increasingly routine. Calls for individual rights to research results have extended the "duty to report" from clinically useful genetic information to traits and ancestry results. ROR has thus been reframed as inherently beneficial to research participants, without a needed focus on who benefits and how. This paper addresses this gap, particularly in the context of PMR aimed at increasing participant diversity, by providing investigator and researcher perspectives on and questions about the assumed value of ROR in PMR. METHODS: Semi-structured interviews with a purposive sample of investigators and researchers across federally funded PMR studies in three national consortia, as well as observations of study activities, focused on how PM researchers conceptualize diversity and implement inclusive practices across research stages, including navigating ROR. RESULTS: Interviewees (1) validated the value of ROR as a benefit of PMR, while others (2) questioned the benefit of clinically actionable results to individuals in the absence of sufficient resources for translating findings into health care for diverse and disadvantaged populations; (3) expressed uncertainties in applying the presumed value of ROR as a benefit for non-clinical results; and (4) and debated when the promise of the value of ROR may undermine trust in PMR, and divert efforts to return value beyond ROR. CONCLUSIONS: Conceptualizations of diversity and inclusion among PM researchers and investigators raise unique ethical questions where unexamined assumptions of the value of ROR inform study recruitment efforts to enroll minoritized and under-represented populations. A lack of consideration for resources and infrastructure necessary to translate ROR into actionable information may hinder trustworthy community-research relationships. Thus, we argue for a more intentional interrogation of ROR practices as an offer of benefit and for whom.

Uncertain futures and unsolicited findings in pediatric genomic sequencing: guidelines for return of results in cases of developmental delay.

BACKGROUND: Massively parallel sequencing techniques, such as whole exome sequencing (WES) and whole genome sequencing (WGS), may reveal unsolicited findings (UFs) unrelated to the diagnostic aim. Such techniques are frequently used for diagnostic purposes in pediatric cases of developmental delay (DD). Yet policy guidelines for informed consent and return of UFs are not well equipped to address specific moral challenges that may arise in these children's situations. DISCUSSION: In previous empirical studies conducted by our research group, we found that it is sometimes uncertain how children with a DD will develop and whether they could come to possess capacities for autonomous decision-making in the future. Parents sometimes felt this brought them into a Catch-22 like situation when confronted with choices about UFs before undergoing WES in trio-analysis (both the parents' and child's DNA are sequenced). An important reason for choosing to consent to WES was to gain more insight into how their child might develop. However, to make responsible choices about receiving or declining knowledge of UFs, some idea of their child's future development of autonomous capacities is needed. This undesirable Catch-22 situation was created by the specific policy configuration in which parents were required to make choices about UFs before being sequencing (trio-analysis). We argue that this finding is relevant for reconfiguring current policies for return of UFs for WES/WGS and propose guidelines that encompass two features. First, the informed consent process ought to be staged. Second, differing guidelines are required for withholding/disclosing a UF in cases of DD appropriate to the level of confidence there is about the child's future developmental of autonomous capacities. CONCLUSION: When combined with a dynamic consent procedure, these two features of our guidelines could help overcome significant moral challenges that present themselves in the situations of children undergoing genomic sequencing for clarifying a DD.

Prospective, multi-site study of healthcare utilization after actionable monogenic findings from clinical sequencing.

As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended health services (laboratory, imaging, and procedural testing) delivered within 12 months of return were compared among individuals with pathogenic or likely pathogenic (P/LP) findings to matched individuals with negative findings before and after return of results. Of 16,218 adults, 477 unselected individuals were found to have a monogenic risk for arrhythmia (n = 95), breast cancer (n = 96), cardiomyopathy (n = 95), colorectal cancer (n = 105), or familial hypercholesterolemia (n = 86). Individuals with P/LP results more frequently received services after return (43.8%) compared to before return (25.6%) of results and compared to individuals with negative findings (24.9%; p < 0.0001). The annual cost of qualifying healthcare services increased from an average of $162 before return to $343 after return of results among the P/LP group (p < 0.0001); differences in the negative group were non-significant. The mean difference-in-differences was $149 (p < 0.0001), which describes the increased cost within the P/LP group corrected for cost changes in the negative group. When stratified by individual conditions, significant cost differences were observed for arrhythmia, breast cancer, and cardiomyopathy. In conclusion, less than half of individuals received billed health services after monogenic return, which modestly increased healthcare costs for payors in the year following return.

