A Survey of Computational Tools to Analyze and Interpret Whole Exome Sequencing Data <s> Methods for Pathway Analysis. <s> KEGG (Kyoto Encyclopedia of Genes and Genomes) is a knowledge base for systematic analysis of gene functions, linking genomic information with higher order functional information. The genomic information is stored in the GENES database, which is a collection of gene catalogs for all the completely sequenced genomes and some partial genomes with up-to-date annotation of gene functions. The higher order functional information is stored in the PATHWAY database, which contains graphical representations of cellular processes, such as metabolism, membrane transport, signal transduction and cell cycle. The PATHWAY database is supplemented by a set of ortholog group tables for the information about conserved subpathways (pathway motifs), which are often encoded by positionally coupled genes on the chromosome and which are especially useful in predicting gene functions. A third database in KEGG is LIGAND for the information about chemical compounds, enzyme molecules and enzymatic reactions. KEGG provides Java graphics tools for browsing genome maps, comparing two genome maps and manipulating expression maps, as well as computational tools for sequence comparison, graph comparison and path computation. The KEGG databases are daily updated and made freely available (http://www. genome.ad.jp/kegg/). <s> BIB001 </s> A Survey of Computational Tools to Analyze and Interpret Whole Exome Sequencing Data <s> Methods for Pathway Analysis. <s> Functional analysis of large gene lists, derived in most cases from emerging high-throughput genomic, proteomic and bioinformatics scanning approaches, is still a challenging and daunting task. The gene-annotation enrichment analysis is a promising high-throughput strategy that increases the likelihood for investigators to identify biological processes most pertinent to their study. Approximately 68 bioinformatics enrichment tools that are currently available in the community are collected in this survey. Tools are uniquely categorized into three major classes, according to their underlying enrichment algorithms. The comprehensive collections, unique tool classifications and associated questions/issues will provide a more comprehensive and up-to-date view regarding the advantages, pitfalls and recent trends in a simpler tool-class level rather than by a tool-by-tool approach. Thus, the survey will help tool designers/developers and experienced end users understand the underlying algorithms and pertinent details of particular tool categories/tools, enabling them to make the best choices for their particular research interests. <s> BIB002 </s> A Survey of Computational Tools to Analyze and Interpret Whole Exome Sequencing Data <s> Methods for Pathway Analysis. <s> Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein-protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease. <s> BIB003 </s> A Survey of Computational Tools to Analyze and Interpret Whole Exome Sequencing Data <s> Methods for Pathway Analysis. <s> Summary: Biomedical Entity-Relationship eXplorer (BEReX) is a new biomedical knowledge integration, search and exploration tool. BEReX integrates eight popular databases (STRING, DrugBank, KEGG, PhamGKB, BioGRID, GO, HPRD and MSigDB) and delineates an integrated network by combining the information available from these databases. Users search the integrated network by entering key words, and BEReX returns a sub-network matching the key words. The resulting graph can be explored interactively. BEReX allows users to find the shortest paths between two remote nodes, find the most relevant drugs, diseases, pathways and so on related to the current network, expand the network by particular types of entities and relations and modify the network by removing or adding selected nodes. BEReX is implemented as a standalone Java application. Availability and implementation: BEReX and a detailed user guide are available for download at our project Web site (http://infos.korea.ac. <s> BIB004 </s> A Survey of Computational Tools to Analyze and Interpret Whole Exome Sequencing Data <s> Methods for Pathway Analysis. <s> Summary: We created a fast, robust and general C++ implementation of a single-nucleotide polymorphism (SNP) set enrichment algorithm to identify cell types, tissues and pathways affected by risk loci. It tests trait-associated genomic loci for enrichment of specificity to conditions (cell types, tissues and pathways). We use a non-parametric statistical approach to compute empirical P-values by comparison with null SNP sets. As a proof of concept, we present novel applications of our method to four sets of genome-wide significant SNPs associated with red blood cell count, multiple sclerosis, celiac disease and HDL cholesterol. Availability and implementation: http://broadinstitute.org/mpg/ snpsea <s> BIB005
After candidate somatic mutations have been identified; one common type of analysis is to determine which pathways are affected by these mutations. Common pathway resources and tools used for these types of analysis include KEGG BIB001 , DAVID BIB002 , STRING  , BEReX BIB004 , DAPPLE BIB003 , and SNPsea BIB005 . KEGG represents one of the most popular databases for pathway analysis. DAVID is a popular online tool for performing functional enrichment analysis based on user defined gene lists. STRING is the largest protein-protein interactions database for querying and searching for interactions between user defined gene lists. BEReX integrates STRING, KEGG, and other data sources to explore biomedical interactions between genes, drugs, pathways, and diseases. Both STRING and BEReX allow users to perform functional enrichment analysis and the flexibility to explore the interactions between user defined gene lists by expanding the networks. DAPPLE (Disease Association Protein-Protein Link Evaluator) uses literature reported protein-protein interactions to identify significant physical connectivity among the genes of interest BIB003 . DAPPLE hypothesizes that genetic variation affects underlying mechanisms only detectable by protein-protein interactions BIB003 . SNPsea is another pathway analysis tool that requires specific SNP data BIB005 . SNPsea calculates linkage disequilibrium between involved genes and uses a sampling approach to determine conditions that are affected by these interactions.