Holm et al.

BMC Pediatrics (2018) 18:225

https://doi.org/10.1186/s12887-018-1200-1

STUDY PROTOCOL Open Access

The BabySeq project: implementing

genomic sequencing in newborns
Ingrid A. Holm1,2* , Pankaj B. Agrawal1,2,3, Ozge Ceyhan-Birsoy4,5,6, Kurt D. Christensen7,8, Shawn Fayer7,
Leslie A. Frankel9,10, Casie A. Genetti1, Joel B. Krier7,8, Rebecca C. LaMay7, Harvey L. Levy1,2, Amy L. McGuire9,
Richard B. Parad2,3,11, Peter J. Park7,12, Stacey Pereira9, Heidi L. Rehm4,5,13, Talia S. Schwartz1, Susan E. Waisbren1,2,
Timothy W. Yu1,2,13, The BabySeq Project Team, Robert C. Green7,8,13† and Alan H. Beggs1,2*†

Abstract
Background: The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period.
The “BabySeq Project” is a randomized trial that explores the medical, behavioral, and economic impacts of integrating
genomic sequencing into the care of healthy and sick newborns.
Methods: Families of newborns are enrolled from Boston Children’s Hospital and Brigham and Women’s Hospital
nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease
variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All
families participate in a disclosure session, which includes the return of results for those in the sequencing arm.
Outcomes are collected through review of medical records and surveys of parents and health care providers and
include the rationale for choice of genes and variants to report; what genomic data adds to the medical management
of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into
the care of healthy and sick newborns.
Discussion: The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic
sequencing and will inform policy decisions related to universal genomic screening of newborns.
Trial registration: The study is registered in ClinicalTrials.gov Identifier: NCT02422511. Registration date: 10 April 2015.
Keywords: Newborn screening, Newborn sequencing, Whole exome sequencing, Methods, Randomized trial, Ethical,
legal, social implications

Background is rapidly becoming feasible and has the potential to

Clinical laboratories are increasingly offering genomic revolutionize healthcare and improve patient outcomes.
sequencing (next generation sequencing of the whole gen- Genomic sequencing may have its greatest lifelong
ome or exome), to diagnose rare disorders, individualize impact on newborns. Not only can genomic sequencing
cancer treatments, and inform drug selection and dosing facilitate diagnoses in sick newborns and infants, it has po-
(pharmacogenomics) [1–10]. Moreover, experts anticipate tential utility in newborn screening by identifying predis-
that health systems will soon expand the use of genomic positions for future disease that can be mitigated through
sequencing more broadly for disease risk assessment, early intervention. In addition, data provided by genomic
carrier testing, prenatal screening, and potentially much sequencing can be a resource for healthcare providers to
more [11–15]. Genomic sequencing at a population level query throughout an individual’s lifetime. The National
Institutes of Health director Dr. Francis Collins has said:
“…whether you like it or not, a complete sequencing of
* Correspondence: ingrid.holm@childrens.harvard.edu; newborns is not far away,” [12] and the previous National
Beggs@enders.tch.harvard.edu
†
Robert C. Green and Alan H. Beggs contributed equally to this work. Institutes of Child Health and Development (NICHD)
1
Division of Genetics and Genomics, The Manton Center for Orphan Disease director Dr. Alan Guttmacher explicitly invoked genomic
Research, Boston Children’s Hospital, Boston, MA, USA sequencing of newborns: “One can imagine the day that
Full list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Holm et al. BMC Pediatrics (2018) 18:225 Page 2 of 10

