Genomic Sequencing for Childhood Risk and Newborn Illness (The BabySeq Project)
Phase: NA
Conditions: Hereditary Disease, Genetic Predisposition to Disease
Sponsor: Brigham and Women's Hospital

 
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Genome Sequence-Based Screening for Childhood Risk and Newborn Illness: The BabySeq 
Project 
 
Study Protocol and Statistical Analysis Plan 
January 27, 2020 
 
Funded by the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child 
Health and Human Development and National Human Genome Research Institute 
Genomic Sequencing and Newborn Screening Disorders (U19) RFA-HD-13-010 
Grant number: U19HD077671 
Project Period: 09/05/2013 – 08/31/2019 
ClinicalTrials.gov Number: NCT02422511 
Multiple Principal Investigators: Robert C. Green, MD, MPH, FACMG and Alan H. Beggs, PhD 
Project Co-Principal Investigators: Ingrid Holm, MD, MPH; Heidi Rehm, PhD, FACMG; Richard 
Parad, MD, MPH; Pankaj Agrawal, MD, MMSC; Amy McGuire, JD, PhD; Peter Park, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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BACKGROUND AND SIGNIFICANCE 
 
Historical Background  
 
Laboratories around the country are now offering CLIA-certified whole exome (WES) or 
whole genome sequencing (WGS) as a clinical service1-4 for molecular characterization of rare 
disorders5,6 and individualized cancer treatments.7,8 However, as costs come down and informatics 
advance, sequencing is likely to be applied much more broadly to pharmacogenomics, risk 
assessment in healthy adults, carrier screening, prenatal screening, and newborn screening.9-13 
NIH leaders recognize that sequencing of newborns may not be far in the future. NIH 
director Dr. Francis Collins has said: “…whether you like it or not, a complete sequencing of 
newborns is not far away”10 and NICHD director, Dr. Alan Guttmacher explicitly invoked genomic 
sequencing of newborns: “One can imagine the day that 99% of newborns will have their genomes 
sequenced immediately at birth."9 As the President’s Council on Bioethics concluded as early as 
2008, it may soon “…prove impossible to hinder the logic of genomic medicine from assimilating the 
currently limited practice of newborn screening into its all-embracing paradigm.’’14,15 As a result, the 
NIH, including the NICHD, NHGRI, and Office of Rare Diseases Research (ORDR) held a 
workshop in 2010 to “identify elements of a trans-NIH research agenda that could inform the 
possible application of new genomic concepts and technologies to newborn screening and child 
health”. This led the NICHD and NHGRI to issue a Request for Applications (RFA) that was 
considered “an initial step along this path” with the purpose of exploring “opportunities to use 
genomic information for broadening our understanding of diseases identified in the newborn 
period”. The NICHD and the NHGRI invited applications that “propose to explore the implications, 
challenges and opportunities associated with the possible use of genomic sequence information in 
the newborn period”. The funding agencies recognized that the “new, sophisticated and increasingly 
cost-effective techniques for DNA-based sequencing and analysis may make it possible to expand 
newborn screening in the future and substantially expand its clinical and public health value”. Our 
group applied for funding under this RFA and our proposal was funded through a cooperative 
agreement (U19). This IRB protocol presents the work to be undertaken. 
The clinical use of genetic tools in the newborn period is currently being approached from 
two directions. First, as noted above, clinical sequencing is being increasingly used in ill children, 
including newborns, to more rapidly and accurately make a diagnosis and guide treatment. For 
example, Children’s Mercy Hospital in Kansas City has pioneered rapid sequencing for infants in 
the NICU.16 Secondly, most disorders screened in state-mandated dried blood spot newborn 
screening are genetic in origin. While the testing for these disorders is largely performed using a 
primary tier of biochemical and tandem mass spectrometry based assays, a few disorders currently 
incorporate DNA based genetic testing in a second testing tier (Cystic Fibrosis, Galactosemia, 
Medium Chain CoA Dehydrogenase Deficiency), and there is rapidly increasing potential for 
expanding this approach. In addition, state-mandated newborn hearing screening is increasingly 
benefiting from second tier genetic testing panels that identify sequence variants in genes 
associated with syndromic and nonsyndromic hearing impairment.17-21 While the broad application 
of genomic sequencing as a primary approach in state-mandated newborn screening is likely far off 
due to costs and controversies surrounding its implementation in a public health program, the 
elective application of this technology as a primary screen or diagnostic tool for sick and well 
newborns may be increasingly imminent and is deserving of study. 
 
Current Clinical Standards  
 
Diagnostic genetic testing (single gene, gene panel, or whole exome/genome sequencing) is 
currently accepted in clinical pediatric care under the following circumstances: 
• 
Diagnosis of symptomatic children thought to have a genetic disorder22-26 

 
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• 
Follow-up or confirmatory testing of children identified on state-mandated biochemical 
newborn screening as at risk for having a genetic disorder27-30  
• 
Selection of treatments in cancers, including childhood cancers31-33 
 
 
Predictive or predispositional genetic testing of children with single gene assays is currently 
accepted in clinical pediatric care where there is a strong family history or identified familial 
mutation for a child onset disorder, or where identifying a genetic risk for an adult-onset disorder 
might lead to preventative interventions during childhood.  
 
A major difference between whole exome or genome sequencing and targeted testing is the 
potential in the former for discovering incidental or secondary findings unrelated to the indication for 
the sequencing but of potential medical importance for clinical care. The American College of 
Medical Genetics (ACMG) has recommended that laboratories that perform whole exome or 
genome sequencing in the clinical setting search for and report on a targeted set of such incidental 
or secondary findings, i.e. pathogenic variants in a list of 56 genes for conditions where the 
individual may be asymptomatic for a long time and where intervention has been clearly 
demonstrated to be efficacious.34 This list includes genes for a number of conditions that are of 
adult-onset, and the ACMG recommends return of these findings in children, regardless of age, as 
the findings in the child may have important implications for the health of the parent.  
 
Most, if not all, commercial laboratories that perform clinical diagnostic testing using whole 
exome or genome sequencing report on the 59 genes recommended by the ACMG. For example, 
the molecular genetics laboratory at Baylor College of Medicine has sequenced well over 2000 
cases, of whom 83% were children and 27% were under 5 years of age (personal communication, 
Dr. Christine Eng). The Baylor lab routinely reports pathogenic variants in the 59 genes 
recommended by the ACMG, recessive carrier variants and pharmacogenomic variants with an 
option for opt-out; and less than 10% of patients or parents elect not to receive these findings. At 
Baylor, physicians may also choose to order an “Expanded Report” that has an even wider array of 
genes screened for deleterious mutations, including treatable adult onset conditions, which has 
been ordered by 26% of the physicians using this service so far.23,35 Partners Healthcare Laboratory 
for Molecular Medicine has issued over 25,000 genetic test reports in the past 10 years, and over 
45 clinical whole genome sequencing reports in the past year that include carrier and 
pharmacogenomic variants and are being included in the Partners medical records. Thus, clinical 
laboratories across the country are already returning incidental or secondary genomic results in 
children related to highly actionable conditions, including adult-onset conditions. Our study is 
consistent with these practices. Our protocol is designed to apply current best medical practices in 
a randomized trial and study the clinical, behavioral, attitudinal and economic outcomes of the 
application of genomic sequencing in the practice of medicine. While genomic sequencing is a new 
technology, the results gleaned from genomic sequencing that will be returned in this protocol are 
conceptually similar to the types of medical information that are currently returned to parents in the 
clinical care of newborns. In addition, while caution has been advocated in providing predictive 
genetic testing in children due to concerns that it could damage the parent-child bond,36 creating 
vulnerable “patients in waiting”,37 there is little evidence to support any harm and this assessment of 
potential harms will be a focus of our study. In this project, we will collect medical, behavioral and 
economic outcomes related to the return of genomic sequencing information to the physicians and 
parents of newborns to better inform the imminent future when this technology will be widely 
available.  
 
 
Prior Research/Preliminary Data 
 
MedSeq Project 

 
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The MedSeq Project (PI Dr. Green) is an NIH-funded U01 award that began in December, 
2011.  The MedSeq Project enrolls only adults, but is otherwise very similar to this Project in that 
patients with genetic disease (hereditary cardiomyopathy) and healthy middle aged adults are 
enrolled in a randomized trial to receive either standard of care, or standard of care plus genomic 
sequencing.  As of this writing, the MedSeq Project has nearly completed its planned enrollment of 
100 patients with cardiomyopathy and 100 healthy middle-aged adults.  The LMM (led by co-PI Dr. 
Heidi Rehm) is generating clinical sequencing reports for the MedSeq Project and will do so as well 
for this Project.  44 sequencing reports have been processed and 24 returned thus far to 
cardiologists and primary care physicians caring for these individuals. The MedSeq Project has 
generated tremendous amount of preliminary data.52,200-226   In the MedSeq Project, there has been 
careful monitoring of both psychological and medical outcomes and thus far, there have been no 
adverse events in the MedSeq Project.  
In this Project, we will be using the same criteria for variant classification and reporting as is 
used in clinical analysis and reporting by the LMM, and in the MedSeq Project, except that variants 
will not be analyzed or reported in genes that are exclusively associated with adult-onset conditions.   
 
