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1.
Diabetes Metab Res Rev ; 36(1): e3204, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31322810

RESUMO

BACKGROUND: A nested case-control (NCC) design within a prospective cohort study can realize substantial benefits for biomarker studies. In this context, it is natural to consider the sample availability in the selection of controls to minimize data loss when implementing the design. However, this violates the randomness required for selection, and it leads to biased analyses. An inverse probability weighting may improve the analysis, but the current approach using weighted Cox regression fails to maintain the benefits of NCC design. METHODS: This paper introduces weighted conditional logistic regression. We illustrate our proposed analysis using data recently investigated in The Environmental Determinants of Diabetes in the Young (TEDDY). Considering the potential data loss, the TEDDY NCC design was moderately selective in its selection of controls. A data-driven simulation study was performed to present the bias correction when a nonrandom control selection was ignored in the analysis. RESULTS: The TEDDY data analysis showed that the standard analysis using conditional logistic regression estimated the parameter: -0.015 (-0.023, -0.007). The biased estimate using Cox regression was -0.011 (95% confidence interval: -0.019, -0.003). Weighted Cox regression estimated -0.013 (-0.026, 0.0004). The proposed weighted conditional logistic regression estimated -0.020 (-0.033, -0.007), showing a stronger negative effect size than the one using conditional logistic regression. The simulation study also showed that the standard estimate of ß ignoring the nonrandom control selection tends to be greater than the true ß (ie, positive relative biases). CONCLUSION: Weighted conditional logistic regression can enhance the analysis by offering flexibility in the selection of controls, while maintaining the matching.

2.
Nat Med ; 25(12): 1865-1872, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792456

RESUMO

Viruses are implicated in autoimmune destruction of pancreatic islet ß cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect ß cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. ß cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to ß cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/virologia , Enterovirus/isolamento & purificação , RNA Viral/isolamento & purificação , Adolescente , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Enterovirus/imunologia , Enterovirus/patogenicidade , Fezes/virologia , Feminino , Humanos , Lactente , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/virologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/virologia , Masculino , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/virologia
3.
BMC Pediatr ; 19(1): 339, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533753

RESUMO

BACKGROUND: Although breastfeeding is touted as providing many health benefits to infants, some aspects of this relationship remain poorly understood. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) is a prospective longitudinal study that follows children from birth through childhood, and collects data on illness events, breastfeeding duration, and time to introduction of formula or foods at 3 month intervals up until 4 years of age and at 6 months intervals thereafter. Exclusive and non-exclusive breastfeeding is examined in relation to the 3-month odds of a respiratory or gastrointestinal infection for 6861 children between the ages of 3-18 months, and 5666 children up to the age of 4 years. Analysis was performed using logistic regression models with generalized estimating equation methodology. All models were adjusted for potential confounding variables. RESULTS: At 3-6 months of age, breastfeeding was found to be inversely associated with the odds of respiratory infections with fever (OR = 0.82, 95% CI = 0.70-0.95), otitis media (OR = 0.76, 95% CI = 0.62-0.94), and infective gastroenteritis (OR = 0.55, 95% CI = 0.46-0.70), although the inverse association with respiratory illnesses was observed only for girls during the winter months. Between 6 and 18 months of age, breastfeeding within any 3 month period continued to be inversely associated with the odds of ear infection and infective gastroenteritis, and additionally with the odds of conjunctivitis, and laryngitis and tracheitis, over the same 3 month period within this age range. However, breastfeeding in this group was associated with increased reports of common cold. Duration of exclusive breastfeeding was inversely associated with the odds of otitis media up to 48 months of age (OR = 0.97, 95% CI = 0.95-0.99) after breastfeeding had stopped. CONCLUSIONS: This study demonstrates that breastfeeding can be protective against multiple respiratory and gastrointestinal acute illnesses in some children up to at least 6 months of age, with duration of exclusive breastfeeding being somewhat protective of otitis media even after breastfeeding has stopped. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00279318 . Date of registration: January 17, 2006 (proactively registered). First Posted: January 19, 2006.

