Clinical research setting.

Overall, participants, and parents of children participating in genomic research studies, generally have strong preferences for, or expectations to receive SSR. Those wanting results that are related to the research question ranged from 47.6% [10] to 97% [6]. Percentages seemed to depend on the genetic condition being studied, whether the decision to receive results was hypothetical or actual (either with or without results having been returned), and the framing of the question. Receiving SSR was also highlighted by participants as a high motivation for participation [30, 32, 64], based on the hope of a cure for themselves and future generations [65].

Investigating a hypothetical context, a study of 103 racially diverse adult patients with late-stage kidney disease participating in a genomic study showed that 62.13% felt it was very important to receive genetic and health results related to the condition under study, with only a small proportion (11.7%) indicating return of results was not important at all [3]. Likewise, in a study of 241 persons with mental disorders, 95% wanted ‘pertinent’ findings to be made available [13]. Studies have shown that participants without an existing health condition are highly interested in receiving all categories of results [5] and generally prefer ‘knowing’ to ‘not knowing’ [40]. Yet, a US-based study of 311 mostly healthy volunteers, referred to as the ClinSeq study, indicated that interest was highest for receiving results for treatable/preventable conditions and carrier status [5]. This accords with other studies where respondents have been most interested in receiving information about genes that are life-threatening or may increase their risks for future health problems, where preventable options are available, or that are likely to change their doctor’s approach to their care [3, 40]. Yet desires for information persist for some participants, both with and without existing medical conditions, even when options for return of information include diseases without known prevention, treatment, or other actionability, and genes with uncertain significance [3, 5, 66, 67]. A study of 219 cognitively normal adults enrolled in longitudinal aging studies indicated that 51.9% wanted Apolipoprotein E (APOE) genotype, despite the fact that Alzheimer’s disease is non-actionable [7].

With hypothetical scenarios, there was a strong preference for results in parents of children participating in research [68]. Interviews with 25 parents of children in an exome sequencing study at the National Institute of Health (NIH) showed that all participants wanted to receive their children’s results [11]. Similarly, 97% of 362 parents of children with rare inherited childhood diseases or pediatric cancer who were participating in one of three large-scale genome research consortia stated a positive right to receive SSR [6].

High levels of interest in learning about results were also expressed by participants making actual decisions about whether they wanted to receive results [1, 2, 12]. Several studies observed that return of results was a key reason for research participation [2, 4, 69, 70] and a survey exploring participation across several Clinical Sequencing Exploratory Research (CSER) consortium sites showed that only 5% who declined did so because they did not want research results returned [71]. In a study of 263 veterans and 1,159 non-veteran adult Mexican-Americans enrolled in genetic family studies aimed at identifying increased susceptibility to diabetes and diabetic nephropathy, 95.7% and 93.1% respectively expressed interest in receiving their SSR [1]. Similarly, in a study of adolescents aged 14–18 years who were either undergoing treatment for substance and conduct problems (SCPs; n = 320) or were non-SCP controls (n = 109), most participants (77.8% of SCPs and 72.5% of non-SCPs) wanted to know results if there were health or behavioral implications [4].

In general, very low proportions of participants– 8.2% of 790 undiagnosed adults and children with conditions suspected to have a primarily monogenic cause and 3% of 506 adult members of families at high genetic risk for cancer–refused all results [72, 73]. However, some studies highlighted that some participants only want results when investigators have assessed the risks and benefits of sharing results with them (68/271; 25.1%), or if the results would be useful for their doctor’s decision-making (74/271; 27.3%) [10]. Surveys and interviews with 35 participants from New York showed that 94% wanted to receive all categories of results [12]. Yet, when participants were asked to nominate which categories of results they wished to receive, 100% wanted pharmacogenetics information, but only 74% wished to receive results regarding conditions which were unpreventable [12]. Studies have found that adults [74] and parents [75, 76] may be uncertain about which results they want and what to do with them. Although 85% of 154 parents of children recruited to studies investigating genetic causes and novel therapeutics for rare diseases, indicated they had a strong/very strong right to receive results, even in situations when the possibility of an ameliorative therapy was uncertain [77], others did not wish to receive results that could not be interpreted or were non-actionable/incurable for their children [78].

Two studies that returned results at study completion–one with 107 men and women from families with a known mismatch repair (MMR) gene mutation and the other with 31 adult participants from the ClinSeq cohort who had received one sequencing result with personal health implications–showed that 79% and 80.6% respectively elected to receive results at the start of the study [8, 9]. A third study of 31 healthy individuals, conducted by Stanford University, showed that receiving exome results to learn more about their health risks was the most common reason for participation [79]. A further study of 162 adults who had a living or deceased parent with Alzheimer’s disease and were randomized to receive or not receive their own APOE genotype showed that some participants randomized to the nondisclosure group were dissatisfied at not receiving their genotyping results [80].

Participants from all these studies present a range of reasons for wanting to receive SSR, which are summarised in Table 5. These reasons differ slightly depending on the condition under investigation and whether the research testing was being conducted in adults or their children. For example, parents of children in an exome sequencing study at the NIH wanted results to identify an explanation for their child’s condition, provide information about their child’s health, coordinate better management for their child’s condition, and prepare for their child’s future healthcare needs [11]. Some wanted answers from genomic sequencing to lead to treatments [75]. Parents also described feelings of responsibility toward their children and desires for control associated with receiving the results [11]. In contrast, adult participants want SSR in order to have greater certainty about personal risk [8, 30], to determine whether they required screening [8], because it was recommended by their healthcare professional or desired by a relative [8], or for insurance or planning purposes [8, 30, 88]. Participants also listed a desire to know health information [5, 12, 81], provide diagnostic certainty [82], prevent disease/improve health [5, 12, 81, 86, 88], adopt better health habits [88] and alter medical management as reasons for wanting their results [5, 82].