Pilot Survey 
In anticipation of our plan to recruit the parents of healthy newborns from the BWH Well 
Newborn Nursery, we conducted a survey of 514 parents within 48 hours after the birth of their 
child. These data indicate that the vast majority of parents (82.7%) reported being somewhat to 
extremely interested in genomic testing for their newborns. 227 None became confused about or 
refused standard NBS.  We asked some of these parents, as well as other parents, the same 
questions 3-24 months after the birth of their infant and their answers were similar.  In particular, 
less than 1% of parents who answered that they were very or extremely interested while in the 
hospital, answered that they were not at all interested at a later date indicating that parental choices 
made on the Newborn Unit appear to be stable.228 
 
 
Manton Center 
The Manton Center for Orphan Disease Research (Director Dr. Beggs) was established in 
2008 with the goals of developing better diagnostic tests and treatments for rare diseases and 
discovering fundamental biological principles that can lead to advances in understanding of 
common diseases. The Gene Discovery Core (GDC), a human research protocol approved by the 
Boston Children’s Hospital (BCH) IRB, was established to help accomplish these goals. Under the 
GDC (medical director, Pankaj Agrawal), patients are enrolled for exome sequencing and other 
molecular analysis, including gene expression assays, protein functional analysis and cell line 
creation, with the aim of identifying the underlying cause of the child's medical problems. To date, 
more than 2,000 individuals have been enrolled in the GDC, and many families with infants in the 
BCH NICU have been successfully approached and enrolled.  Of the families approached, less than 
7% declined participation in the study. As part of Dr. Holms’ project “Returning Research Results in 
Children: Parental Preferences and Expert Oversight” (R01HG006615) her group interviewed 9 
parents of 6 children who received a genetic diagnosis as a result of the GDC's work about their 
experience. All families reported having a positive experience with the project and the return of 
results (personal communication, Dr. Holm). Interestingly, the parents who expressed more 
negative feelings towards their child's diagnosis expected more actionable change after the 
molecular cause was identified. This highlights the need for additional projects to look at the 
outcomes of a genetic diagnosis in a child. 
 
Standards Development in Clinical Practice 
A number of investigators in this Project have been on the forefront of developing clinical 
and research standards in human sequencing.  Drs. Green and Rehm have published recent 
summaries on the use of sequencing in clinical care.4,25,229-231 Drs. Green, Rehm and McGuire, and 

 
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External Advisory Board members Drs. Biesecker and Korf, were all members of the ACMG 
Working Group on the return of incidental findings.34,232-234 These findings advocated that a small 
set of incidental findings be returned to patients of any age, including conditions associated with the 
with highly actionable adult onset conditions. The Project team has elected to return genetic 
information relevant to childhood onset conditions in addition to the small subset highly actionable 
adult-onset conditions.  
Dr. Green was part of an ELSI grant that made recommendations for the return of genetic 
information in research biobanks,235 and is currently part of a separate but similar team creating 
recommendations for the communication of genetic results to family members after the death of an 
individual whose DNA is sequenced as part of a research study.236,237 Dr. Rehm is highly active in 
publishing standards for the utilization of clinical sequencing, 88,238-241 and is co-chair of the ACMG 
Working Group that has created new guidance on the clinical interpretation and reporting of 
sequence variants as presented at the ACMG annual conference in March 2014 and will be 
published shortly. Dr. Rehm is also one of nine principal investigators leading the new NHGRI-
funded Clinical Genome Resource (ClinGen) program that will create standardized and shared 
resources to support the interpretation and use of DNA sequencing data for clinical care. This 
includes a centralized and public database, called ClinVar95, for sharing clinically curated variants 
as well as additional resources provided through a new database called ClinGenDB to enable gene 
and variant curation as well as access to patient data for discovery. Over 85,000 clinically 
interpreted variants have already been shared through ClinVar 
(http://www.ncbi.nlm.nih.gov/clinvar). 
Dr. Agrawal has been utilizing WES/WGS technologies in neonates and children whose 
diagnosis remains unknown despite extensive clinical work up as part of Gene Discovery Core. His 
team has successfully determined the genetic cause of disease for many such families.129,199,242-244 
Dr. Parad introduced multi-mutation DNA testing into CF Newborn Screening, edited a 
supplement to Journal of Pediatrics summarizing the CDC workshop that proposed the 
implementation of CF newborn screening in the US,116 and has co-authored the major 
implementation publications and guidelines for CF IRT/DNA newborn screening algorithms.119,120 
 
Rationale for this Research Project 
 
We believe genomic sequencing can provide substantive benefits to children and their 
parents in the newborn period. We have designed this pilot experiment to explore the impact of 
clinical sequencing in families that desire this information after genetic counseling.  In our study, 
sequencing will be ordered by study physicians who will maintain a clinical relationship with the 
families. 
 
Rationale for Elective Sequencing of Healthy Newborns Born at BWH 
We believe that in rare cases, newborn sequencing will offer an opportunity to discover life-
saving benefit if a pathogenic mutation associated with a treatable childhood condition is uncovered 
early. In addition, pre-symptomatic detection of an affected child or carrier detection will provide the 
possibility of an early warning for management of initial symptoms and future reproductive planning 
for that infant’s family, even if related to childhood diseases that are not treatable. Genomic 
sequencing of healthy babies may become commercially available as the price of sequencing 
declines, and is already being implemented in various health systems.245 Genomic sequencing of 
fetal DNA is also being discussed and may soon be implemented in limited situations (personal 
communication, Drs. Louise Laurent and Diana Bianchi). Thus, we believe that it is critically 
important to systematically study the behavioral, clinical and economic outcomes associated with 
elective sequencing of healthy newborns. 
 
Rationale for Elective Sequencing of Sick Newborns at BCH and the BWH NICU 

 
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A significant portion of newborns in the Neonatal Intensive Care Unit (NICU) and other 
inpatient floors have undiagnosed genetic diseases. Currently, genetic tests are largely sent test by 
test as symptoms develop, delaying diagnosis and appropriate care. Whole exome or whole 
genome sequencing is already being ordered through commercial laboratories for some of these 
cases. For example, there have been at least 69 cases at Boston Children’s Hospital so far where 
clinical whole exome sequencing (WES) has been ordered. Genomic sequencing immediately after 
birth offers an opportunity to make the appropriate diagnosis faster and offer appropriate care more 
quickly to these infants, potentially lowering hospitalization costs. As additional symptoms develop 
(e.g. an infant with liver abnormalities may later develop seizures) the existing sequence can be re-
interrogated rapidly rather than ordering new tests that may take weeks to return.  
 
Utilizing Study Physicians to Deliver Consultations 
 
Throughout this protocol, the term “study physician” will be used to indicate physicians who 
will be providing medical consultations to the families at each study site based on the information 
provided in the two arms of the study. This will typically be Drs. Richard Parad and Joel Krier at 
BWH and Drs. Pankaj Agrawal, Ingrid Holm and Harvey Levy at BCH. The term “non-study 
physicians” is used in this protocol to indicate any physicians caring for the participating infants who 
are not part of the study staff. 
 
 
 
 

 
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SPECIFIC AIMS/RESEARCH OBJECTIVES 
 
The objective of this research protocol is to conduct a pilot randomized clinical trial to assess 
the benefits and risks of adding the information from a genomic sequencing report to physician-
mediated medical care of newborns during their pediatric years. 
 
Aim 1: We will recruit, obtain parental consent and enroll 240 healthy neonates at BWH and 
240 sick neonates at BCH or the BWH or MGH NICU and their parents, randomize them 
within each cohort to either standard-of-care (family history and standard newborn 
screening report) or to standard-of-care plus genomic sequencing. Samples for DNA 
analysis will be collected and forwarded to the clinical laboratory.  
 
Aim 2: A study physician and genetic counselor will meet with each family for a medical 
consultation and physical exam of the infant as appropriate, including discussion of the 
family history and standard newborn screening report. For infants randomized to the 
genomic sequencing arm, the consultation will also incorporate a clinical genomic report 
of CLIA certified sequencing with Sanger confirmation of positive findings. Genomic 
reports will be included in the patient’s chart and sent to physicians involved in the 
infant’s care. 
 
Aim 3: The research team will administer measures of clinical outcomes, behavioral 
responses and healthcare utilization to families enrolled in both arms, while providing 
careful monitoring for the safety of parents and newborns. 
 
Aim 4: The research team will administer surveys to neonatal physicians and community 
physicians regardless of whether or not they are caring for infants whose families have 
enrolled in this study. In addition, physicians who receive genomic reports through the 
study will be surveyed about their understanding and utilization of the genomic reports.  
 
