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Background The stability of protein sequence structure plays an important role in the prevention and treatment of diseases. Results In this paper, particle swarm optimization and tabu search are combined to propose a new method for protein structure prediction. The experimental results show that: for four groups of artificial protein sequences with different lengths, this method obtains the lowest potential energy value and stable structure prediction results, and the effect is obviously better than the other two comparison methods. Taking the first group of protein sequences as an example, our method improves the prediction of minimum potential energy by 127% and 7% respectively. Conclusions Therefore, the method proposed in this paper is more suitable for the prediction of protein structural stability.

BackgroundOver the past few decades, the emergence and maturation of new technologies have substantially reduced the cost of genome sequencing. As a result, the amount of genomic data that needs to be stored and transmitted has grown exponentially. For the standard sequencing data format, FASTQ, compression of the quality score is a key and difficult aspect of FASTQ file compression. Throughout the literature, we found that the majority of the current quality score compression methods do not support random access. Based on the above consideration, it is reasonable to investigate a lossless quality score compressor with a high compression rate, a fast compression and decompression speed, and support for random access.ResultsIn this paper, we propose CMIC, an adaptive and random access supported compressor for lossless compression of quality score sequences. CMIC is an acronym of the four steps (classification, mapping, indexing and compression) in the paper. Its framework consists of the following four parts: classification, mapping, indexing, and compression. The experimental results show that our compressor has good performance in terms of compression rates on all the tested datasets. The file sizes are reduced by up to 21.91% when compared with LCQS. In terms of compression speed, CMIC is better than all other compressors on most of the tested cases. In terms of random access speed, the CMIC is faster than the LCQS, which provides a random access function for compressed quality scores.ConclusionsCMIC is a compressor that is especially designed for quality score sequences, which has good performance in terms of compression rate, compression speed, decompression speed, and random access speed. The CMIC can be obtained in the following way:https://github.com/Humonex/Cmic.

Background Gene co-expression networks (GCNs) are not easily comparable due to their complex structure. In this paper, we propose a tool, Juxtapose, together with similarity measures that can be utilized for comparative transcriptomics between a set of organisms. While we focus on its application to comparing co-expression networks across species in evolutionary studies, Juxtapose is also generalizable to co-expression network comparisons across tissues or conditions within the same species. Methods A word embedding strategy commonly used in natural language processing was utilized in order to generate gene embeddings based on walks made throughout the GCNs. Juxtapose was evaluated based on its ability to embed the nodes of synthetic structures in the networks consistently while also generating biologically informative results. Evaluation of the techniques proposed in this research utilized RNA-seq datasets from GTEx, a multi-species experiment of prefrontal cortex samples from the Gene Expression Omnibus, as well as synthesized datasets. Biological evaluation was performed using gene set enrichment analysis and known gene relationships in literature. Results We show that Juxtapose is capable of globally aligning synthesized networks as well as identifying areas that are conserved in real gene co-expression networks without reliance on external biological information. Furthermore, output from a matching algorithm that uses cosine distance between GCN embeddings is shown to be an informative measure of similarity that reflects the amount of topological similarity between networks. Conclusions Juxtapose can be used to align GCNs without relying on known biological similarities and enables post-hoc analyses using biological parameters, such as orthology of genes, or conserved or variable pathways. Availability A development version of the software used in this paper is available at https://github.com/klovens/juxtapose

