Background Retention of study participants in observational studies is essential to maintaining the representativeness of the population, minimizing selection bias, and assuring sufficient statistical power. The aim of this report is to describe the structures and strategies used to retain participants in The Environmental Determinants of Diabetes in the Young (TEDDY) Study, an observational study of children at increased genetic risk for type 1 diabetes followed in an intensive protocol from birth until age 15. Methods Teague et al’s systematic review of study retention strategies identified four domains: barrier reduction; community building; follow-up/reminder; and tracing strategies (1). TEDDY retention strategies were categorized into each of these domains. A fifth category presented strategies unique to TEDDY. Results TEDDY employed over one hundred retention strategies during the 15 years of follow-up; many could be categorized within the Teague domains. Strategies unique to TEDDY included (1) study structures to support retention; (2) risk communication and education strategies specific to this population; (3) Data-informed retention strategies that addressed protocol challenges in real-time; and (4) implementation of a re-engagement protocol for those who had withdrawn from the study. Conclusion Pediatric cohort studies should include strategies, structures, and resources to address retention at the study's initiation and on an ongoing basis. Retention strategies should not remain static but change with the developmental needs of the child. Collecting and analyzing data on an ongoing basis permits retention strategies to be put in place to address protocol and retention challenges in real time. Trial registration ClinicalTrials.gov Identifier: NCT00279318

Introduction & Objective: Screening for preclinical T1D and early-stage monitoring are typically only accessible in research studies, but will likely soon expand to clinical settings. Potential strategies for conducting monitoring of early-stage T1D in clinical settings must be explored. This study assessed feasibility of remote SMBG in youth with preclinical T1D. Methods: Participants from the Autoimmunity Screening for Kids (ASK) study were eligible if enrolled in ASK ≥6 months prior to this study’s start. Upon enrollment in the SMBG study, participants transitioned to an advanced technology glucometer (OneTouch Verio Reflect®) with remote data sharing capability. 12 months of remotely transferred SMBG data was collapsed into 3-month sums and SMBG frequency was explored with Poisson regression. Results: Data from 42 participants were included (age 13 ± 4.1 years, 62% non-Hispanic white, 62% female, 17% T1D first-degree relative). Frequency of SMBG was highest in the first 3 months (median [IQR]: 3.0 [1.0-8.5]). SMBG frequency decreased over time; there were fewer SMBG in months 4-6 (1.0 [0.0-4.3]), 7-9 (0.0 [0.0-2.3]), and 10-12 (0.0 [0.0-2.0]) (p<0.0001). Conclusion: Use of devices with remote data transfer is one potential tactic to support clinicians in conducting early-stage T1D monitoring. Strategies to sustain engagement are needed; qualitative studies may provide insight into barriers. Disclosure M.E. Pauley: None. C. Geno Rasmussen: None. K.A. Bautista: None. M. Munoz: None. I. Taki: None. F. Sepulveda: None. J. Baxter: None. M. Rewers: Advisory Panel; Sanofi. Other Relationship; Sanofi. Consultant; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Consultant; Provention Bio, Inc. Research Support; Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases. K.M. Simmons: Advisory Panel; Provention Bio, Inc. Consultant; Provention Bio, Inc. Research Support; Provention Bio, Inc., Novartis AG. Consultant; Medtronic. Funding JDRF (2-SRA-2022-1270-S-B); NIH NIDDK (T325T32DK063687); DiabDocs Physician-Scientist Career Development Award: NIH NIDDK (K12DK133995) & The Leona M. and Harry B. Helmsley Charitable Trust to Stanford University (2305-06041)