INCLUSION/EXCLUSION CRITERIA 
 
Newborns and Parents at BWH:  
 
Inclusion criteria:  
1) Infants born at BWH and admitted to the Well Newborn Nursery  
2) At least one biological parent is physically available to have genetic counseling, donate 
DNA, and provide consent for testing the infant. If the second biological parent is known but 
not physically present, the second biological parent must be available to have genetic 
counseling by phone, return a signed consent form by mail, and donate DNA via a mailed 
saliva kit. If there is a “rearing parent” (an individual who is not biologically related to the 
infant, but who is dedicated to raising the child), that individual must also provide consent 
but will not be asked to submit a saliva sample.  
3) Mother (either rearing or biological) carried the pregnancy 
 
Exclusion criteria: 
1) Parents are non-English speaking. (As the study progresses, we will explore the option of 
translating study materials into Spanish.) 
2) Parents are unwilling to have genomic reports placed in the medical record or sent to their 
primary care pediatrician 
3) Mother or father younger than 18 years of age 
4) Mother or father with impaired decisional capacity 

 
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5) Age of infant is older than 90 days  
6) One of a multiple gestation  
7) Any infant in which clinical considerations preclude drawing 1.0 ml of blood 
8) Missing consent of either biological parent (if known) or rearing parent (if applicable) 
 
 
Sick Newborns and Parents at BCH or the BWH or MGH NICU:  
 
Inclusion criteria: 
1) Infants admitted to BCH or the BWH or MGH NICU  
2) At least one biological parent is physically available to have genetic counseling, donate 
DNA, and provide consent for testing the infant. If the second biological parent is known but 
not physically present, the second biological parent must be available to have genetic 
counseling by phone, return a signed consent form by mail, and donate DNA via a mailed 
saliva kit. If there is a “rearing parent” (an individual who is not biologically related to the 
infant, but who is dedicated to raising the child), that individual must also provide consent 
but will not be asked to submit a saliva sample.   
3) Mother (either biological or rearing) carried the pregnancy 
 
Exclusion criteria: 
1) Parents are non-English speaking. (As the study progresses, we will explore the option of 
translating study materials into Spanish.) 
2) Parents are unwilling to have genomic reports in the medical record or sent to their primary 
care pediatrician 
3) Mother or father younger than 18 years of age 
4) Mother or father with impaired decisional capacity 
5) Age of infant on admission is older than 90 days  
6) One of a multiple gestation  
7) Any infant in which clinical considerations preclude drawing 1.0 ml of blood 
8) Hospital admission expected to be less than 72 hours 
9) Missing consent of either biological parent (if known) or rearing parent (if applicable) 
10)  Previously performed exome/genome sequencing on patient 
 
RESEARCH DESIGN AND METHODS 
 
This is a randomized clinical trial evaluating infant and family outcomes, as well as physician 
outcomes, after participation in one of two types of medical consultation. Overall design is 
summarized in Figure 1. Figure 2 summarizes the proposed details of study participation for parents 
and infants. Figure 3 summarizes the proposed details of study participation for physicians. The 
study has been registered on clinicaltrials.gov. 
Specific methods for each Aim are described below. 
 
Aim 1: We will recruit, obtain parental consent and enroll 240 healthy neonates at BWH and 
240 sick neonates at BCH or the BWH or MGH NICU and their parents, randomize them 
within each cohort to either standard-of-care (family history and standard newborn 
screening report) or to standard-of-care plus genomic sequencing. Samples for DNA 
analysis will be collected and forwarded to the clinical laboratory.  
 
1.1.1  Recruitment of Healthy Neonates and Families at BWH 
In an effort to provide potential participants the opportunity to learn about our study in the 
prenatal period, we have created an educational brochure that will be placed in obstetrics practices 

 
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and offices that traditionally have a significant number of patients deliver at BWH (please see the 
attached ‘Genomic Sequencing for Childhood Risk and Newborn Illness Study Brochure’). This 
brochure will include an overview of the study along with the contact information of a study team 
member who will be available to answer any questions potential participants may have about the 
study. We may also present at prenatal classes at BWH to provide families planning to deliver at 
BWH with more information before their hospital stay. We will track which of our participants 
received the educational materials prenatally via questions incorporated into the consent 
discussion. The research study will be introduced to obstetricians through presentations by Dr. 
Richard Parad (see attached “OB Presentation Slides”).  These presentations will give obstetricians 
a background on the project and provide them with contact information for study staff. 
The Department of Pediatric Newborn Medicine at BWH recently hired a Nursery 
Recruitment Research Assistant (RA) to coordinate recruitment in the Well Newborn Nursery 
across multiple research studies, ensuring that parents are only approached about participation in 
appropriate studies and are not overwhelmed by competing offers of enrollment. The Nursery 
Recruitment RA will be trained on our study’s eligibility requirements. After obtaining permission to 
approach parents from the mothers’ Well Newborn Nursery care team, the Nursery Recruitment RA 
will share with parents our Study Brochure (see attached study brochure) and will notify our study 
RA of any parents who express interest in learning more about our study. Our study RA and/or 
genetic counselor will then visit these families in the BWH Well Newborn Nursery and provide more 
information, as detailed below in the Enrollment and Consent section. Preliminary data to support 
the feasibility of recruiting parents while they are inpatients in the immediate post-natal period were 
provided in the previous section on Prior Research/ Preliminary Findings. 
 
1.1.2  Recruitment of Sick Neonates and Families from BCH, BWH and MGH 
Study staff will check in daily with floor clinical staff at each respective hospital to identify 
neonates who were admitted in the past 24-48 hours and who meet the enrollment criteria for the 
study.  For the most part, we will be enrolling all-comers to the BCH inpatient floors and BWH and 
MGH NICU, however we will enrich for a wide-variety of admission reasons and for neonates who 
will spend a longer period of time at BCH/BWH/MGH. We are excluding neonates if they are 
expected to be admitted for less than 72 hours to better fit with our recruitment plan.  The goal is to 
give parents ample time to consider participation.  
After obtaining permission to approach parents from the attending clinical staff, a research 
assistant and/or genetic counselor will approach the parents with the clinical staff to provide a copy 
of the Study Brochure and consent form and answer any initial questions the parents may have. 
Parents who speak to a study staff member and decline participation will be asked if they are willing 
to complete our “decliner form” and/or our “decliner survey” to better understand parents’ reasons 
for decline.   
 
1.2  Pre-enrollment Informational Session and Consent at BWH, MGH, and BCH 
 
An informational session will be scheduled with the parents of both healthy and sick 
newborns who express interest in participating in the study. The genetic counselor (Ms. Genetti, Mr. 
Fayer, or Ms. VanNoy) will meet with the parents, verify their interest in participating in the study 
and initiate the consent process.   
 
In the Pre-enrollment Informational Session, parents will learn from the genetic counselor 
about genetics and genomic sequencing, the study protocol, and the benefits and risks of 
participation, and will have opportunities to ask any questions that they may have. The study 
genetic counselor will discuss the following topics in detail with parents: 
• 
Each infant will be randomly assigned to receive a medical consultation with a study 
physician, in which their infant will be evaluated. Based upon the randomization, this 
consultation will utilize the family history and standard newborn screening report, with or 
without genomic sequencing. There is a 50% chance for each infant to be assigned to the 

 
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group that receives genomic sequencing. 
• 
Genomic sequencing will be limited to one infant per family; parents and other relatives will 
not be sequenced (although parent DNA will be collected in the form of a saliva and/or blood 
sample to be available if needed for targeted confirmation to interpret the infant’s results). 
• 
Brief overview of genetic principles, sequencing and sequence variants/mutations 
• 
Genome-scale sequencing is a new technology and the interpretation of genomic sequence 
results is an evolving science.  Therefore, interpretations made by the clinical team are not 
certain to be accurate or complete 
• 
Sequencing is not a substitute for all types of genetic testing and is not guaranteed to find all 
genetic abnormalities, including known genetic conditions in the family 
• 
The genome reports generated as part of this protocol may provide 5 types of information: 
o Mutations in genes that are associated with childhood-onset recessive diseases, for 
which the newborn is likely a carrier and therefore disease is not expected unless a 
second mutation was missed or not interpretable 
o Mutations for disease predisposition that could be of medical importance during 
childhood for the infant 
o Variants that provide pharmacogenomic information about a selected number of 
agents that are used in the childhood period for treatment 
o ABO and D blood types, plus clinically relevant antigen typing 
o Mutations in genes that are associated with highly actionable adult-onset conditions.  
 
Highly actionable adult-onset genetic conditions are defined as those that are 
likely to be asymptomatic in the childhood period (with onset at the age of 18 
years and older) for which screening and surveillance are available and for 
which treatment or prophylactic measures may be offered. 
 
Guidelines for determining reportable highly actionable adult-onset conditions 
will be based on the American College of Medical Genetics and Genomics 
recommendations regarding reporting of secondary findings in clinical 
sequencing. This ACMG list currently includes 59 genes, 6 of which are 
exclusively adult-onset, and we will adhere to these principles of high 
actionability in selecting genes for return.  
• 
At least one parent must complete the baseline survey within 14 days of enrollment in order 
for the family to continue participating in the study 
• 
The newborn will be followed by a study physician/genetic counselor team who will interpret 
the findings for the parents, and who will provide a clinical report that will be placed in the 
medical record and sent to the newborn’s non-study physician(s) 
• 
Results may have medical implications for other members of the family 
• 
Non-paternity will not be specifically tested for, and if inadvertently discovered, will not be 
disclosed to the family unless considered of medical importance to the health of the family 
• 
Parents and children have legal protections against employment and health insurance 
discrimination under the Genetic Information Non-Discrimination Act (GINA), but GINA does 
not cover life, long-term care, and disability insurance. However, in Massachusetts, there is 
a law (175 §120E) which extends protections to address life, long-term care, and disability 
insurance. If a family were to move out of the state, to another state without a similar law, 
these same protections may not be available. Further, we cannot predict how these laws 
may change before the infant reaches the age of maturity 
• 
In some cases, a finding may prompt follow-up physician visits or testing, some of which 
could incur out-of-pocket expenses that would not be covered by the study 
• 
The raw sequence data will not be returned to study participants or placed in the medical 
record at the time of disclosure 
• 
If the family history obtained during the baseline visit suggests that targeted genetic testing 

 
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for a Mendelian condition should be pursued, the family will receive additional genetic 
counseling, and may be referred for clinical genetic counseling and/or targeted testing for 
this indication 
• 
If parents ask to withdraw their family’s samples and infant’s genomic data from the study, 
any genomic reports on their infant that have already been placed in the electronic medical 
record at BCH, BWH or MGH will have become part of clinical care, and cannot be deleted 
or withdrawn. Any sequences or data that have been uploaded to shared databases such as 
the Database of Genotypes and Phenotypes (dbGaP) cannot be withdrawn.  
• 
Outcome measures will assess parental depression and anxiety. If any participants’ scores 
exceed pre-defined cut-offs, a study physician, genetic counselor, or study psychologist may 
reach out to them. We may alternatively, or in addition to, be discussing their survey 
answers with appropriate clinicians involved in their care.  
 
