Newborn Sequencing in Genomic Medicine and Public Health Jonathan S. Berg, MD, PhD,a Pankaj B. Agrawal, MD, MMSc, b, c Donald B. Bailey Jr., PhD,d Alan H. Beggs, PhD,c Steven E. Brenner, PhD,e Amy M. Brower, PhD,f Julie A. Cakici, BA, BSN,g Ozge Ceyhan-Birsoy, PhD,h Kee Chan, PhD,i Flavia Chen, MPH,j Robert J. Currier, PhD, k Dmitry Dukhovny, MD, MPH,l Robert C. Green, MD, MPH,m Julie Harris-Wai, MPH, PhD,j, n Ingrid A. Holm, MD, MPH,c Brenda Iglesias, o Galen Joseph, PhD,p Stephen F. Kingsmore, MD, DSc,g Barbara A. Koenig, PhD,n Pui-Yan Kwok, MD, PhD,j, q John Lantos, MD,r Steven J. Leeder, PharmD, PhD, r Megan A. Lewis, PhD,d Amy L. McGuire, JD, PhD,s Laura V. Milko, PhD, a Sean D. Mooney, PhD,t Richard B. Parad, MD, MPH, u Stacey Pereira, PhD,s Joshua Petrikin, MD, r Bradford C. Powell, MD, PhD,a Cynthia M. Powell, MD, v Jennifer M. Puck, MD,w Heidi L. Rehm, PhD,h Neil Risch, PhD,j Myra Roche, MS, v Joseph T. Shieh, MD, PhD,j, x Narayanan Veeraraghavan, PhD,g Michael S. Watson, MS, PhD,f Laurel Willig, MD, MS, r Timothy W. Yu, MD, PhD,c Tiina Urv, PhD,y Anastasia L. Wise, PhDo

The rapid development of genomic sequencing technologies has decreased abstract the cost of genetic analysis to the extent that it seems plausible that genome- scale sequencing could have widespread availability in pediatric care. NIH Genomic sequencing provides a powerful diagnostic modality for patients Departments of aGenetics and vPediatrics, University of who manifest symptoms of monogenic disease and an opportunity to detect North Carolina at Chapel Hill School of Medicine, Chapel health conditions before their development. However, many technical, Hill, North Carolina; Divisions of bNewborn Medicine and clinical, ethical, and societal challenges should be addressed before such cGenetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard technology is widely deployed in pediatric practice. This article provides Medical School, Boston, Massachusetts; hLaboratory an overview of the Newborn Sequencing in Genomic Medicine and Public for Molecular Medicine, mDivision of Genetics, and uDepartment of Pediatric Newborn Medicine, Brigham Health Consortium, which is investigating the application of genome-scale and Women’s Hospital, Harvard Medical School, Boston, sequencing in newborns for both diagnosis and screening. Massachusetts; dRTI International, Research Triangle Park, North Carolina; eUniversity of California, Berkeley, California; fAmerican College of Medical Genetics and Genomics, Bethesda, Maryland; gRady Children’s Institute for Genomic Medicine, San Diego, California; iChicago 5 Universal newborn screening (NBS) gene discovery is well documented, School of Public Health, University of Illinois, Chicago, is an extraordinarily successful and it is increasingly being applied Illinois; jInstitute for Human Genetics, nInstitute for Health public health program, preventing as a diagnostic test in children with and Aging, pDepartment of Anthropology, History, and Social Medicine, qCardiovascular Research Institute, and 6, 7 morbidity and mortality through suspected monogenic disorders. Department of Dermatology, xDepartment of Pediatrics, early diagnosis and management of The tangible potential of genomic Benioff Children’s Hospital, and wDepartment of Pediatrics, conditions including rare inborn errors sequencing more broadly in medicine, University of California, San Francisco, California; kGenetic Disease Screening Program, California Department of 1 of metabolism. Conditions such as as part of “personalized” or “precision” Public Health, Sacramento, California; lDepartment of phenylketonuria are not clinically medicine, 8 was foreshadowed in 1990 Pediatrics and Division of Neonatology, Oregon Health & o evident at birth but lead to significant by Walter Gilbert, who extrapolated Science University, Portland, Oregon; National Human Genome Research Institute and yNational Center for irreversible harm or death if not from the exponential growth of DNA Advancing Translational Sciences, National Institutes of treated promptly.2 NBS has saved sequencing that all newborns would Health, Bethesda, Maryland; rDepartment of Pediatrics, s countless lives and vastly improved the have their genomes sequenced by Children’s Mercy Hospital, Kansas City, Missouri; Center for Medical Ethics and Health Policy, Baylor College of quality of children’s lives by allowing 2030 or 2040. The idea that genomic Medicine, Houston, Texas; and tUniversity of Washington, timely therapeutic interventions, and sequencing will someday become part Seattle, Washington of the standard care of newborns is technological advances such as the use Dr Berg conceptualized and designed the study, of tandem mass spectrometry carried forward into today’s dialogue: drafted the initial manuscript, participated in data (MS/MS) have played a significant As we learn more about effective analysis, and reviewed and revised the manuscript; role in expansion of NBS.3, 4 interventions for genetic risk factors, and Drs Agrawal and Parad drafted the initial recognize that interventions early in life manuscript, supervised data collection at 1 of the provide significant advantages, it will sites, participated in data analysis, and reviewed The ability to analyze many or all become more and more compelling to genes in the genome simultaneously determine this information at birth. To cite: Berg JS, Agrawal PB, Bailey DB, et al. provides new opportunities for —F. S. Collins, The Language of Life: DNA genomic medicine. The capacity of Newborn Sequencing in Genomic Medicine and and the Revolution in Personalized Medicine. Public Health. Pediatrics. 2017;139(2):e20162252 genome-scale sequencing for disease New York: Harper Perennial (2010)

