Childhood-onset type 1 diabetes in Western Australia: An update on incidence and temporal trends from 2001 to 2022.

OBJECTIVE: To determine the incidence and incidence trends over 2001-2022 of childhood-onset type 1 diabetes (T1D) in Western Australia and assess the impact of the COVID-19 pandemic. METHODS: Children newly diagnosed with T1D aged 0-14 years in Western Australia from 1 January 2001 to 31 December 2022 were identified from the population-based Western Australian Children's Diabetes Database. Annual age- and sex-specific incidence was calculated, and Poisson regression was used to analyse trends by calendar year, month, sex and age group at diagnosis. Pandemic era impacts were also examined using the regression model adjusted for sex and age group. RESULTS: Between 2001 and 2022, 2311 children (1214 boys, 1097 girls) were newly diagnosed with T1D aged 0-14 years, giving an overall mean annual incidence of 22.9 per 100,000 person-years (95% CI: 22.0, 23.9), with no significant difference observed between boys and girls. A significant linear increasing trend was only observed in 10-14 year olds with boys and girls combined (1.2% per year [IRR 1.012 (95% CI: 1.002, 1.022)]). No significant difference in the incidence was observed between the pre- and post-pandemic period. CONCLUSIONS: The incidence of type 1 diabetes in 0-14 year old Western Australian children continues to increase in the oldest age group. Longer term monitoring of the incidence during the COVID-19 pandemic is needed to determine its impact on this globally unique population which experienced a delayed start to the pandemic with severe containment measures remaining in place until January 2022.

International comparison of glycaemic control in people with type 1 diabetes: an update and extension.

AIMS: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes. METHODS: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA1c (IQR) and proportions of individuals with HbA1c < 58 mmol/mol (<7.5%), 58-74 mmol/mol (7.5-8.9%) and ≥75 mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15-24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA1c < 58 mmol/mol (<7.5%) relative to ≥58 mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA1c category compared to previous estimates were calculated. RESULTS: Median HbA1c varied from 55 to 79 mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA1c < 58 mmol/mol (<7.5%) were 0.91 (0.90-0.92) for women compared to men, 1.68 (1.65-1.71) for people aged <15 years and 0.81 (0.79-0.82) aged15-24 years compared to those aged ≥25 years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA1c  < 58 mmol/l (<7.5%) increased and proportions of people with HbA1c ≥ 75 mmol/mol (≥9.0%) decreased. CONCLUSIONS: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.

Moderate and severe diabetic ketoacidosis at type 1 diabetes onset in children over two decades: A population-based study of prevalence and long-term glycemic outcomes.

OBJECTIVE: To investigate in a population-based pediatric cohort: prevalence of moderate-severe diabetic ketoacidosis (DKA) at type 1 diabetes (T1D) diagnosis over two decades and its association with long-term glycemic control. RESEARCH DESIGN AND METHODS: Children <16 years diagnosed with T1D in Western Australia 2000-2019 were included and followed up for ≤14 years. Moderate-severe DKA at diagnosis was defined as serum pH < 7.2 or bicarbonate<10 mmol/L with hyperglycemia and ketosis. HbA1c was measured ~3-monthly. Trend in prevalence of moderate-severe DKA at diagnosis was investigated using a logistic regression model adjusting for sex, age, socioeconomic status, and area of residence. Long-term glycemic control associated with DKA at diagnosis was investigated using linear mixed models adjusting for the same variables and also for visit frequency, CGM and pump use. RESULTS: Moderate-severe DKA occurred in 534 of 2111 (25.3%) participants. Odds of presenting with moderate-severe DKA increased by 4.1% (95% CI: 2.3, 5.9; p < 0.001) per year. Patients with moderate-severe DKA at diagnosis had higher HbA1c levels than other patients initially; the groups were similar between 2 and 6 years duration; from 7 years HbA1c levels tracked higher in the group with moderate-severe DKA at diagnosis with significant differences at 8 and 12 years (p < 0.05). CONCLUSION: The increasing prevalence of DKA at diagnosis of pediatric T1D is concerning and highlights the need for early detection programs. Unlike a similar US study, this study did not find a consistent, clinically significant relationship between DKA at diagnosis and long-term HbA1c, raising important questions about the influence of other factors on long-term glycemic outcomes.