After completing the Pre-enrollment Session, if parents are unsure and prefer additional time 
to decide about participation, a follow-up conversation will be scheduled. If parents decide that they 
are ready to participate, they will both be asked to answer questions that assess their 
understanding of the information that the genetic counselor has discussed with them focused on the 
topics of 1) the purpose of the study, 2) what is involved in participation; 3) expected outcomes and 
4) possible risks and benefits (please see attached ‘Consent Understanding Questions’). The 
genetic counselor will review any incorrect responses with parents to ensure that they understand 
all critical aspects of study participation; then parents will be asked again to respond to any 
questions that they originally answered incorrectly. Once parents are able to answer all questions 
correctly, they will have the option of enrolling in the study. 
Parents who decide to enroll will sign the consent form for the infant’s participation and to 
allow the study team to review medical records from all medical providers of the infant (including the 
mother’s prenatal records). We will also be accessing billing information from state and institutional 
databases. Parents will also be asked to sign the consent form for their own enrollment (i.e. consent 
to complete surveys and saliva/blood samples for DNA collection). If both biological parents are 
known we will obtain consent from both parents for their infant’s participation, and will obtain saliva 
and/or blood samples from both. We will attempt to consent both parents at the same time, however 
if after exploring several time options, only one parent is available for a consent session prior to 
discharge, we may collect samples from an infant before obtaining consent from the second parent.  
We will then follow up with the second parent to obtain consent.  If they choose not to enroll, or if a 
consent session cannot be organized in a reasonable amount of time, the family will be removed 
from our study. No samples will be sent for analysis until verbal and written consent is obtained 
from both parents (if applicable). If a non-biologically related parent will be rearing the child (e.g. if 
the biological mother has committed to raising the child with someone other than the child’s 
biological father) that individual will also be asked to provide consent for the child’s participation but 
will not provide a DNA sample. Rearing parents will also be asked to complete study surveys.  
For families at both BWH, MGH, and BCH, while we will attempt to complete all consent 
sessions and sample collection prior to discharge of the infant/mother, in some cases, this is 
prohibited by time constraints.  If a family has been approached by our study RA and/or genetic 
counselor and has expressed interest in completing the Pre-enrollment session, but a session 
cannot be scheduled prior to discharge, they will be given the option of returning to either BWH or 
BCH, to complete enrollment at a later date. If they are willing to return, they will participate in the 
Pre-Enrollment Informational Session and sample collection process as detailed above.  
We plan to access medical records and send annual surveys until the infant reaches age 18 
to best capture the effects of genomic sequencing on the entire pediatric period (if the study is still 
ongoing).  Given the long-term nature of the project, if the study remains active, we will contact the 
family after the child’s 13th birthday to obtain assent, and after the child’s 18th birthday to obtain 
consent from the participant.  If we are unable to reach the family and obtain assent/consent from 

 
12
the participant, we will withdraw them from the study.  In some cases, the participant may not be 
cognitively able to provide assent or consent, in which case we will discuss continued participation 
with the parents, document the child’s cognitive ability and obtain documentation of the parent’s 
legal health care proxy status (in the instance that the child turns 18 years).    
A detailed family history will be obtained by the genetic counselor at this stage of enrollment. 
The family history will be utilized later by the laboratory and the consultation team in the 
interpretation and contextualization of the sequencing report, and in the event that the family history 
suggests that a more targeted form of genetic testing should be pursued (such as a family history 
suggestive of Lynch syndrome in the parents), the family will receive additional genetic counseling, 
and may be referred for clinical genetic counseling and/or additional targeted genetic testing for this 
indication. 
**For families who consented to the study prior to the addition of adult-onset findings, and are 
part of the sequencing arm:  
A mailing will be sent out to those families who have already completed their disclosure with a cover 
letter and addendum consent form (see attached). The letter will request that families interested in 
learning more about the actionable adult onset disclosure call study staff to set up a verbal consent 
call. The letter also contains language that states if we do not hear from them with in 2 weeks, a 
member of the study staff will call to assess interest. Uninterested families may also notify the study 
staff by phone or email.  
 
Families who have not yet returned for disclosure will either receive a letter prior to disclosure or will 
be introduced to the addendum consent option at their disclosure session, depending on time 
allowance. Written consent will be obtained for families who choose to receive these results. We will 
require one consent form to be signed by both parents as well as the investigator (genetic 
counselor) who obtains the verbal consent. Verbal consent may be obtained via phone or in person.  
 
As is required for the study in general, both parents must agree to consent to this new class of 
findings. If there is disagreement between the parents the default will be to NOT consent. If a parent 
feels strongly that they want this information for themselves, the study team is happy to refer them 
for clinical evaluation where they can obtain genomic screening through clinical consent. This 
discussion with and among the couple will be mediated by a study genetic counselor who is trained 
to facilitate these types of genetic testing decisions. 
 
A specific script will not be utilized for the verbal consent. However it will be completed by a genetic 
counselor and will touch on the following points:  
• 
Study now allows for the return of a subset of adult onset conditions that are known to be 
highly actionable through treatment and screening. 
• 
Examples of these conditions include a significantly increased lifetime risk for breast or 
colon cancer or certain types of highly heritable heart disease. These do not include 
classes of conditions like  Alzheimer’s disease and other adult onset neurodegenerative 
disorders, since there is little clinical actionability for these conditions in terms of screening, 
prevention and treatment.  
• 
As with the previous consent, both parents must agree 
• 
They may learn this information about themselves as well as their infant. Results must first 
be found in the infant. Parental results will be reported on the infant’s GNSR and will not be 
placed by study staff into the parent’s medical record.  
• 
Review of the risks discussed in the original consent  
• 
Parents are permitted to change their mind at anytime 
• 
Results disclosed reflect our current knowledge of these conditions at the time of 
disclosure, it is possible that new genes or disorders in this category will be discovered in 

 
13
the future and will not be reflected in the report. We will not regularly be reviewing an 
infant’s data to account for such discoveries outside the context of an Indication Based 
Analysis ordered for the infant.  
 
Disclosures for positive results will be completed in person with project genetic counselor and 
physician. Negative results can be done over the phone or in person. 
  
 
1.3  Sample Collection  
 
After receiving permission from the inpatient clinical staff to draw blood, a blood sample 
(through a venipuncture or heel stick) of no more than 1.0 ml may be obtained from each enrolled 
infant. Alternatively, when possible, blood and/or cord blood samples already obtained for clinical 
reasons may be retrieved. In the case that the blood collection for an infant does not yield enough 
DNA for sequencing, we would offer to bring the family back in for a second blood draw should they 
agree to one. This second blood draw will again be approximately 1.0 ml and will be performed by 
clinicians specialized in blood drawing in newborns. We will only draw an additional sample if the 
infant is in the sequencing arm, so that infants in the control arm are not exposed to unnecessary 
risk. These samples will be shipped to the Laboratory for Molecular Medicine (LMM) or other CLIA 
compliant clinical diagnostic facility. Buccal swab samples from the infant, and saliva and/or blood 
samples (approximately 7.0 ml of blood) from both biological parents (if available), will be collected 
and stored at the LMM. Saliva samples or an additional sample (blood, cord blood, or other 
samples already obtained for clinical reasons) will be used if needed for quality control or Sanger 
confirmation of sequence results, or to facilitate the interpretation of results in the newborn (via 
metabolic, biochemical or other analytical testing). Discarded samples, if available and anonymized, 
may be used for other research studies.  
Samples will be collected from all infants and parents enrolled, regardless of the arm to 
which they are assigned, in order to follow the same protocol for all subjects prior to randomization. 
 
1.4  Randomization 
 
Infants within each cohort will be randomized (1:1) to either standard-of-care (family history 
and standard newborn screening report) or to standard-of-care plus genomic sequencing. 
 
Aim 2: A study physician and genetic counselor will meet with each family for a medical 
consultation and physical exam of the infant as appropriate, including discussion of the 
family history and standard newborn screening report. For infants randomized to the 
genomic sequencing arm, the consultation will also incorporate a clinical genomic report 
of CLIA certified sequencing with Sanger confirmation of positive findings. Genomic 
reports will be included in the patient’s chart and sent to physicians involved in the 
infant’s care. 
 
