Sparse machine learning models in bioinformatics

The meaning of parsimony is twofold in machine learning: either the structure or (and) the parameter of a model can be sparse. Sparse models have many strengths. First, sparsity is an important regularization principle to reduce model complexity and therefore avoid overfitting. Second, in many fields, for example bioinformatics, many high-dimensional data may be generated by a very few number of hidden factors, thus it is more reasonable to use a proper sparse model than a dense model. Third, a sparse model is often easy to interpret. In this dissertation, we investigate the sparse machine learning models and their applications in high-dimensional biological data analysis. We focus our research on five types of sparse models as follows. First, sparse representation is a parsimonious principle that a sample can be approximated by a sparse linear combination of basis vectors. We explore existing sparse representation models and propose our own sparse representation methods for high dimensional biological data analysis. We derive different sparse representation models from a Bayesian perspective. Two generic dictionary learning frameworks are proposed. Also, kernel and supervised dictionary learning approaches are devised. Furthermore, we propose fast active-set and decomposition methods for the optimization of sparse coding models. Second, gene-sample-time data are promising in clinical study, but challenging in computation. We propose sparse tensor decomposition methods and kernel methods for the dimensionality reduction and classification of such data. As the extensions of matrix factorization, tensor decomposition techniques can reduce the dimensionality of the gene-sample-time data dramatically, and the kernel methods can run very efficiently on such data. Third, we explore two sparse regularized linear models for multi-class problems in bioinformatics. Our first method is called the nearest-border classification technique for data with many classes. Our second method is a hierarchical model. It can simultaneously select features and classify samples. Our experiment, on breast tumor subtyping, shows that this model outperforms the one-versus-all strategy in some cases. Fourth, we propose to use spectral clustering approaches for clustering microarray time-series data. The approaches are based on two transformations that have been recently introduced, especially for gene expression time-series data, namely, alignment-based and variation-based transformations. Both transformations have been devised in order to take into account temporal relationships in the data, and have been shown to increase the ability of a clustering method in detecting co-expressed genes. We investigate the performances of these transformations methods, when combined with spectral clustering on two microarray time-series datasets, and discuss their strengths and weaknesses. Our experiments on two well known real-life datasets show the superiority of the alignment-based over the variation-based transformation for finding meaningful groups of co-expressed genes. Fifth, we propose the max-min high-order dynamic Bayesian network (MMHO-DBN) learning algorithm, in order to reconstruct time-delayed gene regulatory networks. Due to the small sample size of the training data and the power-low nature of gene regulatory networks, the structure of the network is restricted by sparsity. We also apply the qualitative probabilistic networks (QPNs) to interpret the interactions learned. Our experiments on both synthetic and real gene expression time-series data show that, MMHO-DBN can obtain better precision than some existing methods, and perform very fast. The QPN analysis can accurately predict types of influences and synergies. Additionally, since many high dimensional biological data are subject to missing values, we survey various strategies for learning models from incomplete data. We extend the existing imputation methods, originally for two-way data, to methods for gene-sample-time data. We also propose a pair-wise weighting method for computing kernel matrices from incomplete data. Computational evaluations show that both approaches work very robustly

Gene selection for classification of microarray data based on the Bayes error

<p>Abstract</p> <p>Background</p> <p>With DNA microarray data, selecting a compact subset of discriminative genes from thousands of genes is a critical step for accurate classification of phenotypes for, e.g., disease diagnosis. Several widely used gene selection methods often select top-ranked genes according to their individual discriminative power in classifying samples into distinct categories, without considering correlations among genes. A limitation of these gene selection methods is that they may result in gene sets with some redundancy and yield an unnecessary large number of candidate genes for classification analyses. Some latest studies show that incorporating gene to gene correlations into gene selection can remove redundant genes and improve classification accuracy.</p> <p>Results</p> <p>In this study, we propose a new method, Based Bayes error Filter (BBF), to select relevant genes and remove redundant genes in classification analyses of microarray data. The effectiveness and accuracy of this method is demonstrated through analyses of five publicly available microarray datasets. The results show that our gene selection method is capable of achieving better accuracies than previous studies, while being able to effectively select relevant genes, remove redundant genes and obtain efficient and small gene sets for sample classification purposes.</p> <p>Conclusion</p> <p>The proposed method can effectively identify a compact set of genes with high classification accuracy. This study also indicates that application of the Bayes error is a feasible and effective wayfor removing redundant genes in gene selection.</p

