Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes

BMC Pediatrics

Leonard C Harrison³  Timothy W Jones⁶  Andrew M Cotterill¹  William D Rawlinson⁴  Peter G Colman⁵  Maria E Craig⁷  Jennifer J Couper²  Megan AS Penno⁸ 

[1] Mater Health Services, South Brisbane, Queensland 4101, Australia;Endocrine and Diabetes Department, Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia;Walter and Eliza Hall Institute, Parkville, Victoria 3050, Australia;SOMS Faculty of Medicine, and BABS Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia;Royal Melbourne Hospital, Parkville, Victoria 3050, Australia;Princess Margaret Hospital Department of Endocrinology and Diabetes, School of Paediatrics and Child Health; Telethon Institute of Child Health Research, University of Western Australia, Perth, WA 6008, Australia;Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW 2006, Australia;Discipline of Paediatrics, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia

关键词: Systems biology;    Virus;    Immunity;    Insulin resistance;    Microbiome;    Infancy;    Pregnancy;    Beta cell;    Islet autoimmunity;    Type 1 diabetes;   

Others  :  1144615
DOI  :  10.1186/1471-2431-13-124

 received in 2013-07-29, accepted in 2013-08-12,  发布年份 2013

【 摘 要 】

Background

The incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes.

Methods/design

ENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome-lipidome, insulin resistance, innate and adaptive immune function and viral infections. A systems biology approach will be used to integrate these data. Investigation will be by 3-monthly assessments of the mother during pregnancy, then 3-monthly assessments of the child until 24 months of age and 6-monthly thereafter. The primary outcome measure is persistent islet autoimmunity, defined as the presence of autoantibodies to one or more islet autoantigens on consecutive tests.

Discussion

Defining gene-environment interactions that initiate and/or promote destruction of the insulin-producing beta cells in early life will inform approaches to primary prevention of type 1 diabetes. The strength of ENDIA is the prospective, comprehensive and frequent systems-wide profiling from early pregnancy through to early childhood, to capture dynamic environmental exposures that may shape the development of islet autoimmunity.

Trial registration

Australia New Zealand Clinical Trials Registry ACTRN12613000794707.