2.1  Genomic Sequencing and Reporting 
Genomic sequencing of infants randomized to the sequencing arms will be conducted in a 
CLIA approved sequencing laboratory. Additional genetic testing may be used to help with data 
interpretation and confirmation (for example, chromosomal microarray or Sanger sequencing). Data 
interpretation and individual variant confirmation with Sanger sequencing will be performed at the 
LMM. Variant classification will be based upon current medical practice standards in the laboratory 
for targeted gene panels and other clinical sequencing.88 
 
2.1.1  Genes to be Interrogated and Reported 
When conducting clinical sequencing, the LMM software interrogates approximately 5,000 
disease-associated genes across panels, exomes and genomes. In this protocol, we will restrict our 

 
14
analysis and reporting to approximately 1,751 genes that have been linked to childhood-onset 
diseases (hereafter referred to as Childhood Onset Gene List and see Appendix 1), in addition to a 
small subset of genes (including but not limited to: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, 
and EPCAM) that meet ACMG criteria for highly actionable adult-onset conditions. We will not be 
reporting on genes that are only associated with adult-onset conditions that are not considered to 
be highly actionable such as those for neurodegenerative conditions that have no options for 
prevention or amelioration. 
Before reporting, all genetic variant findings will be confirmed by Sanger sequencing, as per 
standard clinical practice, prior to being included on a report and returned to clinicians and families. 
We may test the parental DNA to confirm/ determine inheritance of a result found in a child. These 
results will be reported on the child’s GNSR. We will not test parental DNA for findings that were not 
first identified in the child. 
Results disclosed will reflect current knowledge of these conditions at the time of disclosure, 
it is possible that new genes or disorders will be discovered in the future and will not be reflected in 
the report. We will not regularly be reviewing an infant’s data to account for such discoveries 
outside the context of an Indication Based Analysis ordered for the infant.  
 
2.1.2  The Genomic Newborn Sequencing Report 
For both sick and healthy infants, a “Genomic Newborn Sequencing Report” (GNSR) will be 
generated that will follow a format already being utilized clinically by the LMM, and in the MedSeq 
Project52 but with modifications to include only genes associated with childhood onset conditions 
and a small subset of highly actionable adult-onset conditions (see example in Appendix 2). 
Separate sections on the GNSR will indicate results under the following headings: 
 
Monogenic Disease Risk: After Sanger confirmation, we will report pathogenic or likely 
pathogenic variants in conditions from the Childhood Onset Disease Gene List (see Appendix 1) 
that are in heterozygous state and are associated with autosomal dominant or X-linked disorders, in 
homozygous or compound heterozygous state and are associated with autosomal recessive 
disorders, or in hemizygous state and are associated with X-linked recessive disorders. 
 
Highly Actionable Adult-Onset Monogenic Disease Risk: After Sanger confirmation, we will 
report pathogenic or likely pathogenic variants in highly actionable adult-onset conditions as 
characterized by the ACMG recommendations that are in heterozygous state and are associated 
with autosomal dominant or X-linked disorders, in homozygous or compound heterozygous state 
and are associated with autosomal recessive disorders, or in hemizygous state and are associated 
with X-linked recessive disorders.   
 
Carrier Risk: After Sanger confirmation, we will report pathogenic or likely pathogenic 
variants in conditions from the Childhood Onset Disease Gene List (see Appendix 1) that are in 
heterozygous state and are associated with recessive disorders.  
 
Pharmacogenomic Associations: After Sanger confirmation, we will report pathogenic 
variants in two genes associated with potentially severe complications from specific medications: 
Glucose-6 Phosphate Dehydrogenase Deficiency (G6PD gene) and Malignant Hyperthermia (RYR1 
gene). As more is known about pharmacogenomics, additional genes may be reported on, but only 
if they are related to medications which may reasonably be given in childhood and if the variants 
are in the PharmGKB Class I or II categories.  
  
Blood and Platelet Antigen Types: After confirmation by conventional serological testing, we 
may return ABO and D blood types, plus clinically relevant platelet antigen typing detected through 
sequencing and confirmed on an FDA-approved chip. 

 
15
 
2.1.3  The Indication-Based Analysis 
For sick babies who have clinical presentations where a genomic analysis may be helpful for 
diagnosis or treatment of a particular presentation, and in the event that one of the healthy babies 
becomes ill with symptoms that warrant such analysis, an “Indication-Based Analysis” (IBA) will be 
generated in response to requests by the baby’s physicians in consultation with the study 
physicians, or by the study physicians. The IBA will include interrogation of disease-associated 
genes associated with the syndrome or clinical features in question as currently practiced in 
medical genetics. In addition, upon request, an IBA may additionally include Evidence Class I and II 
variants from PharmGKB246 for specific indications (e.g. anti-epileptic medication in neonates with 
seizures). Examples of the IBA are shown in Appendices 3 and 4. For every situation in which an 
IBA is requested, the study physician will be in communication with the clinical team or physician 
ordering the IBA and will make sure that a re-query of the genomic sequence is not ordered in lieu 
of a targeted genetic test or panel that would be more appropriate for a specific presentation. 
 
2.2  Obtaining the Standard Newborn Screening Report 
The standard NBS report, by state mandated regulation, is returned to the birth hospital of 
each newborn. For the BWH Well Newborn cohort, the study physician will obtain this standard 
NBS at BWH. Standard NBS is typically repeated on infants admitted to BCH/the BWH or MGH 
NICU and is part of the active chart for sick babies. The study physician will obtain the NBS reports 
for the BCH/BWH/MGH NICU subjects. In both sick and healthy infants, if reports are not available 
in the subject’s hospital chart, they may be requested from the New England Newborn Screening 
Program Laboratory by a study physician. For all infants who were born outside of Massachusetts 
and transferred to BCH, NBS is performed at the time of admission, and a report is issued to BCH.  
Reporting of NBS results to families will occur through their pediatrician, as part of their normal 
clinical care. For the purposes of our study, we will be obtaining the reports and reviewing them with 
families at the time of result disclosure, which will happen after any positive results have been 
disclosed to families by their clinician (see next section).   
 
2.3  Consultation and Disclosure of Randomization Status and Reports 
A study physician and genetic counselor will disclose the infant’s randomization assignment 
and study results during an in-person consultation with each family. The study physician and 
genetic counselor will provide the consultation to families utilizing all available medical information. 
In the sequencing arm of the study, this will include the medical history and examination, family 
history, standard NBS report and sequencing report(s). In the non-sequencing arm of the study, this 
will include the medical history and examination, family history and standard NBS report.   
If an infant dies after enrollment, but before result disclosure, a study genetic counselor will 
call the family and disclose what their randomization arm was.  If they were in the sequencing arm, 
the family will be given the option to receive results as scheduled, postpose the disclosure date to a 
time of their choosing, or decline receiving results.  The study genetic counselor will discuss with 
them the possible benefits of receiving results for risk assessment of future pregnancies and other 
family members.  Families of deceased infants will also be given the choice to return to the hospital 
for result disclosure or to receive results over the phone.  For families who receive results, they will 
be asked to complete modified surveys about the results impact. 
 
2.4  Generating a Clinical Note 
The team of study physician and genetic counselor will generate a clinical note following the 
consultation summarizing the findings of the reports, what was discussed in the consultation, and 
what recommendations were made.  This note will be included in the patient’s chart and forwarded 
to physicians involved in the infant’s care. 
 

 
16
Aim 3: The research team will administer measures of clinical outcomes, behavioral 
responses and healthcare utilization to families enrolled in both arms, while providing 
careful monitoring for the safety of parents and newborns. 
 
3.1  Administration of Outcome Measures 
The study team will collect outcome measures from parents in the domains indicated and at 
the times specified in Table 1. For raw data and adult onset result interviews: Parents who request 
their child's raw data from the BabySeq project will be invited to participate in an interview. We 
expect that we will conduct up to 30 interviews with parents on this topic. 
Each parent who participates in this study will be compensated for each visit and survey 
completed, with remuneration as follows: $15 for the disclosure visit and completing the post-
disclosure survey; $20 for completing the 3-month follow-up survey; and $40 for the 10-month 
follow-up and completing the 10-month follow-up survey. Thus, a parent will receive $75 if he/she 
finishes the study and completes all study surveys from the baseline through the 10-month post-
disclosure survey. If both parents complete all study procedures and surveys, each parent will 
receive $75, for a total of $150 for the family. Parents will receive this remuneration in the form of a 
check. In addition, parking for study visits will be covered by the study. Remuneration will be 
provided at the end of the study. If a parent withdraws from the study, they will be compensated for 
the surveys completed up until the time of withdrawal. If we can obtain long-term funding, we (or our 
younger colleagues) may also send annual surveys to families until the babies turn 18 years to 
assess for how participation in the study affected their family or thought process.  These surveys 
will be similar to the 3-month follow up survey.  At this time, we do not have the funding to provide 
remuneration for the completion of these surveys; however, if funding were to become available we 
plan to offer a small payment. Parents who participate in the raw data, adult onset, or genetic risk 
interviews will receive $50 per family, per interview (we will not compensate each parent separately) 
to compensate them for their time. 
The family will be randomized (and samples sent for sequencing from infants in the genomic 
sequencing arm) after at least one parent has completed the baseline survey. Completion of the 
baseline survey must occur within 14 days after enrollment; otherwise the family’s participation in 
the study will be discontinued. This requirement will be covered in detail in the Pre-enrollment 
Genetic Counseling Session. If a family is to be withdrawn from the study in this way, we will follow 
up with them to collect voluntary withdrawal information, as we do from those who decline to enroll 
during approaches. This information would include demographics, reason for withdrawal, attitudes 
on testing in the newborn period, and some questions similar to our baseline survey (see appendix 
for survey). Parents who request their child's raw data will be required to undergo a genetic 
counseling session with genetic counselors at the parent site (BWH/BCH, covered by their IRB 
protocol). After the genetic counseling session, parents will be asked if they would be willing to 
participate in a 30 minute telephone interview. Parents who 1) parents who received an adult-onset 
result, 2) parents who agreed to receive such results, but did not, and 3) parents who did not agree 
to receive such results will be invited to participate in an interview that will last from 30 minutes to 1 
hour. Additionally, parents who received general genetic risk results will be invited to participate in 
an interview. If they agree to be contacted for interview, we will reach out to set up a time to speak. 
Interviews will be recorded with participants' permission, and parents will be informed that 
participation in the interview is not required in order to receive their child's raw data or for continued 
participation, that they may skip any question they prefer not to answer, and that they may end the 
interview at any time for any reason. See appendix for the consent statement and interview guide. 
 
