Abstract
Purpose
To explore how parents of pediatric patients with cancer perceived the utility of clinical tumor and germline whole-exome sequencing (WES) results.
Patients and Methods
We conducted longitudinal interviews with parents of a diverse pediatric cancer population before disclosure of WES results (n = 64), then 1 to 8 months (n = 33) after disclosure. Interview transcripts were analyzed using a thematic qualitative approach.
Results
Parents identified a broad range of types of utility for their child’s WES results. Even when results did not affect their child’s current treatment, they expressed optimism about future clinical utility for their child, themselves, and other family members. Parents also reported experiencing psychological utility including peace of mind, relief of guilt, and satisfaction of curiosity. Pragmatic utility, such as the ability to plan for the future and make better reproductive decisions, was also described.
Conclusion
Parents of pediatric patients with cancer perceive WES to have broad utility, including psychological and pragmatic utility, even if there is no direct impact on clinical care. Additional research will need to consider how the value of genomic information should be characterized, how risks and benefits should be described, and how these results should inform recommendations and decisions about using WES.
INTRODUCTION
Genomic sequencing (GS) technologies including whole-exome sequencing (WES) and whole-genome sequencing are increasingly being used in cancer clinical research and care.1-5 These technologies are typically valued for their potential to allow evidence-based changes to patients’ treatment. This is particularly true in the context of pediatric practice, in which ethical reservations about the impact of GS information have limited its use in generating direct clinical benefits.6 However, recent policy and position statements have criticized these narrow definitions of utility and argue that testing and disclosure provide value for families and society in addition to individual patients and may be appropriate in a wider set of cases.7-10 Many have argued for a more comprehensive and empirically informed understanding of the utility of GS and have urged that perspectives of individuals receiving sequencing results should be incorporated into the development of clinical practice and coverage guidelines.11-14
The hypothetical interest of parents in receiving GS results for their children with conditions other than cancer has been reported.15-17 Two studies have described the perceptions of parents of children with rare diseases18 and autism spectrum disorders19 regarding GS; these parents found the information useful for reproductive and financial planning19 as well as for finding a conclusive diagnosis and helping with the coping process.18 Recent studies have found that adults undergoing sequencing reported finding value in increased self-awareness,20,21 satisfaction of curiosity,20 legitimation of their condition,21 and support from others.21 To the best of our knowledge, no research has evaluated how parents of pediatric patients with cancer who have received their child’s GS results conceptualize the utility of the information. In this study, we explore the expected and perceived benefits for parents of pediatric patients with cancer who received clinical WES results as part of an ongoing WES implementation trial. Our results can inform evolving policies and practices about recommendations for, funding of, and decision making about the use of WES in clinical cancer care.
PATIENTS AND METHODS
The Baylor Advancing Sequencing in Childhood Cancer Care (BASIC3) study evaluates the impact of integrating clinical germline and tumor WES results into the care of children with newly diagnosed solid tumors at Texas Children’s Cancer Center in Houston, TX. The BASIC3 study enrolled 287 pediatric patients; the consent process and reporting components of the trial as well as the initial germline and tumor exome results have been described.22,23 The study includes providing clinical WES of blood samples for all patients and tumor samples when available (80% of patients enrolled); results were reported in the medical record. The study was approved by the Institutional Review Board of Baylor College of Medicine.
Tumor and germline WES results were disclosed to parents by the patient’s primary oncologist and a study genetic counselor. Categories of germline results consisted of diagnostic findings or variants of uncertain significance related to the child’s phenotype (cancer as well as other diseases, if applicable), medically actionable incidental findings, a small number of pharmacogenomic findings, and the option for carrier status for recessive disorders (> 90% of participants requested this information). Results on nonactionable adult-onset conditions unrelated to the child’s medical problems were not returned. It was explicitly stated in both the informed consent document and consent session that it was unlikely that WES information would provide immediate clinical benefit to patients in terms of current treatment and that the tumor WES results in particular might be more clinically useful if the tumor recurred. Parents were given a copy of their child’s WES report(s) in addition to a counseling letter summarizing findings from the germline WES report in lay language.
