TABLE 1

NSIGHT Project Overviews

BWH, BCH, Baylor College of Medicine Rady, Children’s Mercy Hospital UCSFUniversity of North Carolina
Patient cohortsSick newborns (ICUs).Sick newborns (NICU)Deidentified DBS samples from California NBS programChildren affected with known NBS findings
Healthy newborns (well nursery).Newborn DBS from consenting individuals with primary immunodeficiencyHealthy newborns (prenatal recruitment)
BiospecimensWhole blood (newborns) and saliva (newborns and parents).Whole blood (parent–infant trios)DBS retrieved from NBS program biobankCheek swabs
SequencingExome sequencing.WGSExome sequencingExome sequencing
Illumina Content Exome.Illumina HiSeq 2500, rapid run modeNimblegen v3 captureAgilent V6.0 capture
Illumina HiSeq.Illumina HiSeqIllumina HiSeq
≥100 × mean coverage.40–80 × average coverage40–80 × average coverage
InformaticsAll newborns: analysis of variants in genes responsible for childhood-onset disorders (<18 y).Clinical features translated into phenotype terms and differential diagnosis by Phenomizer (and custom lists)Metabolic disease NBS samples: blinded assessment as an initial screen; second-tier analysis combining genomic, clinical, and MS/MS dataAll participants: primary analysis blinded to phenotype
Sick newborns/Later-onset healthy and sick newborns: indication-based analysis of all variants in genes relevant to the phenotype (if applicable).Immunodeficiency cohort: analysis of genes relevant to patient’s phenotype• Known diagnosis cohort: diagnostic or indication-based analysis based on phenotypic findings
Primary results returnedDiagnostic findings (ICU patients and others with clinical indications).Diagnostic or likely diagnostic findingsNo contact or return of results for metabolic NBS program cohortChildhood-onset medically actionable conditions (all participants)
Highly penetrant childhood-onset or childhood treatable conditions (all participants).Offer clinical confirmatory testing to follow up likely pathogenic variants for immunodeficiency cohortDiagnostic findings (affected cohort)
Secondary results returnedCarrier status for childhood-onset conditions and selected pharmacogenomics (all participants).Incidental genetic disease diagnosis if life-threatening in childhoodNoneParents randomly assigned to decision group can select from 3 categories:
• Childhood-onset non–medically actionable conditions
• Carrier status for recessive conditions
• Adult-onset medically actionable conditions
Psychosocial and medical outcomes researchSurveys of parents and physicians assess impact of genomic sequencing across key domains:Surveys of parents and physicians assess impact of genomic sequencing across key domains:Focus groups with:Surveys with parents assess decision-making about genomic sequencing and its effects on individual and dyadic parent outcomes:
• Attitudes and preferences.• Attitudes and preferences• Parents of immunodeficiency patients• Parents’ collaborative decision-making and conflict
• Health care utilization.• Health care utilization• Healthy pregnant women• Prenatal anxiety (parents of healthy newborns only)
• Health behaviors and intentions.• Health behaviors and intentions• Obstetric and pediatric clinicians• Parental bonding with child
• Decisional satisfaction.• Decisional satisfaction• Attitudes and beliefs about genomic sequencing
• Psychological impact.• Psychological impact• Decision conflict and regret
Psychosocial impact on the family.• Psychosocial impact on the family• Test-related and general distress
Correlation of parents’ attitudes about test results with their health literacy, genomic literacy, anxiety, depression, and religiosity• Beliefs and concerns about the child’s future health
Other project aimsAlthough Sanger confirmation is used for the main project, the study is exploring orthogonal sequencing by 2 NGS methods as an alternative for variant confirmation.Comparison of rate of diagnosis and time to diagnosis in WGS and no-WGS groupsAssess suitability of stored DBS as a source of DNA for deep sequencingSemiquantitative metric to determine medical actionability
Rates and types of actionability measuredElectronic decision aid for parental preference setting