Stages of Type 1 Diabetes.

Panel A: GAD, glutamic acid decarboxylase; IA-2, insulinoma antigen 2; ZnT8, zinc transporter 8. Panel B: For assessment of factors modifying the incidence of islet autoantibody seroconversion, exposures in the period before seroconversion in islet autoimmunity cases (child 1 and child 2) are compared with the corresponding period in children who do not seroconvert during the same follow-up time (child 3), e.g., vertical arrow 1. For assessment of factors modifying the rate of progression from islet autoimmunity to clinical type 1 diabetes, exposure must be studied in the period after seroconversion, but before type 1 diabetes onset. Exposure in children developing type 1 diabetes is compared with the same period for children who do not develop type 1 diabetes during the same follow-up period, e.g., vertical arrow 2. This principle applies to cohort studies and nested case-control studies. Any difference in exposure between child 2 and child 3 in the period after seroconversion, e.g., vertical arrow 3, could be influenced by reverse causation if involving biomarkers or other measures of exposure that could conceivably be influenced by autoimmunity.

* No islet autoimmunity (open circles)

† Islet autoimmunity (closed circles)

‡ Clinical type 1 diabetes

SOURCE: Panel A: Original figure constructed by M. Rewers. Panel B: Adapted from reference 34.