Whole-exome sequencing (WES) has become a standard method for detecting genetic variants in human diseases. Although the primary use of WES data has been the identification of single nucleotide variations and indels, these data also offer a possibility of detecting copy number variations (CNVs) at high resolution. However, WES data have uneven read coverage along the genome owing to the target capture step, and the development of a robust WES-based CNV tool is challenging. Here, we evaluate six WES somatic CNV detection tools: ADTEx, CONTRA, Control-FREEC, EXCAVATOR, ExomeCNV and Varscan2. Using WES data from 50 kidney chromophobe, 50 bladder urothelial carcinoma, and 50 stomach adenocarcinoma patients from The Cancer Genome Atlas, we compared the CNV calls from the six tools with a reference CNV set that was identified by both single nucleotide polymorphism array 6.0 and whole-genome sequencing data. We found that these algorithms gave highly variable results: visual inspection reveals significant differences between the WES-based segmentation profiles and the reference profile, as well as among the WES-based profiles. Using a 50% overlap criterion, 13-77% of WES CNV calls were covered by CNVs from the reference set, up to 21% of the copy gains were called as losses or vice versa, and dramatic differences in CNV sizes and CNV numbers were observed. Overall, ADTEx and EXCAVATOR had the best performance with relatively high precision and sensitivity. We suggest that the current algorithms for somatic CNV detection from WES data are limited in their performance and that more robust algorithms are needed.

OBJECTIVE: Cancer can involve gene dysregulation via multiple mechanisms, so no single level of genomic data fully elucidates tumor behavior due to the presence of numerous genomic variations within or between levels in a biological system. We have previously proposed a graph-based integration approach that combines multi-omics data including copy number alteration, methylation, miRNA, and gene expression data for predicting clinical outcome in cancer. However, genomic features likely interact with other genomic features in complex signaling or regulatory networks, since cancer is caused by alterations in pathways or complete processes. METHODS: Here we propose a new graph-based framework for integrating multi-omics data and genomic knowledge to improve power in predicting clinical outcomes and elucidate interplay between different levels. To highlight the validity of our proposed framework, we used an ovarian cancer dataset from The Cancer Genome Atlas for predicting stage, grade, and survival outcomes. RESULTS: Integrating multi-omics data with genomic knowledge to construct pre-defined features resulted in higher performance in clinical outcome prediction and higher stability. For the grade outcome, the model with gene expression data produced an area under the receiver operating characteristic curve (AUC) of 0.7866. However, models of the integration with pathway, Gene Ontology, chromosomal gene set, and motif gene set consistently outperformed the model with genomic data only, attaining AUCs of 0.7873, 0.8433, 0.8254, and 0.8179, respectively. CONCLUSIONS: Integrating multi-omics data and genomic knowledge to improve understanding of molecular pathogenesis and underlying biology in cancer should improve diagnostic and prognostic indicators and the effectiveness of therapies.

OBJECTIVE: DNA methylation, a regulator of gene expression, plays an important role in diverse biological processes including developmental process, carcinogenesis and aging. In particular, aberrant DNA methylation has been largely observed in several types of cancers. Currently, it is important to extract disease-specific gene sets associated with the regulation of DNA methylation. MATERIALS AND METHODS: Here we propose a novel approach to find the minimum regulatory units of genes, co-methylated and co-expressed gene pairs (MEGP) that are highly correlated gene pairs between DNA methylation and gene expression showing the co-regulatory relationship. To evaluate whether our method is applicable to extract disease-associated genes, we applied our method to a large-scale dataset from the Cancer Genome Atlas extracting significantly associated MEGP and analyzed their functional correlation. RESULTS: We observed that many MEGP physically interacted with each other and showed high semantic similarity with gene ontology terms. Furthermore, we performed gene set enrichment tests to identify how they are correlated in a complex biological process. Our MEGP were highly enriched in the biological pathway associated with ovarian cancers. CONCLUSIONS: Our approach is useful for discovering coordinated epigenetic markers associated with specific diseases.

BACKGROUND: Biclustering has been utilized to find functionally important patterns in biological problem. Here a bicluster is a submatrix that consists of a subset of rows and a subset of columns in a matrix, and contains homogeneous patterns. The problem of finding biclusters is still challengeable due to computational complex trying to capture patterns from two-dimensional features. RESULTS: We propose a Probabilistic COevolutionary Biclustering Algorithm (PCOBA) that can cluster the rows and columns in a matrix simultaneously by utilizing a dynamic adaptation of multiple species and adopting probabilistic learning. In biclustering problems, a coevolutionary search is suitable since it can optimize interdependent subcomponents formed of rows and columns. Furthermore, acquiring statistical information on two populations using probabilistic learning can improve the ability of search towards the optimum value. We evaluated the performance of PCOBA on synthetic dataset and yeast expression profiles. The results demonstrated that PCOBA outperformed previous evolutionary computation methods as well as other biclustering methods. CONCLUSIONS: Our approach for searching particular biological patterns could be valuable for systematically understanding functional relationships between genes and other biological components at a genome-wide level.

