Ethical Issues in Newborn Sequencing Research: The Case Study of BabySeq Lainie Friedman Ross, MD, PhD,a Ellen Wright Clayton, MD, JDb

The BabySeq Project is a study funded by the National Institutes of Health and abstract aimed at exploring the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of both healthy newborns and newborns who are sick. Infants were randomly assigned to receive standard of care or standard of care plus sequencing. The protocol and consent specified that only childhood-onset conditions would be returned. When 1 child was found to carry a BRCA2 mutation despite a negative family history, the research team experienced moral distress about nondisclosure and sought institutional review board permission to disclose. The protocol was then aMacLean Center for Clinical Medical Ethics and modified to require participants to agree to receive results for adult-onset- Departments of Pediatrics, Medicine, and Surgery, The b only conditions as a precondition to study enrollment. The BabySeq team University of Chicago, Chicago, Illinois; and Department of Pediatrics, Center for Biomedical Ethics and Society, asserted that their new protocol was in the child’s best interest because Vanderbilt University Medical Center, Nashville, Tennessee ’ fi having one s parents alive and well provides both an individual child bene t Dr Ross conceptualized and designed the and a “family benefit.” We begin with a short description of BabySeq and the manuscript, drafted the initial manuscript, and controversy regarding predictive genetic testing of children for adult-onset revised the manuscript; Dr Clayton conceptualized conditions. We then examine the ethical problems with (1) the revised and designed the manuscript and made critical revisions on multiple versions; and both authors BabySeq protocol and (2) the concept of family benefit as a justification for approved the final manuscript as submitted and the return of adult-onset-only conditions. We reject family benefit as a moral agree to be accountable for all aspects of the work. reason to expand genomic sequencing of children beyond conditions that DOI: https://doi.org/10.1542/peds.2019-1031 present in childhood. We also argue that researchers should design their Accepted for publication Aug 5, 2019 pediatric studies to avoid, when possible, identifying adult-onset-only genetic Address correspondence to Lainie Friedman Ross, variants and that parents should not be offered the return of this information MD, PhD, Department of Pediatrics, University of if discovered unless relevant for the child’s current or imminent health. Chicago, 5841 S Maryland Ave, MC 6082, Chicago, IL 60637. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). In 2014, the Eunice Kennedy Shriver impacts of integrating genomic Copyright © 2019 by the American Academy of National Institute of Children Health sequencing into the care of study Pediatrics and Human Development and the families of both healthy and sick FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this National Human Genome Research newborns”2,3 via a randomized clinical article to disclose. Institute funded a consortium of 4 trial in which half of participants were FUNDING: Dr Clayton received support from 5U01 grantees to study newborn sequencing randomly assigned to receive standard HG008672-04 and 5RM 1HG009034-02. Funded by the in genomic medicine and public of care (family history and standard National Institutes of Health (NIH). 1 health. One of the awarded projects newborn screening) and half were POTENTIAL CONFLICT OF INTEREST: The authors have was entitled The BabySeq Project randomly assigned to have standard of indicated they have no potential conflicts of interest (Genome Sequence-Based Screening for care plus genomic sequencing. For to disclose. Childhood Risk and Newborn Illness), those in the sequencing arm, a newborn COMPANION PAPER: A companion to this article can a collaboration between Brigham and genomic screening report was be found online at www.pediatrics.org/cgi/doi/10. Women’s Hospital, Boston Children’s generated, “which lists pathogenic or 1542/peds.2019-3111. Hospital and the Broad Institute at likely pathogenic variants in genes that Harvard University, and Baylor College have been strongly linked to childhood- To cite: Ross LF and Clayton EW. Ethical Issues in of Medicine. Its aim was “to explore the onset diseases or diseases for which Newborn Sequencing Research: The Case Study of BabySeq. Pediatrics. 2019;144(6):e20191031 medical, behavioral, and economic intervention is possible during

