Screening Newborns for Type 1 Diabetes Risk: The Early Check Experience
Health Services and Implementation
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Primary Categories:
- Public Health Genetics
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Secondary Categories:
- Public Health Genetics
Introduction:
Early Check is a voluntary newborn screening (NBS) program available to babies born in North Carolina (NC). Parents can choose to screen their newborns for two panels of monogenic conditions and genetic risk for type 1 diabetes (T1D). T1D is a genetically complex condition that is well positioned for NBS trials because of its high prevalence (1:250), heritability, and existence of surveillance using sequential islet autoantibody testing. An FDA approved treatment, teplizumab, can delay clinical symptoms when implemented in autoantibody positive individuals. However, the use of genetic risk scores (GRS) in NBS faces additional implementation challenges beyond those of monogenic conditions. The 67-marker GRS2 used in this study, was developed in a white European cohort but has been shown to perform similarly in Hispanic cohorts; sensitivity in Black and Asian populations is reduced. The aims of this study are to determine GRS marker callability from laboratory genome sequencing (GS) data, parent/guardian uptake, GRS outcomes, and 24 month clinical and psychosocial outcomes.
Methods:
Early Check has offered voluntary NBS via GS using residual dried blood spots since September 2023. Marker missingness thresholds were developed beyond which GRS would not be reported, set at ≥ 1 HLA-DQ marker or ≥ 3 non-HLA-DQ markers. GRS reporting thresholds were set that equate to three categories of lifetime risk (LR) for T1D based on study population distribution: low concern (<2% LR); moderate concern (2-5% LR); or higher concern (>5% LR). We developed reports, educational protocols, educational materials, and autoantibody surveillance and follow-up plans. Autoantibody testing is offered at 9 and 24 months for those with higher concern results and at 24 months for those with moderate concern results.
Results:
After 13 months, approximately 3,000 newborns have been enrolled for monogenic screening with 87% of parents selecting T1D screening. White and Asian parents were significantly more likely to select T1D screening than Black (padj < 0.0001) or Hispanic parents (padj < 0.05). Marker callability from laboratory-provided GS was acceptable for 98.5%. Mean GRSs were significantly lower for Black participants compared to White participants (p < .0001). Overall, 88% were low concern, 7% moderate concern, and 4% higher concern. To date, 53% of higher concern infants who have reached the age of 9 months have attempted autoantibody testing with one infant positive for a single autoantibody.
Conclusion:
Preliminary results from Early Check demonstrate the feasibility of using GS to screen for both monogenic conditions and an exemplar complex condition, T1D. Improved GRSs with equitable performance across ancestry groups is needed before universal NBS application. Ongoing follow-up research with parents and clinicians will assess acceptability, clinical utility, and psychosocial outcomes.
Early Check is a voluntary newborn screening (NBS) program available to babies born in North Carolina (NC). Parents can choose to screen their newborns for two panels of monogenic conditions and genetic risk for type 1 diabetes (T1D). T1D is a genetically complex condition that is well positioned for NBS trials because of its high prevalence (1:250), heritability, and existence of surveillance using sequential islet autoantibody testing. An FDA approved treatment, teplizumab, can delay clinical symptoms when implemented in autoantibody positive individuals. However, the use of genetic risk scores (GRS) in NBS faces additional implementation challenges beyond those of monogenic conditions. The 67-marker GRS2 used in this study, was developed in a white European cohort but has been shown to perform similarly in Hispanic cohorts; sensitivity in Black and Asian populations is reduced. The aims of this study are to determine GRS marker callability from laboratory genome sequencing (GS) data, parent/guardian uptake, GRS outcomes, and 24 month clinical and psychosocial outcomes.
Methods:
Early Check has offered voluntary NBS via GS using residual dried blood spots since September 2023. Marker missingness thresholds were developed beyond which GRS would not be reported, set at ≥ 1 HLA-DQ marker or ≥ 3 non-HLA-DQ markers. GRS reporting thresholds were set that equate to three categories of lifetime risk (LR) for T1D based on study population distribution: low concern (<2% LR); moderate concern (2-5% LR); or higher concern (>5% LR). We developed reports, educational protocols, educational materials, and autoantibody surveillance and follow-up plans. Autoantibody testing is offered at 9 and 24 months for those with higher concern results and at 24 months for those with moderate concern results.
Results:
After 13 months, approximately 3,000 newborns have been enrolled for monogenic screening with 87% of parents selecting T1D screening. White and Asian parents were significantly more likely to select T1D screening than Black (padj < 0.0001) or Hispanic parents (padj < 0.05). Marker callability from laboratory-provided GS was acceptable for 98.5%. Mean GRSs were significantly lower for Black participants compared to White participants (p < .0001). Overall, 88% were low concern, 7% moderate concern, and 4% higher concern. To date, 53% of higher concern infants who have reached the age of 9 months have attempted autoantibody testing with one infant positive for a single autoantibody.
Conclusion:
Preliminary results from Early Check demonstrate the feasibility of using GS to screen for both monogenic conditions and an exemplar complex condition, T1D. Improved GRSs with equitable performance across ancestry groups is needed before universal NBS application. Ongoing follow-up research with parents and clinicians will assess acceptability, clinical utility, and psychosocial outcomes.