Experiences of adults living with refractory epilepsy and their views and expectations on receiving results from whole genome sequencing.

INTRODUCTION: Researchers, clinicians and patients are turning to new innovations in research and clinical practice to further their knowledge in the genetic domain and improve diagnostics or treatment. However, with increased knowledge in genetics, societal issues may arise. Being conscious of these issues is crucial in order to implement standardized and efficient testing on a wider scale that is accessible to a greater number of individuals while simultaneously returning test results, including incidental findings, in a timely manner. METHODS: Within the framework of a genomics research project, we invited 20 participants who suffer from refractory epilepsy to provide insight on their personal experiences with epilepsy, as well as their thoughts on receiving Whole Genome Sequencing (WGS) results and with whom they would feel comfortable sharing these results with. RESULTS: All participants had their own unique experience with epilepsy, such as how they handled their diagnosis, their struggles following the diagnosis, the healthcare services they received, how they shared their diagnosis with others, and how they managed stigmatization from others. Most participants would be eager to know their WGS results, whether the results be related to epilepsy (n = 19), response to pharmaceutical drugs including AEDs (n = 16), comorbidities (n = 19) and incidental findings (n = 15). CONCLUSION: Our findings reinforce the need to improve access to genetic testing for epilepsy patients in clinical settings. Furthermore, while acquiring more genetic knowledge (i.e. WGS) about epilepsy can provide answers for the affected population, it also requires the simultaneous involvement of several medical disciplines, with greater emphasis on genetic and psychological counseling.

Return of Participants' Incidental Genetic Research Findings: Experience from a Case-Control Study of Asthma in an American Indian Community.

The proper communication of clinically actionable findings to participants of genetic research entails important ethical considerations, but has been challenging for a variety of reasons. We document an instance of the return of individual genetic results in the context of a very rural American Indian community, in hopes of providing insight to other investigators about potentially superior or inferior courses of action. This was a case/control study of asthma among 324 pediatric participants. Subsequently, microarray genotype data became available, providing over 2 million variants, incidentally including some conferring risk for conditions for which the American College of Medical Genetics recommends return of results. The study investigators engaged in extensive consultation with the IRB, the tribal government, and local clinicians to better inform our approach. We were able to notify the two participants heterozygous for the one clinically actionable variant identified. One participant welcomed this information and proceeded to obtain further clinical work-up; the other participant declined further follow-up. While demanding considerable time and effort, the return of clinically actionable genetic results is important from both an ethical perspective and to provide an improved trust relationship with the community of research participants.

The right not to know: Non-disclosure of primary genetic test results and genetic counselors' response.

As part of clinical genetic counseling practice, patients may request that their primary genetic test results be disclosed to someone else, such as a relative or referring provider, or request that results be disclosed to no one (non-disclosure). In making these requests, patients employ the ethical principle of the "right not to know," which argues that autonomous individuals can choose not to know relevant health information. Although the right not to know has been well-studied in medicine in general, and in the return of genomic secondary findings, we are not aware of other studies that have explored the return of primary genetic test results when patients request non-disclosure or disclosure to another individual. This study aimed to describe common clinical scenarios in which these requests occur, how genetic counselors respond, and what ethical considerations they employ in their decision-making process. We recruited participants from the National Society of Genetic Counselors' (NSGC) "Student Research Surveys and Reminders" listserv and conducted semi-structured interviews with 11 genetic counselors in the United States who described genetic counseling cases where this occurred. Interviews were transcribed and coded inductively, and themes were identified. Case details varied, but in our study data the requests for non-disclosure were most commonly made by patients with poor, often oncologic, prognoses who requested their test results be disclosed to a family member instead of themselves. Genetic counselors considered similar factors in deciding how to respond to these requests: patient autonomy, medical actionability of results for the patient and family, the relationship between the patient and the person to whom results might be disclosed, and legal or practical concerns. Genetic counselors often made decisions on a case-by-case basis, depending on how relevant each of these factors were. This study adds to the growing body of literature regarding patients' "right not to know" and will hopefully provide guidance for genetic counselors who experience this situation in clinical practice.