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 5. Summary of reasons for wanting and not wanting to receive SSR and UF/SF.

https://doi.org/10.1371/journal.pone.0258646.t005

In a hospital-based study of genetic susceptibility to melanoma, 68% of 19 participants wanted to know their personal risk so they could discuss it with their doctor, so they could use it for preventative purposes (58%), or wanted reassurance that they were not at increased risk (37%). Yet almost half (47%) also wanted to receive results out of curiosity [83]. This interest in receiving results out of curiosity was supported in the study of healthy participants by Sanderson et al [12]. In addition, 74% wanted results to be able to inform their children [83], a finding which has also been recognised by others, along with a desire to tell other family members [12] and for family planning purposes [69, 101]. The ClinSeq study indicated that a proportion were motivated to receive results by their family history of a particular disease [5]. In addition, adults enrolled in the Dominantly Inherited Alzheimer’s Network want SSR in order to participate in a clinical trial [103]. Interestingly, in a study of 246 cancer patients and 315 participants who had a family history of Alzheimer’s disease (but no disease themselves), participants said they would be more likely to want to know their results if they knew the researchers already had access to that information [107]. Yet, participants from three other studies also raised concerns about receiving IRR due to the potential for adverse psychological impact of receiving results that have implications for future health [2, 12], and implications of results for their children, including the impact on insurance, legal issues and privacy [12, 101].

Biobank setting.

Participants in the context of biobanks also express high interest in SSR, with between 57% and 98% wanting results to be returned [33–41, 84, 85, 106, 108–111]. Participants generally expressed higher interest in results that conveyed some sort of actionability [33, 34, 39–41, 112]. For example, in a study of 555 biobank participants recruited in the context of clinical care appointments, 90% wanted results for conditions that are treatable, compared to 64% who wanted results for non-treatable conditions [33]. These participants also showed a preference for receiving results that conveyed high disease risk over low disease risk (79% vs 66%), and risk of serious disease over less serious disease, (83% vs 68%). Yet, 57% expressed interest in receiving uncertain results. This is in contrast to a study which conducted interviews and focus groups with 26 female breast cancer patients who had previously given consent to donate blood or tissue samples to a tissue bank for breast cancer research, in which most participants did not want to receive results of uncertain clinical significance [113]. Another study, which used a discrete choice experiment to survey 351 participants from a Swedish research program, identified a preference to receive life threatening disease risk over other diseases (such as physical disability, mental disease, and physical disease) [40]. They found greater willingness to learn disease risks when the estimate of penetrance was higher, and also when the recipient is able to implement lifestyle changes rather than medical interventions; this proportion increased as did the effectiveness of the interventions [40].

A study of 55 family decision makers who had authorized the donation of deceased loved ones’ tissue, and 22 requesters recruited through an organ procurement organization, showed that 94.3% favored the return of results suggestive of treatable diseases and 84.9% for diseases that could affect their children, compared to 71.7% for non-treatable diseases [39]. Likewise, a study of biobank participants from two regions in Japan also highlighted that the majority of respondents (88.2% from region 1 and 82.3% from region 2) preferred to receive their own genetic information [41]. Interest was highest for diseases that could be modified by lifestyle, as well as adult-onset and actionable conditions, with much less interest expressed in receiving pharmacogenetics and adult-onset non-actionable results [41]. Yet, a second Japanese study conducted an educational workshop with 112 participants and showed that scores for interest in receiving five categories of results–lifestyle diseases, pharmacogenetics, adult-onset non-clinically actionable diseases, non-clinically actionable multifactorial diseases, and all genetic information–significantly decreased after the workshop [114]. However, even in the face of this decrease, over 95% still wanted to know results for the diseases that could be influenced by lifestyle, pharmacogenetics, and adult-onset clinically actionable diseases [114]. In addition, 17 parents of healthy children participating in a biobank wanted to know both childhood- and adult-onset medically actionable conditions for their child and felt it was more important to protect their child’s health than preserve their future autonomy [115]. However, one study of 53 young adult participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) showed only mild interest in receiving SSR and only if they were of clinical relevance [116].

Despite the overall high interest in receiving SSR, studies suggest that expectations for their return differ. Interviews with 109 NUgene biobank participants showed that while 1/3 hoped to be recontacted with results, 1/3 expected results to be returned only if something severe was found, and 1/3 had no expectation that they would be recontacted [117]. This is important as participants were told during the consent process that it was extremely unlikely that they would be contacted with research results that could have a significant impact on their health. A study of 3630 adults, which included 464 biobank participants with a diagnosis of pancreatic cancer, indicated that 62.1% expect to receive SSR; high proportions of participants held expectations that they would be told about ‘bad’ stuff (e.g., health risks for conditions), rather than ‘good’ stuff (e.g., things that do not have associated health risks) [34]. Yet, interviews with 17 cancer patients, 6 first degree relatives and 7 cancer-free controls showed that while many felt researchers should return research reports to patients, over half said there was no moral obligation to do so [37].

