Stakeholder Views on Returning Research Results

CHAPTER TWO

Stakeholder Views on Returning Research Results Susanne B. Haga1, Jennifer Q. Zhao Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, USA 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. What is a Research Result? 3. Guidelines on Returning Research Results 3.1 Biobanks 3.2 Population-based studies 4. Stakeholder Views 4.1 Researchers 4.2 IRBs 4.3 Research participants 5. Extent and Experience with Returning Research Results 6. Overall Analysis of Stakeholder Positions 6.1 Ethical 6.2 Legal 7. Additional Points to Consider 7.1 Informed consent for returning research results 7.2 Communication of research results 7.3 Impact of returning results to affected versus healthy participants 7.4 Provision of follow-up care 7.5 Cost 8. Moving Forward Acknowledgment References

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Abstract While the disclosure of research findings is relevant to all types of biomedical research, it has garnered particular attention with respect to genetics and genomics research due to some of the unique aspects of the data and the high public profile of the field. In this chapter, we review the attitudes of stakeholders (research participants, policymakers, and researchers) to define areas of consensus regarding the issue of returning research results across and within groups. In addition to stakeholder attitudes about obligations and interest in research results, other major related issues related to returning research

Advances in Genetics, Volume 84 ISSN 0065-2660 http://dx.doi.org/10.1016/B978-0-12-407703-4.00002-5

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2013 Elsevier Inc. All rights reserved.

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results, such as informed consent, communication of research results, and cost, are discussed. Given the consensus between stakeholders to return summary reports of a study's outcomes and individual research results of clinical significance, we conclude that the time has come to encourage, if not require, researchers to consider these issues in the developmental planning stages of a project and to plan and budget accordingly.

1. INTRODUCTION Since the completion of the Human Genome Project, vast amounts of genetic and genomic information have been produced from thousands of consenting research participants. Array-based and sequencing technologies have improved and become cheaper and easier to do, resulting in widespread use of these technologies and subsequent generation of large datasets (Mardis, 2011). Alongside advances in genome technologies, the culture and practice of clinical research has become more patient-centered (Kaye et al., 2012), and participants have become more engaged in the research enterprise (Phipps, Fleetwood, & Piraino, 1999; Psillidis, Flach, & Padberg, 1997), playing a greater role in establishing biorepositories and collaborating with researchers (Landy et al., 2012; Terry, Terry, Rauen, Uitto, & Bercovitch, 2007). Additionally, in the clinical setting, the patient–provider relationship is facing changes with the implementation of electronic medical records and convenient patient access to their health information. With the coevolving research dynamics and changes in genomic and informational technologies, it should serve as no surprise that debates have ensued about research participants’ right to access their individual data and researchers’ duty to return research results. The public’s interest in genetics and genomics and associated ethical, legal, and social issues further contribute to this ongoing debate, complicating development of a consensus policy. In this chapter, we will explore the views of key stakeholders (researchers, institutional review boards, and research participants) on this controversial issue and related issues such as informed consent, communication of research results, and cost. This inherently complex issue will continue to pose major challenges for how best to resolve; however, it appears that a consensus is emerging between the stakeholder groups on returning some types of results and now is the time for every researcher to address this issue in their study’s protocols and consent documents.

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2. WHAT IS A RESEARCH RESULT? For more than a decade, the issue of returning research results, particularly in genetics research, has been the topic of great debate. Before considering the issue in depth, it is important to first clarify what is meant by “return of results” (Knoppers & Dam, 2011). Returning research results can refer to at least three types of results: (1) a summary of the study’s findings that does not include any personal data; (2) an individual research result for a participant that would be anticipated, related to the purpose of the study (e.g., a genetic variant associated with heart disease from a study on the genetic risks of heart disease); and (3) an individual research result that was unanticipated and revealed in the analysis of a comprehensive genomics dataset, generally referred to as an “incidental” finding (IF). Broad testing platforms such as whole genome sequencing (WGS) or whole exome sequencing (WES) will enable detection of genetic variants associated with many phenotypes and most certainly result in an increased number of IF results detected (Kohane, Masys, & Altman, 2006). Analysis of a research participant’s whole genome may identify 3955–12,579 genetic findings that warrant disclosure to research participants, a number expected to increase as the clinical significance of new genetic variants is discovered (Cassa et al., 2012). Likewise, incidental findings have also become a critical issue with the clinical use of WGS/WES, leading to the development of guidelines recommending IF disclosure (or offer to disclose) for 57 conditions about disease risk and carrier status (Green et al., 2013).

3. GUIDELINES ON RETURNING RESEARCH RESULTS Several guidelines have been developed with recommended criteria for when to return research results, for any type of study, or for genetic studies specifically and reviewed in depth in several papers (Beskow et al., 2001; Bookman et al., 2006; Canadian Institute of Health Research, 2012; Cassa et al., 2012; Dressler, 2009; Knoppers, Joly, Simard, & Durocher, 2006; National Bioethics Advisory Commission, 1999; National Heart, Lung and Blood Institute, 2004a; National Human Genome Research Institute, 2010; Board on Life Sciences, 2005; Quaid, Jessup, & Meslin, 2004; Terry, 2012; WHO, 1998). In general, while positions have varied between professional, government, and ad hoc groups, it appears that there is growing

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support for the return of individual results over the past decade (Dressler, 2009). In contrast, many research institutions do not have definitive guidelines or policies regarding the return of results and how and by whom these decisions should be made (Dressler et al., 2012). A common denominator of many current policies is the requirement that disclosed results not be harmful and be clinically useful (Shalowitz & Miller, 2005). For example, the NHLBI (Bookman et al., 2006; Fabsitz et al., 2010) identified the availability of a clinical intervention (treatment or preventative) as a key criterion if results were to be returned to study participants. The high bar of clinical validity and utility may be due to the predictive nature of genetic information and its implications for family members (MacNeil & Fernandez, 2006b; Shalowitz & Miller, 2005) but potentially unrealistic to achieve (Biesecker, 2013). Ironically, many clinical genetic tests have not been shown to have more personal utility than clinical utility (Foster, Mulvihill, & Sharp, 2009; Grosse, Kalman, & Khoury, 2010; Grosse & Khoury, 2006). While there is widespread agreement on the criterion of clinical significance, there is some debate about how exactly that should be defined. Some guidelines have defined a specific level of risk (relative risk of 2.0) for a research result to be returned (Bookman et al., 2006), but this was not included in the subsequent revision of the guidelines (Fabsitz et al., 2010). It is of particular interest to note that most groups did not include public or consumer participation, although consideration of participant preferences has been recognized as part of showing respect to participants (Dressler et al., 2012). Most guidelines do not distinguish between anticipated research results and incidental findings. In 2010, Canada’s Tri-Council Policy Statement 2 (TCPS2) states that “researchers have an obligation to disclose. . . any material incidental findings. . .” (italics added; Panel on Research Ethics, 2010). It is worth noting that in the debate about return of incidental findings revealed from clinical WGS/WES testing, there also appears to be general consensus that results with clinical utility should also be returned to patients (Lemke, Halverson, & Ross, 2012). However, there remains substantial discordance between groups about exactly what constitutes a result of clinical significance (Green et al., 2012; Grove, Wolpert, Cho, Lee, & Ormond, 2013). The American College of Medical Genetics and Genomics recommended 57 conditions for which risk should be offered to patients undergoing WGS/WES (Green et al., 2013), although some debate has ensued since the recommendations were published (Burke et al., 2013; Wolf, Annas, & Elias, 2013). Klitzman et al. (2013) suggested that this list could be

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modified for research, but do not specify what changes might be made. A research consortium, known as the Electronic Medical Records and Genomics (eMERGE) Network, discussed a different set of conditions for which research results should be returned to participants (Fullerton, Trinidad, Jarvik, & Burke, 2012).

