Development of a clinical calculator to aid the identification of MODY in pediatric patients at the time of diabetes diagnosis.

Maturity Onset Diabetes of the Young (MODY) is a young-onset, monogenic form of diabetes without needing insulin treatment. Diagnostic testing is expensive. To aid decisions on who to test, we aimed to develop a MODY probability calculator for paediatric cases at the time of diabetes diagnosis, when the existing "MODY calculator" cannot be used. Firth logistic regression models were developed on data from 3541 paediatric patients from the Swedish 'Better Diabetes Diagnosis' (BDD) population study (n = 46 (1.3%) MODY (HNF1A, HNF4A, GCK)). Model performance was compared to using islet autoantibody testing. HbA1c, parent with diabetes, and absence of polyuria were significant independent predictors of MODY. The model showed excellent discrimination (c-statistic = 0.963) and calibrated well (Brier score = 0.01). MODY probability > 1.3% (ie. above background prevalence) had similar performance to being negative for all 3 antibodies (positive predictive value (PPV) = 10% v 11% respectively i.e. ~ 1 in 10 positive test rate). Probability > 1.3% and negative for 3 islet autoantibodies narrowed down to 4% of the cohort, and detected 96% of MODY cases (PPV = 31%). This MODY calculator for paediatric patients at time of diabetes diagnosis will help target genetic testing to those most likely to benefit, to get the right diagnosis.

Breastfeeding duration is not associated with offspring inflammatory bowel disease risk in three population-based birth cohorts.

BACKGROUND AND AIMS: Breastfeeding is critical for offspring health and development. While many observational studies report a protective effect between breastfeeding and inflammatory bowel disease (IBD), the relationship is not well-understood. METHODS: We used prospectively collected data from three population-based birth cohorts (Danish National Birth Cohort, Norwegian Mother, Father, and Child Cohort, and All Babies in Southeast Sweden) and cross-linked national registers to ascertain the impact of breastfeeding duration on offspring IBD risk in each country, using adjusted Cox proportional regression analyses. We performed meta-analyses to determine pooled estimates. RESULTS: We included 148,737 offspring and 169,510 offspring in analyses of exclusive and any breastfeeding duration, respectively. During median follow-up of 16.3 to 22.3 years, between 1996 and 2021, 543 offspring were diagnosed with IBD. In each country, there was no association between exclusive breastfeeding duration and offspring IBD risk after adjusting for birth year (Denmark), offspring sex, parental IBD status, maternal education, smoking during pregnancy, age at delivery, mode of delivery, preterm birth, and small for gestational age. The pooled adjusted hazard ratio for IBD was 1.24 (95% CI 0.94, 1.62, Q =0.16, I2= 0.0%) and 1.02 (95% CI 0.85, 1.21, Q=1.45, I2= 0.0%) among offspring breastfed exclusively for ≥6 months and <4 months, respectively, compared to 4-5 months. Similarly, we found null associations in pooled analyses of any breastfeeding duration and IBD, subtypes Crohn's disease and ulcerative colitis, as well as in cohort-specific analyses. CONCLUSION: In prospectively collected data from three population-based birth cohorts, the duration of exclusive or any breastfeeding was not associated with offspring IBD risk.

Early increase in HbA1c trajectory predicts development of severe microangiopathy in patients with type 1 diabetes: the VISS study.