【 授权许可】

   
2013 Penno et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Diamond Project Group: Incidence and trends of childhood type 1 diabetes worldwide 1990–1999. Diabet Med 2006, 23(8):857-866.
• [2]Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G: Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet 2009, 373(9680):2027-2033.
• [3]Catanzariti L, Faulks K, Moon L, Waters AM, Flack J, Craig ME: Australia’s national trends in the incidence of type 1 diabetes in 0–14-year-olds, 2000–2006. Diabet Med 2009, 26(6):596-601.
• [4]Haynes A, Bower C, Bulsara MK, Jones TW, Davis EA: Continued increase in the incidence of childhood type 1 diabetes in a population-based Australian sample (1985–2002). Diabetologia 2004, 47(5):866-870.
• [5]Taplin CE, Craig ME, Lloyd M, Talyor C, Crock P, Silink M, Howard NJ: The rising incidence of childhood type 1 diabetes in New South Wales, 1990–2002. Med J Aust 2005, 183(5):243-246.
• [6]Knip M: Pathogenesis of type 1 diabetes: implications for incidence trends. Horm Res Paediatr 2011, 76(Suppl 1):57-64.
• [7]Fourlanos S, Varney MD, Tait BD, Morahan G, Honeyman MC, Colman PG, Harrison LC: The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 2008, 31(8):1546-1549.
• [8]Morahan G: Insights into type 1 diabetes provided by genetic analyses. Curr Opin Endocrinol Diabetes Obes 2012, 19(4):263-270.
• [9]Bonifacio E, Warncke K, Winkler C, Wallner M, Ziegler AG: Cesarean section and interferon-induced helicase gene polymorphisms combine to increase childhood type 1 diabetes risk. Diabetes 2011, 60(12):3300-3306.
• [10]Lempainen J, Vaarala O, Makela M, Veijola R, Simell O, Knip M, Hermann R, Ilonen J: Interplay between PTPN22 C1858T polymorphism and cow’s milk formula exposure in type 1 diabetes. J Autoimmun 2009, 33(2):155-164.
• [11]Purohit S, She JX: Biomarkers for type 1 diabetes. Int J Clin Exp Med 2008, 1(2):98-116.
• [12]Couper JJ, Beresford S, Hirte C, Baghurst PA, Pollard A, Tait BD, Harrison LC, Colman PG: Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes. Diabetes Care 2009, 32(1):94-99.
• [13]Colman PG, McNair PD, Gellert S, Kewming K, Schmidli RS, Steele CE, Harrison LC: Development of autoantibodies to islet antigens during childhood: implications for preclinical type 1 diabetes screening. Pediatr Diabetes 2002, 3(3):144-148.
• [14]Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, Winkler C, Ilonen J, Veijola R, Knip M, et al.: Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 2013, 309(23):2473-2479.
• [15]Littman DR, Pamer EG: Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 2011, 10(4):311-323.
• [16]Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R: Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 2010, 107(26):11971-11975.
• [17]Isolauri E: Development of healthy gut microbiota early in life. J Paediatr Child Health 2012, 48(Suppl 3):1-6.
• [18]Johnson CL, Versalovic J: The human microbiome and its potential importance to pediatrics. Pediatrics 2012, 129(5):950-960.
• [19]Rigon G, Vallone C, Lucantoni V, Signore F: Maternal factors pre- and during delivery contribute to gut microbiota shaping in newborns. Front Cell Infect Microbiol 2012, 2:93.
• [20]Australian Institute for Health and Welfare 2011: Australia's welfare 2011. In Australia’s welfare series. Volume 10, Cat. no. AUS 142. Canberra: Australian Institute for Health and Welfare; 2011.
• [21]Kannieappan LM, Deussen AR, Grivell RM, Yelland L, Dodd JM: Developing a tool for obtaining maternal skinfold thickness measurements and assessing inter-observer variability among pregnant women who are overweight and obese. BMC Pregnancy Childbirth 2013, 13(1):42. BioMed Central Full Text
• [22]Australian Government Department of Health and Aging: 2007 Australian National Children’s Nutrition and Physical Activity Survey- Main Findings. http://www.commcarelink.health.gov.au/internet/main/publishing.nsf/Content/66596E8FC68FD1A3CA2574D50027DB86/ webcite$File/childrens-nut-phys-survey.pdf
• [23]Macpherson AJ, Harris NL: Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 2004, 4(6):478-485.
• [24]Locke NR, Stankovic S, Funda DP, Harrison LC: TCR gamma delta intraepithelial lymphocytes are required for self-tolerance. J Immunol 2006, 176(11):6553-6559.
