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Feasibility and validation of an integrated newborn screening algorithm with targeted Next Generation Sequencing (tNGS) technology as part of a 2nd-tier test for Pompe and MPS I

Award Number: R44HD094543
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Feasibility and validation of an integrated newborn screening algorithm with targeted Next Generation Sequencing (tNGS) technology as part of a 2nd-tier test for Pompe and MPS I - ABSTRACT Feasibility and validation of an integrated newborn screening algorithm with targeted Next Generation Sequencing (tNGS) technology as part of a 2nd-tier test for Pompe and MPS I Newborn screening (NBS) utilizes high throughput primary (1st-tier) screening assays paired with referral and clinical follow-up testing to identify babies who are affected with certain inherited disorders. Where necessary, 2nd-tier tests are performed prior to referral for follow-up testing in order to reduce the number of false positives (screen positive samples that are determined to be unaffected). False-positive newborn screens have undesired consequences for both families and the public health lab referral system, including: high cost associated with additional confirmatory testing, extra testing burden on referral centers, parental anxiety, parent-baby bonding issues, and added stress to the baby with additional tests and blood draws. There exists a strong need to reduce the rate of false positive newborn screens by implementing 2nd-tier molecular or biochemical tests prior to referral. This Phase II project will be a continuation of our successful Phase I research, which generated an integrated 2nd-tier targeted next generation sequencing (tNGS) workflow capable of identifying both point mutations and large deletions/duplication events from dried blood spot (DBS) specimens. We will continue to focus on Pompe disease and Mucopolysaccharidosis Type I (MPS I) -- two lysosomal storage disorders that were recently recommended for universal NBS in the U.S., but have been challenging to implement as NBS tests due to the high rates of pseudodeficient variants. Currently, 2nd-tier testing via either additional biochemical analysis or gene sequencing for known pathogenic variants are used to identify pseudodeficiency and reduce false positive test rates. We will expand our novel tNGS 2nd-tier workflow by: 1) developing bioinformatic tools for variants of uncertain significance (VUS) cut-off and cross-reactive immunological material (CRIM) status prediction; 2) improving our existing copy number variability (CNV) caller; and 3) integrating additional enzyme measurements and demographic data with the tNGS score. Demographic data has previously been shown to correlate to measured enzyme activities due to biological factors and DBS sample variability. Our algorithm will provide a better disease state call and associated data for improved follow-up care, provide critical predictions for disease onset and treatment considerations. The 2nd-tier tests developed through this work will be sold initially as a diagnostic send-out service and eventually as kits to public health labs that are currently screening, or planning to screen for Pompe disease and MPS I. Affected individuals who are identified using our tests will be referred to follow-up earlier and will have an accelerated path to disease confirmation and treatment. These features are especially important for Pompe disease, where a delay in therapeutic intervention of just days is known to negatively impact long term health outcomes. The approaches developed through this work have the potential to be expanded to cover dozens of enzyme deficiencies from the same primary dried blood spot sample.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$103,271 )
2024	2021	BAEBIES, INC.	25 ALEXANDRIA WAY	DURHAM	NC	27703	DURHAM	USA	Child Health and Human Development Extramural Research	000	3	12/11/2023	NON-COMPETING CONTINUATION	-$103,271
														Subtotal = -$103,271

Issue Date FY: 2021 ( Subtotal = $793,462 )
2021	2021	BAEBIES, INC.	615 DAVIS DR STE 800	DURHAM	NC	27709	DURHAM	USA	Child Health and Human Development Extramural Research	000	3	12/18/2020	NON-COMPETING CONTINUATION	$793,462
														Subtotal = $793,462

Issue Date FY: 2020 ( Subtotal = $778,727 )
2020	2020	BAEBIES, INC.	615 DAVIS DR STE 800	DURHAM	NC	27709	DURHAM	USA	Child Health and Human Development Extramural Research	000	2	1/7/2020	COMPETING CONTINUATION	$778,727
														Subtotal = $778,727

Grand Total All Awards = $1,468,918

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Feasibility and validation of an integrated newborn screening algorithm with targeted Next Generation Sequencing (tNGS) technology as part of a 2nd-tier test for Pompe and MPS I

Award Number: R44HD094543

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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