INTRODUCTION: To study the HbA1c trajectory from the time of diagnosis to examine if patients at the greatest risk for severe microangiopathy can be identified early allowing clinicians to intervene as soon as possible to avoid complications. RESEARCH DESIGN AND METHODS: In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age, 1983-1987, were followed from diagnosis until 2019. Mean HbA1c was calculated each year for each patient. Severe diabetic microangiopathy was defined as proliferative diabetic retinopathy (PDR) or macroalbuminuria (nephropathy). RESULTS: After 32 years, 27% had developed PDR and 8% macroalbuminuria. Patients with weighted HbA1c (wHbA1c); <57 mmol/mol; <7.4% did not develop PDR or macroalbuminuria. The HbA1c trajectories for patients developing PDR and macroalbuminuria follow separate courses early on and stay separated for 32 years during the follow-up. Patients without severe complications show an initial dip, after which HbA1c slowly increases. HbA1c in patients with severe complications directly rises to a high level within a few years. Mean HbA1c calculated for the period 5-8 years after diabetes onset strongly predicts the development of severe complications. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and higher prevalence of PDR. CONCLUSIONS: The HbA1c trajectory from diabetes onset shows that mean HbA1c for the period 5-8 years after diagnosis strongly predicts severe microangiopathy. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and a higher prevalence of PDR.

Prenatal exposure to environmental contaminants and cord serum metabolite profiles in future immune-mediated diseases.

BACKGROUND: Prenatal exposure to environmental contaminants is a significant health concern because it has the potential to interfere with host metabolism, leading to adverse health effects in early childhood and later in life. Growing evidence suggests that genetic and environmental factors, as well as their interactions, play a significant role in the development of autoimmune diseases. OBJECTIVE: In this study, we hypothesized that prenatal exposure to environmental contaminants impacts cord serum metabolome and contributes to the development of autoimmune diseases. METHODS: We selected cord serum samples from All Babies in Southeast Sweden (ABIS) general population cohort, from infants who later developed one or more autoimmune-mediated and inflammatory diseases: celiac disease (CD), Crohn's disease (IBD), hypothyroidism (HT), juvenile idiopathic arthritis (JIA), and type 1 diabetes (T1D) (all cases, N = 62), along with matched controls (N = 268). Using integrated exposomics and metabolomics mass spectrometry (MS) based platforms, we determined the levels of environmental contaminants and metabolites. RESULTS: Differences in exposure levels were found between the controls and those who later developed various diseases. High contaminant exposure levels were associated with changes in metabolome, including amino acids and free fatty acids. Specifically, we identified marked associations between metabolite profiles and exposure levels of deoxynivalenol (DON), bisphenol S (BPS), and specific per- and polyfluorinated substances (PFAS). IMPACT STATEMENT: Abnormal metabolism is a common feature preceding several autoimmune and inflammatory diseases. However, few studies compared common and specific metabolic patterns preceding these diseases. Here we hypothesized that exposure to environmental contaminants impacts cord serum metabolome, which may contribute to the development of autoimmune diseases. We found differences in exposure levels between the controls and those who later developed various diseases, and importantly, on the metabolic changes associated with the exposures. High contaminant exposure levels were associated with specific changes in metabolome. Our study suggests that prenatal exposure to specific environmental contaminants alters the cord serum metabolomes, which, in turn, might increase the risk of various immune-mediated diseases.

Infant microbes and metabolites point to childhood neurodevelopmental disorders.

This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early-life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immunodysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment.

Time spent outdoors in childhood related to myopia among young adults in the Swedish ABIS cohort.

PURPOSE: Elucidate the prevalence of myopia among young adults from a birth cohort of Swedish children and its relationship to possible risk factors during their childhood. METHODS: Five thousand two hundred young adults, mean 23.4 years and 58% females, participating in the prospective birth cohort All Babies in Southeast Sweden (ABIS) answered a questionnaire including questions regarding health and physical activity, spectacle use, myopia and age at first optical correction. Questionnaires at previous follow-ups at ages 2-3, 5-6 and 8 years included information on type of housing, time outdoors, screen time and hours of reading. Myopia prevalence and associations with potential risk factors were analysed in univariate and multivariate regression models with Bonferroni's correction of p-values. RESULTS: In the ABIS Swedish birth cohort of young adults, the prevalence of myopia was 29%. A univariate logistic regression showed a higher odds ratio for myopia with female gender (OR 1.59; p < 0.05) and a completed and started university education (OR 1.52; p < 0.05). Significantly lower odds ratios were found for hours spent outdoors at 8 years of age (OR 0.82; p < 0.05). Multivariate logistic regression showed a higher odds ratio for myopia in females (OR 1.52-1.57; p < 0.05) and completed and started university education (OR 1.34-1.49; p < 0.05) in all models. In a model including accommodative effort, measured in diopter hours at 8 years of age, hours spent outdoors were associated with a lower odds ratio for myopia (OR 0.86; p < 0.05). No association could be detected between myopia and the type of housing or near work. CONCLUSION: The prevalence of myopia among young adults in a Swedish birth cohort was lower or unchanged compared to previous data. Female gender, higher education and less time spent outdoors in childhood were associated with an increased risk of developing myopia. Recommendations from child health services and schools should be given to stimulate children to spend enough time outdoors.

