Exploiting biomedical web resources: a case study

An increasing number of web resources continue to be extensively used by healthcare operators to obtain more accurate diagnostic results. In particular, health care is reaping the benefits of technological advances in genomic for facing the demand of genetic tests that allow a better comprehension of diagnostic results. Within this context, Gene Ontology (GO) is a popular and effective mean for extracting knowledge from a list of genes and evaluating their semantic similarity. This paper investigates about the potential and any limits of GO ontology as support for capturing information about a set of genes which are supposed to play a significant role in a pathological condition. In particular, we present a case study that exploits some biomedical web resources for devising several groups of functionally coherent genes and experiments about the evaluation of their semantic similarity over GO. Due to the GO structure and content, results reveal limitations that not affect the evaluation of the semantic similarity when genes exhibit simple correlations but influence the estimation of the relatedness of genes belonging to complex organizations

RedundancyMiner: De-replication of redundant GO categories in microarray and proteomics analysis

<p>Abstract</p> <p>Background</p> <p>The Gene Ontology (GO) Consortium organizes genes into hierarchical categories based on biological process, molecular function and subcellular localization. Tools such as GoMiner can leverage GO to perform ontological analysis of microarray and proteomics studies, typically generating a list of significant functional categories. Two or more of the categories are often redundant, in the sense that identical or nearly-identical sets of genes map to the categories. The redundancy might typically inflate the report of significant categories by a factor of three-fold, create an illusion of an overly long list of significant categories, and obscure the relevant biological interpretation.</p> <p>Results</p> <p>We now introduce a new resource, RedundancyMiner, that de-replicates the redundant and nearly-redundant GO categories that had been determined by first running GoMiner. The main algorithm of RedundancyMiner, MultiClust, performs a novel form of cluster analysis in which a GO category might belong to several category clusters. Each category cluster follows a "complete linkage" paradigm. The metric is a similarity measure that captures the overlap in gene mapping between pairs of categories.</p> <p>Conclusions</p> <p>RedundancyMiner effectively eliminated redundancies from a set of GO categories. For illustration, we have applied it to the clarification of the results arising from two current studies: (1) assessment of the gene expression profiles obtained by laser capture microdissection (LCM) of serial cryosections of the retina at the site of final optic fissure closure in the mouse embryos at specific embryonic stages, and (2) analysis of a conceptual data set obtained by examining a list of genes deemed to be "kinetochore" genes.</p

From data towards knowledge: Revealing the architecture of signaling systems by unifying knowledge mining and data mining of systematic perturbation data

Genetic and pharmacological perturbation experiments, such as deleting a gene and monitoring gene expression responses, are powerful tools for studying cellular signal transduction pathways. However, it remains a challenge to automatically derive knowledge of a cellular signaling system at a conceptual level from systematic perturbation-response data. In this study, we explored a framework that unifies knowledge mining and data mining approaches towards the goal. The framework consists of the following automated processes: 1) applying an ontology-driven knowledge mining approach to identify functional modules among the genes responding to a perturbation in order to reveal potential signals affected by the perturbation; 2) applying a graph-based data mining approach to search for perturbations that affect a common signal with respect to a functional module, and 3) revealing the architecture of a signaling system organize signaling units into a hierarchy based on their relationships. Applying this framework to a compendium of yeast perturbation-response data, we have successfully recovered many well-known signal transduction pathways; in addition, our analysis have led to many hypotheses regarding the yeast signal transduction system; finally, our analysis automatically organized perturbed genes as a graph reflecting the architect of the yeast signaling system. Importantly, this framework transformed molecular findings from a gene level to a conceptual level, which readily can be translated into computable knowledge in the form of rules regarding the yeast signaling system, such as "if genes involved in MAPK signaling are perturbed, genes involved in pheromone responses will be differentially expressed"

Assessing the functional coherence of modules found in multiple-evidence networks from Arabidopsis

