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.