4.
J Reprod Immunol ; 127: 1-6, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29550618

RESUMO

BACKGROUND: Autoimmune (type 1) diabetes (T1D) is a frequent chronic disease in children and adolescents globally. Gestational enterovirus (EV) infections have been associated with an increased risk for T1D in the offspring. We test the hypothesis that EV infections during the first trimester were associated with beta cell autoantibodies in mothers of children who developed islet autoantibodies before 7 years of age. MATERIALS AND METHODS: Local registries were used to identify mothers to children born 2000-2007 who developed either beta cell autoantibodies or T1D during follow up. Serum samples from the first trimester were located in the Biobank. A total of 448 index mothers were identified and compared to 891 matched control mothers. EV-IgM was determined in a capture enzyme immunoassay. Beta cell autoantibodies were analyzed in standard radio binding assays. RESULTS: The frequency of EV-IgM in index mothers was 20% (89/448), which did not differ from the control mothers 20% (175/891) (p = 0.922). Index mothers had multiple beta cell autoantibodies more often than control mothers (p = 0.037). Beta cell autoantibodies were increased during the November-April winter months in index compared to control mothers (p = 0.022). The observed difference was possibly explained by the months of February-April (p = 0.014). Concomitant EV-IgM and beta cell autoantibodies tended to be more common among index compared to control mothers (p = 0.039). CONCLUSION: EV-IgM during the first trimester may be associated with beta cell autoantibodies in mothers to children who developed either beta cell autoantibodies or T1D before 7 years of age.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Infecções por Enterovirus/imunologia , Enterovirus/fisiologia , Adulto , Anticorpos Antivirais/sangue , Autoanticorpos/sangue , Autoimunidade , Criança , Feminino , Humanos , Imunidade Materno-Adquirida , Imunoglobulina M/sangue , Células Secretoras de Insulina/imunologia , Exposição Materna/efeitos adversos , Troca Materno-Fetal , Gravidez , Primeiro Trimestre da Gravidez , Risco
5.
Diabetologia ; 61(1): 254, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29080005

RESUMO

The authors regret that the SNP in SH2B3 was incorrectly referred to as rs3184505 instead of rs3184504 on both mentions in this paper (Methods section and Table 1).

6.
J Autoimmun ; 86: 93-103, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28941965

RESUMO

ß-cell autoantibodies against insulin (IAA), GAD65 (GADA) and IA-2 (IA-2A) precede onset of childhood type 1 diabetes (T1D). Incidence of the first appearing ß-cell autoantibodies peaks at a young age and is patterned by T1D-associated genes, suggesting an early environmental influence. Here, we tested if gestational infections and interactions with child's human leukocyte antigen (HLA) and non-HLA genes affected the appearance of the first ß-cell autoantibody. Singletons of mothers without diabetes (n = 7472) with T1D-associated HLA-DR-DQ genotypes were prospectively followed quarterly through the first 4 years of life, then semiannually until age 6 years, using standardized autoantibody analyses. Maternal infections during pregnancy were assessed via questionnaire 3-4.5 months post-delivery. Polymorphisms in twelve non-HLA genes associated with the first appearing ß-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing ß-cell autoantibody in younger children (n = 226, median age at seroconversion 1.8 years) and GADA (n = 212; 3.2 years) in children aged ≥2 years. Gestational infections were not associated with the first appearing ß-cell autoantibodies overall. However, gestational respiratory infections (G-RI) showed a consistent protective influence on IAA (HR 0.64, 95% CI 0.45-0.91) among CTLA4-(AG, GG) children (G-RI*CTLA4 interaction, p = 0.002). The predominant associations of HLA-DR-DQ 4-8/8-4 with IAA and HLA-DR-DQ 3-2/3-2 with GADA were not observed if a G-RI was reported (G-RI*HLA-DR-DQ interaction, p = 0.03). The role of G-RI may depend on offspring HLA and CTLA-4 alleles and supports a bidirectional trigger for IAA or GADA as a first appearing ß-cell autoantibody in early life.