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 :e 20162252 SPECIAL ARTICLE Such predictions raise important economics of such screening must be conditions not currently screened questions: Could genomic sequencing considered before implementation for in newborns? become part of the universal on a population level. Although • What additional clinical standard NBS performed by each the technical features needed for information could be learned from state, replacing conventional rapid genomic sequencing appear genomic sequencing relevant to the biochemical testing, or could it be feasible, interpretation of each clinical care of newborns? offered as an optional supplement? asymptomatic person’s variant How would sequencing be paid for, profile will remain labor intensive for In 2014, 4 groups were funded to and how would parental informed the foreseeable future, and clinically explore newborn sequencing in consent be obtained? What impact useful prediction of future disease different clinical contexts by using would genomic sequencing in may prove elusive. Recognizing these unique study designs ( Table 1 and newborns have on children’s health? trends, the Eunice Kennedy Shriver Fig 1). Each study also included an aim What implications would it have National Institute of Child Health examining ethical, legal, and social for issues such as protecting an and Human Development (NICHD), considerations. This article examines autonomous person’s right not to National Human Genome Research some of the challenges of newborn know? Institute, and the Office of Rare sequencing in 3 distinct clinical Disease Research held a workshop in settings, describes the 4 projects, In the diagnostic setting, the goal December 2010 to identify elements and puts this research in the context of genome-scale sequencing is to of a trans–National Institutes of of current and future strategies for identify genetic variants that provide Health research agenda that could NBS and sequencing of newborns in a molecular etiology for the patient’s inform the possible application of clinical care settings. symptoms. All other variants are new genomic technologies to NBS considered incidental findings (or and child health (https:// www. secondary findings when discovered nichd. nih. gov/ about/ meetings/ CLINICAL SETTINGS FOR NEWBORN through intentional analysis). 9 These 2010- retired/ Documents/ SEQUENCING RESEARCH: DIAGNOSTIC, additional findings differ widely with Newborn_Research_Agenda.pdf). PREVENTIVE, AND PREDICTIVE regard to predictive capacity and A consensus finding was the need The setting in which genomic clinical actionability. Not surprisingly, to examine the technical, clinical, sequencing is performed affects there is disagreement about how social, and ethical issues related to its technical performance, yield, much genomic information should sequencing in the newborn period and potential benefits and harms. be routinely returned in a pediatric in unison. Subsequently, the NICHD In a diagnostic context, newborn setting, 10 – 14 and children and their and the National Human Genome sequencing is much like any other parents are likely to express unique Research Institute issued a funding genetic diagnostic modality, preferences.15, 16 Central challenges opportunity to develop a consortium and the ability to provide a for clinical implementation thus to explore, in a limited but deliberate molecular diagnosis depends on revolve around the boundaries of manner, opportunities to use a number of factors including professional responsibility and genomic information for broadening genetic architecture, phenotypic individual or parental choice, best our understanding of diseases expressivity, locus heterogeneity practices for informed consent and identified in the newborn period, and the fraction of cases accounted determining parental preferences, in the context of public health NBS for by known disorders, mutational standards regarding the types of or clinical sequencing of newborns. spectrum, the types of variants that findings that should be reported, The consortium, called Newborn are detectable by sequencing, and long-term storage of genomic Sequencing in Genomic Medicine and the quality of the assay performed information so that it can be acted on Public Health (NSIGHT), is addressing in the patient. In contrast, the at the appropriate time, and whether 3 key research questions: application of genomic sequencing and how genomic data should be in an asymptomatic newborn reanalyzed and reinterpreted. • For disorders currently substantially depends on the power The application of genomic screened in newborns, how can of genotype to predict disease sequencing in asymptomatic genomic sequencing replicate status in the present or the future. newborns intensifies many of these or augment known NBS results? Thus, a critical question is whether challenges and exposes deep societal Can sequencing replace current genomic variant data can be used to questions about nonmaleficence, screening modalities? accurately predict disease beneficence, autonomy, and the when the pretest probability of preservation of each child’s open • What knowledge could genomic disease is low, especially in cases future. 17 – 19 Additionally, the sequencing provide about where there may be no secondary

Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 BERG et al TABLE 1 NSIGHT Project Overviews BWH, BCH, Baylor College of Rady, Children’s Mercy UCSF University of North Carolina Medicine Hospital Patient cohorts Sick newborns (ICUs). Sick newborns (NICU) Deidentifi ed DBS samples from Children affected with known NBS California NBS program fi ndings Healthy newborns (well Newborn DBS from consenting Healthy newborns (prenatal nursery). individuals with primary recruitment) immunodefi ciency Biospecimens Whole blood (newborns) Whole blood (parent–infant DBS retrieved from NBS program Cheek swabs and saliva (newborns and trios) biobank parents). Sequencing Exome sequencing. WGS Exome sequencing Exome sequencing Illumina Content Exome. Illumina HiSeq 2500, rapid run Nimblegen v3 capture Agilent V6.0 capture mode Illumina HiSeq. Illumina HiSeq Illumina HiSeq ≥100 × mean coverage. 40–80 × average coverage 40–80 × average coverage Informatics All newborns: analysis Clinical features translated Metabolic disease NBS samples: All participants: primary analysis of variants in genes into phenotype terms and blinded assessment as an blinded to phenotype responsible for childhood- differential diagnosis by initial screen; second-tier onset disorders (<18 y). Phenomizer (and custom analysis combining genomic, lists) clinical, and MS/MS data Sick newborns/Later- Immunodefi ciency cohort: • Known diagnosis cohort: onset healthy and sick analysis of genes relevant to diagnostic or indication-based newborns: indication- patient’s phenotype analysis based on phenotypic based analysis of all fi ndings variants in genes relevant to the phenotype (if applicable). Primary results Diagnostic fi ndings (ICU Diagnostic or likely diagnostic No contact or return of results Childhood-onset medically returned patients and others with fi ndings for metabolic NBS program actionable conditions (all clinical indications). cohort participants) Highly penetrant childhood- Offer clinical confi rmatory testing Diagnostic fi ndings (affected onset or childhood to follow up likely pathogenic cohort) treatable conditions (all variants for immunodefi ciency participants). cohort Secondary results Carrier status for Incidental genetic disease None Parents randomly assigned to returned childhood-onset diagnosis if life-threatening decision group can select from conditions and selected in childhood 3 categories: pharmacogenomics (all • Childhood-onset non–medically participants). actionable conditions • Carrier status for recessive conditions • Adult-onset medically actionable conditions

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 3 TABLE 1 Continued BWH, BCH, Baylor College of Rady, Children’s Mercy UCSF University of North Carolina Medicine Hospital Psychosocial and Surveys of parents and Surveys of parents and Focus groups with: Surveys with parents assess medical outcomes physicians assess impact physicians assess impact of decision-making about genomic research of genomic sequencing genomic sequencing across sequencing and its effects on across key domains: key domains: individual and dyadic parent outcomes: • Attitudes and preferences. • Attitudes and preferences • Parents of immunodefi ciency • Parents’ collaborative decision- patients making and confl ict • Health care utilization. • Health care utilization • Healthy pregnant women • Prenatal anxiety (parents of healthy newborns only) • Health behaviors and • Health behaviors and • Obstetric and pediatric • Parental bonding with child intentions. intentions clinicians • Decisional satisfaction. • Decisional satisfaction • Attitudes and beliefs about genomic sequencing • Psychological impact. • Psychological impact • Decision confl ict and regret Psychosocial impact on the • Psychosocial impact on the • Test-related and general distress family. family Correlation of parents’ • Beliefs and concerns about the attitudes about test results child’s future health with their health literacy, genomic literacy, anxiety, depression, and religiosity Other project aims Although Sanger Comparison of rate of Assess suitability of stored DBS Semiquantitative metric to confi rmation is used diagnosis and time to as a source of DNA for deep determine medical actionability for the main project, diagnosis in WGS and no- sequencing the study is exploring WGS groups orthogonal sequencing Rates and types of Electronic decision aid for by 2 NGS methods as an actionability measured parental preference setting alternative for variant confi rmation.

gold standard clinical evaluation Diagnostic Sequencing in the NICU therapeutic or palliative, and by which to validate the genomic Level III and IV NICUs care for many provide answers about prognosis prediction. neonates with genetic disorders, and family recurrence risk. In 20 addition, sequence data could aid in Sequencing in a NICU population including metabolic disorders and 21,22 interpretation of the false-positive of sick infants extends current congenital malformations. NBS results commonly reported molecular diagnostic strategies to a Indeed, genetic disorders and in premature infants because of genomic scale, whereas sequencing congenital anomalies are the their immature organ systems, otherwise healthy infants targets the leading cause of death in the 23 liver enzymatic activity, long-term prevention of future disease and is NICU. Current approaches for parenteral nutrition requirement, more akin to current NBS performed diagnosis of suspected genetic and other comorbid conditions.24 in a public health setting. Sequence disorders in NICU patients include information could also be used to karyotyping, chromosomal guide a patient’s care throughout life microarrays, single-gene testing, Preliminary studies have shown by predicting disease and directing and gene panels. In many cases, potential cost reductions resulting management strategies for clinical the etiologic diagnosis remains from genomic sequencing in neonates scenarios that emerge, blending the elusive despite several rounds of with genetic disorders. 7, 25, 26 predictive, reproductive, diagnostic, genetic testing, and clinical genome- However, uptake has been therapeutic, and prognostic scale sequencing is used for only a impeded by concerns about clinical value of genomic information. small fraction of cases. If genomic interpretation of ambiguous results, The NSIGHT projects differ in the sequencing were used earlier in secondary findings and potential clinical scenarios in which the use the diagnostic process, it could parental anxieties, economic factors of genome-scale sequencing is provide more timely definitive including resistance on the part of being studied, spanning the areas diagnoses and thereby increase the third-party payers in the absence described below. precision of treatments, whether of definitive data on clinical utility

