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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.

SUBMITTER: Zhang S

PROVIDER: S-EPMC8277716 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Biomarker-guided heterogeneity analysis of genetic regulations via multivariate sparse fusion.

Zhang Sanguo S Hu Xiaonan X Luo Ziye Z Jiang Yu Y Sun Yifan Y Ma Shuangge S

Statistics in medicine 20210427 17

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 ...[more]

PMID: 33906263

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Project description:MotivationImaging genetics is an emerging field that studies the influence of genetic variation on brain structure and function. The major task is to examine the association between genetic markers such as single-nucleotide polymorphisms (SNPs) and quantitative traits (QTs) extracted from neuroimaging data. The complexity of these datasets has presented critical bioinformatics challenges that require new enabling tools. Sparse canonical correlation analysis (SCCA) is a bi-multivariate technique used in imaging genetics to identify complex multi-SNP-multi-QT associations. However, most of the existing SCCA algorithms are designed using the soft thresholding method, which assumes that the input features are independent from one another. This assumption clearly does not hold for the imaging genetic data. In this article, we propose a new knowledge-guided SCCA algorithm (KG-SCCA) to overcome this limitation as well as improve learning results by incorporating valuable prior knowledge.ResultsThe proposed KG-SCCA method is able to model two types of prior knowledge: one as a group structure (e.g. linkage disequilibrium blocks among SNPs) and the other as a network structure (e.g. gene co-expression network among brain regions). The new model incorporates these prior structures by introducing new regularization terms to encourage weight similarity between grouped or connected features. A new algorithm is designed to solve the KG-SCCA model without imposing the independence constraint on the input features. We demonstrate the effectiveness of our algorithm with both synthetic and real data. For real data, using an Alzheimer's disease (AD) cohort, we examine the imaging genetic associations between all SNPs in the APOE gene (i.e. top AD gene) and amyloid deposition measures among cortical regions (i.e. a major AD hallmark). In comparison with a widely used SCCA implementation, our KG-SCCA algorithm produces not only improved cross-validation performances but also biologically meaningful results.AvailabilitySoftware is freely available on request.

Dataset Information

Biomarker-guided heterogeneity analysis of genetic regulations via multivariate sparse fusion.

Publications

Biomarker-guided heterogeneity analysis of genetic regulations via multivariate sparse fusion.

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