Objective: To assess anxiety and risk perception among parents whose child screened positive for islet autoantibodies, indicating elevated risk for type 1 diabetes. Research Design and Methods: The Autoimmunity Screening for Kids (ASK) study identified 319 children ages 1-17 years at risk for type 1 diabetes via screening for islet autoantibodies; 280 children with confirmed islet autoantibodies and their caregiver(s) enrolled in a follow-up education and monitoring program to prevent diabetic ketoacidosis at diagnosis. Parents completed questionnaires, including a 6-item version of the State Anxiety Inventory (SAI) to assess anxiety about their child developing type 1 diabetes, and a single question to assess risk perception at each monitoring visit. Results: At the first ASK follow-up monitoring visit, mean parental anxiety was elevated above the clinical cutoff of 40 (SAI: 46.1±11.2). At the second follow-up monitoring visit (i.e., Visit 2), mean anxiety remained elevated but started to trend down. Approximately half (48.9%) of parents reported their child was at increased risk for type 1 diabetes at the initial follow-up monitoring visit (Visit 1). Parents of children with a first-degree relative with type 1 diabetes were more likely to report their child was at increased risk. Conclusions: Most parents of autoantibody positive children have high anxiety about their child developing type 1 diabetes. Information about risk of developing type 1 diabetes is difficult to convey as evidenced by the wide range of risk perception reported in this sample.

Objective: Children identified with stage 1 type 1 diabetes are at high risk for progressing to stage 3 (clinical) diabetes and require accurate monitoring. Our aim was to establish CGM metrics that could predict imminent progression to diabetes. Methods: In the Autoimmunity Screening for Kids study, 91 children persistently islet autoantibody positive (median age 11.5 y, 48% non-Hispanic White, 57% female) with a baseline CGM were followed for development of diabetes for a median of 6 (range:0.2-34) months. Of these, 16 (18%) progressed to clinical diabetes in a median of 4.5 (range:0.4-29 months. Results: Compared to non-progressors, progressors had significantly higher average sensor glucose (119 vs 105 mg/dL) and increased glycemic variability: SD 27 vs 16, CV 21 vs 15, MODD 24 vs 16 and MAGE 43 vs 26. Progressors spent 21% of time above 140 mg/dl (TA140) and 8% above 160 mg/dl, compared to 3% and 1%, respectively, for non-progressors. In survival analyses, the risk of progression to diabetes in one year was 80% in those with TA140 >10%; in contrast, it was only 5% in the other participants. Performance of prediction by receiver operating curve analyses showed area under the curve of >0.89 for both individual and combined CGM metric models. Conclusions: TA140 >10% is associated with a high risk of progression to clinical diabetes within the next year in autoantibody positive children. CGM should be included in the ongoing monitoring of high-risk children and could be used as potential entry criteria for prevention trials.

INTRODUCTION The Autoimmunity Screening for Kids (ASK) study is a large scale pediatric screening study in Colorado for celiac disease (CD) and type 1 diabetes. This is a report of the CD outcomes for the first 9,973 children screened through ASK. METHODS ASK screens children aged 1-17 years for CD using 2 highly sensitive assays for tissue transglutaminase autoantibodies (TGA): a radiobinding (RBA) assay for IgA TGA and an electrochemiluminescence (ECL) assay that detects all TGA isotypes. Children who test positive on either assay are asked to return for confirmatory testing. Those with a confirmed RBA TGA level ≥ 0.1 (twice the upper limit of normal) are referred to the Colorado Center for Celiac Disease for further evaluation; all others are referred to primary care. RESULTS Of the initial 9,973 children screened, 242 children were TGA+ by any assay. Of those initially positive, 185 children (76.4%) have completed a confirmation blood draw with 149 children (80.5%) confirming positive by RBA TGA. Confirmed RBA TGA+ was associated with a family history of CD (odds ratio [OR] = 1.83; 95% confidence interval 1.06-3.16), non-Hispanic white ethnicity (OR = 3.34; 2.32-4.79), and female sex (OR = 1.43; 1.03-1.98). Gastrointestinal symptoms of CD, assessed at the initial screening, were reported equally often among the RBA TGA+ vs TGA- children (32.1% vs 30.5%, P = 0.65). DISCUSSION The initial results of this ongoing mass-screening program confirm a high prevalence of undiagnosed CD autoimmunity in a screened US population. Symptoms at initial screening were not associated with TGA status (see Visual abstract, Supplementary Digital Content 5, http://links.lww.com/AJG/B587).