Downloaded from www.aappublications.org/news by guest on September 30, 2021 4 BERG et al FIGURE 1 A, Diagram of the protocol in progress at BWH and BCH, Boston, Massachusetts. Infants are recruited from the well baby nursery at BWH and from the ICUs at BCH and BWH. After a pre-enrollment session with a study genetic counselor and completion of baseline outcomes, enrolled infants are randomly assigned to receive NBS and family history or NBS, family history, and exome sequencing. Results are disclosed to the family by a study genetic counselor and physician, and postdisclosure outcomes are collected. Follow-up is performed at 3 and 10 months after disclosure. Medical, behavioral, and economic outcomes are collected throughout the study from surveys, medical record reviews, and consultation with the families. B, Diagram of the protocol in progress at NICUs at Children’s Mercy Hospital, Kansas City (CMH) and Rady Children’s Hospital, San Diego (RCHSD). Eligible patients are infants <4 months old in whom a clinical genetic test or genetic consult was ordered, or those with 1 major anomaly or 3 minor structural anomalies, or an abnormal laboratory test suggestive of a genetic disease, or an abnormal response to standard therapy for a major underlying condition. Enrolled infants are randomly assigned to receive standard diagnostic testing or standard tests and rapid WGS of parent–infant trios. Diagnostic results are returned. Primary outcome measures are rate of molecular diagnosis in 28 days, time to diagnosis, and whether the diagnosis provided a change in clinical management. C, Diagram of the NBSeq protocol in progress at UCSF. NBSeq uses archived residual DBS from a very large and diverse population to examine the diagnostic utility of exome sequencing in 2 parallel projects. For metabolic disorders (left), DBS samples from deidentifi ed true positives (TP), false positives (FP), and false negatives (FN) are subjected to exome sequencing, variant calling, and interpretation under blinded models for evaluation of fi rst-tier screening and in conjunction with MS/MS and clinical data for evaluation of second-tier screening. A predetermined list of 93 genes relevant to the metabolic disorders is the basis for the exome assessment. Consented, identifi ed patients with immune disorders with no gene identifi ed (right) also undergo NBS DBS retrieval and exome sequencing and analysis, in this case with a pipeline restricted to immune system genes. Analysis protocols for both

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 5 and cost-effectiveness, and difficulty and 454 false positives that were selecting exactly which disorders ordering tests due to institutional ultimately resolved as nondisease to screen for requires careful concerns over high costs. The process after referral to a metabolic center. 30 consideration of factors such as is also complicated by a need for Genomic sequencing could function age of onset, severity, penetrance, detailed phenotypic information as a multiplexed second-tier treatability, confirmatory testing, for optimal analysis by diagnostic screen, increasing the specificity of and opportunities for surveillance. laboratories. Provisional genomic current MS/MS screening tests by Some genetic conditions will fulfill diagnosis of genetic disease is distinguishing false-positive results the original Wilson and Jungner technically feasible in as little as 26 from true disease and aiding in the criteria for screening,39 – 41 but many hours.27, 28 However, cost is inversely differential diagnosis of nonspecific will not. Thus, there is a need for related to the turnaround time, biochemical profiles. Sequencing scalable methods to determine and the optimal balance of cost and could also confirm conditions which conditions would be clinical utility is unknown. Although identified through other screening appropriate for inclusion in a public some aspects of rapid turnaround methods,31 –33 aid in providing health screening setting. In addition, time can be improved through prognosis and appropriate the current practice of returning technology, limits imposed by variant treatment, 34 – 37 determine the findings consistent with carrier review and clinical interpretation etiology of conditions identified status might be unsustainable given standards will remain, including the through point-of-care testing, 38 and that nearly every person is likely need for communication between provide families with information to be a carrier for a handful of rare the clinical team and the laboratory about pathogenic variants that recessive conditions. for clinical genomic assessment. could be used for family testing. Parental acceptance of testing, given Such analyses could also increase A significant challenge in the the unclear future implications knowledge of correlations between use of sequencing for NBS is for insurability and privacy, is not genotypes and phenotypes and the lack of data regarding the yet known. Finally, the responses might reveal possible genetic analytic and clinical performance of neonatologists and parents to contributions to false positives, such of sequencing as a predictive genomic information warrant more as abnormal MS/MS screening data test. Little is known about the study, and rigorous frameworks for due to carrier status or hypomorphic positive or negative predictive translating such information into variants. These goals will require value of genomic sequencing precision care plans in NICUs remain longitudinal follow-up to obtain in asymptomatic people whose to be developed. clinical data and examine genotype– previous probability of disease is phenotype correlations to ultimately very small. Although it may seem Preventive Sequencing in a Public determine the predictive capacity self-evident that Mendelian diseases Health Setting and clinical impact of genetic would be best identified from Current NBS yields few false- variants. genetic sequence, this assumption negative results but does incur remains to be demonstrated substantial numbers of false Genomic sequencing could also and may not be true. Monogenic positives, with attendant emotional be deployed as a first-tier screen, illnesses are often influenced by and financial costs. 29 For example, particularly for rare disorders additional and as-yet-unidentified in a study of 176 186 specimens that currently lack methods for genetic or environmental factors, screened by MS/MS, there were 51 conventional biochemical NBS. whereas MS/MS measures true positives, 2 false negatives, In the public health context, analytes that are typically closer

