Annotation Enrichment Analysis is a widely used analytical methodology to process data generated by high-throughput genomic and proteomic experiments such as gene expression microarrays. The analysis uncovers and summarizes discriminating background information for sets of genes identified by the previous processing stages (e.g., a set of differentially expressed genes, a cluster). Enrichment analysis algorithms attach annotations to the genes and then discover statistical fluctuations of individual annotation terms in a given gene subset. The annotation terms represent different aspects of biological knowledge and come from databases such as GO, BIND, KEGG. Typical statistical models used to detect enrichments or depletions of annotation terms are hypergeometric, binomial and X2. At the end, the discovered information is utilized by human experts to find biological interpretations of the experiments. The main drawback of AEA is that it isolates and tests for overrepresentation of isolated individual annotation terms or groups of similar terms. As a result, AEA is limited in its ability to uncover complex phenomena involving relationships between multiple annotation terms from various knowledge bases. Also, AEA assumes that annotations describe the whole object of interest, which makes it difficult to apply it to sets of compound objects (e.g., sets of protein-protein interactions) and to sets of objects having an internal structure (e.g., protein complexes). To overcome this shortcoming, we propose a novel logic-based Annotation Concept Synthesis and Enrichment Analysis (ACSEA) approach. In this approach, the source annotation information, experimental data and uncovered enriched annotations are represented as First-Order Logic (FOL) statements. ACSEA uses the fusion of inductive logic reasoning with statistical inference to uncover more complex phenomena captured by the experiments. The proposed paradigm allows a synthesis of enriched annotation concepts that better describe the observed biological processes. The methodological advantage of Annotation Concept Synthesis and Enrichment Analysis is six-fold. Firstly, it is easier to represent complex, structural annotation information. Information already captured and formalized in OWL and RDF knowledge bases can be directly utilized. Secondly, it is possible to synthesize and analyze complex annotation concepts. Thirdly, it is possible to perform the enrichment analysis for sets of aggregate objects (such as sets of genetic interactions, physical protein-protein interactions or sets of protein complexes). Fourthly, annotation concepts are straightforward to interpret by a human expert. Fifthly, the logic data model and logic induction are a common platform that can integrate specialized analytical tools (e.g. tools for numerical, structural and sequential analysis). Sixthly, used statistical inference methods are robust on noisy and incomplete data, scalable and trusted by human experts in the field. In this thesis we developed and implemented the ACSEA approach. We evaluate it on large-scale datasets from several microarray experiments and on a clustered genome-wide genetic interaction network using different biological knowledge bases. Also, we define a statistical model of experimental and annotation data and evaluate ACSEA on synthetic datasets. The discovered interpretations are more enriched in terms of P- and Q-values than the interpretations found by AEA, are highly integrative in nature, and include analysis of quantitative and structured information present in the knowledge bases. The results suggest that ACSEA can significantly boost the effectiveness of the processing of high-throughput experiment data.

Annotation Enrichment Analysis is a widely used analytical methodology to process data generated by high-throughput genomic and proteomic experiments such as gene expression microarrays. The analysis uncovers and summarizes discriminating background information for sets of genes identified by the previous processing stages (e.g., a set of differentially expressed genes, a cluster). Enrichment analysis algorithms attach annotations to the genes and then discover statistical fluctuations of individual annotation terms in a given gene subset. The annotation terms represent different aspects of biological knowledge and come from databases such as GO, BIND, KEGG. Typical statistical models used to detect enrichments or depletions of annotation terms are hypergeometric, binomial and X2. At the end, the discovered information is utilized by human experts to find biological interpretations of the experiments. The main drawback of AEA is that it isolates and tests for overrepresentation of isolated individual annotation terms or groups of similar terms. As a result, AEA is limited in its ability to uncover complex phenomena involving relationships between multiple annotation terms from various knowledge bases. Also, AEA assumes that annotations describe the whole object of interest, which makes it difficult to apply it to sets of compound objects (e.g., sets of protein-protein interactions) and to sets of objects having an internal structure (e.g., protein complexes). To overcome this shortcoming, we propose a novel logic-based Annotation Concept Synthesis and Enrichment Analysis (ACSEA) approach. In this approach, the source annotation information, experimental data and uncovered enriched annotations are represented as First-Order Logic (FOL) statements. ACSEA uses the fusion of inductive logic reasoning with statistical inference to uncover more complex phenomena captured by the experiments. The proposed paradigm allows a synthesis of enriched annotation concepts that better describe the observed biological processes. The methodological advantage of Annotation Concept Synthesis and Enrichment Analysis is six-fold. Firstly, it is easier to represent complex, structural annotation information. Information already captured and formalized in OWL and RDF knowledge bases can be directly utilized. Secondly, it is possible to synthesize and analyze complex annotation concepts. Thirdly, it is possible to perform the enrichment analysis for sets of aggregate objects (such as sets of genetic interactions, physical protein-protein interactions or sets of protein complexes). Fourthly, annotation concepts are straightforward to interpret by a human expert. Fifthly, the logic data model and logic induction are a common platform that can integrate specialized analytical tools (e.g. tools for numerical, structural and sequential analysis). Sixthly, used statistical inference methods are robust on noisy and incomplete data, scalable and trusted by human experts in the field. In this thesis we developed and implemented the ACSEA approach. We evaluate it on large-scale datasets from several microarray experiments and on a clustered genome-wide genetic interaction network using different biological knowledge bases. Also, we define a statistical model of experimental and annotation data and evaluate ACSEA on synthetic datasets. The discovered interpretations are more enriched in terms of P- and Q-values than the interpretations found by AEA, are highly integrative in nature, and include analysis of quantitative and structured information present in the knowledge bases. The results suggest that ACSEA can significantly boost the effectiveness of the processing of high-throughput experiment data.