Assuntos
Antígeno CTLA-4/metabolismo , Células Secretoras de Insulina/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Infecções Respiratórias/imunologia , Autoanticorpos/metabolismo , Feminino , Idade Gestacional , Glutamato Descarboxilase/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/metabolismo , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Lactente , Insulina/imunologia , Masculino , Polimorfismo Genético , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Infecções Respiratórias/epidemiologia
7.
Diabetologia ; 61(1): 193-202, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28990147

RESUMO

AIMS/HYPOTHESIS: During the A/H1N1 2009 (A/California/04/2009) pandemic, mass vaccination with a squalene-containing vaccine, Pandemrix®, was performed in Sweden and Finland. The vaccination was found to cause narcolepsy in children and young adults with the HLA-DQ 6.2 haplotype. The aim of this study was to investigate if exposure to Pandemrix® similarly increased the risk of islet autoimmunity or type 1 diabetes. METHODS: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, children are followed prospectively for the development of islet autoimmunity and type 1 diabetes. In October 2009, when the mass vaccination began, 3401 children at risk for islet autoimmunity and type 1 diabetes were followed in Sweden and Finland. Vaccinations were recorded and autoantibodies against insulin, GAD65 and insulinoma-associated protein 2 were ascertained quarterly before the age of 4 years and semi-annually thereafter. RESULTS: By 5 August 2010, 2413 of the 3401 (71%) children observed as at risk for an islet autoantibody or type 1 diabetes on 1 October 2009 had been vaccinated with Pandemrix®. By 31 July 2016, 232 children had at least one islet autoantibody before 10 years of age, 148 had multiple islet autoantibodies and 96 had developed type 1 diabetes. The risk of islet autoimmunity was not increased among vaccinated children. The HR (95% CI) for the appearance of at least one islet autoantibody was 0.75 (0.55, 1.03), at least two autoantibodies was 0.85 (0.57, 1.26) and type 1 diabetes was 0.67 (0.42, 1.07). In Finland, but not in Sweden, vaccinated children had a lower risk of islet autoimmunity (0.47 [0.29, 0.75]), multiple autoantibodies (0.50 [0.28, 0.90]) and type 1 diabetes (0.38 [0.20, 0.72]) compared with those who did not receive Pandemrix®. The analyses were adjusted for confounding factors. CONCLUSIONS/INTERPRETATION: Children with an increased genetic risk for type 1 diabetes who received the Pandemrix® vaccine during the A/H1N1 2009 pandemic had no increased risk of islet autoimmunity, multiple islet autoantibodies or type 1 diabetes. In Finland, the vaccine was associated with a reduced risk of islet autoimmunity and type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Vacinas contra Influenza/efeitos adversos , Esqualeno/química , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Autoimunidade/fisiologia , Feminino , Finlândia , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Masculino , Vacinação
8.
JAMA Pediatr ; 171(12): 1217-1225, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29052687

RESUMO

Importance: Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. Objective: To test the association between early-life antibiotic use and islet or celiac disease (CD) autoimmunity in genetically at-risk children prospectively followed up for type 1 diabetes (T1D) or CD. Design, Setting, and Participants: HLA-genotyped newborns from Finland, Germany, Sweden, and the United States were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY) study between November 20, 2004, and July 8, 2010. The dates of analysis were November 20, 2004, to August 31, 2014. Individuals from the general population and those having a first-degree relative with T1D were enrolled if they had 1 of 9 HLA genotypes associated with a risk for T1D. Exposures: Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. Main Outcomes and Measures: Islet autoimmunity and CD autoimmunity were defined as being positive for islet or tissue transglutaminase autoantibodies at 2 consecutive clinic visits at least 3 months apart. Hazard ratios and 95% CIs calculated from Cox proportional hazards regression models were used to assess the relationship between antibiotic use in early life before seroconversion and the development of autoimmunity. Results: Participants were 8495 children (49.0% female) and 6558 children (48.7% female) enrolled in the TEDDY study who were tested for islet and tissue transglutaminase autoantibodies, respectively. Exposure to and frequency of use of any antibiotic assessed in this study in early life or before seroconversion did not influence the risk of developing islet autoimmunity or CD autoimmunity. Cumulative use of any antibiotic during the first 4 years of life was not associated with the appearance of any autoantibody (hazard ratio [HR], 0.98; 95% CI, 0.95-1.01), multiple islet autoantibodies (HR, 0.99; 95% CI, 0.95-1.03), or the transglutaminase autoantibody (HR, 1.00; 95% CI, 0.98-1.02). Conclusions and Relevance: The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD.