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 144, number 6, December 2019:e20191031 SPECIAL ARTICLE childhood.”2 For newborns with did the authors detail the perceived the child’s autonomy to decide as an a specific clinical presentation that benefit from the discovery. adult whether to undergo testing. potentially had a genetic etiology, an indication-based analysis was Because of their moral distress, the Sequencing raises the possibility of performed.2 researchers proposed to modify their discovering genetic information protocol to offer the optional return unrelated to the clinical question, The study researchers sought to of adult-onset-only genetic variants if known as “incidental” or “secondary” enroll 200 newborns and their both parents agreed. In response to findings. Although the American parents into each cohort (healthy the IRB’s concern that some parents College of Medical Genetics and infants and infants admitted to the might still not receive results under Genomics (ACMG) issued a statement “ NICU), but despite 22 months of the revised protocol, the researchers in 2012 that patients should be given recruitment and approaching 3860 modified the amendment to require the option of not receiving certain or fi ”15 families, they were only able to participants to receive results for secondary ndings, new recruit 268 infants (6.9%), 45 of 436 adult-onset-only conditions as recommendations in 2013 mandated “ (10.3%) from the NICU and 223 of a precondition to participate in the that laboratories performing clinical 5 3424 (6.5%) from the well-baby study. They explained that this sequencing seek and report … nursery.3 Overall, 159 infants were “avoids the ethical dilemma of mutations in all subjects, …”16 sequenced, 127 healthy infants and laboratory personnel knowing irrespective of age , a form of 32 infants in the NICU.4 something that is widely considered opportunistic screening, despite to be actionable but cannot be acknowledging that there are In January 2019, Holm et al5 reported returned.”5 They asserted that their “insufficient data on penetrance and that a male infant enrolled from the new protocol was in the child’s best clinical utility to fully support these 17 cardiac ICU at Boston Children’s interest because “the best interest of recommendations.” The original list Hospital was identified with a BRCA2 the child includes not only the child’s included 57 genes, which was quickly mutation despite a negative family future autonomy to make a decision revised to 56 genes, and has now history. The team wanted to return about what the child wants to know been increased to 59 genes (ACMG 17 these results despite the facts that (1) about him- or herself, but also having 59). the consent form clearly stated that his or her parents alive and well,”5 Many ACMG members objected to only childhood-onset conditions which they describe as “family – these recommendations.18 23 In would be returned,(2) the benefit.” After a brief description of response to the criticism that the new institutional review board (IRB) had the debate regarding predictive recommendations contradicted approved the study knowing that only genetic testing of children for adult- earlier policies about predictive childhood-onset conditions would be onset-only conditions in the clinical genetic testing of children, the ACMG returned, and (3) the study had and research settings, we examine (1) responded that the earlier policies obtained a US Food and Drug the ethical challenges raised by the were focused on children with “a Administration nonsignificant risk revised BabySeq protocol and (2) the known family history of risk, with the determination on the basis of the plan ethical problems with the concept of expectation that the child will be to return only the results of family benefit. offered testing at an age when he or conditions that could manifest in she can make an informed decision childhood.5 The team went back to about testing,”24 whereas the IRB and obtained permission to BACKGROUND: PREDICTIVE GENETIC opportunistic screening applied to recontact the infant’s parents to offer TESTING OF CHILDREN FOR ADULT-ONSET-ONLY CONDITIONS unsuspecting families for whom the the return of adult-onset-only information may benefit the child and fi ndings. The parents consented and There is a consensus within the parents. However, in April 2014, in were told the results. Although either pediatric, genetics, and ethics response to additional stakeholder parent could have been the BRCA2 communities, in the Unites States and feedback,25 the ACMG modified its fi carrier, when the ndings were globally, that children should not be clinical recommendation to allow shared, the mother recalled some tested for adult-onset-only 6–14 patients (and parents) to opt out of distant paternal relatives with breast conditions. The arguments to opportunistic screening and the and/or ovarian cancer, and she was support this position are as follows: return of the ACMG 59 results.26 referred to a familial cancer genetic (1) the information is not clinically risk clinic. The authors did not detail relevant to the child, and so testing is The ACMG guidelines were focused whether she went to the familial “not medically indicated” and could on the clinical setting, whereas cancer genetic risk clinic or whether create anxiety without any potential BabySeq is a research protocol. she was found to be the carrier, nor for intervention; and (2) it preserves Traditionally, research results were

Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 ROSS and CLAYTON not returned to participants. In What options did the team have to That is, the mandatory return of 2002, several researchers began avoid this discovery? The BabySeq results in BabySeq restricts parental to argue for informing clinical team could have devised an analytic freedom to choose what research trial participants about aggregate pipeline to deliver only the results they want to know because it results,27,28 but many institutions information intended for the project, requires the reporting of AMCG 59 had no policies on when, how, or it could have elected to sequence results as a precondition of or what results should be returned.29 the whole genome or exome but not participation even though the The arguments in favor of to interrogate the adult-onset-only mandatory return of genetic research returning results were both regions unless there was substantial results is not consistent with many of ethical (promoting trust and reason to suspect that they were the sequencing guidelines and respecting participants as pertinent to the child’s immediate consensus statements in the United – partners in research) and pragmatic clinical care rather than to other States and globally.38 42 (returning results could increase research goals. International In this case, however, a cancer risk enrollment). guidelines support a more targeted variant was identified, and even if it approach, limiting search to genes Within the decade, spurred on by were avoidable, the team was left in relevant to the primary indication public interest, the focus turned to the position to decide what to do with when possible.41,42 Their failure to returning individual participants’ the information. A major driver for employ a more targeted approach research results.30,31 A large body of the mandatory return of results by created a situation that could have scholarship addresses the return of BabySeq was the moral distress of been avoided. these research results.32,33 The providers and laboratorians, a not- National Heart, Lung, and Blood Although the parents in BabySeq uncommon emotion when providers Institute published 2 conference were re-consented about whether to and families disagree about what is in reports focused on reporting genetic receive adult-only-onset information, a patient’s best interest or when results in research studies in which the revised protocol going forward patients refuse life-saving they concluded that participants requires disclosure of all ACMG 59 interventions.44 In the clinical should not be forced to receive results to all who undergo genetics context, providers may results.34,35 Other reports were sequencing, even if the only person experience moral distress when focused on the return of pediatric sequenced is a newborn and the patients refuse actionable genetic – results.36 39 Members of the Return results are adult-onset-only testing, fail to obtain appropriate of Results committees of the Clinical conditions. There is no opt-out policy, surveillance, or refuse to share Sequencing Exploratory Research making the return of results in actionable genetic information with Consortium and the Electronic BabySeq more demanding than the family. In contrast, in the research Medical Records Network Consent, ACMG recommendations, which were setting, providers are often more Education, Regulation, and designed for the clinical setting, limited as to what they can offer, do, Consultation Working Group, 2 where providers have more stringent and say, given protocol restrictions. national multicenter projects obligations to patients than The providers’ distress does not (or actively engaged in returning researchers have to participants.26,43 at least should not) trump the research results, specifically argued participants’ interests or preferences, To be clear, participation in BabySeq that parents should have a right particularly if agreed to beforehand in is voluntary, and most parents to refuse secondary results in the consent process. (.90%) refuse. Given that research involving children “unless sequencing is not standard of care, In the case of children, providers and the return of results is of high health even for infants in the NICU, the 45 researchers do not get to impose on significance to the minor in sets of parents who enrolled their families their view of what is best. childhood.”40 NICU infants may have perceived the Clinicians could conceivably seek research protocol as a unique a court order to override parental ETHICAL CHALLENGES RAISED BY THE opportunity to learn about their refusals to obtain genetic testing of REVISED PROTOCOL child’s condition and to obtain children for adult-onset-only The original BabySeq protocol was information that could help providers disorders, asserting that the parents’ focused on the return of childhood- best treat their child. Under the actions constituted medical neglect, onset conditions, but the research revised protocol, parents may elect to but they would almost surely fail. sequencing methods identified enroll their ill children, although it Although providers may argue that a BRCA2 mutation, 1 of 3 genes may mean getting unwanted a particular genetic test is in a child’s classified as adult-onset-only in the information that is not relevant to best interest, the courts will intervene ACMG 59 list. their child’s current health status. only if the parents acts are abusive or