BackgroundBioimaging techniques offer a robust tool for studying molecular pathways and morphological phenotypes of cell populations subjected to various conditions. As modern high resolution 3D microscopy provides access to an ever-increasing amount of high quality images, there arises a need for their analysis in an automated, unbiased and simple way.Segmentation of structures within cell nucleus, which is the focus of this paper, presents a new layer of complexity in the form of dense packing and significant signal overlap.At the same time the available segmentation tools provide a steep learning curve for new users with limited technical background. This is especially apparent in bulk processing of image sets, which requires the use of some form of programming notation.ResultsIn this paper, we present PartSeg, a tool for segmentation and reconstruction of 3D microscopy images, optimised for the study of cell nucleus. PartSeg integrates refined versions of several state-of-the-art algorithms, including a new multi-scale approach for segmentation and quantitative analysis of 3D microscopy images.The features and user-friendly interface of PartSeg were carefully planned with biologists in mind, based on analysis of multiple use cases and difficulties encountered with other tools, to offer ergonomic interface with a minimal entry barrier. Bulk processing in an ad-hoc manner is possible without the need for programmer support. As the size of datasets of interest grows, such bulk processing solutions become essential for proper statistical analysis of results.Advanced users can use PartSeg components as a library within Python data processing and visualisation pipelines, for example within Jupyter notebooks. The tool is extensible so that new functionality and algorithms can be added by the use of plugins.For biologists the utility of PartSeg is presented in several scenarios, showing the quantitative analysis of nuclear structures.ConclusionsIn this paper, we have presented PartSeg which is a tool for precise and verifiable segmentation and reconstruction of 3D microscopy images. PartSeg is optimised for cell nucleus analysis and offers multiscale segmentation algorithms best-suited for this task. PartSeg can also be used for bulk processing of multiple images and its components can be reused in other systems or computational experiments.Contactg.bokota@cent.uw.edu.pl, a.magalska@nencki.edu.pl, d.plewczynski@cent.uw.edu.pl

BackgroundProtein-protein interactions(PPIs) engage in dynamic pathological and biological procedures constantly in our life. Thus, it is crucial to comprehend the PPIs thoroughly such that we are able to illuminate the disease occurrence, achieve the optimal drug-target therapeutic effect and describe the protein complex structures. However, compared to the protein sequences obtainable from various species and organisms, the number of revealed protein-protein interactions is relatively limited. To address this dilemma, lots of research endeavor have investigated in it to facilitate the discovery of novel PPIs. Among these methods, PPI prediction techniques that merely rely on protein sequence data are more widespread than other methods which require extensive biological domain knowledge.ResultsIn this paper, we propose a multi-modal deep representation learning structure by incorporating protein physicochemical features with the graph topological features from the PPI networks. Specifically, our method not only bears in mind the protein sequence information but also discerns the topological representations for each protein node in the PPI networks. In our paper, we construct a stacked auto-encoder architecture together with a continuous bag-of-words (CBOW) model based on generated metapaths to study the PPI predictions. Following by that, we utilize the supervised deep neural networks to identify the PPIs and classify the protein families. The PPI prediction accuracy for eight species ranged from 96.76% to 99.77%, which signifies that our multi-modal deep representation learning framework achieves superior performance compared to other computational methods.ConclusionTo the best of our knowledge, this is the first multi-modal deep representation learning framework for examining the PPI networks.

Background During procedures for conducting multiple sequence alignment, that is so essential to use the substitution score of pairwise alignment. To compute adaptive scores for alignment, researchers usually use Hidden Markov Model or probabilistic consistency methods such as partition function. Recent studies show that optimizing the parameters for hidden Markov model, as well as integrating hidden Markov model with partition function can raise the accuracy of alignment. The combination of partition function and optimized HMM, which could further improve the alignment’s accuracy, however, was ignored by these researches. Results A novel algorithm for MSA called ProbPFP is presented in this paper. It intergrate optimized HMM by particle swarm with partition function. The algorithm of PSO was applied to optimize HMM’s parameters. After that, the posterior probability obtained by the HMM was combined with the one obtained by partition function, and thus to calculate an integrated substitution score for alignment. In order to evaluate the effectiveness of ProbPFP, we compared it with 13 outstanding or classic MSA methods. The results demonstrate that the alignments obtained by ProbPFP got the maximum mean TC scores and mean SP scores on these two benchmark datasets: SABmark and OXBench, and it got the second highest mean TC scores and mean SP scores on the benchmark dataset BAliBASE. ProbPFP is also compared with 4 other outstanding methods, by reconstructing the phylogenetic trees for six protein families extracted from the database TreeFam, based on the alignments obtained by these 5 methods. The result indicates that the reference trees are closer to the phylogenetic trees reconstructed from the alignments obtained by ProbPFP than the other methods. Conclusions We propose a new multiple sequence alignment method combining optimized HMM and partition function in this paper. The performance validates this method could make a great improvement of the alignment’s accuracy.