Assuntos
Antibacterianos/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Doença Celíaca/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Fatores Etários , Antibacterianos/administração & dosagem , Autoanticorpos/sangue , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Doença Celíaca/epidemiologia , Doença Celíaca/genética , Pré-Escolar , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Relação Dose-Resposta a Droga , Esquema de Medicação , Uso de Medicamentos/estatística & dados numéricos , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Antígenos HLA-DR/genética , Teste de Histocompatibilidade , Humanos , Lactente , Ilhotas Pancreáticas/imunologia , Masculino , Estudos Prospectivos , Medição de Risco/métodos , Sensibilidade e Especificidade , Estados Unidos/epidemiologia
9.
Diabetologia ; 60(10): 1931-1940, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28770319

RESUMO

AIMS/HYPOTHESIS: Respiratory infections and onset of islet autoimmunity are reported to correlate positively in two small prospective studies. The Environmental Determinants of Diabetes in the Young (TEDDY) study is the largest prospective international cohort study on the environmental determinants of type 1 diabetes that regularly monitors both clinical infections and islet autoantibodies. The aim was to confirm the influence of reported respiratory infections and to further characterise the temporal relationship with autoantibody seroconversion. METHODS: During the years 2004-2009, 8676 newborn babies with HLA genotypes conferring an increased risk of type 1 diabetes were enrolled at 3 months of age to participate in a 15 year follow-up. In the present study, the association between parent-reported respiratory infections and islet autoantibodies at 3 month intervals up to 4 years of age was evaluated in 7869 children. Time-dependent proportional hazard models were used to assess how the timing of respiratory infections related to persistent confirmed islet autoimmunity, defined as autoantibody positivity against insulin, GAD and/or insulinoma antigen-2, concordant at two reference laboratories on two or more consecutive visits. RESULTS: In total, 87,327 parent-reported respiratory infectious episodes were recorded while the children were under study surveillance for islet autoimmunity, and 454 children seroconverted. The number of respiratory infections occurring in a 9 month period was associated with the subsequent risk of autoimmunity (p < 0.001). For each 1/year rate increase in infections, the hazard of islet autoimmunity increased by 5.6% (95% CI 2.5%, 8.8%). The risk association was linked primarily to infections occurring in the winter (HR 1.42 [95% CI 1.16, 1.74]; p < 0.001). The types of respiratory infection independently associated with autoimmunity were common cold, influenza-like illness, sinusitis, and laryngitis/tracheitis, with HRs (95% CI) of 1.38 (1.11, 1.71), 2.37 (1.35, 4.15), 2.63 (1.22, 5.67) and 1.76 (1.04, 2.98), respectively. CONCLUSIONS/INTERPRETATION: Recent respiratory infections in young children correlate with an increased risk of islet autoimmunity in the TEDDY study. Further studies to identify the potential causative viruses with pathogen-specific assays should focus especially on the 9 month time window leading to autoantibody seroconversion.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Infecções Respiratórias/imunologia , Adolescente , Autoanticorpos/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fatores de Risco
10.
Diabetes Care ; 40(9): 1167-1172, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28663383

RESUMO

OBJECTIVE: To assess parent anxiety in response to genetic and islet autoantibody (IA) testing in children at increased genetic risk for type 1 diabetes followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study. RESEARCH DESIGN AND METHODS: Parent anxiety about TEDDY children's risk was assessed with the State Anxiety Inventory (SAI). Parents completed the SAI when the child was 3, 6, and 15 months old and annually thereafter. Children were tested for IA every 3 months for 4 years and every 6 months thereafter. Parent SAI scores of 6,799 children followed with IA testing for at least 1 and up to 6 years were examined. RESULTS: At study inception, parents showed high levels of anxiety in response to their child's increased genetic type 1 diabetes risk; mothers were more anxious than fathers, and parents with diabetes in the family were more anxious than parents with no family history. In response to repeated IA-negative (IA-) test results, parent anxiety declined to normal levels. Anxiety increased in parents faced with an IA-positive (IA+) test result. Parents faced with two or more types of IA+ test results showed particularly high levels of anxiety (all P < 0.001). CONCLUSIONS: Infant genetic screening for type 1 diabetes raises parent anxiety when the child is at increased risk, but anxiety dissipates over time in cases of repeated IA- results. IA+ results heighten parent anxiety, and parents faced with two or more types of IA+ results may experience considerable anxiety for longer periods.