Demographic and clinical characteristics of a population-based pediatric cohort of type 1 and type 2 diabetes in Western Australia (1999-2019).

OBJECTIVES: To determine demographic and clinical characteristics of youth diagnosed with type 1 (T1D) or type 2 (T2D) diabetes aged ≤15 years from 1999 to 2019 in Western Australia, and examine time to first diagnosis of diabetes complications. METHODS: A retrospective cohort study was conducted of patients identified from the population-based, prospective Western Australian Children's Diabetes Database and longitudinal data extracted for available demographic and clinical variables. Patients were followed from diagnosis to transition to adult services, death, or December 31, 2019. Cox proportional hazards regression models were used to analyse time to first diagnosis of hypertension, high cholesterol or microalbuminuria, after adjusting for sex, age at diagnosis, time period of diagnosis, hemoglobin A1c , and body max index Z-score. RESULTS: 2438 eligible patients were identified (2209 [91%] T1D: 229 [9%] T2D). The mean age at diagnosis was lower in patients with T1D (8.5 [±4.0] vs. 12.7 [±2.0] years). A higher proportion of patients with T2D were female (58% vs. 47%) and of Aboriginal ethnicity (59% vs. 2%). The median HbA1c (interquartile range) at diagnosis was lower 8.9% [6.7, 11.5] (74 mmol/mol [50, 102]) versus 11.6% [10.1, 13.3] (103 mmol/mol [87, 122]) and mean body max index Z-score higher (2.05 [±0.66] vs. 0.37 [±0.95]), in patients with T2D compared to T1D. Patients with T2D had a higher risk of hypertension, high cholesterol, and microalbuminuria (aHR 3.39 [95%CI:2.04, 5.63], 2.69 [95%CI:1.21, 5.98], and 19.79 [95%CI:10.99, 35.64] respectively).

Incidence of type 1 diabetes in 0 to 14 year olds in Australia from 2002 to 2017.

OBJECTIVE: To determine the incidence of childhood onset type 1 diabetes in Australia from 2002 to 2017, and analyze incidence rate trends by calendar year, sex, and age at diagnosis. RESEARCH DESIGN AND METHODS: Children newly diagnosed with type 1 diabetes aged <15 years between 2002 and 2017 were identified from the National Diabetes Register, estimated to be ~99% complete. Data were obtained for diagnosis year, sex, age, and residential State/Territory at time of diagnosis. Population estimates by year, sex, single year of age, and State/Territory were obtained from the Australian Bureau of Statistics and Poisson regression used to examine incidence and trends by calendar year, sex, and age group at diagnosis. RESULTS: Between 2002 and 2017, there were 16 783 newly diagnosed cases of type 1 diabetes in children aged < 15 years (8684 boys: 8099 girls), giving a mean incidence of 25.0/1 00 000 person years (95%CI: 24.6, 25.4). A sinusoidal pattern in the incidence rate trend was observed with 5-yearly cycles providing the best model fit. No significant difference was observed in boys compared to girls (IRR 0.98 [95%CI: 0.95, 1.01]). Compared to 0 to 4 year olds, the mean incidence was 75% higher in 5 to 9 year olds, and 224% higher in 10 to 14 year olds. A decreasing incidence rate trend was observed in 0 to 4 year old boys and girls. CONCLUSIONS: This study reports updated incidence and incidence rate trends in children and adolescents diagnosed with type 1 diabetes in Australia. A cyclical pattern in incidence trend persists, with an overall decreasing trend observed only in the youngest age group.

Changes in pancreatic exocrine function in young at-risk children followed to islet autoimmunity and type 1 diabetes in the ENDIA study.

