UK Islet Autoantibody Registry

BACKGROUND AND RATIONALE Type 1 diabetes can be identified in the pre-clinical phase Understanding of the natural history of Type 1 diabetes (T1D) has made it possible to diagnose children, young people and adults (CYPA) in the preclinical phase. The presence of ≥ 2 Islet autoantibodies (IAb) in serum, to 4 different proteins (insulin, Glutamic Acid Decarboxylase (GADA), insulinoma-2-associated autoantibodies (IA-2A), and/or zinc transporter 8 autoantibodies (ZnT8A) identifies individuals who will develop T1D. The latency period before clinical diagnosis can last months or years, with individuals with ≥2 IAb moving between stage 1 (normoglycaemia), stage 2 (dysglycaemia) to stage 3 (hyperglycaemia), or clinical disease.

Data from combined longitudinal cohorts shows that ≥ 2 IAb in children predicts that stage 3 T1D will develop in over 80% over the next 15 years, and near 100% over a lifetime, whereas only around 10-15% children with a single IAb progress to insulin requirement. Individuals may therefore live for many years with the knowledge they may develop T1D .

Potential benefits of early identification of T1D Identifying T1D before symptoms develop has several potential advantages, including reducing presentation with life-threatening diabetic ketoacidosis (DKA) and its associated morbidity, and potentially reducing the psychological trauma at diagnosis which some families liken to 'post-traumatic distress' . Reducing DKA and hospitalisations can also reduce associated health care costs. Screening identifies individuals suitable for trials to prevent or delay T1D. Therapies are now being trialled in stage 2 T1D, for example, the ATG prevention trial 'STOP-T1D'.

Concerns about screening Informing someone that they have positive IAb may cause psychological stress. For example, the Fr1da study, which has now tested > 170,000 children for IAb, found that informing parents of their child's positive IAb result induced stress (assessed by the Patient Health Questionnaire-9); this stress declined after 12 months of follow up. Within the registry, the investigators have recourse to the advice of a senior clinical psychologist, who can provide signposting support for individuals identified through the registry, if psychological concerns arise.

Screening initiatives Until recently, screening strategies have focussed on first-degree relatives (FDR) of individuals with T1D, who have a 15 times higher risk of developing stage 3 T1D compared to the general population. However, since > 85% of people with T1D do not have a family history, general population screening efforts have been started.

There are now several different screening programs in the UK identifying children, young people and adults with IAbs. It is anticipated that there are approximately 700 such children and adults from the different research platforms. These individuals do not typically present to their general practitioner as they have no symptoms, and therefore it is extremely rare to know of such individuals in the UK. Individuals can also be identified from clinical care (personal communication Besser & Randell, BSPED). In order to answer our research questions, the investigators need a mechanism to identify, recruit and consent such individuals into a single combined registry.

Inclusion criteria

• Male or female, aged 6 months - 70 years
• IAb positive (≥ 1) to any of the following: insulin/GAD/IA2/ZnT8, confirmed in a reference laboratory.
• Participant is willing and able to give informed consent for participation in the study (≥ 16 years old), or for < 16 years, parental/guardian consent (plus assent, where appropriate)
• Living in the UK
• For ADDRESS-2 participants only: have taken part in a blood draw as part of ADDRESS-2
• For the qualitative interviews: Have been living with (or is a parent/guardian of a child who has been living with) a positive IAb result for ≥ 6 months.

Exclusion criteria

• Ongoing subcutaneous insulin requirement