Background Collective cell migration is a significant and complex phenomenon that affects many basic biological processes. The coordination between leader cell and follower cell affects the rate of collective cell migration. However, there are still very few papers on the impacts of the stimulus signal released by the leader on the follower. Tracking cell movement using 3D time-lapse microscopy images provides an unprecedented opportunity to systematically study and analyze collective cell migration. Results Recently, deep reinforcement learning algorithms have become very popular. In our paper, we also use this method to train the number of cells and control signals. By experimenting with single-follower cell and multi-follower cells, it is concluded that the number of stimulation signals is proportional to the rate of collective movement of the cells. Such research provides a more diverse approach and approach to studying biological problems. Conclusion Traditional research methods are always based on real-life scenarios, but as the number of cells grows exponentially, the research process is too time consuming. Agent-based modeling is a robust framework that approximates cells to isotropic, elastic, and sticky objects. In this paper, an agent-based modeling framework is used to establish a simulation platform for simulating collective cell migration. The goal of the platform is to build a biomimetic environment to demonstrate the importance of stimuli between the leading and following cells.

Background Deep learning techniques have been successfully applied to bioimaging problems; however, these methods are highly data demanding. An approach to deal with the lack of data and avoid overfitting is the application of data augmentation, a technique that generates new training samples from the original dataset by applying different kinds of transformations. Several tools exist to apply data augmentation in the context of image classification, but it does not exist a similar tool for the problems of localization, detection, semantic segmentation or instance segmentation that works not only with 2 dimensional images but also with multi-dimensional images (such as stacks or videos). Results In this paper, we present a generic strategy that can be applied to automatically augment a dataset of images, or multi-dimensional images, devoted to classification, localization, detection, semantic segmentation or instance segmentation. The augmentation method presented in this paper has been implemented in the open-source package CLoDSA. To prove the benefits of using CLoDSA, we have employed this library to improve the accuracy of models for Malaria parasite classification, stomata detection, and automatic segmentation of neural structures. Conclusions CLoDSA is the first, at least up to the best of our knowledge, image augmentation library for object classification, localization, detection, semantic segmentation, and instance segmentation that works not only with 2 dimensional images but also with multi-dimensional images.

Background Fast and accurate automatic segmentation of skeletal muscle cell image is crucial for the diagnosis of muscle related diseases, which extremely reduces the labor-intensive manual annotation. Recently, several methods have been presented for automatic muscle cell segmentation. However, most methods exhibit high model complexity and time cost, and they are not adaptive to large-scale images such as whole-slide scanned specimens. Methods In this paper, we propose a novel distributed computing approach, which adopts both data and model parallel, for fast muscle cell segmentation. With a master-worker parallelism manner, the image data in the master is distributed onto multiple workers based on the Spark cloud computing platform. On each worker node, we first detect cell contours using a structured random forest (SRF) contour detector with fast parallel prediction and generate region candidates using a superpixel technique. Next, we propose a novel hierarchical tree based region selection algorithm for cell segmentation based on the conditional random field (CRF) algorithm. We divide the region selection algorithm into multiple sub-problems, which can be further parallelized using multi-core programming. Results We test the performance of the proposed method on a large-scale haematoxylin and eosin (H &E) stained skeletal muscle image dataset. Compared with the standalone implementation, the proposed method achieves more than 10 times speed improvement on very large-scale muscle images containing hundreds to thousands of cells. Meanwhile, our proposed method produces high-quality segmentation results compared with several state-of-the-art methods. Conclusions This paper presents a parallel muscle image segmentation method with both data and model parallelism on multiple machines. The parallel strategy exhibits high compatibility to our muscle segmentation framework. The proposed method achieves high-throughput effective cell segmentation on large-scale muscle images.

Background Long reads provide valuable information regarding the sequence composition of genomes. Long reads are usually very noisy which renders their alignments on the reference genome a daunting task. It may take days to process datasets enough to sequence a human genome on a single node. Hence, it is of primary importance to have an aligner which can operate on distributed clusters of computers with high performance in accuracy and speed. Results In this paper, we presented IMOS, an aligner for mapping noisy long reads to the reference genome. It can be used on a single node as well as on distributed nodes. In its single-node mode, IMOS is an Improved version of Meta-aligner (IM) enhancing both its accuracy and speed. IM is up to 6x faster than the original Meta-aligner. It is also implemented to run IM and Minimap2 on Apache Spark for deploying on a cluster of nodes. Moreover, multi-node IMOS is faster than SparkBWA while executing both IM (1.5x) and Minimap2 (25x). Conclusion In this paper, we purposed an architecture for mapping long reads to a reference. Due to its implementation, IMOS speed can increase almost linearly with respect to the number of nodes in a cluster. Also, it is a multi-platform application able to operate on Linux, Windows, and macOS.