3.1. Biobanks Biobanks raise a different set of challenges than traditional single investigator-led research studies with respect to the issue of returning research results. Biobanks are not typically directly involved in the generation of data, but facilitate the conduct of research on tissue specimens that they collect and maintain (Wallace & Kent, 2011). Studies using biobank samples tend to be more exploratory, hypothesis-generating rather than hypothesis-testing, and thus, such findings would lack validation. As a result, since many genetic association discoveries are not validated (Ioannidis, 2007), researchers may be strongly reluctant to disclose individual results. While biobanks may have a vested interest to advance the health of its donors, such as with a national biobank supported by public funds, they may be considered the “middle man” or firewall between donors and researchers, protecting the identity of donors while accommodating the needs of their “clients” (researchers). Individuals that donate tissue specimens to a biobank typically sign a broad consent allowing for their sample to be used by multiple researchers for different studies. Keeping track of which sample has been included in what study and then having the biobank serve as a mediator between the researcher and donor can be an extremely complex, if not an unreasonable, task. Thus, it is of no surprise that biobank policies vary considerably on the return of research results (Forsberg, Hansson, & Evers, 2013; Haga & Beskow, 2008; Terry, 2012; Wolf et al., 2012), if the issue is even addressed at all ( Johnson, Lawrenz, & Thao, 2012b). In their study of research involving human biological tissues, the National Bioethics Advisory Commission (1999) recommended that IRBs require investigators to address plans to return research results in their study proposal. The UK Biobank will post summaries of study findings for which biobank samples have been used, but an individual donor will not likely know which study(ies) their tissue sample was used in. The information leaflet available to prospective donors clearly states that “none of your results will be given to you or your doctors (even if the results do not seem to be normal)” (UK Biobank Information

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Leaflet, 2010). In contrast, the national biobank of Estonia permits access to individual results and even provides access to a genetic counselor upon request (Estonian Genome Center, 2001). A review of international genomic biobank policies and guidelines reported ambiguity in statements regarding return of results, particularly between anticipated research results and incidental findings, and potentially misleading language of the therapeutic benefit of results (Zawati & Knoppers, 2012). Some have advocated for the return of clinically actionable results for serious conditions if the identity of the biobanked sample can be traced to the donor (Wolf et al., 2012). A cryptographic approach could be used to protect the identity of the participant if results are returned (Hunter, Hopfer, Terry, & Coors, 2012).

3.2. Population-based studies Likewise, large population-based studies share many of the same characteristics of biobanks, posing similar challenges to the return of results (Knoppers, Deschenes, Zawati, & Tasse, 2013). Such studies can last many years and span generations of families, and the oft-used open consents mean that participants may not be aware of what studies their samples are used for. Some large research initiatives, such as the Coriell Personalized Medicine Collaborative (CPMC), offer participants access to data that are deemed to have clinical significance as decided by an oversight board (Keller et al., 2010). In contrast, the Personalized Genome Project provides a report to all participants of genetic variants with some association with a given phenotype and posts all sequence data and other clinical information about participants online, available to the general public and participants (Ball et al., 2012). The Public Population Project in Genomics and Society released a policy guidance in 2013, recommending that general findings should be disseminated to participants when possible (Knoppers et al., 2013). Specifically, for studies where the consent included an option for the return of results, the group recommended if the results are analytically valid and clinically significant and actionable, researchers should consider returning the results (Knoppers et al., 2013). However, the logistics of returning results to participants in large-scale studies may make it impossible to do so (Edwards et al., 2011).

4. STAKEHOLDER VIEWS Three primary stakeholders in the debate about returning research results are researchers, institutional review boards (IRBs), and participants (or the parent/guardian of a minor). This trifecta represents those who

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design, carry out, and potentially will communicate research results to participants (researchers); those who govern the conduct of human subjects research (IRBs); and those who consent to participate in research and are ultimately impacted by the research results they receive (participants). Several studies have explored the attitudes of these three groups, showing a difference of opinion within and between stakeholders and changes in attitudes over time (particularly of researchers). Other groups such as clinicians, funding agencies, professional organizations, patient advocacy groups, and family members also may be affected by or involved in decisions regarding the return of results to research participants. However, despite the numerous studies and growing experience with returning results, the issue remains largely unresolved, being addressed on case-by-case decisions about the return of research results.

4.1. Researchers Many studies of researchers’ attitudes regarding return of results have been conducted. Overall, the return of a summary report of the study’s outcomes is widely supported by researchers (Cox, Moghaddam, Bird, & Elkan, 2011; Dressler, 2009; Miller, Hayeems, Li, & Bytautas, 2012b; Partridge et al., 2004; Partridge & Winer, 2002; Rigby & Fernandez, 2005). The National Cancer Institute’s Children’s Oncology Group, a multisite research network, recently develops a policy specifically regarding the return of summary reports, recommending that they be provided for several types of studies and made easily accessible to participants through a website (Fernandez et al., 2012). Summary reports are often considered the least burdensome for researchers to disseminate but show respect to participants and enable them to gain some sense of fulfillment that they contributed to advancing the current understanding of a disease. Furthermore, summary reports may be the only type of feedback that can be provided if the samples are collected anonymously or pooled. However, these study summaries may dilute the value of results as participants will be left with uncertainty regarding the significance of the findings for their health (e.g., whether they were found to be at high or low risk and whether they were in inferior or placebo arm) (Cox et al., 2011; Shalowitz & Miller, 2005). With respect to individuals’ results, several studies have reported that researchers also support the return results of clinical significance to participants (Edwards et al., 2011; Hayeems, Miller, Li, & Bytautas, 2011; Partridge et al., 2004; Ramoni et al., 2013). However, this current position

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has evolved from general reluctance to return results a few decades ago and the desire to strictly separate the goals of research and clinical care. Some scholars and researchers appear uncertain about their obligation to return results and have expressed concerns of harming participants given the uncertainty of many of the findings (Johnson, Lawrenz, & Thao, 2012a; Johnson, Ross, & Thao, 2006; Miller, Christensen, Giacomini, & Robert, 2008; Miller, Ross, Giacomini, & Robert, 2008; Zawati & Rioux, 2011). One of the most pressing challenges faced by researchers is deciding what type of result should be returned (Miller, Christensen, et al., 2008). While there is general consensus that the result should be clinically significant, defining “clinical significance” is challenging (Hayeems et al., 2011; Klitzman et al., 2013). Despite all of the available data, lack of clarity in the interpretation of genetic data and uncertainty about the severity of conditions in different populations create a difficult task to determine if certain genetic data are clinically relevant enough to be presented to participants. In addition, positive predictive value, penetrance, and potential personal utility should be considered. However, the question remains of how one should define the thresholds for each of these factors. In fact, in one study, genetics researchers assigned a higher value to the level of penetrance than clinical utility (Klitzman et al., 2013). To illustrate the divided opinions among researchers, study sites of an international registry study developed different policies regarding return of individual results, mainly differing based on each site’s interpretation of whether certain variations were clinically significant (Keogh et al., 2013). The criteria for returning incidental findings do not appear to differ from anticipated (or unspecified) research results, as researchers have indicated that anticipated data should also demonstrate clinical utility before being offered to participants (Brandt et al., 2013; Klitzman et al., 2013). One study reported that a sizable proportion of researchers (19%) were supportive of returning results of unknown clinical significance (Hayeems et al., 2011); 16% would offer to provide all genetic variants identified through WGS/WES (Klitzman et al., 2013). Researcher attitudes have also been ascertained for a number of related issues to returning results. For example, regarding their perceived duty to search for incidental data with demonstrated clinical utility in a genomics dataset, a survey of Canadian researchers reported that they did not feel an obligation to search for such results in genomics datasets (Fernandez et al., 2013). If the results were otherwise identified, however, the researchers indicated that participants had a right to access them, regardless if they were incidental or anticipated results (Fernandez et al., 2013).