Atopic Dermatitis in Early Childhood and Risk of Inflammatory Bowel Disease: A Scandinavian Birth Cohort Study.

OBJECTIVE: To examine the association between early-life atopic manifestations and later risk of inflammatory bowel disease (IBD), for which prospective data are scarce. STUDY DESIGN: The population-based All Babies in Southeast Sweden (ABIS) and Norwegian Mother, Father, and Child (MoBa) cohorts follow children from birth (ABIS 1997-1999; MoBa 2000-2009) to the end of 2021. Based on validated questionnaires, parents prospectively reported information on asthma, food-related allergic symptoms, atopic dermatitis, and allergic rhinitis by age 3. IBD was defined by ≥ 2 diagnostic records in the national health registries. Cox regression estimated hazard ratios adjusted (aHRs) for parental IBD, atopy, education level, smoking habits, and national origin. Cohort-specific estimates were pooled using a random-effects model. RESULTS: We compiled data on 83 311 children (ABIS, n = 9041; MoBa, n = 74 270). In over 1 174 756 person-years of follow-up, 301 participants were diagnosed with IBD. Children with atopic dermatitis at age 3 had an increased risk of IBD (pooled aHR = 1.46 [95% CI = 1.13-1.88]), Crohn's disease (pooled aHR = 1.53 [95%CI = 1.04-2.26]), and ulcerative colitis (pooled aHR = 1.78 [95%CI = 1.15-2.75]). Conversely, any atopic manifestation by age 3 was not associated with IBD (pooled aHR = 1.20 [95%CI = 0.95-1.52]), nor were analyses specifically focused on early-life food-related allergic symptoms, asthma, and allergic rhinitis. CONCLUSION: While atopic manifestations in early childhood were overall not associated with IBD, children with atopic dermatitis specifically were at increased risk of developing IBD, suggesting shared etiologic traits; these findings might be useful in identifying at-risk individuals for IBD.

Tobacco smoke exposure in early childhood and later risk of inflammatory bowel disease: A Scandinavian birth cohort study.

OBJECTIVES: To examine the association between early-life smoking exposure and later risk of inflammatory bowel disease (IBD). METHODS: We followed 115,663 participants from the Norwegian Mother, Father and Child (MoBa) and All Babies in Southeast Sweden (ABIS) cohorts from birth (1997-2009) through 2021. IBD was identified through national patient registers. Validated questionnaire data defined maternal smoking during pregnancy, maternal environmental tobacco smoke (ETS) exposure during pregnancy, and child ETS exposure by age 12 and 36 months. Cox regression was used to estimate adjusted hazard ratios (aHRs) for sex, maternal age, education level, parental IBD and origin. Cohort-specific estimates were pooled using a random-effects model. RESULTS: During 1,987,430 person-years of follow-up, 444 participants developed IBD (ABIS, n=112; MoBa, n=332). Any vs. no maternal smoking during pregnancy yielded a pooled aHR of 1.30 (95%CI=0.97-1.74) for offspring IBD. Higher level of maternal smoking during pregnancy (compared to no smoking, average ≥6 cigarettes/day: pooled aHR=1.60 [95%CI 1.08-2.38]) was associated with offspring IBD, whereas a lower smoking level was not (average 1-5 cigarettes/day: pooled aHR=1.09 [95%CI=0.73-1.64]). Child ETS exposure in the first year of life was associated with later IBD (any vs. no ETS, pooled aHR=1.32 [95%CI=1.03-1.69]). Estimates observed for child ETS exposure by 36 months were similar but not statistically significant. CONCLUSIONS: In this prospective Scandinavian cohort study, children exposed to higher levels of maternal smoking during pregnancy or ETS during the first year of life were at increased risk of later IBD.

