title: The TrialNet Natural History Study of the Development of Type 1 Diabetes: objectives, design, and initial results.
abstract: OBJECTIVE
  TrialNet's goal to test preventions for type 1 diabetes has created an opportunity to gain new insights into the natural history of pre-type 1 diabetes. The TrialNet Natural History Study (NHS) will assess the predictive value of existing and novel risk markers for type 1 diabetes and will find subjects for prevention trials.
  
  
  METHODS
  The NHS is a three-phase, prospective cohort study. In phase 1 (screening), pancreatic autoantibodies (glutamic acid decarboxylase, insulin, ICA-512, and islet cell antibodies) are measured. Phase 2 (baseline risk assessment) includes oral glucose tolerance tests (OGTTs) in antibody-positive subjects and estimation of 5-yr diabetes risks according to the OGTT and number of confirmed positive antibody tests. Phase 3 (follow-up risk assessments) requires OGTTs every 6 months. In phases 2 and 3, samples are collected for future tests of T-lymphocyte function, autoantibody isotypes, RNA gene expression, and proteomics. The primary outcome is diabetes onset.
  
  
  RESULTS
  Of 12 636 relatives screened between March 2004 and December 2006, 605 (4.8%) were positive for at least one biochemical antibody. Of these, 322 were confirmed antibody positive and completed phase 2, of whom 296 subjects were given preliminary 5-yr diabetes risks of <25% (n = 132), > or =25% (n = 36), and > or =50% (n = 128) where the latter two categories represent different subjects based on number of confirmed positive antibodies (2, > or =25%; 3 or more, > or =50%) and/or an abnormal OGTT (> or =50%).
  
  
  CONCLUSIONS
  The NHS is identifying potential prevention trial subjects and is assembling a large cohort that will provide new natural history information about pre-type 1 diabetes. Follow-up to diabetes will help establish the biological significance and clinical value of novel type 1 diabetes risk markers.
authors.affiliation: Division of Endocrinology and Metabolism, University of Western Ontario, London, ON, Canada. jl.mahon@lhsc.on.ca
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Mahon
authors.forename: Jay M
authors.initials: JM
authors.lastname: Sosenko
authors.forename: Lisa
authors.initials: L
authors.lastname: Rafkin-Mervis
authors.forename: Heidi
authors.initials: H
authors.lastname: Krause-Steinrauf
authors.forename: John M
authors.initials: JM
authors.lastname: Lachin
authors.forename: Clinton
authors.initials: C
authors.lastname: Thompson
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Palmer
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
authors.forename: Joseph
authors.initials: J
authors.lastname: Wolfsdorf
authors.forename: Jay S
authors.initials: JS
authors.lastname: Skyler
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000276:immunology; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007223:Infant; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D018579:Patient Selection; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012107:Research Design; D012307:Risk Factors; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D015415:Biomarkers