Annotation Enrichment Analysis is a widely used analytical methodology to process data generated by high-throughput genomic and proteomic experiments such as gene expression microarrays. The analysis uncovers and summarizes discriminating background information for sets of genes identified by the previous processing stages (e.g., a set of differentially expressed genes, a cluster). Enrichment analysis algorithms attach annotations to the genes and then discover statistical fluctuations of individual annotation terms in a given gene subset. The annotation terms represent different aspects of biological knowledge and come from databases such as GO, BIND, KEGG. Typical statistical models used to detect enrichments or depletions of annotation terms are hypergeometric, binomial and X2. At the end, the discovered information is utilized by human experts to find biological interpretations of the experiments. The main drawback of AEA is that it isolates and tests for overrepresentation of isolated individual annotation terms or groups of similar terms. As a result, AEA is limited in its ability to uncover complex phenomena involving relationships between multiple annotation terms from various knowledge bases. Also, AEA assumes that annotations describe the whole object of interest, which makes it difficult to apply it to sets of compound objects (e.g., sets of protein-protein interactions) and to sets of objects having an internal structure (e.g., protein complexes). To overcome this shortcoming, we propose a novel logic-based Annotation Concept Synthesis and Enrichment Analysis (ACSEA) approach. In this approach, the source annotation information, experimental data and uncovered enriched annotations are represented as First-Order Logic (FOL) statements. ACSEA uses the fusion of inductive logic reasoning with statistical inference to uncover more complex phenomena captured by the experiments. The proposed paradigm allows a synthesis of enriched annotation concepts that better describe the observed biological processes. The methodological advantage of Annotation Concept Synthesis and Enrichment Analysis is six-fold. Firstly, it is easier to represent complex, structural annotation information. Information already captured and formalized in OWL and RDF knowledge bases can be directly utilized. Secondly, it is possible to synthesize and analyze complex annotation concepts. Thirdly, it is possible to perform the enrichment analysis for sets of aggregate objects (such as sets of genetic interactions, physical protein-protein interactions or sets of protein complexes). Fourthly, annotation concepts are straightforward to interpret by a human expert. Fifthly, the logic data model and logic induction are a common platform that can integrate specialized analytical tools (e.g. tools for numerical, structural and sequential analysis). Sixthly, used statistical inference methods are robust on noisy and incomplete data, scalable and trusted by human experts in the field. In this thesis we developed and implemented the ACSEA approach. We evaluate it on large-scale datasets from several microarray experiments and on a clustered genome-wide genetic interaction network using different biological knowledge bases. Also, we define a statistical model of experimental and annotation data and evaluate ACSEA on synthetic datasets. The discovered interpretations are more enriched in terms of P- and Q-values than the interpretations found by AEA, are highly integrative in nature, and include analysis of quantitative and structured information present in the knowledge bases. The results suggest that ACSEA can significantly boost the effectiveness of the processing of high-throughput experiment data.

