Return Of Incidental Findings Research Articles

Return of non-ACMG recommended incidental genetic findings to pediatric patients: considerations and opportunities from experiences in genomic sequencing

BackgroundThe uptake of exome/genome sequencing has introduced unexpected testing results (incidental findings) that have become a major challenge for both testing laboratories and providers. While the American College of Medical Genetics and Genomics has outlined guidelines for laboratory management of clinically actionable secondary findings, debate remains as to whether incidental findings should be returned to patients, especially those representing pediatric populations.MethodsThe Sequencing Analysis and Diagnostic Yield working group in the Clinical Sequencing Evidence-Generating Research Consortium has collected a cohort of pediatric patients found to harbor a genomic sequencing-identified non-ACMG-recommended incidental finding. The incidental variants were not thought to be associated with the indication for testing and were disclosed to patients and families.ResultsIn total, 23 "non-ACMG-recommended incidental findings were identified in 21 pediatric patients included in the study. These findings span four different research studies/laboratories and demonstrate differences in incidental finding return rate across study sites. We summarize specific cases to highlight core considerations that surround identification and return of incidental findings (uncertainty of disease onset, disease severity, age of onset, clinical actionability, and personal utility), and suggest that interpretation of incidental findings in pediatric patients can be difficult given evolving phenotypes. Furthermore, return of incidental findings can benefit patients and providers, but do present challenges.ConclusionsWhile there may be considerable benefit to return of incidental genetic findings, these findings can be burdensome to providers and present risk to patients. It is important that laboratories conducting genomic testing establish internal guidelines in anticipation of detection. Moreover, cross-laboratory guidelines may aid in reducing the potential for policy heterogeneity across laboratories as it relates to incidental finding detection and return. However, future discussion is required to determine whether cohesive guidelines or policy statements are warranted.

Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach

BackgroundAs genomic sequencing moves closer to clinical implementation, there has been an increasing acceptance of returning incidental findings to research participants and patients for mutations in highly penetrant, medically actionable genes. A curated list of genes has been recommended by the American College of Medical Genetics and Genomics (ACMG) for return of incidental findings. However, the pleiotropic effects of these genes are not fully known. Such effects could complicate genetic counseling when returning incidental findings. In particular, there has been no systematic evaluation of psychiatric manifestations associated with rare variation in these genes.ResultsHere, we leveraged a targeted sequence panel and real-world electronic health records from the eMERGE network to assess the burden of rare variation in the ACMG-56 genes and two psychiatric-associated genes (CACNA1C and TCF4) across common mental health conditions in 15,181 individuals of European descent. As a positive control, we showed that this approach replicated the established association between rare mutations in LDLR and hypercholesterolemia with no visible inflation from population stratification. However, we did not identify any genes significantly enriched with rare deleterious variants that confer risk for common psychiatric disorders after correction for multiple testing. Suggestive associations were observed between depression and rare coding variation in PTEN (P = 1.5 × 10–4), LDLR (P = 3.6 × 10–4), and CACNA1S (P = 5.8 × 10–4). We also observed nominal associations between rare variants in KCNQ1 and substance use disorders (P = 2.4 × 10–4), and APOB and tobacco use disorder (P = 1.1 × 10–3).ConclusionsOur results do not support an association between psychiatric disorders and incidental findings in medically actionable gene mutations, but power was limited with the available sample sizes. Given the phenotypic and genetic complexity of psychiatric phenotypes, future work will require a much larger sequencing dataset to determine whether incidental findings in these genes have implications for risk of psychopathology.