We conducted semistructured interviews with one parent of BASIC3 study patients in either English or Spanish as preferred by the parent. If another parent or other family member was present, they were invited to participate as well. Only parents of patients who underwent both blood and tumor sequencing were eligible to participate. To ensure that we would have sufficient participation throughout the longitudinal project, we oversampled for predisclosure interviews (n = 64). These were conducted with parents after consent and enrollment in the study but before disclosure of WES results (predisclosure). Second interviews (n = 33) took place 1 to 8 months after disclosure of WES results (postdisclosure). Figure 1 explains participant attrition throughout the study. Interviews lasted an average of 50 minutes and were conducted at a time and location convenient for the parent, most frequently at the time of one of their child’s clinical appointments. Interviews were audio-recorded and typically involved one parent. Participants received $25 as compensation for completion of each interview. Data included in this analysis are from interviews conducted from the start of the study in August 2012 to April 2016.
Fig 1.
Study participant attrition.
All interviews were transcribed verbatim, and the transcripts were reviewed for accuracy and uploaded to ATLAS.ti v 7.5.11 (Scientific Software Development, Berlin, Germany), a qualitative data management software program. We used thematic qualitative analysis,24 first taking a deductive coding approach to create codes on the basis of main research questions and then an inductive approach to create additional codes to identify themes on the basis of the statements of the interview participants. All potentially identifying information was removed, and parents were referred to only by their study identification number, noted in brackets after each quotation.
We calculated descriptive statistics for parents’ demographic characteristics, evaluating differences between interview participants and overall study participants’ sex and race/ethnicity by using χ2 tests. Statistical analyses were conducted by using SPSS 24 (IBM, Armonk, NY). All P values were two-sided and with statistical significance set at P < .05.
RESULTS
Our study enrolled a highly diverse set of families. Demographic information from all parents who completed predisclosure interviews are provided in Table 1. Sex and race/ethnicity of the parents interviewed did not differ from the demographics of the full study population (all P < .05).
Table 1.
Demographic Characteristics
We have previously published results of the predisclosure interviews with both parents and physicians describing their expectations about the potential challenges of incorporating WES into the clinical care of pediatric cancer.25 This article reports on the broad range of ways in which parents anticipated finding value (predisclosure) and then actually found value (postdisclosure) in their child’s WES results. Table 2 offers a typology of the various dimensions of utility identified by parents. Representative quotes illustrating each dimension are included in Table 3.
Table 2.
Typology of Utility for WES of Childhood Patients With Cancer
Table 3.
Parents’ Descriptions of Utility of Tumor and Germline WES
Although the focus of this article is the range of ways in which parents found participation in the BASIC3 study valuable, it is worth noting that parents described few concerns about having GS information.
Clinical Utility
Parents were informed as part of the consent process that participation in the study was highly unlikely to change their child’s treatment plan. Even so, in predisclosure interviews some parents expressed hope that their children’s WES results might provide clinical benefits for their children either in the short term or in the future, including tailored treatments and information about the need for additional genetic testing or surveillance.
As expected, only a minority (33% of those interviewed postdisclosure) of tumor reports included somatic mutations categorized by the laboratory as being of proven or potential clinical relevance.23 Even when such a mutation was found, the information was not used immediately because the child was undergoing standard treatment. However, some parents, including both those whose child was found to have a tumor mutation and those who received a negative report, believed that it could be used to personalize treatment in the future if the tumor returned.
Before and after disclosure, parents were clear that germline genomic information was valuable not only for their child with cancer. Many referred to preventing illness in themselves, other children, and other family members. Postdisclosure interviews revealed that parents found germline information useful when the germline report revealed actionable findings and also when it did not.
Psychological Utility
Parents also reported expecting or experiencing psychological benefits, that is, improved mental (as opposed to physical) states, as a result of their participation in the BASIC3 study. Interestingly, many parents discussed the psychological impact of genomic information on themselves rather than on the patient or other family members.
One of the strongest themes emerging from our analysis was that parents felt the need to know why their child had developed cancer. They hoped that the tumor or germline WES reports would offer an answer to a question bothering them. Of the 33 families interviewed postdisclosure, only 11 had received information identifying a potentially clinically relevant mutation in the child’s tumor, and one had received information about a cancer-related germline mutation. That most parents did not get information explaining their child’s cancer caused disappointment among some participants whereas others were grateful for any findings that were returned.
Some parents looking to explain their child’s cancer articulated in predisclosure interviews that they hoped the results would offer exculpatory information. They felt that a better understanding of the cancer’s source would remove the guilt associated with worrying that they had passed the disease on or that they had done something to cause it. Relief from guilt associated with the possibility of passing on a cancer gene was also identified by parents as a source of utility after receiving genomic information about tumor mutations.
There were parents who stated that the information offered them peace of mind after they had received a negative result. When no increased risks were identified, they cited relief from a burden of worry about the patient and about other family members. The potential value of eliminating possible common hereditary causes of the child’s cancer was not mentioned in the consent form, but parents perceived a negative result as valuable nonetheless.