Background Recently, Pereira Zanetti, Biller and Meidanis have proposed a new definition of a rearrangement distance between genomes. In this formulation, each genome is represented as a matrix, and the distance d is the rank distance between these matrices. Although defined in terms of matrices, the rank distance is equal to the minimum total weight of a series of weighted operations that leads from one genome to the other, including inversions, translocations, transpositions, and others. The computational complexity of the median-of-three problem according to this distance is currently unknown. The genome matrices are a special kind of permutation matrices, which we study in this paper. In their paper, the authors provide an \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$O\left (n^{3}\right)$\end{document}On3 algorithm for determining three candidate medians, prove the tight approximation ratio \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\frac {4}{3}$\end{document}43, and provide a sufficient condition for their candidates to be true medians. They also conduct some experiments that suggest that their method is accurate on simulated and real data. Results In this paper, we extend their results and provide the following: Three invariants characterizing the problem of finding the median of 3 matricesA sufficient condition for uniqueness of medians that can be checked in O(n)A faster, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$O\left (n^{2}\right)$\end{document}On2 algorithm for determining the median under this conditionA new heuristic algorithm for this problem based on compressed sensingA \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$O\left (n^{4}\right)$\end{document}On4 algorithm that exactly solves the problem when the inputs are orthogonal matrices, a class that includes both permutations and genomes as special cases. Conclusions Our work provides the first proof that, with respect to the rank distance, the problem of finding the median of 3 genomes, as well as the median of 3 permutations, is exactly solvable in polynomial time, a result which should be contrasted with its NP-hardness for the DCJ (double cut-and-join) distance and most other families of genome rearrangement operations. This result, backed by our experimental tests, indicates that the rank distance is a viable alternative to the DCJ distance widely used in genome comparisons. Electronic supplementary material The online version of this article (10.1186/s12859-018-2131-4) contains supplementary material, which is available to authorized users.

Background The primary goal of pathway analysis using transcriptome data is to find significantly perturbed pathways. However, pathway analysis is not always successful in identifying pathways that are truly relevant to the context under study. A major reason for this difficulty is that a single gene is involved in multiple pathways. In the KEGG pathway database, there are 146 genes, each of which is involved in more than 20 pathways. Thus activation of even a single gene will result in activation of many pathways. This complex relationship often makes the pathway analysis very difficult. While we need much more powerful pathway analysis methods, a readily available alternative way is to incorporate the literature information. Results In this study, we propose a novel approach for prioritizing pathways by combining results from both pathway analysis tools and literature information. The basic idea is as follows. Whenever there are enough articles that provide evidence on which pathways are relevant to the context, we can be assured that the pathways are indeed related to the context, which is termed as relevance in this paper. However, if there are few or no articles reported, then we should rely on the results from the pathway analysis tools, which is termed as significance in this paper. We realized this concept as an algorithm by introducing Context Score and Impact Score and then combining the two into a single score. Our method ranked truly relevant pathways significantly higher than existing pathway analysis tools in experiments with two data sets. Conclusions Our novel framework was implemented as ContextTRAP by utilizing two existing tools, TRAP and BEST. ContextTRAP will be a useful tool for the pathway based analysis of gene expression data since the user can specify the context of the biological experiment in a set of keywords. The web version of ContextTRAP is available at http://biohealth.snu.ac.kr/software/contextTRAP. Electronic supplementary material The online version of this article (doi:10.1186/s12859-016-1335-8) contains supplementary material, which is available to authorized users.