BACKGROUNDS: We aimed to monitor pancreatic exocrine function longitudinally in relation to the development of islet autoimmunity (IA) and type 1 diabetes (T1D) in at-risk children with a first-degree relative with T1D, who were followed prospectively in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. METHODS: Fecal elastase-1 (FE-1) concentration was measured longitudinally in 85 ENDIA children from median age 1.0 (IQR 0.7,1.3) year. Twenty-eight of 85 children (progressors) developed persistent islet autoantibodies at median age of 1.5 (IQR 1.1,2.5) years, of whom 11 went on to develop clinical diabetes. The other 57 islet autoantibody-negative children (non-progressors) followed similarly were age and gender-matched with the progressors. An adjusted linear mixed model compared FE-1 concentrations in progressors and non-progressors. RESULTS: Baseline FE-1 did not differ between progressors and non-progressors, or by HLA DR type or proband status. FE-1 decreased over time in progressors in comparison to non-progressors (Wald statistic 5.46, P = .02); in some progressors the fall in FE-1 preceded the onset of IA. CONCLUSIONS: Pancreatic exocrine function decreases in the majority of young at-risk children who progress to IA and T1D.

Higher frequency of vertebrate-infecting viruses in the gut of infants born to mothers with type 1 diabetes.

BACKGROUND: Microbial exposures in utero and early life shape the infant microbiome, which can profoundly impact on health. Compared to the bacterial microbiome, very little is known about the virome. We set out to characterize longitudinal changes in the gut virome of healthy infants born to mothers with or without type 1 diabetes using comprehensive virome capture sequencing. METHODS: Healthy infants were selected from Environmental Determinants of Islet Autoimmunity (ENDIA), a prospective cohort of Australian children with a first-degree relative with type 1 diabetes, followed from pregnancy. Fecal specimens were collected three-monthly in the first year of life. RESULTS: Among 25 infants (44% born to mothers with type 1 diabetes) at least one virus was detected in 65% (65/100) of samples and 96% (24/25) of infants during the first year of life. In total, 26 genera of viruses were identified and >150 viruses were differentially abundant between the gut of infants with a mother with type 1 diabetes vs without. Positivity for any virus was associated with maternal type 1 diabetes and older infant age. Enterovirus was associated with older infant age and maternal smoking. CONCLUSIONS: We demonstrate a distinct gut virome profile in infants of mothers with type 1 diabetes, which may influence health outcomes later in life. Higher prevalence and greater number of viruses observed compared to previous studies suggests significant underrepresentation in existing virome datasets, arising most likely from less sensitive techniques used in data acquisition.

Role of HLA-DQ typing and anti-tissue transglutaminase antibody titers in diagnosing celiac disease without duodenal biopsy in type 1 diabetes: A study of the population-based pediatric type 1 diabetes cohort of Western Australia.

AIM: The primary aim of the present study was to determine if it is cost effective to use human leukocyte antigen (HLA) typing as a first-line screening test for celiac disease (CD) in children with type 1 diabetes (T1D), as recommended by the European Society of Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). The second aim was to investigate whether anti-tissue transglutaminase IgA (anti-tTGA) antibodies can be used to diagnose CD without the need for a confirmatory duodenal biopsy in T1D. METHODS: Data for all T1D patients aged <18 years, who attended the diabetes clinics in Western Australia up to June 2017, were extracted from the Western Australian Children's Diabetes Database (WACDD) and analyzed for their demographic data and CD permissive HLA alleles (DQ2, DQ8, and DQ7). For T1D patients already diagnosed with CD, the mode of diagnosis of CD, anti-tTGA titers, and CD permissive HLA alleles were analyzed. RESULTS: Of the 936 eligible T1D patients identified, HLA-DQ typing was available for 551 (59%). Of these 551 patients, 504 (91.2%) were positive for celiac permissive HLA alleles. Eight percent (n = 75) of the T1D patients had a co-diagnosis of CD. High anti-tTGA titers were observed in those who were diagnosed with a positive duodenal biopsy. CONCLUSION: HLA-DQ typing is not cost effective as a first-line screening test for CD in T1D patients because of over-representation of CD permissive HLA alleles in this group. Anti-tTGA titers may be useful in diagnosing CD in T1D without duodenal biopsy, as high levels were found to be strongly predictive of CD.

Incidence of childhood onset type 1 diabetes in Western Australia from 1985 to 2016: Evidence for a plateau.

