A polynomial time biclustering algorithm for finding approximate expression patterns in gene expression time series

<p>Abstract</p> <p>Background</p> <p>The ability to monitor the change in expression patterns over time, and to observe the emergence of coherent temporal responses using gene expression time series, obtained from microarray experiments, is critical to advance our understanding of complex biological processes. In this context, biclustering algorithms have been recognized as an important tool for the discovery of local expression patterns, which are crucial to unravel potential regulatory mechanisms. Although most formulations of the biclustering problem are NP-hard, when working with time series expression data the interesting biclusters can be restricted to those with contiguous columns. This restriction leads to a tractable problem and enables the design of efficient biclustering algorithms able to identify all maximal contiguous column coherent biclusters.</p> <p>Methods</p> <p>In this work, we propose <it>e</it>-CCC-Biclustering, a biclustering algorithm that finds and reports all maximal contiguous column coherent biclusters with approximate expression patterns in time polynomial in the size of the time series gene expression matrix. This polynomial time complexity is achieved by manipulating a discretized version of the original matrix using efficient string processing techniques. We also propose extensions to deal with missing values, discover anticorrelated and scaled expression patterns, and different ways to compute the errors allowed in the expression patterns. We propose a scoring criterion combining the statistical significance of expression patterns with a similarity measure between overlapping biclusters.</p> <p>Results</p> <p>We present results in real data showing the effectiveness of <it>e</it>-CCC-Biclustering and its relevance in the discovery of regulatory modules describing the transcriptomic expression patterns occurring in <it>Saccharomyces cerevisiae </it>in response to heat stress. In particular, the results show the advantage of considering approximate patterns when compared to state of the art methods that require exact matching of gene expression time series.</p> <p>Discussion</p> <p>The identification of co-regulated genes, involved in specific biological processes, remains one of the main avenues open to researchers studying gene regulatory networks. The ability of the proposed methodology to efficiently identify sets of genes with similar expression patterns is shown to be instrumental in the discovery of relevant biological phenomena, leading to more convincing evidence of specific regulatory mechanisms.</p> <p>Availability</p> <p>A prototype implementation of the algorithm coded in Java together with the dataset and examples used in the paper is available in <url>http://kdbio.inesc-id.pt/software/e-ccc-biclustering</url>.</p

Formal Concept Analysis for Identifying Biclusters with Coherent Sign Changes

In this paper we are studying the task of finding coherent-sign-changes biclusters in a binary matrix. This task can be applied to the interpretation of gene expression data, where such a bicluster represents a set of experiments that affect a set of genes in a consistent way. We start with a binary table and study biclustering methods based on FCA and partition pattern structures. Pattern concepts provide biclusters and their hierarchical relation, which can be used to analyze the profile of genes in the given expression data. Our approach is purely symbolic, so we can detect larger biclusters and work with rather complex data

Fouille de données complexes et biclustering avec l'analyse formelle de concepts

Knowledge discovery in database (KDD) is a process which is applied to possibly large volumes of data for discovering patterns which can be significant and useful. In this thesis, we are interested in data transformation and data mining in knowledge discovery applied to complex data, and we present several experiments related to different approaches and different data types.The first part of this thesis focuses on the task of biclustering using formal concept analysis (FCA) and pattern structures. FCA is naturally related to biclustering, where the objective is to simultaneously group rows and columns which verify some regularities. Related to FCA, pattern structures are its generalizations which work on more complex data. Partition pattern structures were proposed to discover constant-column biclustering, while interval pattern structures were studied in similar-column biclustering. Here we extend these approaches to enumerate other types of biclusters: additive, multiplicative, order-preserving, and coherent-sign-changes.The second part of this thesis focuses on two experiments in mining complex data. First, we present a contribution related to the CrossCult project, where we analyze a dataset of visitor trajectories in a museum. We apply sequence clustering and FCA-based sequential pattern mining to discover patterns in the dataset and to classify these trajectories. This analysis can be used within CrossCult project to build recommendation systems for future visitors. Second, we present our work related to the task of antibacterial drug discovery. The dataset for this task is generally a numerical matrix with molecules as rows and features/attributes as columns. The huge number of features makes it more complex for any classifier to perform molecule classification. Here we study a feature selection approach based on log-linear analysis which discovers associations among features.As a synthesis, this thesis presents a series of different experiments in the mining of complex real-world data.L'extraction de connaissances dans les bases de données (ECBD) est un processus qui s'applique à de (potentiellement larges) volumes de données pour découvrir des motifs qui peuvent être signifiants et utiles. Dans cette thèse, on s'intéresse à deux étapes du processus d'ECBD, la transformation et la fouille, que nous appliquons à des données complexes. Nous présentons de nombreuses expérimentations s'appuyant sur des approches et des types de données variés.La première partie de cette thèse s'intéresse à la tâche de biclustering en s'appuyant sur l'analyse formelle de concepts (FCA) et aux pattern structures. FCA est naturellement liées au biclustering, dont l'objectif consiste à grouper simultanément un ensemble de lignes et de colonnes qui vérifient certaines régularités. Les pattern structures sont une généralisation de la FCA qui permet de travailler avec des données plus complexes. Les "partition pattern structures'' ont été proposées pour du biclustering à colonnes constantes tandis que les "interval pattern structures'' ont été étudiées pour du biclustering à colonnes similaires. Nous proposons ici d'étendre ces approches afin d'énumérer d'autres types de biclusters : additif, multiplicatif, préservant l'ordre, et changement de signes cohérents.Dans la seconde partie, nous nous intéressons à deux expériences de fouille de données complexes. Premièrement, nous présentons une contribution dans la quelle nous analysons les trajectoires des visiteurs d'un musée dans le cadre du projet CrossCult. Nous utilisons du clustering de séquences et de la fouille de motifs séquentiels basée sur l'analyse formelle de concepts pour découvrir des motifs dans les données et classifier les trajectoires. Cette analyse peut ensuite être exploitée par un système de recommandation pour les futurs visiteurs. Deuxièmement, nous présentons un travail sur la découverte de médicaments antibactériens. Les jeux de données pour cette tâche, généralement des matrices numériques, décrivent des molécules par un certain nombre de variables/attributs. Le grand nombre de variables complexifie la classification des molécules par les classifieurs. Ici, nous étudions une approche de sélection de variables basée sur l'analyse log-linéaire qui découvre des associations entre variables.En somme, cette thèse présente différentes expériences de fouille de données réelles et complexes