Background Mass spectrometry (MS) is producing high volumes of data supporting oncological sciences, especially for translational research. Most of related elaborations can be carried out by combining existing tools at different levels, but little is currently available for the automation of the fundamental steps. For the analysis of MALDI/TOF spectra, a number of pre-processing steps are required, including joining of isotopic abundances for a given molecular species, normalization of signals against an internal standard, background noise removal, averaging multiple spectra from the same sample, and aligning spectra from different samples. In this paper, we present Geena 2, a public software tool for the automated execution of these pre-processing steps for MALDI/TOF spectra. Results Geena 2 has been developed in a Linux-Apache-MySQL-PHP web development environment, with scripts in PHP and Perl. Input and output are managed as simple formats that can be consumed by any database system and spreadsheet software. Input data may also be stored in a MySQL database. Processing methods are based on original heuristic algorithms which are introduced in the paper. Three simple and intuitive web interfaces are available: the Standard Search Interface, which allows a complete control over all parameters, the Bright Search Interface, which leaves to the user the possibility to tune parameters for alignment of spectra, and the Quick Search Interface, which limits the number of parameters to a minimum by using default values for the majority of parameters. Geena 2 has been utilized, in conjunction with a statistical analysis tool, in three published experimental works: a proteomic study on the effects of long-term cryopreservation on the low molecular weight fraction of serum proteome, and two retrospective serum proteomic studies, one on the risk of developing breat cancer in patients affected by gross cystic disease of the breast (GCDB) and the other for the identification of a predictor of breast cancer mortality following breast cancer surgery, whose results were validated by ELISA, a completely alternative method. Conclusions Geena 2 is a public tool for the automated pre-processing of MS data originated by MALDI/TOF instruments, with a simple and intuitive web interface. It is now under active development for the inclusion of further filtering options and for the adoption of standard formats for MS spectra. Electronic supplementary material The online version of this article (doi:10.1186/s12859-016-0911-2) contains supplementary material, which is available to authorized users.

Background Accurate annotation of protein function is the key to understanding life at the molecular level and has great implications for biomedicine and pharmaceuticals. The rapid developments of high-throughput technologies have generated huge amounts of protein–protein interaction (PPI) data, which prompts the emergence of computational methods to determine protein function. Plagued by errors and noises hidden in PPI data, these computational methods have undertaken to focus on the prediction of functions by integrating the topology of protein interaction networks and multi-source biological data. Despite effective improvement of these computational methods, it is still challenging to build a suitable network model for integrating multiplex biological data. Results In this paper, we constructed a heterogeneous biological network by initially integrating original protein interaction networks, protein-domain association data and protein complexes. To prove the effectiveness of the heterogeneous biological network, we applied the propagation algorithm on this network, and proposed a novel iterative model, named Propagate on Heterogeneous Biological Networks (PHN) to score and rank functions in descending order from all functional partners, Finally, we picked out top L of these predicted functions as candidates to annotate the target protein. Our comprehensive experimental results demonstrated that PHN outperformed seven other competing approaches using cross-validation. Experimental results indicated that PHN performs significantly better than competing methods and improves the Area Under the Receiver-Operating Curve (AUROC) in Biological Process (BP), Molecular Function (MF) and Cellular Components (CC) by no less than 33%, 15% and 28%, respectively. Conclusions We demonstrated that integrating multi-source data into a heterogeneous biological network can preserve the complex relationship among multiplex biological data and improve the prediction accuracy of protein function by getting rid of the constraints of errors in PPI networks effectively. PHN, our proposed method, is effective for protein function prediction.

Background In recent years, huge improvements have been made in the context of sequencing genomic data under what is called Next Generation Sequencing (NGS). However, the DNA reads generated by current NGS platforms are not free of errors, which can affect the quality of downstream analysis. Although error correction can be performed as a preprocessing step to overcome this issue, it usually requires long computational times to analyze those large datasets generated nowadays through NGS. Therefore, new software capable of scaling out on a cluster of nodes with high performance is of great importance. Results In this paper, we present SparkEC, a parallel tool capable of fixing those errors produced during the sequencing process. For this purpose, the algorithms proposed by the CloudEC tool, which is already proved to perform accurate corrections, have been analyzed and optimized to improve their performance by relying on the Apache Spark framework together with the introduction of other enhancements such as the usage of memory-efficient data structures and the avoidance of any input preprocessing. The experimental results have shown significant improvements in the computational times of SparkEC when compared to CloudEC for all the representative datasets and scenarios under evaluation, providing an average and maximum speedups of 4.9$$\times$$ × and 11.9$$\times$$ × , respectively, over its counterpart. Conclusion As error correction can take excessive computational time, SparkEC provides a scalable solution for correcting large datasets. Due to its distributed implementation, SparkEC speed can increase with respect to the number of nodes in a cluster. Furthermore, the software is freely available under GPLv3 license and is compatible with different operating systems (Linux, Windows and macOS).