99% of newborns will have their genomes sequenced Overview of study design
immediately at birth” [11]. As the President’s Council on The BabySeq Project study design was informed by a
Bioethics concluded as early as 2008, it may “…prove preexisting program, The MedSeq Project, [18–20] a ran-
impossible to hinder the logic of genomic medicine from domized clinical trial assessing the impact of integrating
assimilating the currently limited practice of newborn genome sequencing into clinical medicine in adults. Baby-
screening into its all-embracing paradigm” [16]. Seq is a randomized clinical trial that explores the impact
This vision led the NICHD and National Human Gen- of sequencing newborns in two cohorts, healthy and sick
ome Research Institute (NHGRI) to jointly issue a Request newborns (Fig. 1), and evaluates infant, family, and clinician
for Applications (RFA) to explore “opportunities to use outcomes. Within each cohort, families are randomized to
genomic information for broadening our understanding of a modified standard of care (family history and standard
diseases identified in the newborn period.” Four groups newborn screening [NBS]) or to a modified standard of
were funded under this RFA and comprise the Newborn care plus genomic sequencing. For those in the genomic
Sequencing In Genomic medicine and public HealTh sequencing arm a Newborn Genomic Sequencing Report
(NSIGHT) consortium (https://www.genome.gov/ (NGSR) is generated, which lists pathogenic or likely patho-
27558493/newborn-sequencing-in-genomic-medici- genic variants in genes that have been strongly linked to
ne-and-public-health-nsight/) [17]. The primary goal of childhood-onset diseases or diseases for which intervention
our NSIGHT grant, the “BabySeq Project”, is to explore is possible during childhood [21]. For newborns with a
the medical, behavioral, and economic impacts of integrat- specific clinical presentation that potentially has a genetic
ing genomic sequencing into the care of healthy and sick etiology, a more in-depth analysis of the newborn’s se-
newborns. Here, we describe the design of the Project. quence targeted to that presentation is available (Indication
Based Analysis, IBA). Parents complete surveys over the
baby’s first year of life, and the baby’s provider/s complete
Methods surveys over the course of the study.
Study investigators
The BabySeq Project team includes a diverse group of The IRB and FDA
investigators with expertise in genetics/genomics, neonat- The BabySeq Project investigators are based at Boston
ology, newborn screening, bioinformatics, molecular Children’s Hospital (BCH), Brigham and Woman’s Hos-
genetics, clinical trial design, ethics, and psychosocial, pital (BWH), and Baylor College of Medicine (BCM). All
behavioral, and health outcomes measurement. The study participant activities occur at BCH and BWH, and the
includes an External Advisory Board with members drawn IRBs at both institutions approved the protocol with the
from clinical genetics, molecular genetics, neonatology, “greater than minimal risk with potential for benefit” risk
newborn screening, and ethics. determination. BCM collects and analyzes data on the

Fig. 1 BabySeq Study Design Overview

Holm et al. BMC Pediatrics (2018) 18:225 Page 3 of 10

ethics and psychosocial impact of newborn sequencing concerns have been raised about the potential for negative
and was approved by their IRB through an expedited psychosocial impact on families and health care providers
process. of sequencing healthy newborns and returning results
The four NSIGHT studies underwent review by the Food unrelated to a diagnosed medical condition, [27–29] and
and Drug Administration (FDA) and the procedure for that unnecessary testing ordered by clinicians in response
sequencing, interpretation, reporting, and data collection in to the results could increase parental anxiety and health
the BabySeq Project was determined to be a non-significant care costs [27]. Randomizing families allows us to evaluate
risk device study according to the investigational device the medical, economic, and behavioral outcomes related to
exemptions (IDE) regulation (21 CFR 812). parental impact and clinician decision-making in a manner
while reducing biases generated by families that volunteer
Rationale for a two cohort design to study sick and for the study.
healthy newborns
A significant portion of newborns in the Neonatal Inten-
sive Care Unit (NICU) have a condition with a genetic Population and recruitment
component [22]. Currently the most common practice for Population
these cases is to send single or multiple gene tests until a The targeted enrollment for the BabySeq Project is
diagnosis is made, potentially leading to delays in diagno- approximately 200 newborns and their parents in each
sis and implementing appropriate care. Genomic sequen- cohort: 1) healthy: the BWH Well Baby Nursery, and 2)
cing immediately after birth may streamline the process of sick: the BWH NICU, and BCH NICUs and other ICUs
genetic testing by permitting the correct diagnosis to be (see Table 1, inclusion and exclusion criteria). Within
made faster, potentially lowering hospitalization costs and each cohort participants are randomized 1:1 WES:Stan-
improving clinical outcomes. Moreover, if additional dard of care. The newborn’s primary care provider and
symptoms develop, an already existing sequence can be provider/s in the NICU/ICU are also invited to partici-
re-interrogated and analysis targeted to those symptoms, pate. For this sample size we estimate statistical power
leading to an answer more rapidly than ordering new to be > 95% at α = 0.05 to test hypotheses that parents in
genetic tests piecemeal. Although genomic sequencing is the WES arm will report no greater personal distress or
being increasingly used in sick children, including disruptions to parent-child relationships than parents in
newborns, [23, 24] at many institutions the high cost and the control arm. We also estimate that we will have over
difficulty in obtaining reimbursement by insurance com- 95% power to test hypotheses that parents in the WES
panies, [25] as well as uncertainty about the management arm will perceive greater utility in the information they
of secondary findings, limits its use. As a result, studying receive than parents in the control arm.
the implementation of sequencing sick newborns remains
a priority, as it is not currently accessible in many settings.
Sequencing healthy newborns may also provide par-
ents with genetic information that predicts risk for gen- Table 1 Inclusion and Exclusion Criteria
etic diseases. There is precedence for predictive genetic Inclusion criteria:
testing of newborns: state-mandated newborn screening Infants born at BWH and admitted to the Well Newborn Nursery,
identifies conditions for which early intervention im- or to the BCH or BWH ICU
proves outcomes [26]. Furthermore, predictive genetic At least one biological parent to have genetic counseling, donate
DNA, and provide consent for testing the infant
testing is accepted in the care of children with a family
history of a child-onset disorder, or disorders where Exclusion criteria:
there are preventative interventions available during Parents are non-English speaking
childhood. The elective application of newborn genomic Parents unwilling to have genomic reports placed in the medical
sequencing to healthy newborns expands on the new- record or sent to their primary care pediatrician
born screening and predictive testing currently in place. Mother or father younger than 18 years of age
In addition, identification of a newborn’s carrier status Mother or father with impaired decisional capacity
can facilitate parental testing and reproductive planning Age of infant is older than 42 days
for the family.
One of a multiple gestation

