A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children

Abstract

Aims/hypothesis Progression to type 1 diabetes in children and adolescents is not uniform. Based on individual genetic background and environment, islet autoimmunity may develop at variable age, exhibit different autoantibody profiles and progress to clinical diabetes at variable rates. Here, we aimed to quantify the qualitative dynamics of sequential islet autoantibody profiles in order to identify longitudinal patterns that stratify progression rates to type 1 diabetes in multiple-autoantibody-positive children. Methods Qualitative changes in antibody status on follow-up and progression rate to diabetes were analysed in 88 children followed from birth in the prospective BABYDIAB study who developed multiple autoantibodies against insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and/or zinc transporter 8 (ZnT8A). An algorithm was developed to define similarities in sequential autoantibody profiles and hierarchical clustering was performed to group children with similar profiles. Results We defined nine clusters that distinguished children with respect to their sequential profiles of IAA, GADA, IA-2A and ZnT8A. Progression from first autoantibody appearance to clinical diabetes between clusters ranged from 6% (95% CI [0, 16.4]) to 73% (28.4, 89.6) within 5 years. Delayed progression was observed in children who were positive for only two autoantibodies, and for a cluster of 12 children who developed three or four autoantibodies but were IAA-negative in their last samples, nine of whom lost IAA positivity during follow-up. Among all children who first seroconverted to IAA positivity and developed at least two other autoantibodies (n = 57), the 10 year risk of diabetes was 23% (0, 42.9) in those who became IAA-negative during follow-up compared with 76% (58.7, 85.6) in those who remained IAA-positive (p = 0.004). Conclusions/interpretation The novel clustering approach provides a tool for stratification of islet autoantibodypositive individuals that has prognostic relevance, and new opportunities in elucidating disease mechanisms. Our data suggest that losing IAA reactivity is associated with delayed progression to type 1 diabetes in multiple-islet-autoantibodypositive children.Wolfgang zu Castell and Peter Achenbach contributed equally to this study. Electronic supplementary materialThe online version of this article

Joint modeling of longitudinal autoantibody patterns and progression to type 1 diabetes: results from the TEDDY study

“…It is also known that the combination of different autoantibodies as well as the autoantibody titer is associated with progression time [5]. For insulin autoantibodies (IAA), both their titers around seroconversion and their mean levels over time have been found to be associated with progression to T1D [2,6], and similar findings have been recently reported for other islet autoantibodies [7–9]. Nevertheless detailed analyses of autoantibody titers over time are lacking.…”

Передбачення Розвитку Цукрового Діабету 1-Го Типу Та діагностика Його Асимптомної Фази За допомогою Автоантитіл До острівців Лангерганса Підшлункової Залози У людини Задовго До виникнення У неї Захворювання

“…Недавно были получены данные, позволяющие прийти к заключению, что утрата IAA-реактивности ассоциирована с замедлением прогресса СД-1 у детей, позитивных ко многим ОАА [26].…”

Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study

“…All SNAIL participants had mAabs, but the proportion of individuals with each autoantibody varied between study cohorts. The first antibodies to be detected in about two-thirds of young children in BABYDIAB were IAA and their loss was associated with delayed progression [25]. In the SNAIL cohorts, IAA were more common in the first mAab-positive samples from BABYDIAB and ABIS children, but half of BOX and Pittsburgh family study participants were also IAA-positive in their first sample, despite most being tested first as adults.…”