3.2  Safety Monitoring of Parents and Newborns 
The study physician and genetic counselor will provide clinical consultation to the family and 
will have multiple clinical opportunities to respond to parents’ questions and provide clinical advice, 
including responding to distress, confusion or parental requests for additional information or 

 
17
additional medical services. For example, if after the disclosure session, it is the clinical judgment of 
the study physician or genetic counselor that the parents seem particularly anxious or distressed, 
the study physician and/or genetic counselor may consult with study psychologist Dr. Susan 
Waisbren, who is also an expert on parent-child bonding and parental stress. The study physician 
or Dr. Waisbren will make referrals to the parent’s primary care physician and/or a mental health 
professional if it is determined that such a referral is clinically indicated or if the patient requests a 
referral. 
 
In addition to this clinical monitoring, outcome measures outlined in Table 1 will also serve 
to monitor the safety of parents. If any participants exceed pre-defined cut-off scores for depression 
or anxiety, the genetic counselor will be alerted and will review the case with the study physician. 
The study physician, genetic counselor or Dr. Waisbren may contact the parents by phone for 
further psychosocial assessment, and referrals to the parent’s primary care physician and/or a 
mental health professional will be made if it is determined that such a referral is clinically indicated 
or if the patient requests a referral. When appropriate, if there is a social worker or clinical mental 
health provider already involved with a family (as is the case for all families in the BCH NICU), we 
will consult with the clinical provider to determine appropriate follow-up if a parent exceeds any pre-
defined cut-off scores for depression or anxiety on their survey.  
 
Parental Withdrawal from Study Participation 
Parents may request to withdraw from the study at any time by contacting study staff. One of 
the study genetic counselors will speak with the parent(s) to discuss their reasons for wanting to 
withdraw. The genetic counselor will complete a Study Withdrawal Form that indicates whether the 
participant wishes to withdraw only from future surveys or additionally requests that samples and 
genome data be destroyed, specifying whether the request is for infant samples, parental samples 
or both.  
Once the Study Withdrawal Form has been received, if the parent(s) elects destruction of 
samples, the lab will be notified to destroy any remaining blood and buccal samples from the infant, 
as well as saliva and blood samples from the parents. If analysis of sequence data is ongoing, it will 
be halted and samples destroyed. Variant files and genome reports will be deleted from laboratory 
and study records.  
Once the GNSRs or IBAs have already been placed in the electronic medical record at 
BCH, BWH or MGH, they will have become part of clinical care, and cannot be deleted or 
withdrawn, a point that will be stressed during the consenting appointment. In addition, any 
sequences that have been uploaded to NIH databases cannot be withdrawn, and this too will be 
stressed during the consenting appointment. 
If an infant dies prior to results disclosure, the infant’s parents will be contacted and be given 
the option of receiving study results. If they do wish to learn the results, they may either return for 
an in-person results disclosure session, or they may choose to have results disclosed to them over 
the phone. If parents do not wish to learn of study results immediately, they will be given the option 
of having results disclosed to them at some point in the future. We will not send study surveys to 
the infant’s parents or physicians. If the genetic cause for the neonate’s illness was not found as 
part of this protocol, parents will be offered enrollment in the Gene Discovery Core of The Manton 
Center for Orphan Disease Research (“Manton” for short). Manton is a research study through BCH 
that offers a genomic sequencing test for sick or deceased children to look for the cause of their 
health problems. As part of the Manton study, if the genomic sequencing test finds genetic variants 
that might explain the child’s health issues, parents receive those results. Parents do not receive 
other types of genetic results on their child and they do not complete surveys. Parents’ participation 
in Manton will be completely optional. 
 
Aim 4: The research team will administer surveys to neonatal physicians and community 
physicians regardless of whether or not they are caring for infants whose families have 

 
18
enrolled in this study. In addition, physicians who receive genomic reports through the 
study will be surveyed about their understanding and utilization of the genomic reports.  
 
The availability of non-study physicians who care for infants born at BWH and/or infants 
admitted to BCH/the BWH or MGH NICU provides an additional opportunity to evaluate the impact 
of genomic sequencing in a newborn setting; specifically, how such information is perceived, 
understood and utilized by the babies’ pediatricians and other physicians. Non-study physicians will 
not be required to participate in surveys, but the study team will administer online surveys to those 
non-study physicians who are willing to participate, in the domains indicated and at the times 
specified in Table 1. Each survey will be preceded by online text that briefly outlines the purpose of 
the research study, key investigators, funding source, inclusion criteria, study procedures and 
duration, remuneration, voluntary nature of participation, confidentiality protections, and study 
genetic counselors’ contact information. Clicking past this page and completing the survey will 
serve as the physician’s consent for each of the surveys. Non-study physicians who do not 
complete the surveys but who are taking care of infants enrolled in the study will still be free to 
contact the study physicians and genetic counselors with questions or feedback, just as they would 
with any clinical consultants. Each non-study physician will be asked to complete the baseline 
survey once, the end of study survey once, and the post-disclosure survey each time they receive a 
GNSR/IBA on one of their patients. 
Non-study physicians will receive $50 for each survey completed in the form of a gift card. 
 
If a physician no longer wishes to participate in the study surveys, he or she can choose not 
to complete future surveys. Physicians caring for the infants in this study will continue to receive the 
clinical reports generated or collected by the study, as well as consultation letters from the study 
physician and genetic counselor. 
 
DATA ACCESS AND STORAGE 
 
An important aspect of this study is the placement of the GNSR and IBA in the medical 
record for care providers to have access to the medical information on the report. The implications 
of placing the reports in the medical record are as follows:  
• 
All sample procurement, sample handling, and analysis will be performed in a CLIA-
compliant manner and confirmed with established methods such as Sanger sequencing.  
Samples and results will therefore be conducted as part of the clinical practice of medicine.   
• 
Reports for each participant will be placed in the electronic medical record system for the 
institution through which they were enrolled (BCH, BWH, or MGH).   
• 
If the medical record of a study participant is transferred to another institution as requested 
by the family in accordance to the institutions’ medical record release policies, the reports 
generated by the study (family history, clinical consultation note(s) and GNSR/IBA) would 
also be transferred. A study physician or genetic counselor will be available to discuss the 
reports with other physicians if requested.  
• 
When infants from BCH/the BWH or MGH NICU are discharged to other hospitals or 
released home under the care of a local pediatrician, the same results will be transferred as 
part of the medical records, and the study staff will be available to answer questions from 
the new health care provider. Many of these families will also return to BCH for specialist 
care, so their follow-up can be monitored through reviewing medical records in the BCH 
system.  
• 
Full sequence results, or “raw data” resulting from sequencing will not be placed in the 
medical records. Only the GNSRs and IBAs will be placed in the medical record.  
 
Data generated from the sequencing will be transferred securely and stored securely behind 

 
19
a firewall.  Recruitment information, collected medical and family history and randomization status 
will be kept in a password-protected database.  Any research files will be kept in a locked filing 
cabinet.  
 
Sharing Samples and Data for All Subjects 
• 
Parents’ responses on study surveys may be shared with other researchers within and 
outside BWH, MGH and BCH. These responses will be de-identified unless parents have 
consented to sharing their identifiable information. 
• 
Phenotype information about the infants in this study will be shared in de-identified form with 
federal databases such as dbGaP and may be shared with other databases so that they can 
be made available to qualified researchers outside of BWH, MGH and BCH. Consent 
language will explicitly point this out to participant families. 
 