Annotation Enrichment Analysis is a widely used analytical methodology to process data generated by high-throughput genomic and proteomic experiments such as gene expression microarrays. The analysis uncovers and summarizes discriminating background information for sets of genes identified by the previous processing stages (e.g., a set of differentially expressed genes, a cluster). Enrichment analysis algorithms attach annotations to the genes and then discover statistical fluctuations of individual annotation terms in a given gene subset. The annotation terms represent different aspects of biological knowledge and come from databases such as GO, BIND, KEGG. Typical statistical models used to detect enrichments or depletions of annotation terms are hypergeometric, binomial and X2. At the end, the discovered information is utilized by human experts to find biological interpretations of the experiments. The main drawback of AEA is that it isolates and tests for overrepresentation of isolated individual annotation terms or groups of similar terms. As a result, AEA is limited in its ability to uncover complex phenomena involving relationships between multiple annotation terms from various knowledge bases. Also, AEA assumes that annotations describe the whole object of interest, which makes it difficult to apply it to sets of compound objects (e.g., sets of protein-protein interactions) and to sets of objects having an internal structure (e.g., protein complexes). To overcome this shortcoming, we propose a novel logic-based Annotation Concept Synthesis and Enrichment Analysis (ACSEA) approach. In this approach, the source annotation information, experimental data and uncovered enriched annotations are represented as First-Order Logic (FOL) statements. ACSEA uses the fusion of inductive logic reasoning with statistical inference to uncover more complex phenomena captured by the experiments. The proposed paradigm allows a synthesis of enriched annotation concepts that better describe the observed biological processes. The methodological advantage of Annotation Concept Synthesis and Enrichment Analysis is six-fold. Firstly, it is easier to represent complex, structural annotation information. Information already captured and formalized in OWL and RDF knowledge bases can be directly utilized. Secondly, it is possible to synthesize and analyze complex annotation concepts. Thirdly, it is possible to perform the enrichment analysis for sets of aggregate objects (such as sets of genetic interactions, physical protein-protein interactions or sets of protein complexes). Fourthly, annotation concepts are straightforward to interpret by a human expert. Fifthly, the logic data model and logic induction are a common platform that can integrate specialized analytical tools (e.g. tools for numerical, structural and sequential analysis). Sixthly, used statistical inference methods are robust on noisy and incomplete data, scalable and trusted by human experts in the field. In this thesis we developed and implemented the ACSEA approach. We evaluate it on large-scale datasets from several microarray experiments and on a clustered genome-wide genetic interaction network using different biological knowledge bases. Also, we define a statistical model of experimental and annotation data and evaluate ACSEA on synthetic datasets. The discovered interpretations are more enriched in terms of P- and Q-values than the interpretations found by AEA, are highly integrative in nature, and include analysis of quantitative and structured information present in the knowledge bases. The results suggest that ACSEA can significantly boost the effectiveness of the processing of high-throughput experiment data.

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With the ever increasing amount of high-throughput molecular profile data, biologists need versatile tools to enable them to quickly and succinctly analyze their data. Furthermore, pathway databases have grown increasingly robust with the KEGG database at the forefront. Previous tools have color-coded the genes on different pathways using differential expression analysis. Unfortunately, they do not adequately capture the relationships of the genes amongst one another. Structure Enrichment Analysis (SEA) thus seeks to take biological analysis to the next level. SEA accomplishes this goal by highlighting for users the sub-pathways of a biological pathways that best correspond to their molecular profile data in an easy to use GUI interface.