Four studies explicitly explored participants reasons for wanting to receive SSR in the biobank setting [36, 84]. They identified benefits to participants’ and their families’ health [36, 85], motivation to adopt healthier lifestyles [36], earlier diagnosis or prevention [36, 84], and improvements in chances for better treatment as key reasons for wanting results [36, 84]. Participants also mentioned personal utility, finding meaning in knowing their own or their family members’ genetic information, the possibility for future planning [85], including taking out long term insurance [36] and family planning, a sense of obligation or responsibility to their family, having ownership over their results [85], and wanting to be a good parent to their children [36].

Clinical research setting.

In a study of 904 participants from the US-based Northwest Cancer Genetics Registry, which included 340 patients with cancer, participants strongly endorsed that researchers have an ethical obligation to return results that would affect their health or health care [44]. A study of 205 patients attending an outpatient clinic in the USA showed a significant increase (p<0.001) in interest to participate in a hypothetical genomic research study when they were told that results would be offered following study completion [48]. Sixty-eight percent of these respondents said they would want results returned for heart disease, 67% for diabetes type 2, 70% for cancer and 61% for obesity [48]. Another study of 25 adult parents of children who were inpatients at a pediatric hospital, showed that 64% of parents wanted results for both preventable and non-preventable conditions returned, whereas 35% just wanted to receive results for preventable conditions for their children. Similarly, 76% of parents wanted both severe and non-severe conditions, 16% wanted results suggesting severe conditions only, and 8% only wanted results for non-severe conditions returned [42]. Yet, a study of patients with mental disorders showed that patients and family members were willing not to receive findings if doing so would compromise the research [13].

Patients discuss wanting to know their results out of personal curiosity [48] or peace of mind [89], because it may provide personal health benefit [48], clinical utility [89] or actionability [42, 52], or to inform their children of their risks [89]. A qualitative study of 25 parents highlighted that participants considered ‘actionability’ as a broad concept, encompassing aspects such as medical interventions, lifestyle modifications, education, mental preparation, and planning, including insurance, housing, and finances [42].

Biobank setting.

In contrast to the findings of Sundby et al., in a study of 1903 pancreatic cancer patients, their spouses, and other blood relatives, 76.3% of patients said that regardless of the cost, researchers should offer results to research participants [49]. Surveys with 2,960 parents of children from Boston Children’s Hospital felt that results would reduce stress over a search for the child’s diagnosis and help them look out for symptoms for early screening [52]. One study has suggested that parents are interested in receiving more information about their children than about themselves; 84.6% of 1060 parents/guardians of children who had received care at Boston Children’s Hospital indicating they probably or definitely wanted to receive SSR about themselves and 88% wanting them for their children [50]. Interest reduced considerably when asked to specify the categories of results they wanted.

Clinical research setting.

A large number of studies have assessed public views on return of SSR in the context of clinical research. Overall, interest in SSR is high [44, 91, 121–124], ranging from 73–100% [13, 49, 53, 54, 57–59]. Although some studies showed high support for receiving all types of results [121], the most support has been shown for results relating to an increased risk of an actionable, treatable, or preventable condition [59, 91, 125, 126] but also for conditions that are do not currently have treatment options [53, 91]. While some studies have suggested that respondents favour receiving results for serious conditions [91, 124], responses to results concerning life-threatening or fatal disorders have been mixed [124]. However, respondents in a study of 100 adults, who were recruited based on the fact they had never worked in genetics, disagreed with the idea that that definition of benefit for returning SSR should be limited to clinical benefit [122].

Studies also indicate members of the public wish to receive information about non-medical traits and information that could change over time [91]. In fact, 59% of respondents in the Dutch study stated that researchers have a duty to inform participants about mutations, even when the consequences for their health are unclear [125]. Interestingly, the magnitude of risk did not appear to be relevant for most respondents in one study, with many suggesting they wanted to receive information about both very highly elevated and also only slightly elevated risks of conditions [91].

Studies show that members of the public express a range of reasons for wanting to receive their SSR. Some of these are based in desires to improve health, such as that having results can directly help treat or avoid disease or can motivate them to plan or take action relating to their health, now or in the future [56, 91–93]. Some held expectations that results would impact on the management of their existing conditions, or those of their family members [59]. Yet, for others, results were wanted more out of curiosity, or because they felt a sense of ownership or empowerment from knowing the information in their genes [91, 97]. One study utilized a deliberative strategy with 19 Alaska Native and American Indian community members [92]. These stakeholders desired results for individual purposes, such as promotion of autonomy, privacy, empowerment to make informed decisions, early detection of disease, and improved preventative care, but also to empower and improve health at the population level and increase public health knowledge [92].

However, interest in SSR is not universal. One study of 1418 members of the general public in Missouri indicated that only 12.5% were extremely interested in receiving results regardless of whether there was an available treatment [7]. In another US-based study of 1515 respondents, 12% stated that they would not want or need any SSR to be returned and 56% agreed it would be fair to only receive results that were treatable or preventable [53]. Respondents also showed less interest in receiving results relating to common diseases or that showed major changes in disease risk [53]. Assessment of attitudes of 41 African American parents in Washington, showed that only 15% wanted SSR that could provide answers about an illness or health condition they were currently affected by [59]. In the same study, 26% of non-African American parents did not want to receive any results for themselves or their children [93].

A large proportion of public sentiment behind not wanting to receive SSR appears to be based in concern for the implications of the information, both for personal mental health but also more broadly. Studies have shown that some members of the public fear what they may learn from the results, and that this could lead to distress, depression, or an inability to cope with the information [56, 59, 91, 93]. This was particularly the case with untreatable conditions due to the inevitability that the condition would develop and lack of control over its course [91]. Others expressed concerns about availability of health, life and long-term care insurance and that an SSR might not be actionable if a person were to lose their health insurance [56, 59]. Some respondents were concerned about the potential for inaccurate or uncertain results [56, 93], whereas others either ‘felt healthy’ or did not have a family history and therefore did not consider themselves to be at risk [97].

