The TrialNet Natural History Study of the Development of Type 1 Diabetes: objectives, design, and initial results.
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.
Mahon
Jeffrey L
JL
Division of Endocrinology and Metabolism, University of Western Ontario, London, ON, Canada. jl.mahon@lhsc.on.ca
Sosenko
Jay M
JM
Rafkin-Mervis
Lisa
L
Krause-Steinrauf
Heidi
H
Lachin
John M
JM
Thompson
Clinton
C
Bingley
Polly J
PJ
Bonifacio
Ezio
E
Palmer
Jerry P
JP
Eisenbarth
George S
GS
Wolfsdorf
Joseph
J
Skyler
Jay S
JS
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
D001323:Autoantibodies; D015415:Biomarkers