Feasibility of Genomic Newborn Screening Through Public Health Laboratories

PROJECT ABSTRACT Newborn screening (NBS) by whole genome sequencing (NBSxWGS) offers the potential to identify infants at risk for genetic conditions that are treatable or preventable early in life. Integrating NBSxWGS into the existing U.S. state- and territorial-based Public Health Laboratory (PHL) systems as a first-tier screening method presents substantial practical and ethical challenges. Our NBSxWGS Collaboratory team (the “Collaboratory”) combines the experience of complementary teams that are leaders in the fields of newborn genomic screening and PHL implementation to assess the real-world feasibility of such integration. The ScreenPlus team has conducted NBS research utilizing multilingual in-person recruitment, collection of routine dried blood spots for research, and seamless integration with the New York State PHL to successfully recruit, screen and deliver results to over 65,000 infants at six hospitals for a lysosomal disorders supplemental pilot and over 28,000 additional infants at eight hospitals for an analyte plus gene sequencing approach. The BabySeq team has coordinated multi-site enrollment, randomization, and data collection from over 1,000 infants in the first year of life at nine U.S. recruitment sites to gather medical, behavioral and economic outcomes of newborn sequencing using whole exome/genome sequencing. The Association of Public Health Laboratories (APHL) is the sole national organization dedicated to the interests of PHLs, and operates a centralized secure, web-based data repository with harmonized performance metrics from nearly all U.S. NBS programs. APHL has executed 51 Data Use Agreements representing more than 99% of U.S. newborns, 70 implementation funding awards for expanded NBS, 16 site reviews, and over 20 molecular program assessments using a community-informed framework. GeneDx has evaluated over 750,000 clinical exomes and genomes, has clinically classified over one million variants, and has experience in NBSxWGS using residual blood spots from over 18,000 infants in New York State and North Carolina. We secured in-kind support from Illumina and GeneDx to provide high quality CAP/CLIA-accredited WGS, variant interpretation, and orthogonal confirmation for a to-be-selected gene panel in up to 30,000 infants at no cost to the Collaboratory, allowing the full NIH budget to support other critical feasibility activities. Ariadne Labs has expertise in implementation science, which it will contribute to this program. In partnership with a Community Advisory Board (CAB) our multidisciplinary, multi-state team of leaders in the ELSI of NBS will be embedded in the study and will guide, monitor, and study the ELSI of all aspects of the study. Our assessment of feasibility focuses on scientific feasibility, encompassing gene selection, WGS pipeline performance, variant interpretation, confirmatory testing, and medical follow-up; programmatic feasibility, reflecting the ability to implement efficient, scalable workflows across birthing centers and PHLs in multiple states; and human feasibility, addressing parental consent, uptake, acceptability, and communication among all stakeholders. These three dimensions correspond to widely used domains of feasibility in implementation research, enabling a comprehensive framework for evaluating NBSxWGS in public health. An early and essential goal will be to establish consensus among the Collaboratory academic team, APHL, CAB, PHLs, and NIH on criteria and thresholds that will define Scientific, Programmatic, and Human feasibility and to explore these through the four Functions outlined in the Research Opportunity Announcement. Our team brings unparalleled strengths to each Function of the Collaboratory. The goals of Function 1 are overall administration, onboarding of PHLs, establishing the Community of Practice, IRB approvals, and communication among all stakeholders - building upon our deep experience in coordinating interdisciplinary teams and large genomic trials in infants (ScreenPlus, BabySeq and APHL’s administrative credibility and leadership among the PHLs). The goals of Function 2 are to establish the workflow for recruitment, consent and return of results, building upon the experience of both ScreenPlus, BabySeq, and prior studies in recruiting, enrolling and returning genomic results. The goals of Function 3 are to sequence, confirm, and report on a study-created, agreed-upon gene list - building upon our experience developing a gene list through consensus and the expertise of GeneDx as a leading U.S. sequencing center. The goals of Function 4 are to create and fully embed CAB and ELSI perspectives, and with the entire Collaboratory, explore the tensions surrounding consent, parental understanding of risks, benefits, privacy and distress - led by national ELSI experts in NBS, and building on their ELSI work. Our team brings additional innovation by (1) integrating exclusively with the existing APHL infrastructure, and (2) conducting two embedded studies comparing in-person postnatal vs. hybrid prenatal recruitment (within Function 2) and a longitudinal cohort study to examine the psychosocial impact of positive WGS results (within Function 4). Together our Collaboratory of national leaders across the full spectrum of NBSxWGS brings the vision, expertise, and infrastructure necessary to rigorously evaluate the scientific, programmatic, and human feasibility of implementing NBSxWGS at scale in a way that is both sustainable for public health systems and trusted by families nationwide.