Download Genomic Sequencing in the General Newborn Population

ELSI Considerations and IRB Responses to
Genomic Sequencing in the General Newborn
Population
Caroline Weipert, MS, CGC and Meghan Towne, MS, CGC
Brigham and Women’s Hospital and Boston Children’s Hospital
New England Genetics Collaborative Annual Meeting
Portsmouth, NH – April 10, 2015
Overview
Background on genomic sequencing in newborns
What is the BabySeq project?
What type of results will be returned to families?
Ethical considerations in the project design
Responses from the IRB reviews
Discussion
Poll
• If your newborn was in the NICU, would you
be interested in learning about genetic risks
for childhood-onset diseases?
– Including, but not limited to, the condition for
which they were admitted to the NICU?
• If your newborn was healthy, would you be
interested in learning about genetic risks for
childhood-onset diseases?
“Whether you like it or not, a
complete [genomic]
sequencing of newborns is
not far away.”
Francis Collins, Director, National Institutes of
Health, 2009
What is the rationale for studying
genome sequencing in newborns?
Next generation sequencing (NGS) is
currently used clinically in NICUs
• Companies are offering platforms which target this
population
Pan-ethnic carrier panels are being
offered prenatally to individuals with
no a priori increased risk
Direct-to-consumer companies and
public knowledge/desire for NGS
continues to grow
Next generation sequencing (NGS) is
currently used in NICUs
• Companies are offering platforms which target this
population
Pan ethnic carrier panels are being
offered prenatally to individuals with
no a priori increased risk
Direct-to-consumer companies and
public knowledge/desire for NGS
continues to grow
Next generation sequencing (NGS) is
currently used clinically in NICUs
• Companies are offering platforms which target this
population
Pan-ethnic carrier panels are being
offered prenatally to individuals with
no a priori increased risk
Direct-to-consumer companies and
public knowledge/desire for NGS
continues to grow
Next generation sequencing (NGS) is
currently used clinically in NICUs
• Companies are offering platforms which target this
population
Pan-ethnic carrier panels are being
offered prenatally to individuals with
no a priori increased risk
Direct-to-consumer companies and
public knowledge/desire for NGS
continues to grow
Sequencing of newborns is
underway
Sequencing of newborns is
underway
Inova Childhood Longitudinal Cohort Study
• Plans to enroll 5,000 families pre-birth (with
over 2,000 consented so far)
• Generating WGS data on parent-child trios
– Also including analysis of gene
expression, DNA methylation, and
microRNA data
• Will follow children until age 18
What is the “Genomic
Sequencing for Childhood Risk
and Newborn Illness”
(BabySeq) Project?
BabySeq U19 Grant
NIH-funded 5 year research study exploring the
impact of genomic sequencing of newborns on
families and providers
Medical
Individual and public health?
Behavioral
Physician and parent behavior?
Economic
The healthcare system?
The Research Team
Brigham and Women’s
Hospital
Boston Children’s
Hospital
Baylor College of
Medicine
Project Principal Investigator
Robert Green, MD, MPH
Project Principal Investigator
Alan Beggs, PhD
Principal Investigator
Amy McGuire, JD, PhD
Study Physicians
Richard Parad, MD, MPH
Joel Krier, MD, MMSc
Study Physicians
Ingrid Holm, MD, MPH
Pankaj Agrawal, MD, MMSc
Research Fellows
Stacey Pereira, PhD
Jill Robinson, MA
Genetic Counselor
Caroline Weipert, MS, CGC
Genetic Counselor
Meghan Towne, MS, CGC
Research Assistants
Rebecca Walsh
Lily Hoffman-Andrews
Research Assistants
Talia Schwartz
Renee Pelletier
Project Overview
Pre-Enrollment Genetic Counseling,
Consent, Blood Draw, Family History with Genetic Counselor
240 Newborns in NICU at BCH and Parents
Randomization
Randomization
•Standard NBS
•Family History
•Standard NBS
•Family History
•Genome Report
•Standard NBS
•Family History
•Standard NBS
•Family History
•Genome Report
Optional:
•Indication-Based
Report
Consultation and Results Disclosure with Genetic Counselor and Study Physician.
Consultation Note and Testing Reports placed in Medical Record
and sent to other care providers.
