Internal tandem duplication (ITD) of the FMS-like tyrosine kinase (FLT3) gene is associated with poor clinical outcomes in patients with acute myeloid leukemia. Although recent methods for detecting FLT3-ITD from next-generation sequencing (NGS) data have replaced traditional ITD detection approaches such as conventional PCR or fragment analysis, their use in the clinical field is still limited and requires further information. Here, we introduce ITDetect, an efficient FLT3-ITD detection approach that uses NGS data. Our proposed method allows for more precise detection and provides more detailed information than existing in silico methods. Further, it enables FLT3-ITD detection from exome sequencing or targeted panel sequencing data, thereby improving its clinical application. We validated the performance of ITDetect using NGS-based and experimental ITD detection methods and successfully demonstrated that ITDetect provides the highest concordance with the experimental methods. The program and data underlying this study are available in a public repository.

MOTIVATION: Pathway analyses have led to more insight into the underlying biological functions related to the phenotype of interest in various types of omics data. Pathway-based statistical approaches have been actively developed, but most of them do not consider correlations among pathways. Because it is well known that there are quite a few biomarkers that overlap between pathways, these approaches may provide misleading results. In addition, most pathway-based approaches tend to assume that biomarkers within a pathway have linear associations with the phenotype of interest, even though the relationships are more complex. RESULTS: To model complex effects including non-linear effects, we propose a new approach, Hierarchical structural CoMponent analysis using Kernel (HisCoM-Kernel). The proposed method models non-linear associations between biomarkers and phenotype by extending the kernel machine regression and analyzes entire pathways simultaneously by using the biomarker-pathway hierarchical structure. HisCoM-Kernel is a flexible model that can be applied to various omics data. It was successfully applied to three omics datasets generated by different technologies. Our simulation studies showed that HisCoM-Kernel provided higher statistical power than other existing pathway-based methods in all datasets. The application of HisCoM-Kernel to three types of omics dataset showed its superior performance compared to existing methods in identifying more biologically meaningful pathways, including those reported in previous studies. AVAILABILITY AND IMPLEMENTATION: The HisCoM-Kernel software is freely available at http://statgen.snu.ac.kr/software/HisCom-Kernel/. The RNA-seq data underlying this article are available at https://xena.ucsc.edu/, and the others will be shared on reasonable request to the corresponding author. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Drug repositioning reveals novel indications for existing drugs and in particular, diseases with no available drugs. Diverse computational drug repositioning methods have been proposed by measuring either drug-treated gene expression signatures or the proximity of drug targets and disease proteins found in prior networks. However, these methods do not explain which signaling subparts allow potential drugs to be selected, and do not consider polypharmacology, i.e. multiple targets of a known drug, in specific subparts. RESULTS: Here, to address the limitations, we developed a subpathway-based polypharmacology drug repositioning method, PATHOME-Drug, based on drug-associated transcriptomes. Specifically, this tool locates subparts of signaling cascading related to phenotype changes (e.g. disease status changes), and identifies existing approved drugs such that their multiple targets are enriched in the subparts. We show that our method demonstrated better performance for detecting signaling context and specific drugs/compounds, compared to WebGestalt and clusterProfiler, for both real biological and simulated datasets. We believe that our tool can successfully address the current shortage of targeted therapy agents. AVAILABILITY AND IMPLEMENTATION: The web-service is available at http://statgen.snu.ac.kr/software/pathome. The source codes and data are available at https://github.com/labnams/pathome-drug. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

To build up a state-of-the-art semantic scene segmentation model, a balanced combination between coarsely and finely contextual details is required for eliminating class-wise ambiguities and reaching high accuracy of pixel-wise labeling, respectively. Accordingly, with deep learning integration, prior works have achieved impressive performance in general, but found difficulties in correctly labeling medium to small objects. For the purpose of overcoming such issue, this paper proposes a deep convolutional network with bracket-style decoder, namely B-Net, to leverage the utilization of features learned at middle layers in the backbone networks (encoder) for constructing a final prediction map of densely enhanced semantic information. In particular, every feature map of interest combines with its adjacent version of higher spatial resolution through lateral connection modules to produce finer outputs that repeat such routine round-by-round until retrieving the finest-resolution map for dense prediction. Consequently, benchmarking results on CamVid dataset showed the effectiveness of the proposed method with mean class-wise accuracy, pixel-wise accuracy, and mean union intersection of 76.2%, 87.1%, and 66.4%, respectively.

Motivation: Despite the need for separate tools to analyze family-based data, there are only a handful of tools optimized for family-based big data compared to the number of tools available for analyzing population-based data. Results: ONETOOL implements the properties of well-known existing family data analysis tools and recently developed methods in a computationally efficient manner, and so is suitable for analyzing the vast amount of variant data available from sequencing family members, providing a rich choice of analysis methods for big data on families. Availability and implementation: ONETOOL is freely available from http://healthstat.snu.ac.kr/software/onetool/. Supplementary information: Supplementary data are available at Bioinformatics online.