Biobank setting.

Members of the public generally express high hypothetical preferences (91–98%) for receiving SSR from biobanks [60–63]. This is the case both for themselves and also for their children, as evidenced by a study of 141 individuals across 15 focus groups where, of the 7 focus groups that discussed return of children’s results, members of 6 of the groups said that some or all of results of children <18 years should be returned to their parents [61]. Desires to receive SSR related to all types of findings; of 4659 adult Americans surveyed, 91% wanted to receive results about health risks, regardless of their actionability, 95% wanted to know if they were at increased genetic risk for something treatable (e.g., asthma), 96% wanted to know if they were at increased genetic risk for something untreatable (e.g., Alzheimer’s disease), and 96% wanted to know if they were at increased genetic risk for “a bad reaction to certain types of medicine” [62]. A study of 45 adult African American caregivers of children recruited through a health centre showed that 89% were interested in receiving IRR for asthma, 93% for Alzheimer’s disease, 80% for a gene change shown to be more common in a racial group, and 82% for SSR with uncertain significance [56]. Another article citing the same research cohort also indicated that SSR for non-actionable results were met with more opposition than those that were actionable and that, although respondents generally desired information about Alzheimer’s and dementia, they did not wish receive information about other mental disorders [55].

Yet, some respondents were "ambivalent" about return of SSR from biobanks, suggesting that they donate altruistically and therefore would not feel entitled to receive them [127]. Some respondents suggested they would not want SSR because it would be “too much information” (8%), because IRR predicting future illness would worry them (17%) or were just “not that interested” (7%) [62]. Respondents have also been quite divided in their interest to receive results concerning life-threatening or fatal disorders [55].

Clinical research setting.

Three studies assessed views of a range of professionals in the clinical research context [18, 128, 129]. For two of these, a large proportion of their cohort was comprised of researchers. As such, they have been discussed within the researcher stakeholder section below. The third interviewed 14 senior professionals from the Netherlands and the UK with expertise a range of areas, such as clinical care, genetics research, molecular genetics, and health care management [129]. The professionals held varying views about whether there was a duty to recontact participants in response to SSR. While some felt there was no duty because research and clinical care have different aims, others felt that the preferences of the participants should guide whether results are returned [129]. Issues such as workload burdens and difficulties identifying to whom results should be returned were also raised.

Biobank setting.

At an interactive workshop, a group of 9 human research ethics committees (HREC) members, 10 researchers, 3 health consumers, and 7 "others" including genetic counselors and members of genetic support groups, were asked about their views on returning biobank results to participants [130]. Professionals were generally not supportive of returning results because of the additional time and resources it would require and the difficulties obtaining consent for result return [130]. In contrast, a study of 17 Dutch key figures in the field with a mixture of disciplinary backgrounds suggested more positive views towards returning results to biobank participants [131]. Participants suggested that individual findings for which treatment options are available should be reported regardless of parental wishes but that late onset non-treatable conditions in children should not be returned [131]. Views varied considerably depending on the background of the participant. Biobank experts felt it was important to distinguish between validated, health-related, and actionable findings compared to those without health-related significance. Medical practitioners in the study felt an obligation to return these findings, but not others [131]. Patient representatives were more liberal with which information should be disclosed to parents than other participants [131].

Clinical research setting.

Two studies explored views relating to the clinical research setting. One study which included 74 psychiatrists and 28 clinical geneticists showed that clinical geneticists and psychiatrists were less positive about receiving any kinds of findings for themselves compared to people with mental disorders or relatives [13]. Psychiatrists and clinical geneticists were also less positive about receiving genomic findings compared with blood donors. The second study, which interviewed 25 pediatric and adult physicians and non-genetic specialists (in oncology and cardiology), suggested that these practitioners only wanted to receive results for their patients where clear actions could be taken, such as the identification of earlier interventions or new care pathways [132]. However, the clinicians also had a number of concerns about returning results to patients. Some of these related to potential for harm to participants, such as anxiety or distress, false negatives, turning healthy individuals into ‘patients-in-waiting’, subjecting people to unnecessary investigations, and genetic discrimination. Yet other concerns related to their own lack of preparedness to return the results and provide support and the extra time required [132].

Biobank setting.

One study, which assessed views of healthcare providers working in both public and private practice on return of results from biobanks, suggested that they felt biobank participants had a strong right to know results [127]. However, they also reported being conflicted because the results also have implications for family members, flagging that result recipients require proper support and guidance with how to manage them.

Clinical research setting.

Seventeen studies have investigated views of researchers on returning IRR [44, 76, 84, 119, 18, 128, 133–143]. A study of 39 psychiatric genetic researchers from 17 countries indicated that the majority of participants were either not returning results at all or had returned results but were not doing so in a systematic way [137]. In a study of 74 genomics researchers (which included medical geneticists, genetics researchers, and clinicians), only 8.1% said results should not be returned [134], and interviews with 23 researchers (both clinical and non-clinical) who investigate Autism Spectrum Disorder generally felt that results that explain the cause of autism should be disclosed [76]. High support for return of results was seen in other studies [44, 137, 142].