• [25]Pozzilli P, Signore A, Williams AJ, Beales PE: NOD mouse colonies around the world–recent facts and figures. Immunol Today 1993, 14(5):193-196.
• [26]Suzuki T: Diabetogenic effects of lymphocyte transfusion on the NOD or NOD nude mouse. In Immune deficient animals in biomedical research. Edited by Rygaard J, Brunner N, Graem N, Spang-Thomson M. Basel: Karger; 1987:112-116.
• [27]Funda DP, Fundova P, Harrison LC: Environmental-mucosal interactions in the natural history of type 1 diabetes: the germ-free (GF) NOD mouse model. In Proceedings of the 7th Immunology of Diabetes Society Meeting. vol. 41. Edited by Sanjeevi CB, Gale EAM. New York: Ann N Y Acad Sci; 2005.
• [28]Kawaguchi-Miyashita M, Shimizu K, Nanno M, Shimada S, Watanabe T, Koga Y, Matsuoka Y, Ishikawa H, Hashimoto K, Ohwaki M: Development and cytolytic function of intestinal intraepithelial T lymphocytes in antigen-minimized mice. Immunology 1996, 89(2):268-273.
• [29]Brown CT, Davis-Richardson AG, Giongo A, Gano KA, Crabb DB, Mukherjee N, Casella G, Drew JC, Ilonen J, Knip M, et al.: Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One 2011, 6:e25792.
• [30]Shehadeh N, Gelertner L, Blazer S, Perlman R, Etzioni A: The importance of insulin content in infant diet: suggestion for a new infant formula period. Acta Pediatr 2001, 90:93-95.
• [31]Narendran P, Mannering SI, Harrison LC: Proinsulin-a pathogenic autoantigen in type 1 diabetes. Autoimmun Rev 2003, 2(4):204-210.
• [32]Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, et al.: Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009, 139(3):485-498.
• [33]Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, Drew JC, Ilonen J, Knip M, Hyoty H, et al.: Toward defining the autoimmune microbiome for type 1 diabetes. ISME J 2011, 5(1):82-91.
• [34]de Goffau MC, Luopajarvi K, Knip M, Ilonen J, Ruohtula T, Harkonen T, Orivuori L, Hakala S, Welling GW, Harmsen HJ, Vaarala O: Fecal microbiota composition differs between children with beta-cell autoimmunity and those without. Diabetes 2013, 62:1238-1244.
• [35]Brown CT, Davis-Richardson AG, Giongo A, Gano KA, Crabb DB, Mukherjee N, Casella G, Drew JC, Ilonen J, Knip M, et al.: Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One 2011, 6(10):e25792.
• [36]Kondrashova A, Reunanen A, Romanov A, Karvonen A, Viskari H, Vesikari T, Ilonen J, Knip M, Hyoty H: A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland. Ann Med 2005, 37(1):67-72.
• [37]Seiskari T, Kondrashova A, Viskari H, Kaila M, Haapala AM, Aittoniemi J, Virta M, Hurme M, Uibo R, Knip M, et al.: Allergic sensitization and microbial load–a comparison between Finland and Russian Karelia. Clin Exp Immunol 2007, 148(1):47-52.
• [38]Calcinaro F, Dionisi S, Marinaro M, Candeloro P, Bonato V, Marzotti S, Corneli RB, Ferretti E, Gulino A, Grasso F, et al.: Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 2005, 48(8):1565-1575.
• [39]Rasmussen T, Stene LC, Samuelsen SO, Cinek O, Wetlesen T, Torjesen PA, Ronningen KS: Maternal BMI before pregnancy, maternal weight gain during pregnancy, and risk of persistent positivity for multiple diabetes-associated autoantibodies in children with the high-risk HLA genotype: the MIDIA study. Diabetes Care 2009, 32(10):1904-1906.
• [40]Bonifacio E, Pfluger M, Marienfeld S, Winkler C, Hummel M, Ziegler AG: Maternal type 1 diabetes reduces the risk of islet autoantibodies: relationships with birthweight and maternal HbA(1c). Diabetologia 2008, 51(7):1245-1252.
• [41]Koczwara K, Bonifacio E, Ziegler AG: Transmission of maternal islet antibodies and risk of autoimmune diabetes in offspring of mothers with type 1 diabetes. Diabetes 2004, 53(1):1-4.
• [42]Elfving M, Lindberg B, Lynch K, Mansson M, Sundkvist G, Lernmark A, Ivarsson SA: Number of islet autoantibodies present in newly diagnosed type 1 diabetes children born to non-diabetic mothers is affected by islet autoantibodies present at birth. Pediatr Diabetes 2008, 9(2):127-134.
• [43]Lamb MM, Yin X, Zerbe GO, Klingensmith GJ, Dabelea D, Fingerlin TE, Rewers M, Norris JM: Height growth velocity, islet autoimmunity and type 1 diabetes development: the diabetes autoimmunity study in the young. Diabetologia 2009, 52(10):2064-2071.
