An Adaptive Clinical Trial of BeginNGS Newborn Screening for Hundreds of Genetic Diseases by Genome Sequencing

Each year 98% of US newborns receive screening (NBS) of dried blood spots (DBS) for at least 35 Recommended Uniform Screening Panel (RUSP) genetic disorders for diagnosis and treatment at/before onset of symptoms. About 6,600 true positive infants are identified per year. NBS is well-accepted and has proven clinical utility. Between 2010 and 2022, however, while many new therapeutic interventions for childhood genetic diseases showed clinical utility and/or were approved by the Food and Drug Administration (FDA), only 6 disorders were added to the RUSP. As a result, \~700 childhood genetic diseases have effective treatments but are not yet screened by NBS, and affected children experience delayed diagnosis and treatment, and poor outcomes. To solve this problem the investigators are developing BeginNGS - NBS by genome sequencing (GS) of DBS for, ultimately, \~700 severe, childhood genetic diseases with effective therapeutic interventions. BeginNGS is adaptive: genetic disorders are added (or removed) as evidence emerges that early treatment improves (or does not improve) outcomes. BeginNGS version 1 (v1, 388 genetic disorders) had good sensitivity (88.8%) and false positive rate (0.27%) in a retrospective study of 458,000 subjects. An exploratory prospective clinical trial comparing BeginNGS v2 (with 409 disorders) and rapid diagnostic genome sequencing (RDGS) identified reportable findings in 24 (34%) of 71 acutely ill newborns who were not suspected of having a genetic disease. Only 2 of those disorders were detected by standard NBS. The investigators propose a single group, multicenter, adaptive clinical trial to compare utility, acceptability, feasibility, and cost effectiveness of BeginNGS (experimental intervention) with standard NBS (control) in a minimum of 10,000 neonates (aged \<28 days, maximum of 100,000). The primary objective of the trial is to generate evidence to support broad implementation of BeginNGS. An adaptive design was chosen rather than a traditional, fixed design to allow accumulating results to make the trial more efficient, informative, and ethical by addition or removal of BeginNGS disorders and genetic variants, population enrichment (for minority racial, ethnic, and ancestral groups), and sample size re-estimation. Adaptive design will also facilitate meta-analysis with other clinical trials of NBS-by-GS, providing greater power to test utility in ultra-rare genetic diseases. NBS-by-GS has the potential to transform the way childhood genetic diseases are diagnosed and treatments started. Preliminary data suggest that national adoption of BeginNGS in all births has the potential to improve outcomes of \>50,000 US children per year.