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Regarding return of results for children (to parents/guardians), genetics researchers have indicated that clinically significant, highly penetrant results such as BRCA1 or BRCA2 should be offered (Klitzman et al., 2013). In addition, the same survey reported that more than half believed that carrier status data should also be made available to children and their guardians (Klitzman et al., 2013). These beliefs are in contrast to the current clinical guidelines for genetic testing in children, which recommend that testing in children be performed only when results can inform immediate clinical care; otherwise, testing should be delayed until the child reaches an age when they can consent (Fallat et al., 2013; Ross, Saal, David, & Anderson, 2013).

4.2. IRBs IRBs serve to protect the welfare of research participants, but it is not quite clear what their role is with respect to returning results. Despite the many recommendations that have been developed, there is no national consensus policy, and thus, IRBs are left with developing their own institutional policy or adopting an existing set of recommendations deemed appropriate for their institution and community. A review of publicly available documents from IRB websites showed variability and sometimes conflicting statements with respect to the type of result mentioned and institutional policy on (non)disclosure in informed consent templates or guidance documents (Simon, Shinkunas, Brandt, & Williams, 2012). However, the small number of reported IRB policies suggests that research institutions are struggling to develop policies on returning research results, leaving researchers unsure about how to address the issue, if at all (Kozanczyn, Collins, & Fernandez, 2007; MacNeil & Fernandez, 2006a). Indeed, most researchers in one study reported that they were unaware of their institution’s policy regarding return of research results or believed that they did not have a specific policy available (Fernandez et al., 2013). The existence of an institutional policy may be impacted by the attitudes and interests of IRB chairs and members on the issue of returning results. One survey reported strong support of IRB chairs for returning results (MacNeil & Fernandez, 2006a). Lemke, Trinidad, Edwards, Starks, and Wiesner (2010) reported that 78% of individuals involved in human subjects protections (primarily IRB members) believed that researchers had an ethical obligation to return individual results with clinical significance. Similarly, findings of a survey of IRB members found that a high proportion

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agreed that individual results of clinical significance should be made available to research participants, but only if the participant has agreed to be recontacted about anticipated results or an incidental finding (Dressler et al., 2012). However, for an untreatable disease such as Alzheimer disease, one study found that IRB chairs were divided on whether results should be returned to participants (Wolf, Catania, Dolcini, Pollack, & Lo, 2008). Alternatively, the lack of institutional policies may be due to IRBs’ uncertainty regarding their exact role on returning results, perhaps perceiving themselves as more of an overseer or partner with researchers rather than the final arbiter on returning results for a given study (Dressler et al., 2012). Furthermore, if clinical utility is a required criterion for results to be returned to participants, IRBs may find themselves in a position outside of their role of research oversight, and thus, their authority is unclear (Dressler et al., 2012). Some have suggested that IRBs need to take a more active role in reviewing studies to identify potential incidental findings that should be offered to research participants (Keane, 2008), whereas others have suggested a collaborative approach between participants, IRBs, and researchers to determine the most appropriate policy for their local institution (Dressler, 2009; Dressler et al., 2012).

4.3. Research participants The success of large-scale genomics research initiatives will depend on the support and participation of the public, and therefore, their views are critically important on the issue of returning research results. As such, several studies have reported that the majority of participants favored access to individual results (Bollinger, Scott, Dvoskin, & Kaufman, 2012; Fernandez et al., 2007; Kaufman, Murphy, Scott, & Hudson, 2008; Lakes et al., 2013; Murphy et al., 2008; O’Daniel & Haga, 2011; Partridge, Burstein, Gelman, Marcom, & Winer, 2003; Snowdon, Garcia, & Elbourne, 1998), even results with no known clinical significance (Bollinger et al., 2012; Daack-Hirsch et al., 2013; Kaufman et al., 2008; Meulenkamp et al., 2010; Wendler & Emanuel, 2002), or if the data are upsetting (Schulz, Riddle, Valdimirsdottir, Abramson, & Sklar, 2003). Furthermore, several studies have reported that participants desire to be involved in decisions about what types of data should be disclosed or not (Bollinger et al., 2012; Kaufman et al., 2008; Lakes et al., 2013; Murphy et al., 2008; O’Daniel & Haga, 2011). A survey of participants in genetics research in the United States and Spain reported that 48% desired to always have access

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to individual research results; 25% indicated they would only be interested in results with clinical significance (Ruiz-Canela, Valle-Mansilla, & Sulmasy, 2011). Similarly, patient advocacy groups supported the return of research results to participants, whether positive or negative (Partridge & Winer, 2002). Research participants are also interested in receiving summary reports of a study’s outcomes (Cox et al., 2011; Meulenkamp et al., 2010; Partridge et al., 2003) but, given the choice, prefer to have access to individual research findings (Dixon-Woods, Jackson, Windridge, & Kenyon, 2006). One major concern with returning results is the issue of therapeutic misconception or participants who enroll in a research study believing that they will gain some medical benefit (Clayton & Ross, 2006; Meltzer, 2006). In particular, participants may enroll in a research study for the explicit purpose of obtaining information not otherwise possible about their condition or that of their child’s (Baret & Godard, 2011; Sanderson et al., 2013). The return of results can further conflate participants’ misunderstanding of the purpose of research and lead to confusion about the significance of the results to their health or that of their family members (Clayton & Ross, 2006). But some have reported that participants can distinguish between a clinical test and a research finding (Baret & Godard, 2011), and thus, perhaps with the appropriate educational materials and informed consent, this issue may not pose a major problem. Some participants may simply desire to learn of the research findings but have no intention to “use” or expect to clinically benefit from the result (Baret & Godard, 2011). 4.3.1 Vulnerable populations: Children Some discussion has also occurred about returning research results to children (Abdul-Karim et al., 2013; Avard, Senecal, Madadi, & Sinnett, 2011; Hens, Nys, Cassiman, & Dierickx, 2011). As children are unable to consent to the return of research results (as well as to their participation in the study), their lack of decision-making and autonomy poses an ethical dilemma. Thus, the decision to return results that are not of immediate benefit to the child and potentially of weak validity should be carefully considered. In the clinical setting, decisions on genetic testing in children should be motivated by the benefits to the child (Fallat et al., 2013; Ross, Saal, David, & Anderson, 2013), though if testing is not for immediate benefit, it should be delayed until the child reaches an age where she/he can participate in the decision-making process (assent to testing) and/or legally provide informed consent (Wilfond et al., 1995).