BACKGROUND: Identification of multi-markers is one of the most challenging issues in personalized medicine era. Nowadays, many different types of omics data are generated from the same subject. Although many methods endeavor to identify candidate markers, for each type of omics data, few or none can facilitate such identification. RESULTS: It is well known that microRNAs affect phenotypes only indirectly, through regulating mRNA expression and/or protein translation. Toward addressing this issue, we suggest a hierarchical structured component analysis of microRNA-mRNA integration ("HisCoM-mimi") model that accounts for this biological relationship, to efficiently study and identify such integrated markers. In simulation studies, HisCoM-mimi showed the better performance than the other three methods. Also, in real data analysis, HisCoM-mimi successfully identified more gives more informative miRNA-mRNA integration sets relationships for pancreatic ductal adenocarcinoma (PDAC) diagnosis, compared to the other methods. CONCLUSION: As exemplified by an application to pancreatic cancer data, our proposed model effectively identified integrated miRNA/target mRNA pairs as markers for early diagnosis, providing a much broader biological interpretation.

BACKGROUND: As one possible solution to the "missing heritability" problem, many methods have been proposed that apply pathway-based analyses, using rare variants that are detected by next generation sequencing technology. However, while a number of methods for pathway-based rare-variant analysis of multiple phenotypes have been proposed, no method considers a unified model that incorporate multiple pathways. RESULTS: Simulation studies successfully demonstrated advantages of multivariate analysis, compared to univariate analysis, and comparison studies showed the proposed approach to outperform existing methods. Moreover, real data analysis of six type 2 diabetes-related traits, using large-scale whole exome sequencing data, identified significant pathways that were not found by univariate analysis. Furthermore, strong relationships between the identified pathways, and their associated metabolic disorder risk factors, were found via literature search, and one of the identified pathway, was successfully replicated by an analysis with an independent dataset. CONCLUSIONS: Herein, we present a powerful, pathway-based approach to investigate associations between multiple pathways and multiple phenotypes. By reflecting the natural hierarchy of biological behavior, and considering correlation between pathways and phenotypes, the proposed method is capable of analyzing multiple phenotypes and multiple pathways simultaneously.

This paper presents a novel background subtraction method that is flexible for various background scenarios. The method includes automated-directional masking (ADM) algorithm for adaptive background modeling and historical intensity pattern reference (HIPaR) algorithm for foreground segmentation. By selecting an appropriate mask in a set based on directional feature, ADM updates background smoothly and precisely following a boundary-based strategy with an intensity correction rule. In order to segment foreground, HIPaR refers intensity patterns of previous backgrounds and input frames and then compares their mean difference with a checking threshold to make foreground decision. Experimental results prove that our proposed ADM-HIPaR outperforms other state-of-the-art methods in terms of foreground detection accuracy.

This paper proposes a novel digital image water-marking method, namely SMLE, that allows to intelligently embed a gray-scale watermark image into a color host image in the wavelet domain. By decomposing a gray-scale image to binary images in digits ordering from Least Significant Bit (LSB) to Most Significant Bit (MSB), binary bits are efficiently embedded to optimal wavelet coefficient blocks using a quantization technique which encodes wavelet coefficient differences to either of two pre-identified thresholds for corresponding 0-bits or 1-bits. To boost visual quality, an embedding rule is improved by equal spreading coefficient adjustment on two middle-frequency sub-bands instead of only one as existing approaches. Additionally, 2D Otsu algorithm, more proficient than 1D Otsu algorithm for binary classification under attacking scenarios, is modified to flexibly calculate an optimal threshold for high-rate watermark extraction. According to experimental results, our proposed SMLE watermarking model produces remarkable impercepti-bility as well as high robustness against common digital image transformations and mostly does better than other existing methods at same payload rate.

MOTIVATION: To address 'missing heritability' issue, many statistical methods for pathway-based analyses using rare variants have been proposed to analyze pathways individually. However, neglecting correlations between multiple pathways can result in misleading solutions, and pathway-based analyses of large-scale genetic datasets require massive computational burden. We propose a Pathway-based approach using HierArchical components of collapsed RAre variants Of High-throughput sequencing data (PHARAOH) for the analysis of rare variants by constructing a single hierarchical model that consists of collapsed gene-level summaries and pathways and analyzes entire pathways simultaneously by imposing ridge-type penalties on both gene and pathway coefficient estimates; hence our method considers the correlation of pathways without constraint by a multiple testing problem. RESULTS: Through simulation studies, the proposed method was shown to have higher statistical power than the existing pathway-based methods. In addition, our method was applied to the large-scale whole-exome sequencing data with levels of a liver enzyme using two well-known pathway databases Biocarta and KEGG. This application demonstrated that our method not only identified associated pathways but also successfully detected biologically plausible pathways for a phenotype of interest. These findings were successfully replicated by an independent large-scale exome chip study. AVAILABILITY AND IMPLEMENTATION: An implementation of PHARAOH is available at http://statgen.snu.ac.kr/software/pharaoh/ CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

There is an increasing interest in the pathway analysis of multiple genes and complex traits in association studies. Recently, a number of methods of pathway analysis have been developed to detect the novel pathways associated with human complex traits. In this paper, we propose a novel statistical approach for competitive pathway analysis based on Structural Equation Modeling (CPA-SEM), taking advantage of prior knowledge on existing relationships between genes in a pathway. Our CPA-SEM identifies pathways associated with traits of interest. The CPA-SEM approach is different from the previous SEM-based approaches in that it considers all possible sub-pathways into account and performs permutation based robust analysis. We applied the proposed CPA-SEM method to gene expression data of gastric cancer (GSE27342), and found that mTOR signaling pathway was significantly associated with gastric cancer. This pathway has previously been reported to be associated with gastric cancer. In conclusion, our CPA-SEM analysis provides a better understanding of biological mechanism by identifying pathways associated with a trait of interest.