Rationale for a randomized design Any infant in which clinical considerations preclude drawing 1.0 ml
of blood
A randomized controlled trial of whole exome sequencing
Clinical exome ordered before the time of enrollment
(WES) vs. modified standard of care is an uncommon study
design for genomic sequencing studies and provides a high Missing consent of either biological parent (if known) or rearing
parent (if applicable)
degree of methodological rigor. This is important because
Holm et al. BMC Pediatrics (2018) 18:225 Page 4 of 10

Recruitment Data and sample collection at enrollment

A detailed 3-generation pedigree is obtained from the par-
Newborns and their parents The BabySeq research ents. One mL of blood by venipuncture is collected from
staff first screen the newborns/families to determine the newborn, divided into two 0.5 mL aliquots. Saliva
eligibility. Permission to approach an eligible family is samples are collected from both biological parents, unless
obtained from health care staff in the clinical unit. not possible (e.g., anonymous sperm or egg donation).
Parents are introduced to the study by the staff from the
clinical unit and/or the BabySeq project. Interested fam- Review of medical records and family history report
ilies complete a pre-enrollment information session with Parents provide medical record releases for the newborn’s
a genetic counselor to learn about the study. pediatric records, state newborn screening results, and the
mother’s obstetric records. Records of subsequent care are
Health care providers Parents provide the name of their requested when the infant is 6 weeks old and are reviewed
newborn’s primary care provider. Health care provider/s of in preparation for the results disclosure session. Medical
sick newborns include BWH and BCH Neonatology facul- records are requested and reviewed on an annual basis.
ties, who were invited to enroll at the beginning of the
study. Additional specialist care providers are identified by Genomic sequencing
the parents, and by the research staff through the electronic For newborns randomized to the genomic sequencing
medical record. All providers are contacted and asked to arm, DNA obtained from one of the 0.5 mL blood samples
complete a baseline survey. Regardless of whether or not is used for WES; the second 0.5 mL aliquot is held as a
they complete a baseline survey, all primary care providers back-up. An aliquot of the DNA is sent to the
and providers involved in a newborn’s care during the CLIA-certified Clinical Research Sequencing Platform at
course of the study are asked to complete an online the Broad Institute, Cambridge, MA where WES is per-
post-disclosure survey. formed on an Illumina HiSeq platform. Variant interpret-
It should be noted that participation of the newborn’s ation and reporting is performed at the CLIA-certified
provider/s is optional and non-participation does not Partners HealthCare Laboratory for Molecular Medicine
disqualify the newborn and family from enrollment or (LMM), Cambridge, MA. Variants are filtered and classified
continuation in the study. according to previously described approaches [19] and pro-
fessional guidelines [30]. Genes are classified using the Clin-
Consent ical Genome Resource (ClinGen) Gene Curation Working
The consent process for the families starts with a Group framework (https://www.clinicalgenome.org/curatio-
pre-enrollment information session conducted by a genetic n-activities/gene-disease-validity/). Variants to be returned
counselor, which includes an overview of study logistics, are confirmed by Sanger sequencing or digital droplet PCR.
basic genetics education, review of types of reportable The average length of time from DNA extraction to comple-
results, and a discussion of risks and benefits. After the tion of the report is 16 weeks.
session and prior to signing the consent form, the parents If testing the parents could aid in the interpretation of a
are administered 18 consent-understanding questions and variant in the newborn, e.g., determining de novo occur-
incorrect responses are reviewed with the parents. Consent rence, or determining the phase of two variants identified
is required from both biological parents, if known, and from in a recessive gene, DNA is extracted from the parents’
non-biological legal guardians, if applicable. Following con- saliva samples and Sanger sequencing of the variant is
sent, each parent receives a baseline survey. At least one performed. Parental origin is not routinely determined for
parent must complete the baseline survey within 14 days in carrier variants found in the newborn. Parental DNA does
order to confirm study participation, providing families time not undergo WES.
to consider the study following discharge from the hospital.
Families who do not complete a baseline survey are consid- Reporting
ered to have passively withdrawn from the study. Once one A Newborn Genomic Sequencing Report (NGSR) is gener-
baseline survey is completed, the newborn is considered ated for newborns randomized to the genomic sequencing
fully enrolled and is randomized to a study arm. arm that includes pathogenic and likely pathogenic variants
For providers, completing the survey constitutes con- that indicate risk, or carrier status, for highly penetrant
sent to the study. conditions presenting and/or managed during childhood.
We anticipated that approximately 5% of newborns would
Parents who decline to participate in the BabySeq project have a reportable monogenic disease risk variant [31–33]
Parents who decline upon initial approach or after the and that roughly 90% will be a carrier for a reportable
pre-enrollment information session, are offered a brief condition [19, 20]. Given the prevalence of carrier status,
“decliner survey” that queries their reasons for declining. this allows us a greater opportunity to observe short-term
Holm et al. BMC Pediatrics (2018) 18:225 Page 5 of 10