FIGURE 1 Continued applications undergo refi nement based on integration of observed sensitivity and specifi city with genome analysis tools. Enrollees with immune disorders can obtain confi rmational clinical gene testing, and their assessment of risks, benefi ts, and uncertainties of exome sequencing for NBS are solicited. D, Diagram of the North Carolina Newborn Exome Sequencing for Universal Screening protocol in progress at the University of North Carolina at Chapel Hill. This study is enrolling healthy newborns, identifi ed prenatally, and children affected with known conditions identifi ed through standard NBS (metabolic disorders, hearing loss, pulmonary disorders). Parents use an electronic decision aid in addition to an in-person consultation with a genetic counselor to determine whether to have their child undergo sequencing. Exome sequencing is performed, with analysis of a panel of genes associated with childhood- onset medically actionable conditions (NGS-NBS) for all participants and indication-based analysis for patients from the diagnosed cohort. Participants are randomly assigned at the time of return of results. Parents in the control arm receive only the primary diagnostic fi ndings and NGS-NBS results, whereas parents in the decision arm will use the electronic decision aid to choose between 3 additional categories of optional genomic information (adult-onset medically actionable conditions, childhood-onset non–medically actionable conditions, and carrier status for recessive conditions). Parents will also participate in longitudinal surveys to assess their responses to the genomic information.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 6 BERG et al to relevant phenotypes. Even for increasingly be available. Within carrying. However, some findings the best-studied diseases, there this spectrum is the potential may be at odds with professional are substantial challenges in for genomic information to alert guidance that genetic testing in interpreting rare variants. Variant clinicians to reconsider the family asymptomatic minors should selection algorithms that maximize history or interpret physical generally be done only when sensitivity necessarily sacrifice examination findings in a new identification before adulthood specificity, leading to increased light, and potentially the ability is needed to prevent harm and false-positive results and to benefit other family members directly benefit the child. 11, 13, 17 The potential downstream harms before they develop a disease. potential to query genome-scale data due to unnecessary medical Pharmacogenomic variants could in children for secondary findings interventions. A strategy of guide the real-time selection has elicited vigorous debate over excluding “variants of uncertain and dosing of medications, the ethical boundaries of return significance” (which by definition yielding safer and more effective of results. The argument has been have poor predictive value) from treatments. Recessive carrier made that benefit to family (eg, genomic screening results may be traits detected in newborns could a parent who is unknowingly at necessary. Historically, the focus alert parents to genetic risks that risk) may be a valid consideration of NBS on preventable disorders provide information valuable to in decisions regarding return of has led to low tolerance for false- reproductive planning. Common results for actionable adult-onset negative screening results. With variation for complex conditions conditions in children. 45, 46 Genome- genomic sequencing it might be may motivate families to be more scale sequencing and analysis in necessary to shift the screening vigilant about diet and other newborns would probably require paradigm from finding all affected lifestyle choices. Finally, there is modification of current informed individuals to finding an optimal the potential for voluntary personal consent procedures41, 47 compared proportion of cases for a larger exploration of one’s own genomic with a targeted screen focusing on number of potentially treatable data. a restricted number of conditions. conditions. If implemented across the entire If genomic sequence data are population, genomic sequencing Predictive Sequencing of Newborns available, parents will need to would fundamentally alter in Genomic Medicine make decisions about whether to contemporary public health NBS The broadest vision of genomic learn about additional categories procedures, necessitating innovative medicine, and potentially the of information that may predict approaches to facilitate parental most challenging for societal and future events about their child with decision-making. Alternatively, practical reasons, involves the differing levels of certainty and such testing could be implemented use of sequence data to guide a ability to intervene, ranging from through voluntary, out-of-pocket patient’s care throughout life. childhood-onset conditions that testing. Genomic sequencing reveals may not have direct interventions information well beyond the or preventive measures, adult-onset Expanding genomic sequencing scope of conventional NBS. Some medically actionable conditions, in newborns to include a broad of this information could result or carrier status for recessive range of conditions demands a in medical action, but most will disorders. Studies suggest that close partnership between clinical not, raising questions of exactly parents are interested in their providers and parents, similar what information should be child’s genetic variants, even to other areas of medicine in reported and when.42, 43 Variant when that information has no which shared decision-making data could conceivably be held defined clinical utility, 44 although is becoming the norm.48, 49 for future diagnostic analysis these preferences have largely Determining criteria for disclosure in the event that the patient been elicited in hypothetical of information will be a challenge develops symptoms of a genetic scenarios and may not reflect real- for clinicians and policymakers condition. Currently, our ability to life choices. and will require development interpret genetic variants is largely of decisional supports to help confined to simple monogenic Genomic information may enable parents determine the information and oligogenic conditions. As families to become aware of they want to learn. 50 The clinical we learn to use multifactorial otherwise unsuspected familial risks, interactions needed for support of models for risk stratification or including potentially actionable parental decision-making would management in a clinically useful adult-onset conditions in the move this activity beyond the realm way, additional information will infant that a parent is unknowingly of current public health service