• [44]Winkler C, Marienfeld S, Zwilling M, Bonifacio E, Ziegler AG: Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes? Diabetologia 2009, 52(10):2072-2078.
• [45]Knerr I, Wolf J, Reinehr T, Stachow R, Grabert M, Schober E, Rascher W, Holl RW: The ‘accelerator hypothesis’: relationship between weight, height, body mass index and age at diagnosis in a large cohort of 9,248 German and Austrian children with type 1 diabetes mellitus. Diabetologia 2005, 48(12):2501-2504.
• [46]Clarke SL, Craig ME, Garnett SP, Chan AK, Cowell CT, Cusumano JM, Kordonouri O, Sambasivan A, Donaghue KC: Increased adiposity at diagnosis in younger children with type 1 diabetes does not persist. Diabetes Care 2006, 29(7):1651-1653.
• [47]Hypponen E, Virtanen SM, Kenward MG, Knip M, Akerblom HK: Obesity, increased linear growth, and risk of type 1 diabetes in children. Diabetes Care 2000, 23(12):1755-1760.
• [48]Colman PG, Steele C, Couper JJ, Beresford SJ, Powell T, Kewming K, Pollard A, Gellert S, Tait B, Honeyman M, et al.: Islet autoimmunity in infants with a type I diabetic relative is common but is frequently restricted to one autoantibody. Diabetologia 2000, 43(2):203-209.
• [49]Couper JJ, Steele C, Beresford S, Powell T, McCaul K, Pollard A, Gellert S, Tait B, Harrison LC, Colman PG: Lack of association between duration of breast-feeding or introduction of cow’s milk and development of islet autoimmunity. Diabetes 1999, 48(11):2145-2149.
• [50]Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E: Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 2003, 290(13):1721-1728.
• [51]Virtanen SM, Knip M: Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age. Am J Clin Nutr 2003, 78(6):1053-1067.
• [52]Norris JM, Barriga K, Klingensmith G, Hoffman M, Eisenbarth GS, Erlich HA, Rewers M: Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA 2003, 290(13):1713-1720.
• [53]Stene LC, Witso E, Torjesen PA, Rasmussen T, Magnus P, Cinek O, Wetlesen T, Ronningen KS: Islet autoantibody development during follow-up of high-risk children from the general Norwegian population from three months of age: design and early results from the MIDIA study. J Autoimmun 2007, 29(1):44-51.
• [54]Virtanen SM, Kenward MG, Erkkola M, Kautiainen S, Kronberg-Kippila C, Hakulinen T, Ahonen S, Uusitalo L, Niinisto S, Veijola R, et al.: Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes. Diabetologia 2006, 49(7):1512-1521.
• [55]Knip M, Virtanen SM, Seppa K, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hamalainen AM, Paronen J, et al.: Dietary intervention in infancy and later signs of beta-cell autoimmunity. New England Journal of Medicine 2010, 363(20):1900-1908.
• [56]Frederiksen B, Kroehl M, Lamb MM, Seifert J, Barriga K, Eisenbarth GS, Rewers M, Norris JM: Infant exposures and development of type 1 diabetes mellitus: the diabetes autoimmunity study in the young (DAISY). JAMA Pediatr 2013. doi:10.1001/jamapediatrics.2013.317.
• [57]Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, Wabitsch M, O’Brien PE, Harrison LC: Pro-inflammatory CD11c + CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 2010, 59(7):1648-1656.
• [58]Hofman PL, Regan F, Jackson WE, Jefferies C, Knight DB, Robinson EM, Cutfield WS: Premature birth and later insulin resistance. New England Journal of Medicine 2004, 351(21):2179-2186.
• [59]Petrovsky N, Harrison LC: Diurnal rhythmicity of human cytokine production: a dynamic disequilibrium in T helper cell type 1/T helper cell type 2 balance? J Immunol 1997, 158(11):5163-5168.
• [60]Petrovsky N, Kyvik KO, Bonnevie-Nielsen V, Beck-Nielsen H, Green A, Harrison LC: Evidence from twins for acquired cellular immune hyperactivity in type 1 diabetes. Immunology 2002, 106(4):584-589.
• [61]Antonelli A, Fallahi P, Ferrari SM, Pupilli C, d’Annunzio G, Lorini R, Vanelli M, Ferrannini E: Serum Th1 (CXCL10) and Th2 (CCL2) chemokine levels in children with newly diagnosed Type 1 diabetes: a longitudinal study. Diabet Med 2008, 25(11):1349-1353.
• [62]Yeung WC, Al-Shabeeb A, Pang CN, Wilkins MR, Catteau J, Howard NJ, Rawlinson WD, Craig ME: Children with islet autoimmunity and enterovirus infection demonstrate a distinct cytokine profile. Diabetes 2012, 61(6):1500-1508.
• [63]Chase HP, Cooper S, Osberg I, Stene LC, Barriga K, Norris J, Eisenbarth GS, Rewers M: Elevated C-reactive protein levels in the development of type 1 diabetes. Diabetes 2004, 53(10):2569-2573.