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 144, number 6, December 2019 3 neglectful.45,46 Courts would not case of an infant who carries 2 parents who might not otherwise be require clinical genetic testing of pathogenic variants of BRCA2. BRCA aware of their own risks, which could a young child for a condition that causes adult-onset-only breast cancer lead to preventive or therapeutic presents in adulthood when no in the heterozygous state but can interventions that indirectly benefit intervention or surveillance is needed cause Fanconi anemia in the the child. That is, opportunistic in childhood, even in a high-risk homozygous state.49,50 Masking the screening offers family benefit. family, because the variant does not BRCA gene could lead to a failure to The ACMG has been arguing for the pose an imminent threat to the child. identify this health risk in a child. concept of family benefit at least since However, Alter et al51 note the The argument that there is an coauthoring, with the Health following: obligation to identify and then report Resources and Services genes associated with adult-onset- The small group of patients with biallelic Administration, Newborn Screening: mutations in BRCA2 is distinctive in the only conditions is even more severity of the phenotype, and early Toward a Uniform Screening Panel misguided in families of children who onset and high rates of leukemia and and System in 2006: are critically ill. In these cases, specific solid tumors, and may comprise Historically, screening has focused on sequencing is performed in an effort an extreme variant of Fanconi anemia. conditions for which the improvement in to improve the particular infant’s Several of the alleles were not associated outcome for the infant has been with cancer in presumed carriers, and … care. Notably, other investigators who substantial. However the nature of thus counseling presents more genetic disease is such that knowledge of 51 have explored the role of sequencing uncertainties than usual. its presence can be of value to other in these infants have specifically family members. Previously, this factor That is, children with this form of chosen not to look for secondary has not been considered by newborn 47,48 47 Fanconi anemia will present with 52 findings. Saunders et al screening programs. phenotypic findings that would justify published a methodology for rapid 53 BRCA genetic testing for diagnostic Natowicz criticized the task force whole-genome sequencing in the “ purposes. Even those who value the for including a calculation of the NICU that masked many potential fi identification of both parents as BRCA bene ts to the family and to society of findings for expediency because the — carriers must pause, however, given early intervention not just the aim was to provide information that fi ” “ that several of the variants were not bene t for the baby because it shifts could inform emergent decision- associated with increased cancer the emphasis of newborn screening making. Similarly, in 2016, Smith 48 risks and reporting back the results away from the medical interest of the et al stated that: ” might lead to unnecessary screening child alone. Others objected to the fi fi Only con rmed causative sequence and interventions. Harms from fact that family bene t was rated to changes that explain the observed be as important as clinical treatability phenotype are communicated to the masking are rare and are outweighed parents by the treating physician and/or by the benefits of focusing resources when deciding what conditions to a certified genetic counselor. Because the on the child’s immediate needs. include in a uniform screening primary analysis is directed toward the panel.54 neonate with specific clinical findings, 55 we do not evaluate for or report any of PROBLEMS WITH THE CONCEPT OF Wilfond et al offered 2 arguments the 56 genes identified by the American FAMILY BENEFIT in support of family benefit. One College of Medical Genetics as reportable benefit is derivative: by identifying an fi In its original recommendation to incidental ndings, unless directly actionable adult-onset risk, the child related to the underlying clinical provide opportunistic screening, the 48 benefits because prevention and presentation. ACMG stated that “after sequencing treatment can promote the parent’s a child for a primary indication, it In the case that triggered the protocol health, which enables the parent to becomes relatively easy for change in BabySeq, the child died care for the child. The other benefitis a laboratory to report a limited without leaving the hospital. independent of a direct benefit to the number of variants for conditions Knowledge about late-onset child. It supports respecting the that could be medically important to conditions were a moot point for the authority of parents to balance the that child’s future or to the rest of the child. If we want to know about competing interests of family family.”16 The ACMG argued that the parents’ risks, we should test them. members without state intervention risks to the child “were outweighed unless their decision falls below One objection to masking is that some by the potential benefits to the future a threshold that constitutes abuse genes have .1 function and health of the child and the child’s and/or neglect. excluding those associated with parents of discovering an incidental adult-onset-only conditions could finding for which intervention might Wilfond et al55 examined the primary hide the cause of the child’s health be possible.”16 The real focus was to objections to testing children for problems. Consider, for example, the provide risk information to the adult-onset-only conditions: (1) the

