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Parents perspectives on whole genome sequencing for their children: qualified enthusiasm?
  1. J A Anderson1,2,3,
  2. M S Meyn4,5,6,7,8,
  3. C Shuman4,5,6,9,
  4. R Zlotnik Shaul1,3,8,10,
  5. L E Mantella11,12,
  6. M J Szego3,13,14,15,
  7. S Bowdin4,6,8,
  8. N Monfared4,
  9. R Z Hayeems4,10,16
  1. 1 Department of Bioethics, The Hospital for Sick Children, Toronto, Canada
  2. 2 Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, Toronto, Canada
  3. 3 Joint Centre for Bioethics, University of Toronto, Toronto, Canada
  4. 4 The Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Canada
  5. 5 Department of Molecular Genetics, University of Toronto, Toronto, Canada
  6. 6 Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Canada
  7. 7 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada
  8. 8 Department of Paediatrics, University of Toronto, Toronto, Canada
  9. 9 Genetic Counselling, The Hospital for Sick Children, Toronto, Canada
  10. 10 Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Canada
  11. 11 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
  12. 12 Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada
  13. 13 St. Joseph's Health Centre, Toronto, Canada
  14. 14 The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada
  15. 15 Department of Family and Community Medicine, University of Toronto, Toronto, Canada
  16. 16 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
  1. Correspondence to Dr Randi Zlotnik Shaul, Department of Bioethics, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; randi.zlotnik-shaul{at}sickkids.ca

Abstract

Objective To better understand the consequences of returning whole genome sequencing (WGS) results in paediatrics and facilitate its evidence-based clinical implementation, we studied parents' experiences with WGS and their preferences for the return of adult-onset secondary variants (SVs)—medically actionable genomic variants unrelated to their child's current medical condition that predict adult-onset disease.

Methods We conducted qualitative interviews with parents whose children were undergoing WGS as part of the SickKids Genome Clinic, a research project that studies the impact of clinical WGS on patients, families, and the healthcare system. Interviews probed parents' experience with and motivation for WGS as well as their preferences related to SVs. Interviews were analysed thematically.

Results Of 83 invited, 23 parents from 18 families participated. These parents supported WGS as a diagnostic test, perceiving clear intrinsic and instrumental value. However, many parents were ambivalent about receiving SVs, conveying a sense of self-imposed obligation to take on the ‘weight’ of knowing their child's SVs, however unpleasant. Some parents chose to learn about adult-onset SVs for their child but not for themselves.

Conclusions Despite general enthusiasm for WGS as a diagnostic test, many parents felt a duty to learn adult-onset SVs. Analogous to ‘inflicted insight’, we call this phenomenon ‘inflicted ought’. Importantly, not all parents of children undergoing WGS view the best interests of their child in relational terms, thereby challenging an underlying justification for current ACMG guidelines for reporting incidental secondary findings from whole exome and WGS.

  • Genethics
  • Genetic Screening/Testing
  • Family
  • Children
  • Genetic Information

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Introduction

Whole genome sequencing (WGS) promises to provide a transformative set of tools for gene discovery and healthcare, but fully integrating WGS into clinical care involves major ethical challenges.1–3 Traditionally, genetic testing assumed a focused diagnostic inquiry. The comprehensive hypothesis-free nature of WGS challenges this approach because WGS data also can be used to generate secondary predictive findings, perform clinical re-analysis and conduct gene discovery research.

The ethical challenges associated with WGS are compounded in the context of paediatrics. Since children have limited decision-making capacity, there is a long-standing policy in genetics to defer genetic testing for adult-onset disorders until the patient is capable.4–7 Decision-making is further complicated by the fact that the majority of clinically relevant secondary variants (SVs) identified by WGS in a child are inherited, with health implications for parents, siblings and other relatives. Despite evolving guidelines,8–11 vigorous debate,12–18 and surveys of healthcare providers and the general public,19–29 there is a paucity of published empirical evidence examining the perceived benefits and risks of WGS from the perspective of individuals actually enrolled in WGS.19

Given the unknown consequences of returning WGS results, here we report on the first phase of a larger study examining early experiences with WGS: parent perceptions of WGS and the preference-sensitive consent process followed by the Genome Clinic at The Hospital for Sick Children (SickKids) in Toronto, Canada.

