Biomarker‐guided heterogeneity analysis of genetic regulations via multivariate sparse fusion

Abstract

Heterogeneity is a hallmark of many complex diseases. There are multiple ways of defining heterogeneity, among which the heterogeneity in genetic regulations, for example, gene expressions (GEs) by copy number variations (CNVs), and methylation, has been suggested but little investigated. Heterogeneity in genetic regulations can be linked with disease severity, progression, and other traits and is biologically important. However, the analysis can be very challenging with the high dimensionality of both sides of regulation as well as sparse and weak signals. In this article, we consider the scenario where subjects form unknown subgroups, and each subgroup has unique genetic regulation relationships. Further, such heterogeneity is "guided" by a known biomarker.We develop a multivariate sparse fusion (MSF) approach, which innovatively applies the penalized fusion technique to simultaneously determine the number and structure of subgroups and regulation relationships within each subgroup.An effective computational algorithm is developed, and extensive simulations are conducted. The analysis of heterogeneity in the GE-CNV regulations in melanoma and GE-methylation regulations in stomach cancer using the TCGA data leads to interesting findings. K E Y W O R D Sbiomarker, genetic regulations, heterogeneity analysis, multivariate sparse fusion INTRODUCTIONHeterogeneity is a hallmark of many complex diseases. 1,2 There are multiple ways of defining heterogeneity. In "classic" biomedicine, heterogeneity is often defined based on clinical characteristics. With the increasing popularity of high-throughput profiling, there has been a surge of heterogeneity analysis based on high-dimensional molecular data. 3,4 A famous early example is the re-characterization of breast cancer subtypes based on gene expression (GE) profiles. 3