Screening for islet autoantibodies (IAb) followed by education and monitoring of children at high risk for type 1 diabetes (T1D) substantially reduces incidence of diabetic ketoacidosis at diagnosis. We assess parental anxiety and accuracy of risk perception as part of ASK screening, education and monitoring program. The 10-y risk of clinical diabetes is 70% in children positive for multiple IAb, 50% with single high-affinity, and 2% with single low-affinity (confirmed twice). As of March 2020, ASK had screened for IAb 23,847 general population children and further monitored 280, including 136 with 50-70% high risk and 144 with 2% lower risk; 9% had a first degree relative (FDR) with T1D. At each visit, parental risk perception and anxiety were assessed using the State Anxiety Inventory (SAI), with a score >40 denoting elevated anxiety. Reported here are results from the 1st visit (N=280) and for those with a 2nd visit (N=119). At the 1st visit, parental anxiety was elevated (mean SAI=46.1) with no difference by child’s risk status, family history, or by which parent responded. SAI was significantly higher in ethnic minorities than in non-Hispanic whites (p<0.0001). Anxiety decreased between the 1st and 2nd education and monitoring visit from a mean of 46.1 to 43.8 (p=0.024), most notably in parents of high risk children (44.9 to 42.7 p=0.009) and FDRs (44.6 to 38.6, p=0.059). Accuracy of risk perception was low at 49% and did not improve at the 2nd visit. FDR compared to non-FDR (83% vs. 46%, p=0.004) and parents of high risk compared to low risk children had a more accurate risk perception (61% vs. 37% p <0.0001). Parental anxiety after learning of a child’s positive screening result decreased rapidly in families enrolled in monitoring. However, accurate perception of T1D risk appears less malleable during the initial 3-6 months of the monitoring. Tailored intervention for parents with inaccurate risk perception may be warranted. Disclosure C. Geno rasmussen: None. J. Baxter: None. F. Dong: None. K. A. Bautista: None. F. Sepulveda: None. D. Felipe-morales: None. M. Rewers: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; RTI, Research Support; Self; Janssen Research & Development, LLC, JDRF. Funding JDRF (3-SRA-2018-564-M-N)

Our goal was to explore feasibility of screening for pre-symptomatic type 1 diabetes (T1D) and celiac disease (CD) in the general population. Efficiency of and barriers to sustainable screening in various health care settings are described. From 2017-2019, the ASK study screened 23,578 children in Colorado. Of those, 0.94% were positive for islet (95% CI 0.82-1.08) and 2.10% for transglutaminase (95% CI 1.92-2.29) autoantibodies. The screening aimed to engage providers in hospital specialty clinics (HSC), emergency departments (ED), private primary care (PPC), government primary care (GPC), diabetes center (BDC), community events (CE), and retail clinics (RC). ASK provided, as needed, on-site screening staff, provider reimbursement, and electronic consenting. Efficiency was defined as #screened/research staff full-time effort per week. The majority (72%) of screenings were completed at an ED or HSC, with 91% of screenings conducted by ASK staff. Highest screening efficiency was in the ED (Figure 1). While efficient, RC yielded small numbers. Challenges to screening program implementation included inconsistent provider time and commitment, limited clinic space, competing priorities, and research constraints. Translation to a sustainable screening in primary care will need to address these challenges in a practice-specific fashion. Disclosure C.R. Geno Rasmussen: None. K. Waugh: None. J. Baxter: None. A. Steck: None. B.I. Frohnert: None. M. Rewers: None. Funding JDRF (3-SRA-2018-564-M-N)

