Islet Autoantibody Levels Differentiate Progression Trajectories in Individuals With Presymptomatic Type 1 Diabetes

Abstract

In our previous data-driven analysis of evolving patterns of islet autoantibodies (IAb) against insulin (IAA), GAD (GADA), and islet antigen 2 (IA-2A), we discovered three trajectories, characterized according to multiple IAb (TR1), IAA (TR2), or GADA (TR3) as the first appearing autoantibodies. Here we examined the evolution of IAb levels within these trajectories in 2,145 IAb-positive participants followed from early life and compared those who progressed to type 1 diabetes (n = 643) with those remaining undiagnosed (n = 1,502). With use of thresholds determined by 5-year diabetes risk, four levels were defined for each IAb and overlaid onto each visit. In diagnosed participants, high IAA levels were seen in TR1 and TR2 at ages <3 years, whereas IAA remained at lower levels in the undiagnosed. Proportions of dwell times (total duration of follow-up at a given level) at the four IAb levels differed between the diagnosed and undiagnosed for GADA and IA-2A in all three trajectories (P < 0.001), but for IAA dwell times differed only within TR2 (P < 0.05). Overall, undiagnosed participants more frequently had low IAb levels and later appearance of IAb than diagnosed participants. In conclusion, while it has long been appreciated that the number of autoantibodies is an important predictor of type 1 diabetes, consideration of autoantibody levels within the three autoimmune trajectories improved differentiation of IAb-positive children who progressed to type 1 diabetes from those who did not.

Figure 1

Visualization of the entire data set by trajectory and IAb level comparing diagnosed and undiagnosed individuals and illustrating the differences. Three autoimmune trajectories and their component states overlaid with autoantibody levels toward type 1 diabetes. The diagram includes three subfigures summarizing the three respective trajectories and their component states overlaid with the IAb levels: TR1, TR2, and TR3. Each subfigure consists of two plots (top, bottom); the top plot shows trajectories for the diagnosed (D), and the bottom shows those for the undiagnosed (UD). The table on the left includes three columns: 1) component state label, 2) IAb type (GADA, IAA, or IA-2A), and 3) the total number of participants per state (row). The waterfall chart on the right shows visits (dots) colored according to the IAb level (gray, L0; blue, L1; orange, L2; red, L3). y-axis represents component states, and x-axis represents age of participants in years. In TR1, most diagnosed children advance from TR1-0 (IAb negative) to TR1-1 (positive for multiple IAb) and TR1-2 (IA-2A positive). The distributions of autoantibody levels over age show higher proportion of IAA L3 (red) in early age of the diagnosed participants compared with the undiagnosed participants. In TR2, the diagnosed participants frequently have IAA L3 (red) at early ages across all positive states, whereas the undiagnosed participants have fewer IAA positive visits and those with L3 are spread across ages. In TR3, both the diagnosed and the undiagnosed participants advance to IAb-positive states, TR3-1 and TR3-2, but the timing is later for the undiagnosed.

Figure 2

Summary of IAb levels at each visit by age comparing diagnosed and undiagnosed individuals. Normalized proportions of autoantibody levels over age are depicted. The diagram shows 48 panels (6 rows, 8 columns) summarizing the normalized proportion of autoantibody levels over participants’ age. Component panels represent the diagnosed and undiagnosed groups for each of the eight IAb-positive states (TR1-1, TR1-2, TR2-1, TR2-2, TR2-3, TR2-4, TR3-1, TR3-2) and three IAb types (GADA, IAA, IA-2A). For example, TR1-1 indicates the first positive component state of trajectory TR1, predominantly multiple IAb first. Each panel includes a stacked bar chart that shows the proportion of visits in percentage (y-axis), which are broken down into stacks of four IAb levels, over ages of participants in years (x-axis). We excluded visits with no autoantibody measurement and age ranges with <10 observations. In TR1-1, TR2-1, and TR2-2, the proportion of the highest IAA level (L3) at early ages (<2 years) tends to be higher for the diagnosed participants than for the undiagnosed. In TR3-1, the proportion of the highest GADA level (L3) at early ages (<2 years) appears higher for the diagnosed compared with the undiagnosed participants. D, diagnosed; UD, undiagnosed.

Figure 3

Development of autoantibody levels and dwell times for individual participants sorted by duration of follow-up. The diagram includes six panels (two rows and three columns) summarizing the dwell time of individual participants at each autoantibody level (gray, L0; blue, L1; orange, L2; red, L3) for three IAb (GADA, IAA, IA-2A) over their ages in years (x-axis) per trajectory (column) and per diagnosis (row). In each panel, we sorted participants (horizontal bars) by their age at last observation with increasing order from top to bottom. Overall, the undiagnosed participants have longer follow-up time as seen in the horizontal length of bars across the board. Most of the diagnosed participants tend to show dynamic changes of autoantibody levels and longer dwell times at higher levels over the follow-up period compared with the undiagnosed participants. In all trajectories an evolution to high levels of IA-2A frequently precedes diagnosis. D, diagnosed; UD, undiagnosed.

Figure 4

Development of autoantibody levels and dwell times for individual participants sorted by their maximum IA-2A level. The diagram includes six panels (two rows: diagnosed, undiagnosed; three columns: TR1, TR2, TR3) summarizing the dwell time of individual participants at each autoantibody level (gray, L0; blue, L1; orange, L2; red, L3) for three IAb (GADA, IAA, IA-2A) over their ages per trajectory per diagnosis. In each panel, participants in each trajectory (column) are sorted by the maximum level of IA-2A with increasing order from top to bottom. More than one-half of diagnosed participants across the three trajectories reach high IA-2A levels (L2, L3) during follow-up. On the other hand, a majority of undiagnosed participants across the three trajectories stay IA-2A negative (L0) during follow-up. D, diagnosed; UD, undiagnosed.