Intelligent Computing for Big Data

Recent advances in artificial intelligence have the potential to further develop current big data research. The Special Issue on ‘Intelligent Computing for Big Data’ highlighted a number of recent studies related to the use of intelligent computing techniques in the processing of big data for text mining, autism diagnosis, behaviour recognition, and blockchain-based storage

Infinite feature selection: a graph-based feature filtering approach

We propose a filtering feature selection framework that considers a subset of features as a path in a graph, where a node is a feature and an edge indicates pairwise (customizable) relations among features, dealing with relevance and redundancy principles. By two different interpretations (exploiting properties of power series of matrices and relying on Markov chains fundamentals) we can evaluate the values of paths (i.e., feature subsets) of arbitrary lengths, eventually go to infinite, from which we dub our framework Infinite Feature Selection (Inf-FS). Going to infinite allows to constrain the computational complexity of the selection process, and to rank the features in an elegant way, that is, considering the value of any path (subset) containing a particular feature. We also propose a simple unsupervised strategy to cut the ranking, so providing the subset of features to keep. In the experiments, we analyze diverse setups with heterogeneous features, for a total of 11 benchmarks, comparing against 18 widely-known yet effective comparative approaches. The results show that Inf-FS behaves better in almost any situation, that is, when the number of features to keep are fixed a priori, or when the decision of the subset cardinality is part of the process

Multivariate methods for interpretable analysis of magnetic resonance spectroscopy data in brain tumour diagnosis

Malignant tumours of the brain represent one of the most difficult to treat types of cancer due to the sensitive organ they affect. Clinical management of the pathology becomes even more intricate as the tumour mass increases due to proliferation, suggesting that an early and accurate diagnosis is vital for preventing it from its normal course of development. The standard clinical practise for diagnosis includes invasive techniques that might be harmful for the patient, a fact that has fostered intensive research towards the discovery of alternative non-invasive brain tissue measurement methods, such as nuclear magnetic resonance. One of its variants, magnetic resonance imaging, is already used in a regular basis to locate and bound the brain tumour; but a complementary variant, magnetic resonance spectroscopy, despite its higher spatial resolution and its capability to identify biochemical metabolites that might become biomarkers of tumour within a delimited area, lags behind in terms of clinical use, mainly due to its difficult interpretability. The interpretation of magnetic resonance spectra corresponding to brain tissue thus becomes an interesting field of research for automated methods of knowledge extraction such as machine learning, always understanding its secondary role behind human expert medical decision making. The current thesis aims at contributing to the state of the art in this domain by providing novel techniques for assistance of radiology experts, focusing on complex problems and delivering interpretable solutions. In this respect, an ensemble learning technique to accurately discriminate amongst the most aggressive brain tumours, namely glioblastomas and metastases, has been designed; moreover, a strategy to increase the stability of biomarker identification in the spectra by means of instance weighting is provided. From a different analytical perspective, a tool based on signal source separation, guided by tumour type-specific information has been developed to assess the existence of different tissues in the tumoural mass, quantifying their influence in the vicinity of tumoural areas. This development has led to the derivation of a probabilistic interpretation of some source separation techniques, which provide support for uncertainty handling and strategies for the estimation of the most accurate number of differentiated tissues within the analysed tumour volumes. The provided strategies should assist human experts through the use of automated decision support tools and by tackling interpretability and accuracy from different anglesEls tumors cerebrals malignes representen un dels tipus de càncer més difícils de tractar degut a la sensibilitat de l’òrgan que afecten. La gestió clínica de la patologia esdevé encara més complexa quan la massa tumoral s'incrementa degut a la proliferació incontrolada de cèl·lules; suggerint que una diagnosis precoç i acurada és vital per prevenir el curs natural de desenvolupament. La pràctica clínica estàndard per a la diagnosis inclou la utilització de tècniques invasives que poden arribar a ser molt perjudicials per al pacient, factor que ha fomentat la recerca intensiva cap al descobriment de mètodes alternatius de mesurament dels teixits del cervell, tals com la ressonància magnètica nuclear. Una de les seves variants, la imatge de ressonància magnètica, ja s'està actualment utilitzant de forma regular per localitzar i delimitar el tumor. Així mateix, una variant complementària, la espectroscòpia de ressonància magnètica, malgrat la seva alta resolució espacial i la seva capacitat d'identificar metabòlits bioquímics que poden esdevenir biomarcadors de tumor en una àrea delimitada, està molt per darrera en termes d'ús clínic, principalment per la seva difícil interpretació. Per aquest motiu, la interpretació dels espectres de ressonància magnètica corresponents a teixits del cervell esdevé un interessant camp de recerca en mètodes automàtics d'extracció de coneixement tals com l'aprenentatge automàtic, sempre entesos com a una eina d'ajuda per a la presa de decisions per part d'un metge expert humà. La tesis actual té com a propòsit la contribució a l'estat de l'art en aquest camp mitjançant l'aportació de noves tècniques per a l'assistència d'experts radiòlegs, centrades en problemes complexes i proporcionant solucions interpretables. En aquest sentit, s'ha dissenyat una tècnica basada en comitè d'experts per a una discriminació acurada dels diferents tipus de tumors cerebrals agressius, anomenats glioblastomes i metàstasis; a més, es proporciona una estratègia per a incrementar l'estabilitat en la identificació de biomarcadors presents en un espectre mitjançant una ponderació d'instàncies. Des d'una perspectiva analítica diferent, s'ha desenvolupat una eina basada en la separació de fonts, guiada per informació específica de tipus de tumor per a avaluar l'existència de diferents tipus de teixits existents en una massa tumoral, quantificant-ne la seva influència a les regions tumorals veïnes. Aquest desenvolupament ha portat cap a la derivació d'una interpretació probabilística d'algunes d'aquestes tècniques de separació de fonts, proporcionant suport per a la gestió de la incertesa i estratègies d'estimació del nombre més acurat de teixits diferenciats en cada un dels volums tumorals analitzats. Les estratègies proporcionades haurien d'assistir els experts humans en l'ús d'eines automatitzades de suport a la decisió, donada la interpretabilitat i precisió que presenten des de diferents angles