Semantic Biclustering

Tato disertační práce se zaměřuje na problém hledání interpretovatelných a prediktivních vzorů, které jsou vyjádřeny formou dvojshluků, se specializací na biologická data. Prezentované metody jsou souhrnně označovány jako sémantické dvojshlukování, jedná se o podobor dolování dat. Termín sémantické dvojshlukování je použit z toho důvodu, že zohledňuje proces hledání koherentních podmnožin řádků a sloupců, tedy dvojshluků, v 2-dimensionální binární matici a zárove ň bere také v potaz sémantický význam prvků v těchto dvojshlucích. Ačkoliv byla práce motivována biologicky orientovanými daty, vyvinuté algoritmy jsou obecně aplikovatelné v jakémkoli jiném výzkumném oboru. Je nutné pouze dodržet požadavek na formát vstupních dat. Disertační práce představuje dva originální a v tomto ohledu i základní přístupy pro hledání sémantických dvojshluků, jako je Bicluster enrichment analysis a Rule a tree learning. Jelikož tyto metody nevyužívají vlastní hierarchické uspořádání termů v daných ontologiích, obecně je běh těchto algoritmů dlouhý čin může docházet k indukci hypotéz s redundantními termy. Z toho důvodu byl vytvořen nový operátor zjemnění. Tento operátor byl včleněn do dobře známého algoritmu CN2, kde zavádí dvě redukční procedury: Redundant Generalization a Redundant Non-potential. Obě procedury pomáhají dramaticky prořezat prohledávaný prostor pravidel a tím umožňují urychlit proces indukce pravidel v porovnání s tradičním operátorem zjemnění tak, jak je původně prezentován v CN2. Celý algoritmus spolu s redukčními metodami je publikován ve formě R balííčku, který jsme nazvali sem1R. Abychom ukázali i možnost praktického užití metody sémantického dvojshlukování na reálných biologických problémech, v disertační práci dále popisujeme a specificky upravujeme algoritmus sem1R pro dv+ úlohy. Zaprvé, studujeme praktickou aplikaci algoritmu sem1R v analýze E-3 ubikvitin ligázy v trávicí soustavě s ohledem na potenciál regenerace tkáně. Zadruhé, kromě objevování dvojshluků v dat ech genové exprese, adaptujeme algoritmus sem1R pro hledání potenciálne patogenních genetických variant v kohortě pacientů.This thesis focuses on the problem of finding interpretable and predic tive patterns, which are expressed in the form of biclusters, with an orientation to biological data. The presented methods are collectively called semantic biclustering, as a subfield of data mining. The term semantic biclustering is used here because it reflects both a process of finding coherent subsets of rows and columns in a 2-dimensional binary matrix and simultaneously takes into account a mutual semantic meaning of elements in such biclusters. In spite of focusing on applications of algorithms in biological data, the developed algorithms are generally applicable to any other research field, there are only limitations on the format of the input data. The thesis introduces two novel, and in that context basic, approaches for finding semantic biclusters, as Bicluster enrichment analysis and Rule and tree learning. Since these methods do not exploit the native hierarchical order of terms of input ontologies, the run-time of algorithms is relatively long in general or an induced hypothesis might have terms that are redundant. For this reason, a new refinement operator has been invented. The refinement operator was incorporated into the well-known CN2 algorithm and uses two reduction procedures: Redundant Generalization and Redundant Non-potential, both of which help to dramatically prune the rule space and consequently, speed-up the entire process of rule induction in comparison with the traditional refinement operator as is presented in CN2. The reduction procedures were published as an R package that we called sem1R. To show a possible practical usage of semantic biclustering in real biological problems, the thesis also describes and specifically adapts the algorithm for two real biological problems. Firstly, we studied a practical application of sem1R algorithm in an analysis of E-3 ubiquitin ligase in the gastrointestinal tract with respect to tissue regeneration potential. Secondly, besides discovering biclusters in gene expression data, we adapted the sem1R algorithm for a different task, concretely for finding potentially pathogenic genetic variants in a cohort of patients