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 7 provision and into the clinical medical treatments. 52 The benefits The Clinical and Social Implications domain. Workforce shortages of detecting true positives must of 2-Day Genome Results in may present significant obstacles therefore be balanced against the Acutely III Newborns project, led if genome-scale sequencing magnitude of harms. by Rady Children’s Institute for were to become widely available Genomic Medicine and Children’s in the public health setting, 51 Mercy Hospital, studies the use of suggesting that new and more NSIGHT RESEARCH GROUPS, STUDY rapid whole genome sequencing scalable materials and procedures DESIGNS, AND KEY QUESTIONS BEING (WGS) at 2 large level-IV NICUs for communicating the potential ADDRESSED (∼1000 admissions per year) benefits and risks of learning such Each of the 4 members of the in children’s hospitals (Fig 1B). information would need to be NSIGHT Consortium independently WGS was adapted for diagnosis developed, validated, and designed and implemented of rare genetic diseases in NICUs, deployed. Systems may need to be study designs that focus on including shortening the minimum established that enable parents somewhat different populations time to provisional diagnosis to to request certain results from and research questions (Fig 1 and 26 hours, increasing the analytic their child’s genomic information Table 1). sensitivity and specificity of over time, allowing them to decide variant detection to >99.5%, iteratively as their values and Genome Sequence-Based and gaining US Food and Drug perceptions of risk change or as Screening for Childhood Risk Administration approval to report their child attains an age to assent and Newborn Illness project a provisional diagnosis verbally to or consent. (Fig 1A), led by Brigham and an attending neonatologist if death Women’s Hospital (BWH) and was imminent and the diagnosis would inform implementation of The complexities of genomic result Boston Children’s Hospital (BCH) a treatment that could change the interpretation currently demand at Harvard Medical School and outcome.27, 28 The current study is a trained geneticists and genetic by Baylor College of Medicine, prospective, randomized controlled counselors to provide guidance and is a randomized controlled trial follow-up management. As genomic assessing the impact of providing trial of the diagnostic utility, cost- medicine becomes more mainstream genomic sequencing information effectiveness, and psychosocial in health care, a broader range of to parents and physicians of implications of rapid WGS at the 2 health care providers will need to newborns (clinicaltrials.gov NICUs (clinicaltrials.gov identifier interact with genetic information, identifier NCT02422511). The NCT02225522). As part of this which is likely to be increasingly study is enrolling a cohort of study, doctors and parents are viewed as 1 of many risk factors healthy newborns approached in surveyed about their perceptions influencing future conditions; the postpartum period from the of the risks and benefits of rapidly reports will have to be constructed BWH Well Baby Nursery and a obtaining WGS results. with clarity that makes them useful cohort of sick newborns from the for pediatricians and primary care BWH NICU and the ICUs at BCH. The goal of the Sequencing of providers. The potential use of this Within each cohort newborns Newborn Blood Spot DNA to type of genomic information over are randomly assigned to either Improve and Expand Newborn time would necessitate development the control arm (conventional Screening (NBSeq) project, led by of new infrastructure to manage NBS results and a detailed family the University of California, San reporting, reanalysis, storage, history) or the experimental Francisco (UCSF) and collaborating and integration with electronic arm (genomic sequencing in institutions, is to evaluate the health records. Such data could addition to conventional NBS and potential application of exome be used for iterative phenotyping a detailed family history). Parents sequencing to public health NBS of the individual to define the and physicians are surveyed to by using dried blood spots (DBS) clinical relevance of genetic assess the impact of the genomic (Fig 1C). The project explores the variants. However, thresholds for information across several key feasibility of exome sequencing to reporting or acting on potentially domains including attitudes and augment or replace current relevant variants would have to preferences, health care utilization, MS/MS technologies in NBS. Exome be calibrated against the possible health behaviors and intentions, sequencing is performed at UCSF harms of false-positive results or decisional satisfaction, and on deidentified archival DBS from overdiagnosis, which would lead to psychosocial impact on the all California newborns found to unnecessary, dangerous, or costly family. 53 have metabolic disorders in the

Downloaded from www.aappublications.org/news by guest on September 30, 2021 8 BERG et al TABLE 2 Cross-Consortium Working Groups the study will reveal the spectrum Ethical, Legal, Economic, and Common Data Elements Outcomes and Measure of results parents decide to learn, Social Issues issues surrounding returning Key questions Key questions Key questions these findings, and consequences • Differences in perceptions • Identify common data elements • Identify common outcome of decision-making and results of benefi ts and risks of in the NSIGHT projects to measures in the NSIGHT disclosure. sequencing between be collected systematically projects to be collected symptomatic and across the consortium systematically across the asymptomatic populations consortium • Parent willingness to accept • Collaboration with NBSTRN to • Considerations of the overall sequencing and factors use LPDR for individual cohort cost/benefi t ratio of newborn CROSS-CUTTING CONSORTIUM associated with parents’ and combined cohort analysis sequencing ACTIVITIES decisions where applicable • Extent to which parents are • Defi ne data elements to be Although the research projects willing to accept uncertainties shared more broadly, in a address distinct research questions inherent in test interpretation deidentifi ed fashion, with and have unique study designs, other researchers in the NBSTRN the 4 NSIGHT groups participate • How key stakeholders make in consortium activities that build decisions about whom to test, on the strengths at each site and how to share results, under harmonize data collection to what circumstances, and with improve cross-cutting analysis what goals • Public policy regarding use (Table 2). An ethical, legal, and of genome sequencing as social implications workgroup part of mandated screening brings together the perspectives programs of each project regarding the LPDR, Longitudinal Pediatric Data Resource (https://www. nbstrn. org/ research- tools/ longitudinal- pediatric- data- resource ). responses of clinicians, families, payers, and other stakeholders; parental informed consent and past decade, as well as samples infants affected with conditions decision-making; and implications 19,60 that were false positives on the identified through standard NBS for public health NBS programs. MS/MS screening. Sequence data and a cohort of healthy newborns The Common Data Elements from newborn DBS54 are also being whose parents are approached workgroup is charged with creating interrogated in a cohort of 50 for participation prenatally (Fig a common set of data elements patients who have been clinically 1D). Parents will use an electronic collected across the 4 research diagnosed with immunodeficiency decision aid to assist in decisions groups to enable data sharing disorders to determine whether about exome sequencing. 57 After and combined data analysis. The sequencing DBS as part of NBS providing informed consent at an Outcomes and Measures workgroup could facilitate early diagnosis in-person study visit, those who examines the standardized and optimal management of non– accept sequencing will receive instruments being used by each severe combined immunodeficiency results from a “next-generation group to assess stakeholder immune defects. Stakeholder views, sequencing newborn screening responses to newborn sequencing perspectives, and value preferences (NGS-NBS)” panel of genes to facilitate cross-consortium about the potential expansion of implicated in childhood-onset analyses. The NSIGHT Consortium is NBS are being evaluated through medically actionable conditions. 58 working closely with the Newborn focus groups.55 In addition, legal and Parents will also be enrolled in Screening Translational Research constitutional issues surrounding a randomized trial of decision- Network (NBSTRN) Coordinating the potential use of genome- making regarding whether to Center, housed at the American scale analysis in NBS are being learn about 3 types of additional College of Medical Genetics examined. 56 genomic findings in their child and Genomics. The NBSTRN, by using the electronic decision created as part of the NICHD’s The North Carolina Newborn Exome aid (clinicaltrials.gov identifier Hunter Kelly Newborn Screening Sequencing for Universal Screening NCT02826694). The study seeks to Research Program to create a study at the University of North understand how parents think about shared research infrastructure Carolina at Chapel Hill evaluates and consider different categories of to support NBS researchers, exome sequencing from saliva information,59 and, combined with provides a mechanism to increase samples in 2 groups: children and longitudinal quantitative surveys, understanding of conditions that

