Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
[Preprint]. 2025 Mar 13:2025.03.06.25323229.
doi: 10.1101/2025.03.06.25323229.

Type 1 Diabetes Polygenic Scores Improve Diagnostic Accuracy in Pediatric Diabetes Care

Raymond J Kreienkamp  1   2   3   4 , Aaron J Deutsch  2   3   4 , Alicia Huerta-Chagoya  2   3   4 , Erin M Borglund  5 , Jose C Florez  2   3   4 , Jason Flannick  4   6 , Miriam S Udler  2   3   4
Affiliations

Type 1 Diabetes Polygenic Scores Improve Diagnostic Accuracy in Pediatric Diabetes Care

Raymond J Kreienkamp et al. medRxiv. .

Update in

Abstract

Background: Accurately classifying pediatric diabetes can be challenging for providers, and misclassification can result in suboptimal care. In recent years, type 1 diabetes (T1D) polygenic scores, which quantify one's genetic risk for T1D based on T1D risk allele burden, have been developed with good discriminating capacity between T1D and not-T1D. These tools have the potential to improve significantly diagnostic provider accuracy if used in clinic.

Methods: We applied T1D polygenic scores to a group of pediatric patients (n=1846) with genetic data available in the Boston Children's Hospital PrecisionLink Biobank, including 96 individuals diagnosed with T1D.

Results: Patients with a clinical diagnosis of T1D had higher T1D polygenic scores compared to controls (Wilcoxon rank-sum P<0.0001). Sixty-nine of the 74 individuals with diabetes and a T1D polygenic score exceeding an externally validated cutoff for distinguishing T1D from not-T1D were confirmed to have T1D. There were multiple cases where T1D polygenic scores would have clinical utility. An elevated T1D polygenic score suggested T1D in a pancreatic autoantibody (PAA)- negative individual with negative MODY genetic testing and a phenotype matching T1D. A low T1D polygenic score accurately indicated atypical diabetes in an individual found to have HNF1B-MODY. One individual had positive PAA, but the provider noted that the patient may not have classic T1D, as later suggested by a low T1D polygenic score.

Conclusion: T1D polygenic scores already have clinical utility to aid in the accurate diagnosis of pediatric diabetes. Efforts are now needed to advance their use in clinical practice.

Keywords: genetics; pediatric diabetes; polygenic scores.

PubMed Disclaimer

Conflict of interest statement

MSU and JCF have received grant support from Novo Nordisk (unrelated to this manuscript). MSU has received royalties for contributions to UptoDate, Inc. JCF has participated on an advisory board for Alveus Therapeutics.

Figures

Figure 1.
Figure 1.
T1D Polygenic Score Performance in Boston Children’s Hospital PrecisionLink Biobank (PLB). (A) T1D_GRS_EUR performance in PLB for all individuals, European ancestry individuals, and non-European (Other) ancestry individuals, without diabetes or with T1D. Dotted line is 12.88, the optimal point for distinguishing T1D from not-T1D. (B) T1D_GRS_EUR performance in European PLB in controls, T1D, T2D, CFRD, and SIH. Dotted line is 12.88, the optimal point for distinguishing T1D from not-T1D. T1D, type 1 diabetes; T2D, type 2 diabetes; CFRD, cystic fibrosis-related diabetes; SIH, steroid-induced hyperglycemia; ****, Wilcoxon rank-sum P<0.0001.
Figure 2.
Figure 2.
Receiver Operating Characteristic Curves for T1D Polygenic Scores. Receiver operating characteristic curves for T1D_GRS_EUR for differentiating control and T1D in all individuals and European ancestry individuals.
Figure 3.
Figure 3.
Cases with Improved Diagnostic Accuracy with T1D Polygenic Score. (A) T1D_GRS_EUR score for a European ancestry individual with autoantibody-negative T1D compared to PLB scores for European ancestry controls and individuals with T1D. Note case has score greater than point with highest Youden index and more consistent with T1D. (B) T1D_GRS_EUR score for a European ancestry individual with MODY compared to PLB scores for European ancestry controls and individuals with T1D. Note score is significantly lower than point with highest Youden index, suggestive of not-T1D. (C) T1D_GRS_AFR and T1D_GRS_EUR score for African ancestry individual with an unclear diabetes diagnosis. Score is less than point with highest Youden index in both scores, suggesting not-T1D.
See this image and copyright information in PMC

References

    1. Hathout EH, Thomas W, El-Shahawy M, Nahab F, Mace JW. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics. 2001. Jun;107(6):E102. - PubMed
    1. Umpaichitra V, Banerji MA, Castells S. Autoantibodies in children with type 2 diabetes mellitus. J Pediatr Endocrinol Metab. 2002. Apr;15 Suppl 1:525–30. - PubMed
    1. Brooks-Worrell BM, Greenbaum CJ, Palmer JP, Pihoker C. Autoimmunity to islet proteins in children diagnosed with new-onset diabetes. J Clin Endocrinol Metab. 2004. May;89(5):2222–7. - PubMed
    1. Reinehr T, Schober E, Wiegand S, Thon A, Holl R, Group DP-WS. Beta-cell autoantibodies in children with type 2 diabetes mellitus: subgroup or misclassification? Arch Dis Child. 2006. Jun;91(6):473–7. - PMC - PubMed
    1. Fornari E, Barbetti F, Iafusco D, Lombardo F, Miraglia Dal Giudice E, Rabbone I, et al. Type 2 diabetes in pediatrics. Minerva Pediatr (Torino). 2021. Dec;73(6):549–62. - PubMed

Publication types

LinkOut - more resources