Do Electrochemiluminescence Assays Improve Prediction of Time to Type 1 Diabetes in Autoantibody-Positive TrialNet Subjects?

Epidemiology/Health Services Research

¹Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
²Department of Pediatrics, University of Colorado Denver, Aurora, CO
³Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO
⁴Pediatrics Epidemiology Center, University of South Florida, Tampa, FL
⁵University of Miami School of Medicine, Miami, FL

Diabetes Care 2016 Oct; 39(10): 1738-1744. https://doi.org/10.2337/dc16-0302

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Figure 1
Development of diabetes by ECL status. A: All subjects (n = 1,287). B: Subjects positive for one autoantibody by RIAs (n = 902). C: Subjects positive for two or more autoantibodies by RIAs (n = 385). Survival analysis was performed for the development of diabetes since initial visit according to ECL positivity using the log-rank test. ECL-GADA/ECL-IAA pos, positive for both ECL-GADA and ECL-IAA; ECL-GADA pos, positive for ECL-GADA only; ECL-IAA pos, positive for ECL-IAA only; ECL-GADA/ECL-IAA neg, negative for both ECL-GADA and ECL-IAA.
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Figure 2
ROC curves comparing DPTRS alone vs. DPTRS and ECL. ROC curves were generated to examine the addition of ECL positivity to the DPTRS. DPTRS, DPTRS alone; model, includes ECL positivity in addition to DPTRS.

Table 1

Characteristics of TrialNet autoantibody-positive subjects (n = 1,287)

Characteristics	Ab⁺ subjects without diabetes (n = 1,110)	Ab⁺ subjects with diabetes (n = 177)	P value
Age at initial visit (years)	16 (9–37)	10 (7–14)	<0.0001
Age at last visit (years)	19 (12–39)	11 (8–17)	<0.0001
Sex, female	669 (60)	88 (50)	0.02
Multiple (≥2) Ab⁺ at initial visit	249 (22)	136 (77)	<0.0001
HLA DR3/4-DQ8 (yes)	71 (15)	33 (25)	0.007
BMI at initial visit (% underweight/normal/overweight/obese)	1/57/22/20	2/62/18/18	0.35

Data are median (IQR) or n (%), unless specified otherwise. Boldface type indicates P < 0.05. Ab⁺, autoantibody positive.

Table 2

Multivariate Cox proportional hazards models in TrialNet subjects (n = 759)

Covariate	HR (95% CI)	P value
Age	0.99 (0.97–1.01)	0.354
Sex (female)	0.94 (0.67–1.32)	0.736
AUC glucose (units = 100)	1.02 (1.01–1.03)	<0.0001
AUC C-peptide (units = 100)	0.76 (0.69–0.82)	<0.0001
Fasting C-peptide	1.45 (1.12–1.87)	0.004
Number of positive antibodies by RIAs	2 vs. 1: 2.80 (1.66–4.73)	<0.0001
	3 vs. 1: 3.33 (2.04–5.46)
	4 vs. 1: 3.81 (2.15–6.74)
ECL (GADA or IAA): positive vs. negative	6.90 (2.46–19.32)	0.0002

Six multivariate Cox proportional hazards models were compared with base model. Association with progression to type 1 diabetes was analyzed. Only results of best multivariate model are shown. The base model contained age, sex, AUC C-peptide, fasting C-peptide, AUC glucose, and number of positive antibodies by RIAs. Other models included base model and adding antibodies by RIAs or ECL results (as continuous or categorical value). The model with ECL-IAA and ECL-GADA combined had the lowest AIC and thus was the best model. A total of 150 out of the 759 subjects developed diabetes. Boldface type indicates P < 0.05.