Dynamic consent, communication and return of results in large-scale health data reuse: Survey of public preferences.

Dynamic consent forms a comprehensive, tailored approach for interacting with research participants. We conducted a survey study to inquire how research participants evaluate the elements of consent, information provision, communication and return of results within dynamic consent in a hypothetical health data reuse scenario. We distributed a digital questionnaire among a purposive sample of patient panel members. Data were analysed using descriptive and nonparametric inferential statistics. Respondents favoured the potential to manage changing consent preferences over time. There was much agreement between people favouring closer and more specific control over data reuse approval and those in favour of broader approval, facilitated by an opt-out system or an independent data reuse committee. People want to receive more information about reuse, outcomes and return of results. Respondents supported an interactive model of research participation, welcoming regular, diverse and interactive forms of communication, like a digital communication platform. Approval for reuse and providing meaningful information, including meaningful return of results, are intricately related to facilitating better communication. Respondents favoured return of actionable research results. These findings emphasize the potential of dynamic consent for enabling participants to maintain control over how their data are being used for which purposes by whom. Allowing different options to shape a dynamic consent interface in health data reuse in a personalized manner is pivotal to accommodate plurality in a flexible though robust manner. Interaction via dynamic consent enables participants to tailor the elements of participation they deem relevant to their own preferences, engaging diverse perspectives, interests and preferences.

Phenotypes of undiagnosed adults with actionable OTC and GLA variants.

Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMDs and can lead to protocols that improve clinical detection, counseling, and management. Using data from 57,340 participants in two hospital biobanks, we assessed the frequency and phenotypes of individuals with pathogenic/likely pathogenic variants (PLPVs) in two IMD genes: GLA, associated with Fabry disease, and OTC, associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in GLA or OTC. We identified three individuals (2 male, 1 female) with PLPVs in GLA, all of whom were undiagnosed, and three individuals (3 female) with PLPVs in OTC, two of whom were undiagnosed. All three individuals with PLPVs in GLA (100%) had symptoms suggestive of mild Fabry disease, and one individual (14.2%) had an ischemic stroke at age 33, likely indicating the presence of classic disease. No individuals with PLPVs in OTC had documented hyperammonemia despite exposure to catabolic states, but all (100%) had chronic symptoms suggestive of attenuated disease, including mood disorders and migraines. Our findings suggest that GLA and OTC variants identified via a genotype-first approach are of high penetrance and that population screening of these genes can be used to facilitate stepwise phenotyping and appropriate care.

Parents' Perspectives on Secondary Genetic Ancestry Findings in Pediatric Genomic Medicine.