BACKGROUND: Clustering-based methods on gene-expression analysis have been shown to be useful in biomedical applications such as cancer subtype discovery. Among them, Matrix factorization (MF) is advantageous for clustering gene expression patterns from DNA microarray experiments, as it efficiently reduces the dimension of gene expression data. Although several MF methods have been proposed for clustering gene expression patterns, a systematic evaluation has not been reported yet. RESULTS: Here we evaluated the clustering performance of orthogonal and non-orthogonal MFs by a total of nine measurements for performance in four gene expression datasets and one well-known dataset for clustering. Specifically, we employed a non-orthogonal MF algorithm, BSNMF (Bi-directional Sparse Non-negative Matrix Factorization), that applies bi-directional sparseness constraints superimposed on non-negative constraints, comprising a few dominantly co-expressed genes and samples together. Non-orthogonal MFs tended to show better clustering-quality and prediction-accuracy indices than orthogonal MFs as well as a traditional method, K-means. Moreover, BSNMF showed improved performance in these measurements. Non-orthogonal MFs including BSNMF showed also good performance in the functional enrichment test using Gene Ontology terms and biological pathways. CONCLUSIONS: In conclusion, the clustering performance of orthogonal and non-orthogonal MFs was appropriately evaluated for clustering microarray data by comprehensive measurements. This study showed that non-orthogonal MFs have better performance than orthogonal MFs and K-means for clustering microarray data.

MOTIVATION: MicroRNAs miRNAs play important roles in gene regulation and are regarded as key components in gene regulatory pathways. Systematically understanding functional roles of miRNAs is essential to define core transcriptional units regulating key biological processes. Here, we propose a method based on the probabilistic graphical model to identify the regulatory modules of miRNAs and the core regulatory motifs involved in their ability to regulate gene expression. RESULTS: We applied our method to datasets of different sources from Arabidopsis consisting of miRNA-target pair information, upstream sequences of miRNAs, transcriptional regulatory motifs and gene expression profiles. The graphical model used in this study can efficiently capture the relationship between miRNAs and diverse conditions such as various developmental processes, thus allowing us to detect functionally correlated miRNA regulatory modules involved in specific biological processes. Furthermore, this approach can reveal core transcriptional elements associated with their miRNAs. The proposed method found clusters of miRNAs, as well as putative regulators controlling the expression of miRNAs, which were highly related to diverse developmental processes of Arabidopsis. Consequently, our method can provide hypothetical miRNA regulatory circuits for functional testing that represent transcriptional events of miRNAs and transcriptional factors involved in gene regulatory pathways.

BACKGROUND: MicroRNAs (miRNAs) are small and noncoding RNAs that play important roles in various biological processes. They regulate target mRNAs post-transcriptionally through complementary base pairing. Since the changes of miRNAs affect the expression of target genes, the expression levels of target genes in specific biological processes could be different from those of non-target genes. Here we demonstrate that gene expression profiles contain useful information in separating miRNA targets from non-targets. RESULTS: The gene expression profiles related to various developmental processes and stresses, as well as the sequences of miRNAs and mRNAs in Arabidopsis, were used to determine whether a given gene is a miRNA target. It is based on the model combining the support vector machine (SVM) classifier and the scoring method based on complementary base pairing between miRNAs and mRNAs. The proposed model yielded low false positive rate and retrieved condition-specific candidate targets through a genome-wide screening. CONCLUSION: Our approach provides a novel framework into screening target genes by considering the gene regulation of miRNAs. It can be broadly applied to identify condition-specific targets computationally by embedding information of gene expression profiles.

