Abstract
Infections are implicated in the etiology of type 1 diabetes mellitus (T1DM); however, conflicting epidemiologic evidence makes designing effective strategies for presymptomatic screening and disease prevention difficult. Considering the temporality and combination in which infections occur may provide valuable insights into understanding T1DM etiology but is rarely studied due to limited longitudinal datasets and insufficient analytical techniques. The objective of this work was to demonstrate a computational approach to classify the temporality and combination of infections in presymptomatic T1DM. We present a sequential data mining pipeline that leverages routinely collected infectious disease data from a prospective cohort study, the Environmental Determinants of Diabetes in the Young (TEDDY) study, to extract, interpret, and compare infection sequences. We then utilize this pipeline to assess risk for developing presymptomatic biomarkers of islet autoimmunity and clinical onset of T1DM. Overall, we identified 229 significant sequential rules that increased the risk for developing presymptomatic biomarkers of islet autoimmunity or clinical onset of T1DM. Multiple significant sequential rules involving varicella increased the risk for all presymptomatic biomarker-specific outcomes, while a single significant sequential rule involving parasites significantly increased risk for T1DM. Significant sequential rules involving respiratory illnesses were differentially represented among the presymptomatic biomarkers of islet autoimmunity and clinical onset of T1DM. Risk for T1DM was significantly increased by a single episode of sixth disease at 12 months, representing the only single-event sequence that increased disease risk. Together, these findings provide the first insights into the timing and combination of infections in T1DM etiology, which may ultimately lead to personalized disease screening and prevention strategies. The sequential data mining pipeline developed in this work demonstrates how temporal data mining can be used to address clinically meaningful questions. This method can be adapted to other presymptomatic factors and clinical conditions.