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 9 are currently part of routine NBS Design and implementation of or may be future candidates for rapid high-throughput methods ABBREVIATIONS screening. The NBSTRN resources, will be essential to maximize BCH: Boston Children’s Hospital tools, and network of experts are the benefit of sequencing for BWH: Brigham and Women’s used in population-based pilots of certain conditions in the neonatal Hospital new screening technologies and population. Longitudinal follow-up DBS: dried blood spots natural history studies of screened of parents will allow the study MS/MS: tandem mass conditions. NSIGHT Consortium of parental decision-making, spectrometry investigators also maintain close measure parental preferences in NBS: newborn screening ties with other National Institutes of real-world settings, and assess NBSeq: Sequencing of Newborn Health–funded consortia including test-related stress or anxiety. Blood Spot DNA to the Clinical Sequencing Exploratory Medical outcomes of the children Improve and Expand Research consortium61 and who undergo sequencing will need Newborn Screening Clinical Genome Resource to be monitored over many years. NBSTRN: Newborn Screening consortium.62 Ultimately, these data will aid in Translational Research the development of best clinical Network practices and provide guidance on NGS-NBS: next-generation CONCLUSIONS the implementation of sequencing sequencing newborn in newborns. Although genomic screening Data gathered from the projects sequencing will expand our ability NICHD: Eunice Kennedy Shriver in the NSIGHT Consortium to diagnose conditions and offer National Institute of will address technical, clinical, personalized treatments, health Child Health and Human and ethical questions that care providers and public health Development are fundamental to the future entities must be good stewards of NSIGHT: Newborn Sequencing in consideration of sequencing this technology, ensuring careful Genomic Medicine and in newborns. The projects will attention to ethical standards Public Health determine the feasibility and and evidence-based outcomes in UCSF: the University of utility of this technology in critical making recommendations about its California, San Francisco care and public health settings. use. WGS: whole genome sequencing

and revised the manuscript; Dr Bailey conceptualized and designed the study and reviewed and revised the manuscript; Dr Beggs conceptualized and designed the study, drafted the initial manuscript, coordinated and supervised data collection at 1 of the sites, participated in data analysis, and reviewed and revised the manuscript; Dr Brenner drafted the initial manuscript, conceptualized and designed the study, designed the data collection instruments, participated in data analysis, and reviewed and revised the manuscript; Dr Brower drafted the initial manuscript, designed data collection instruments, and reviewed and revised the manuscript; Ms Cakici and Dr Petrikin participated in data analysis, designed data collection instruments, coordinated and supervised data collection at 1 of the sites, and reviewed and revised the manuscript; Drs Ceyhan-Birsoy and Chan, Ms Chen, and Drs Leeder, Shieh, and Yu drafted the initial manuscript, participated in data analysis, and reviewed and revised the manuscript; Dr Currier drafted the initial manuscript, conceptualized and designed the study, designed the dried blood spot data collection instruments, coordinated and supervised data collection at 1 of the sites, participated in data analysis, and reviewed and revised the manuscript; Drs Dukhovny and Pereira drafted the initial manuscript, designed data collection instruments, participated in data analysis, and reviewed and revised the manuscript; Dr Green conceptualized and designed the study, drafted the initial manuscript, supervised data collection at one of the sites, participated in data analysis, and reviewed and revised the manuscript; Drs Harris-Wai, B. Powell, and Veeraraghavan participated in data analysis and reviewed and revised the manuscript; Dr Holm drafted the initial manuscript, coordinated and supervised data collection at one of the sites, participated in data analysis, and reviewed and revised the manuscript; Ms Iglesias participated in programmatic oversight and reviewed and revised the manuscript; Dr Joseph participated in data analysis, designed data collection instruments, and reviewed and revised the manuscript;Dr Kingsmore conceptualized and designed the study, drafted the initial manuscript, participated in data analysis, designed data collection instruments, coordinated and supervised data collection at 1 of the sites, and reviewed and revised the manuscript;Dr Koenig conceptualized and designed the study, drafted the initial manuscript, participated in data analysis, designed data collection instruments, and reviewed and revised the manuscript; Drs Kwok and Puck conceptualized and designed the study, participated in data analysis, coordinated and supervised data collection at 1 of the sites, and reviewed and revised the manuscript; Dr Lantos drafted the initial manuscript, participated in data analysis, coordinated and supervised data collection at 1 of the sites, and reviewed and revised the manuscript; Dr Lewis drafted the initial manuscript, designed the electronic decision aid, and reviewed and revised the manuscript; Drs McGuire and Rehm drafted the initial manuscript, designed data collection instruments, coordinated and supervised data collection at 1 of the sites, participated in data analysis, and reviewed and revised the manuscript; Dr Milko and Mr Watson supervised data collection at 1 of the sites and reviewed and revised the manuscript; Dr Mooney participated in data analysis, coordinated and supervised data collection at 1 of the sites, and reviewed and revised the manuscript; Dr C. Powell conceptualized and designed the study, drafted the initial manuscript, coordinated and supervised data collection at 1 of the sites, and reviewed and revised the manuscript; Dr Risch conceptualized and designed the study, participated in data analysis, and reviewed and revised the manuscript; Ms Roche coordinated and supervised data collection at 1 of the sites and reviewed and revised the manuscript; Dr Willig drafted the initial manuscript, participated in data analysis, designed data collection instruments, coordinated and supervised data collection at one of the sites, and reviewed and revised the manuscript; Drs Urv and Wise conceptualized and designed the study, drafted