Prevalence and Predictive Factors for Celiac Disease in Children With Type 1 Diabetes: Whom and When to Screen? A Nationwide Longitudinal Cohort Study of Swedish Children.

OBJECTIVE: To examine the prevalence and predictive factors for celiac disease (CD) after a diagnosis of type 1 diabetes (T1D) in children and adolescents, to improve the current screening guidelines. RESEARCH DESIGN AND METHODS: The association between sex, age at T1D diagnosis, HLA, and diabetes autoantibodies, and a diagnosis of CD was examined in 5,295 children with T1D from the Better Diabetes Diagnosis study in Sweden. RESULTS: The prevalence of biopsy-proven CD was 9.8%, of which 58.2% already had a CD diagnosis before or at T1D onset. Almost all, 95.9%, were diagnosed with CD within 5 years after the T1D diagnosis. Younger age at the T1D diagnosis and being homozygote for DQ2 increased the risk of CD after T1D, but neither sex nor diabetes-related autoantibodies were associated with the risk. CONCLUSIONS: Age at and time after diabetes diagnosis should be considered in screening guidelines for CD in children with T1D.

Predictive biomarkers of rapidly developing insulin deficiency in children with type 1 diabetes.

INTRODUCTION: The rate of progression to complete insulin deficiency varies greatly in type 1 diabetes. This constitutes a challenge, especially when randomizing patients in intervention trials aiming to preserve beta cell function. This study aimed to identify biomarkers predictive of either a rapid or slow disease progression in children with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: A retrospective, longitudinal cohort study of children (<18 years) with type 1 diabetes (N=46) was included at diagnosis and followed until complete insulinopenia (C-peptide <0.03 nmol/L). Children were grouped into rapid progressors (n=20, loss within 30 months) and slow progressors (n=26). A sex-matched control group of healthy children (N=45) of similar age was included for comparison. Multiple biomarkers were assessed by proximity extension assay (PEA) at baseline and follow-up. RESULTS: At baseline, rapid progressors had lower C-peptide and higher autoantibody levels than slow. Three biomarkers were higher in the rapid group: carbonic anhydrase 9, corticosteroid 11-beta-dehydrogenase isozyme 1, and tumor necrosis factor receptor superfamily member 21. In a linear mixed model, 25 proteins changed over time, irrespective of group. One protein, a coxsackievirus B-adenovirus receptor (CAR) increased over time in rapid progressors. Eighty-one proteins differed between type 1 diabetes and healthy controls. Principal component analysis could not distinguish between rapid, slow, and healthy controls. CONCLUSIONS: Despite differences in individual proteins, the combination of multiple biomarkers analyzed by PEA could not distinguish the rate of progression in children with new-onset type 1 diabetes. Only one marker was altered significantly when considering both time and group effects, namely CAR, which increased significantly over time in the rapid group. Nevertheless, we did find some markers that may be useful in predicting the decline of the C-peptide. Moreover, these could potentially be important for understanding type 1 diabetes pathogenesis.

Breast-feeding decreases the risk of developing psoriasis through early adulthood.