MOTIVATION: MicroRNAs (miRNAs) and mRNAs constitute an important part of gene regulatory networks, influencing diverse biological phenomena. Elucidating closely related miRNAs and mRNAs can be an essential first step towards the discovery of their combinatorial effects on different cellular states. Here, we propose a probabilistic learning method to identify synergistic miRNAs involving regulation of their condition-specific target genes (mRNAs) from multiple information sources, i.e. computationally predicted target genes of miRNAs and their respective expression profiles. RESULTS: We used data sets consisting of miRNA-target gene binding information and expression profiles of miRNAs and mRNAs on human cancer samples. Our method allowed us to detect functionally correlated miRNA-mRNA modules involved in specific biological processes from multiple data sources by using a balanced fitness function and efficient searching over multiple populations. The proposed algorithm found two miRNA-mRNA modules, highly correlated with respect to their expression and biological function. Moreover, the mRNAs included in the same module showed much higher correlations when the related miRNAs were highly expressed, demonstrating our method's ability for finding coherent miRNA-mRNA modules. Most members of these modules have been reported to be closely related with cancer. Consequently, our method can provide a primary source of miRNA and target sets presumed to constitute closely related parts of gene regulatory pathways.

MOTIVATION: An important issue in stem cell biology is to understand how to direct differentiation towards a specific cell type. To elucidate the mechanism, previous studies have focused on identifying the responsible gene regulators, which have, however, failed to provide a systemic view of regulatory modules. To obtain a unified description of the regulatory modules, we characterized major stem cell species by employing a co-clustering latent variable model (LVM). The LVM-based method allowed us to elucidate the cell type-specific transcription factors, using genomic sequences as well as expression profiles. RESULTS: We used a list of genes enriched in each of 21 stem cell subpopulations, and their upstream genomic sequences. The LVM-based study allowed us to uncover the regulatory modules for each stem cell cluster, e.g. GABP and E2F for the proliferation phase, and Ap2alpha and Ap2gamma for the quiescence phase. Furthermore, the identities of the stem cell clusters were well revealed by the constituent genes that were directly targeted by the modules. Consequently, our analytical framework was demonstrated to be useful through a detailed case study of stem cell differentiation and can be applied to problems with similar characteristics.

BACKGROUND: To infer the tree of life requires knowledge of the common characteristics of each species descended from a common ancestor as the measuring criteria and a method to calculate the distance between the resulting values of each measure. Conventional phylogenetic analysis based on genomic sequences provides information about the genetic relationships between different organisms. In contrast, comparative analysis of metabolic pathways in different organisms can yield insights into their functional relationships under different physiological conditions. However, evaluating the similarities or differences between metabolic networks is a computationally challenging problem, and systematic methods of doing this are desirable. Here we introduce a graph-kernel method for computing the similarity between metabolic networks in polynomial time, and use it to profile metabolic pathways and to construct phylogenetic trees. RESULTS: To compare the structures of metabolic networks in organisms, we adopted the exponential graph kernel, which is a kernel-based approach with a labeled graph that includes a label matrix and an adjacency matrix. To construct the phylogenetic trees, we used an unweighted pair-group method with arithmetic mean, i.e., a hierarchical clustering algorithm. We applied the kernel-based network profiling method in a comparative analysis of nine carbohydrate metabolic networks from 81 biological species encompassing Archaea, Eukaryota, and Eubacteria. The resulting phylogenetic hierarchies generally support the tripartite scheme of three domains rather than the two domains of prokaryotes and eukaryotes. CONCLUSION: By combining the kernel machines with metabolic information, the method infers the context of biosphere development that covers physiological events required for adaptation by genetic reconstruction. The results show that one may obtain a global view of the tree of life by comparing the metabolic pathway structures using meta-level information rather than sequence information. This method may yield further information about biological evolution, such as the history of horizontal transfer of each gene, by studying the detailed structure of the phylogenetic tree constructed by the kernel-based method.

Committee machines are known to improve generalization performance by combining the predictions of many different individual learners. Evolutionary algorithms generate multiple models that can be combined to build a committee machine. This paper uses Bayesian evolutionary algorithms (BEAs) as a solution to evolve individual learners and build a committee machine. BEAs are based on the Bayesian evolutionary framework in which evolutionary computation is the process of repeatedly updating the posterior distribution of a population to find an individual with the maximum posteriori probability. BEAs evolve the number of centroids and the centroids' positions and widths for radial basis function (RBF) networks which are individual learners, and then the algorithms find an optimal committee from many different individuals. Empirical results show the machine's convergence characteristics and accuracy.

Evolutionary neural trees (ENTs) are tree-structured neural networks constructed by evolutionary algorithms. We use ENTs to build predictive models of time series data. Time series data are typically characterized by dynamics of the underlying process and thus the robustness of predictions is crucial. We describe a method for making more robust predictions by building committees of ENTs, i.e. CENTs. The method extends the concept of mixing genetic programming (MGP) which makes use of the fact that evolutionary computation produces multiple models as output instead of just one best. Experiments have been performed on the laser time series in which the CENTs outperformed the single best ENTs. We also discuss a theoretical foundation of CENTs using the Bayesian framework for evolutionary computation.