To disclose, or not to disclose? Perspectives of clinical genomics professionals toward returning incidental findings from genomic research

BackgroundClinical genomic professionals are increasingly facing decisions about returning incidental findings (IFs) from genetic research. Although previous studies have shown that research participants are interested in receiving IFs, yet there has been an argument about the extent of researcher obligation to return IFs. We aimed in this study to explore the perspectives of clinical genomics professionals toward returning incidental findings from genomic research.MethodsWe conducted a national survey of a sample (n = 113) of clinical genomic professionals using a convenient sampling. A self-administered questionnaire was used to explore their attitudes toward disclosure of IFs, their perception of the duties to return IFs and identifying the barriers for disclosure of IFs. A descriptive analysis was employed to describe participants' responses.ResultsSixty-five (57.5%) respondents had faced IFs in their practice and 31 (27.4%) were not comfortable in discussing IFs with their research subjects. Less than one-third of the respondents reported the availability of guidelines governing IFs. The majority 84 (80%) and 69 (62.7%) of the study participants indicated they would return the IFs if the risk of disease threat ≥ 50% and 6–49%, respectively and 36 (31.9%) reported they have no obligation to return IFs.ConclusionClinical genomics professionals have positive attitudes and perceptions toward the returning IFs from genomic research, yet some revealed no duty to do so. Detailed guidelines must be established to provide insights into how genomics professionals should be handled IFs.

The preferences of potential stakeholders in psychiatric genomic research regarding consent procedures and information delivery

BackgroundGenomic sequencing plays an increasing role in genetic research, also in psychiatry. This raises challenges concerning the validity and type of the informed consent and the return of incidental findings. However, no solution currently exists on the best way to obtain the informed consent and deliver findings to research subjects. AimsThis study aims to explore the attitudes among potential stakeholders in psychiatric genomic research toward the consenting procedure and the delivery of incidental findings. MethodsWe developed a cross-sectional web-based survey among five groups of stakeholders. A total of 2637 stakeholders responded: 241 persons with a mental disorder, 671 relatives, 1623 blood donors, 74 psychiatrists, and 28 clinical geneticists. ResultsThe stakeholders wanted active involvement as 92.7% preferred a specific consent and 85.1% wanted to receive information through a dynamic consent procedure. The majority of stakeholders preferred to receive genomic information related to serious or life-threatening health conditions through direct contact (69.5%) with a health professional, i.e. face-to-face consultation or telephone consultation (82.4%). Persons with mental disorders and relatives did not differ in their attitudes from the other stakeholder groups. ConclusionThe findings illustrate that the stakeholders want to be more actively involved and consider consent as a reciprocal transaction between the involved subjects and the researchers in the project. The results highlight the importance of collaboration between researchers and clinical geneticists as the latter are trained, through their education and clinical experience, to return and explain genomic data to patients, relatives, and research subjects.

Perspectives on Genetic Testing and Return of Results from the First Cohort of Presymptomatically Tested Individuals At Risk of Huntington Disease.

This qualitative study gathered opinions about genetic testing from people who received presymptomatic testing for Huntington's disease (HD) 20-30years ago and have lived with the implications of that testing for decades. During the last section of a semi-structured interview, participants were asked open-ended questions about their opinions on the importance of autonomy in the decision to be tested for HD, whether a formal HD testing protocol is necessary, whether physician ordering for HD is acceptable without a formal protocol, whether online direct-to-consumer (DTC) genetic testing for HD is acceptable, and whether incidental/secondary findings should be returned in the context of whole exome/genome sequencing. Most-but not all-participants were in favor of an individual's right to decide whether and when to pursue HD testing, use of a formal HD testing protocol, and returning medically actionable secondary findings. However, the majority of participants were opposed not only to physician ordering and DTC HD testing in the absence of a formal protocol but also to returning a secondary finding of an expanded HD allele. This study presents the opinions of a unique and extremely well-informed cohort on issues that need to be taken into careful consideration by genetic counselors and other medical professionals who are developing genetic testing protocols, making decisions about the availability of genetic tests, and making decisions about whether and how to return incidental findings.

Returning Incidental Findings in Low-Resource Settings: A Case of Rescue?

