Researchers’ views on return of incidental genomic research results: qualitative and quantitative findings

PurposeComprehensive genomic analysis including exome and genome sequencing is increasingly being utilized in research studies, leading to the generation of incidental genetic findings. It is unclear how researchers plan to deal with incidental genetic findings.MethodsWe conducted a survey of the practices and attitudes of 234 members of the US genetic research community and performed qualitative semistructured interviews with 28 genomic researchers to understand their views and experiences with incidental genetic research findings.ResultsWe found that 12% of the researchers had returned incidental genetic findings, and an additional 28% planned to do so. A large majority of researchers (95%) believe that incidental findings for highly penetrant disorders with immediate medical implications should be offered to research participants. However, there was no consensus on returning incidental results for other conditions varying in penetrance and medical actionability. Researchers raised concerns that the return of incidental findings would impose significant burdens on research and could potentially have deleterious effects on research participants if not performed well. Researchers identified assistance needed to enable effective, accurate return of incidental findings.ConclusionThe majority of the researchers believe that research participants should have the option to receive at least some incidental genetic research results.     

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.     

Return of results in a global survey of psychiatric genetics researchers: practices,attitudes, and knowledge

PurposePatient-participants in psychiatric genetics research may be at an increased risk for negative psychosocial impacts related to the return of genetic research results. Examining psychiatric genetics researchers’ return of results practices and perspectives can aid the development of empirically informed and ethically sound guidelines.MethodsA survey of 407 psychiatric genetics researchers from 39 countries was conducted to examine current return of results practices, attitudes, and knowledge.ResultsMost respondents (61%) reported that their studies generated medically relevant genomic findings. Although 24% have returned results to individual participants, 52% of those involved in decisions about return of results plan to return or continue to return results. Respondents supported offering “medically actionable” results related to psychiatric disorders (82%), and the majority agreed non–medically actionable risks for Huntington (71%) and Alzheimer disease (64%) should be offered. About half (49%) of respondents supported offering reliable polygenic risk scores for psychiatric conditions. Despite plans to return, only 14% of researchers agreed there are adequate guidelines for returning results, and 59% rated their knowledge about how to manage the process for returning results as poor.ConclusionPsychiatric genetics researchers support returning a wide range of results to patient-participants, but they lack adequate knowledge and guidelines.     

Psychiatric genetics researchers' views on offering return of results to individual participants

In the middle of growing consensus that genomics researchers should offer to return clinically valid, medically relevant, and medically actionable findings identified in the course of research, psychiatric genetics researchers face new challenges. As they uncover the genetic architecture of psychiatric disorders through genome‐wide association studies and integrate whole genome and whole exome sequencing to their research, there is a pressing need for examining these researchers' views regarding the return of results (RoR) and the unique challenges for offering RoR from psychiatric genetics research. Based on qualitative interviews with 39 psychiatric genetics researchers from different countries operating at the forefront of their field, we provide an insider's view of researchers' practices regarding RoR and the most contentious issues in psychiatry researchers' decision‐making around RoR, including what are the strongest ethical, scientific, and practical arguments for and against offering RoR from this research. Notably, findings suggest that psychiatric genetics researchers (85%) overwhelmingly favor offering RoR of at least some findings, but only 22% of researchers are returning results. Researchers identified a number of scientific and practical concerns about RoR, and about how to return results in a responsible way to patients diagnosed with a severe psychiatric disorder. Furthermore, findings help highlight areas for further discussion and resolution of conflicts in the practice of RoR in psychiatric genetics research. As the pace of discovery in psychiatric genetics continues to surge, resolution of these uncertainties gains greater urgency to avoid ethical pitfalls and to maximize the positive impact of RoR.     

Psychiatric genomics researchers’ perspectives on best practices for returning results to individual participants

PurposeLarge-scale array-based and sequencing studies have advanced our understanding of the genetic architecture of psychiatric disorders, but also increased the potential to generate an exponentially larger amount of clinically relevant findings. As genomic testing becomes more widespread in psychiatry research, urgency grows to establish best practices for offering return of results (RoR) to individuals at risk or diagnosed with a psychiatric disorder.MethodsWe interviewed an international sample (n = 39) of psychiatric genetics researchers to examine conceptualizations of “best practices” for RoR to individual research participants.ResultsWhile the vast majority of researchers do not offer RoR, most believed medically actionable findings (85%) and clinically valid but non–medically actionable findings (54%) should be offered. Researchers identified three main areas for improvement: interfacing with individual participants; interdisciplinary training, guidance, and integration; and quality planning and resource allocation for returning results.ConclusionThere are significant gaps between researchers’ visions for “best” versus “actual” RoR practices. While researchers call for participant-centered practices, including consent practices that consider any special needs of participants with psychiatric disorders, return of individually meaningful results, and effective follow-up and provisions for treatment, the current reality is that consent and RoR practices lack standardized and evidence-based norms.     