Pragmatic Utility
Many parents stated that they thought GS information would have practical value for them in terms of planning other aspects of their lives. Most parents interviewed postdisclosure (32 [97%] of 33) had opted to receive information about carrier status in the germline WES reports, and the vast majority of these participants (31 [97%] of 32) received information indicating that they were carriers for one or more generally rare recessive conditions (the laboratory reported pathogenic variants for any recessive disorder in Online Mendelian Inheritance in Man [OMIM]). Many of those who received carrier status information valued the fact that they believed it offered the ability to make better reproductive decisions. Some parents felt that this information would be useful to their affected child, and others stated that it would be relevant to their own decision making.
Finally, several parents identified the value of being able to plan for the future and the possibility of additional health problems. Although few of the parents in our postdisclosure cohort (three [9%] of 33) received results indicating that their family was at increased genetic risk for other cancers or diseases, many reported being grateful for any information that could prevent them from being surprised by a similar occurrence again, consistent with results in the predisclosure interviews.25
DISCUSSION
The results of this qualitative analysis demonstrate that parents’ perception of the value of WES information in the context of childhood cancer extends well beyond a narrow definition of clinical utility focused on diagnosis, prognosis, and therapeutic management. Our diverse cohort of parents described other dimensions of utility, including the psychological and pragmatic value of having this information.
Existing literature typically classifies any utility that is not grounded in a change of medical management as personal utility. This project’s analysis offers a more nuanced description of the various facets of personal utility than has been articulated previously. Even so, connections can be drawn with the limited available data accumulated in other contexts, echoing findings of recent studies suggesting that patients and their families believe that sequencing information is useful in a wide variety of ways.
The belief that information will have future clinical value even if it does not have an impact on clinical decision making at the time of the disclosure was found in our analysis and in other work.21 With respect to psychological utility, our results mirror those suggesting that parents and patients place enormous value on establishing a causal explanation for a disease or condition.19,21 Similarly, our data support a finding that parents of children with serious diseases seek confirmation that the disease was not the fault of the parents.18 As other studies have shown,19,20 our participants reported that having genomic information may be valuable in and of itself, even if it does not lead to any significant changes in their lives or experiences. The possibility that this information could have an impact on reproductive decision making was identified as important for many parents in other contexts as well.19
Available literature on pediatric GS has not described the extent to which utility for individuals other than the patient is considered by those making decisions about WES, although this is clearly a theme in adult contexts. As Table 2 highlights, our data clearly document the extent to which these others, particularly siblings, play a prominent role in the perceptions of decision makers. Finally, our study has described parents’ perceptions in the unique context of decision making about WES in pediatric cancer.
The experiences and perspectives of the parents interviewed offer evidence to buttress emerging critiques of a narrow view of utility. Our data support the view of Botkin et al13 that, “softer outcomes, such as psychological impacts, behavior changes, and social impacts, are particularly important in the assessment of many genetic tests” and illustrate the importance of recognizing a wide range of utility. The finding that parents of pediatric patients with cancer perceive the value of genomic information so broadly has several significant ethical implications for whether and how WES is integrated into clinical practice.
First, a few of the responses given by parents suggest that their perceived value of WES information may be disproportionate to its clinical implications. Despite being told that it was unlikely that the WES results would change or improve their child’s medical care in the short term, many parents still cited hopes of tailored treatment. Parents also expressed confidence that the results would define a specific treatment approach in case of recurrence, even in several cases in which no tumor mutations were identified. In addition, the peace of mind that parents described having after getting a negative germline report may reflect an overestimation of the family’s risk reduction estimate, even though the disclosure and counseling letter notes that WES does not identify all cancer susceptibility findings. Although it is not novel to note concerns about the accuracy of decision makers’ understanding of complex genomic data, the question of how to ethically account for parents’ possibly exaggerated perceptions of the utility of a negative report (there are no reliable data on how exaggerated this might be) seems particularly salient in the context of pediatric cancer.
Second, the data demonstrate that parents put significant weight on the perceived benefits of WES information for themselves, their other children, and other family members. The nature of genetic and genomic technologies is that they have implications for individuals beyond the index patient, an aspect that parents seemed acutely aware of and that shaped their experience with WES. This finding raises questions about the degree to which utility for nonpatients should have an impact on sequencing recommendations, health care coverage, and disclosures.
