Incidental findings: the time is not yet ripe for a policy for biobanks

Incidental findings (IFs) are acknowledged to be among the most important ethical issues to consider in biobank research. Genome-wide association studies and disease-specific genetic research might reveal information about individual participants that are not related to the research purpose, but may be relevant to those participants'' future health. In this article, we provide a synopsis of arguments for and against the disclosure of IFs in biobank research. We argue that arguments that do not distinguish between communications about pathogenic conditions and complex genetic risk for diseases fail, as preferences and decisions may be far more complex in the latter case. The principle of beneficence, for example, often supports the communication of incidentally discovered diseases, but if communication of risk is different, the beneficence of such communication is not equally evident. By conflating the latter form of communication with the former, the application of ethical principles to IFs in biobank research sometimes becomes too easy and frictionless. Current empirical surveys of people''s desire to be informed about IFs do not provide sufficient guidance because they rely on the same notion of risk communication as a form of communication about actual health and disease. Differently designed empirical research and more reflection on biobank research and genetic risk information is required before ethical principles can be applied to support the adoption of a reasonable and comprehensive policy for handling IFs.A much discussed problem associated with biobank research is the return to participants of incidental findings (IFs): ‘a finding concerning an individual research participant that has a potential health or reproductive importance and is discovered in the course of conducting research but is beyond the aims of the study.''¹ How should such information be handled ethically responsibly in genome-wide association studies and disease-specific genetic research?In this paper, we argue that the discussion up until now has neglected a distinction that should be held in the forefront of the discussion, especially concerning genetic biobank research: the distinction between an incidentally discovered disease and an incidentally discovered increased genetic risk for disease of unclear predictive value. Biobank research and rapidly increasing studies in genomics, proteomics, and nutrigenomics continue to identify many genes and biomarkers associated with risk of disease. Genetic testing for monogenic disorders are well established in health services, but little is yet known of the best way to handle complex risk information associated with multifactorial disorders in which the predictive importance of individual elements – genetic, epigenetic, or environmental – will differ for different individuals. The value of being informed about an incidentally discovered genetic risk (be it inherited or caused by a virus) is therefore much more difficult to ascertain than that for an incidentally discovered pathogenic condition revealed, for example, in a brain imaging study.The aim of this paper is to exhibit the absence of a distinction between disease and complex genetic risk for disease in the discussion, and to show how the arguments therefore fail to address the more complex kinds of IFs that increasingly arise in biobank research. Further research should be conducted before the arguments can be considered conclusive.Disease risks can be discovered also in imaging studies, of course, a blood vessel with thin walls can imply an increased risk for stroke. Our focus in this paper, however, is on genetic biobank research, where IFs increasingly concern multifactorial risks for disease having both genetic and environmental dimensions, which we believe introduce complications that so far have not been addressed.     

Managing incidental findings and research results in genomic research involving biobanks and archived data sets

Biobanks and archived data sets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings and individual research results of potential health, reproductive, or personal importance to individual contributors (using “biobank” here to refer both to collections of samples and collections of data). This article reports recommendations from a 2-year project funded by the National Institutes of Health. We analyze the responsibilities involved in managing the return of incidental findings and individual research results in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). We suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When reidentification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities to (1) clarify the criteria for evaluating findings and the roster of returnable findings, (2) analyze a particular finding in relation to this, (3) reidentify the individual contributor, and (4) recontact the contributor to offer the finding. We suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and are clinically actionable should generally be offered to consenting contributors. This article specifies 10 concrete recommendations, addressing new biobanks as well as those already in existence.Genet Med 2012:14(4):361–384     

To disclose,or not to disclose? Context matters

Progress in understanding childhood disease using next-generation sequencing (NGS) portends vast improvements in the nature and quality of patient care. However, ethical questions surrounding the disclosure of incidental findings (IFs) persist, as NGS and other novel genomic technologies become the preferred tool for clinical genetic testing. Thus, the need for comprehensive management plans and multidisciplinary discussion on the return of IFs in pediatric research has never been more immediate. The aim of this study is to explore the views of investigators concerning the return of IFs in the pediatric oncology research context. Our findings reveal at least four contextual themes underlying the ethics of when, and how, IFs could be disclosed to participants and their families: clinical significance of the result, respect for individual, scope of professional responsibilities, and implications for the healthcare/research system. Moreover, the study proposes two action items toward anticipatory governance of IF in genetic research with children. The need to recognize the multiplicity of contextual factors in determining IF disclosure practices, particularly as NGS increasingly becomes a centerpiece in genetic research broadly, is heightened when children are involved. Sober thought should be given to the possibility of discovering IF, and to proactive discussions about disclosure considering the realities of young participants, their families, and the investigators who recruit them.     