Institutional review board perspectives on obligations to disclose genetic incidental findings to research participants

PurposeResearchers’ obligations to disclose genetic incidental findings (GIFs) have been widely debated, but there has been little empirical study of the engagement of institutional review boards (IRBs) with this issue.MethodsThis article presents data from the first extensive (n = 796) national survey of IRB professionals’ understanding of, experience with, and beliefs surrounding GIFs.ResultsMost respondents had dealt with questions about GIFs (74%), but only a minority (47%) felt prepared to address them. Although a majority believed that there is an obligation to disclose GIFs (78%), there is still not consensus about the supporting ethical principles. Respondents generally did not endorse the idea that researchers’ additional time and effort (7%), and lack of resources (29%), were valid reasons for diminishing a putative obligation. Most (96%) supported a right not to know, but this view became less pronounced (63%) when framed in terms of specific case studies.ConclusionsIRBs are actively engaged with GIFs but have not yet reached consensus. Respondents were uncomfortable with arguments that could be used to limit an obligation to return GIFs. This could indicate that IRBs are providing some of the impetus for the trend toward returning GIFs, although questions remain about the relative contribution of other stakeholders.     

An empirical examination of the management of return of individual research results and incidental findings in genomic biobanks

PurposeThe purpose of this study was to examine and document the management and return of individual research results and incidental findings to research participants among biobanks.MethodsA comprehensive Internet search was completed to identify biobanks and collect available documents about biobanks and their procedures and policies regarding the return of results. The Internet search was supplemented by an e-mail request to gather further such documents. A total of 2,366 documents were collected for analysis from a sample of 85 biobanks.ResultsThe major finding of this empirical work is that the majority of the biobanks in the sample do not address the return of individual research results and incidental findings in their publicly available documents.ConclusionThe results suggest that there is a need for more discussion and guidance about the most appropriate ways for biobanks to consider the return of individual research results and incidental findings and generate policies and procedures that address this issue.Genet Med 2012:14(4):444–450     

Is “incidental finding” the best term?: a study of patients’ preferences

PurposeThere is debate within the genetics community about the optimal term to describe genetic variants unrelated to the test indication but potentially important for health. Given the lack of consensus and the importance of adopting terminology that promotes effective clinical communication, we sought the opinion of clinical genetics patients.MethodsSurveys and focus groups with two patient populations were conducted. Eighty-eight survey participants were asked to rank four terms according to how well each describes results unrelated to the test indication: incidental findings, secondary findings, additional findings, and ancillary findings. Participants in six focus groups were guided through a free-thought exercise to describe the desired attributes of such a term and then asked to formulate the best term to represent this concept.ResultsThe term additional findings had the most first-choice rankings by survey participants, followed by secondary findings, incidental findings, and ancillary findings. Most focus group participants preferred the term additional findings; they also gave reasons why other terms were not optimal.ConclusionAdditional findings was preferred because it was more neutral and accessible than other terms currently in use. Patient perceptions and comprehension will be framed by the terminology used by healthcare providers. Thus, patient opinions should be considered by medical genetics professionals.     

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     

Exploring concordance and discordance for return of incidental findings from clinical sequencing

PurposeThe aim of this study was to explore specific conditions and types of genetic variants that specialists in genetics recommend should be returned as incidental findings in clinical sequencing.MethodsSixteen specialists in clinical genetics and/or molecular medicine selected variants in 99 common conditions to return to the ordering physician if discovered incidentally through whole-genome sequencing. For most conditions, the specialists independently considered three molecular scenarios for both adults and minor children: a known pathogenic mutation, a truncating variant presumed pathogenic (where other truncating variants are known to be pathogenic), and a missense variant predicted in silico to be pathogenic.ResultsOn average, for adults and children, respectively, each specialist selected 83.5 and 79.0 conditions or genes of 99 in the known pathogenic mutation categories, 57.0 and 53.5 of 72 in the truncating variant categories, and 33.4 and 29.7 of 72 in the missense variant categories. Concordance in favor of disclosure within the adult/known pathogenic mutation category was 100% for 21 conditions or genes and 80% or higher for 64 conditions or genes.ConclusionSpecialists were highly concordant for the return of findings for 64 conditions or genes if discovered incidentally during whole-exome sequencing or whole-genome sequencing.Genet Med 2012:14(4):405–410     