Data Storage and Sharing for Newborns in the Sequenced Group 
• 
All genetic data from infants will be stored at the LMM for at least two years after the end of 
the study. Variant files of genomic sequencing data and genomic reports will be stored at 
the LMM indefinitely. 
• 
Sequence and/or variant file data, along with phenotype data and data extracted from the 
medical record, will be shared in de-identified form with NIH databases such as dbGaP and 
may be shared with other databases so that they can be made available to qualified 
researchers outside of BWH, MGH and BCH, in accordance to the NIH’s Genomic Data 
Sharing policies. Consent language will explicitly point this out to participant families. 
• 
Should a family member request their entire genome or “raw” genomic data, we will first 
request that they speak with the genetic counselor or study physician to discuss the reasons 
for their request, and remind them that the protocol does not permit this sharing during the 
course of the study.  However, we will provide the contact information of the sequencing lab 
and the date of study conclusion upon which they may contact the laboratory to request their 
data according to the lab's standard clinical practice.  
 
BIOSTATISTICAL ANALYSIS 
 
This project, while large and complex, is nevertheless a pilot project designed to explore a 
large number of areas, generating empirical data that will inform future large-scale trials and future 
decision-making around the use of sequencing in newborns.  The sample size is justified in terms of 
several key comparisons and hypotheses (see below), but much of the value of the project as a 
whole will come from descriptive and exploratory analyses that emerge from the many interests and 
questions raised by the investigators in genomic sequencing, sequence interpretation, clinical 
genetics, ethics and policy that are part of this multi-disciplinary team.        
Descriptive statistics will be used to characterize parents in terms of demographic variables, 
personal and family history, perceptions of genetic concepts, health care utilization/ cost-
effectiveness and dispositions. Descriptive statistics will also be used to characterize the medical 
impact, psychological impact and personal utility of genomic sequencing of newborns. For 
measures where we have both baseline and follow-up survey data we will use standard pre-post 
analyses (e.g., paired t-tests, repeated measures analyses) to assess whether significant changes 
occurred in these domains following receipt of test results. An initial step in our quantitative data 
analytic plan will be to determine potential differences between the two groups of respondents, 
healthy infants and sick infants. Given that healthy infants do not have any particular underlying 
condition for which a genetic test may be ordered (unlike the sick patients), it will be important to 
determine the appropriateness of pooling parents of patients from these two groups across 
analyses, or whether they should be analyzed separately. We will therefore examine whether 

 
20
respondents from the two groups differ at baseline on key demographic characteristics as well as 
on our main outcomes of interest.  Additionally, we will be analyzing the impact on medical care for 
participants admitted to BCH/the BWH or MGH NICU and post-discharge care for both well and sick 
infants. We anticipate conducting analyses related to duration of stay, number of tests ordered, 
administrative/ visit fees, and costs of diagnostic work-ups.  For qualitative analyses, a qualitative 
investigator will lead analysis of raw data interviews. Interviews will be transcribed verbatim and 
stripped of identifying information before analysis. Analysis will focus on themes related to parents' 
motivations for requesting and expectations of their child's raw genomic information. 
A number of hypotheses have been identified as particularly salient to the goals of the 
project. 
 
Hypothesis 1: Parents of newborns randomized to genomic sequencing will report no 
greater distress or disruptions to parent-child relationships than parents of newborns 
randomized to standard newborn screening 
 
We hypothesize that scores of anxiety, depression, and distress among parents of 
newborns receiving genomic sequencing in addition to standard newborn screening will be no 
greater than scores among parents of newborns who receive standard newborn screening only. We 
will conduct a repeated measures analysis of variance to compare the trends on each measure 
over time in the genomic sequencing and standard newborn screening groups. The regression 
models for these analyses will consider the Edinburgh Postnatal Depression Scale anxiety and 
depression scores, separately, in addition to Parental Stress Scores, IES scores, as the dependent 
variables with randomization arm, cohort (healthy and sick newborns), time, and the interaction 
between time and randomization arm as the primary independent variables. These analytical 
procedures permit a choice of correlation structures (e.g., exchangeable or autoregressive) or the 
use of the robust empirical covariance structure computed by the "sandwich" estimator (generalized 
estimating equations) to account for the association among repeated observations within the same 
individual over time.247 In addition, these procedures use all available observations for analyses and 
do not exclude those participants who may have a missing observation at one or two time points. A 
significant interaction effect in these models suggests that the two groups have different trends 
(change scores) over time. Finally, we will adjust for covariates such as age, gender, race, and 
education in the regression models to evaluate potential differences in trends between the 
randomization arms, while accounting for potential differences in these covariates. Following 
guidelines from the CONSORT Statement248 we will define non-inferiority as evident if 95% 
confidence intervals for mean differences between protocols is entirely less than a pre-specified 
margin of 5 points after adjusting for other factors. Given the sample size proposed, we estimate 
that we will have at least 90% power for analyses of each outcome examined in Hypothesis 1.  
 
Hypothesis 2: Parents of sick newborns randomized to genomic sequencing will report 
greater post-disclosure utility of the genomic sequencing compared to parents of healthy 
newborns randomized to genomic sequencing. 
We will measure personal utility as a function of (1) satisfied expectations, (2) decisional 
regret, (3) attitudes toward genomic sequencing and (4) willingness to pay for genomic services. As 
socioeconomic backgrounds of the BWH, MGH and BCH infants may be different, we may adjust 
for reported or imputed family income. We will use multiple linear regression on measures of 
expectations, attitudes and willingness to pay to test whether changes from baseline on each 
measure is greater among parents with sick newborns are greater than changes from baseline 
among parents of healthy newborns, after adjusting for covariates such as age, gender, race, and 
education. Similarly, multiple linear regression will test whether parents of sick newborns have 
lower decisional regret about pursuing genomic sequencing than parents of healthy newborns, after 
adjusting for key covariates. Assuming 120 parents in each cohort among those randomized to 
genomic sequencing arm, and similar variances among outcomes as observed in other studies,249-

 
21
251 we will have over 99% power to detect differences on each outcome that have been clinically 
meaningful in other studies (i.e., a difference of 1 on a 7-point scale for expectations,251 a difference 
of 16 on a 0-100 scale for decisional regret,249 and a difference of approximately $150 on a 
willingness to pay scale)250 assuming Type I error rates of 5%. 
 
Hypothesis 3: Parents of newborns randomized to genomic sequencing will request more 
healthcare services than parents of newborns randomized to standard newborn screening.  
Healthcare service requests will be assessed through a series of yes/no items where 
parents will report whether or not they sought specific follow-up services for their child, such as 
referrals to specialists, as well as an adapted subscale of the Billings and Moos Coping Measure.252 
Responses to these items will be analyzed using generalized estimating equations and multiple 
linear regression to compare randomization arms on summary scores after adjusting for key 
covariates. Assuming 240 parents in each randomization arm, and assuming that among those in 
the genomic sequencing arm, similar variances in outcomes are observed as in other studies,249-251 
we will have over 95% power to detect differences on both information seeking253 and service 
requests254 that have been clinically meaningful in other studies (i.e., a difference of 1.0 on a 10-
point scale for information seeking, a difference of 0.5 on a 4-point scale for service utilization) 
assuming Type I error rates of 5%. 
 
RISKS AND DISCOMFORTS 
 
Common Risks to Infants 
 
Venipuncture carries a risk of minor discomfort and bruising. There can be minor transient 
oral bleeding at the time of sample collection using a buccal swab.  
 
Uncommon Risks to Infants 
 
There are theoretical risks of disclosing unexpected genetic risk information about an infant. 
Children who later learn about genetic risk information from their parents may have preferred not to 
have learned this, and learning it could provoke psychological distress in the child.  If parents learn 
that infants are at increased risk for a particular medical condition, risks to the child include 
alteration of the parent-child relationship. There is also potential for various forms of discrimination 
(insurance, employment) as the child ages into adulthood. There are currently no systematic data 
available substantiating these risks. Additional medical tests that are stimulated by genomic reports 
in infants may lead to iatrogenic harms that would not have occurred in the absence of genetic 
information. As with any research study, there is a risk for the loss of privacy or confidentiality. 
 
Common Risks to Parents 
 
Venipuncture (if performed) carries a risk of minor discomfort and bruising. There are no 
known risks to sample collection using saliva collection.  
 
Uncommon Risks to Parents 
 
The risks to the parents of the infants enrolled in this study is that they could learn genetic 
risk information that makes them anxious, generates discord between parents, impairs bonding with 
their child, causes them to treat their child as vulnerable, or causes their clinicians to recommend 
medical testing or procedures that they did not anticipate. We may test the parental DNA to confirm/ 
determine inheritance of a result found in their child. These results will be reported on the child’s 
GNSR. We will not return parental DNA findings that were not first identified in the child. We will not 
return information about misattributed paternity or ancestry that could cause emotional distress 
unless medically necessary for the health of the infant, but the chain of events initiated by genetic 
follow-up within a family could reveal these issues as it sometimes does in the clinical practice of 
genetics. There may be medical costs from tests ordered and/or additional office visits as a result 

 
22
from specific genetic information discovered. Additional medical tests may lead to iatrogenic harms 
that would not have occurred in the absence of genetic information. As with any research study, 
there is a risk for the loss of privacy or confidentiality.  
 
