Biclustering of Gene Expression Data Based on SimUI Semantic Similarity Measure

Biclustering is an unsupervised machine learning technique that simultaneously clusters genes and conditions in gene expression data. Gene Ontology (GO) is usually used in this context to validate the biological relevance of the results. However, although the integration of biological information from different sources is one of the research directions in Bioinformatics, GO is not used in biclustering as an input data. A scatter search-based algorithm that integrates GO information during the biclustering search process is presented in this paper. SimUI is a GO semantic similarity measure that defines a distance between two genes. The algorithm optimizes a fitness function that uses SimUI to integrate the biological information stored in GO. Experimental results analyze the effect of integration of the biological information through this measure. A SimUI fitness function configuration is experimentally studied in a scatter search-based biclustering algorithmMinisterio de Ciencia e Innovación TIN2011-28956-C02-02Ministerio de Ciencia e Innovación TIN2014-55894-C2-RJunta de Andalucía P12-TIC-1728Universidad Pablo de Olavide APPB81309

Pairwise gene GO-based measures for biclustering of high-dimensional expression data

Background: Biclustering algorithms search for groups of genes that share the same behavior under a subset of samples in gene expression data. Nowadays, the biological knowledge available in public repositories can be used to drive these algorithms to find biclusters composed of groups of genes functionally coherent. On the other hand, a distance among genes can be defined according to their information stored in Gene Ontology (GO). Gene pairwise GO semantic similarity measures report a value for each pair of genes which establishes their functional similarity. A scatter search-based algorithm that optimizes a merit function that integrates GO information is studied in this paper. This merit function uses a term that addresses the information through a GO measure. Results: The effect of two possible different gene pairwise GO measures on the performance of the algorithm is analyzed. Firstly, three well known yeast datasets with approximately one thousand of genes are studied. Secondly, a group of human datasets related to clinical data of cancer is also explored by the algorithm. Most of these data are high-dimensional datasets composed of a huge number of genes. The resultant biclusters reveal groups of genes linked by a same functionality when the search procedure is driven by one of the proposed GO measures. Furthermore, a qualitative biological study of a group of biclusters show their relevance from a cancer disease perspective. Conclusions: It can be concluded that the integration of biological information improves the performance of the biclustering process. The two different GO measures studied show an improvement in the results obtained for the yeast dataset. However, if datasets are composed of a huge number of genes, only one of them really improves the algorithm performance. This second case constitutes a clear option to explore interesting datasets from a clinical point of view.Ministerio de Economía y Competitividad TIN2014-55894-C2-

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

Biclustering sobre datos de expresión génica basado en búsqueda dispersa

Falta palabras claveLos datos de expresión génica, y su particular naturaleza e importancia, motivan no sólo el desarrollo de nuevas técnicas sino la formulación de nuevos problemas como el problema del biclustering. El biclustering es una técnica de aprendizaje no supervisado que agrupa tanto genes como condiciones. Este doble agrupamiento lo diferencia del clustering tradicional sobre este tipo de datos ya que éste sólo agrupa o bien genes o condiciones. La presente tesis presenta un nuevo algoritmo de biclustering que permite el estudio de distintos criterios de búsqueda. Dicho algoritmo utiliza esquema de búsqueda dispersa, o scatter search, que independiza el mecanismo de búsqueda del criterio empleado. Se han estudiado tres criterios de búsqueda diferentes que motivan las tres principales aportaciones de la tesis. En primer lugar se estudia la correlación lineal entre los genes, que se integra como parte de la función objetivo empleada por el algoritmo de biclustering. La correlación lineal permite encontrar biclusters con patrones de desplazamiento y escalado, lo que mejora propuestas anteriores. En segundo lugar, y motivado por el significado biológico de los patrones de activación-inhibición entre genes, se modifica la correlación lineal de manera que se contemplen estos patrones. Por último, se ha tenido en cuenta la información disponible sobre genes en repositorios públicos, como la ontología de genes GO, y se incorpora dicha información como parte del criterio de búsqueda. Se añade un término extra que refleja, por cada bicluster que se evalúe, la calidad de ese grupo de genes según su información almacenada en GO. Se estudian dos posibilidades para dicho término de integración de información biológica, se comparan entre sí y se comprueba que los resultados son mejores cuando se usa información biológica en el algoritmo de biclustering. Las tres aportaciones descritas, junto con una serie de pasos intermedios, han dado lugar a resultados publicados tanto en revistas como en conferencias nacionales e internacionales

Similitud funcional de genes basada en conocimiento biológico

Programa de Doctorado en Tecnología e Ingeniería del SoftwareOver the last few year, our knowledge about biological processes in living organisms has greatly expanded both in quantity and resolution, mostly thanks to the introduction of high-throughput sequencing technology. Making sense of these vast amount of biological data through methods such as automated learning is therefore critical to gain further insights into the molecular mechanisms behind fundamental biological processes. This work aims at establishing the quality of new genetic model based on actual biological data. First, a tool for analyzing the coherence of a group of genes according to their common role in metabolic processes is developed. This tool allows the evaluation and validation of different gene sets obtained through any clustering technique. Additionally, a novel measure of functional similarity of a group of genes has been introduced. This measure, called GFD, is based on the Gene Ontology, and it assigns a numerical value to a gene set for each of the three GO ontologies. Concretely, GFD computes the similarity based only on the most common and specific functionality of the genes. GFD compre favorably against the most relevant measures. Our approach is especially relevant in the study of genes that are involved in several functions.Universidad Pablo de Olavide de Sevilla. Departamento de Deporte e InformáticaPostprin