Physicians' attitudes toward race,genetics, and clinical medicine

PurposeThis qualitative study explored black and white general internists' attitudes about the relevance of race in clinical care; views of the relationships among race, genetics, and disease; and expectations about the future of genetics and health.MethodsWe conducted 10 racially concordant focus groups of primary care physicians in five metropolitan areas in the United States. Ninety board certified or eligible general internists (50 self-identified whites and 40 self-identified blacks) participated in the study. Analysis included a two-stage independent review and adjudication process.ResultsBoth black and white physicians concluded that the race of the patient is medically relevant but did not agree upon why race is important in clinical decisions. They were reticent to make connections among race, genetics, and disease and asserted that genetics has a limited role in explaining racial differences in health. However, they were enthusiastic about the future of genomic medicine, believing that the main benefit will be the potential to improve the efficacy of commonly used drugs.ConclusionsUnderstanding the similarities and differences between black and white physicians' attitudes and beliefs about race, health and genetics is important for the translation of genomics to clinical care.     

Genetics researchers' and IRB professionals' attitudes toward genetic research review: a comparative analysis

PurposeGenetic research involving human participants can pose challenging questions related to ethical and regulatory standards for research oversight. However, few empirical studies describe how genetic researchers and institutional review board (IRB) professionals conceptualize ethical issues in genetic research or where common ground might exist.MethodsParallel online surveys collected information from human genetic researchers (n = 351) and IRB professionals (n = 208) regarding their views about human participant oversight for genetic protocols.ResultsA range of opinions were observed within groups on most issues. In both groups, a minority thought it likely that people would be harmed by participation in genetic research or identified from coded genetic data. A majority of both groups agreed that reconsent should be required for four of the six scenarios presented. Statistically significant differences were observed between groups on some issues, with more genetic researcher respondents trusting the confidentiality of coded data, fewer expecting harms from reidentification, and fewer considering reconsent necessary in certain scenarios.ConclusionThe range of views observed within and between IRB and genetic researcher groups highlights the complexity and unsettled nature of many ethical issues in genome research. Our findings also identify areas where researcher and IRB views diverge and areas of common ground.Genet Med 2012:14(2):236–242     

Mapping the incidentalome: estimating incidental findings generated through clinical pharmacogenomics testing

PurposeGreater clinical validity and economic feasibility are driving the more widespread use of multiplex genetic technologies in routine clinical care, especially for applications in pharmacogenomics. Empirical data on the numbers and types of incidental findings generated through such testing are needed to develop policies and practices related to their clinical use. Of particular importance are disparities in findings relevant to different ancestry groups.MethodsThe Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment Resource, or PREDICT, is an institutional program to implement prospective clinical genotyping of 34 pharmacogenomic-related genes to guide drug selection and dosing. We curated 5,566 journal articles to quantify and characterize the incidental, nonpharmacogenomic genotype–phenotype associations that could be generated through this clinical genotyping project.ResultsWe identified 372 putative incidental genotype–phenotype associations that might be revealed in patients undergoing clinical genotyping for pharmacogenomic purposes. Of these, 287 associations were supported by at least one study demonstrating an odds ratio ≥2.0 or ≤0.5. Numbers of potentially relevant findings varied widely by ancestry group.ConclusionRigorous clinical policies for the clinical management of incidental findings are needed because the sheer number of significant findings could prove overwhelming to health-care institutions, providers, and patients.     

Attitudes of nearly 7000 health professionals,genomic researchers and publics toward the return of incidental results from sequencing research

Genome-wide sequencing in a research setting has the potential to reveal health-related information of personal or clinical utility for the study participant. There is increasing pressure to return research findings to participants that may not be related to the project aims, particularly when these could be used to prevent disease. Such secondary, unsolicited or ''incidental findings'' (IFs) may be discovered unintentionally when interpreting sequence data, or as the result of a deliberate opportunistic screen. This cross-sectional, web-based survey investigated attitudes of 6944 individuals from 75 countries towards returning IFs from genome research. Participants included four relevant stakeholder groups: 4961 members of the public, 533 genetic health professionals, 843 non-genetic health professionals and 607 genomic researchers who were invited via traditional media, social media and professional e-mail list-serve. Treatability and perceived utility of incidental results were deemed important with 98% of stakeholders personally interested in learning about preventable life-threatening conditions. Although there was a generic interest in receiving genomic information, stakeholders did not expect researchers to opportunistically screen for IFs in a research setting. On many items, genetic health professionals had significantly more conservative views compared with other stakeholders. This finding demonstrates a disconnect between the views of those handling the findings of research and those participating in research. Exploring, evaluating and ultimately addressing this disconnect should form a priority for researchers and clinicians alike. This social sciences study offers the largest dataset, published to date, of attitudes towards issues surrounding the return of IFs from sequencing research.     

