Type 1 Diabetes National Screening Pilot: General Practice Feasibility and Acceptability Study

BRIEF NAME & WHY: A single-arm implementation pilot exploring the feasibility and acceptability of a type 1 diabetes screening program for the general paediatric population embedded into primary care in Australia, comprising of genetic-risk stratified screening at routine immunisations and/or health check appointments (between 6 weeks to 6 months of age) with autoantibody follow-up testing for 'increased chance children' from 12 months to 5 years of age. WHAT (MATERIALS & PROCEDURES): MATERIALS: **INFORMATION MATERIALS: Parents/guardians of eligible children will be offered a study brochure upon clinic check-in. Families who express interest in participating will be provided with a hard-copy Participant Information Statement and Consent Form by their GP or Practice Nurse. Parent/guardians will also be provided with any relevant information relating to their child’s screening result (+/- follow-up result if required) e.g. explanation of the result, +/- recommendations for follow-up testing +/- specialist referral. GPs and Practice Nurses will be provided with information and training regarding T1D and study screening and follow-up pathways and procedures. **CONSUMABLES: On-site screening sample collection kits will be provided to the GP practices for either heel prick dried bloodspots (single-use retractable lancets and Whatman 903 Proteinsaver cards) or saliva swabs (ORAcollect OC-175, DNA Genotek), depending on the protocol at the time. Follow-up dried bloodspot kits also containing single-use retractable lancets and Whatman 903 Proteinsaver cards will be provided to GP practices for on-site sampling as required (described below). PROCEDURES **RECRUITMENT (SCREENING) & FOLLOW-UP: Parents/guardians of children aged 6 weeks to 6 months who are attending a routine immunisation and/or health check appointment will be offered to have their child screened (polygenic risk i.e. T1D GRS2 score) using either a heel prick dried bloodspot or saliva swab,depending on the protocol at the time. Both sample collection methods are simple and quick to perform (<5 mins) and will be integrated into these routine appointments, rather than a stand-alone study appointment/visit. Recruitment (i.e. screening phase) will be open for up to 16 weeks at each site, but will cease sooner if recruitment targets are met (n=300 children in total). - Low genetic chance children - Children identified as having a genetically ‘low chance’ of type 1 diabetes will not be offered any follow-up testing. - Increased genetic chance children - Children identified as having a genetically ‘increased chance’ of type 1 diabetes will be offered follow-up testing for type 1 diabetes autoantibodies (finger or heel prick dried bloodspot) at 12 months of age, also during their routine immunisation/health check appointment. Positive autoantibody screens will be confirmed via a venous blood draw at a local pathology centre. Increased chance children who return a negative autoantibody test result will be offered ongoing annual follow-up autoantibody testing until they reach 5 years of age. **POLYGENIC RISK (GRS2): Screening samples (dried bloodspot/saliva) will be analysed at Pacific Northwest Research Institute, USA. Samples will have their DNA extracted, quantitated and normalised and then genotyped using a custom type 1 diabetes and coeliac disease-specific single nucleotide polymorphism (SNP) panel (84 SNPs). Polygenic risk scores (T1D GRS2 scores) will be calculated for each sample. The polygenic risk score is a numerical summary of an individual's risk of type 1 diabetes, rather than diagnostic result. It is calculated as the weighted sum of the risk associated with 67 SNPs. Individual scores will be reported as either ‘low chance‘ or ‘increased chance’ of developing type 1 diabetes in childhood, rather than reported as numerical scores. Children with a GRS2 score of 19.09 or above will be considered to have an ‘increased chance’ of developing type 1 diabetes (risk of type 1 diabetes: 2.4% or ~1 in 40 children vs general population risk: 0.3% or 1 in 300 children). This group represents the top 10th centile of the population by type 1 diabetes risk (i.e. 1 in every 10 children will receive an ‘increased chance’ result) and captures ~80% of all future cases of type 1 diabetes diagnosed in childhood. Most children (9 in 10 children) will be below this threshold and considered to have a ‘low chance’ of developing type 1 diabetes in childhood (risk: 0.08% or 8 in 10,000 children vs general population risk: 0.3% or 1 in 300 children). Coeliac disease risk scores will not be returned to families. **AUTOANTIBODY ANALYSIS: Follow-up dried bloodspot samples will be tested for four islet autoantibodies (insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen 2 (IA-2A) and zinc transporter 8 (ZnT8A)) at Royal Melbourne Hospital using the antibody detection by agglutination-PCR (ADAP) assay for islet autoantibodies (sensitivity: 85%, specificity: 98%). Confirmation venous serum samples will be analysed in a two-step process at Royal Melbourne Hospital using the 3 Screen assay (RSR Ltd) for GADA, IA-2A and ZnT8A and individual radioimmunoassay for IAA. Where the 3 Screen is positive, confirmatory individual ELISAs for GADA, IA-2A and ZnT8A will be conducted. Samples will be concurrently analysed for HbA1c and random blood glucose at a local pathology laboratory to allow T1D staging, if detected. WHO DELIVERED/PROVIDED THE INTERVENTION & WHERE: The ‘intervention’ (i.e. sample collection for polygenic risk score analysis) will be performed by trained GPs or Practice Nurses during participating children's routine immunisation +/- health check appointments using on-site collection kits provided by the Pilot.