Researchers were more supportive of returning results if they explain the cause of the condition under study [76], relate to treatable or preventable conditions [137, 142], and have clinical utility [134], clinical relevance [135], or if the result is available as a clinical test [134]. However, one study also showed support for returning results that provided non-medical actionability (54%) because it could lead to behavior change or because patients had a right to know [136]. Another study showed some support for results that are medically relevant but not actionable (45%) and higher support for returning risk for Huntington disease (71%) and Alzheimer’s disease risk (64%) for planning purposes [142]. There was very little support for returning VUS. Researchers also discussed other benefits of returning results, such as the ability to allow for early interventions [136], plan their futures [137], to improve quality of life [136], and the potential to lower their environmental risks for psychiatric disease and reduce stigma associated with mental illness [136]. Researchers also suggested returning results shows respect for patient-participant autonomy and recognizes participants’ ownership of their data [142].

However, despite these favourable views, others raised concerns about the uncertainty of the information being returned to participants [137, 140], the potential impact on scientific progress [140], burden on researchers who cannot provide the necessary support [136] or lack of infrastructure and resources [143], and blurring lines between research and clinical care [136, 140]. Others held concerns for participants’ privacy and confidentiality [128, 137], discrimination from insurance companies and banks [143], their ability to retain control of their data [137] and ensuring informed consent [18, 137]. In addition, researchers were worried about the potential for adverse psychological reactions from returning results, including worry [136], confusion [136, 137], anxiety, guilt [137], and stigmatization [137]. Respondents in one study raised concerns that returning IRR would mean that participants use the information to make clinical decisions, which would then place clinical demands on researchers [139]. Another study stressed the need for results to be disclosed by a physician who can explain the significance of the findings and the importance of results being communicated to participants in a personalized manner [84]. In addition, two studies suggested that relatively high proportions of researchers were not giving consideration to returning results to participants [133, 135]. One study of 105 genetics/genomics researchers indicated that, at the time, only 54% had considered the issue of returning research results, 28% had offered to return IRR, and only two of these incorporated this into the study planning [135].

Biobank setting.

Five studies assessed views of researchers on returning SSR to biobank participants [144–148]. The first, a study of 80 researchers involved in biobanks, showed that 74% reported that biobank participants only need to be informed of results if they have treatment or prevention implications and 95% reported that it was fine for participants not to find out about SSR where health implications are unclear [145]. This could be related to the fact that 81% were concerned that returning results might frighten patient-participants and 66% believed that information on genetic variation could influence insurance premiums. In addition, 91% of respondents stated that patients are not more entitled than healthy participants to receive SSR (defined in the study as ‘genetic variations that in some form or other may be relevant for a specific individual participant’) [145].

Another study, which assessed views of 10 directors of Cooperative Group cancer clinical trial biobanks, showed that all participants completely disagree that the Cooperative Group Bank should be responsible for disclosure of results to patients, a view which was heavily influenced by lack of adequate funding to accommodate this process [144]. In contrast, of 18 researchers involved in pediatric biobanking from 10 different countries in the third study, most researchers wanted to keep connections with patients that had biospecimens and data stored to be able to provide them (or their relatives) with relevant information from ongoing research projects [146]. Interviews with 19 researchers from Saudi Arabia showed differing views: some thought returning SSR was a moral and professional duty whereas others felt returning results was not consistent with the goals of medical research [148].

Clinical research setting.

Five studies, all from North America, explored views of IRBs on the return of SSR [44, 149–152]. Generally, members of IRBs thought that research findings should be returned, provided participants want to know their results [44, 150]. However, while in one study 15/22 (68%) agreed that participants should ‘probably’ or ‘definitely’ be offered the choice to receive results that may be useful for participants’ or family’s health [151], another study indicated that a large majority of the 65 Chairs of US IRBs studied favoured offering the result to participants, even if there is a lack of clear utility associated with the findings [149]. One study explored views of a cohort of Canadian IRB members, coordinators, and chairs on returning IRR [152]. They found 50% (30/60) supported returning results when they indicated a probable medical condition or explanation for a response to a medication [152]. Interestingly, a study of 208 IRB professionals and 351 human genetic researchers showed that in two separate scenarios, IRB professionals were more likely to agree that individual research results should be returned to participants than researchers [44].

Biobank setting.

One study addressed views of IRBs on the return of results related to study-specific results in the biobank setting. An Indian interview-based study of 21 ethics committee members and 22 researchers, showed that IRB members were unsure about their duty to review SSR and make decisions about their return [147]. They also held concerns about the need for a counselor or physician to convey research findings and participants suggested biobanks could have a coordinating centre that could assist interactions between sample donors and researchers, including playing a role in return of findings [147].

Clinical research context.

Research participants generally expressed high interest in receiving UF, with values in most studies ranging from 61–100% depending on the nature of the UF [6, 11, 13, 66, 69, 71, 72, 87, 153–158]. Although participants were keen to receive all types of UF [77, 154, 158, 159], studies that asked respondents to specify which types of UF they wished to receive showed participants were most interested in receiving those that could have implications for their health [66, 156]. For example, a study of 58 adult volunteers in an ongoing family study of bipolar disorder showed that 97% wanted to receive UF that could have health implications [66]. However, 83% of the cohort still desired UF regardless of whether they were actionable. Similarly, responses from 219 adult parents of affected children who were receiving whole exome sequencing indicated that while 73% wanted to know all UF, this increased to between 93% and 97% for UF for which there was effective treatment and intervention, such as breast and ovarian cancer, hemochromatosis, arrhythmia, and cardiomyopathy [156]. However, these parents also expressed high interest in results that conveyed no personal disease risk information, such as pharmacogenetics (98%), carrier status (95%), and ancestry (96%). Positive views towards receiving carrier status have been shown by others [104, 155, 160].

