Aims/hypothesis <p>Accurate understanding of type 1 diabetes risk is critical for optimisation of counselling, monitoring and interventions, yet even within established staging classifications, individual time to clinical disease varies. Previous work has associated IA-2A positivity with increased type 1 diabetes progression but a comprehensive assessment of the impact of screening for IA-2A positivity across the natural history of autoantibody positivity has not been performed. We asked whether IA-2A would consistently be associated with higher risk of progression within and across established stages of type 1 diabetes in a large natural history study.</p> Methods <p>Genetic, autoantibody and metabolic data from adult and paediatric autoantibody-negative (<i>n</i>=192) and autoantibody-positive (<i>n</i>=4577) relatives of individuals with type 1 diabetes followed longitudinally in the Type 1 Diabetes TrialNet Pathway to Prevention Study were analysed. Cox regression was used to compare cumulative incidences of clinical diabetes by autoantibody profiles and disease stages.</p> Results <p>Compared with IA-2A⁻ individuals, IA-2A⁺ individuals had higher genetic risk scores and clinical progression risk within single-autoantibody-positive (5.3-fold increased 5 year risk), stage 1 (2.2-fold increased 5 year risk) and stage 2 (1.3-fold increased 5 year risk) type 1 diabetes categories. Individuals with single-autoantibody positivity for IA-2A showed increased metabolic dysfunction and diabetes progression compared with people who were autoantibody negative, those positive for another single autoantibody, and IA-2A⁻ stage 1 individuals. Individuals at highest risk within the single-IA-2A⁺ category included children (HR 14.2 [95% CI 1.9, 103.1], <i>p</i>=0.009), individuals with IA-2A titres above the median (HR 3.5 [95% CI 1.9, 6.6], <i>p</i>&lt;0.001), individuals with high genetic risk scores (HR 1.4 [95% CI 1.2,1.6], <i>p</i>&lt;0.001) and individuals with <i>HLA DR4</i>-positive status (HR 3.7 [95% CI 1.6, 8.3], <i>p</i>=0.002). When considering all autoantibody-positive individuals, progression risk was similar for euglycaemic IA-2A⁺ individuals and dysglycaemic IA-2A⁻ individuals.</p> Conclusions/interpretation <p>IA-2A positivity is consistently associated with increased progression risk throughout the natural history of type 1 diabetes development. Individuals with single-autoantibody positivity for IA-2A have a greater risk of disease progression than those who meet stage 1 criteria but who are IA-2A⁻. Approaches to incorporate IA-2A⁺ status into monitoring strategies for autoantibody-positive individuals should be considered.</p> Graphical Abstract <p></p>