In a carefully argued article, Haley K. Sullivan and Benjamin E. Berkman address the important question of whether investigators have a duty to report incidental findings to research participants in low-resource settings. They suggest that the duty to rescue offers the most plausible justification for the duty to return incidental findings, and they explore the implications of this duty for the context of research in low-resource settings. While I think they make valuable headway on an important problem, in this commentary, I identify a significant difference between the paradigmatic rescue case and the return of incidental findings in low-resource settings. This difference, I suggest, implies that their framework may be too narrow in scope. If investigators (and their sponsors) really wish to fulfill their duty to rescue, they must consider factors that are left out of Sullivan and Berkman's framework.

Incidental Findings in Low-Resource Settings.

Much new global genetic research employs whole genome sequencing, which provides researchers with large amounts of data. The quantity of data has led to the generation and discovery of more incidental or secondary findings and to vigorous theoretical discussions about the ethical obligations that follow from these incidental findings. After a decade of debate in the genetic research community, there is a growing consensus that researchers should, at the very least, offer to return incidental findings that provide high-impact, medically relevant information, when it is not unduly burdensome to the research enterprise to do so. Much as genetic research has been limited to U.S. and European settings, the incidental findings debate has primarily focused on research conducted in high-income countries. In a 2015 paper, Alberto Ortiz-Osorno, Linda Ehler, and Judith Brooks note salient differences between the circumstances of research participants in low- and high-resource settings that alter the analysis of when and why incidental findings should be offered to research participants. In this article, we expand on their analysis and present a framework for thinking about how investigators' obligations to return genomic data might change in low-resource settings, particularly in settings where participants do not have access to the medical care needed to treat, assess, or monitor incidental findings that are actionable in settings with plentiful resources.

Patients' Attitudes Towards the Return of Incidental Findings After Research with Residual Tissue: A Mixed Methods Study.

To investigate the attitudes of patients toward the return of individual research results from scientific research with residual tissue. We recruited 1319 patients from 6 Dutch hospitals. In total, 673 patients (51% response rate) completed the questionnaire and 146 were interviewed. Based on the questionnaire data, the majority of respondents (92%) wanted to be informed of incidental findings about both a curable (92%) and an incurable (76%) disease. Respondents' wishes to be informed about incidental findings did not vary significantly as a function of patient demographics or type of disease. The interview data show that respondents wished to be informed about incidental findings because they considered it to be normal practice; they expected the information to be of benefit for their health. Information should be provided by their physician. Yet, most respondents (84%) would consent to research even if they would not be informed about incidental findings, primarily because they recognized that there might be practical problems in providing such information, and because they valued scientific research highly. We conclude that, while the majority of patients want to be informed about incidental findings, they also recognize that this may be difficult.

Value of Genetic Incidental Findings Related to Cancer Causing Genes

Purpose: Generation of incidental findings (IFs) from whole genome and exome sequencing raise several questions about the return of IFs to donors in the research setting. One important aspect that is highly understudied is whether individuals from the general public value the return of IFs and what individual characteristics are associated with these values. Methods: We used a willingness to pay (WTP) survey—an economic tool—to evaluate the values individuals place on the information provided by a genetic counseling consultation providing IFs for cancer causing genes. An online survey was administered through ResearchMatch, a national registry, in June 2015. Along with demographics, attitudinal and health-related questions, survey respondents were asked WTP questions to reveal the values for IFs information specifically for cancer causing genes. Results: The average WTP of 94 respondents was $161 (95% CI: $132-202) for a one-time IF consultation for cancer causing genes. Income was significantly associated with WTP. Respondents with annual household incomes ≥$80,000, on average, were WTP $75 more for a counseling consultation in comparison to those with incomes ≤$39,999 raising concerns for the ability to pay for IFs. The strongest predictor of WTP was respondents’ perceptions regarding the importance of genetic health information for preventing diseases. Conclusions: Understanding individuals’ value of information on IFs can help guide policy and normative recommendations. Future research should include individual preferences for return of IFs, explore if return of IFs may be harmful, and evaluate how it may impact subsequent treatment, health-related behaviors, non-health-related behaviors, and healthcare disparity. Implications for Cancer Survivors: This research provides insight into how individuals value identification of genetic related risk for cancer. This has important implications for those who may want to know if they are susceptible for re-occurrence risk and risk of family members.