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.     

The beliefs, motivations, and expectations of parents who have enrolled their children in a genetic biorepository

PurposeLittle is known about parental attitudes toward return of individual research results (IRRs) in pediatric genomic research. The aim of this study was to understand the views of the parents who enrolled their children in a genomic repository in which IRRs will be returned.MethodsWe conducted focus groups with parents of children with developmental disorders enrolled in the Gene Partnership (GP), a genomic research repository that offers to return IRRs, to learn about their understanding of the GP, motivations for enrolling their children, and expectations regarding the return of IRRs.ResultsParents hoped to receive IRRs that would help them better understand their children’s condition(s). They understood that this outcome was unlikely, but hoped that their children’s participation in the GP would contribute to scientific knowledge. Most parents wanted to receive all IRRs about their child, even for diseases that were severe and untreatable, citing reasons of personal utility. Parents preferred electronic delivery of the results and wanted to designate their preferences regarding what information they would receive.ConclusionIt is important for researchers to understand participant expectations in enrolling in a research repository that offers to disclose children’s IRRs in order to effectively communicate the implications to parents during the consenting process.Genet Med 2012:14(3):330–337     

Down syndrome: issues to consider in a national registry, research database and biobank

As the quality of life for individuals with Down syndrome continues to improve due to anticipatory healthcare, early intervention, mainstreaming in schools, and increased expectations, the lack of basic information regarding individuals with Down syndrome is being recognized, and the need to facilitate research through a national registry, research database and biobank is being discussed. We believe that there should not be ownership of the samples and information, but instead prefer stewardship of the samples and information to benefit the participants who provided them. We endorse a model with data and sample managers and a research review board to interface between the investigators and participants. Information and samples would be coded, and only a few data managers would know the relationship between the codes and identifying information. Research results once published should be included in an online newsletter. If appropriate, individual results should be shared with participants. A Down syndrome registry, research database and biobank should be accountable to participants, families, medical care providers, government, and funding sources.     

Return of individual research results and incidental findings in the clinical trials cooperative group setting

The National Cancer Institute (NCI)-funded cooperative group cancer clinical trial system develops experimental therapies and often collects samples from patients for correlative research. The cooperative group bank (CGB) system maintains biobanks with a current policy not to return research results to individuals. An online survey was created, and 10 directors of CGBs completed the surveys asking about understanding and attitudes in changing policies to consider return of incidental findings (IFs) and individual research results (IRRs) of health significance. The potential impact of the 10 consensus recommendations of Wolf et al. presented in this issue are examined. Reidentification of samples is often not problematic; however, changes to the current banking and clinical trial systems would require significant effort to fulfill an obligation of recontact of subjects. Additional resources, as well as a national advisory board would be required to standardize implementation.Genet Med 2012:14(4):411–416     

Potential harms, anonymization, and the right to withdraw consent to biobank research

This paper discusses the potential harms involved in biobank research and how ethical review, informed consent, withdrawals, and anonymization of samples should be handled in the light of these harms. There is less risk involved in biobank research than in human subject research; it should therefore be treated differently. In our view, anonymization should not be an automatically permissible response to requests for withdrawal. Nor should a request for withdrawal necessarily stop research on identifiable samples. Apart from not being particularly appropriate for protecting the interests of individuals, anonymization of samples has a negative impact on research. We suggest that the current view on withdrawal from research, supported by the Declaration of Helsinki and subsequent ethical guidelines, be abandoned in the context of biobank research and be replaced by an approach inspired by the Nuremberg Code. This approach requires those wishing to withdraw their samples from research to present sufficient reason for doing so. Our interpretation of 'sufficient reason' includes all those involving genuine, deeply felt concerns that are not based on misconceptions. Still, this underlines the fact that we all share a responsibility for health research and that no one should take withdrawal from biobank research lightly.     

