Objective
The Fr1da-Plus study addresses an early stage of type 1 diabetes (preclinical or asymptomatic type 1 diabetes), identified by the detection of multiple islet autoantibodies, and asks whether it is feasible to introduce population-based screening for early stage type 1 diabetes into a public health childhood prevention program, by continuing and advancing the Fr1da model project in Bavaria, Germany. Within Fr1da-Plus we will further determine the feasibility of a population (public health) islet autoantibody screening in order to evaluate whether such a screening can be recommended as a standard preventive health measure. We also aim to determine the feasibility of screening in two age groups, and with a combination of islet autoantibodies and genetics, we want to provide estimates of the prevalence of early stage type 1 diabetes in infancy, and determine how early stage type 1 diabetes in infancy is associated with environmental factors. Furthermore, we will notify and follow-up of children with high risk for development of an early stage of type 1 diabetes, and want to establish a resource for recruitment into prevention trials and natural history studies.
Background Rationale
Type 1 diabetes is one of the most common chronic diseases of childhood with an incidence that is increasing yearly in European countries. The prevalence of type 1 diabetes in the age-group under 20 years is 0.3-0.5%. Diagnosis is usually made by blood glucose measurements at the time of acute life-threatening onset of the disease. The acute disease onset requires hospitalization, and the metabolic decompensation that accompanies acute clinical onset is a major complication for patients. Both the decompensation and the adaptation of the family to the disease and its treatment are expensive burdens. Early diagnosis of type 1 diabetes could avoid the acute disease onset and markedly reduce the prevalence of metabolic decompensation and the hospitalization days required. Furthermore, it would open the path to population-based prevention of the disease.
Description of Project
Type 1 diabetes can be diagnosed at an early stage, which is still free of symptoms via islet autoantibody detection. Early diagnosis of type 1 diabetes during an early stage can prevent severe metabolic decompensation that frequently occurs during hyperglycemia and insulin deficiency at the clinical manifestation of type 1 diabetes. Preventive teaching, education, and monitoring may lead to prevention of severe metabolic decompensation and ketoacidosis and allow preparation of families and children for insulin replacement therapy.
The Fr1da study was designed as a model project in order to introduce public health screening for early stage type 1 diabetes (confirmed positive multiple beta-cell autoantibodies) in Bavaria, Germany, in the context of compulsory preventive medical check-ups during early childhood. Fr1da-Plus is a continuation and advancement of the Fr1da study with three novel elements: 1) the inclusion of a newly developed luciferase immune-precipitation system (LIPS) IAA assay to the screening, 2) the notification and follow-up of children with one single confirmed positive beta-cell autoantibody and a genetic risk score associated with high risk to develop early stage type 1 diabetes, and 3) the screening of children in two age groups. The screening will be performed for a period of approximately 36 months (Jan 2019 – Dec 2021) on 85,000 children from Bavaria, Germany. 65,000 children aged 2-5 years and 15,000 children aged 9-10 years are expected to be screened for the first time, while 5,000 children aged 9-10 years are expected to be re-screened after first screening in the Fr1da study.
Within the Fr1da-Plus study we will continue testing the feasibility of a population (public health) islet autoantibody screening in order to evaluate whether such a screening can be recommended as a standard preventive health measure. Furthermore, we want to determine the feasibility of screening in two age groups, and with a combination of islet autoantibodies and genetics. We aim to provide estimates of the prevalence of early stage or asymptomatic type 1 diabetes in infancy and high risk to develop early stage type 1 diabetes in infancy, and determine how early stage type 1 diabetes in infancy is associated with environmental factors. We also want to establish a resource for recruitment into prevention trials and natural history studies.
Capillary blood will be drawn for screening and will be analysed for beta-cell autoantibodies using a combined 3-Screen-ELISA assay and a LIPS assay. If at least two positive beta-cell autoantibodies are detected, the diagnosis of an early stage 1 diabetes will be made. If one positive beta-cell autoantibody is detected in combination with a high genetic risk score, the status of high risk to develop early stage 1 diabetes will be made. Children with early stage type 1 diabetes or high risk to develop early stage type 1 diabetes and their parents will be invited to participate in teaching and education sessions. Each child will receive a preventive monitoring plan for regular testing of glucose, HbA1c, OGTT, and growth in order to prevent severe metabolic decompensation and ketoacidosis. An anxiety and stress assessment will be performed to evaluate the psychological impact of an early diagnosis. Families will be offered to participate in further research and prevention studies as available. We believe that this project will have a major impact on the implementation of screening for early stage type 1 diabetes as a standard into the preventive health program in Germany, and eventually other countries, and will set new standards for early diagnosis of type 1 diabetes and teaching.
Anticipated Outcome
The Fr1da-Plus study is a continuation and advancement of the Fr1da model project in Bavaria, Germany, and has a major impact on the implementation of screening for early stage type 1 diabetes as a standard into the preventive health program in Germany that can be adopted by other countries. Furthermore, it will help to prevent diabetic ketoacidosis on a population level as well as to reduce the burden of the families. The project will set new standards for early diagnosis of type 1 diabetes. It allows targeted training, education, psychological preparation to deal with the insulin therapy and metabolic monitoring. In addition the project will provide the opportunity to notify and follow-up of children with high risk to develop early stage type 1 diabetes and to assess environmental determinants for early stage type 1 diabetes. It will also provide a validation cohort for findings from other cohorts and will provide an unprecedented opportunity to design primary and secondary prevention studies to delay or prevent the onset of hyperglycemia and insulin dependence on a broad population based level and with relatively rapid recruitment capacity.
Relevance to T1D
The project will reduce disease severity and risk of metabolic decompensation and provide the opportunity to prevent hyperglycemia.