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Parents may perceive significant benefit from having access to their child’s research results and some benefits may accrue not only to the child but also to the family (Fallat et al., 2013). African–American parents that had consented to enroll their children in biobank-based research were interested in the results for their children and believed they should be involved in such decisions (Halverson & Ross, 2012). Some parents seek to access research results of their child in order to gain some insight and “peace of mind” about the cause of their child’s condition (Miller, Hayeems, & Bytautas, 2010). Even if the results were anticipated to be distressing, parents and adolescents enrolled in cancer research were interested in learning of the research results (Fernandez, Taweel, Kodish, & Weijer, 2005) and overwhelmingly believed they had a right to the results (Fernandez et al., 2007, 2009). The majority of adolescents and parents recognized the need for the results to undergo some type of review prior to disclosure, but they also felt strongly that they should not be the “last to know” (Fernandez et al., 2007).

4.3.2 Underserved minority populations Far fewer reports have been published about the attitudes of underserved minority groups on the issue of returning research results. Given the underrepresentation of minorities in genomics research (Haga, 2010; Kanakamedala & Haga, 2012) and disparities in having clinical genetic testing (Armstrong, Micco, Carney, Stopfer, & Putt, 2005; Forman & Hall, 2009; Suther & Kiros, 2009), understanding of their attitudes about this issue may help determine how it may impact the likelihood of participation in genetics research overall. Of the handful of papers published, the majority of individuals of minority populations are interested in accessing their research results (Lemke, Bick, Dimmock, Simpson, & Veith, 2013; Lemke et al., 2012; O’Daniel & Haga, 2011; Yu, Crouch, Jamal, Tabor, & Bamshad, 2013). One of the main reasons that minorities may participate in biobanks or genomics research is to learn more about their personal disease risks and that of their family, suggesting that participants are anticipating return of some data and likely confusing clinical testing and research (Lemke et al., 2012; Sanderson et al., 2013; Streicher et al., 2011). However, some reasons why minorities may not be interested in learning of their research results may differ from other groups, such as lack of trust, psychological impact, lack of access to health care, and access by law enforcement to their research results (Yu, Crouch, et al., 2013). In addition, other risks with obtaining individual research results such as loss of

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confidentiality, lack of financial support to obtain follow-up care, and distress have been reported (Lemke et al., 2012). From a community perspective, sharing of even a summary of the study’s findings may show respect to the community and those who participated and researchers’ interest in promoting the welfare of the group. For example, participants from the North American aboriginal Mohawk community greatly appreciated learning about a study’s findings for their community regarding diabetes and heart disease (Montour & Macaulay, 1998). As a result, several changes were made across the community to reduce the risk of these diseases, and many individuals sought help to evaluate their personal risk and adopt healthier lifestyles (Montour & Macaulay, 1998). 4.3.3 Returning research results to relatives of research participants In the clinical setting, there has been a long-running debate about the return of genetic test results to relatives who may clinically benefit from the knowledge, potentially seeking testing for themselves (Offit, Groeger, Turner, Wadsworth, & Weiser, 2004). In the research setting, a related issue is the return of results to relatives of deceased participants (Black & McClellan, 2011). Both researchers and participants have expressed support for the return of a summary report of the study’s outcomes to families of deceased participants (Cox et al., 2011; Partridge et al., 2003). However, it has been argued that disclosing a participant’s research results to family members may violate HIPAA rules (Rothstein, 2012). With respect to individual results, the debate also appears to revolve around the same issues as with returning results to participants. Chan et al. (2012) reported their group’s experience with returning research results to relatives of a deceased participant in the ClinSeq study. In this case, the research team had contacted the research participant to complete some follow-up assessments and learned that the participant had passed away. Family members of the deceased participant, many of whom were first-degree relatives, requested access to the genotype data gathered from the study. Since clinically significant results were made available to all study participants (Biesecker et al., 2009) and first-degree relatives may benefit from knowledge of the findings, the research team acquiesced to the family’s request for the genotype data. Based on their experience, the ClinSeq research team advocates a “passive” approach of disclosure to family members of deceased research participants (e.g., disclosing results upon request only). Ormondroyd et al. (2007) reported that family members recognized the risk of anxiety (and some experienced it) with learning of a deceased family member’s genetic risk

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for breast cancer identified in a research study but still decided it was in their best interest given the high risk and available options for intervention. Likewise, parents may exhibit a range of psychological reactions upon learning of the likely genetic cause or diagnosis of a deceased child (Sexton & Metcalfe, 2008). Similar to clinical practice guidelines, international guidelines have favored return of results to participants’ relatives if they may substantially benefit (Knoppers et al., 2006). In a commentary about the Chan group’s experience and in contrast to the policy developed for the ClinSeq study (Chan et al., 2012), Fullerton et al. (2012) recommended that research results of clinical utility be offered to family members, preferably first-degree relatives who would benefit the most. A survey of Canadian genomics researchers supported returning results to family members (i.e., siblings), particularly if there were available clinical interventions (Fernandez et al., 2013).

5. EXTENT AND EXPERIENCE WITH RETURNING RESEARCH RESULTS Despite current evidence that research participants would like the option of accessing research results and the growing support of researchers and IRBs, even if of little clinical utility, the practice does not appear to be very common (Table 2.1). Several reasons have been given for not returning results, including time constraints, costs, effort required to recontact participants, lack of national or institutional policies or protocols, limited access to genetic counselors or other clinical providers to return results, psychological harm, and potential for therapeutic misconception (Fernandez, Kodish, Shurin, & Weijer, 2003; Hayeems et al., 2011; Keogh et al., 2013; Ramoni et al., 2013; Rigby & Fernandez, 2005). Even while there is general consensus that a clinically useful research result should be returned, researchers appear to disagree about what specific variants should be returned, how they should be communicated, or who should cover the costs (Dressler et al., 2012). For example, the international Colon Cancer Family Registry of more than 35,000 recontacted 1634 participants who were identified to carry a mutation in the mismatch repair or MutYH gene. Depending on the policy of the clinical study site (differing by country), interested participants either were provided genetic counseling and confirmatory testing or were referred to a genetic counselor associated with the research study (Keogh et al., 2013). As participants had to cover

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Table 2.1 Reported practices of returning results Disease(s)

Research population

Reference

Results returned

Fernandez et al. (2013)

Multiple 68% of Canadian genomics researchers reported returning results at least once

Not specified

Ramoni et al. (2013) 4% (7/126) of GWAS authors Multiple reported returning results

Not specified

Klitzman et al. (2013)

Multiple 12% of US genetics researchers reported returning incidental genetic findings; 28% returned research results related to the purpose of the study

Not specified

Ruiz-Canela et al. (2011)

32% of participants of genetics Multiple research in the United States and Spain reported being offered access to their research results; 63% of these participants reported that they were offered access to both individual and summary results

Adults

Partridge et al. (2004)

60% of clinical investigators surveyed reported offering results <20% of the time

Adult

Cancer and leukemia

Childhood Fernandez, Kodish, 2/202 consent forms from cancer Taweel, Shurin, and studies by the Children’s Weijer (2003) Oncology Group offered participants option to receive research results; 10/202 consent forms included option to provide new information after the study was completed

Children

Miller et al. (2012b) 69% of genetics researchers of Autism and autism or cystic fibrosis cystic fibrosis surveyed shared a summary report with participants

Children

Heaney et al. (2010) 24% returned individual results

Adults/ children

Multiple conditions

Continued

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Table 2.1 Reported practices of returning results—cont'd Reference

Results returned

Disease(s)

Christensen et al. (2011)

Invasive 27 participants recontacted; 19 (70%) accepted the offer to primary melanoma learn of their CDKN2A genotype

Siegfried et al. (2013)