Background There is a widening gap between the throughput of massive parallel sequencing machines and the ability to analyze these sequencing data. Traditional assembly methods requiring long execution time and large amount of memory on a single workstation limit their use on these massive data. Results This paper presents a highly scalable assembler named as SWAP-Assembler for processing massive sequencing data using thousands of cores, where SWAP is an acronym for Small World Asynchronous Parallel model. In the paper, a mathematical description of multi-step bi-directed graph (MSG) is provided to resolve the computational interdependence on merging edges, and a highly scalable computational framework for SWAP is developed to automatically preform the parallel computation of all operations. Graph cleaning and contig extension are also included for generating contigs with high quality. Experimental results show that SWAP-Assembler scales up to 2048 cores on Yanhuang dataset using only 26 minutes, which is better than several other parallel assemblers, such as ABySS, Ray, and PASHA. Results also show that SWAP-Assembler can generate high quality contigs with good N50 size and low error rate, especially it generated the longest N50 contig sizes for Fish and Yanhuang datasets. Conclusions In this paper, we presented a highly scalable and efficient genome assembly software, SWAP-Assembler. Compared with several other assemblers, it showed very good performance in terms of scalability and contig quality. This software is available at: https://sourceforge.net/projects/swapassembler

Acquiring genomes at single-cell resolution has many applications such as in the study of microbiota. However, deep sequencing and assembly of all of millions of cells in a sample is prohibitively costly. A property that can come to rescue is that deep sequencing of every cell should not be necessary to capture all distinct genomes, as the majority of cells are biological replicates. Biologically important samples are often sparse in that sense. In this paper, we propose an adaptive compressed method, also known as distilled sensing, to capture all distinct genomes in a sparse microbial community with reduced sequencing effort. As opposed to group testing in which the number of distinct events is often constant and sparsity is equivalent to rarity of an event, sparsity in our case means scarcity of distinct events in comparison to the data size. Previously, we introduced the problem and proposed a distilled sensing solution based on the breadth first search strategy. We simulated the whole process which constrained our ability to study the behavior of the algorithm for the entire ensemble due to its computational intensity. In this paper, we modify our previous breadth first search strategy and introduce the depth first search strategy. Instead of simulating the entire process, which is intractable for a large number of experiments, we provide a dynamic programming algorithm to analyze the behavior of the method for the entire ensemble. The ensemble analysis algorithm recursively calculates the probability of capturing every distinct genome and also the expected total sequenced nucleotides for a given population profile. Our results suggest that the expected total sequenced nucleotides grows proportional to log of the number of cells and proportional linearly with the number of distinct genomes. The probability of missing a genome depends on its abundance and the ratio of its size over the maximum genome size in the sample. The modified resource allocation method accommodates a parameter to control that probability. The squeezambler 2.0 C++ source code is available at http://sourceforge.net/projects/hyda/ . The ensemble analysis MATLAB code is available at http://sourceforge.net/projects/distilled-sequencing/ .

Background Deciphering proportions of constitutional cell types in tumor tissues is a crucial step for the analysis of tumor heterogeneity and the prediction of response to immunotherapy. In the process of measuring cell population proportions, traditional experimental methods have been greatly hampered by the cost and extensive dropout events. At present, the public availability of large amounts of DNA methylation data makes it possible to use computational methods to predict proportions. Results In this paper, we proposed PRMeth, a method to deconvolve tumor mixtures using partially available DNA methylation data. By adopting an iteratively optimized non-negative matrix factorization framework, PRMeth took DNA methylation profiles of a portion of the cell types in the tissue mixtures (including blood and solid tumors) as input to estimate the proportions of all cell types as well as the methylation profiles of unknown cell types simultaneously. We compared PRMeth with five different methods through three benchmark datasets and the results show that PRMeth could infer the proportions of all cell types and recover the methylation profiles of unknown cell types effectively. Then, applying PRMeth to four types of tumors from The Cancer Genome Atlas (TCGA) database, we found that the immune cell proportions estimated by PRMeth were largely consistent with previous studies and met biological significance. Conclusions Our method can circumvent the difficulty of obtaining complete DNA methylation reference data and obtain satisfactory deconvolution accuracy, which will be conducive to exploring the new directions of cancer immunotherapy. PRMeth is implemented in R and is freely available from GitHub (https://github.com/hedingqin/PRMeth).

