A personalised approach for identifying disease-relevant pathways in heterogeneous diseases

Abstract

Numerous time-course gene expression datasets have been curated for studying the biological dynamics that drive disease progression; and nearly as many methods have been proposed to analyse them. However, barely any method exists that can appropriately model time-course data and at the same time account for heterogeneity that entails many complex diseases. Most methods manage to fulfil either one of those qualities, but not both. The lack of appropriate methods hinders our capability of understanding the disease process and pursuing preventive or curative treatments. Here, we present a method that models time-course data in a personalised manner, i.e. for each case-control pair individually, using Gaussian processes in order to identify differentially expressed genes (DEGs); and combines the lists of DEGs on a pathway-level using a permutation-based empirical hypothesis testing in order to overcome gene-level variability and inconsistencies prevalent to heterogeneous datasets from complex diseases. Our method can be applied to study the time-course dynamics as well as specific time-windows of heterogeneous diseases. We apply our personalised approach on two longitudinal type 1 diabetes (T1D) datasets to determine perturbations that take place during early prognosis of the disease as well as in time-windows before seroconversion and clinical onset of T1D. By comparing to non-personalised methods, we demonstrate that our approach is biologically motivated and can reveal more insights into progression of heterogeneous diseases. With its robust capabilities of identifying immunologically interesting and disease-relevant pathways, our approach could be useful for predicting certain events in the progression of heterogeneous diseases and even biomarker identification.\n\nAvailabilityThe implemented code of our personalised approach will be available online upon publication.