10-month Follow-up Consultation and Exam with Study Physician
and Genetic Counselor
Medical Record Review
Outcomes collected. Study Physicians and GCs available for
questions from parents, NICU MDs and outside MDs
240 Healthy Newborns at BWH and Parents
Results Reported
Family
History
Report
Genomic
Standard Newborn
Newborn Sequencing
Screening
Report
Results
(if applicable)
All results will be summarized in the consultation note that
goes into the MR and is sent to pediatricians
What type of results will be
returned to families?
What types of genetic results are included on the
Genomic Newborn Sequencing Report?
1. Disease-causing variants previously associated with childhood-onset
single gene disorders
2. “Carrier” status for childhood-onset disorders that should not cause
disease in the infant, but may indicate additional testing or may have
reproductive implications for the infant and other family members
3. Pharmacogenomic variants:
•Malignant hyperthermia (RYR1 gene)
severe adverse reactions to certain anesthetic gases and muscle relaxants
•Glucose-6-phosphate dehydrogenase deficiency (G6PD gene)
hemolytic crises caused by certain antibiotics, antimalarial drugs and
environmental exposures
4. Blood Type
Identifying Genes to Report
~3,300 disease-associated genes
Evidence-based gene-disease
association review
• Evidence for
causing disease
• Age of onset
• Penetrance
• Phenotype category
• Carrier phenotype
• Inheritance pattern
Criteria for including a variant in the
BabySeq report
GNSR
IBGR
Specific disease
suspected
Strong
Moderate
Limited
High
Moderate
Low
Childhood
Adulthood
Gene-disease
evidence level
Penetrance
Age of onset
Would these genes be reported to
families as part of the ‘Genomic
Newborn Sequencing Report’ (GNSR) ?
Gene
Disease
APC
Familial adenomatous polyposis (early onset colon
cancer)
Report in
GNSR?
Would these genes be reported to
families as part of the ‘Genomic
Newborn Sequencing Report’ (GNSR) ?
Gene
Disease
Report in
GNSR?
APC
Familial adenomatous polyposis (early onset
colon cancer)
Yes
May present during childhood, actionable in childhood
Would these genes be reported to
families as part of the ‘Genomic
Newborn Sequencing Report’ (GNSR) ?
Gene
Disease
Report in
GNSR?
APC
Familial adenomatous polyposis (early onset colon
cancer)
Yes
BRCA1
Breast cancer
Would these genes be reported to
families as part of the ‘Genomic
Newborn Sequencing Report’ (GNSR) ?
Gene
Disease
Report in
GNSR?
APC
Familial adenomatous polyposis (early onset colon
cancer)
Yes
BRCA1
Breast cancer
No
Never been reported to present in childhood, not actionable in childhood
Would these genes be reported to
families as part of the ‘Genomic
Newborn Sequencing Report’ (GNSR) ?
Gene
Disease
Report in
GNSR?
APC
Familial adenomatous polyposis (early onset colon
cancer)
Yes
BRCA1
Breast cancer
No
CP
Aceruloplasminemia (gradual iron accumulation in
the brain and other organs)
Would these genes be reported to
families as part of the ‘Genomic
Newborn Sequencing Report’ (GNSR) ?
Gene
Disease
Report in
GNSR?
APC
Familial adenomatous polyposis (early onset colon
cancer)
Yes
BRCA1
Breast cancer
No
CP
Aceruloplasminemia (gradual iron
accumulation in the brain and other organs)
Yes
Does not present in childhood, but is actionable in childhood
Would these genes be reported to
families as part of the ‘Genomic
Newborn Sequencing Report’ (GNSR) ?
Gene
Disease
Report in
GNSR?
APC
Familial adenomatous polyposis (early onset colon
cancer)
Yes
BRCA1
Breast cancer
No
CP
Aceruloplasminemia (gradual iron accumulation in
the brain and other organs)
Yes
MECP2
Rett syndrome
Would these genes be reported to
families as part of the ‘Genomic
Newborn Sequencing Report’ (GNSR) ?
Gene
Disease
Report in
GNSR?
APC
Familial adenomatous polyposis (early onset colon
cancer)
Yes
BRCA1
Breast cancer
No
CP
Aceruloplasminemia (gradual iron accumulation in
the brain and other organs)
Yes
MECP2
Rett syndrome
Yes
Childhood-onset diseases will be reported regardless of availability of
treatment or medical actionability.