Background The discovery of critical biomarkers is significant for clinical diagnosis, drug research and development. Researchers usually obtain biomarkers from microarray data, which comes from the dimensional curse. Feature selection in machine learning is usually used to solve this problem. However, most methods do not fully consider feature dependence, especially the real pathway relationship of genes. Results Experimental results show that the proposed method is superior to classical algorithms and advanced methods in feature number and accuracy, and the selected features have more significance. Method This paper proposes a feature selection method based on a graph neural network. The proposed method uses the actual dependencies between features and the Pearson correlation coefficient to construct graph-structured data. The information dissemination and aggregation operations based on graph neural network are applied to fuse node information on graph structured data. The redundant features are clustered by the spectral clustering method. Then, the feature ranking aggregation model using eight feature evaluation methods acts on each clustering sub-cluster for different feature selection. Conclusion The proposed method can effectively remove redundant features. The algorithm’s output has high stability and classification accuracy, which can potentially select potential biomarkers.

BackgroundDue to the growing amount of COVID-19 research literature, medical experts, clinical scientists, and researchers frequently struggle to stay up to date on the most recent findings. There is a pressing need to assist researchers and practitioners in mining and responding to COVID-19-related questions on time.MethodsThis paper introduces CoQUAD, a question-answering system that can extract answers related to COVID-19 questions in an efficient manner. There are two datasets provided in this work: a reference-standard dataset built using the CORD-19 and LitCOVID initiatives, and a gold-standard dataset prepared by the experts from a public health domain. The CoQUAD has a Retriever component trained on the BM25 algorithm that searches the reference-standard dataset for relevant documents based on a question related to COVID-19. CoQUAD also has a Reader component that consists of a Transformer-based model, namely MPNet, which is used to read the paragraphs and find the answers related to a question from the retrieved documents. In comparison to previous works, the proposed CoQUAD system can answer questions related to early, mid, and post-COVID-19 topics.ResultsExtensive experiments on CoQUAD Retriever and Reader modules show that CoQUAD can provide effective and relevant answers to any COVID-19-related questions posed in natural language, with a higher level of accuracy. When compared to state-of-the-art baselines, CoQUAD outperforms the previous models, achieving an exact match ratio score of 77.50% and an F1 score of 77.10%.ConclusionCoQUAD is a question-answering system that mines COVID-19 literature using natural language processing techniques to help the research community find the most recent findings and answer any related questions.

Background With the development of noninvasive imaging technology, collecting different imaging measurements of the same brain has become more and more easy. These multimodal imaging data carry complementary information of the same brain, with both specific and shared information being intertwined. Within these multimodal data, it is essential to discriminate the specific information from the shared information since it is of benefit to comprehensively characterize brain diseases. While most existing methods are unqualified, in this paper, we propose a parameter decomposition based sparse multi-view canonical correlation analysis (PDSMCCA) method. PDSMCCA could identify both modality-shared and -specific information of multimodal data, leading to an in-depth understanding of complex pathology of brain disease. Results Compared with the SMCCA method, our method obtains higher correlation coefficients and better canonical weights on both synthetic data and real neuroimaging data. This indicates that, coupled with modality-shared and -specific feature selection, PDSMCCA improves the multi-view association identification and shows meaningful feature selection capability with desirable interpretation. Conclusions The novel PDSMCCA confirms that the parameter decomposition is a suitable strategy to identify both modality-shared and -specific imaging features. The multimodal association and the diverse information of multimodal imaging data enable us to better understand the brain disease such as Alzheimer’s disease.

Background Accurate segmentation and recognition algorithm of lung nodules has great important value of reference for early diagnosis of lung cancer. An algorithm is proposed for 3D CT sequence images in this paper based on 3D Res U-Net segmentation network and 3D ResNet50 classification network. The common convolutional layers in encoding and decoding paths of U-Net are replaced by residual units while the loss function is changed to Dice loss after using cross entropy loss to accelerate network convergence. Since the lung nodules are small and rich in 3D information, the ResNet50 is improved by replacing the 2D convolutional layers with 3D convolutional layers and reducing the sizes of some convolution kernels, 3D ResNet50 network is obtained for the diagnosis of benign and malignant lung nodules. Results 3D Res U-Net was trained and tested on 1044 CT subcases in the LIDC-IDRI database. The segmentation result shows that the Dice coefficient of 3D Res U-Net is above 0.8 for the segmentation of lung nodules larger than 10 mm in diameter. 3D ResNet50 was trained and tested on 2960 lung nodules in the LIDC-IDRI database. The classification result shows that the diagnostic accuracy of 3D ResNet50 is 87.3% and AUC is 0.907. Conclusion The 3D Res U-Net module improves segmentation performance significantly with the comparison of 3D U-Net model based on residual learning mechanism. 3D Res U-Net can identify small nodules more effectively and improve its segmentation accuracy for large nodules. Compared with the original network, the classification performance of 3D ResNet50 is significantly improved, especially for small benign nodules.

