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

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

Baylor College of Medicine, Boston Children's Hospital, Broad Institute, Dartmouth-Hitchcock Medical Center, Harvard Pilgrim Health Care, Howard University, HudsonAlpha Institute for Biotechnology, Massachusetts General Hospital, Icahn School of Medicine at Mount Sinai, University of Alabama at Birmingham, National Center for Advancing Translational Sciences (NCATS), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

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.

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.

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.

Pathogenic (P) and likely pathogenic (LP) variants identified relevant to infant's health (dominant or biallelic recessive disease risks)

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)

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)

Baseline, post-disclosure (3 months after enrollment), 6 months post-disclosure (9 months after enrollment)

Signs or symptoms of monogenic disease risk or recessive condition present in infant's biological family

Baseline, post-disclosure (3 months after enrollment), 6 months post-disclosure (9 months after enrollment)

Any phenotype that develops in an infant suspected to have a genetic cause, or any genetic testing ordered as part of clinical care

Cost of healthcare services that were recommended for infants and parents as part of study disclosure session

All health sector costs observed in medical records and survey questions regarding family out-of-pocket expenses

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