reactions, health care expenditures, short-term medical given a copy of the family history report, NBS report, and,
benefits, potential effects on parental bonding, and how for those in the sequencing arm, the NGSR.
such information affects parents’ reproductive decisions.
Additionally, pharmacogenomic variants in genes with
strong evidence for relevance in medications used in the Reporting in the medical record and to providers
childhood period (e.g. RYR1, G6PD, or TPMT variants) are After disclosure of results, the genetic counselor and phys-
included on the NGSR. ician prepare a note summarizing the visit. This note, along
An IBA is performed and included on the NGSR for with the family history report, NBS report, and, for those in
sick newborns with a specific indication at the time of the sequencing arm, the NGSR, are mailed to the parents
enrollment, or if a genetic indication is revealed through and faxed to the infant’s pediatrician and other providers.
the record review or later in follow-up for any subject. These documents are uploaded to the infant’s medical rec-
This analysis, unlike the NGSR, also contains variants of ord at BWH or BCH. Electronic reports are also available
uncertain significance (VUS) in genes associated with through a GeneInsight Clinic instance where physicians are
the indication. notified of any variant classification changes [34–37].
Results are signed-out by American Board of Medical
Genetics and Genomics (ABMGG)-certified clinical mo-
lecular geneticists. (See Ceyhan-Birsoy, et al., 2016 [21] for Outcomes
a description of gene curation). Outcomes addressed throughout the development and
The NGSR structure and content is based on the Gen- execution of the study
ome Reports developed for the MedSeq project [19, 20]. We have created a multi-step process in the clinical
The first page has a “results summary” of the findings domain, where one has not existed before, providing
followed by an “interpretation summary”, which includes comprehensive sequencing of newborns in a randomized
“monogenic disease risk variants” and “carrier status vari- controlled trial format. Development of this process,
ants” sections. The reported findings are summarized in a encompassing 1) protocol development, 2) recruitment
table that includes information on the disease, inheritance, and enrollment, 3) genomic sequencing, 4) analysis of the
gene transcript, variant, allele state, classification, and sequencing data in an organized and timely manner, 5)
penetrance. If the parents were tested for a variant found report generation, 6) return of the findings to participants
in the newborn, the parent of origin is included in the and providers, and 7) placement of the information in the
table. If an IBA was requested, the “interpretation sum- medical records. In addition we will assess economic
mary” includes “variants relevant to the indication for outcomes, which is in and of itself, an important element
testing” and a similar table summarizing details, including of this study. The development and implementation of an
coverage statistics for particular genes associated with that effective workflow will provide important information on
indication. Finally, there is a “recommendations” section. what works and what the pitfalls are.
The next page of “detailed variant information” has Additional outcomes include:
additional detail about the variant, disease, familial risks,
and reproductive risk. This organizational structure allows a) Socioeconomic and demographic characteristics of
participants and providers easy access to the important parents choosing to enroll in a newborn genomic
information, and to the details if desired. sequencing study.
b) The process and rationale for choice of genes and
variants to report, which of those findings should
Disclosure be included or excluded, and categories of
Results for both arms of the study are disclosed to parents information (e.g., dominant adult onset conditions)
during an in-person session at the BWH or BCH by a that are not being returned but perhaps should be.
study genetic counselor and physician. The family is told c) Assessing optimal formats for reporting genomic
which arm they are in, and there is a discussion of the results.
family history report (written by the genetic counselor d) Contributions of genomic data to medical
based on the pedigree obtained at enrollment) and the management of infants in the ICU.
standard NBS report. Parents in the sequencing arm also e) Cost differentials of genomic sequencing between
receive the NGSR, and results of an IBA (if performed). A sick and healthy babies.
study physician (most of whom are trained in clinical f ) Identification of hidden but discoverable
genetics) performs a physical examination to identify phenotypes in babies that have risk variants, and if
dysmorphic features or minor anomalies that might have they are not immediately perceivable (as in infants
been previously missed, and infants in the control arm with cardiac risks), the presence of “subclinical
who may have benefited from sequencing. Families are phenotypes” that can be explored.
Holm et al. BMC Pediatrics (2018) 18:225 Page 6 of 10