DECIDE: a Decision Support Tool to Facilitate Parents' Choices Regarding Genome-Wide Sequencing.

We describe the rationale, development, and usability testing for an integrated e-learning tool and decision aid for parents facing decisions about genome-wide sequencing (GWS) for their children with a suspected genetic condition. The online tool, DECIDE, is designed to provide decision-support and to promote high quality decisions about undergoing GWS with or without return of optional incidental finding results. DECIDE works by integrating educational material with decision aids. Users may tailor their learning by controlling both the amount of information and its format - text and diagrams and/or short videos. The decision aid guides users to weigh the importance of various relevant factors in their own lives and circumstances. After considering the pros and cons of GWS and return of incidental findings, DECIDE summarizes the user's responses and apparent preferred choices. In a usability study of 16 parents who had already chosen GWS after conventional genetic counselling, all participants found DECIDE to be helpful. Many would have been satisfied to use it alone to guide their GWS decisions, but most would prefer to have the option of consulting a health care professional as well to aid their decision. Further testing is necessary to establish the effectiveness of using DECIDE as an adjunct to or instead of conventional pre-test genetic counselling for clinical genome-wide sequencing.

Genomic Big Data and Privacy: Challenges and Opportunities for Precision Medicine

Genome science is rapidly shifting from research labs and biobanks to the clinical setting. The resulting genomic big data, or large-scale networked genetic material, is a disruptive technology. On one hand, clinical genomics advances life-saving innovation through precision medicine. On the other, the digital databases they are built upon raise new concerns for informational risk to personal privacy. While a traditional biomedical approach focuses on risks and benefits to the human body, our socio-technical analysis sheds lights on the emerging terrain of the human body as digital code. In this paper, we analyze emerging issues related to clinical genomics based on a 3-year collaborative clinical research project to develop a genomic test for Acute Myeloid Leukemia (AML) cancer in British Columbia (BC), the first of its kind in Canada. We found the most pressing issues for genomic researchers and clinicians were challenges around informed consent, return of results and return of incidental findings. In light of technological advances and the emerging context of networked privacy, we outline several recommendations for best practices in diffusing clinical genomics to the healthcare system.

A Systematic Review of the Management of Incidental Findings in Genomic Research.

Information empowerment has been the greatest gain of genomics, yet it also poses serious threat to its survival, especially when the information is incidental. There may be an emerging consensus that actionable incidental findings be returned. But this has not been supported by any systematic review. Future directions are equally missing. These are significant gaps.To fill these gaps, an online search on PubMed and Genetics in Medicine website was conducted between 20th of August to 23rd of October, 2013; combining certain filters and phrases, such as ‘return incidental findings’. Nineteen (19) articles were selected from an avalanche of results, and reviewed. The review confirms a majority support for return of clinically actionable findings. The result also shows that the support represents views of Northern Americans. Critical contributions of Africans, Asians and Europeans are missing in this discourse. I recommended studies in this direction.