Methods

Study setting

The SickKids Genome Clinic is a clinical research project serving as a test-bed for determining the diagnostic and predictive performance of WGS as well as evaluating the practical and ethical challenges of integrating WGS into routine paediatric healthcare. These challenges include assessing the consequences of actively searching for secondary medically significant variants and designing an innovative consent process. The Genome Clinic protocol includes actively searching the child's WGS results for clinically actionable medically significant variants in 2800+ disease genes listed in the ClinGen database. Variants in ClinGen genes that predict a childhood-onset disorder are returned for all children enrolled in the study. Parents are given the option to (1) learn about those SVs that were found in their child's genome that predict medically actionable adult-onset disease and (2) undergo focused conventional genetic testing in order to learn if they carry any of the SVs found in their children. During the consent process, participants are informed about the potential risks and benefits associated with secondary predictive analyses. The Genome Clinic consent process rests on a broad interpretation of best interests according to which the identification of adult-onset disease-associated variants (eg, the BRCA1 or BRCA2 breast/ovarian cancer predisposition genes) may be in the child's best interests if this information can be used to reduce risk/improve health in their parent(s). We have provided an extended analysis of this approach in Anderson et al.13

Sample and recruitment

Potential participants were drawn from the population of patients referred to the Genome Clinic: (and their parents) children undergoing conventional clinical genetics tests (eg, microarray or targeted gene panel testing (definitions in box 1) for the purpose of initial or supplementary diagnosis. To determine comparative diagnostic performance, all Genome Clinic participants pursued WGS and one conventional test. Clinical indications for microarray+WGS included developmental delay and/or congenital anomalies, while clinical indications for gene panel +WGS included complex disorders of suspected genetic aetiology for which a targeted panel test is available (eg, epilepsy). The Research Ethics Board at The Hospital for Sick Children approved this study and informed consent was obtained from all participants. All parents of children invited to enroll in Genome Clinic were eligible to be interviewed for this qualitative substudy. Index children with capacity to consent to WGS were also eligible to enroll. Individuals who were non-English speaking or cognitively impaired were excluded. Importantly, all interviews took place after WGS was initiated but before any diagnostic or predictive results were returned.

Box 1

Definition of terms

Microarray: a genetic test that looks for extra (duplicated) or missing (deleted) DNA segments. These are termed copy number variants. Microarray currently is the recommended first tier test for children with developmental delay and/or congenital anomalies.

Gene panel test: a genetic test that simultaneously examines a number of different genes looking for potential disease-causing sequence variants.

Whole genome sequencing (WGS): a laboratory process designed to simultaneously assess all of the variants in an individual's genome. Bioinformatic filtering is frequently used to suppress identification of secondary predictive variants from WGS data.

Primary variant: an alteration in a disease-causing gene that is thought to play a role in causing the individual's health problems that triggered genetic testing.

Secondary variant: an alteration in a disease-causing gene that is not related to the individual's health problem(s) that prompted genetic testing, but may be related to other health risks, at present or in the future.

Data collection

We conducted semistructured, open-ended, qualitative interviews. Capacity to consent was assessed by probing potential participants' understanding of relevant study elements during the consent process. The phase 1 interview focused on participants' understanding of the primary goals an secondary effects of WGS; information needs related to WGS; motivations and expectations with respect to WGS; and reasoning related to choices made during the consent process concerning medically actionable SVs. Phase 2 interviews will probe the experience of receiving WGS results. Consistent with established qualitative research methods,30 our interview guides were flexible and iterative to allow for further exploration of topics that arose during the course of the interviews. Parents were asked to complete a short questionnaire at the completion of the interview to capture sociodemographic characteristics and feedback related to the informed consent process.

Data management and analysis

Interviews were 30–60 min in duration, audio-taped, and transcribed verbatim. Interview transcripts were coded and analysed following the principles of interpretive description, an approach used to support rich description and low-inference interpretations.30 ,31 We adopted a mixed strategy for coding, starting with codes derived from our interview guide, and allowing new codes to emerge from the data. We pursued a specific thematic analysis for the subgroup who chose to learn only some SVs or were undecided about this option. To ensure credibility and trustworthiness, each transcript was analysed by two independent coders and interpretive discrepancies were reviewed and resolved by discussion. Data collection continued until thematic saturation was achieved. Sociodemographic questionnaire data were analysed by frequency counts.

Results

Participant characteristics

Recruitment took place over an 8–month period. Parents and capable index children were eligible to participate. Of the eligible individuals, 25 parents from 18 families agreed to participate (two interviews failed to record and could not be analysed). The majority of participants (21/23; 88%) were well-educated (ie, university or graduate degree) and employed full time (12/23; 61%). Most had a provisional clinical diagnosis for their child's condition (17/23; 68%), and most had previous experience with diagnostic genetic testing for their child (16/23; 72%) (table 1). Overall, participants' feedback on the consent process was positive. Majorities reported that the amount of information provided and time taken to review the information was appropriate (19/23; 83%) and that the information provided about secondary findings was balanced (21/23; 91%).

Table 1

Sample characteristics

Thematic analysis

Positive views regarding primary variants

(See online supplementary table S1 for data supporting our analysis in this section).