<p>Abstract</p> <p>Background</p> <p>Combining multiple evidence-types from different information sources has the potential to reveal new relationships in biological systems. The integrated information can be represented as a relationship network, and clustering the network can suggest possible functional modules. The value of such modules for gaining insight into the underlying biological processes depends on their functional coherence. The challenges that we wish to address are to define and quantify the functional coherence of modules in relationship networks, so that they can be used to infer function of as yet unannotated proteins, to discover previously unknown roles of proteins in diseases as well as for better understanding of the regulation and interrelationship between different elements of complex biological systems.</p> <p>Results</p> <p>We have defined the functional coherence of modules with respect to the Gene Ontology (GO) by considering two complementary aspects: (i) the fragmentation of the GO functional categories into the different modules and (ii) the most representative functions of the modules. We have proposed a set of metrics to evaluate these two aspects and demonstrated their utility in <it>Arabidopsis thaliana</it>. We selected 2355 proteins for which experimentally established protein-protein interaction (PPI) data were available. From these we have constructed five relationship networks, four based on single types of data: PPI, co-expression, co-occurrence of protein names in scientific literature abstracts and sequence similarity and a fifth one combining these four evidence types. The ability of these networks to suggest biologically meaningful grouping of proteins was explored by applying Markov clustering and then by measuring the functional coherence of the clusters.</p> <p>Conclusions</p> <p>Relationship networks integrating multiple evidence-types are biologically informative and allow more proteins to be assigned to a putative functional module. Using additional evidence types concentrates the functional annotations in a smaller number of modules without unduly compromising their consistency. These results indicate that integration of more data sources improves the ability to uncover functional association between proteins, both by allowing more proteins to be linked and producing a network where modular structure more closely reflects the hierarchy in the gene ontology.</p

Analysis and implementation of methods for the text categorization

Text Categorization (TC) is the automatic classification of text documents under pre-defined categories, or classes. Popular TC approaches map categories into symbolic labels and use a training set of documents, previously labeled by human experts, to build a classifier which enables the automatic TC of unlabeled documents. Suitable TC methods come from the field of data mining and information retrieval, however the following issues remain unsolved. First, the classifier performance depends heavily on hand-labeled documents that are the only source of knowledge for learning the classifier. Being a labor-intensive and time consuming activity, the manual attribution of documents to categories is extremely costly. This creates a serious limitations when a set of manual labeled data is not available, as it happens in most cases. Second, even a moderately sized text collection often has tens of thousands of terms in that making the classification cost prohibitive for learning algorithms that do not scale well to large problem sizes. Most important, TC should be based on the text content rather than on a set of hand-labeled documents whose categorization depends on the subjective judgment of a human classifier. This thesis aims at facing the above issues by proposing innovative approaches which leverage techniques from data mining and information retrieval. To face problems about both the high dimensionality of the text collection and the large number of terms in a single text, the thesis proposes a hybrid model for term selection which combines and takes advantage of both filter and wrapper approaches. In detail, the proposed model uses a filter to rank the list of terms present in documents to ensure that useful terms are unlikely to be screened out. Next, to limit classification problems due to the correlation among terms, this ranked list is refined by a wrapper that uses a Genetic Algorithm (GA) to retaining the most informative and discriminative terms. Experimental results compare well with some of the top-performing learning algorithms for TC and seems to confirm the effectiveness of the proposed model. To face the issues about the lack and the subjectivity of manually labeled datasets, the basic idea is to use an ontology-based approach which does not depend on the existence of a training set and relies solely on a set of concepts within a given domain and the relationships between concepts. In this regard, the thesis proposes a text categorization approach that applies WordNet for selecting the correct sense of words in a document, and utilizes domain names in WordNet Domains for classification purposes. Experiments show that the proposed approach performs well in classifying a large corpus of documents. This thesis contributes to the area of data mining and information retrieval. Specifically, it introduces and evaluates novel techniques to the field of text categorization. The primary objective of this thesis is to test the hypothesis that: text categorization requires and benefits from techniques designed to exploit document content. hybrid methods from data mining and information retrieval can better support problems about high dimensionality that is the main aspect of large document collections. in absence of manually annotated documents, WordNet domain abstraction can be used that is both useful and general enough to categorize any documents collection. As a final remark, it is important to acknowledge that much of the inspiration and motivation for this work derived from the vision of the future of text categorization processes which are related to specific application domains such as the business area and the industrial sectors, just to cite a few. In the end, it is this vision that provided the guiding framework. However, it is equally important to understand that many of the results and techniques developed in this thesis are not limited to text categorization. For example, the evaluation of disambiguation methods is interesting in its own right and is likely to be relevant to other application fields