g) Medical, behavioral, and economic impacts of but the nature of the BabySeq Project and its study popu-
integrating genomic sequencing into the care lation required revised or novel measures for some out-
of healthy and sick newborns. comes where there were no existing instruments.
Parent surveys are administered at four time points
Medical, behavioral and psychosocial outcomes over the infant’s first year of life: enrollment, following
To objectively measure the impact of genomic newborn the results disclosure, and 3 and 10 months after results
sequencing on parents and care providers, the goals are: disclosure (Fig. 2). Because the BabySeq Project is specif-
ically investigating the risks and benefits of genomic se-
1. To compare the impact on parents of receiving a quencing in the newborn period, the surveys address the
NGSR vs. standard of care, using clinical data and psychosocial impact of sequencing on parent-child and
surveys measuring psychological and psychosocial parent-parent relationships during this critical formative
impact, perceived utility, and behavioral responses. period [38]. Family Systems Theory suggests that an
2. To evaluate the experience and actions of the event that affects one member of a family will affect the
clinicians who receive the genomic reports entire family system [39]. Therefore, the parent surveys
compared to standard care. assess parents’ perceptions of their child, child-centered
stress, parent-child relationships, partner relationships,
BabySeq addresses these goals by analyzing clinical data and parental depression and anxiety.
and surveying parents and clinicians. Medical outcomes Provider surveys assess their knowledge, attitudes, and
include time to final diagnosis, time to initiation of opti- perspectives concerning genomic information at enroll-
mal therapy, length of hospital stay, and survival. Building ment and at the study end. Each time they receive a
on previous research [20], BabySeq also collects outcome NGSR, providers also complete a survey assessing their
data on key domains, including attitudes and preferences, attitudes toward the results and their recommendations
healthcare utilization, health behaviors and intentions, for follow-up healthcare.
decisional satisfaction, and psychological impact (Table 2). Both parent and providers receive a monetary incentive
The project employs validated measures when possible, for completing the surveys.