Downloaded from www.aappublications.org/news by guest on September 25, 2021 4 ROSS and CLAYTON potential to cause adverse would attend, presumably, at her own offer is morally neutral, which it is psychological impact and (2) expense. Even if the mother were not. All pediatric professional depriving the child of a right to an found to be a carrier, how much more statements argue against predictive open future. They argued that these of a risk she actually faces compared genetic testing of children for adult- objections failed because (1) the data with other women who are onset conditions to respect the child’s fail to reveal evidence of significant premenopausal is unknown given interests to decide for or against harm56 and (2) respect for parental that the high pathogenicity of the testing as an adult.6–14 As such, the authority to raise their children mutations in the ACMG 59 is based on provider should counsel against such according to their own values means studies in which high-risk families testing, even if the provider may respecting parental decisions that were enrolled. The meaning of these accede to the parental demands. foreclose options for their children variants in a woman with a less Rather than requiring testing and and shape the direction of their compelling family history has not reporting results of adult-onset ’ 55 children s lives. been adequately studied. Claims of genetic disorders in children on the 55 high risk may be premature or even fi The arguments by Wilfond et al are – basis of bene t to others in the family, wrong,57,58,63 65 particularly for flawed, in part, because they are providers and researchers should minorities who are usually focused on the wrong people. oppose testing and reporting of underrepresented in genetics Although families may consider the – results even if parents can insist on research.66 69 In any event, even if interests of other family members in getting them. Pediatric providers are she is at high risk, she could not be their decision-making for a child,57,58 moral agents and should counsel required to pursue follow-up because the primary focus of health care directively against predictive testing it has been decades since the law has providers must be the child’s well- and reporting of results for adult- – required women to undergo even life- being.59 61 To focus otherwise is to onset-only conditions in children in saving medical treatment so that they treat the children as means for the both the clinical and research can care for their children.70 ends of others (their parents).62 If we settings, as Carl Elliott explains: want to reduce morbidity and Third, both the ACMG and Wilfond Finally, it is important to realize that the mortality of adults, we can test adults. et al55 acknowledge that data about doctor is not a mere instrument of the Interrogation of the areas of the short- and long-term risks and harms patient’s wishes…[but] is also a moral genome that identify adult-onset-only (as well as benefits) of returning agent who should be held accountable for his actions. If a patient undergoes conditions takes additional work and genetic information about adult- a harmful procedure, the moral resources by the laboratorians and onset-only conditions are scant. They responsibility for that action does not additional work on the clinicians and assume that identifying variants belong to the patient alone; it is shared researchers in counseling families alone is a positive outcome before by the doctor who performs it. Thus and providing follow-up evaluation data are obtained on the a doctor is in the position of deciding not simply whether a subject’s choice is and care. These results are not as psychological and health outcomes, reasonable or morally justifiable, but easy to interpret and return as they and they ignore the risks, which whether he is morally justified in helping are often made out to be, and they include unnecessary testing due to the subject accomplish it.71 take large amounts of resources that false-positives or incomplete may detract from the research aims. penetrance, as well as stigma, THE CONTROVERSY SURROUNDING THE The parents in BabySeq were not discrimination, and anxiety. At DISCLOSURE OF SECONDARY FINDINGS demanding these results and had minimum, the returning of research Requiring that all parents who consented to participate without results that have no immediate authorize sequencing of their child be expecting to receive adult-onset-only clinical indications for the child informed about adult-onset-only results. Given the low participation should be voluntary and not conditions included in the ACMG 59 rate in BabySeq, it will be important mandatory. assumes that the benefits of to see whether the policy change