Landmark models to define the age-adjusted risk of developing stage 1 type 1 diabetes across childhood and adolescence

Abstract

Background Autoimmune diseases are often preceded by an asymptomatic autoantibody-positive phase. In type 1 diabetes, the detection of autoantibodies to pancreatic islet antigens in genetically at-risk children is prognostic for future clinical diabetes. Testing for islet autoantibodies is, therefore, performed in a range of clinical studies. Accurate risk estimates that consider the a priori genetic risk and other risk modifiers are an important component of screening. The age of an individual is an under-appreciated risk modifier. The aim of this study was to provide age-adjusted risk estimates for the development of autoantibodies across childhood in genetically at-risk children. Methods The prospective BABYDIAB and BABYDIET studies included 2441 children from birth who had a first-degree relative with type 1 diabetes. Children were born between 1989 and 2006 and were regularly followed from birth for the development of islet autoantibodies and diabetes. A landmark analysis was performed to estimate the risk of islet autoantibodies at birth and at the age 3.5, 6.5 and 12.5 years. Exponential decay curves were fitted for the risk by the age of 20 years. Results The risk of islet autoantibodies by the age of 20 years was 8%, 4.6%, 2.6% and 0.9%, at the landmark ages of birth, 3.5, 6.5 and 12.5 years, respectively. The short-term risks (within 6 years of follow-up) at these landmark ages were 5.3%, 2.9%, 1.8% and 1%, respectively. The decline in autoantibody risk with age was modelled using a one-phase exponential decay curve ( r = 0.99) with a risk half-life of 3.7 years. This risk decay model was remarkably consistent when the outcome was defined as islet autoantibody-positive or multiple islet autoantibody-positive and when the study cohort was stratified by HLA risk genotype. A similar decay model was observed for coeliac disease-associated transglutaminase antibodies in the same cohort. Unlike the risk of developing islet autoantibodies, the rate of developing clinical diabetes in children who were islet autoantibody-positive did not decline with age. Conclusion The risk of developing autoantibodies drops exponentially with age in children with a first-degree relative with type 1 diabetes. Electronic supplementary material The online version of this article (10.1186/s12916-019-1360-3) contains supplementary material, which is available to authorized users.

An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood

“…The follow-up time or horizon was set to 5 years from the landmark age. Because we expected a decline in risk (7), onephase exponential decay functions were used to describe the 5-year horizon risk with increasing age. The curves describe the residual risk of developing islet autoantibodies in the subsequent 5 years for children who were negative at each landmark age.…”

Enteroviruses and T1D: Is It the Virus, the Genes or Both which Cause T1D

“…It is detected by any of the ICA, IAA, GAD, IA-2 and ZnT8 auto-antibodies and follows the exponential decay model starting in the first year of life in genetically at-risk children in affected families with first-degree relatives with T1D (FDR). Indeed, children who developed autoimmunity in the first year of life had the highest risk of T1D [ 51 ], which is further increased in those children with the high-risk HLA-DR3-DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotypes [ 24 , 51 ].…”

Birth and coming of age of islet autoantibodies

“…The age at screening is also important. For first‐degree relatives of patients with type 1 diabetes, the risk of developing islet autoantibodies decreases exponentially with age, with a half‐life of 3–4 years . This has practical implications.…”