Bioinformatics applied to human genomics and proteomics: development of algorithms and methods for the discovery of molecular signatures derived from omic data and for the construction of co-expression and interaction networks

[EN] The present PhD dissertation develops and applies Bioinformatic methods and tools to address key current problems in the analysis of human omic data. This PhD has been organised by main objectives into four different chapters focused on: (i) development of an algorithm for the analysis of changes and heterogeneity in large-scale omic data; (ii) development of a method for non-parametric feature selection; (iii) integration and analysis of human protein-protein interaction networks and (iv) integration and analysis of human co-expression networks derived from tissue expression data and evolutionary profiles of proteins. In the first chapter, we developed and tested a new robust algorithm in R, called DECO, for the discovery of subgroups of features and samples within large-scale omic datasets, exploring all feature differences possible heterogeneity, through the integration of both data dispersion and predictor-response information in a new statistic parameter called h (heterogeneity score). In the second chapter, we present a simple non-parametric statistic to measure the cohesiveness of categorical variables along any quantitative variable, applicable to feature selection in all types of big data sets. In the third chapter, we describe an analysis of the human interactome integrating two global datasets from high-quality proteomics technologies: HuRI (a human protein-protein interaction network generated by a systematic experimental screening based on Yeast-Two-Hybrid technology) and Cell-Atlas (a comprehensive map of subcellular localization of human proteins generated by antibody imaging). This analysis aims to create a framework for the subcellular localization characterization supported by the human protein-protein interactome. In the fourth chapter, we developed a full integration of three high-quality proteome-wide resources (Human Protein Atlas, OMA and TimeTree) to generate a robust human co-expression network across tissues assigning each human protein along the evolutionary timeline. In this way, we investigate how old in evolution and how correlated are the different human proteins, and we place all them in a common interaction network. As main general comment, all the work presented in this PhD uses and develops a wide variety of bioinformatic and statistical tools for the analysis, integration and enlighten of molecular signatures and biological networks using human omic data. Most of this data corresponds to sample cohorts generated in recent biomedical studies on specific human diseases

Cancer subtype identification pipeline: a classifusion approach

Classification of cancer patients into treatment groups is essential for appropriate diagnosis to increase survival. Previously, a series of papers, largely published in the breast cancer domain have leveraged Computational Intelligence (CI) developments and tools, resulting in ground breaking advances such as the classification of cancer into newly identified classes - leading to improved treatment options. However, the current literature on the use of CI to achieve this is fragmented, making further advances challenging. This paper captures developments in this area so far, with the goal to establish a clear, step-by-step pipeline for cancer subtype identification. Based on establishing the pipeline, the paper identifies key potential advances in CI at the individual steps, thus establishing a roadmap for future research. As such, it is the aim of the paper to engage the CI community to address the research challenges and leverage the strong potential of CI in this important area. Finally, we present a small set of recent findings on the Nottingham Tenovus Primary Breast Carcinoma Series enabling the classification of a higher number of patients into one of the identified breast cancer groups, and introduce Classifusion: a combination of results of multiple classifiers

Performance of Feature Selection Methods

High-throughput biological technologies offer the promise of finding feature sets to serve as biomarkers for medical applications; however, the sheer number of potential features (genes, proteins, etc.) means that there needs to be massive feature selection, far greater than that envisioned in the classical literature. This paper considers performance analysis for feature-selection algorithms from two fundamental perspectives: How does the classification accuracy achieved with a selected feature set compare to the accuracy when the best feature set is used and what is the optimal number of features that should be used? The criteria manifest themselves in several issues that need to be considered when examining the efficacy of a feature-selection algorithm: (1) the correlation between the classifier errors for the selected feature set and the theoretically best feature set; (2) the regressions of the aforementioned errors upon one another; (3) the peaking phenomenon, that is, the effect of sample size on feature selection; and (4) the analysis of feature selection in the framework of high-dimensional models corresponding to high-throughput data