Implementation of Whole Genome Sequencing as Screening in a Diverse Cohort of Healthy Infants

Study Overview
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Brief Summary
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This research study is exploring the use of genomic sequencing in the newborn period to screen healthy babies for current and future health risks. The study will enroll a diverse cohort of 500 healthy infants and their parents from Boston, MA; New York City, NY; and Birmingham, AL. A small blood sample will be collected from each infant, and whole genome sequencing will be performed in 1/2 of the cohort following a randomized controlled trial design. 3 months later, the randomization status and sequencing results will be shared with parents and pediatricians. Investigators will study the medical, behavioral, and economic outcomes of genomic sequencing to better understand how this technology can be implemented in outpatient primary care settings.

Detailed Description
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The objective of this research protocol is to assess the impacts of genomic sequencing in healthy infants from ethnically and racially diverse communities as part of routine pediatric care. Investigators will enroll a cohort of 500 healthy, ethnically and racially diverse infants from Boston, Massachusetts; New York City, New York; and Birmingham, Alabama, with planned expansion to other U.S. cities and recruitment sites. As part of this study, a stakeholder board comprised of diverse community members will provide early and regular feedback throughout the study on anticipated and ongoing community reaction to the work with sensitivity to historical injustices and cultural diversity Primary care pediatricians from each recruitment site will be enrolled for a brief genomics education curriculum. Only infants whose healthcare providers have joined the study will be enrolled. A small blood sample will be obtained from each enrolled infant. Participants will randomized (1:1) to receive either a family history report or a family history report plus whole genome sequencing. Genome sequencing data will be analyzed for pathogenic and likely pathogenic variants in genes associated with childhood-onset disease risks, as well as highly actionable adult-onset disease risks. If infants have a dominant risk identified, parents may choose to be screened as part of the study. The study team will disclose the infant's randomization status and study results during a consultation with each family, and results will be sent to the infant's pediatrician. Parents will be surveyed at three time points over the 12 months after enrollment: baseline, immediately post-disclosure (approximately 3 months after enrollment), and 6 months post-disclosure. Surveys will assess psychosocial impacts of newborn sequencing. Chart reviews will be performed to assess the medical outcomes and healthcare utilization costs of newborn genome sequencing.

Official Title
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Implementation of Whole Genome Sequencing as Screening in a Diverse Cohort of Healthy Infants (1U01TR003201-01A1)

Conditions
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Genetic Predisposition to Disease, Hereditary Diseases

Intervention / Treatment
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* Genetic: Genome Sequencing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infant participants Has not previously had exome or genome sequencing Age 0-12 months Seen for well-baby pediatric care at a recruiting site Primary healthcare provider completed the genomics education program At least one parent or guardian able to participate in the study Parent participants Biological parent or legal guardian of an infant participating in the study 18 years of age or older Unimpaired decision-making capacity English or Spanish speaking Available to have genetic counseling and provide consent for testing the infant Exclusion Criteria: Parents are unwilling to have genomic reports placed in the medical record or sent to their primary care pediatrician Any infant in which clinical considerations preclude collecting blood via heel stick

Ages Eligible for Study
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Minimum Age: 0 Months
Maximum Age: 12 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial (control group vs. genome sequencing intervention)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequencing cohort<br>Infants receive genome sequencing with analysis of approximately 1000 genes associated with childhood-onset and highly actionable adult-onset disease risks. Pathogenic and likely pathogenic variants are reported to the child's parents and pediatrician. Participants also receive a detailed family history report and standard well-child care. | Genetic: Genome Sequencing<br>* 20 times read depth (20x) next-generation whole genome sequencing with comprehensive analysis.<br>|
| No Intervention: Control cohort<br>Infants receive a detailed family history report plus standard well-child care. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monogenic disease risks (MDRs) | Pathogenic (P) and likely pathogenic (LP) variants identified relevant to infant's health (dominant or biallelic recessive disease risks) | 3 months after enrollment | 
| Carrier status variants | P and LP variants identified as recessive carrier status in infant | 3 months after enrollment | 
| MDR-associated phenotype | Signs or symptoms of monogenic disease risk identified by genome sequencing | 3 months after enrollment and 1-year post-disclosure (15 months after enrollment) | 
| Parent-Child Relationship | Parenting Stress Index, 4th Edition Short Form (scored as a percentile 0 - 100%, higher scores indicate increased stress); Vulnerable Baby Scale (scored 0 -50, higher scores indicate increased perceptions of child vulnerability) | Baseline, post-disclosure (3 months after enrollment), 6 months post-disclosure (9 months after enrollment) | 
| Partner Relationship | Kansas Marital Satisfaction Scale (Scored 3 to 21, higher scores indicate better marital quality; Partner Blame (novel, higher scores indicate increased blame) | Baseline, post-disclosure (3 months after enrollment), 6 months post-disclosure (9 months after enrollment) | 
| Personal Distress | General Anxiety Disorder-7, Patient Health Questionnaire (PHQ)-9 , Self-Blame | Baseline, post-disclosure (3 months after enrollment), 6 months post-disclosure (9 months after enrollment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MDR-associated family history | Signs or symptoms of monogenic disease risk or recessive condition present in infant's biological family | 3 months after enrollment and 1-year post-disclosure (15 months after enrollment) | 
| Feelings about genomic testing | Feelings About genomiC Testing Results (FACToR) Questionnaire | Baseline, post-disclosure (3 months after enrollment), 6 months post-disclosure (9 months after enrollment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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genome sequencing, newborn screening, preventive medicine