Third, it is uncertain which of these varied types of utility should be used to justify a recommendation for genomic sequencing of a patient and his or her family. Although it is clear that clinical utility could justify the use of this technology by third-party payers, it has not been generally accepted that the possibility of finding psychological or pragmatic utility offer the same grounding for a testing recommendation. Consideration should be given to whether these types of utility are sufficient justification for WES or whether they ought to be given second-tier status.
Finally, the insights offered by this study raise questions about the nature of the informed consent process in the clinical and research settings for GS that is used with parents of children with serious diseases. Specifically, further consideration should be given to which types of utility merit inclusion in a consent conversation. Current practice is to identify and clearly communicate possible psychological and social risks (such as anxiety or loss of insurance), but corresponding possible benefits (such as peace of mind or reproductive planning) are not typically discussed; instead, the focus is usually on narrow definitions of potential medical benefits. Our results suggest that this differential treatment of the different types of risks and benefit may not be coherent and that both may be of great importance to decision makers. We describe additional types of utility spontaneously identified by a diverse cohort of parents that shaped their WES experience, which suggests that additional work is required to ensure that all of the appropriate risks and benefits are discussed with parents who are consenting to genomic trials or testing.
Our study had several limitations. First, this interview-based analysis used open-ended questions and so was not designed to assess the prevalence of various perspectives on genomic information. Accurate characterization of the frequency of various responses would require a methodology that included greater numbers of participants and more discrete response options. Second, because parents’ understanding of their child’s WES results was not directly evaluated, we were not able to characterize parents’ comprehension of the information they were given at disclosure or the degree to which their understanding of utility was shaped by various elements of the study (ie, the consent process, education and counseling, and the information contained in the tumor and germline reports). Finally, because our study was conducted with parents of pediatric patients with cancer, our findings might be limited to this population and may not be generalizable to other pediatric patient populations.
Longitudinal interviews with a diverse cohort of parents of pediatric patients with cancer identified a broad range of anticipated and experienced utility through the integration of WES into their children’s medical care. Parents cited possible clinical utility for the patient, themselves, and for their other family members, and also described psychological and pragmatic benefits for these parties as well. These findings raise ethical questions about how clinicians, patients, families, and insurers should think about and incorporate WES into the care of pediatric patients with cancer.
ACKNOWLEDGMENTS
The authors thank Robin Raesz-Martinez, study coordinator, Sarah Scollon and Katie Bergstrom, study genetic counselors, and Uma Ramamurthy and her team at the Baylor College of Medicine Institute for Clinical and Translational Research and especially thank the oncologists and parents who participated in this study.
Footnotes
Supported by Grant No. 1U01HG006485 from the National Human Genome Research Institute, National Cancer Institute (BASIC3 study). The BASIC3 study is a Clinical Sequencing Exploratory Research (CSER) program project.
Presented at the Clinical Sequencing Exploratory Research Project Meeting, April 25-26, 2016, and at the American Society for Human Genetics 2016 Annual Meeting, Vancouver, BC, Canada, October 18-22, 2016.
AUTHOR CONTRIBUTIONS
Conception and design: Melody J. Slashinsky, D. Williams Parsons, Sharon E. Plon, Laurence B. McCullough, Amy L. McGuire
Financial support: D. Williams Parsons, Sharon E. Plon, Amy L. McGuire
Provision of study materials or patients: D. Williams Parsons, Sharon E. Plon
Collection and assembly of data: Janet Malek, Melody J. Slashinsky, Jill O. Robinson, Amanda M. Gutierrez, Laurence B. McCullough
Data analysis and interpretation: Janet Malek, Melody J. Slashinsky, Jill O. Robinson, D. Williams Parsons, Laurence B. McCullough, Amy L. McGuire
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Parental Perspectives on Whole-Exome Sequencing in Pediatric Cancer: A Typology of Perceived Utility
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc.
Janet Malek
No relationship to disclose
Melody J. Slashinski
No relationship to disclose
Jill O. Robinson
No relationship to disclose
Amanda M. Gutierrez
No relationship to disclose
D. Williams Parsons
Patents, Royalties, Other Intellectual Property: Co-inventor on current and pending patents related to cancer genes discovered through sequencing of several adult cancer types. Participates in royalty sharing related to those patents.
Sharon E. Plon
Stock and Other Ownership Interests: Insulet, Lexicon Pharmaceuticals
Consulting or Advisory Role: Baylor Miraca Genetics Laboratories
Laurence B. McCullough
No relationship to disclose
Amy L. McGuire
No relationship to disclose
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