Objectives:  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.

Research design and 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), ≥25% (n = 36), and ≥50% (n = 128) where the latter two categories represent different subjects based on number of confirmed positive antibodies (2, ≥25%; 3 or more, ≥50%) and/or an abnormal OGTT (≥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.