A study of 362 parents of children with rare inherited childhood diseases or pediatric cancer also indicated elevated interest in UF for non-treatable fatal conditions relating to themselves (83%), which was only slightly lower than their interest in UF for fatal treatable/preventable conditions (87%) [6]. Yet, while 92% of this group wanted to know about UF for treatable conditions in their child, this dropped to 65% for non-treatable conditions and only 70% wanted to know uncertain results. This lower interest to receive SF for non-treatable conditions also seems to be reflected in adults. A study of 152 of ‘cognitively intact adults’ offered SF showed that while 76% of participants intended to learn some or all categories of SF and values ranged from 61–63% for receiving pharmacogenetic, carrier status, SNPs, and APOE variants, this dropped to 49% for rare, highly penetrant, unpreventable/untreatable, progressive conditions [155]. In contrast, of 149 parents of children recruited to studies investigating genetic causes and novel therapeutics for rare diseases, only 15% decided they did not want to receive UF that indicated risk of death in their children [77].

Studies indicate that participants (or their parents in the case of minors) want to receive UF for health-related planning and to be prepared [69, 87], to make lifestyle changes [69], out of curiosity [87] or because they are information seekers [69], because they have personal experience with health conditions, or because feel obligations to family members [87]. Some parents may also feel a moral obligation toward their children [75] or believe UF will provide them with a better understanding of the primary condition [100]. Interestingly, a study of 241 persons with mental disorders showed that although 91% thought that participants should receive UF, they believed that researchers should not actively search for SF [13].

However, three studies showed results that were not in line with the general trend. These included a study of 25 parents of children who had exome sequencing study of which only 50% wanted to learn UF relating to carrier status for children [11] and another which found that 16/23 (70%) parents were ambivalent about genomic sequencing, predominantly due to the possibility of UF [75]. The third exception was the study of 16 patient-participants with rare disease (or parents) who were offered the option to receive SF which identified mixed responses; while some wanted to receive all findings, regardless of actionability, others did not, particularly when they were for non-treatable conditions or of uncertain significance [161]. However, the interviews also indicated that these participants had an expectation that if they declined receiving UF now they would be offered the test again at a later stage. Parents have expressed not wanting to receive UF for their children because they are balancing the benefits and risks of knowing [69, 75], and small numbers of parents who were worried have raised concerns regarding insurance discrimination [69, 75], potential emotional/psychological impacts [69, 75, 104, 105], and anxiety brought on by secondary results [69].

Overall, there did not appear to be a difference between views of participants who were asked about hypothetical desires for UF and those who were actually deciding to receive these types of findings. However, a study of 155 individuals offered non-medically actionable SF as a second-tier test indicated that a lower proportion of participants actually requested to receive one or more categories (32%) compared to their decision immediately after their initial diagnostic disclosure consultation (76%) [105]. Another study of 223 participants of research studies using exome sequencing showed that preference for UF dropped from 76% at baseline to 65% after pre-test counseling, suggesting that receiving information and deliberation during the counseling process may change preferences for UF [87].

Biobank setting.

No studies explored participants’ preferences for returning UF or SF in the biobank setting.

Clinical research setting.

Only two studies explored parents’ preferences for receiving UF for their children [95]. In interviews with parents of children affected by rare diseases, all 15 participants felt that knowing and receiving UF was empowering [95]. Parents also discuss wanting to be more aware of clinical risks for their child, to take responsibility for their child’s health, and to allow them to plan (e.g., through proactive financial and health measures) and support their child [95]. However, parents also mention that they want their child’s results because they have a right to know them and in order to exercise control over information that is relevant to their child with the goal of improving care [95]. Parents also want to know their child’s carrier status so they can prepare their children for the future [95]. A Dutch study conducted 673 surveys and 146 interviews with patients [90]. They found that participants wanted to receive UF for curable (92%) and incurable conditions (76%), and also where the risk of developing the condition was high (84%) and low (79%) [90].

Biobank setting.

No studies explored patients’ or parents’ preferences for returning UF or SF in the biobank setting.

Clinical research setting.

Many of the studies assessing participants’ responses and outcomes of receiving IRR were quite positive. Studies have shown high [87] or moderate to high satisfaction with decisions to receive results [8, 174]. Ten studies that asked participants whether they regretted participating in the research showed that either most [175, 176] or all of the participant reported little [155] or no regret at taking part and receiving IRR [79, 87, 174, 177–181]. In fact, a study of 202 participants–comprised of roughly half healthy adults and half patients with either hypertrophic cardiomyopathy or dilated cardiomyopathy–who received health information based on either family history alone or family history and genomic sequencing information, found that those who received genomic results reported lower average levels of decisional regret [182]. In addition, a study of 152 adults randomized to be offered SF found that participants who chose not to receive SF were more likely to feel regret than those who chose to learn SF [155]. However, one study of 117 adult participants of a ClinSeq Study in whom a variant associated with coronary artery disease risk was identified and returned showed that decision regret was significantly different between participant groups; those with VUS-low results (meaning that the evidence relating to the pathogenicity of these variants is approaching ‘likely benign’) reported greater regret than those with VUS-high results (where the evidence was approaching ‘likely pathogenic’) [183]. This suggests that uncertainty resulting from lack of information about the variants identified increased decisional regret [183]. Returning results to parents led to greater satisfaction as did offering a choice about which results to receive [184].