Analysis and implementation of methods for the text categorization

Text Categorization (TC) is the automatic classification of text documents under pre-defined categories, or classes. Popular TC approaches map categories into symbolic labels and use a training set of documents, previously labeled by human experts, to build a classifier which enables the automatic TC of unlabeled documents. Suitable TC methods come from the field of data mining and information retrieval, however the following issues remain unsolved. First, the classifier performance depends heavily on hand-labeled documents that are the only source of knowledge for learning the classifier. Being a labor-intensive and time consuming activity, the manual attribution of documents to categories is extremely costly. This creates a serious limitations when a set of manual labeled data is not available, as it happens in most cases. Second, even a moderately sized text collection often has tens of thousands of terms in that making the classification cost prohibitive for learning algorithms that do not scale well to large problem sizes. Most important, TC should be based on the text content rather than on a set of hand-labeled documents whose categorization depends on the subjective judgment of a human classifier. This thesis aims at facing the above issues by proposing innovative approaches which leverage techniques from data mining and information retrieval. To face problems about both the high dimensionality of the text collection and the large number of terms in a single text, the thesis proposes a hybrid model for term selection which combines and takes advantage of both filter and wrapper approaches. In detail, the proposed model uses a filter to rank the list of terms present in documents to ensure that useful terms are unlikely to be screened out. Next, to limit classification problems due to the correlation among terms, this ranked list is refined by a wrapper that uses a Genetic Algorithm (GA) to retaining the most informative and discriminative terms. Experimental results compare well with some of the top-performing learning algorithms for TC and seems to confirm the effectiveness of the proposed model. To face the issues about the lack and the subjectivity of manually labeled datasets, the basic idea is to use an ontology-based approach which does not depend on the existence of a training set and relies solely on a set of concepts within a given domain and the relationships between concepts. In this regard, the thesis proposes a text categorization approach that applies WordNet for selecting the correct sense of words in a document, and utilizes domain names in WordNet Domains for classification purposes. Experiments show that the proposed approach performs well in classifying a large corpus of documents. This thesis contributes to the area of data mining and information retrieval. Specifically, it introduces and evaluates novel techniques to the field of text categorization. The primary objective of this thesis is to test the hypothesis that: text categorization requires and benefits from techniques designed to exploit document content. hybrid methods from data mining and information retrieval can better support problems about high dimensionality that is the main aspect of large document collections. in absence of manually annotated documents, WordNet domain abstraction can be used that is both useful and general enough to categorize any documents collection. As a final remark, it is important to acknowledge that much of the inspiration and motivation for this work derived from the vision of the future of text categorization processes which are related to specific application domains such as the business area and the industrial sectors, just to cite a few. In the end, it is this vision that provided the guiding framework. However, it is equally important to understand that many of the results and techniques developed in this thesis are not limited to text categorization. For example, the evaluation of disambiguation methods is interesting in its own right and is likely to be relevant to other application fields

Multivariate Models and Algorithms for Systems Biology

Rapid advances in high-throughput data acquisition technologies, such as microarraysand next-generation sequencing, have enabled the scientists to interrogate the expression levels of tens of thousands of genes simultaneously. However, challenges remain in developingeffective computational methods for analyzing data generated from such platforms. In thisdissertation, we address some of these challenges. We divide our work into two parts. Inthe first part, we present a suite of multivariate approaches for a reliable discovery of geneclusters, often interpreted as pathway components, from molecular profiling data with replicated measurements. We translate our goal into learning an optimal correlation structure from replicated complete and incomplete measurements. In the second part, we focus on thereconstruction of signal transduction mechanisms in the signaling pathway components. Wepropose gene set based approaches for inferring the structure of a signaling pathway.First, we present a constrained multivariate Gaussian model, referred to as the informed-case model, for estimating the correlation structure from replicated and complete molecular profiling data. Informed-case model generalizes previously known blind-case modelby accommodating prior knowledge of replication mechanisms. Second, we generalize theblind-case model by designing a two-component mixture model. Our idea is to strike anoptimal balance between a fully constrained correlation structure and an unconstrained one.Third, we develop an Expectation-Maximization algorithm to infer the underlying correlation structure from replicated molecular profiling data with missing (incomplete) measurements.We utilize our correlation estimators for clustering real-world replicated complete and incompletemolecular profiling data sets. The above three components constitute the first partof the dissertation. For the structural inference of signaling pathways, we hypothesize a directed signal pathway structure as an ensemble of overlapping and linear signal transduction events. We then propose two algorithms to reverse engineer the underlying signaling pathway structure using unordered gene sets corresponding to signal transduction events. Throughout we treat gene sets as variables and the associated gene orderings as random.The first algorithm has been developed under the Gibbs sampling framework and the secondalgorithm utilizes the framework of simulated annealing. Finally, we summarize our findingsand discuss possible future directions