Systematic Assessment of Immune Marker Variation in Type 1 Diabetes: A Prospective Longitudinal Study.

Cate Speake,Nikole Perdue,Johnna D Wesley,Henry T Bahnson,Carla J Greenbaum,Minh N Pham,Erinn Lanxon-Cookson,William W Kwok,Birgit Sehested Hansen,David Friedrich,Matthias Von Herrath

doi:10.3389/fimmu.2019.02023

Abstract

Immune analytes have been widely tested in efforts to understand the heterogeneity of disease progression, risk, and therapeutic responses in type 1 diabetes (T1D). The future clinical utility of such analytes as biomarkers depends on their technical and biological variability, as well as their correlation with clinical outcomes. To assess the variability of a panel of 91 immune analytes, we conducted a prospective study of adults with T1D (<3 years from diagnosis), at 9–10 visits over 1 year. Autoantibodies and frequencies of T-cell, natural killer cell, and myeloid subsets were evaluated; autoreactive T-cell frequencies and function were also measured. We calculated an intraclass correlation coefficient (ICC) for each marker, which is a relative measure of between- and within-subject variability. Of the 91 analytes tested, we identified 35 with high between- and low within-subject variability, indicating their potential ability to be used to stratify subjects. We also provide extensive data regarding technical variability for 64 of the 91 analytes. To pilot the concept that ICC can be used to identify analytes that reflect biological outcomes, the association between each immune analyte and C-peptide was also evaluated using partial least squares modeling. CD8 effector memory T-cell (CD8 EM) frequency exhibited a high ICC and a positive correlation with C-peptide, which was also seen in an independent dataset of recent-onset T1D subjects. More work is needed to better understand the mechanisms underlying this relationship. Here we find that there are a limited number of technically reproducible immune analytes that also have a high ICC. We propose the use of ICC to define within- and between-subject variability and measurement of technical variability for future biomarker identification studies. Employing such a method is critical for selection of analytes to be tested in the context of future clinical trials aiming to understand heterogeneity in disease progression and response to therapy.

Highlights

The identification of highly effective disease-modifying therapies remains a critical gap in type 1 diabetes (T1D)
As T-cells are thought to play a role in T1D pathology, many aspects of Tcell frequency, function, and phenotype have been tested as potential biomarkers of disease or response to therapy
We identified a panel of markers with low within-subject and high between-subject variability that associate with C-peptide levels shortly after T1D diagnosis

Summary

INTRODUCTION

The identification of highly effective disease-modifying therapies remains a critical gap in type 1 diabetes (T1D). Given the promise of immunotherapy development in T1D, there is much interest in using immune analytes as biomarkers to predict clinical course and response to therapy For such biomarkers to be implemented, it is critical to understand the variability of each marker between and within individuals as well as its relationship to clinical outcomes. As T-cells are thought to play a role in T1D pathology, many aspects of Tcell frequency, function, and phenotype have been tested as potential biomarkers of disease or response to therapy These features have been measured in both global T-cell populations [6,7,8,9,10] and antigen-specific subsets using a variety of methods (e.g., multimer/tetramer, ELISpot, and FluoroSpot assays) [11,12,13,14]. The association of the marker with the highest VIP score was confirmed in an independent cohort of recentonset T1D subjects [T1DAL, NCT00965458 [4]]

Study Design

Study Design and Subject Recruitment

DISCUSSION

ETHICS STATEMENT