Families of 92 participants recontacted and offered individual research results

Research population

Adults

Genetic dilated Adults cardiomyopathy

the costs of confirmatory testing on their own, uptake of confirmatory genetic testing ranged from 56% to 86% (Keogh et al., 2013). Some studies may choose to only recontact participants when mutations/variations associated with an increased disease risk are identified (Christensen et al., 2011; Siegfried et al., 2013), thereby substantially reducing overall costs. However, a negative result may also have clinical utility and be of interest to participants, though more difficult to measure (Partridge & Winer, 2002; Partridge et al., 2005). A number of studies have assessed the impact of receiving research results, from both genetic and nongenetic studies, and the responses have been mixed (Shalowitz & Miller, 2008). Few adverse psychological responses have been reported (Christensen et al., 2011), and if so, the adverse impact is short-term, even for conditions such as Alzheimer disease (Roberts et al., 2010). Other studies have shown a rather divided response to the results, likely influenced by participant expectations and current health status (Lorimer et al., 2011). With respect to behavior, few studies have assessed how participants used or acted upon the research result. Participants informed of their risk of Alzheimer disease showed some impact on lifestyle behaviors (Vernarelli et al., 2010; Zick et al., 2005). Ironically, for diseases with clinical utility such as melanoma, no changes to health behaviors were observed in participants who received their research result (Christensen et al., 2011). Only a minority of participants who received results about retinoblastoma even shared them with their physician (Schulz et al., 2003). Given that one of the primary justifications for returning results is the potential to improve the welfare of participants, this lack of impact suggests that participants either may not understand the clinical significance of the findings or have not followed up with their clinical provider. The reportedly limited impact of learning of one’s genetics research result does not differ

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from assessments of the impact of genetic risk obtained in the clinical or direct-to-consumer setting (Bloss, Schork, & Topol, 2011; McBride, Koehly, Sanderson, & Kaphingst, 2010). Receipt of summary research results, even those of a serious nature or negative finding, has resulted in some increased anxiety in participants about the study’s personal implications, but many demonstrate that the results are favorably received without significant psychological impacts by the majority of research participants (Bunin, Kazak, & Mitelman, 1996; Partridge et al., 2005; Schulz et al., 2003; Snowdon et al., 1998).

6. OVERALL ANALYSIS OF STAKEHOLDER POSITIONS Overall, the issue of returning research results pivots on the ethical and legal obligations. In support of the ethical principles of respect, autonomy, beneficence, and reciprocity, several have declared there is an ethical obligation to return results of clinical significance (Fernandez, Kodish, & Weijer, 2003a; Knoppers et al., 2006; Ravitsky & Wilfond, 2006; Shalowitz & Miller, 2005). However, it is unclear if researchers have an ethical obligation to search for results for clinical significance. It is unclear what legal obligations researchers must comply with regarding return of results and the period of obligation. If returning results become standard practice for all genetics research, the line between research and clinical care will be blurred, roles and responsibilities of both researchers and IRBs will be expanded, and the additional costs required to responsibly return results may adversely impact research progress overall and societal benefit. These adverse implications on the research enterprise for the greater good must be weighed against the benefit to the individual participant.

6.1. Ethical One of the most common reasons given by ethicists, researchers, and IRB members in support of returning research results is respect for participants (Angrist, 2011; Dressler, 2009; Dressler et al., 2012; Fernandez & Weijer, 2006; Heaney, Tindall, Lucas, & Haga, 2010; Meacham, Starks, Burke, & Edwards, 2010; Shalowitz & Miller, 2005). Likewise, it has been suggested that investigators have an ethical responsibility to offer participants access to a summary of research results out of respect (Bredenoord, Kroes, Cuppen, Parker, & van Delden, 2011; Knoppers et al., 2006; MacNeil & Fernandez, 2006b). Respect should also be given to participants’ preferences

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regarding their interest in learning of the results (Dressler et al., 2012), particularly their right not to know (Knoppers et al., 2006). However, not all scholars agree with the movement toward returning results of clinical significance to participants (Beskow et al., 2001; Ossorio, 2006; Parker, 2006). If participants come to expect that some results will be returned if they participate in the study, genetic and genomic studies may become perceived as a form of clinical care, risking therapeutic misconception (Bredenoord et al., 2011; Clayton & Ross, 2006). While a physician’s primary concern is the care and well-being of the patient, a researcher’s goal is to answer scientific questions. Returning results tend to blur the distinction between clinical care and research, shifting the latter toward the former (Clayton & McGuire, 2012; Delany-Moretlwe, Stadler, Mayaud, & Rees, 2011; Miller, Giacomini, Ahern, Robert, & de Laat, 2008), and may adversely impact achievement of their research goals by shifting funds and efforts. The combination of participants’ expectations and researchers’ perceived obligation to return results has led to this quasi-research/clinical testing environment that actually may compromise both the research goals and provision of clinical benefit (Miller, Giacomini, et al., 2008). However, blurring the line between “research” and “treatment” is not necessarily viewed as a problem, but rather a natural and necessary evolution that may warrant adjustments to the oversight system (Kass et al., 2013; Largent, Joffe, & Miller, 2011; Tunis, Stryer, & Clancy, 2003). The distinction is further complicated for participants who are also patients and for researchers who also practice medicine, especially if the patient–provider relationship becomes a participant–researcher relationship (Morreim, 2005). If researchers were required to offer to disclose research results, one unexpected consequence is that some clinician investigators may be less likely to enroll their own patients, as it may complicate the differing roles of researcher and clinician (Partridge et al., 2004). Some have suggested that the role of a researcher should not be blurred with that of a clinician, and therefore, researchers have no obligation to return research results, even of clinical utility (Dressler & Juengst, 2006). If a relationship does not exist between the individual donor/participant and the researcher, some argue that it is more difficult to justify disclosure of results out of respect for the participant (Ravitsky & Wilfond, 2006). Others have contended that the extent of the relationship is irrelevant if the results can improve the welfare of the participant (Dressler & Juengst, 2006; FryerEdwards & Fullerton, 2006). This is particularly relevant for biobank research, where there typically is no relationship between the donor and

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researcher (Meyer, 2008). Furthermore, since biobanks are often established for the benefit of public health, some have suggested that individual results should not be returned (Forsberg, Hansson, & Eriksson, 2009). A major argument for not returning results, particularly for “unfavorable results,” is the desire to do no harm to participants (Hayeems et al., 2011). However, from the perspective of participants, the lack of clinical validity or utility of a research result may not be perceived as harmful, but the general practice of returning research results considered a benefit (Baret & Godard, 2011; O’Daniel & Haga, 2011). Indeed, access to individual research result is considered an incentive or benefit to participate in a genomic cohort study (Kaufman et al., 2008; Meulenkamp et al., 2010). Furthermore, it seems “paradoxical” that while participants are able to autonomously decide to participate in a research study with given risks and benefits, they are not considered able to make a similar decision with respect to learning of the research results (Baret & Godard, 2011). Brand (2005) suggests that the research community would lose credibility with this double standard and that only researchers can and should decide about accessibility to results. In addition, the extra time and resources required to return research results over the course of a study may act as a deterrent and compel reallocation of funds from other research efforts (Fernandez, Kodish, Shurin, et al., 2003; Fernandez, Skedgel, & Weijer, 2004; Partridge et al., 2003; Rigby & Fernandez, 2005). Clinical research is intended to advance understanding of a particular disease or its prevention, diagnosis, or treatment for the greater population of those affected with the condition. Thus, research budgets may be reduced in order to accommodate perceived obligations to the individual research participant, thus potentially limiting the scope or size of a given study and, ultimately, the strength of evidence. The consequences of not offering access to research data are unclear. Partridge and Winer (2002) suggest that failure to provide research results may account for lower enrollment rates in clinical studies. Christensen et al. (2011) confirmed this hypothesis by finding that returning results increased participants’ reported likelihood of participation in future research. Others have reported the favored status of genetics research participants and/or obligation to provide greater access to services, information, or clinical care compared to patients seeking these services who are not enrolled in genetic studies (Hayeems et al., 2013; Miller, Hayeems, Li, & Bytautas, 2012a). Aligning with the movement of evidence-based, patient-centered care, the research enterprise should also consider considering the preferences and needs of research participants and adapt with the changing attitudes (Wolf, 2013).