Assuntos
Ansiedade/psicologia , Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/psicologia , Pais/psicologia , Alelos , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Feminino , Finlândia , Seguimentos , Testes Genéticos , Alemanha , Humanos , Lactente , Insulina/sangue , Masculino , Fatores de Risco , Suécia , Estados Unidos
11.
Diabetes Care ; 40(9): 1194-1202, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28646072

RESUMO

OBJECTIVE: We tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes. RESEARCH DESIGN AND METHODS: Infants with HLA-DR high-risk genotypes were prospectively followed for diabetes-related autoantibodies. Single nucleotide polymorphisms (SNPs) came from the Illumina ImmunoChip and environmental exposure data were by parental report. Children were followed to age 6 years. RESULTS: Insulin autoantibodies occurred earlier than GAD antibody (GADA) and then declined, while GADA incidence rose and remained constant (significant in HLA-DR4 but not in the DR3/3 children). The presence of SNPs rs2476601 (PTPN22) and rs2292239 (ERBB3) demonstrated increased risk of both autoantibodies to insulin (IAA) only and GADA only. SNP rs689 (INS) was protective of IAA only, but not of GADA only. The rs3757247 (BACH2) SNP demonstrated increased risk of GADA only. Male sex, father or sibling as the diabetic proband, introduction of probiotics under 28 days of age, and weight at age 12 months were associated with IAA only, but only father as the diabetic proband and weight at age 12 months were associated with GADA only. Mother as the diabetic proband was not a significant risk factor. CONCLUSIONS: These results show clear differences in the initiation of autoimmunity according to genetic factors and environmental exposures that give rise to IAA or GADA as the first appearing indication of autoimmunity.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Interação Gene-Ambiente , Criança , Diabetes Mellitus Tipo 1/sangue , Feminino , Seguimentos , Predisposição Genética para Doença , Antígenos HLA/sangue , Antígeno HLA-DR4/sangue , Humanos , Insulina/sangue , Anticorpos Anti-Insulina/sangue , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Fatores de Risco
13.
Pediatrics ; 139(3)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28219962

RESUMO

BACKGROUND AND OBJECTIVES: Psychological symptoms can be associated with celiac disease; however, this association has not been studied prospectively in a pediatric cohort. We examined mother report of psychological functioning in children persistently positive for tissue transglutaminase autoantibodies (tTGA), defined as celiac disease autoimmunity (CDA), compared with children without CDA in a screening population of genetically at-risk children. We also investigated differences in psychological symptoms based on mothers' awareness of their child's CDA status. METHODS: The Environmental Determinants of Diabetes in the Young study followed 8676 children to identify triggers of type 1 diabetes and celiac disease. Children were tested for tTGA beginning at 2 years of age. The Achenbach Child Behavior Checklist assessed child psychological functioning at 3.5 and 4.5 years of age. RESULTS: At 3.5 years, 66 mothers unaware their child had CDA reported more child anxiety and depression, aggressive behavior, and sleep problems than 3651 mothers of children without CDA (all Ps ≤ .03). Unaware-CDA mothers also reported more child anxiety and depression, withdrawn behavior, aggressive behavior, and sleep problems than 440 mothers aware of their child's CDA status (all Ps ≤.04). At 4.5 years, there were no differences. CONCLUSIONS: In 3.5-year-old children, CDA is associated with increased reports of child depression and anxiety, aggressive behavior, and sleep problems when mothers are unaware of their child's CDA status. Mothers' knowledge of their child's CDA status is associated with fewer reports of psychological symptoms, suggesting that awareness of the child's tTGA test results affects reporting of symptoms.


Assuntos
Doença Celíaca/psicologia , Agressão/psicologia , Ansiedade/etiologia , Autoanticorpos/sangue , Doença Celíaca/imunologia , Pré-Escolar , Depressão/etiologia , Europa (Continente) , Feminino , Proteínas de Ligação ao GTP/imunologia , Humanos , Estudos Longitudinais , Masculino , Mães , Estudos Prospectivos , Transtornos do Sono-Vigília/etiologia , Transglutaminases/imunologia , Estados Unidos
14.
Clin Gastroenterol Hepatol ; 15(5): 694-702.e5, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27840181