Objective: To assess the costs and project the potential lifetime cost-effectiveness of the ongoing Autoimmunity Screening for Kids (ASK) Program, a large-scale pre-symptomatic type 1 diabetes screening program for children and adolescents in the metro Denver region. Research Design and Methods: We report the resource utilization, costs, and effectiveness measures from the ongoing ASK program as compared to usual care (i.e., no screening). Additionally, we report a practical screening scenario by including utilization and costs relevant to routine screening in clinical practice. Finally, we project the potential cost-effectiveness of ASK and routine screening by identifying clinical benchmarks (i.e., DKA events avoided, HbA1c improvements vs. no screening) needed to meet value thresholds of $50,000 to $150,000 per quality-adjusted life year (QALY) gained over a lifetime horizon. Results: Cost per case detected was $4,700 for ASK screening and $14,000 for routine screening. To achieve value thresholds of $50,000 to $150,000 per QALY gained, screening costs would need to be offset by cost savings through 20% reductions in DKA events at diagnosis in addition to 0.1% (1.1 mmol/mol) improvements in HbA1c over a lifetime as compared to no screening for patients that develop type 1 diabetes. Value thresholds were not met from avoiding DKA events alone in either scenario. Conclusions: Pre-symptomatic type 1 diabetes screening may be cost-effective in areas with high prevalence of DKA and infrastructure facilitating screening and monitoring if the benefits of avoiding DKA events and improved HbA1c persist over long-run time horizons. As more data are collected from ASK, the model will be updated with direct evidence on screening effects.

The aim of this study was to conduct a prospective analysis of the association between negative life events (NLEs) and respiratory infections in children genetically at risk for islet autoimmunity (IA) and type 1 diabetes (T1D). Long- and short-term temporal associations between NLEs and rate of respiratory infection episodes (RIEs) in 5,618 children in The Environmental Determinants of Diabetes in the Young study for at least 1 up to 4 years were analysed. All models were adjusted for demographic, day care, season of infection, and psychosocial factors associated with the rate of child RIEs between study visits. The rate of child RIEs was 26% higher in Europe (Sweden, Finland, Germany) than in the United States (rate ratio [RR] = 1.26, p < 0.001). However, the percentage of child NLEs (odds ratio [OR] = 1.18, p < 0.001) and mother NLEs (OR = 1.83, p < 0.001) was higher in the United States compared with Europe. In both continents (Europe, RR = 1.12, p < 0.001; United States, RR = 1.07, p = 0.006), high child cumulative NLEs (>1 NLE per year since study inception) was significantly associated with an increased rate of child RIEs. This large-scale prospective study confirms observations that stress may increase the susceptibility for infections in paediatric populations and suggests at least one mechanism by which stress could increase risk for IA and T1D in genetically at risk children.

Objective The capacity to precisely predict progression to type 1 diabetes (T1D) in young children over a short time span is an unmet need. We sought to develop a risk algorithm to predict progression in children with high-risk human leukocyte antigen (HLA) genes followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Methods Logistic regression and 4-fold cross-validation examined 38 candidate predictors of risk from clinical, immunologic, metabolic, and genetic data. TEDDY subjects with at least one persistent, confirmed autoantibody at age 3 were analyzed with progression to T1D by age 6 serving as the primary endpoint. The logistic regression prediction model was compared to two non-statistical predictors, multiple autoantibody status, and presence of insulinoma-associated-2 autoantibodies (IA-2A). Results A total of 363 subjects had at least one autoantibody at age 3. Twenty-one percent of subjects developed T1D by age 6. Logistic regression modeling identified 5 significant predictors - IA-2A status, hemoglobin A1c, body mass index Z-score, single-nucleotide polymorphism rs12708716_G, and a combination marker of autoantibody number plus fasting insulin level. The logistic model yielded a receiver operating characteristic area under the curve (AUC) of 0.80, higher than the two other predictors; however, the differences in AUC, sensitivity, and specificity were small across models. Conclusions This study highlights the application of precision medicine techniques to predict progression to diabetes over a 3-year window in TEDDY subjects. This multifaceted model provides preliminary improvement in prediction over simpler prediction tools. Additional tools are needed to maximize the predictive value of these approaches.