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6.2. Legal One of the barriers to returning results cited by researchers is the need to confirm research results by a clinical laboratory. Specifically, laboratory testing to inform clinical care must be performed in a clinical laboratory operating in compliance with the Clinical Laboratory Improvement Amendments (CLIA) in the United States. However, the legal requirement is not entirely clear and finding a CLIA-certified laboratory to confirm a research finding can be challenging, particularly for rare diseases or a new gene or variant (Lyon, 2012). Thus, some researchers have returned results that have not been confirmed by a CLIA-certified laboratory since they may be the only group providing testing for a particular condition and if failure to disclose could cause harm. For some researchers, validation of research results is a critical factor influencing their attitudes about whether or not a result should be returned, with a substantially smaller proportion in one survey agreeing that results of clinical significance but not validated in a CLIA-certified laboratory should be returned compared to results that were validated in a CLIA-certified laboratory (Edwards et al., 2011). Another area of discussion is researchers’ duty to look for incidental findings (Richardson, 2008; Wolf, Paradise, & Caga-anan, 2008). The use of WES/WGS in research will provide a comprehensive raw dataset that can be analyzed in a very limited or broad manner. While researchers will be seeking evidence to test the hypothesis or trends to develop a hypothesis, they may stumble across information deemed clinically significant or may completely miss it. Several recommendations have been developed regarding the management of incidental findings (Wolf et al., 2012; Wolf, Lawrenz, et al., 2008). With respect to actually looking for incidental (a conflict in terms as it would not really be incidental if one was obligated to look for it), the issue was recently debated in the July 2013 edition of the American Journal of Bioethics. Some have advocated that there is no obligation for researchers to search for incidental findings (Gliwa & Berkman, 2013). However, from the perspective of clinicians, there should be a duty to search with the ultimate goal of improving patient care, particularly since they possess data and skill set that no other laboratory may have that could significantly impact the welfare of a given patient and/or family (Ross & Reiff, 2013). However, unlike clinicians, researchers will not have access to the clinical history of a given participant, which may affect data interpretation, and therefore should not be obligated to search for incidental findings (Costain & Bassett, 2013). Similarly, there has been substantial debate about

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clinicians (and testing laboratories) to search and report incidental findings from clinical use of WES/WGS as recommended by the ACMG (Green et al., 2013; Ross, Rothstein, & Clayton, 2013; Wolf et al., 2013). In both the clinical and research context, the obligation to look and report incidental findings remains unclear. Another legal issue discussed in the literature is whether researchers are obligated to recontact participants about any significant changes in the interpretation of results based on new evidence and, if so, how long does that obligation remain. Wade and Kalfoglou (2006) argued that if the roles are blurred between researcher and clinician, then the researcher has a similar responsibility to the clinician to recontact participants if the interpretation of an individual research result has changed based on new evidence that may improve their well-being, even if the initial result was not returned to the participant. Some have maintained that researchers’ duty to return results is limited to the duration of the study (Fabsitz et al., 2010; Fernandez et al., 2013), while others have suggested that the definition of clinical significance needs to recognize the dynamic evidence basis, which may thus affect the length of obligation to return results (Dressler et al., 2012). Regardless, the length of time should be disclosed in the informed consent document (Wade & Kalfoglou, 2006).

7. ADDITIONAL POINTS TO CONSIDER While much of the debate in the literature has focused on understanding stakeholder perspectives, the practice of returning results is quite complex and involves careful consideration of several factors, including informed consent, communication of test result, provisions for follow-up care, and cost. This is not a complete list but includes some of the commonly debated issues related to returning results.

7.1. Informed consent for returning research results The 1993 federal Institutional Review Board (IRB) Guidebook recommended that IRBs consider the balance of risks and benefits of data disclosure to research participants. During the study design process, investigators should consider whether the data are of robust quality to be made available to research participants. Participants should be informed of the status of research findings with respect to what information will be accessible and when. This recommendation has been reiterated in recent years

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(Dressler, 2009; Dressler et al., 2012); however, evidence suggests that this is not common practice (Heaney et al., 2010), perhaps due to researchers’ lack of awareness of the issue, IRBs’ failure to raise the issue or the institution’s default policy that no results will be returned, or lack of anticipation that any result would be found that should be offered to the participant. In particular, the consent document should include information about whether or not research results would be returned, and if so, what types of results may be returned, potentially providing options for participants to indicate if they wish to be recontacted about any results. In the event that multiple types of results may be uncovered in a given study (i.e., if using WGS/WES), then definitions or criteria about what type of result will be offered to participants should be clearly described (Wolf, Catania, et al., 2008). While offering to return results to participant is an act of respect to the participant, it is equally important to be respectful of participant preferences, as some may wish not to be recontacted about their research results. In order to accommodate participant preferences, these will have to be ascertained during enrollment of the study, likely during the consent process. Rothstein (2006) proposes that participants be provided the option to indicate the types of data they desire to have access to (a tiered disclosure policy), if any. With appropriate education, participants can distinguish between the different types of research results that may be generated for a given study and make an informed decision about their preferences (Bollinger et al., 2012; Lakes et al., 2013; O’Daniel & Haga, 2011). In addition, given that very personal reasons may impact participants’ preferences for research results, they should also have the option to change their decision (Lakes et al., 2013). In some cases, a study could change its policy based on the data accumulated and potentially offer to return results to select (i.e., those carrying a particular mutation) or all research participants. A survey of US researchers reported that the consent forms of 37% of respondents provided the option to return genetics research results related to the purpose of the study; 26% of respondents included the option to disclose incidental findings (Klitzman et al., 2013). Dressler (2009) also found a similar trend. Eighty percent of researchers indicated that participants should be provided the option to decide what types of incidental findings they would be interested in learning (Klitzman et al., 2013). In contrast, given concerns about the potential harms of unvalidated or inconclusive data, particularly for individual results, Shalowitz and Miller (2005) suggested that the option of access to research results should be provided but not necessarily encouraged. Half of researchers surveyed in one

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study believed that results should be returned if a participant requests them (Edwards et al., 2011). Furthermore, the uncertain nature of the results should be emphasized (IRB Guidebook, 2002; Shalowitz & Miller, 2005), which may include that the results have not been confirmed in a CLIA-certified laboratory and the recommendation to do so before any clinical action is taken based on the result. Others have suggested that some research participants may be confused about the distinction between clinical care and clinical research, and therefore, the risk of “therapeutic misconception” must be addressed (Dresser, 2002; Fried, 2001; Miller & Brody, 2003). The informed consent for a Northwestern University genetics database initially included an option for participants to indicate if they wish to be recontacted if results that “may have a significant impact on [their] healthcare” were identified (Ormond, 2006). Due to the overwhelming majority of participants (96%) who consented to be recontacted, concerns regarding participants’ expectation that they would be recontacted resulted in removal of this option from the informed consent document (Ormond, 2006; Ormond, Smith, Cirino, Chisholm, & Wolf, 2004). Because of potential risks associated with learning of a particular research result, some have suggested that a second consent should be obtained prior to disclosure of research results (Fernandez, Kodish, & Weijer, 2003a; Fernandez, et al., 2003b). However, this could be a lengthy process, if consent is to be obtained for every condition for which a genetic variant has been identified, particularly if WGS/WES is performed (Klitzman et al., 2013) Roberts et al. (2010) reported their experience in developing a protocol for the return of research results for a genetic epidemiology study of melanoma (called “Genes, Environment, and Melanoma” or GEM). The return of results to interested participants was carried out under a separate IRB protocol with its own informed consent document. Reaching an agreement among the study investigators involved a series of discussions for several months regarding many of the challenges discussed in this paper but resulted in the development of a successful strategy, with appropriate educational materials, to offer return of results to research participants (Christensen et al., 2011).