will Fourth, although Wilfond et al55 opportunistic screening outweigh the decrease enrollment. believe that the data are sufficiently risks and harms, which has not been Second, even if the secondary findings equivocal that pediatricians should be proven.72,73 In fact, those sections of are valid, parental benefits are not neutral in counseling parents about the genome associated with adult- ensured unless participants requesting secondary findings, we onset-only conditions should not be understand their need for follow-up argue that pediatricians should take analyzed at all unless pertinent to and can afford the necessary testing a directive stance in opposition. A that child’s immediate medical care. and treatments. BabySeq is not neutral position suggests not only Although we believe that there is designed to support the mother that there is equipoise about the much to be learned from BabySeq and beyond making a referral, which she benefits and risks but also that the the other newborn sequencing in

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 144, number 6, December 2019 5 genomic medicine and public health parents that everything is not and 4. Ceyhan-Birsoy O, Murry JB, Machini K, projects, the researchers should not cannot be returned and that research et al; BabySeq Project Team. intentionally search for adult-onset- teams do not interrogate or disclose Interpretation of genomic sequencing only conditions. every variant of unknown results in healthy and ill newborns: Am significance because of time, cost, and results from the BabySeq Project. fi J Hum Genet. 2019;104(1):76–93 Even if secondary ndings are not the sheer size of the genome (6 billion intentionally sought, cases may occur bp). Nor are researchers under any 5. Holm IA, McGuire A, Pereira S, et al; in which known variants for later- obligation to interrogate the genome BabySeq Project Team. Returning onset conditions are identified: expect a genomic result for an adult-onset 74 fully, but, again, this must be made the unexpected. We believe that clear in the consent process. However, condition to the parents of a newborn: insights from the BabySeq Project. studies should be designed to participants may be able to request Pediatrics. 2019;143(suppl 1):S37–S43 minimize the risk of identifying genes and obtain their raw data under the associated with adult-onset-only Health Information Portability and 6. American Society of Human Genetics conditions. We believe that a policy of Accountability Act to seek additional Board of Directors; American College of nondisclosure of adult-onset-only analyses not provided by the Medical Genetics Board of Directors. Points to consider: ethical, legal, and conditions is ideal, even when such researchers.32,77 genes are identified incidentally. This psychosocial implications of genetic fi needs to be explained in the consent How secondary research ndings will testing in children and adolescents. Am – process so that parents do not expect be handled needs to be addressed J Hum Genet. 1995;57(5):1233 1241 otherwise. We support this position upfront through a robust and 7. Committee on Bioethics. Ethical issues out of respect for the child’s future transparent consent process. with genetic testing in pediatrics. autonomy as an adult to decide what Additional psychosocial and clinical Pediatrics. 2001;107(6):1451–1455 data about the benefits and harms genetic information he or she wants 8. Committee on Bioethics; Committee on that accrue from the return of results and with whom he or she wants to Genetics; American College of Medical share it. should be collected to inform future Genetics and Genomics Social, Ethical, policy discussions. and Legal Issues Committee. Ethical and We realize that there are those who policy issues in genetic testing and disagree (who support disclosure of screening of children. Pediatrics. 2013; all ACMG high-risk alleles and other ABBREVIATIONS 131(3):620–622 actionable secondary findings55,75,76). ACMG: American College of Medical 9. Ross LF, Saal HM, David KL, Anderson At minimum, all participants and Genetics and Genomics RR; American Academy of Pediatrics; their surrogates should have the right IRB: institutional review board American College of Medical Genetics to refuse learning about all research and Genomics. Technical report: ethical findings, even if researchers will feel and policy issues in genetic testing and distressed about knowing screening of children [published information that they believe is useful REFERENCES correction appears in Genet Med. 2013; and actionable. The strongest case for 15(4):321]. Genet Med. 2013;15(3): 1. 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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2019/11/10/peds.2 019-1031 References This article cites 67 articles, 15 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2019/11/10/peds.2 019-1031#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Ethics/Bioethics http://www.aappublications.org/cgi/collection/ethics:bioethics_sub Genetics http://www.aappublications.org/cgi/collection/genetics_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

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