Minimizing Risks to Infants and Parents 
 
Study physicians and genetic counselors will oversee the interpretation and disclosure of 
sequencing results consistent with the current practice of medicine.  Elements of that care and 
additional protocol measures taken to mitigate risk to infants and parents will include the following:
 
 
• 
Parents enrolled in this study will undergo a detailed informed consent process, including a 
Pre-enrollment Genetic Counseling Session, which includes discussion of each of these 
risks and prepares the parent for the possible results that could be discovered.  
• 
Study staff will oversee collection of family history information to ensure it is as robust as 
possible in order to assist in interpreting genome results and to allow for risk counseling. 
• 
Disclosure of all results will be led by the study physician and genetic counselor.  
• 
Study personnel will take every precaution to keep subjects’ personal identifiers confidential 
and protect each subject’s privacy. 
• 
The study team feels that the benefit of potential early diagnosis and treatment for highly 
actionable adult onset conditions likely outweighs the risk of disclosing this information, 
which is consistent with the clinical recommendations of the American College of Medical 
Genetics and Genomics, which recommends return of these findings in children, regardless 
of age, as the findings in the child may have important implications for the health of the 
parent. 
• 
All decisions about medical follow-up will be led by the study physician and genetic 
counselor and all non-study physicians caring for enrolled infants will be alerted that this 
specialty team is available for consultation. 
• 
Families will be sent an annual letter reminding them of their participation in the study and 
providing them with study staff contact information should they have questions or wish to 
withdraw. 
• 
Interview data will be stored on BCM,BCH, or BWH encrypted and password-protected 
computers. 
 
Risks to Non-study Physicians Caring for Enrolled Infants 
Study physicians will be generating clinical consultation notes for all study participants. As in 
other aspects of the practice of medicine, these specialized consultations may or may not be useful 
in the care of these patients.  
Non-study physicians caring for these infants could be confused by novel information that is 
outside of their expertise and comfort zone and concerned that they will make inappropriate 
decisions with regard to the patients that are under their care. Pediatricians may feel uncomfortable 
with genomic information in the medical record about their patients derived from this study. It is also 
possible that genetic information may be used inappropriately by non-study physicians, leading to 
unnecessary diagnostic tests or harm to the infant.  
 
Minimizing Risks to Non-study Physicians Caring for Enrolled Infants 
A study physician and genetic counselor will be available and on-call at all times through a common 
study pager, to support families and to support any non-study care providers who have questions or 
concerns. Risks will further be mitigated by the role of the study physicians in following the study 
patients over time, and making recommendations based on the genomic reports. Even after the 
termination of the study, clinical geneticists at BWH and BCH will be available for consultative 
follow-up to families and non-study physicians. 
 
 

 
23
POTENTIAL BENEFITS 
 
Potential Benefits to Infants and Parents 
There is a possibility that information learned through this study would provide an infant and 
the infant’s parents with more information about genetic disorders/risk in their family. Furthermore, it 
may be possible to identify a genetic predisposition in an individual before it manifests in symptoms, 
potentially allowing therapies and treatments to begin earlier. Identifying genetic information may 
provide personal utility, such as financial planning and family planning.  
Sick infants in this study could benefit from a molecular diagnosis discovered through 
genomic sequencing, or could benefit from receiving drug response variants to help guide treatment 
decisions.  
 
Potential Benefits to Non-study Physicians Caring for Enrolled Infants 
Non-study physicians may benefit from receiving consultations results generated through 
this study that may give useful information regarding the clinical care of their patients. Non-study 
physicians may learn more about genetics and genomic sequencing as a result of participating in 
this study. Non-study physicians may also benefit from a strengthened relationship with the parents 
who are enrolled in this study. 
 
Potential Benefits to Society 
This study aims to identify the potential benefits and pitfalls of adding genomic sequencing 
to standard NBS in a pilot population of information-seeking families. We believe that the potential 
advancement of scientific and public health knowledge from this study will allow guidance for future 
implementation of sequencing as a voluntary addition to standard NBS. Results from this study may 
provide insights into how genomic information may be incorporated into pediatric medicine and 
identify areas of further study for subsequent randomized trials to examine the impact of delivering 
genomic information to physicians and their patients and families.  
 
Costs 
There is no cost to participate in the study. Families will be informed that while genomic 
sequencing, interpretation and meetings with study physician and genetic counselor will be covered 
by the research study, any additional follow-up testing or consultations recommended by study 
physicians or other physicians involved in the infant’s care will not be covered by the research 
study, and may or may not be covered by their insurance. This is addressed in the consent form 
and will be discussed during the Pre-enrollment Genetic Counseling and informed consent session. 
 
Equitable Selection of Subjects 
Study participants will include newborns and their parents who are interested in newborn 
genomic sequencing and who are English speaking. Within this group, every effort will be made to 
enroll a diversity of ethnicity. We recognize that participants may not be representative of the 
general population in terms of their attitudes toward and interest in sequencing, health behaviors, or 
demographics (e.g. socioeconomic status). We will keep these limitations in mind when analyzing 
and interpreting results. 
 
Given the wide range of potential findings from the study and their implications for the health 
of the newborn and family, we will exclude those who do not speak English to ensure that 
participants thoroughly understand the informed consent process, implications of study participation 
and study results, and content of their consultations with the study genetic counselor and physician. 
 
Individuals with impaired decision-making capacity will be excluded from the study because 
of the need for parents to thoroughly understand the informed consent process, implications of 

 
24
study participation and study results, and content of their consultations with the study genetic 
counselor and physician. 
 
MONITORING AND QUALITY ASSURANCE 
 
Data and Safety Monitoring  
As described above, genomic results will be disclosed in the context of an in-person clinical 
visit with a genetic counselor/study physician team who will adhere to current clinical standards of 
medical practice in all regards. To collect research outcomes, we will administer validated scales of 
emotional impact and family bonding to parents immediately post-disclosure, and at 3 months and 
10 months post-disclosure, and if future funding allows, and families agree, we will seek to follow 
families in both arms on an annual basis until the end of the study or until their child reaches age 
18. The study physicians will use their clinical judgment, along with standardized scales 
administered through the protocol, to identify any families experiencing emotional distress or 
confusion and will schedule additional clinical follow-up visits and phone calls as needed with these 
families, and when appropriate discuss survey answers with clinicians already involved with the 
family (i.e. a social worker or clinical mental health provider). Study physicians and genetic 
counselors will also be available to the non-study physicians who receive the genomic reports to 
help ensure that the data from these reports is used in an appropriate way.  All families will be 
asked to return in person to their study site at approximately 10 months post-results disclosure for a 
consultation with a study physician and genetic counselor, at which time additional referrals (if 
needed) can be made and management recommendations communicated to the infant’s 
community/primary care physician. If the family is unable to come to an in-person visit, a 
videoconferencing call will be set up.  In the rare cases that both an in-person visit and a video 
conference is not possible, a phone call check-in may be made as well.  We will also be requesting 
and reviewing the infant’s records at this time as well.    
 
Additionally, the members of our external advisory board (EAB) who will also serve as a Data 
Safety Monitoring Board (DSMB) are: 
 
Bruce R. Korf, MD, PhD (Chair) 
Leslie Biesecker, MD 
Steve Cederbaum, MD 
Alex Kemper, MD, MPH 
Jim Lupski, MD, PhD 
Sharon Terry, MA 
 
Any serious adverse events (e.g. major psychiatric decline requiring clinical intervention, 
hospitalization, death that is linked to the disclosure of genomic information) will be reported both to 
the IRB and the DSMB at the time that the event is identified. For all other metrics, the EAB/DSMB 
will review data annually. The EAB/DSMB will review recruitment statistics, decline and drop-out 
rates and reasons, as well as any non-serious adverse events (e.g. changes in anxiety or distress 
scales that do not rise to the level of serious adverse events). We will ask the committee to review 
this information and generate a report to be submitted to the IRB during the protocol’s continuing 
review. Any special reports that come from the DSMB in these instances will be submitted to the 
IRB as soon as they are available.  
 
Outcomes Monitoring 
Please refer to sections 3.1 and 3.2 above for a description of the ways in which we will 
carefully monitor infant and parent outcomes.  

 
25
 
Adverse Event Reporting Guidelines  
If a participant expresses emotional distress related to study participation, or provides survey 
responses suggesting impaired family bonding or emotional distress, they will be referred to a study 
physician or study psychologist for further psychosocial assessment as described above. All serious 
such cases, including those requiring a referral to mental health professional or other therapeutic 
intervention, will be reported to the IRB as per the current IRB reporting guidelines and at the 
annual continuing review for the protocol.  
 
PRIVACY AND CONFIDENTIALITY 
 
 
All reports placed in the medical records of participating infants will be subject to all privacy 
protections afforded clinical information.  As such, they will be vulnerable to discovery by insurance 
companies within the limits of the law and under current protections afforded by the Genetic 
Insurance Nondiscrimination Act and the Massachusetts Law which extends GINA’s protections 
(175 §120E). 
 
Outcomes data collected as part of this research study will be kept in locked cabinets and 
on password protected computer files. 
 
When genomic data are uploaded to dbGaP and/or other databases for sharing with 
qualified research investigators, no information will be uploaded that could lead to the identification 
of these research participants.  However, since genome data is a unique dataset (like fingerprints or 
retinal scans), and since advanced computational techniques may allow deductions with other 
publically available datasets, it is unlikely but may be possible in the future for unscrupulous 
individuals to identify research participants through these datasets.  This possibility will be 
discussed in the Pre-enrollment Genetic Counseling Sessions and in the consent process. 
We will obtain a Certificate of Confidentiality as another layer of confidentiality protection for 
participants in this study. 
 
 
 
 
 

 
26
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