RESUMO

BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of gluten immunogenicity in patients with celiac disease. We studied temporal associations between infections and the development of celiac disease autoimmunity, and examined effects of HLA alleles, rotavirus vaccination status, and infant feeding. METHODS: We monitored 6327 children in the United States and Europe carrying HLA risk genotypes for celiac disease from 1 to 4 years of age for presence of tissue transglutaminase autoantibodies (the definition of celiac disease autoimmunity), until March 31, 2015. Parental reports of gastrointestinal and respiratory infections were collected every third month from birth. We analyzed time-varying relationships among reported infections, rotavirus vaccination status, time to first introduction of gluten, breastfeeding, and risk of celiac disease autoimmunity using proportional hazard models. RESULTS: We identified 13,881 gastrointestinal infectious episodes (GIE) and 79,816 respiratory infectious episodes. During the follow-up period, 732 of 6327 (11.6%) children developed celiac disease autoimmunity. A GIE increased the risk of celiac disease autoimmunity within the following 3 months by 33% (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.11-1.59). This risk increased 2-fold among children born in winter and introduced to gluten before age 6 months (HR, 2.08; 95% CI, 1.46-2.98), and increased 10-fold among children without HLA-DQ2 alleles and breastfed for fewer than 4 months (HR, 9.76; 95% CI, 3.87-24.8). Risk of celiac disease autoimmunity was reduced in children vaccinated against rotavirus and introduced to gluten before age 6 months (HR, 0.57; 95% CI, 0.36-0.88). CONCLUSIONS: Gastrointestinal infections increase the risk of celiac disease autoimmunity in children with genetic susceptibility to this autoimmune disorder. The risk is modified by HLA genotype, infant gluten consumption, breastfeeding, and rotavirus vaccination, indicating complex interactions among infections, genetic factors, and diet in the etiology of celiac disease in early childhood.


Assuntos
Doença Celíaca/epidemiologia , Doença Celíaca/etiologia , Gastroenterite/complicações , Adulto , Pré-Escolar , Dieta/métodos , Suscetibilidade a Doenças , Europa (Continente)/epidemiologia , Feminino , Genótipo , Antígenos HLA/genética , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Infecções Respiratórias/complicações , Medição de Risco , Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Estados Unidos/epidemiologia
15.
Sci Rep ; 6: 30828, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27561809

RESUMO

Regression models are extensively used in many epidemiological studies to understand the linkage between specific outcomes of interest and their risk factors. However, regression models in general examine the average effects of the risk factors and ignore subgroups with different risk profiles. As a result, interventions are often geared towards the average member of the population, without consideration of the special health needs of different subgroups within the population. This paper demonstrates the value of using rule-based analysis methods that can identify subgroups with heterogeneous risk profiles in a population without imposing assumptions on the subgroups or method. The rules define the risk pattern of subsets of individuals by not only considering the interactions between the risk factors but also their ranges. We compared the rule-based analysis results with the results from a logistic regression model in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Both methods detected a similar suite of risk factors, but the rule-based analysis was superior at detecting multiple interactions between the risk factors that characterize the subgroups. A further investigation of the particular characteristics of each subgroup may detect the special health needs of the subgroup and lead to tailored interventions.


Assuntos
Pacientes Desistentes do Tratamento , Algoritmos , Criança , Pré-Escolar , Estudos Clínicos como Assunto , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Seleção de Pacientes , Análise de Regressão , Fatores de Risco
16.
Diabetes Care ; 39(9): 1535-42, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27311490

RESUMO

OBJECTIVE: ß-Cell autoantibodies are a feature of the preclinical phase of type 1 diabetes. Here, we asked how frequently they revert in a cohort of children at risk for type 1 diabetes and whether reversion has any effect on type 1 diabetes risk. RESEARCH DESIGN AND METHODS: Children were up to 10 years of age and screened more than once for insulin autoantibody, GAD antibody, and insulinoma antigen-2 antibodies. Persistent autoantibody was defined as an autoantibody present on two or more consecutive visits and confirmed in two reference laboratories. Reversion was defined as two or more consecutive negative visits after persistence. Time-dependent Cox regression was used to examine how reversion modified the risk of development of multiple autoantibodies and type 1 diabetes. RESULTS: Reversion was relatively frequent for autoantibodies to GAD65 (19%) and insulin (29%), but was largely restricted to children who had single autoantibodies (24%) and rare in children who had developed multiple autoantibodies (<1%). Most (85%) reversion of single autoantibodies occurred within 2 years of seroconversion. Reversion was associated with HLA genotype, age, and decreasing titer. Children who reverted from single autoantibodies to autoantibody negative had, from birth, a risk for type 1 diabetes of 0.14 per 100 person-years; children who never developed autoantibodies, 0.06 per 100 person-years; and, children who remained single-autoantibody positive, 1.8 per 100 person-years. CONCLUSIONS: Type 1 diabetes risk remained high in children who had developed multiple ß-cell autoantibodies even when individual autoantibodies reverted. We suggest that monitoring children with single autoantibodies for at least 1 year after seroconversion is beneficial for stratification of type 1 diabetes risk.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/imunologia , Soroconversão , Autoanticorpos/sangue , Autoanticorpos/imunologia , Criança , Pré-Escolar , Feminino , Genótipo , Glutamato Descarboxilase/imunologia , Humanos , Insulina/imunologia , Anticorpos Anti-Insulina/sangue , Anticorpos Anti-Insulina/imunologia , Masculino , Estudos Prospectivos , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Medição de Risco/métodos , Fatores de Risco
17.
Public Health Nutr ; 19(5): 804-13, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26088478