Lack of nAChR Activity Depresses Cochlear Maturation and Up-Regulates GABA System Components: Temporal Profiling of Gene Expression in α9 Null Mice

It has previously been shown that deletion of chrna9, the gene encoding the alpha9 nicotinic acetylcholine receptor (nAChR) subunit, results in abnormal synaptic terminal structure. Additionally, all nAChR-mediated cochlear activity is lost, as characterized by a failure of the descending efferent system to suppress cochlear responses to sound. In an effort to characterize the molecular mechanisms underlying the structural and functional consequences following loss of alpha9 subunit expression, we performed whole-transcriptome gene expression analyses on cochleae of wild type and alpha9 knockout (alpha9(-/-)) mice during postnatal days spanning critical periods of synapse formation and maturation.Data revealed that loss of alpha9 receptor subunit expression leads to an up-regulation of genes involved in synaptic transmission and ion channel activity. Unexpectedly, loss of alpha9 receptor subunit expression also resulted in an increased expression of genes encoding GABA receptor subunits and the GABA synthetic enzyme, glutamic acid decarboxylase. These data suggest the existence of a previously unrecognized association between the nicotinic cholinergic and GABAergic systems in the cochlea. Computational analyses have highlighted differential expression of several gene sets upon loss of nicotinic cholinergic activity in the cochlea. Time-series analysis of whole transcriptome patterns, represented as self-organizing maps, revealed a disparate pattern of gene expression between alpha9(-/-) and wild type cochleae at the onset of hearing (P13), with knockout samples resembling immature postnatal ages.We have taken a systems biology approach to provide insight into molecular programs influenced by the loss of nicotinic receptor-based cholinergic activity in the cochlea and to identify candidate genes that may be involved in nicotinic cholinergic synapse formation, stabilization or function within the inner ear. Additionally, our data indicate a change in the GABAergic system upon loss of alpha9 nicotinic receptor subunit within the cochlea

On Solving Selected Nonlinear Integer Programming Problems in Data Mining, Computational Biology, and Sustainability

This thesis consists of three essays concerning the use of optimization techniques to solve four problems in the fields of data mining, computational biology, and sustainable energy devices. To the best of our knowledge, the particular problems we discuss have not been previously addressed using optimization, which is a specific contribution of this dissertation. In particular, we analyze each of the problems to capture their underlying essence, subsequently demonstrating that each problem can be modeled as a nonlinear (mixed) integer program. We then discuss the design and implementation of solution techniques to locate optimal solutions to the aforementioned problems. Running throughout this dissertation is the theme of using mixed-integer programming techniques in conjunction with context-dependent algorithms to identify optimal and previously undiscovered underlying structure

Bayesian Biclustering on Discrete Data: Variable Selection Methods

Biclustering is a technique for clustering rows and columns of a data matrix simultaneously. Over the past few years, we have seen its applications in biology-related fields, as well as in many data mining projects. As opposed to classical clustering methods, biclustering groups objects that are similar only on a subset of variables. Many biclustering algorithms on continuous data have emerged over the last decade. In this dissertation, we will focus on two Bayesian biclustering algorithms we developed for discrete data, more specifically categorical data and ordinal data.Statistic

Gene expression data analysis using novel methods: Predicting time delayed correlations and evolutionarily conserved functional modules

Microarray technology enables the study of gene expression on a large scale. One of the main challenges has been to devise methods to cluster genes that share similar expression profiles. In gene expression time courses, a particular gene may encode transcription factor and thus controlling several genes downstream; in this case, the gene expression profiles may be staggered, indicating a time-delayed response in transcription of the later genes. The standard clustering algorithms consider gene expression profiles in a global way, thus often ignoring such local time-delayed correlations. We have developed novel methods to capture time-delayed correlations between expression profiles: (1) A method using dynamic programming and (2) CLARITY, an algorithm that uses a local shape based similarity measure to predict time-delayed correlations and local correlations. We used CLARITY on a dataset describing the change in gene expression during the mitotic cell cycle in Saccharomyces cerevisiae. The obtained clusters were significantly enriched with genes that share similar functions, reflecting the fact that genes with a similar function are often co-regulated and thus co-expressed. Time-shifted as well as local correlations could also be predicted using CLARITY. In datasets, where the expression profiles of independent experiments are compared, the standard clustering algorithms often cluster according to all conditions, considering all genes. This increases the background noise and can lead to the missing of genes that change the expression only under particular conditions. We have employed a genetic algorithm based module predictor that is capable to identify group of genes that change their expression only in a subset of conditions. With the aim of supplementing the Ustilago maydis genome annotation, we have used the module prediction algorithm on various independent datasets from Ustilago maydis. The predicted modules were cross-referenced in various Saccharomyces cerevisiae datasets to check its evolutionarily conservation between these two organisms. The key contributions of this thesis are novel methods that explore biological information from DNA microarray data