7.2. Communication of research results If it is determined that a research result should be offered to a research participant, the next question is what process should be implemented to communicate the result in a safe and effective manner to optimize

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comprehension and minimize harm. Results may be shared or offered to participants by mail, phone, online, or in person. Among the potential options for returning results in person are the principal investigator, a research coordinator, a genetic counselor, and the participant’s personal physician. However, there are limited data to suggest that one approach is superior to another (Cox et al., 2011). Some have suggested that the choice of mode of communication of research results should be based on the significance of the results, level of risk, or type of study intervention (i.e., drug) (Fernandez, Skedgel, & Weijer, 2004; Shalowitz & Miller, 2008). For example, a study of a new drug for children with leukemia would warrant an in-person discussion intervention (Fernandez et al., 2004). Participants may prefer to receive the results from a health provider (preferably their own physician) (Caulfield et al., 2008; Fong, Braun, & Chang, 2004; Mancini et al., 2010; McGuire, Caulfield, & Cho, 2008; Partridge et al., 2003; Ruiz-Canela et al., 2011; Sarradon-Eck et al., 2012) or a health provider associated with the research team (Meulenkamp et al., 2010). Likewise, some researchers believe that a health professional or genetics specialist should be involved in delivery of research results deemed clinically significant (Dressler, 2009; Klitzman et al., 2013; Meacham et al., 2010; Ruiz-Canela et al., 2011). Fernandez et al. (2013) reported that most of the researchers surveyed in their study believed that genetic counseling should be offered before returning genomics research results. Just over half of the survey respondents indicated that they would feel comfortable discussing genomics research results with participants, though more than half of the respondents were also medical geneticists (Fernandez et al., 2013). However, researcher accessibility to and support for health providers with the appropriate training to communicate research results may vary (Hayeems et al., 2011). Given the different preferences and costs associated with each communication approach, if possible, it may be desirable to offer participants to be recontacted the option to choose how to receive results. For example, one study offered participants interested in receiving their genotype the option to obtain them by phone or in person via a boardcertified counselor (all opted to receive results by phone) (Roberts et al., 2010). Likewise, there does not appear to be a clear preference among researchers or participants on the best approach to disseminate a summary of a study’s findings (Cox et al., 2011; Partridge et al., 2003), suggesting that obtaining a preferred method of recontact during the consent process is as important as obtaining consent to be recontacted about summary or

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individual research results. If given the choice between a short printed synopsis of the study’s findings or a longer, more detailed description, participants preferred the longer version in order to have access to technical information and graphic presentations (Brealey et al., 2010). Parents and adolescents with cancer enrolled in research preferred that study outcomes with positive implications be returned by letter or e-mail summary (Fernandez et al., 2007, 2009). However, they preferred for study outcomes with negative implications to be returned in person or by phone (Fernandez et al., 2007, 2009). In contrast, a study on breast cancer found that participants preferred to receive negative findings by mail (Partridge et al., 2005). Older participants also preferred a letter by mail instead of the Internet (Dalal et al., 2010). The involvement of a health professional in the return of research results may have dual benefits and risks. Delivery of research results by a health professional may confuse participants about the clinical significance of the findings and, thereby, contribute to therapeutic misconceptions. The fact that some participants prefer for research results to be reported back by their physicians suggests that there may be a lack of distinction between research and clinical care. Alternatively, some participants have a closer relationship with their physician and may simply feel more comfortable discussing the results with someone they know and trust and who would be able to interpret and advise on follow-up care based on their clinical history and other risk factors. On the other hand, by having a health professional review the results with a research participant, the participant may be more inclined to trust the opinion of a health professional rather than a researcher about the clinical significance of the result for their health and only seek follow-up care if recommended by the health provider. As with any type of health information, the manner in which research results are communicated and the language used to describe one’s results can significantly impact how participants may respond. Results communicated in person by a clinician may be perceived to be more significant and serious, and therefore, participants may feel a greater need or obligation to seek follow-up care. The presentation and language used to describe the results can impact participant comprehension (Baylor et al., 2013), particularly if the results are received by mail or accessed online without the benefit of discussing them with the researcher or clinician (Darbyshire & Price, 2012). Results accessed online may cause anxiety for some participants if they do not have an option to contact someone knowledgeable about the study to answer questions (Partridge et al., 2009). For summary reports of

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study outcomes, many large studies have opted to use a website to provide this type of information (Fernandez et al., 2012). If researchers have not set up a study-specific website, participants can be referred to www. clinicaltrials.gov when the results are uploaded (required to be posted one year after study completion) if the study has been registered (Tse, Williams, & Zarin, 2009). Similarly, some have suggested that participants access individual results through a web-based portal (Kohane & Taylor, 2010; Yu, Jamal, Tabor, & Bamshad, 2013; Zhao & Haga, 2013). For example, the CPMC has developed a secure site for participants to access select results (Keller et al., 2010). Instead of selectively returning results, Yu, Jamal, et al. (2013) proposed to apply a participant open access-type model, enabling participants to self-select the results and use it as a reference source over their lifetime. The unique circumstances of biobanks warrant different approaches to return research results. For example, one proposal suggested that biobank administrators recontact study participants if a clinically actionable result was found in a study of the participant’s donated tissue (Hunter et al., 2012). However, the biobank administrator would not directly communicate the result, but instead would request that participant designate a health provider to whom the result would be shared.

7.3. Impact of returning results to affected versus healthy participants Whereas traditional medical genetics research is often limited to affected families or small populations, genomics research frequently involves both healthy and affected individuals. The increased size of study populations is due in part to the increased number of factors (e.g., genotypes) analyzed, the low relative risks attributed to genetic factors, and the wide range of environmental variables that may confound risk calculations. No existing policies to our knowledge make the distinction between returning results to affected individuals versus healthy individuals. However, we believe this distinction is important with respect to estimating the benefits and potential harms associated with disclosure of research findings. If the primary criterion for returning research results is clinical utility, the benefit/risk ratio may differ between affected individuals and healthy individuals (Table 2.2). The requirement for clinical utility may be a less important factor for affected individuals if their disease is under control and they have learned to cope with how the disease may be affecting their quality of life. Likewise, returning results to an affected individual may be linked to fewer psychosocial risks

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Table 2.2 Comparison of benefits of research results returned to affected and unaffected participants Disease status of research participant Potential clinical benefit

Affected

• • • •

To confirm clinical diagnosis To modify treatment For reproductive decision-making To inform risk status and testing for relatives

Unaffected

•

To identify individuals at increased risk that would benefit from intervention or early therapy To diagnose an individual with a disease that has not yet manifested

•

than returning predictive risk information to a healthy individual. While clinical validity remains an important criterion for both affected and healthy individuals, it may also have less importance for affected individuals since the information is not used to predict risk. However, the validity of the result is critical if it is to be used for family/reproductive planning purposes. The penetrance of genetic variants in individuals without a family history may be reduced or unknown, and thus, some results may be of questionable clinical significance in healthy participants (Klitzman et al., 2013).