Downloaded from www.aappublications.org/news by guest on September 30, 2021 10 BERG et al the initial manuscript, participated in programmatic oversight, and reviewed and revised the manuscript; and all authors approved the fi nal manuscript as submitted. DOI: 10.1542/peds.2016-2252 Accepted for publication Nov 15, 2016 Address correspondence to Jonathan S. Berg, MD, PhD, Department of Genetics, The University of North Carolina at Chapel Hill, 120 Mason Farm Rd, Chapel Hill, NC 27599-7264. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Bailey receives funding from the John Merck Fund and Ovid Therapeutics; Dr Beggs received a 1-time ad hoc consultancy in early 2016 from Human Longevity Inc; Dr Brenner receives research support from Tata Consultancy Services; Dr Green is compensated for speaking or advisory services by AIA, Genome Medical, Helix, Illumina, Invitae, Prudential, and Roche; Dr McGuire is an unpaid consultant to Human Longevity Inc; Dr Parad is an unpaid scientifi c advisor to Parabase Genomics, and he has stock valued at <$50 on a next-generation sequencing NICU-based gene panel diagnostic test; Dr Puck’s spouse is employed by Invitae, a clinical gene sequencing company; Dr Willig has a patent for a bioinformatics pipeline and data analysis tool for genome sequencing; Dr Yu consults for Claritas Genomics, a commercial genomic medicine company that offers DNA diagnostic services including single-gene, panel, and exome sequencing; and the remaining authors have indicated they have no fi nancial relationships relevant to this article to disclose. FUNDING: Supported by National Institute of Health grants 1U19HD077693, 1U19HD077632, 1U19HD077627, and 1U19HD077671. Newborn Screening Translational Research Network is funded through a contract from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HHSN275201300011C). Funded by the National Institutes of Health (NIH). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 13 Newborn Sequencing in Genomic Medicine and Public Health Jonathan S. Berg, Pankaj B. Agrawal, Donald B. Bailey Jr., Alan H. Beggs, Steven E. Brenner, Amy M. Brower, Julie A. Cakici, Ozge Ceyhan-Birsoy, Kee Chan, Flavia Chen, Robert J. Currier, Dmitry Dukhovny, Robert C. Green, Julie Harris-Wai, Ingrid A. Holm, Brenda Iglesias, Galen Joseph, Stephen F. Kingsmore, Barbara A. Koenig, Pui-Yan Kwok, John Lantos, Steven J. Leeder, Megan A. Lewis, Amy L. McGuire, Laura V. Milko, Sean D. Mooney, Richard B. Parad, Stacey Pereira, Joshua Petrikin, Bradford C. Powell, Cynthia M. Powell, Jennifer M. Puck, Heidi L. Rehm, Neil Risch, Myra Roche, Joseph T. Shieh, Narayanan Veeraraghavan, Michael S. Watson, Laurel Willig, Timothy W. Yu, Tiina Urv and Anastasia L. Wise Pediatrics originally published online January 17, 2017;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2017/01/15/peds.2 016-2252 References This article cites 59 articles, 19 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2017/01/15/peds.2 016-2252#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Genetics http://www.aappublications.org/cgi/collection/genetics_sub Public Health http://www.aappublications.org/cgi/collection/public_health_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

Downloaded from www.aappublications.org/news by guest on September 30, 2021 Newborn Sequencing in Genomic Medicine and Public Health Jonathan S. Berg, Pankaj B. Agrawal, Donald B. Bailey Jr., Alan H. Beggs, Steven E. Brenner, Amy M. Brower, Julie A. Cakici, Ozge Ceyhan-Birsoy, Kee Chan, Flavia Chen, Robert J. Currier, Dmitry Dukhovny, Robert C. Green, Julie Harris-Wai, Ingrid A. Holm, Brenda Iglesias, Galen Joseph, Stephen F. Kingsmore, Barbara A. Koenig, Pui-Yan Kwok, John Lantos, Steven J. Leeder, Megan A. Lewis, Amy L. McGuire, Laura V. Milko, Sean D. Mooney, Richard B. Parad, Stacey Pereira, Joshua Petrikin, Bradford C. Powell, Cynthia M. Powell, Jennifer M. Puck, Heidi L. Rehm, Neil Risch, Myra Roche, Joseph T. Shieh, Narayanan Veeraraghavan, Michael S. Watson, Laurel Willig, Timothy W. Yu, Tiina Urv and Anastasia L. Wise Pediatrics originally published online January 17, 2017;

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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