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. 2024 Dec 5;111(12):2643-2667.
doi: 10.1016/j.ajhg.2024.10.020.

Genome-based newborn screening for severe childhood genetic diseases has high positive predictive value and sensitivity in a NICU pilot trial

Stephen F Kingsmore  1 , Meredith Wright  2 , Lauren Olsen  2 , Brandan Schultz  2 , Liana Protopsaltis  2 , Dan Averbuj  2 , Eric Blincow  2 , Jeanne Carroll  3 , Sara Caylor  2 , Thomas Defay  4 , Katarzyna Ellsworth  2 , Annette Feigenbaum  5 , Mia Gover  6 , Lucia Guidugli  2 , Christian Hansen  2 , Lucita Van Der Kraan  2 , Chris M Kunard  7 , Hugh Kwon  2 , Lakshminarasimha Madhavrao  2 , Jeremy Leipzig  8 , Yupu Liang  4 , Rebecca Mardach  5 , William R Mowrey  4 , Hung Nguyen  2 , Anna-Kaisa Niemi  5 , Danny Oh  2 , Muhammed Saad  2 , Gunter Scharer  6 , Jennifer Schleit  6 , Shyamal S Mehtalia  7 , Erica Sanford  6 , Laurie D Smith  6 , Mary J Willis  6 , Kristen Wigby  6 , Rebecca Reimers  9
Affiliations

Genome-based newborn screening for severe childhood genetic diseases has high positive predictive value and sensitivity in a NICU pilot trial

Stephen F Kingsmore et al. Am J Hum Genet. .

Abstract

Large prospective clinical trials are underway or planned that examine the clinical utility and cost effectiveness of genome-based newborn screening (gNBS). One gNBS platform, BeginNGS, currently screens 53,575 variants for 412 severe childhood genetic diseases with 1,603 efficacious therapies. Retrospective evaluation of BeginNGS in 618,290 subjects suggests adequate sensitivity and positive predictive value (PPV) to proceed to prospective studies. To inform pivotal clinical trial design, we undertook a pilot clinical trial. We enrolled 120 infants in a regional neonatal intensive care unit (NICU) who were not under consideration for rapid diagnostic genome sequencing (RDGS). Each enrollee received BeginNGS and two index tests (California state NBS and RDGS). California NBS identified 4 of 4 true positive (TP) findings (TP rate 3.6%, sensitivity 100%) and 11 false positive (FP) findings (PPV 27%). RDGS identified 41 diagnostic findings in 36 neonates (diagnostic rate 30%). BeginNGS identified 5 of 6 on-target TP disorders (TP rate 4.2%, 95% confidence interval 1%-8%, sensitivity 83%) and no FPs (PPV 100%). Changes in management were anticipated following the return of 27 RDGS results in 25 enrollees (clinical utility [CU] 21%), 3 of 4 NBS TPs (CU 2.7%), and all BeginNGS TPs (CU 4.2%). The incidence of actionable genetic diseases in NICU infants not being considered for RDGS suggests (1) performance of RDGS in ∼20% of admissions misses many genetic diagnoses, (2) NICU enrollment in gNBS trials will greatly increase power to test endpoints, and (3) NICUs may be attractive for early implementation of consented BeginNGS screening.

Keywords: clinical trial; clinical utility; genome sequencing; infant; neonatal intensive care unit; newborn screening; positive predictive value; rapid diagnostic genome sequencing; sensitivity; severe childhood genetic disease.

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Conflict of interest statement

Declaration of interests C.M.K. and S.S.M. are employees and shareholders of Illumina, Inc. W.R.M., Y.L., and T.D. are employees and shareholders of Alexion, AstraZeneca Rare Disease. J.L. is an employee and shareholder of TileDB, Inc.

Figures

None
Graphical abstract
Figure 1
Figure 1
STARD diagram reporting flow of participants through the study URDGS, ultra-rapid diagnostic genome sequencing; CA NBS, California state newborn screening; RDGS, rapid diagnostic genome sequencing; gNBS.2k, genome sequencing-based NBS employing the 2,000 top-ranked genes in 27 gNBS programs.
Figure 2
Figure 2
Venn diagrams of disorders Shown are disorders identified by CA NBS (yellow), RDGS (pink), BeginNGS (blue), and gNBS.2k (purple) tests (A) and those anticipated to change early childhood management (B).
See this image and copyright information in PMC

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