Most participants reported either positive or neutral impacts of receiving results, both when they were related to the study and also for UF/SF [9, 65, 79, 153, 157, 159, 174–176, 178, 179, 181, 182, 185, 187, 190, 191, 195]. A study of 17 research participants and family members who received UF showed that most (16/17) found the process mainly positive or useful and were thankful for being told they have the disease, both for their own wellbeing and also because it provides valuable knowledge for their children [153]. Another study of 31 adult participants in the ClinSeq cohort found that participants expressed relief that the result did not suggest a more serious condition, reassurance about their current healthcare, and satisfaction that they were able to access surveillance [9]. Most participants in the study (27/31) reported that their feelings about their result became more positive over time. This finding was supported by another study of 133 individuals who received testing for the CDKN2A gene for melanoma, where both carriers and noncarriers reported greater levels of hopefulness 6 months after disclosure than beforehand [176].

Similarly, although reports from 223 participants suggest modest impact from receiving IRR, they too expressed relief, either that an increased risk was not identified, or that the results were not indicative of more severe health consequences [87]. Interviews with 12 individuals from the Integrated Personal Omics Profiling project showed that while the majority of participants were underwhelmed by their results, several expressed feelings of validation or closure when their results could play a role in an existing health condition [79]. Other studies have also identified relief [79, 176, 185], gratitude [176], feelings of greater control [174], and that receiving results was valuable [174] and would influence medical treatment [182]. Additionally, assessment of 10 scientists and researchers who received results from genomic sequencing showed no apparent adverse events or reactions from disclosure of SF; variants were found in 9/10 participants [208]. There was also no evidence of adverse effects on self-rated health, quality of life, or emotional experience among either carriers or noncarriers tested for CDKN2A melanoma risk 6 months after disclosure [176].

However, some studies identified negative or mixed emotions from receiving IRR [174–178, 182, 196, 202]. A study of 10 women who had participated in the Australian Ovarian Cancer Study to determine prevalence of BRCA1 and BRCA2 mutations and 15 next of kin showed that interviewees had mixed responses to receiving feedback; many of the relatives were initially distressed, particularly if they had not realised their mother had participated in the study [196]. Another study of 3 adults diagnosed with invasive breast cancer in whom BRCA1 or BRCA2 mutations were identified and then returned also showed mixed reactions, including some guilt, although one year after confirmatory testing all of the interviewees considered that there were more advantages than disadvantages to receiving the information [202]. Individuals identified to be carriers of the at-risk CDKN2A variant for melanoma (n = 15) reported higher distress, higher uncertainty, and lower positive feelings immediately after receiving their result than noncarriers [176].

A few participants in the study of 35 individuals who underwent whole genome sequencing expressed negative reactions, such as concern, disappointment, indifference, confusion, and a desire for more results [175]. Similarly, 54% of 543 healthy participants from within four projects of the PeopleSeq Consortium were disappointed that their results did not tell them more information [174]. Participants from the study of 202 healthy adults and patients with either hypertrophic cardiomyopathy or dilated cardiomyopathy who had received genetic results were more likely to feel they had received a lot, or even too much information compared to those who received family history information alone [182]. They were also generally less satisfied with their understanding and felt lower levels of confidence in their ability to explain results to family members [182]. Interestingly, a study of 24 individuals who participated in a genotype driven study on cystic fibrosis (9 participants with CF and 15 from a biobank cohort) showed that biobank participants were usually less sure than CF patients about why they had been selected and how they should conceive of themselves and their health, suggesting that being recruited based in genotype may create uncertainty for participants [203].

Some studies have suggested aspects across a range of different domains of utility that participants feel they gained through return of IRR. Participants appreciate the potential for surveillance and the ability to seek targeted medical care, which can lead to early detection and/or disease prevention, both for themselves and also their family members [9, 87, 198]. They also express empowerment from the knowledge of the genetic cause of their condition or, in the case of other information, such as carrier status or pharmacogenetic information, highlighted the importance of sharing this with family [87]. A study of 18 volunteers who agreed to have a genetic test for the FTO gene related to obesity believed that knowing their result would motivate them to try to control their weight in the future [195]. Another study showed parents valued having an answer and being able to put a name to their child’s condition, as well as the ability to predict and manage their child’s future health [177]. They also discussed the benefits of reproductive planning for any family member and being able to help science [177]. Focus groups with 24 members of the Hmong community in the USA who received pharmacogenetic results showed that as well providing benefit through allowing for changes in their medication, participants also identified that returning results benefited the broader community [187].

In relation to psychological outcomes, several studies have shown low levels of distress [87, 192], low levels of concern [190, 191], low levels of negative emotions [159], and high rates of wellbeing from receiving IRR [8]. In Sanderson et al’s 35 healthy adult participants, no changes were detected in anxiety, depression or quality of life in response to receiving results between baseline and later measures [175]. Similarly, a project that tested 19 adult participants with a personal history of melanoma for genetic susceptibility to the condition showed no significant psychological harm from disclosure [83]. Event-specific distress was also low in these participants. Despite this, mutation carriers reported greater subjective concern about test results and also perceived their risks for another melanoma to be higher than non-carriers. In addition, a study of 13 adult family members of deceased men with early-onset prostate cancer who had participated in a study and who had been found to have a BRCA2 mutation showed that some participants experienced distress and anxiety, although this was resolved through genetic counseling [198].