Overall, participants were supportive of WGS as a novel diagnostic test for identifying the genetic cause of their child's clinical condition. Participants valued WGS because they ‘wanted answers’ concerning their child's condition and they were hopeful that it would provide those answers (19/23; 83%). Participants also valued WGS because they hoped it might lead to improved treatment (10/23; 43%), provide information useful for family planning purposes (12/23; 52%) and contribute to the advancement of science, technology and practice (10/23; 43%).

Mixed views regarding secondary variants

Despite support for WGS as a diagnostic test, many parents (16/23; 70%) also expressed ambivalence about this new test. Ambivalence stemmed from the required balancing between perceived benefits and risks associated with SVs as well as from a sense that they would be remiss as parents to not know what is knowable.

Participants' characterised SVs as positive in two ways: they may enable prevention of/preparation for unanticipated health vulnerabilities in the child (17/23; 74%) and they may enable knowledge about and potential mitigation of parental health risks (12/23; 52%).It gives us the tools to look for early signs of anything that could possibly affect her later in life… to catch it earlier… -1022-02 …also finding other things we might be prone [to]… You know, just for example, I might have an indicator for breast cancer… -1023

Participants' characterised SVs as potentially concerning in four ways: the potential for psychological distress (18/23; 78%), the potential for insurance discrimination (14/23; 61%), making sense of ambiguous findings (8/23; 35%), and managing the ‘weight’ of inflicted insight (8/23; 35%).How is he supposed to go on and live a happy and productive life… when… he has pretty much a guillotine hanging over his head of all these possible things that are going to go wrong? -1030-02 I was concerned about things like our ability to get insurance and if it would in any way, shape or affect his ability to obtain insurance -1013-02 …even now I still have questions like, OK, she's susceptible to childhood diabetes, is that a definitive answer, is that going to happen, is it possible, probable, 100%? -009-02 I just hadn't appreciated all the implications… This information is, you know, it's heavy…-016-01

Fourteen participants chose to receive all SVs for both their child and themselves. That said, many of these participants expressed conflicting views about SVs in their interview. Indeed, 50% (7/14) expressed some reservations about receiving all SVs but chose to receive them nonetheless. Participants 1013-2 and 009-02, whose misgivings were quoted above, are among this group.

We pursued a specific thematic analysis of the subgroup of participants (9/23) who chose not to learn about all types of SVs (for themselves, their child or both). None of these parents chose to learn all SVs related to themselves. Four made different choices for their child than they did for themselves, choosing to learn more about their children. In some cases, parents expressed what might be called a duty to know information pertaining to the health of their children.…you're damned if you do because then you know of potential problems down the road that you have to worry about… whereas if we were just blissfully unaware and he died younger than he would have liked then, you know, there's, there could be that guilt there of having had the opportunity to find out and not taking it…-1030-02

Discussion

Our findings regarding parents' assessment of the diagnostic value of WGS support previous studies.15 ,29 ,32 Similarly, the risks of SV disclosure reported by our parental cohort have been identified before: potential insurance implications,4 ,10 ,15 ,33 ,34 psychological distress10 ,16 ,18 ,34 and inflicted insight,16 ,18 among others. However, we also uncovered novel forms of ambivalence toward SVs felt by parents of children undergoing WGS that have not been previously explored in this context.

To begin to understand these results, it is important to appreciate the circumstances many of the participating parents are facing. They are heavily invested in finding an accurate diagnosis for their child and for many, enrolment in the Genome Clinic represents a potentially hopeful step in an exhaustive and, so far, ineffective diagnostic journey. Since choices regarding SVs are presented as an inseparable part of WGS in the Genome Clinic consent process, the benefits and risks of discovering both primary and SVs using WGS are fully explored. Despite their misgivings regarding SVs, most parents said yes to the receipt of all or some of them. However, our data suggest that some parents' choices about SVs were driven by a perceived moral obligation to learn, to the extent possible, the full range of current and future risks for their children, no matter how unpleasant. Faced with this opportunity parents felt they had no choice.

By analogy with the term ‘inflicted insight’, we call this phenomenon ‘inflicted ought’. In our view, ‘inflicted ought’ is a subspecies of a more general phenomenon related to freedom and responsibility. On the one hand, options provide choice, enhance freedom, and empower individuals to make decisions for themselves. On the other hand, optionality increases responsibility, and this can be perceived as a heavy burden.35 The term ‘inflicted ought’ is meant to capture this sense of burden, imposed by the choices on offer, as articulated by some of the parents in our study.

Inflicted ought need not pose a threat to informed consent, but it does complicate our interpretation of parental attitudes toward WGS. As indicated by the conflict between parents' affirmative choices related to learning SVs during the consent process, and their concerns elicited during the study interview, seemingly clear choices may obscure the complex weighing of costs and benefits behind those choices. By preparing families for potential test outcomes and exploring potential ambivalence toward SVs during the consent process, we are likely to better serve their interests.