7.4. Provision of follow-up care The obligation to provide ancillary care to research participants has garnered attention in recent years (Dickert & Wendler, 2009; Richardson & Belsky, 2004). Although most research studies do not include any provision for follow-up or ancillary care, researchers may feel some obligation to provide access to care if possible (Miller et al., 2012a). Some might consider returning research results to qualify as providing ancillary (as a form of diagnosis or risk assessment) (Dickert & Wendler, 2009), but then the issue becomes whether the obligation should be extended to provide additional care to manage the diagnostic/predictive information. In genetics and genomics, with greater patient access to genetic information, by way of either direct-to-consumer (DTC) testing or access to research results, a similar concern has been raised that participants may seek follow-up care that is unnecessary, costly, and potentially risky (McGuire & Burke, 2008). If a result (anticipated or incidental) returned to the participant from the study warrants follow-up care, the participant may not have the means to pay for healthcare expenses related to this finding. Indeed, this has been reported as a

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reason for not wanting to learn of one’s individual research result (Heaney et al., 2010; O’Daniel & Haga, 2011). Thus, if a second consent is obtained to access individual results, it would be prudent to inform participants about the disease and the type of care that may be warranted to prevent or treat the condition.

7.5. Cost Cost has been often mentioned as a major barrier to offering participants individual results, given the time-intensive and lengthy process required to ethically return results to participants (Fernandez, Kodish, Shurin, et al., 2003; Fernandez et al., 2004; Partridge et al., 2003; Rigby & Fernandez, 2005). Indeed, following the publication of guidelines for biobanks regarding the return of results, Bledsoe et al. (2013) raise the issue of cost as a major impediment to implementing the guidelines. Assessment of costs of returning results must consider several elements including the need for clinical support, duration of obligation to return results, and validation of results in a CLIA-certified laboratory (Fernandez et al., 2004). Some guidelines recommend that the participant cover the costs associated with validating a test results (Bookman et al., 2006), whereas others suggest researchers should budget for these expenses as part of the overall study (The American Society of Human Genetics, 1996). For example, the study protocol of the Familial Dilated Cardiomyopathy (FDC) Research Project states that all consented adult members of a family be notified in writing that a mutation was identified (Siegfried et al., 2013). Participants are recommended to meet with a genetic counselor and have the research finding confirmed in a CLIAcertified laboratory (Siegfried et al., 2013). However, the cost of counseling and test confirmation must be covered by the participant. To date, 23 individuals from 10 of the 51 families notified have paid to confirm the mutation in a CLIA-certified laboratory (Siegfried et al., 2013). A wide range of uptake of confirmatory testing was also reported in the international Colon Cancer Family Registry where participants had to cover the costs (Keogh et al., 2013). If costs are covered by the research budget or institution, they could be significantly lower if only participants found to have mutations/ variations associated with an increased disease risk are recontacted as was done in the FDC project and other studies (Christensen et al., 2011; Siegfried et al., 2013). Costs of returning results are associated with the time required to develop protocols for return of results, time of a health professional or

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training of research staff, time required to recontact participants to offer return of results and obtain consent, and preparation of educational materials and follow-up documents (Christensen et al., 2011; Dinnett et al., 2005). The uptake has not always matched participants’ reportedly high interest of research results (Dinnett et al., 2005; Mancini et al., 2010; Partridge et al., 2005), thus likely influenced by disease type and participant characteristics. Thus, asking about interest in the results during the consent process and preferred mode of communication could save researchers’ substantial time and effort and designing the protocol on returning results after assessing participants’ preferences. The National Institutes of Health does not have an official policy regarding including expenses in a budget proposal. However, unless decisions about returning results are made during the planning phase of a study, costs will not likely be budgeted. More than likely, the effort, cost, and infrastructure required to safely return results will likely be shifted from other research efforts (Dressler & Juengst, 2006; Ossorio, 2006, 2012).

8. MOVING FORWARD In general, the attitudes of many researchers, IRBs, and participants appear to have converged on returning results of clinical significance. However, despite this general consensus, the actual practice appears stymied by a lack of an agreed-upon definition of “clinical significance” and uncertainty about how to actually return results. Given the extent and popularity of genetics and genomics research in the media, it seems inevitable that participants will begin to more frequently request information about a study’s findings if not their own results. Rather than waiting for the flood of requests and attempting to respond to participants’ request one at a time, it would seem more practical and demonstrate respect for participants if researchers addressed this issue proactively. Thus, researchers should be encouraged or required to address this issue in the IRB application and potentially the grant application and provide a brief rationale of their decision on whether or not to return a summary report or individual result. The absence of an institutional or national policy on returning research results should not deter researchers from considering the issue. Indeed, an institutional or national policy may be overly restrictive and not give researchers the flexibility to consider the issue within the context of their study, current evidence, and the study population. This will also help remind researchers to disclose the policy in the informed consent document and budget accordingly. Aligning with other efforts to provide open access to study results

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(Tse et al., 2009), the first and easiest step may be to encourage communication of a study’s findings. As described earlier, this can be accomplished in several ways and, if using a study website or e-mail, can be done relatively inexpensively. Consideration of the implications of returning individual research results from the perspective of the participant may help researchers decide what type of results, potentially using a community participatorybased approach (Boyer, Mohatt, Pasker, Drew, & McGlone, 2007; Zusevics, 2013), to offer back to participants while taking into account a variety of factors including threshold of uncertainty, positive predictive value, and magnitude of harm (Dressler, 2009). In addition to the myriad guidelines and recommendations from various groups, several approaches have been proposed to help researchers consider the issue of returning results (Kollek & Petersen, 2011). Ravitsky and Wilfond (2006) suggest implementing a risk-based framework to determine whether (or which) results should be disclosed to participants, which would be utilized on a case-by-case basis. To assist both researcher and IRBs and given differences in opinion regarding clinical significance of given research results, some groups have suggested or have established the use of an oversight advisory board that can consider the types of findings that may be revealed by a study and decide whether or not it is appropriate to offer such a research result to participant (Dressler, 2009; Keller et al., 2010; Kohane et al., 2007). Ultimately, the uptake in the practice of returning results has been slow, but the attitudes of the major stakeholders have begun to align, which may pave the way for greater discussion of how to return results in a safe and appropriate manner, moving away from discussions on whether or not to return results.

ACKNOWLEDGMENT The authors are deeply indebted to the assistance of Ms. Rachel Mills with the preparation of this manuscript.

REFERENCES Abdul-Karim, R., Berkman, B. E., Wendler, D., Rid, A., Khan, J., Badgett, T., et al. (2013). Disclosure of incidental findings from next-generation sequencing in pediatric genomic research. Pediatrics, 131(3), 564–571. Angrist, M. (2011). You never call, you never write: Why return of ‘omic’ results to research participants is both a good idea and a moral imperative. Personalized Medicine, 8(6), 651–657.

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