Age and perceived risks and benefits of preventive genomic screening

PurposeAs genome sequencing moves from research to clinical practice, sequencing technologies focused on “medically actionable” targets are being promoted for preventive screening despite the dearth of systematic evidence of risks and benefits and of criteria for selection of screening subjects. This study investigates researchers’ and research participants’ perceptions of these issues within the context of a preventive genomic screening study, GeneScreen.MethodsWe recorded researcher deliberations regarding age eligibility criteria and the risks and benefits of screening, and conducted interviews with 50 GeneScreen participants about their motivations for joining and their perceptions of risks and benefits.ResultsResearchers made assumptions about who would want and benefit from screening based on age. After discussion, researchers opted not to have an upper age limit for enrollment. Participants of all ages perceived similar benefits, including prevention, treatment, and cascade testing, and similar risks, such as insurance discrimination and worry.ConclusionWhile clinical benefits of preventive genomic screening for older adults are debatable, our respondents perceived a range of benefits of screening in both clinical and research settings. Researchers and clinicians should carefully consider decisions about whether to exclude older adults and whether to provide information about benefits and risks across age groups.     

Researchers’ views on informed consent for return of secondary results in genomic research

PurposePrevious studies have suggested that genomic investigators generally favor offering to return at least some secondary findings to participants and believe that participants’ preferences should determine the information they receive. We surveyed investigators to ascertain their views on four models of informed consent for this purpose: traditional consent, staged consent, mandatory return, and outsourced consent.MethodsWe performed an online survey of the views regarding return of secondary results held by 198 US genetic researchers drawn from our subject pool for an earlier study. Potential participants were identified through the National Institutes of Health RePORTER database and abstracts from the 2011 American Society of Human Genetics meeting.ResultsUnder circumstances in which resource constraints are not an issue, approximately a third of respondents would endorse either staged consent or traditional consent; outsourced consent and mandatory return are favored by only a small minority. However, taking resource constraints into account, roughly half the sample would favor traditional consent, with support for staged consent dropping to 13%.ConclusionDespite their liabilities, traditional approaches to consent are seen as the most viable under current circumstances. However, there is considerable interest in staged consent, assuming the infrastructure to support it can be provided.Genet Med17 8, 644–650.     

Stakeholder views on secondary findings in whole-genome and whole-exome sequencing: a systematic review of quantitative and qualitative studies

PurposeAs whole-exome sequencing (WES) and whole-genome sequencing (WGS) move into routine clinical practice, it is timely to review data that might inform the debate regarding secondary findings (SF) and the development of policies that maximize participant benefit.MethodsWe systematically searched for qualitative and quantitative studies that explored stakeholder views on SF in WES/WGS. Framework analysis was undertaken to identify major themes.ResultsForty-four articles reporting the views of 11,566 stakeholders were included. Stakeholders were broadly supportive of returning “actionable” findings, but definitions of actionability varied. Stakeholder views on SF disclosure exist along a spectrum: potential WES/WGS recipients’ views were largely influenced by a sense of rights, whereas views of genomics professionals were informed by a sense of professional responsibility. Experience with genetic illness and testing resulted in greater caution about SF, suggesting that truly informed decisions require an understanding of the implications and limitations of WES/WGS and possible findings.ConclusionThis review suggests that bidirectional interaction during consent might best facilitate informed decision making about SF and that dynamic forms of consent, allowing for changing preferences, should be considered. Research exploring views from wider perspectives and from recipients who have received SF is critical if evidence-based policies are to be achieved.Genet Med 19 3, 283–293.     

A semiquantitative metric for evaluating clinical actionability of incidental or secondary findings from genome-scale sequencing

PurposeAs genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis.MethodsWe established a semiquantitative metric to assess five elements of actionability: severity and likelihood of the disease outcome, efficacy and burden of intervention, and knowledge base, with a total score from 0 to 15.ResultsThe semiquantitative metric was applied to a list of putative actionable conditions, the list of genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return when deleterious variants are discovered as secondary/incidental findings, and a random sample of 1,000 genes. Scores from the list of putative actionable conditions (median = 12) and the ACMG list (median = 11) were both statistically different than the randomly selected genes (median = 7) (P < 0.0001, two-tailed Mann-Whitney test).ConclusionGene–disease pairs having a score of 11 or higher represent the top quintile of actionability. The semiquantitative metric effectively assesses clinical actionability, promotes transparency, and may facilitate assessments of clinical actionability by various groups and in diverse contexts.