Dimensionality Reduction, Feature Selection and Visualization of Biological Data

Due to the high dimensionality of most biological data, it is a difficult task to directly analyze, model and visualize the data to gain biological insight. Thus, dimensionality reduction becomes an imperative pre-processing step in analyzing and visualizing high-dimensional biological data. Two major approaches to dimensionality reduction in genomic analysis and biomarker identification studies are: Feature extraction, creating new features by combining existing ones based on a mapping technique; and feature selection, choosing an optimal subset of all features based on an objective function. In this dissertation, we show how our innovative reduction schemes effectively reduce the dimensionality of DNA gene expression data to extract biologically interpretable and relevant features which result in enhancing the biomarker identification process.

To construct biologically interpretable features and facilitate Muscular Dystrophy (MD) subtypes classification, we extract molecular features from MD microarray data by constructing sub-networks using a novel integrative scheme which utilizes protein-protein interaction (PPI) network, functional gene sets information and mRNA profiling data. The workflow includes three major steps: First, by combining PPI network structure and gene-gene co-expression relationship into a new distance metric, we apply affinity propagation clustering (APC) to build gene sub-networks; secondly, we further incorporate functional gene sets knowledge to complement the physical interaction information; finally, based on the constructed sub-network and gene set features, we apply multi-class support vector machine (MSVM) for MD sub-type classification and highlight the biomarkers contributing to the sub-type prediction. The experimental results show that our scheme could construct sub-networks that are more relevant to MD than those constructed by the conventional approach. Furthermore, our integrative strategy substantially improved the prediction accuracy, especially for those ‘hard-to-classify' sub-types.

Conventionally, pathway-based analysis assumes that genes in a pathway equally contribute to a biological function, thus assigning uniform weight to genes. However, this assumption has been proven incorrect and applying uniform weight in the pathway analysis may not be an adequate approach for tasks like molecular classification of diseases, as genes in a functional group may have different differential power. Hence, we propose to use different weights for the pathway analysis which resulted in the development of four weighting schemes. We applied them in two existing pathway analysis methods using both real and simulated gene expression data for pathways. Weighting changes pathway scoring and brings up some new significant pathways, leading to the detection of disease-related genes that are missed under uniform weight.

To help us understand our MD expression data better and derive scientific insight from it, we have explored a suite of visualization tools. Particularly, for selected top performing MD sub-networks, we displayed the network view using Cytoscape; functional annotations using IPA and DAVID functional analysis tools; expression pattern using heat-map and parallel coordinates plot; and MD associated pathways using KEGG pathway diagrams. We also performed weighted MD pathway analysis, and identified overlapping sub-networks across different weight schemes and different MD subtypes using Venn Diagrams, which resulted in the identification of a new sub-network significantly associated with MD. All those graphically displayed data and information helped us understand our MD data and the MD subtypes better, resulting in the identification of several potentially MD associated biomarker pathways and genes.