• [64]Mericq V, Piccardo C, Cai W, Chen X, Zhu L, Striker GE, Vlassara H, Uribarri J: Maternally transmitted and food-derived glycotoxins: a factor preconditioning the young to diabetes? Diabetes Care 2010, 33(10):2232-2237.
• [65]Stene LC, Joner G: Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case–control study. Am J Clin Nutr 2003, 78(6):1128-1134.
• [66]Norris JM, Yin X, Lamb MM, Barriga K, Seifert J, Hoffman M, Orton HD, Baron AE, Clare-Salzler M, Chase HP, et al.: Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA 2007, 298(12):1420-1428.
• [67]Bailey R, Cooper JD, Zeitels L, Smyth DJ, Yang JH, Walker NM, Hypponen E, Dunger DB, Ramos-Lopez E, Badenhoop K, et al.: Association of the vitamin D metabolism gene CYP27B1 with type 1 diabetes. Diabetes 2007, 56(10):2616-2621.
• [68]Ramos-Lopez E, Bruck P, Jansen T, Herwig J, Badenhoop K: CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes/Metabolism Research Reviews 2007, 23(8):631-636.
• [69]Zhang J, Li W, Liu J, Wu W, Ouyang H, Zhang Q, Wang Y, Liu L, Yang R, Liu X, et al.: Polymorphisms in the vitamin D receptor gene and type 1 diabetes mellitus risk: an update by meta-analysis. Mol Cell Endocrinol 2012, 355(1):135-142.
• [70]Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM: Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001, 358(9292):1500-1503.
• [71]Simpson M, Brady H, Yin X, Seifert J, Barriga K, Hoffman M, Bugawan T, Baron AE, Sokol RJ, Eisenbarth G, et al.: No association of vitamin D intake or 25-hydroxyvitamin D levels in childhood with risk of islet autoimmunity and type 1 diabetes: the diabetes autoimmunity study in the young (DAISY). Diabetologia 2011, 54(11):2779-2788.
• [72]Bowyer L, Catling-Paull C, Diamond T, Homer C, Davis G, Craig ME: Vitamin D, PTH and calcium levels in pregnant women and their neonates. Clin Endocrinol (Oxf) 2009, 70(3):372-377.
• [73]Zhang Y, Bandala-Sanchez E, Harrison LC: Revisiting regulatory T cells in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 2012, 19(4):271-278.
• [74]Bluestone JA, Herold K, Eisenbarth G: Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010, 464(7293):1293-1300.
• [75]Sadlon TJ, Wilkinson BG, Pederson S, Brown CY, Bresatz S, Gargett T, Melville EL, Peng K, D’Andrea RJ, Glonek GG, et al.: Genome-wide identification of human FOXP3 target genes in natural regulatory T cells. J Immunol 2010, 185(2):1071-1081.
• [76]Bandala-Sanchez E, Zhang Y, Reinwald S, Dromey JA, Lee BH, Qian J, Bohmer RM, Harrison LC: T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor Siglec-10. Nat Immunol 2013, 14:741-748.
• [77]Petrovsky N, Harrison LC: Cytokine-based human whole blood assay for the detection of antigen-reactive T cells. J Immunol Methods 1995, 186(1):37-46.
• [78]Yeung WC, Rawlinson WD, Craig ME: Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. Br Med J 2011, 342:d35.
• [79]Craig ME, Howard NJ, Silink M, Rawlinson WD: Reduced frequency of HLA DRB1*03-DQB1*02 in children with type 1 diabetes associated with enterovirus RNA. J Inf Dis 2003, 187(10):1562-1570.
• [80]Oikarinen S, Martiskainen M, Tauriainen S, Huhtala H, Ilonen J, Veijola R, Simell O, Knip M, Hyoty H: Enterovirus RNA in blood is linked to the development of type 1 diabetes. Diabetes 2011, 60(1):276-279.
• [81]Tapia G, Cinek O, Rasmussen T, Witso E, Grinde B, Stene LC, Ronningen KS: Human enterovirus RNA in monthly fecal samples and islet autoimmunity in Norwegian children with high genetic risk for type 1 diabetes: the MIDIA study. Diabetes Care 2011, 34(1):151-155.
• [82]Stene LC, Oikarinen S, Hyoty H, Barriga KJ, Norris JM, Klingensmith G, Hutton JC, Erlich HA, Eisenbarth GS, Rewers M: Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the diabetes and autoimmunity study in the young (DAISY). Diabetes 2010, 59(12):3174-3180.
• [83]Lempainen J, Tauriainen S, Vaarala O, Makela M, Honkanen H, Marttila J, Veijola R, Simell O, Hyoty H, Knip M, et al.: Interaction of enterovirus infection and cow’s milk-based formula nutrition in type 1 diabetes-associated autoimmunity. Diabetes Metab Res Rev 2012, 28(2):177-185.