Abstract ED02-04: Returning germline results to cancer patients

Abstract Patient-centered communication, defined as providing clear, understandable information with active patient participation, can be especially challenging in the return of germline sequencing results for cancer patients. In this session, Dr. Plon will review some of the recently developed projects that involve performing whole exome or genome sequencing of pediatric and adult cancer patients including the return of germline results to patients/families as part of the study design. Several trials are well underway through the NHGRI Clinical Sequencing Exploratory Research Consortium including the Baylor College of Medicine Advancing Sequencing in Childhood Cancer Care (BASIC3) study which examines the clinical utility of tumor and germline WES in the setting of solid tumor (both CNS and non-CNS pediatric oncology patients). Issues that investigators need to consider which will be discussed include: (1) consenting patients/parents to clinical genomics, (2) the range of pathogenic mutations related to the patient's phenotype being returned, (3) how to handle variants of uncertain significance in cancer genes, (4) how to approach the return of incidental findings, (5) planning for the possibility of patient demise prior to return of results and (5) what forms of validation are being used prior to returning results including the issue of the potential for inferring germline results in tests that are designed to be “tumor only”. Dr. Plon will provide their experience with disclosure of germline whole exome sequencing results to parents of recently diagnosed childhood cancer patients in the BASIC3 study. The WES are disclosed to families by the patient's pediatric oncologist and one of two study genetic counselors. The disclosure visits (over 150 to date) are audio-recorded, transcribed and the text analyzed by Dr. Richard Street and his team using previously validated methodologies. The transcripts are analyzed for both the number of statements made by practitioners and families as well as more detailed analysis of disclosures with clinically important findings. The primary findings were: (a) the oncologists from this single large childhood cancer center varied greatly in how they utilized the genetic counselors during the encounters for discussion of both tumor and germline findings (b) genetic counselors made more recommendations based on the WES findings than did oncologists; (c) clinicians engaged in more partnership-building and supportive talk after they gained more experience presenting WES reports; and (e) checking for parent understanding was infrequent. Through this analysis we have developed a more streamlined format for disclosure which is generalizable to other germline findings and will be discussed in the session including: (1) there is substantial interest from families in obtaining germline findings when embarking on tumor sequencing, (2) families are less concerned about separating tumor and germline findings - their primary emphasis is on those genomic findings that result in specific actions for the patient or family members and (3) discussion of the more technical but less clinically relevant findings such as variants of uncertain significance can be minimized in disclosing genomic results. Supported by NHGRI/NCI 1U01HG006485. Citation Format: Sharon E. Plon. Returning germline results to cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr ED02-04.

65: Incidental Genetic Findings and Patient Preferences Regarding Return of Results in a Population of Patients With Unexplained Ataxia Undergoing Next-Generation Sequencing

Background: As broad-based genomics assays, such as whole exome and whole genome sequencing, are adopted as clinical diagnostic tools, the identification and reporting of incidental findings becomes a salient issue. The estimated chance of identifying a highly penetrant, pathogenic incidental finding is between 1%-5% in individuals seeking whole exome sequencing. We elicited patient preferences regarding return of incidental findings and developed methods for identifying such findings in a group of …

Societal preferences for the return of incidental findings from clinical genomic sequencing: a discrete-choice experiment.

An important challenge with the application of next-generation sequencing technology is the possibility of uncovering incidental genomic findings. A paucity of evidence on personal utility for incidental findings has hindered clinical guidelines. Our objective was to estimate personal utility for complex information derived from incidental genomic findings. We used a discrete-choice experiment to evaluate participants' personal utility for the following attributes: disease penetrance, disease treatability, disease severity, carrier status and cost. Study participants were drawn from the Canadian public. We analyzed the data with a mixed logit model. In total, 1200 participants completed our questionnaire (available in English and French). Participants valued receiving information about high-penetrance disorders but expressed disutility for receiving information on low-penetrance disorders. The average willingness to pay was $445 (95% confidence interval [CI] $322-$567) to receive incidental findings in a scenario where clinicians returned information about high-penetrance, medically treatable disorders, but only 66% of participants (95% CI 63%-71%) indicated that they would choose to receive information in that scenario. On average, participants placed an important value ($725, 95% CI $600-$850) on having a choice about what type of findings they would receive, including receipt of information about high-penetrance, treatable disorders or receipt of information about high-penetrance disorders with or without available treatment. The predicted uptake of that scenario was 76% (95% CI 72%-79%). Most participants valued receiving incidental findings, but personal utility depended on the type of finding, and not all participants wanted to receive incidental results, regardless of the potential health implications. These results indicate that to maximize benefit, participant-level preferences should inform the decision about whether to return incidental findings.