Choices of incidental findings of individuals undergoing genome wide sequencing,a single center's experience

Genome wide sequencing is an emerging clinical tool that may provide information on genetic variants that are not directly related to the patient's primary disorder. These incidental findings (IFs) may include information about conditions that can be treated and may also indicate conditions for which treatments are not currently available. Data is currently limited regarding what IFs an individual would want to disclose. This study reports on 305 individual choices for return of IFs that were completed at the Medical College of Wisconsin's clinical sequencing laboratory. Individuals were given access to five categories of IFs to select from: no incidental findings, untreatable childhood disorders, treatable adulthood disorders, untreatable adulthood disorders, and carrier of a disorder. Retrospective chart review was conducted and individual choices were recorded and analyzed. The majority of individuals (76.1%) selected every IF to be reported, 14.4% wanted a subset of the options, and 9.5% did not want any IFs reported. This study contributes to the limited data that demonstrates what an individual would actually choose when undergoing genetic sequencing. Furthermore, this data supports the opinion that individuals want and utilize the ability to choose the findings reported.     

Offering aggregate results to participants in genomic research: opportunities and challenges

Although issues involved in offering individual results to participants in genomic research have received considerable attention, communication of aggregate results has been the subject of relatively little ethical analysis. Offering participants aggregate results is typically assumed to be a good thing, and studies have found that a significant majority of biobank research participants, when asked about their interest in aggregate results, say that access to such information would be important. Even so, return of aggregate results remains a relatively uncommon practice. In this article, we explore the opportunities involved in communicating aggregate results to participants in genomic research, including affirming the value of research participation, informing participants about research being conducted based on broad consent for future unspecified research, educating participants and the public about the research process, and building trust in the research enterprise. We also explore some of the challenges, including the complex intersection between individual and aggregate results, as well as practical hurdles. We conclude by offering our preliminary recommendations concerning the provision of aggregate results and an agenda for much-needed future research.Genet Med 2012:14(4):490–496     

Evaluation of biobank constitution and use: multicentre analysis in France and propositions for formalising the activities of research ethics committees

Biobanks are collections of biological material and related files gathered and stored for clinical or research purposes. Here, we investigated the questions raised during the evaluation of biobanks by biomedical Research Ethics Committees (RECs), particularly in the context of genetic research. We sent a questionnaire to all RECs in France to survey their concerns and the ethical criteria used when evaluating research involving the storage of biological samples. Most of the RECs think that they should be consulted to evaluate the constitution of biobanks. The proportion of RECs of this opinion depended on whether the biobank is being constituted in the absence of an associated research project (initially created for clinical purposes or for undefined research) (14/28), whether the biobank is being constituted for research use (21/28) or whether an existing research biobank is being re-used (19/28). Views diverged concerning the way ethics principles are applied, showing that REC evaluations of biobanks might be formalised at each of the following steps: constitution, use and re-use. In this paper, we suggest concrete elements that could be integrated into the application of the new French law concerning the protection of the human beings participating in research as well as into international recommendations.     

Disclosure of insurability risks in research and clinical consent forms

Genetic testing results and research findings raise concerns about access to genetic information by insurers. Recently, the Canadian Life and Health Insurance Association reaffirmed its prerogative to request, for underwriting purposes, the disclosure of clinical and research genetic test results if the participant/patient or his physician has knowledge of the results. Studies have shown that access to genetic information to determine insurability can, in limited instances, lead to actual, or fear of, genetic discrimination, result in individuals refusing to undergo testing or declining participation in genomic research, and being asked to pay higher premiums or denied access to certain types of insurance. Obtaining informed consent for genetic testing and genomic research is crucial and should take into account the potential need to disclose possible insurability risks to patients and participants. Our study analyzed clinical and research consent forms, templates and guidelines from Quebec to investigate two questions: (1) whether consent forms include clauses providing information on potential insurability risks and (2) when such potential risks are included, what information is provided and how it is formulated. Our findings show that current information on insurability risks in Quebec’s forms/guidelines lack coherence, potentially resulting in patients/participants receiving inconsistent information.     

Two large-scale surveys on community attitudes toward an opt-out biobank

Although US research regulations allow for de-identified biorepositories to be developed without formal informed consent from the patients whose samples are included, it is unknown whether this model will be well-received by community members. Based on early evidence that such a biobank could be successful if patients who object have the opportunity to opt-out, Vanderbilt University developed a biorepository named BioVU that follows this model. This study reports the findings from two large-scale surveys among communities important to this biorepository. In the first, a population-based phone survey of Nashville residents, we found that approval for BioVU is high (93.9%) and that this approval is similar among all population groups. A hypothetical biobank that does not obtain some form of written permission is much less well received. In the second, an online survey of Vanderbilt University faculty and staff, we found a higher level of support for BioVU (94.5%) among faculty and staff working throughout the university. In this survey, employees least likely to approve of BioVU are those employees who prefer not to receive medical care at Vanderbilt University. These surveys demonstrate the highest level of approval for a genomic biobank ever reported in the literature, even among groups traditionally cautious about such research. This high level of approval may reflect increasing comfort with genomic research over time combined with the effect that trust in a specific institution can have on approval for an operating biobank compared with approval of a hypothetical biobank.     