• [84]Honeyman MC, Coulson BS, Stone NL, Gellert SA, Goldwater PN, Steele CE, Couper JJ, Tait BD, Colman PG, Harrison LC: Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 2000, 49(8):1319-1324.
• [85]Honeyman MC, Stone NL, Falk BA, Nepom G, Harrison LC: Evidence for molecular mimicry between human T cell epitopes in rotavirus and pancreatic islet autoantigens. J Immunol 2010, 184(4):2204-2210.
• [86]Hull B, Dey A, Mahajan D, Menzies R, McIntyre PB: Immunisation coverage annual report, 2009. Commun Dis Intell 2011, 35(2):132-148.
• [87]Tate JE, Curns AT, Cortese MM, Weintraub ES, Hambidge S, Zangwill KM, Patel MM, Baggs JM, Parashar UD: Burden of acute gastroenteritis hospitalizations and emergency department visits in US children that is potentially preventable by rotavirus vaccination: a probe study using the now-withdrawn rotashield vaccine. Pediatrics 2009, 123(3):744-749.
• [88]Simell O, Niinikoski H, Ronnemaa T, Raitakari OT, Lagstrom H, Laurinen M, Aromaa M, Hakala P, Jula A, Jokinen E, et al.: Cohort profile: the STRIP study (Special Turku Coronary Risk Factor Intervention Project), an infancy-onset dietary and life-style intervention trial. Int J Epidemiol 2009, 38(3):650-655.
• [89]Oresic M, Gopalacharyulu P, Mykkanen J, Lietzen N, Makinen M, Nygren H, Simell S, Simell V, Hyoty H, Veijola R, et al.: Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes. Diabetes 2013,  . doi:10.2337/db13-0159
• [90]Rakyan VK, Beyan H, Down TA, Hawa MI, Maslau S, Aden D, Daunay A, Busato F, Mein CA, Manfras B, et al.: Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genet 2011, 7(9):e1002300.
• [91]Zhang Y, Maksimovic J, Naselli G, Qian J, Blewitt ME, Oshlack A, Harrison LC: Genome-wide DNA methylation analysis identifies hypomethylated genes with the forkhead-binding motif in human regulatory T cells. Bloodin press
• [92]Teddy Study Group: The environmental determinants of diabetes in the young (TEDDY) study: study design. Pediatr Diabetes 2007, 8(5):286-298.
• [93]Akerblom HK: The trial to reduce IDDM in the genetically at risk (TRIGR) study: recruitment, intervention and follow-up. Diabetologia 2011, 54(3):627-633.
• [94]Roll U, Christie MR, Fuchtenbusch M, Payton MA, Hawkes CJ, Ziegler AG: Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood. Diabetes 1996, 45(7):967-973.
• [95]Hodge A, Patterson AJ, Brown WJ, Ireland P, Giles G: The anti cancer council of Victoria FFQ: relative validity of nutrient intakes compared with weighed food records in young to middle-aged women in a study of iron supplementation. Aust N Z J Public Health 2000, 24(6):576-583.
• [96]Chasan-Taber L, Schmidt MD, Roberts DE, Hosmer D, Markenson G, Freedson PS: Development and validation of a pregnancy physical activity questionnaire. Med Sci Sports Exerc 2004, 36(10):1750-1760.
• [97]Johnson RK, Driscoll P, Goran MI: Comparison of multiple-pass 24-hour recall estimates of energy intake with total energy expenditure determined by the doubly labeled water method in young children. J Am Diet Assoc 1996, 96(11):1140-1144.
• [98]Golley RK, Hendrie GA: The impact of replacing regular- with reduced-fat dairy foods on children’s wider food intake: secondary analysis of a cluster RCT. Eur J Clin Nutr 2012, 66(10):1130-1134.
• [99]Duncanson K, Burrows T, Collins C: Study protocol of a parent-focused child feeding and dietary intake intervention: the feeding healthy food to kids randomised controlled trial. BMC Publ Health 2012, 12:564. BioMed Central Full Text
• [100]Australian Bureau of Statistics: Australian Demographic Statistics Tables. In Australian Demographics Statistics, Dec 2012. Volume 31010DO002_201212. Edited by Australian Bureau of Statistics. Canberra; 2013.
• [101]Collett D: Modelling Survival Data in Medical Research. 2nd edition. Florida: Chapman & Hall/CRC Press LLC; 2003.
• [102]SocialBaker: Australia Facebook Statistics. [http://www.socialbakers.com/facebook-statistics/australia webcite]
• [103]National Health and Medical Research Council 2007: National Statement on Ethical Conduct in Human Research 2007 - Updated 2009. In NHMRC Publications. vol. E72. Edited by Australian Government. Canberra; 2007.
• [104]Colagiuri SBA, Gomez M, Fitzgerald B, Buckley A, Colagiuri R: DiabCo$t Australia Type 1: Assessing the burden of Type 1 Diabetes in Australia. Canberra: Diabetes Australia; 2009.