A unified graph model based on molecular data binning for disease subtyping

Abstract

Molecular disease subtype discovery from omics data is an important research problem in precision medicine. The biggest challenges are the skewed distribution and data variability in the measurements of omics data. These challenges complicate the efficient identification of molecular disease subtypes defined by clinical differences, such as survival. Existing approaches adopt kernels to construct patient similarity graphs from each view through pairwise matching. However, the distance functions used in kernels are unable to utilize the potentially critical information of extreme values and data variability which leads to the lack of robustness. In this paper, a novel robust distance metric (ROMDEX) is proposed to construct similarity graphs for molecular disease subtypes from omics data, which is able to address the data variability and extreme values challenges. The proposed approach is validated on multiple TCGA cancer datasets, and the results are compared with multiple baseline disease subtyping methods. The evaluation of results is based on Kaplan-Meier survival time analysis, which is validated using statistical tests e.g, Cox-proportional hazard (Cox p-value). We reject the null hypothesis that the cohorts have the same hazard, for the P-values less than 0.05. The proposed approach achieved best P-values of 0.00181, 0.00171, and 0.00758 for Gene Expression, DNA Methylation, and MicroRNA data respectively, which shows significant difference in survival between the cohorts. In the results, the proposed approach outperformed the existing state-of-the-art (MRGC, PINS, SNF, Consensus Clustering and Icluster+) disease subtyping approaches on various individual disease views of multiple TCGA datasets.

Keywords: Clustering analysis; Disease subtyping; Graph modelling; Patient similarity; Robust statistics; Similarity kernels.