Would these genes be reported to
families as part of the ‘Genomic
Newborn Sequencing Report’ (GNSR) ?
Gene
Disease
Report in
GNSR?
APC
Familial adenomatous polyposis (early onset colon
cancer)
Yes
BRCA1
Breast cancer
No
CP
Aceruloplasminemia (gradual iron accumulation in
the brain and other organs)
Yes
MECP2
Rett syndrome
Yes
APP
Alzheimer’s disease
Would these genes be reported to
families as part of the ‘Genomic
Newborn Sequencing Report’ (GNSR) ?
Gene
Disease
Report in
GNSR?
APC
Familial adenomatous polyposis (early onset colon
cancer)
Yes
BRCA1
Breast cancer
No
CP
Aceruloplasminemia (gradual iron accumulation in
the brain and other organs)
Yes
MECP2
Rett syndrome
Yes
APP
Alzheimer’s disease
No
Never been reported to present in childhood, not actionable in childhood
Ethical Considerations in
Project Design
ELSI Aims
• Describe the views of parents randomized to
receive GNSR towards genomic sequencing
of their newborns
• Compare the impact on parents of receiving
GNSR versus standard NBS
– Psychological impact
– Personal utility
– Behavioral response
• Evaluate the experience and actions of
pediatricians who receive GNSR
Discussion Around Design
• Study design formulated over a year of
discussions
– Funding began 09/2013; first draft of IRB protocol
submitted 10/2014
– Met 4+ times a month
– Discussed logistics and ethical issues which may
rise
• Carefully considered many approaches
• Dan Navon, PhD is a Sociologist who has
been observing these discussions and doing
a “study in a study”
Ethical Considerations
• What will be the criteria for what results are
reported?
• Implications of returning genomic sequencing
information for healthy infants?
• Should we report on risks for adult-onset
conditions?
• What happens if an infant passes away before
results disclosure?
• What will be the long term effects?
– How will this impact insurability?
– Will this impact the child’s autonomy as they get
older?
– Will there be an impact on parental bonding?
Questions About Result Return
Should the data returned to both cohorts
be the same?
• Wanted to balance only reporting known, clinically valid results to
healthy infants and following clinical practices for sick infants
No: established the IBGR to allow for the most meaningful results to go to the
NICU cohort, while narrowing the aperture for return to healthy infants
Should parents set preferences for what
data they learn?
• Wanted to set-up the project with as much parallels to
clinical care as possible
– No in-depth consenting protocol currently for NBS
– Logistically, reviewing these options would be difficult for both
this study and clinical application
No: enrollment would mean that families could receive any result which
meets reporting criteria
Questions about Pediatrician
Involvement
• How will we educate/involve the pediatricians of the
families?
Questions about Neonatologist
Involvement
• How to ensure that clinical treatment is continued
without being impacted by enrollment of the family?
•
Randomized trial, so if a neonatologist doesn’t order clinical testing
because the infant is enrolled there is still a 50% chance the child
will not get sequencing
IRB Review Responses
Dual IRB Review
• Asked for review from only one IRB
– BCH to be primary review site
– BWH to cede review
• Different formats and required language in
consent documents for both institutions
• Incorporate feedback from both IRBs
– Different review dates
– Conflicting opinions (more on that later)
Approach to Dual IRB Review
• Met with chairs and admins from both
committees at the start of the process
• Waited until we could incorporate comments
from both boards before submitting revisions
• Addressed both committee’s concerns in
each review
– If comments conflicted, justified why we chose to
“side” with one board over the other
• BWH issued conditional approval after 2 fullcommittee reviews
• BCH had 3 full-committee meetings and 2
rounds of administrative review after
conditional approval
IRB Comments
Only enrolling parents who have already had a child?
Childhood-onset vs. adult-onset disease?
Recruitment: prenatal vs. perinatal?
Consent from whom?
What if an infant passes away before results disclosure?
Differentiating between clinical care (NBS) and genome sequencing
Only enrolling parents who have
already had a child?
Both IRBs suggested only enrolling parents
who previously had children, as they “may
have a better understanding of the implications
of participating in such a protocol”
“…experienced parents tend to be
less excitable and more even-keeled”
Our Response
• No evidence in literature to support increased
distress or vulnerability among first-time parents
• Those who already have kids at home may be
under more stress
• May reduce representativeness of our sample
population
• Parents with other children may find the results
more useful (carrier status)
IRBs agreed to let us approach first-time
parents
Childhood-onset vs. adult-onset
disease?