Analysing functional genomics data using novel ensemble, consensus and data fusion techniques

Motivation: A rapid technological development in the biosciences and in computer science in the last decade has enabled the analysis of high-dimensional biological datasets on standard desktop computers. However, in spite of these technical advances, common properties of the new high-throughput experimental data, like small sample sizes in relation to the number of features, high noise levels and outliers, also pose novel challenges. Ensemble and consensus machine learning techniques and data integration methods can alleviate these issues, but often provide overly complex models which lack generalization capability and interpretability. The goal of this thesis was therefore to develop new approaches to combine algorithms and large-scale biological datasets, including novel approaches to integrate analysis types from different domains (e.g. statistics, topological network analysis, machine learning and text mining), to exploit their synergies in a manner that provides compact and interpretable models for inferring new biological knowledge. Main results: The main contributions of the doctoral project are new ensemble, consensus and cross-domain bioinformatics algorithms, and new analysis pipelines combining these techniques within a general framework. This framework is designed to enable the integrative analysis of both large- scale gene and protein expression data (including the tools ArrayMining, Top-scoring pathway pairs and RNAnalyze) and general gene and protein sets (including the tools TopoGSA , EnrichNet and PathExpand), by combining algorithms for different statistical learning tasks (feature selection, classification and clustering) in a modular fashion. Ensemble and consensus analysis techniques employed within the modules are redesigned such that the compactness and interpretability of the resulting models is optimized in addition to the predictive accuracy and robustness. The framework was applied to real-word biomedical problems, with a focus on cancer biology, providing the following main results: (1) The identification of a novel tumour marker gene in collaboration with the Nottingham Queens Medical Centre, facilitating the distinction between two clinically important breast cancer subtypes (framework tool: ArrayMining) (2) The prediction of novel candidate disease genes for Alzheimer’s disease and pancreatic cancer using an integrative analysis of cellular pathway definitions and protein interaction data (framework tool: PathExpand, collaboration with the Spanish National Cancer Centre) (3) The prioritization of associations between disease-related processes and other cellular pathways using a new rule-based classification method integrating gene expression data and pathway definitions (framework tool: Top-scoring pathway pairs) (4) The discovery of topological similarities between differentially expressed genes in cancers and cellular pathway definitions mapped to a molecular interaction network (framework tool: TopoGSA, collaboration with the Spanish National Cancer Centre) In summary, the framework combines the synergies of multiple cross-domain analysis techniques within a single easy-to-use software and has provided new biological insights in a wide variety of practical settings