Motivation Translational bioinformatics(TBI) has been defined as ‘the development and application of informatics methods that connect molecular entities to clinical entities’ [1], which has emerged as a systems theory approach to bridge the huge wealth of biomedical data into clinical actions using a combination of innovations and resources across the entire spectrum of biomedical informatics approaches [2]. The challenge for TBI is the availability of both comprehensive knowledge based on genes and the corresponding tools that allow their analysis and exploitation. Traditionally, biological researchers usually study one or only a few genes at a time, but in recent years high throughput technologies such as gene expression microarrays, protein mass-spectrometry and next-generation DNA and RNA sequencing have emerged that allow the simultaneous measurement of changes on a genome-wide scale. These technologies usually result in large lists of interesting genes, but meaningful biological interpretation remains a major challenge. Over the last decade, enrichment analysis has become standard practice in the analysis of such gene lists, enabling systematic assessment of the likelihood of differential representation of defined groups of genes compared to suitably annotated background knowledge. The success of such analyses are highly dependent on the availability and quality of the gene annotation data. For many years, genes were annotated by different experts using inconsistent, non-standard terminologies. Large amounts of variation and duplication in these unstructured annotation sets, made them unsuitable for principled quantitative analysis. More recently, a lot of effort has been put into the development and use of structured, domain specific vocabularies to annotate genes. The Gene Ontology is one of the most successful examples of this where genes are annotated with terms from three main clades; biological process, molecular function and cellular component. However, there are many other established and emerging ontologies to aid biological data interpretation, but are rarely used. For the same reason, many bioinformatic tools only support analysis analysis using the Gene Ontology. The lack of annotation coverage and the support for them in existing analytical tools to aid biological interpretation of data has become a major limitation to their utility and uptake. Thus, automatic approaches are needed to facilitate the transformation of unstructured data to unlock the potential of all ontologies, with corresponding bioinformatics tools to support their interpretation. Approaches In this thesis, firstly, similar to the approach in [3,4], I propose a series of computational approaches implemented in a new tool OntoSuite-Miner to address the ontology based gene association data integration challenge. This approach uses NLP based text mining methods for ontology based biomedical text mining. What differentiates my approach from other approaches is that I integrate two of the most wildly used NLP modules into the framework, not only increasing the confidence of the text mining results, but also providing an annotation score for each mapping, based on the number of pieces of evidence in the literature and the number of NLP modules that agreed with the mapping. Since heterogeneous data is important in understanding human disease, the approach was designed to be generic, thus the ontology based annotation generation can be applied to different sources and can be repeated with different ontologies. Secondly, in respect of the second challenge proposed by TBI, to increase the statistical power of the annotation enrichment analysis, I propose OntoSuite-Analytics, which integrates a collection of enrichment analysis methods into a unified open-source software package named topOnto, in the statistical programming language R. The package supports enrichment analysis across multiple ontologies with a set of implemented statistical/topological algorithms, allowing the comparison of enrichment results across multiple ontologies and between different algorithms. Results The methodologies described above were implemented and a Human Disease Ontology (HDO) based gene annotation database was generated by mining three publicly available database, OMIM, GeneRIF and Ensembl variation. With the availability of the HDO annotation and the corresponding ontology enrichment analysis tools in topOnto, I profiled 277 gene classes with human diseases and generated ‘disease environments’ for 1310 human diseases. The exploration of the disease profiles and disease environment provides an overview of known disease knowledge and provides new insights into disease mechanisms. The integration of multiple ontologies into a disease context demonstrates how ‘orthogonal’ ontologies can lead to biological insight that would have been missed by more traditional single ontology analysis.

Microarray technology allows measurement of the expression levels of thousand of genes simultaneously. Several gene set analysis (GSA) methods are widely used for extracting useful information from microarrays, for example identifying differentially expressed pathways associated with a particular biological process or disease phenotype. Though GSA methods like Gene Set Enrichment Analysis (GSEA) are widely used for pathway analysis, these methods are solely based on statistics. Such methods can be awkward to use if knowledge of specific pathways involved in particular biological processes are the aim of the study. Here we present a novel method (Knowledge Based Gene Set Analysis: KB-GSA) which integrates knowledge about user-selected pathways that are known to be involved in specific biological processes. The method generates an easy to understand graphical visualization of the changes in expression of the genes, complemented with some common statistics about the pathway of particular interest.

Genetic regulatory networks are of great importance in terms of scientific interests and practical medical importance. Since a number of high-throughput measurement devices are available, such as microarrays and sequencing techniques, regulatory networks have been intensively studied over the last decade. Based on these high-throughput data sets, statistical interpretations of these billions of bits are crucial for biologist to extract meaningful results. In this thesis, we compare a variety of existing regression models and apply them to construct regulatory networks which span trancription factors and microRNAs. We also propose an extended algorithm to address the local optimum issue in finding the Maximum A Posterjorj estimator. An E. coli mRNA expression microarray data set with known bona fide interactions is used to evaluate our models and we show that our regression networks with a properly chosen prior can perform comparably to the state-of-the-art regulatory network construction algorithm. Finally, we apply our models on a p53-related data set, NCI-60 data. By further incorporating available prior structural information from sequencing data, we identify several significantly enriched interactions with cell proliferation function. In both of the two data sets, we select specific examples to show that many regulatory interactions can be confirmed by previous studies or functional enrichment analysis. Through comparing statistical models, we conclude from the project that combining different models with over-representation analysis and prior structural information can improve the quality of prediction and facilitate biological interpretation. Keywords: regulatory network, variable selection, penalized maximum likelihood estimation, optimization, functional enrichment analysis.

<p>Microarray technology allows measurement of the expression levels of thousand of genes simultaneously. Several gene set analysis (GSA) methods are widely used for extracting useful information from microarrays, for example identifying differentially expressed pathways associated with a particular biological process or disease phenotype. Though GSA methods like Gene Set Enrichment Analysis (GSEA) are widely used for pathway analysis, these methods are solely based on statistics. Such methods can be awkward to use if knowledge of specific pathways involved in particular biological processes are the aim of the study. Here we present a novel method <strong><em>(Knowledge Based Gene Set Analysis: KB-GSA</em></strong>) which integrates knowledge about user-selected pathways that are known to be involved in specific biological processes. The method generates an easy to understand graphical visualization of the changes in expression of the genes, complemented with some common statistics about the pathway of particular interest.</p>