The efficacy of islet autoantibody screening with or without genetic pre-screening strategies for the identification of presymptomatic type 1 diabetes

Abstract

Early detection of type 1 diabetes, in its presymptomatic stage, offers significant clinical advantages, including treatment that can delay disease onset. Current screening focuses on identifying islet autoantibody positivity, with proposed optimal testing at ages 2, 6 and 10 years potentially achieving up to 80% sensitivity. However, challenges arise from participation rates and costs associated with multiple screenings. Genetic pre-screening has been suggested as a complementary strategy to target high-risk individuals prior to autoantibody testing, but its real-world benefits remain uncertain. Broad genetic selection strategies, based on family history, HLA typing or polygenic risk scores, can identify subsets of the population at elevated risk. However, these approaches face issues like low recall rates, socioeconomic biases and limited applicability across diverse ancestries. Additionally, the cost-effectiveness and infrastructure requirements of integrating genetic testing into routine healthcare remain significant hurdles. The combined use of genetic and autoantibody testing could improve predictive value, especially with innovations like point-of-care genetic testing. Yet, the ultimate success of any screening programme depends less on specific strategies and more on maximising public and healthcare-provider engagement, ensuring high participation, and addressing socioeconomic and demographic disparities. Digital-health infrastructure may play a crucial role in improving recall rates and maintaining follow-up adherence. In conclusion, while repeated islet autoantibody screening remains the most effective standalone approach, conducting genetic screening prior to islet autoantibody testing may be practical in certain contexts, provided that sufficient resources and equitable strategies are employed. Public engagement and robust infrastructure are essential to realising the full potential of early type 1 diabetes detection programmes.

Fig. 1

Sensitivity of identifying youth who will develop type 1 diabetes (T1D) by 18 years of age during the presymptomatic early stage of disease, according to recall participation rate. Strategies shown include: (1) islet autoantibody (AAb) screening only (single screen, grey/blue solid line; two-age screen, light-blue solid line; three-age screen, dark-blue solid line); (2) genetic pre-screening with subsequent AAb screening at 2, 6 and 10 years of age in those identified at high genetic risk of T1D (dark-brown dashed line, strategy A [identifying youth with a first-degree relative with T1D or with HLA-DR3 or HLA-DR4-DQ8 haplotypes]; light-brown dashed line, strategy B [identifying youth with GRS2 >80th centile [12]]; yellow dashed line, strategy C [identifying individuals with a first-degree relative with T1D or DR3/DR4-DQ8 or HLA-DR4-DQ8/DR4-DQ8 genotypes]); and (3) combined genetic and islet AAb testing, followed by islet AAb testing in those with high genetic risk for T1D (i.e. individuals with a first-degree relative with T1D or HLA-DR3/DR4-DQ8 or HLA-DR4-DQ8/DR4-DQ8 genotypes; red solid line). The participation rate is assumed to be 100% for the first test (islet AAb or genetic); participant recall rates are defined on the x-axis for each subsequent test in the strategy

Fig. 2

Islet autoantibody (AAb) screening with or without genetic pre-selection. Models are presented for islet AAb screening at age 2, 6 and 10 years without genetic pre-selection, and with genetic pre-selection using the GRS2 at a threshold that selects 20% of children for subsequent islet AAb testing. The models are based on 100% participation at the first screening (of islet AAbs or for genetic pre-selection), and 50% participation loss at each subsequent screening step. The blue filled circles represent those selected by genetic pre-selection. The proportion of future tested refers to the estimated proportion of those who develop type 1 diabetes (T1D) by 18 years of age at each step. The proportion of future T1D identified refers to the estimated proportion of those who develop T1D by 18 years of age that are identified by the screen at each step. A summary of those identified, lost because they did not return for testing (recall loss), and lost because the islet AAb screen failed to identify them (AAb fail) or because they were excluded by the genetic pre-selection threshold (genetic loss) is also shown