Table 2 Variable Domains

Variable Domains Parents Physicians
Baseline Post-Disclosure 3-Mo 10-Mo Baseline Post-Disclosure End of Study
Attitudes X X X X
Confidence X X X X X
Perceived Utility X X X X X X
Genetic Perception X X X X
Sociodemographics X X
Healthcare Utilization X
Report Utilization X
Information Seeking X
Preparedness & Interest X X
Parent-Child Relationship X X X X
Personal Distress (Depression/Anxiety) X X X X
Child-Centered Stress X X
Partner Relationship X X X X
Perceptions of Child X X X X
Health Behaviors & Intentions X X X X
Social Support X X
World View X X X
Health History X
Trust X
Satisfaction X X X
Understanding & Recall X
Holm et al. BMC Pediatrics (2018) 18:225 Page 7 of 10

Fig. 2 BabySeq Parental and Physician Survey Timeline

Economic outcomes group previously reported [40] where nearly 85%.of par-
Economic outcomes associated with sequencing of new- ents approached in the BWH Well Baby Nursery were at
borns are collected. Medical record reviews and diagnoses least somewhat interested in the hypothetical possibility
are collected in all subjects over the first year of life. Cost of their newborn undergoing WES. However, our actual
data related to diagnostic laboratory testing and other enrollment rate has been significantly lower, leading us
medical procedures, medical visits, as well as parental time to identify and address hurdles to enrollment. Early on
lost from work will be compared between the sequenced we discovered that one of the primary logistical hurdles
and control arms. was the short time frame for enrollment, since healthy
newborns are generally discharged by 48 h of life, which
Recording adverse events does not give parents who are busy caring for their new-
Standardized questionnaires for depression or anxiety are born much time to consider their decision to enroll and
included in each survey. If a parent receives a score above complete the baseline survey. We adapted by providing
the cut-off for being clinically at-risk on instruments meas- parents 2 weeks after discharge to complete the baseline
uring depression or anxiety, or endorses the statement survey, allowing them time to consider their decision
“The thought of harming myself has occurred to me/ and complete the survey outside of the hectic post-
Thoughts that you would be better off dead or of hurting partum environment.
yourself in some way” (Edinburgh Postnatal Depression Additionally we instituted a “decliner survey” and based
Scale//Patient Health Questionnaire – 9), they were on assessment of the results changed some procedures to
contacted by the study psychologist (SW) to ensure that be less burdensome, including allowing parents to return
they had adequate supports and were not in danger of for a consent session after discharge, and changing the
self-harm or hurting the baby. The study psychologist or 10-month post disclosure in-person visit to a survey and
genetic counselor may refer the parent to their primary care phone check-in with a genetic counselor.
provider, a mental health professional, or emergency room
if indicated or requested.
Consent process
Recruitment There was concern that some parents might not understand
Through an iterative process of periodic assessment, we the potential implications for their family of having their
have maximized enrollment. Initial enrollment predic- newborn sequenced. To address this issue, we instituted the
tions for the BabySeq Project were based on a hypothet- brief post-counseling survey to ensure parents understood
ical project similar to the BabySeq Project that our the core information from the counseling session.
Holm et al. BMC Pediatrics (2018) 18:225 Page 8 of 10