Objective: Detection of pre-symptomatic T1D by islet autoantibody (IA) screening prevents hospitalization and diabetic ketoacidosis at clinical onset. It is unknown if presence of diabetic symptoms and random blood glucose predict islet autoantibodies. We report the efficacy of random blood glucose (RBG) measurement, among those who reported multiple symptoms for T1D, for detecting T1D autoimmunity. Methods: In 2017-18, the Autoimmunity Screening for Kids (ASK) study screened 14,418 Denver children 1-17 y old for autoantibodies to insulin, GAD, IA-2, and ZnT8. At the time of screening, the parent and/or child were asked whether or not the child had increased urination, thirst, weight loss or vomiting in the last 3 months. If two or more symptoms were reported, RBG was tested using a glucometer and IA testing was fast-tracked with results available in <7 days. Results: Of the children screened, 0.9% were positive for multiple IA or a single high-affinity IA conferring, respectively, a 44% and 29% 5-year risk of clinical T1D. A fast-track protocol with RBG testing was applied to 501/12,726 children screened between 6/2017-12/2018, flagged for priority testing. Ten (2%) of the 501 fast-track participants had multiple or single high-affinity IA, compared to 91/12,050 (0.8%) IA in those with one or no symptoms (p=0.002). At screening, children found later to have multiple or high-affinity IA more often reported ≥2 symptoms: 9.6% (10/104) compared with low-affinity IA, 4.3% (11/254, p=0.05), or negative, 4.9% (602/12,368, p=0.03). Among those with increased thirst and polyuria, 16/358 (4.5%) had IA. For IA positive, none reported all symptoms (12 IA neg reported all symptoms). RBG>140 mg/dl was detected in 1/14 (7.1%) children with multiple symptoms and IA vs. 15/440 (3.4%) children with symptoms and no IA (p=0.5). None had RBG>200. Conclusions: Symptoms history is helpful but RBG is not, in finding children with pre-symptomatic T1D. Disclosure K. Waugh: None. B.I. Frohnert: None. M. Rewers: None. J. Baxter: None. C.R. Geno Rasmussen: None. Funding JDRF

Probiotics are linked to positive regulatory effects on the immune system. The aim of the study was to examine the association between the exposure of probiotics via dietary supplements or via infant formula by the age of 1 year and the development of celiac disease autoimmunity (CDA) and celiac disease among a cohort of 6520 genetically susceptible children. Use of probiotics during the first year of life was reported by 1460 children. Time-to-event analysis was used to examine the associations. Overall exposure of probiotics during the first year of life was not associated with either CDA (n = 1212) (HR 1.15; 95%CI 0.99, 1.35; p = 0.07) or celiac disease (n = 455) (HR 1.11; 95%CI 0.86, 1.43; p = 0.43) when adjusting for known risk factors. Intake of probiotic dietary supplements, however, was associated with a slightly increased risk of CDA (HR 1.18; 95%CI 1.00, 1.40; p = 0.043) compared to children who did not get probiotics. It was concluded that the overall exposure of probiotics during the first year of life was not associated with CDA or celiac disease in children at genetic risk.

Early detection can prevent morbidity associated with type 1 diabetes (T1D) and celiac disease (CD). ASK is a 4-year program with the goal to screen Denver metro-area children for pre-symptomatic T1D and CD, increase public awareness of these diseases, and provide evidence for universal screening. We are reporting first-ever prevalence data for pre-symptomatic T1D and CD in the U.S. general population children aged 2-17 y. In 2017, ASK approached ∼15,000 children for consent, screened 5090 with results available for 4915. Study participant age, sex, and race/ethnicity closely reflected Denver’s general population; 4% had a T1D first-degree relative (FDR). Standard radiobinding assays (RBA) and more specific electrochemiluminescence (ECL) assays for autoantibodies to insulin, GAD, IA-2, ZnT8 and transglutaminase (TGA) were used for screening and confirmation. Children with confirmed persistent islet autoantibodies received follow-up with education to prevent DKA, psychological support, and referrals to prevention trials or clinical services. Multiple islet autoantibodies, predicting a 44% 5-y risk of T1D, were found in 32 (0.7%) children; of the 30 children retested to date, all remained persistently positive, six developed dysglycemia and one progressed to T1D. A single islet autoantibody, confirmed as high-affinity by ECL (29% 5-y risk of T1D), was found in 27 (0.5%); 18/19 children retested remained positive, 5 developed dysglycemia and one T1D. Over 86% (50/59) of the screening-detected children at risk for T1D did not have an FDR with T1D. The prevalence of TGA by both RBA and ECL was 2.2% and persistent in 74/76 (97%) children retested so far. This novel population-based screening program for the two most common autoimmune diseases of childhood reports high prevalence of pre-symptomatic T1D and CD in Denver children. Prospective follow-up of screening-detected cases for clinical outcomes and cost-effectiveness analysis will inform potential future universal screening. Disclosure C.R. Geno Rasmussen: None. M. Rewers: None. J. Baxter: None. K. Waugh: None. A. Steck: None. B.I. Frohnert: None. L. Yu: None. E. Liu: None.

