Predictors of Transitions From GADA as the Initial Autoantibody to Multiple Autoantibodies of Type 1 Diabetes in Children at Risk by a Dynamic Prediction Model

Abstract

<p><strong>Objective:</strong> To design a dynamic prediction model for estimating the time of progression from a single glutamic acid decarboxylase autoantibody (GADA) to multiple islet autoantibodies and type 1 diabetes in children, exploring different longitudinally measured risk variables.</p><p><strong>Research Design and Methods:</strong> GADA-positive children (<em>n</em> = 379) participating in The Environmental Determinants of Diabetes in the Young (TEDDY) study were followed for the appearance of additional autoantibodies against either insulin autoantibody (IAA), insulinoma-like 2 autoantibody (IA-2A), or zinc transporter 8 antibody (ZnT8A) and type 1 diabetes. A dynamic prediction model was designed, including trajectories of longitudinal risk variables, autoantibody titers, and metabolic variables (C-peptide, glucose, and HbA1c) together with time-invariant variables (gender, age at GADA positivity, and high-risk HLA genotypes).</p><p><strong>Results:</strong> Transition risk from GADA to multiple autoantibodies was increased by lower age (<em>p</em> < 0.001) and by increased GADA titers during follow-up (<em>p</em> < 0.001), and was less likely in children with HLA DQ2/X but not DQ2/8 (<em>p</em> = 0.004). The transition risk from multiple autoantibodies without IA-2A to IA-2A positivity was associated with increased levels of 2 h glucose following oral glucose tolerance test (OGTT) (<em>p</em> < 0.001) and increased ZnT8A titers (<em>p</em> < 0.001). Increasing HbA1c (<em>p</em> < 0.001) and GADA titers (<em>p</em> < 0.001) were associated with an increased risk of transition from GADA only to type 1 diabetes; while increasing HbA1c (<em>p</em> < 0.001) was associated with the transition from multiple autoantibodies to type 1 diabetes. Risk of transition from multiple autoantibodies, including IA-2A to type 1 diabetes was also associated with 2 h glucose level (<em>p</em> < 0.001).</p><p><strong>Conclusion:</strong> The dynamic prediction model presented an individual time-specific risk of transition from a single GADA to multiple autoantibodies and type 1 diabetes.</p>