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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02023

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

 Cate Speake1,  Henry T. Bahnson1,  Johnna D. Wesley2,  Nikole Perdue2, David Friedrich2,  Minh Pham2, Erinn Lanxon-Cookson2,  William W. Kwok1, Birgit Sehested-Hansen3,  Matthias G. Von Herrath2 and Carla J. Greenbaum1*
  • 1Benaroya Research Institute, United States
  • 2Novo Nordisk (United States), United States
  • 3Novo Nordisk (Denmark), Denmark

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.

Keywords: variability, Immune assays, clinical trial, type 1 diabetes, insulin secretion

Received: 21 Apr 2019; Accepted: 09 Aug 2019.

Copyright: © 2019 Speake, Bahnson, Wesley, Perdue, Friedrich, Pham, Lanxon-Cookson, Kwok, Sehested-Hansen, Von Herrath and Greenbaum. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Carla J. Greenbaum, Benaroya Research Institute, Seattle, 98101-2795, Washington, United States, cjgreen@benaroyaresearch.org