BACKGROUND: Psoriasis is a genetically determined systemic skin disease, although environmental trigger factors are required for disease manifestation. Some of these triggers, such as stress, infections, and drug exposure, have been identified. OBJECTIVE: To explore the role of early nutrition as a risk factor for the development of psoriasis. METHODS: Parents in the ABIS (All Babies in Southeast Sweden) (n= 16145) prospective birth cohort answered questionnaires at birth and by the child's age of 1 and 3 years. Diagnosis of psoriasis was received from the Swedish National Patient Register and National Drug Prescription Register. Statistical analyses were conducted using custom-written R scripts. RESULTS: Individuals breastfed for less than 4 months and receiving infant formula before 4 months were associated with a higher risk of psoriasis (OR 1.84; p=0.018, and OR 1.88; p=0.015 respectively). At the 3-year follow-up, the increased consumption of fish, especially from the Baltic Sea, increased the risk of psoriasis (OR9.61; p=0.003). In addition, the risk of psoriasis increased following large milk consumption (OR2.53; p=0.040). CONCLUSION: Our study underscores, for the first time, the impact of very early nutrition on the manifestation of psoriasis through early adulthood. Exclusive breastfeeding for 4 months seems protective.

Assisting the implementation of screening for type 1 diabetes by using artificial intelligence on publicly available data.

The type 1 diabetes community is coalescing around the benefits and advantages of early screening for disease risk. To be accepted by healthcare providers, regulatory authorities and payers, screening programmes need to show that the testing variables allow accurate risk prediction and that individualised risk-informed monitoring plans are established, as well as operational feasibility, cost-effectiveness and acceptance at population level. Artificial intelligence (AI) has the potential to contribute to solving these issues, starting with the identification and stratification of at-risk individuals. ASSET (AI for Sustainable Prevention of Autoimmunity in the Society; www.asset.healthcare ) is a public/private consortium that was established to contribute to research around screening for type 1 diabetes and particularly to how AI can drive the implementation of a precision medicine approach to disease prevention. ASSET will additionally focus on issues pertaining to operational implementation of screening. The authors of this article, researchers and clinicians active in the field of type 1 diabetes, met in an open forum to independently debate key issues around screening for type 1 diabetes and to advise ASSET. The potential use of AI in the analysis of longitudinal data from observational cohort studies to inform the design of improved, more individualised screening programmes was also discussed. A key issue was whether AI would allow the research community and industry to capitalise on large publicly available data repositories to design screening programmes that allow the early detection of individuals at high risk and enable clinical evaluation of preventive therapies. Overall, AI has the potential to revolutionise type 1 diabetes screening, in particular to help identify individuals who are at increased risk of disease and aid in the design of appropriate follow-up plans. We hope that this initiative will stimulate further research on this very timely topic.

Early-life diet and risk of inflammatory bowel disease: a pooled study in two Scandinavian birth cohorts.

OBJECTIVE: We assessed whether early-life diet quality and food intake frequencies were associated with subsequent IBD. DESIGN: Prospectively recorded 1-year and 3-year questionnaires in children from the All Babies in Southeast Sweden and The Norwegian Mother, Father and Child Cohort Study were used to assess diet quality using a Healthy Eating Index and intake frequency of food groups. IBD was defined as >2 diagnoses in national patient registers. Cox regression yielded HRs adjusted (aHRs) for child's sex, parental IBD, origin, education level and maternal comorbidities. Cohort-specific results were pooled using a random-effects model. RESULTS: During 1 304 433 person-years of follow-up, we followed 81 280 participants from birth through childhood and adolescence, whereof 307 were diagnosed with IBD. Compared with low diet quality, medium and high diet quality at 1 year of age were associated with a reduced risk of IBD (pooled aHR 0.75 (95% CI=0.58 to 0.98) and 0.75 (95% CI=0.56 to 1.00)). The pooled aHR per increase of category was 0.86 (0.74 to 0.99). Pooled aHR for children 1 year old with high versus low fish intake was 0.70 (95% CI=0.49 to 1.00) for IBD, and showed association with reduced risk of UC (pooled aHR=0.46; 95% CI=0.21, 0.99). Higher vegetable intake at 1 year was associated with a risk reduction in IBD. Intake of sugar-sweetened beverages was associated with an increased risk of IBD. Diet quality at 3 years was not associated with IBD. CONCLUSION: In this Scandinavian birth cohort, high diet quality and fish intake in early life were associated with a reduced risk of IBD.