OBJECTIVE: To determine the incidence of childhood type 1 diabetes mellitus (T1D) in Western Australia from 2011 to 2016, and to examine the temporal trends between 1985 and 2016. METHODS: An observational cohort study was undertaken of all children newly diagnosed with T1D aged 0 to 14 years in Western Australia from 1985 to 2016. Cases were identified from the Western Australian Children's Diabetes Database, a population-based diabetes register previously estimated to be >99% complete. Annual age-standardized and age- and sex-specific incidence rates were calculated and the Joinpoint Regression Program used to identify any significant changes in trends over the study period. RESULTS: A total of 2499 cases were included (1272 boys, 1227 girls). The overall mean annual incidence was 19.1/100 000 person years (95% confidence interval, CI: 18.3-19.8), with no significant difference found between boys and girls. The mean annual incidence of 12.1/100 000 person years (95% CI: 11.1-13.1) in 0 to 4-years was significantly lower than that observed in 5 to 9 (21.6/100 000 [95% CI: 20.2-23.0]) and 10 to 14 (23.5/100 000 [95% CI: 22.1-25.0]) years. Joinpoint regression analysis identified a significant change in the temporal trend occurring in 2003. From 1985 to 2003, the incidence increased on an average of 3.3% per year (95% CI: 1.9-4.7). However, from 2003 to 2016, no significant change in the temporal trend occurred (-0.6% per year [95% CI: -2.4-1.2]). CONCLUSIONS: This study provides evidence for a possible plateauing in the incidence of childhood T1D in Western Australia, following a peak in 2003. Ongoing monitoring of the incidence will be essential to determine how temporal trends continue to evolve.

Comparable glycemic outcomes for pediatric type 1 diabetes patients in metropolitan and non-metropolitan regions of Western Australia: A population-based study.

BACKGROUND: Pediatric patients diagnosed with type 1 diabetes (T1D) in Western Australia (WA) are managed by a single, specialist multidisciplinary diabetes service based at a central tertiary hospital in the capital city, Perth, which provides outreach care in regional centers. OBJECTIVE: To investigate the hypothesis that outcomes for a contemporary, population-based pediatric T1D cohort, managed by a single tertiary service are similar for metropolitan and non-metropolitan patients using this model of care. To confirm that the cohort is indeed population based, a secondary aim of the study was to determine the case ascertainment of the Western Australian Children's Diabetes Database (WACDD). METHODS: Data for all T1D patients aged <18 years, who attended the diabetes clinics (metropolitan and non-metropolitan), at least once in 2014, were extracted from the WACDD and outcomes including HbA1c and severe hypoglycemia (SH) rates analyzed. RESULTS: In 2014, a total of 1017 patients (492 females, 525 males) attended the diabetes clinics (54% metropolitan and 46% non-metropolitan). After adjusting for age, sex, diabetes duration, and insulin regimen, region of clinic was not a significant predictor of mean HbA1c or SH rate. The case ascertainment of the WACDD was estimated to be 99.9% complete for children diagnosed with T1D aged <15 years between 2002 and 2012. CONCLUSIONS: This study reports similar glycemic outcomes for patients attending diabetes clinics in metropolitan and non-metropolitan areas of WA, suggesting that a model of care provided as outreach from a specialized diabetes service is effective in achieving equitable glycemic outcomes.

Severe hypoglycemia rates are not associated with HbA1c: a cross-sectional analysis of 3 contemporary pediatric diabetes registry databases.