An important issue in genetic association studies is gene-gene interaction (epistasis) underlying common complex diseases that are affected by multiple genetic factors. Although many methods have been proposed to analyze epistasis, the interpretation of the identified gene-gene interactions is not straightforward. In order to efficiently provide the statistical interpretation and biological evidences of gene-gene interactions, we developed the VizEpis, a tool for visualizing of gene-gene interactions in genetic association analysis and mapping of epistatic interaction to the biological evidence from public interaction databases. Using interaction network and circular plot, the VizEpis provides to explore the interaction network integrated with biological evidences in epigenetic regulation, splicing, transcription, translation and post-translation level. To aid statistical interaction in genotype level, the VizEpis provides pairwise checkerboard, forest, and funnel. VizEpis provides for the user-specified variants with statistical interaction to find biological evidences.

BACKGROUND: Many disease phenotypes are outcomes of the complicated interplay between multiple genes, and multiple phenotypes are affected by a single or multiple genotypes. Therefore, joint analysis of multiple phenotypes and multiple markers has been considered as an efficient strategy for genome-wide association analysis, and in this work we propose an omnibus family-based association test for the joint analysis of multiple genotypes and multiple phenotypes. RESULTS: The proposed test can be applied for both quantitative and dichotomous phenotypes, and it is robust under the presence of population substructure, as long as large-scale genomic data is available. Using simulated data, we showed that our method is statistically more efficient than the existing methods, and the practical relevance is illustrated by application of the approach to obesity-related phenotypes. CONCLUSIONS: The proposed method may be more statistically efficient than the existing methods. The application was developed in C++ and is available at the following URL: http://healthstat.snu.ac.kr/software/mfqls/ .

This paper introduces an accurate and robust facial expression recognition (FER) system. For feature extraction, the proposed FER system employs stepwise linear discriminant analysis (SWLDA). SWLDA focuses on selecting the localized features from the expression frames using the partial F-test values, thereby reducing the within class variance and increasing the low between variance among different expression classes. For recognition, the hidden conditional random fields (HCRFs) model is utilized. HCRF is capable of approximating a complex distribution using a mixture of Gaussian density functions. To achieve optimum results, the system employs a hierarchical recognition strategy. Under these settings, expressions are divided into three categories based on parts of the face that contribute most toward an expression. During recognition, at the first level, SWLDA and HCRF are employed to recognize the expression category; whereas, at the second level, the label for the expression within the recognized category is determined using a separate set of SWLDA and HCRF, trained just for that category. In order to validate the system, four publicly available data sets were used, and a total of four experiments were performed. The weighted average recognition rate for the proposed FER approach was 96.37% across the four different data sets, which is a significant improvement in contrast to the existing FER methods.

MOTIVATION: Individuals in each family are genetically more homogeneous than unrelated individuals, and family-based designs are often recommended for the analysis of rare variants. However, despite the importance of family-based samples analysis, few statistical methods for rare variant association analysis are available. RESULTS: In this report, we propose a FAmily-based Rare Variant Association Test (FARVAT). FARVAT is based on the quasi-likelihood of whole families, and is statistically and computationally efficient for the extended families. FARVAT assumed that families were ascertained with the disease status of family members, and incorporation of the estimated genetic relationship matrix to the proposed method provided robustness under the presence of the population substructure. Depending on the choice of working matrix, our method could be a burden test or a variance component test, and could be extended to the SKAT-O-type statistic. FARVAT was implemented in C++, and application of the proposed method to schizophrenia data and simulated data for GAW17 illustrated its practical importance. AVAILABILITY: The software calculates various statistics for the analysis of related samples, and it is freely downloadable from http://healthstats.snu.ac.kr/software/farvat. CONTACT: [email protected] or [email protected] SUPPLEMENTARY INFORMATION: supplementary data are available at Bioinformatics online.

To provide robust healthcare services and personalized recommendations details relating to a patient's daily life activities, profile information, and personal experience is of vital importance. This paper focuses on improvement in general health status of elderly patients through the use of an innovative service which align dietary intake with activity information. Personalized healthcare services based on the patient's activities of daily living and their shared experience, are provided as outputs. A knowledge driven approach has been used where all the daily life activities, social interactions, and profile information are modeled in an ontology. The semantic context is exploited that enables fine-grained situation analysis for recommendation of personalized services and decision support. Preliminary experimental results for the dynamic nature of the systems and its corresponding personalized recommendations have been found to be encouraging.