Stakeholders' perspectives on biobank-based genomic research: systematic review of the literature.

The success of biobank-based genomic research is widely dependent on people's willingness to donate their tissue. Thus, stakeholders' opinions should be considered in the development of best practice guidelines for research and recruiting participants. We systematically analyzed the empirical literature describing different stakeholders' views towards ethical questions with regard to type of consent, data sharing and return of incidental findings. Patients are more open to one-time general consent than the public. Only a small proportion desires recontact if the research aim changed. A broad consent model would prevent only a small proportion of patients from participating in research. Although professionals are concerned about a risk of reidentification, patients and the public support data sharing and find that the benefit of research outweighs the potential risk of reidentification. However, they desire detailed information about the privacy protection measures. Regarding the return of incidental findings, the public and professionals focus on clinically actionable results, whereas patients are interested in receiving as much information as possible. For professionals, concrete guidelines that help managing the return of incidental findings should be warranted. For this it would be helpful addressing the different categories - actionable, untreatable and inheritable diseases - upfront with patients and public.

Patients' views on incidental findings from clinical exome sequencing

This article characterizes the opinions of patients and family members of patients undergoing clinical genomic-based testing regarding the return of incidental findings from these tests. Over sixteen months, we conducted 55 in-depth interviews with individuals to explore their preferences regarding which types of results they would like returned to them. Responses indicate a diversity of attitudes toward the return of incidental findings and a diversity of justifications for those attitudes. The majority of participants also described an imperative to include the patient in deciding which results to return rather than having universal, predetermined rules governing results disclosure. The results demonstrate the importance of a patient centered-approach to returning incidental findings.

When Should Genome Researchers Disclose Misattributed Parentage?

Researchers need a decision-making framework about disclosing a finding of misattributed parentage that accounts for nonclinical factors like the effects of personal identity and familial relationships.

Translating genomic discoveries to the clinic in pediatric oncology.

The present study describes the recent advances in the identification of targetable genomic alterations in pediatric cancers, along with the progress and associated challenges in translating these findings into therapeutic benefit. Each field within pediatric cancer has rapidly and comprehensively begun to define genomic targets in tumors that potentially can improve the clinical outcome of patients, including hematologic malignancies (leukemia and lymphoma), solid malignancies (neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), and brain tumors (gliomas, ependymomas, and medulloblastomas). Although each tumor has specific and sometimes overlapping genomic targets, the translation to the clinic of new targeted trials and precision medicine protocols is still in its infancy. The first clinical tumor profiling studies in pediatric oncology have demonstrated feasibility and patient enthusiasm for the personalized medicine paradigm, but have yet to demonstrate clinical utility. Complexities influencing implementation include rapidly evolving sequencing technologies, tumor heterogeneity, and lack of access to targeted therapies. The return of incidental findings from the germline also remains a challenge, with evolving policy statements and accepted standards. The translation of genomic discoveries to the clinic in pediatric oncology continues to move forward at a brisk pace. Early adoption of genomics for tumor classification, risk stratification, and initial trials of targeted therapeutic agents has led to powerful results. As our experience grows in the integration of genomic and clinical medicine, the outcome for children with cancer should continue to improve.

Collectivizing Rescue Obligations in Bioethics

Bioethicists invoke a duty to rescue in a wide range of cases. Indeed, arguably, there exists an entire medical paradigm whereby vast numbers of medical encounters are treated as rescue cases. The intuitive power of the rescue paradigm is considerable, but much of this power stems from the problematic way that rescue cases are conceptualized—namely, as random, unanticipated, unavoidable, interpersonal events for which context is irrelevant and beneficence is the paramount value. In this article, I critique the basic assumptions of the rescue paradigm, reframe the ethical landscape in which rescue obligations are understood, and defend the necessity and value of a wider social and institutional view. Along the way, I move back and forth between ethical theory and a concrete case where the duty to rescue has been problematically applied: the purported duty to regularly return incidental findings and individual research results in genomic and genetic research.