From gene function to improved health: genome research in the United Kingdom

The United Kingdom has a prestigious track record in genetic and genomic research, with the structure of DNA, and delivery of a third of the human genome being significant landmarks. UK genomic research benefits from a variety of funding sources in both the public and private sector, and efforts to co-ordinate research strategies. Here we describe how this investment has impacted on the UK research capacity and highlight examples of progress in translating genetic information into improved healthcare.     

BioGrid Australia facilitates collaborative medical and bioinformatics research across hospitals and medical research institutes by linking data from diverse disease and data types

BioGrid Australia is a federated data linkage and integration infrastructure that uses the Internet to enable patient specific information to be utilized for research in a privacy protected manner, from multiple databases of various data types (e.g. clinical, treatment, genomic, image, histopathology and outcome), from a range of diseases (oncological, neurological, endocrine and respiratory) and across more than 20 health services, universities and medical research institutes. BioGrid has demonstrated an ability to facilitate powerful research into the causation of human disease and the prediction of disease and treatment outcomes. BioGrid has successfully implemented technology and processes that allow researchers to efficiently extract data from multiple sources, without compromising data security and privacy. This article reviews BioGrid's first seven years and how it has overcome 9 of its top 10 challenges.     

Categorization of cancer through genomic complexity could guide research and management strategies

Cancer management decisions are currently informed by cancer type and clinical stage, as well as age, health condition, and individual patient needs. Cancer is a genetic disease and recent genomic studies have revealed the genomic landscape of multiple tumour types. This has led to readily available catalogues of genomic features for many cancers and efforts to incorporate such information into treatment decisions. From this has evolved the concept that mutation‐based taxonomies may supersede the current cell of origin‐based categorization of neoplasia. Unfortunately, genomic features as clinically actionable information may not be directly transferable between tumour types, due to the importance of cellular and genomic context. However, we believe that high‐level views of different genomic landscapes could broadly inform research study design and treatment strategies. Herein, we use ovarian and bone cancer as examples to propose a genomic complexity‐based categorization for cancer. In addition to informing clinical study design, we describe how this categorization scheme could impact (i) improvement of accuracy of histological diagnoses, (ii) stratification of patients for targeted therapies, (iii) research study design, and (iv) personalized treatment strategies. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Am I a control?: Genotype-driven research recruitment and self-understandings of study participants

PurposeGenotype-driven research recruitment complicates traditional study roles and may leave those recruited worried about unwelcome surprises from their DNA. This study investigated the ways that individuals experience genotype-driven recruitment, and conceptualize their roles as research participants.MethodsIndividual interviews were conducted with the participants of a genotype-driven study on cystic fibrosis. The eligibility criteria included the presence of one of two genetic variants. We interviewed 24 of these participants: 9 had cystic fibrosis and 15 had been selected from a biobank as “healthy volunteers.”ResultsParticipants with cystic fibrosis expressed no concerns about the eligibility criteria and saw themselves as part of a close-knit research community. However, biobank participants were unsure about why they had been selected and how they should think about themselves relative to the study. They sometimes reacted with anxiety to genetic information that they perceived to connect them with cystic fibrosis.ConclusionBeing recruited for a study on the basis of one’s genotype may raise uncertainties about the meaning and implications of the genotypic information. People without the disease under study may require especially clear and detailed explanations of what researchers already know about their genetic makeup, in terms of future risk for themselves or their children.Genet Med 2012:14(12):983–989     

Researchers' opinions towards the communication of results of biobank research: a survey study

Eighty Dutch investigators (response 41%) involved in biobank research responded to a web-based survey addressing communication of results of biobank research to individual participants. Questions addressed their opinion towards an obligation to communicate results and related issues such as ownership of blood samples, privacy, therapeutic relationship, costs and implications for participants. Most researchers (74%) indicated that participants only have to be informed when results have implications for treatment or prevention. Researchers were generally not inclined to provide more feedback to patients as compared with healthy participants, nor were they inclined to provide feedback in return for participants' contribution to the biobank. Our results demonstrate major and significant differences in opinion about the feedback of individual results within the community of biobank researchers.