Saliva offers a relatively noninvasive method for measuring analytes such as cortisol, holding particular promise for use in pediatric populations on a large scale if a rigorous collection protocol is feasible in diverse settings. The Environmental Determinants of Diabetes in the Young study protocol, conducted in centers in the United States, Sweden, Finland, and Germany, used salivary collection to assess cortisol level as a physiologic marker of stress. Saliva was collected using Sorbettes from subjects at 3.5, 4.5, and 5.5 years of age. Parents collected a morning sample, and staff collected pre- and post-blood draw samples. Feasibility was assessed based on protocol completion, adherence with instructions, factors affecting adherence, and sufficiency of saliva sample for cortisol determination. Collection of saliva samples in a diverse pediatric population is feasible. Establishing non-invasive and acceptable methods for collecting physiological parameters of stress will allow better exploration of determinants of health in this important population.

Objective To identify predictors of later study withdrawal among participants active in The Environmental Determinants of Diabetes in the Young (TEDDY) for 1 year. Methods Multiple logistic regression was used to discriminate 3,042 children active in TEDDY for the first 3 years from 432 children who withdrew in Years 2 or 3. Predictor variables were tested in blocks—demographic, maternal lifestyle behaviors, stress and child illness, maternal reactions to child’s increased diabetes risk, in-study behaviors—and a final best model developed. Results Few demographic factors predicted study withdrawal. Maternal lifestyle behaviors, accuracy of the mother’s risk perception, and in-study behaviors were more important. Frequent child illnesses were associated with greater study retention. Conclusions Demographic measures are insufficient predictors of later study withdrawal among those active in a study for at least 1 year; behavioral/psychological factors offer improved prediction and guidance for the development of retention strategies.

ObjectiveType 1 diabetes (T1D) or celiac disease (CD) develops in at least 2% of the general population. Early detection of disease-specific autoimmunity and subsequent monitoring would be possible if screening tests were more widely available. Currently, screening for islet autoimmunity is available only in a research setting, and CD-specific autoimmunity screening is limited to those in high-risk groups. This study assessed the feasibility of incorporating T1D and CD autoantibody screening into a pediatric practice.MethodsPatient engagement strategies, blood collection preference, blood sample volume, rate of autoantibody detection in the general population, and parental satisfaction were assessed. Over 5weeks, research staff recruited 200 patients, aged 2-6yr from two pediatric practices in the Denver area to be screened for islet autoantibodies (IAs) and the transglutaminase antibody.ResultsOf the 765 parents approached, 200 (26%) completed the same-day screening. Of the 565 subjects who did not complete the screening, 345 expressed interest, but were unable to make a participation decision. A finger stick, compared with a venous draw, was the preferred method of sample collection. Both methods yielded sufficient blood volume for autoantibody determination. IAs or the transglutaminase antibody were detected in 11 subjects. Parents expressed satisfaction with all aspects of participation.ConclusionsThe results of this study suggest that it is feasible to conduct this type of screening in a pediatric clinic. Such screening could lead to increased disease awareness and the possible benefits that can result from early detection.