OBJECTIVE: To examine the association between glycated hemoglobin (HbA1c) and severe hypoglycemia rates in patients with type 1 diabetes receiving usual care, by analysing data from the US Type 1 Diabetes Exchange (T1DX), German/Austrian Diabetes Patienten Verlaufsdokumenation (DPV), and Western Australian Children Diabetes Database (WACDD) diabetes registries. METHODS: Data for patients with type 1 diabetes, aged <18 years with a minimum duration of diabetes of 2 years, were extracted from each registry for a 12-month observation period between 2011 and 2012 (7,102 T1DX, 18,887 DPV, and 865 WACDD). Rates of severe hypoglycemia (self-reported loss of consciousness/convulsion) were estimated per 100 patient-years and analyzed by HbA1c, source registry, treatment regimen, and age group. RESULTS: Overall, the severe hypoglycemia rate per 100 patient years was 7.1, 3.3, and 6.7 in T1DX, DPV, and WACDD patients, respectively. Lower HbA1c was not associated with an increased rate of severe hypoglycemia when examined by source registry, treatment regimen, or age group. CONCLUSION: An inverse relationship between mean HbA1c and risk of severe hypoglycemia was not observed in this study of 3, independent cohorts of children and adolescents with type 1 diabetes. Investigation in other large, longitudinal cohorts is recommended to further characterize the contemporary relationship between glycemic control and risk of severe hypoglycemia rates in pediatric patients with type 1 diabetes.

Regular peaks and troughs in the Australian incidence of childhood type 1 diabetes mellitus (2000-2011).

AIMS/HYPOTHESIS: The aim of this study was to determine the incidence and incidence rate trends for type 1 diabetes mellitus in children aged 0-14 years, Australia-wide, from 2000 to 2011. METHODS: Cases of type 1 diabetes mellitus diagnosed in 0- to 14-year-olds were identified from the National (insulin-treated) Diabetes Register, with a 97% ascertainment rate. Annual age-standardised, sex- and age-specific incidences were calculated and Poisson regression was used to analyse the incidence by calendar year, sex and age at diagnosis. Non-linear temporal trends were analysed using sine and cosine functions applied to Poisson regression models for 3, 4, 5, 6 and 7 year cycles, and the Akaike information criterion was used to assess goodness of fit. RESULTS: A total of 11,575 cases (6,049 boys and 5,526 girls) of childhood type 1 diabetes mellitus were registered between 2000 and 2011, giving a mean incidence of 23.6 per 100,000 person-years (95% CI 23.2, 24.0). The mean incidence was 4.9% (95% CI 1.1%, 8.8%) higher in boys than in girls. Compared with 0- to 4-year-olds, the mean incidence was 65% higher in 5- to 9-year-olds and 208% higher in 10- to 14-year-olds. A 5 year cyclical variation in incidence was observed overall, in both sexes and in all age groups. An average annual increase in incidence was observed only in the 10- to 14-year-old age group (increase of 1.2% per year [95% CI 0.4%, 2.1%]). CONCLUSIONS/INTERPRETATION: A sinusoidal pattern was observed in the incidence rate trend of childhood type 1 diabetes mellitus in Australia. The 5-yearly peaks and troughs in incidence rate trends observed Australia-wide corroborate findings previously reported for Western Australia and require further investigation.

Developing Primary Intervention Strategies to Prevent Allergic Disease.

Allergic diseases are a major cause of morbidity in the developed world, now affecting up to 40 % of the population with no evidence that this is abating. If anything, the prevalence of early onset allergic diseases such as eczema and food allergy appears to be still increasing. This is almost certainly due to the changing modern environment and lifestyle factors, acting to promote immune dysfunction through early perturbations in immune maturation, immune tolerance and regulation. This early propensity to inflammation may also have implications for the rising risk of other inflammatory non-communicable diseases (NCDs) later in life. Identifying risk factors and pathways for preventing early onset immune disease like allergy is likely to have benefits for many aspects of human health, particularly as many NCDs share similar risk factors. This review focuses on recent advances in primary intervention strategies for promoting early immune health and preventing allergic disease, highlighting the current evidence-based guidelines where applicable and areas requiring further investigation.

Maternal smoking during pregnancy and the risk of childhood type 1 diabetes in Western Australia.