Criteria for reporting information about the economic impact and burden on the
In advance of enrollment, we reviewed over 1400 genes healthcare system of newborn genomic sequencing. We
for strength of disease association, inheritance pattern, hope that the results from the BabySeq Project will inform
age of onset, and penetrance, with approximately 800 policy decisions related to universal genomic screening of
meeting criteria for return in the Project [17]. As variants newborns.
in un-curated genes are identified in participants, they
Abbreviations
need to be assessed in real time. In addition, because new ABMGG: American Board of Medical Genetics and Genomics; BCH: Boston
information regarding a gene’s role in disease is constantly Children’s Hospital; BCM: Baylor College of Medicine; BWH: Brigham and
reported in the literature, we update the curation as each Woman’s Hospital; CLIA: Clinical Laboratory Improvement Amendments;
ClinGen: Clinical Genome Resource; DNA: Deoxyribonucleic acid; FDA: Food
new potentially pathogenic variant is identified. As a re- and Drug Administration; IBA: Indication Based Analysis; IDE: Investigational
sult, some variants in genes initially not on the returnable device exemptions; IRB: Institutional Review Board; LMM: Laboratory for
list may be reclassified as returnable, while others may be Molecular Medicine; NBS: Newborn Screening; NGSR: Newborn Genomic
Sequencing Report; NHGRI: National Human Genome Research Institute;
removed. While the reference gene list is not utilized for NICHD: National Institutes of Child Health and Development; NICU: Neonatal
variant filtration, the pre-curated data significantly reduces Intensive Care Unit; NSIGHT: Newborn Sequencing In Genomic Medicine and
the time spent on results interpretation, since it allows the Public Health; PCR: Polymerase chain reaction; RFA: Request for Applications;
VUS: Variants of Uncertain Significance; WES: Whole Exome Sequencing
assessment process for pre-curated genes to focus solely
on reviewing any new information that became available Acknowledgements
since the last update [17]. The authors would like to acknowledge the BabySeq Project Team for their
help in the development and execution of the study.
Members of the BabySeq Project Team: Pankaj B. Agrawal, Alan H. Beggs,
Assessing outcomes Wendi N. Betting, Carrie L. Blout, Ozge Ceyhan-Birsoy, Kurt D. Christensen,
As we decided on outcome measures we needed to strike Pamela Diamond, Dmitry Dukhovny, Kathryn E. Dunn, Shawn Fayer, Leslie A.
Frankel, Casie A. Genetti, Chet Graham, Robert C. Green, Amanda M. Gutierrez,
a balance between obtaining a comprehensive picture of Maegan Harden, Margaret H. Helm, Lillian Hoffman-Andrews, Ingrid A. Holm,
parents’ experiences and minimizing the burden with long Joel B. Krier, Matthew S. Lebo, Kaitlyn B. Lee, Harvey L. Levy, Xingquan Lu, Sarah
surveys and multiple questionnaires. In addition, because S. Kalia, Kalotina Machini, Amy L. McGuire, Jaclyn B. Murry, Medha Naik, Tiffany
Nguyen, Richard B. Parad, Hayley A. Peoples, Stacey Pereira, Devan Petersen,
newborns ages 0–6 weeks of age are enrolled, the study Uma Ramamurthy, Vivek Ramanathan, Heidi L. Rehm, Amy Roberts, Jill O.
subjects vary in age at each survey time point, creating Robinson, Serguei Roumiantsev, Talia S. Schwartz, Eleanor B. Steffens, Meghan
complications in designing age-appropriate measures for C. Towne, Tina K. Truong, Grace E. VanNoy, Susan E. Waisbren, Caroline M.
Weipert, Timothy W. Yu.
each encounter. In addition, newborns randomized to the
genomic sequencing arm will have results of varying Funding
nature and severity and we needed to be thoughtful in This work was supported by grant U19 HD077671 from the Eunice Kennedy
Shriver National Institute of Child Health and Human Development and
how we compare the experiences of families who received National Human Genome Research Institute of The National Institutes of
results with differing degrees of impact. Ideally, we will be Health.
following these families longitudinally beyond the first
Availability of data and materials
year of life, since we recognize that collecting data for only Data sharing is not applicable to this article as no datasets were generated
the first year of life is a short time period. or analyzed during the current study.

Author’s contributions
Discussion IAH, PBA, OCB, KDC, SF, LAF, CAG, JBK, RCL, HLL, ALM, RBP, PJP, SP, TSS,
The BabySeq project is a study of the implementation of HLR SEW, TWY, RCG and AHB contributed to the conceptualization and
WES in newborns, and uses a randomization scheme that design of the study; participated in the acquisition, analysis, and
interpretation of data; drafted and revised the article; approved of the
will allow us to definitively address some of the concerns version to be published; and agree to be accountable for all aspects of the
that have been raised in this field about potentially nega- work in ensuring that questions related to the accuracy or integrity of any
tive psychological impacts of presenting genomic informa- part of the work are appropriately investigated and resolved. All authors
read and approved the final manuscript.
tion to families of newborn infants. The study is complex
and the process of designing and beginning implementa- Ethics approval and consent to participate
tion will lead to several important insights into the best The BCH, BWH, and BCM IRBs have approved this study. All parents
provided consent for their child and themselves to participate in the
ways to deliver genomic medicine in a newborn setting.
study. All health care providers consented to the study by completing
As genomic sequencing becomes further integrated into the survey, which constitutes consent.
clinical care, the incorporation of genomic sequencing into
universal newborn screening becomes a real possibility. Consent for publication
Not applicable.
The BabySeq Project will provide objective data regarding
the risks and benefits of newborn genomic sequencing in Competing interests
terms of the health impacts on the child, the psychosocial Authors have declared competing interest as follows:
HLR is employed by Partners Healthcare and Broad Institute that offer fee-based
implications for the family, and the ways in which clinicians clinical sequencing. TWY is a founder of and consultant for Claritas Genomics, a
use the information. This study also provides preliminary diagnostic company for children with complex genetic disorders. RCG receives
Holm et al. BMC Pediatrics (2018) 18:225 Page 9 of 10