IRB questioned whether it is ethical to only
disclose risk for childhood-onset diseases
“…[is it] appropriate to not disclose genes
associated with adult-onset disease that
could potentially be prevented (e.g. the
genes associated with high risk of breast
and ovarian cancer)”
Our Response
• Current standard of care is to not
return perform testing in children for
adult-onset disease
• We felt that including adult-onset
conditions could impact family’s
decision-making
IRBs agreed to let us restrict reporting to
childhood-onset conditions
Recruitment: prenatal vs. perinatal
IRB questioned whether it may be more
appropriate to approach parents before delivery
“[What is] the wisdom of approaching parents at a
time when they are overwhelmed by a life-changing
event and thus unlikely to have the focus
necessary to consider study participation and its
accompanying long-term consequences…”
Our Response
• BabySeq pilot data
• Multiple clinical protocols enroll in
Newborn Nursery/NICU
• Multi-step consent process with an attempt
to educate in the prenatal period
– Will provide study brochures in OB offices
– Parents have 2 weeks to complete baseline
survey to finalize enrollment
IRBs agreed to modified enrollment plan
with focus on prenatal exposure
Consent from whom?
IRB requested that we require consent from
both biological parents, and ‘rearing parent’
(if applicable)
“Results of testing have implications for biological
parents and siblings but may also have
implications for parents who are not biological
parents but are rearing the subject…”
Our Response
• Agree to require consent from both biological
parents (and rearing parent)
– If biological parent is known, but not involved in the
upbringing of the child, they will need to be consented
– If biological parent is unknown (i.e. anonymous sperm
donor), then their consent is not needed
• Will track demographic information of those
excluded from participation
IRBs outlined several family structures
with instructions for who to consent
What if an infant passes away before
results disclosure?
IRB requested clarification about how this
will be handled and how it may impact
families’ participation
“…family did not want the results but there were
findings that could have implications for other children
or family members, whether there is any ethical
obligation to inform the family or pediatrician.”
Our Response
• Families will be asked if they would still like to
receive results, with an option to delay decisionmaking
• If there are medically actionable findings, a GC
will discuss the possible benefits of having this
information, but the family will be able to opt out
– Family will still have the option to decline and results
will not be placed in MR
IRBs still considering this approach
Differentiating between clinical care
(NBS) and genome sequencing
Many questions regarding how the protocol
will interface with NBS
“The consent form offers to provide a list of NBS conditions if
requested. However members asked that this be given to all
families as part of the consent process, not simply offered.”
“In order to reduce any perception… that [NBS]
is part of clinical care…please remove the
discussion of newborn screening from the
consent form's introductory section.”
Our Response
• Clinical protocol for NBS will be followed
as standard of care
• We will review the NBS results with family
at disclosure session
– Abnormal results should have already been
reported to families
– Consented to know that normal results are not
reported by pediatricians as standard of care
IRBs requiring that we contact pediatricians to
confirm any abnormal results were disclosed
Ensuring there is no coercion for
participating
Questions regarding compensation to families
“…uncomfortable with the minimal compensation
offered to families. They felt that the nominal
“…a
concern
that forthe
lower
income,
less
amount
almost
minimizes
serious
nature
of
educated participating”
parents, an easy $150 might
tip their decision making in favor of
participating”
“…wondered if compensation should be
offered at all.”
Our Response
• Will offer compensation to increase
likelihood of continued involvement
• Will decrease coercion by
– Involving the clinical staff
– Allowing for “passive declining”
– Stressing the voluntary nature of the project
IRB agreed with this approach
Current Protocol Status
• Conditional approval at both sites,
– Anticipated full-approval any day
– Hope to approach our first families in 2 weeks
• Consent is 20 pages; additional 4 documents
as part of the consenting process
• Consent monitor will be used at both sites
• “Pilot” for the first 5 families enrolled at each
site
– Submit recruitment data to IRBs for approval for
continual enrollment
– Demographics for families which enrolled vs.
declined enrollment
Poll
• If your newborn was in the NICU,
would you enroll in BabySeq?
• If your newborn was healthy, would
you enroll in BabySeq?