RESUMO

OBJECTIVE: Non-compliance with food record submission can induce bias in nutritional epidemiological analysis and make it difficult to draw inference from study findings. We examined the impact of demographic, lifestyle and psychosocial factors on such non-compliance during the first 3 years of participation in a multidisciplinary prospective paediatric study. DESIGN: The Environmental Determinants of Diabetes in the Young (TEDDY) study collects a 3 d food record quarterly during the first year of life and semi-annually thereafter. High compliance with food record completion was defined as the participating families submitting one or more days of food record at every scheduled clinic visit. SETTING: Three centres in the USA (Colorado, Georgia/Florida and Washington) and three in Europe (Finland, Germany and Sweden). SUBJECTS: Families who finished the first 3 years of TEDDY participation (n 8096). RESULTS: High compliance was associated with having a single child, older maternal age, higher maternal education and father responding to study questionnaires. Families showing poor compliance were more likely to be living far from the study centres, from ethnic minority groups, living in a crowded household and not attending clinic visits regularly. Postpartum depression, maternal smoking behaviour and mother working outside the home were also independently associated with poor compliance. CONCLUSIONS: These findings identified specific groups for targeted strategies to encourage completion of food records, thereby reducing potential bias in multidisciplinary collaborative research.


Assuntos
Viés , Registros de Dieta , Cooperação do Paciente , Adolescente , Criança , Pré-Escolar , Colorado , Características da Família , Feminino , Finlândia , Florida , Georgia , Alemanha , Humanos , Lactente , Estilo de Vida , Masculino , Avaliação Nutricional , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Suécia , Washington
18.
J Pediatr Psychol ; 41(3): 373-83, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26412232

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 1/etiologia , Estudos Epidemiológicos , Estilo de Vida , Mães/estatística & dados numéricos , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos Multicêntricos como Assunto , Fatores de Risco
19.
Diabetologia ; 58(5): 980-7, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25660258

RESUMO

AIMS/HYPOTHESIS: Islet autoantibodies, in addition to elevated blood glucose, define type 1 diabetes. These autoantibodies are detectable for a variable period of time before diabetes onset. Thus, the occurrence of islet autoantibodies is associated with the beginning of the disease process. The age at, and order in, which autoantibodies appear may be associated with different genetic backgrounds or environmental exposures, or both. METHODS: Infants with HLA-DR high-risk genotypes (DR3/4, DR4/4, DR4/8 and DR3/3) were enrolled and prospectively followed with standardised autoantibody assessments quarterly throughout the first 4 years of life and then semi-annually thereafter. RESULTS: Autoantibodies appeared in 549/8,503 (6.5%) children during 34,091 person-years of follow-up. Autoantibodies at 3 (0.1%) and 6 (0.2%) months of age were rare. Of the 549, 43.7% had islet autoantibodies to insulin (IAA) only, 37.7% had glutamic acid decarboxylase autoantibodies (GADA) only, 13.8% had both GADA and IAA only, 1.6% had insulinoma antigen-2 only and 3.1% had other combinations. The incidence of IAA only peaked within the first year of life and declined over the following 5 years, but GADA only increased until the second year and remained relatively constant. GADA only were more common than IAA only in HLA-DR3/3 children but less common in HLA-DR4/8 children. CONCLUSIONS/INTERPRETATION: Islet autoantibodies can occur very early in life and the order of appearance was related to HLA-DR-DQ genotype.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/imunologia , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Ilhotas Pancreáticas/imunologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Feminino , Genótipo , Humanos , Insulina/genética , Masculino
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