Prediction of the Development of Islet Autoantibodies through Integration of Environmental, Genetic, and Metabolic Markers
The Environmental Determinants of the Diabetes in the Young (TEDDY) study has prospectively followed, from birth, children at increased genetic risk of type 1 diabetes. We evaluated the potential of machine learning to identify new biomarkers that predict imminent (within 6 months) development of persistent islet autoantibodies to insulin, GAD or IA-2 in TEDDY participants through integration of time-invariant risk factors with time-varying metabolomics. The predictive modeling was initiated with over 220 potential biomarkers; through ensemble-based feature evaluation, the optimal model included 42 biomarkers, returning a cross-validated receiver operating characteristic area under the curve of 0.74. The model identified a principal set of 20 time-invariant markers, including 16 single nucleotide polymorphisms and two HLA-DR genotypes, gestational age, and exposure to a prebiotic formula. Integration of the metabolome identified 22 high-priority metabolites and lipids, including adipic acid and ceramide d42:0, that predicted development of islet autoantibodies, dependent upon the time horizon. The majority (86%) of metabolites that predicted development of islet autoantibodies belonged to 3 pathways: lipid oxidation, phospholipase A2 signaling, and pentose phosphate pathway. TEDDY data suggest that these metabolic processes may play a role in triggering islet autoimmunity.
Revised: January 7, 2021 |
Published: February 1, 2021
Webb-Robertson B.M., L.M. Bramer, B.A. Stanfill, S.M. Reehl, E.S. Nakayasu, T.O. Metz, and B. Frohnert, et al. 2021.Prediction of the Development of Islet Autoantibodies through Integration of Environmental, Genetic, and Metabolic Markers.Journal of Diabetes 13, no. 2:143-153.PNNL-SA-146734.doi:10.1111/1753-0407.13093