AIMS/HYPOTHESIS: The aim of this study was to investigate the association between maternal smoking during pregnancy and type 1 diabetes in the offspring, using complete population data sources available in Western Australia. METHODS: A prospective cohort study was undertaken with cases defined as children born in Western Australia between 1998 and 2008 who were diagnosed with type 1 diabetes at <15 years of age up to 31 December 2010. Eligible cases were identified from the prospective, population-based Western Australian Children's Diabetes Database. Record linkage was performed to identify perinatal records of cases from the Western Australian Midwives' Notification System, which contains data on >99% of all births in Western Australia. Cox regression was used to analyse the data and adjust for recognised risk factors such as birthweight, gestational age, maternal age and socioeconomic status. RESULTS: The unadjusted HR for babies born to mothers who smoked during pregnancy being diagnosed with childhood type 1 diabetes was 0.70 (95% CI: 0.50, 0.97). After adjustment, the confidence interval widened but the point estimate remained relatively unchanged at 0.76 (95% CI: 0.54, 1.08). CONCLUSIONS/INTERPRETATION: Analyses of data from this population-based study indicate that maternal smoking during pregnancy may be associated with a reduced risk of childhood type 1 diabetes. Further investigation in larger populations with more detailed smoking data could lead to novel hypotheses regarding mechanisms that influence the immunopathogenesis of type 1 diabetes in early life.

Improved Glycemic Outcomes With Diabetes Technology Use Independent of Socioeconomic Status in Youth With Type 1 Diabetes.

OBJECTIVE: Technology use in type 1 diabetes (T1D) is impacted by socioeconomic status (SES). This analysis explored relationships between SES, glycemic outcomes, and technology use. RESEARCH DESIGN AND METHODS: A cross-sectional analysis of HbA1c data from 2,822 Australian youth with T1D was undertaken. Residential postcodes were used to assign SES based on the Index of Relative Socio-Economic Disadvantage (IRSD). Linear regression models were used to evaluate associations among IRSD quintile, HbA1c, and management regimen. RESULTS: Insulin pump therapy, continuous glucose monitoring, and their concurrent use were associated with lower mean HbA1c across all IRSD quintiles (P < 0.001). There was no interaction between technology use and IRSD quintile on HbA1c (P = 0.624), reflecting a similar association of lower HbA1c with technology use across all IRSD quintiles. CONCLUSIONS: Technology use was associated with lower HbA1c across all socioeconomic backgrounds. Socioeconomic disadvantage does not preclude glycemic benefits of diabetes technologies, highlighting the need to remove barriers to technology access.

Environmental Determinants of Islet Autoimmunity (ENDIA) longitudinal prospective pregnancy to childhood cohort study of Australian children at risk of type 1 diabetes: parental demographics and birth information.

INTRODUCTION: The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is an ongoing Australian prospective cohort study investigating how modifiable prenatal and early-life exposures drive the development of islet autoimmunity and type 1 diabetes (T1D) in children. In this profile, we describe the cohort's parental demographics, maternal and neonatal outcomes and human leukocyte antigen (HLA) genotypes. RESEARCH DESIGN AND METHODS: Inclusion criteria were an unborn child, or infant aged less than 6 months, with a first-degree relative (FDR) with T1D. The primary outcome was persistent islet autoimmunity, with children followed until a T1D diagnosis or 10 years of age. Demographic data were collected at enrollment. Lifestyle, clinical and anthropometric data were collected at each visit during pregnancy and clinical pregnancy and birth data were verified against medical case notes. Data were compared between mothers with and without T1D. HLA genotyping was performed on the ENDIA child and all available FDRs. RESULTS: The final cohort comprised 1473 infants born to 1214 gestational mothers across 1453 pregnancies, with 80% enrolled during pregnancy. The distribution of familial T1D probands was 62% maternal, 28% paternal and 11% sibling. The frequency of high-risk HLA genotypes was highest in T1D probands, followed by ENDIA infants, and lowest among unaffected family members. Mothers with T1D had higher rates of pregnancy complications and perinatal intervention, and larger babies of shorter gestation. Parent demographics were comparable to the Australian population for age, parity and obesity. A greater percentage of ENDIA parents were Australian born, lived in a major city and had higher socioeconomic advantage and education. CONCLUSIONS: This comprehensive profile provides the context for understanding ENDIA's scope, methodology, unique strengths and limitations. Now fully recruited, ENDIA will provide unique insights into the roles of early-life factors in the development of islet autoimmunity and T1D in the Australian environment. TRIAL REGISTRATION NUMBER: ACTRN12613000794707.