Progression of type 1 diabetes is associated with high levels of soluble PD-1 in islet autoantibody-positive children.

AIMS/HYPOTHESIS: Type 1 diabetes is an autoimmune disorder that is characterised by destruction of pancreatic beta cells by autoreactive T lymphocytes. Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb+) children to identify molecules related to type 1 diabetes progression. METHODS: We measured the levels of 14 sICM in the sera of AAb+ children (n=57) compared to those with recent-onset type 1 diabetes (n=79) and healthy children (n=44), obtained from two cohorts. AAb+ children were followed up and divided based on their progression to type 1 diabetes (AAbP) or not (AAbNP) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAbP children. RESULTS: We found that AAb+ children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb+ children who progressed to type 1 diabetes (AAbP) had higher sICM concentrations than non-progressors (AAbNP). Further, sICM levels decreased in AAbP children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; p=0.007). CONCLUSIONS/INTERPRETATION: This study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoimmune diabetes.

Impact of Environmental Exposures on Human Breast Milk Lipidome in Future Immune-Mediated Diseases.

The composition of human breast milk (HBM) exhibits significant variability both between individuals and within the same individual. While environmental factors are believed to play a role in this variation, their influence on breast milk composition remains inadequately understood. Herein, we investigate the impact of environmental factors on HBM lipid composition in a general population cohort. The study included mothers (All Babies In Southeast Sweden study) whose children later progressed to one or more immune-mediated diseases later in life: type 1 diabetes (n = 9), celiac disease (n = 24), juvenile idiopathic arthritis (n = 9), inflammatory bowel disease (n = 7), hypothyroidism (n = 6), and matched controls (n = 173). Lipidome of HBM was characterized by liquid chromatography combined with high-resolution mass spectrometry. We observed that maternal age, body mass index, diet, and exposure to perfluorinated alkyl substances (PFASs) had a marked impact on breast milk lipidome, with larger changes observed in the milk of those mothers whose children later developed autoimmune diseases. We also observed differences in breast milk lipid composition in those mothers whose offspring later developed autoimmune diseases. Our study suggests that breast milk lipid composition is modified by a complex interaction between genetic and environmental factors, and, importantly, this impact was significantly more pronounced in those mothers whose offspring later developed autoimmune/inflammatory diseases. Our findings also suggest that merely assessing PFAS concentration may not capture the full extent of the impact of chemical exposures; thus, the more comprehensive exposome approach is essential for accurately assessing the impact of PFAS exposure on HBM and, consequently, on the health outcomes of the offspring.

Cumulative incidence of type 1 diabetes in two cohorts of children with different national gluten recommendations in infancy.

AIMS: Between 1985 and 1996, Sweden experienced an "epidemic" of celiac disease with a fourfold increase in incidence in young children. Timing and amount of gluten introduced during infancy have been thought to explain this "epidemic". We aimed to study whether the cumulative incidence of type 1 diabetes differs between children born during the "epidemic" compared to children born after. METHODS: This is a national register study in Sweden comparing the cumulative incidence of type 1 diabetes in two birth cohorts of 240 844 children 0-17 years old born 1992-1993, during the "epidemic", and 179 530 children born 1997-1998, after the "epidemic". Children diagnosed with type 1 diabetes were identified using three national registers. RESULTS: The cumulative incidence of type 1 diabetes by the age of 17 was statistically significantly higher in those born after the "epidemic" 0.77% than in those born during the "epidemic" 0.68% (p < 0.001). CONCLUSION: The incidence of type 1 diabetes is higher in those born after the epidemic compared to those born during the epidemic, which does not support the hypothesis that gluten introduction increases the incidence of T1D. Changes in gluten introduction did not halt the increased incidence of type 1 diabetes in Sweden.