compensation for speaking or consultation from AIA, GenePeeks, Helix, Illumina, 17. Berg JS, Agrawal PB, Bailey DB Jr, Beggs AH, Brenner SE, Brower AM, Cakici
Ohana, Prudential, and Veritas, and is co-founder and advisor to Genome JA, Ceyhan-Birsoy O, Chan K, Chen F, et al. Newborn sequencing in
Medical, Inc. IAH, PBA, OCB, KDC, SF, LAF, CAG, JBK, RCL, HLL, ALM, RBP, PJP, SP, genomic medicine and public health. Pediatrics. 2017:2016–252.
TSS, SEW, and AHB declare no competing interests. 18. Vassy JL, Christensen KD, Schonman EF, Blout CL, Robinson JO, Krier JB,
Diamond PM, Lebo M, Machini K, Azzariti DR, et al. The impact of whole-
genome sequencing on the primary care and outcomes of healthy adult
Publisher’s Note patients: a pilot randomized trial. Ann Intern Med. 2017:M17–0188.
Springer Nature remains neutral with regard to jurisdictional claims in 19. McLaughlin HM, Ceyhan-Birsoy O, Christensen KD, Kohane IS, Krier J,
published maps and institutional affiliations. Lane WJ, Lautenbach D, Lebo MS, Machini K, MacRae CA, et al. A
systematic approach to the reporting of medically relevant findings
Author details from whole genome sequencing. BMC Med Genet. 2014;15:134. https://
1 doi.org/10.1186/s12881-014-0134-1.
Division of Genetics and Genomics, The Manton Center for Orphan Disease
Research, Boston Children’s Hospital, Boston, MA, USA. 2Department of 20. Vassy JL, Lautenbach DM, McLaughlin HM, Kong SW, Christensen KD, Krier J,
Pediatrics, Harvard Medical School, Boston, MA, USA. 3Division of Newborn Kohane IS, Feuerman LZ, Blumenthal-Barby J, Roberts JS, et al. The MedSeq
Medicine, Boston Children’s Hospital, Boston, MA, USA. 4Laboratory for project: a randomized trial of integrating whole genome sequencing into clinical
Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, medicine. Trials. 2014;15(85) https://doi.org/10.1186/1745-6215-15-85.
MA, USA. 5Department of Pathology, Brigham and Women’s Hospital, 21. Ceyhan-Birsoy O, Machini K, Lebo MS, Yu TW, Agrawal PB, Parad RB, Holm
Harvard Medical School, Boston, MA, USA. 6Department of Pathology, IA, McGuire A, Green RC, Beggs AH, et al. A curated gene list for reporting
Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7Division of results of newborn genomic sequencing. Genet Med. 2017; 19(7):809–18.
Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, 22. Petrikin JE, Willig LK, Smith LD, Kingsmore SF. Rapid whole genome
MA, USA. 8Harvard Medical School, Boston, MA, USA. 9Center for Medical sequencing and precision neonatology. Semin Perinatol. 2015;39(8):623–31.
Ethics and Health Policy, Baylor College of Medicine, Houston, TX, USA. https://doi.org/10.1053/j.semperi.2015.09.009. Epub 2015 Oct 1029.
10
Department of Psychological, Health and Learning Sciences, University of 23. Bhattacharjee A, Sokolsky T, Wyman SK, Reese MG, Puffenberger E, Strauss K,
Houston College of Education, Houston, TX, USA. 11Department of Pediatric Morton H, Parad RB, Naylor EW. Development of DNA confirmatory and
Newborn Medicine, Brigham and Women’s Hospital, Boston, MA, USA. high-risk diagnostic testing for newborns using targeted next-generation
12
Department of Biomedical Informatics, Harvard Medical School, Boston, DNA sequencing. Genet Med. 2015;17(5):337–47. https://doi.org/10.1038/
MA, USA. 13The Broad Institute of MIT and Harvard, Cambridge, MA, USA. gim.2014.117. Epub 2014 Sep 1025.
24. Miller NA, Farrow EG, Gibson M, Willig LK, Twist G, Yoo B, Marrs T,
Received: 22 August 2017 Accepted: 27 June 2018 Corder S, Krivohlavek L, Walter A, et al. A 26-hour system of highly
sensitive whole genome sequencing for emergency management of
genetic diseases. Genome Med. 2015;7:100. https://doi.org/10.1186/
s13073-015-0221-8.
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