The discordance between parents' preferences for themselves and their preferences for their children also challenges assumptions underlying the consent process used by the Genome Clinic. Past clinical genetic testing paradigms have generally favoured withholding information about SVs associated with medically actionable adult-onset disorders found in children since testing/disclosure was not considered to be in the best interest of the child.36 As noted above, the creators of the Genome Clinic consent process interpreted best interests more broadly, arguing that the presence of an previously unsuspected disease-associated variant (eg, BRCA 1 or 2) in the child has potential health implications for the parent, and knowledge about parental disease risks, in turn, has implications for the best interests of the child.13 Following Salter, we refer to this approach to best interests as relational, by contrast with traditional, individualistic approaches.37

From a relational perspective, other things being equal, we would expect parents to choose similarly for their child and themselves for the reasons just stated: we are starting from the assumption that knowledge about disease risks faced by both parent(s) and child is in the best interests of the child. In fact, four of the nine parents in our subgroup made different choices for their child than themselves, choosing to learn about SVs found in their child's genome but refusing to learn their own. These findings suggest that a significant minority of the parents in our study did not consider knowledge of their own disease risks to be in the best interests of their child. Assuming parents' choices are driven by how they perceive their child's best interests, possible interpretations suggest themselves: (1) other things were not equal, that is, factors other than their own disease risks weighed more heavily in parents' assessments of their child's relational best interests; (2) these parents failed to appreciate the connection between their own best interests and the best interests of their child or (3) these parents employed an individualistic—as opposed to relational—approach to best interests.

These data are only suggestive, as we did not explicitly ask parents to reflect on the notion of best interests—this disjuncture emerged from the data itself. It is worth noting, however, that similar data were found in the broader population enrolled in the Genome Clinic from which our sample was drawn (n=223): among parents who decided to learn their child's adult-onset SVs and carrier variants, 22% chose not to learn or were undecided about learning their own status for the same risk variants.38 Taken together, these data raise questions about the logic underpinning the consent process followed by the Genome Clinic, questions that require further examination. Perhaps parents simply need additional information concerning the connection between their own best interests and the best interests of their child. Alternatively, parents may reject a relational approach to their child's best interests altogether when explicitly asked. This finding would require a reconsideration of the consent process—and the logic that supports it.

Importantly, our findings also raise questions about the ACMG's recently published guidelines concerning incidental findings in exome and genome sequencing, as these guidelines also adopt a relational approach to best interests. According to the ACMG, ‘the ethical concerns about providing clinicians of children with genetic risk information about adult-onset diseases were outweighed by the potential benefit to the future health of the child and the child's parent’ (emphasis ours).8 If, as our findings suggest, parents do not always view the best interests of their child in relational terms, this aspect of the ACMG's rationale is undermined and their case for disclosing risk information about adult-onset diseases is weakened.

Limitations

We acknowledge several limitations. Though our study was open to capable youth, and potential participants who opted not to participate, we were unable to recruit anyone from these subpopulations. Since it is likely that these groups contain individuals with serious reservations about WGS testing, the absence of these individuals from our sample constitutes a limitation. As well, the majority of parent participants were highly educated; while this is comparable to studies with similar parent cohorts,39 our findings may not be representative of parents who have less formal education. Finally, participants received extensive explicit counselling regarding the potential risks and benefits of participation—including insurance discrimination—during the consent process; participants' related concerns were not unprompted.

Conclusion

Given our incomplete knowledge of the risks and benefits of returning WGS results in the paediatric setting, there is a critical need to study the experiences of children (and their parents) undergoing diagnostic WGS. Our study is the first to examine these issues empirically in the context of actual participation in WGS in a Canadian paediatric, non-cancer population.40 The data gleaned from this component of the study, combined with pending data from phase 2 parent interviews, should have multiple downstream impacts. These include evidence-based standards for informed consent, improved educational materials for patients and families and new communication paradigms for genetic counsellors and other healthcare providers.

Acknowledgments

We thank the Genome Clinic parent participants for sharing their experiences and the Accelerator Grant in Genomic Medicine, from the McLaughlin Centre, University of Toronto, for providing funds to support this work. We thank the Centre for Genetic Medicine at SickKids for its instrumental role in supporting the Genome Clinic.

References

Footnotes

  • Contributors All authors have substantial contributions to the conception or design of the work; the acquisition, analysis or interpretation of data for the work; drafted the work or revised it critically for important intellectual content; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding McLaughlin Centre, University of Toronto (MC-2013-15).

  • Competing interests None.

  • Ethics approval The Research Ethics Board of The Hospital for Sick Children, Toronto, Canada.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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