PURPOSE: With advances in genome sequencing technologies, large-scale genome-wide sequencing has advanced our understanding of disease risk and etiology and contributes to the rapidly expanding genomic health services in pediatric settings. Because it is possible to return ancestry estimates following clinical genomic sequencing, it is important to understand the interest in ancestry results among families who may have the option of receiving these results. METHODS: We conducted 26 semi-structured qualitative telephone interviews of parents with children/newborns with likely genetic conditions from two studies of clinical genome sequencing. Using a purposive sampling approach, we selected parents from the SouthSeq cohort, Clinical Sequencing Evidence-Generating Research (CSER Phase 2) project active in Alabama, Mississippi, and Louisiana, or an earlier Clinical Sequencing Exploratory Research (CSER Phase 1) initiative based in the same region. Our interviews focused on parental knowledge about, attitudes on, interest in, and preferences for receiving genetic ancestry results following clinical genome sequencing in the neonatal intensive care unit or in pediatric clinics. FINDINGS: Overall, parents prioritized clinical results or results that would help guide the diagnosis and treatment of their child, but they were also interested in any genetic result, including genetic ancestry, that potentially could enhance the meaning of information on disease risk, prevention and screening guidance, or family planning. While parents thought that ancestry results would help them learn about themselves and their heritage, the had concerns over the privacy, security, and accuracy of genetic ancestry information, although parents indicated that they had greater trust in ancestry findings provided as part of clinical care compared with those offered commercially. Parents also wanted ancestry results to be returned in a timely manner by knowledgeable staff, with kid-friendly materials and online tools available to aid, as needed, in the understanding of their results. IMPLICATIONS: Taken together, our results highlight that despite being in high-stress situations, such as having a newborn in the neonatal intensive care unit, parents were interested in receiving genetic ancestry results along with their clinically relevant findings.

Research participants' perspectives about the return of uninformative genomic test results in a clinical research setting.

The majority of genomic sequencing and microarray results are clinically uninformative, meaning that they do not suggest a need for any behavioral action or medical intervention. Prior studies have shown that recipients of uninformative genomic testing results ("uninformative results" hereafter) may incorrectly interpret them to imply a lowered risk of disease or false reassurance about future health risks. Few studies have examined how patients understand uninformative results when they are returned in a research setting, where there is wide variation in analytical specifications of testing, interpretation and reporting practices, and resources to support the return of results. We conducted cross-sectional interviews (N = 17) to explore how a subset of research participants in one genomics study at the National Institutes of Health reacted to and understood their uninformative test results, which were returned to them via a patient portal without genetic counseling. We found that most participants did not remember the details of the informed consent process, including the distinction between "primary" and "secondary" findings. Participants had questions about what genes were tested for and, in most cases, requested a list of the genes covered. Several participants incorrectly assumed that autosomal recessive carrier results would have been reported to them if detected. Some participants interpreted their uninformative results to mean that they could forgo prenatal testing, and participants had mixed expectations about whether their results might be reinterpreted in the future. These themes suggest that there are specific challenges to returning uninformative results in research settings. Educational supplements to uninformative test reports may be most useful if they contextualize results in relation to other types of clinical genetic or genomic testing that may be made available to research participants in their lifetimes.

Ethical, legal, and social implications (ELSI) and challenges in the design of a randomized controlled trial to test the online return of cancer genetic research results to U.S. Black women.

BACKGROUND: A central challenge to precision medicine research efforts is the return of genetic research results in a manner that is effective, ethical, and efficient. Formal tests of alternate modalities are needed, particularly for racially marginalized populations that have historically been underserved in this context. METHODS: We are conducting a randomized controlled trial (RCT) to test scalable modalities for results return and to examine the clinical utility of returning genetic research results to a research cohort of Black women. The primary aim is to compare the efficacy of two communication modalities for results return: 1) a conventional modality that entails telephone disclosure by a Board-certified genetic counselor, and 2) an online self-guided modality that entails results return directly to participants, with optional genetic counselor follow-up via telephone. The trial is being conducted among participants in the Black Women's Health Study (BWHS), where targeted sequencing of 4000 participants was previously completed. RESULTS: Several ethical, legal, and social implications (ELSI) and challenges presented, which necessitated substantial revision of the original study protocol. Challenges included chain of custody, re-testing of research results in a CLIA lab, exclusion of VUS results, and digital literacy. Bioethical principles of autonomy, justice, non-maleficence, and beneficence were considered in the design of the study protocol. CONCLUSION: This study is uniquely situated to provide critical evidence on the effectiveness of alternative models for genetic results return and provide further insight into the factors influencing access and uptake of genetic information among U.S. Black women. CLINICALTRIALS: gov: NCT04407611.