A number of studies have explored psychological outcomes in response to receiving APOE results in various iterations of the REVEAL study [80, 185, 192, 193, 199, 201, 209, 210]. These studies have explored responses to receiving versus not receiving genetic risk results, receiving deterministic versus susceptibility information, and also to different ways of disclosing results. The initial publication from this study, reporting on 162 adults who had a parent with Alzheimer’s Disease (AD) suggested genotype disclosure did not adversely affect participants’ psychological wellbeing, or lead to anxiety or depression with group means of these measures rating well below clinical cut off scores [193]. A subsequent study comparing disclosure of results of susceptibility testing within the REVEAL study (n = 101) versus deterministic testing in another study by University of Washington (n = 22) showed similar low levels of distress in both cohorts [192]. Another study where 162 participants were randomized into disclosure (n = 111) and non-disclosure (n = 51) arms showed no significant differences in distress between the two arms, yet did report differences between APOE e4+ and e4- at 6 weeks, 6 months and 12 months [80]. Although participants reported higher likelihood of perceived risk and an overall negative effect of disclosure in the APOE e4+ group, they were no less likely to say they would retest than the APOE e4- group and attributed their psychological state to factors other than the results [80].

A study comparing extended, in-person APOE result disclosure with a condensed disclosure process suggested that 45% of their 269 participants reported an increase in depressive symptoms although only 9% were above the clinical cut off at 6 months [199]. Reports of increased depression at 12 months were associated with lower causal attribution to genetics and higher perceived risk of developing AD and level of concern decreased significantly more in those who received e4- results than e4+ [199]. In a study that compared outcomes from disclosing risks for AD alone with AD plus Coronary Artery Disease (CAD), 24% of participants reported moderate anxiety, depression, or test-related distress at one or more follow-up time points with no difference between the AD-only and AD+CAD groups [210]. In this study, mean distress scores and anxiety were greater in participants that received e4+ results but only for those in the AD only group. Another study that included 111 participants with mild cognitive impairment who were randomized into disclosure (n = 75) and non-disclosure arms (n = 39), showed that mean anxiety and depression scores in both arms were below clinical cut-offs at all time points [209]. Those in the disclosure arm who were e4- had lower test-related distress and greater positive impact than those who were e4+ [209]. Interestingly, individual scores for anxiety, depression, and hopelessness were more likely to be above clinical cut-offs, indicating cause for concern, if they were in the non-disclosure than the disclosure group [209].

Several studies have also assessed behavioral change in response to IRR. Most of these studies have shown little to no behavioral change [8, 79, 83, 87, 198, 206, 207] nor intentions to change behavior [183]. For example, disclosure of IRR in participants of the melanoma study had very little impact on motivating participants to adopt more prevention behaviors, such as wearing long sleeve shirts or pants when exposed to the sun or performing self-examinations, even in those who were identified to carry pathogenic variants in CDKN2A [83]. Family members of men with early-onset prostate cancer were less likely to engage with information and have screening if they were sceptical about the relative that informed them of their risk, if they were younger, and if they were afraid of cancer [198]. Although a study of 107 men and women from families with a known MMR gene mutation (which increases cancer risk) showed a slight increase in screening measures among participants, irrespective of test result, this was not significant [8].

Yet, participants do appear to take some steps based on receiving results. More participants in the MMR study who received an IRR indicating a pathogenic mutation took further steps to discuss screening than those who were negative [8]. In a study of 68 individuals without cardiomyopathy who had received VUS for a cardiomyopathy gene, 15 went on to engage in health-related behavior change: nine had cardiac testing (for some of whom there were clinical indications) and 12 made lifestyle changes [205]. The study of healthy individuals who were randomized to receive testing for either AD+CAD or AD alone showed that 57% reported changing at least one health behavior at 12 months in response to genetic risk disclosure [210]. Although this was more likely in the AD+CAD group than AD alone, this finding was independent of genotype [210]. In the ClinSeq cohort, 25/31 participants sought information about the variant and its associated health condition online after receiving their result [9]. Yet, of the seven healthy participants that received likely pathogenic or pathogenic rare disease associations, only 2 had acted on their results [175].

Biobank setting.

Four studies explored the outcomes from returning IRR to biobank participants [204]. Surveys were conducted with 55 participants who were part of a cohort of people with pancreatic cancer who were tested for variants in CDKN2A for melanoma risk, explored the outcomes from returning SSR to biobank participants [204]. They found that CDKN2A carriers worried more about developing pancreatic cancer than non-carriers at predisclosure, immediately post disclosure, and also 6 months later [204]. In addition, more carriers thought they had a higher than average chance of developing melanoma at predisclosure and 6 months post-disclosure than non-carriers, which remained significant after excluding those with history of melanoma [204]. An Estonian study that returned pathogenic variants in BRCA1/2 genes to 22 biobanks participants found they generally felt calm and relaxed following genetic counselling, although a small number of participants reported feeling tense or worried [197]. A second Estonian study, in which 16p11.2 CNVs were reported back to 5 carriers, showed most were relieved and were coping with the information, although two said they were slightly worried [186]. In addition, surveys with ten thoracic aortic dissection biobank participants in the USA who received pathogenic variants showed low levels of psychological distress, negative feelings, uncertainty and privacy concerns [188].

In the two studies that explored behavior change in response to results was generally poor [186, 204]. Most participants in the CDKN2A did not have their results confirmed by a clinical laboratory, less than half had enacted pancreatic checks, and less than a third had had a skin test by 6 months follow up [204]. In the Estonian study that reported UF, two respondents visited a genetic specialist and this led to a treatment modification for one participant [186].