Background Gene co-expression networks are widely studied in the biomedical field, with algorithms such as WGCNA and lmQCM having been developed to detect co-expressed modules. However, these algorithms have limitations such as insufficient granularity and unbalanced module size, which prevent full acquisition of knowledge from data mining. In addition, it is difficult to incorporate prior knowledge in current co-expression module detection algorithms. Results In this paper, we propose a novel module detection algorithm based on topology potential and spectral clustering algorithm to detect co-expressed modules in gene co-expression networks. By testing on TCGA data, our novel method can provide more complete coverage of genes, more balanced module size and finer granularity than current methods in detecting modules with significant overall survival difference. In addition, the proposed algorithm can identify modules by incorporating prior knowledge. Conclusion In summary, we developed a method to obtain as much as possible information from networks with increased input coverage and the ability to detect more size-balanced and granular modules. In addition, our method can integrate data from different sources. Our proposed method performs better than current methods with complete coverage of input genes and finer granularity. Moreover, this method is designed not only for gene co-expression networks but can also be applied to any general fully connected weighted network.

Background The desire to understand genomic functions and the behavior of complex gene regulatory networks has recently been a major research focus in systems biology. As a result, a plethora of computational and modeling tools have been proposed to identify and infer interactions among biological entities. Here, we consider the general question of the effect of perturbation on the global dynamical network behavior as well as error propagation in biological networks to incite research pertaining to intervention strategies. Results This paper introduces a computational framework that combines the formulation of Boolean networks and factor graphs to explore the global dynamical features of biological systems. A message-passing algorithm is proposed for this formalism to evolve network states as messages in the graph. In addition, the mathematical formulation allows us to describe the dynamics and behavior of error propagation in gene regulatory networks by conducting a density evolution (DE) analysis. The model is applied to assess the network state progression and the impact of gene deletion in the budding yeast cell cycle. Simulation results show that our model predictions match published experimental data. Also, our findings reveal that the sample yeast cell-cycle network is not only robust but also consistent with real high-throughput expression data. Finally, our DE analysis serves as a tool to find the optimal values of network parameters for resilience against perturbations, especially in the inference of genetic graphs. Conclusion Our computational framework provides a useful graphical model and analytical tools to study biological networks. It can be a powerful tool to predict the consequences of gene deletions before conducting wet bench experiments because it proves to be a quick route to predicting biologically relevant dynamic properties without tunable kinetic parameters.

Background Essential proteins have great impacts on cell survival and development, and played important roles in disease analysis and new drug design. However, since it is inefficient and costly to identify essential proteins by using biological experiments, then there is an urgent need for automated and accurate detection methods. In recent years, the recognition of essential proteins in protein interaction networks (PPI) has become a research hotspot, and many computational models for predicting essential proteins have been proposed successively. Results In order to achieve higher prediction performance, in this paper, a new prediction model called TGSO is proposed. In TGSO, a protein aggregation degree network is constructed first by adopting the node density measurement method for complex networks. And simultaneously, a protein co-expression interactive network is constructed by combining the gene expression information with the network connectivity, and a protein co-localization interaction network is constructed based on the subcellular localization data. And then, through integrating these three kinds of newly constructed networks, a comprehensive protein–protein interaction network will be obtained. Finally, based on the homology information, scores can be calculated out iteratively for different proteins, which can be utilized to estimate the importance of proteins effectively. Moreover, in order to evaluate the identification performance of TGSO, we have compared TGSO with 13 different latest competitive methods based on three kinds of yeast databases. And experimental results show that TGSO can achieve identification accuracies of 94%, 82% and 72% out of the top 1%, 5% and 10% candidate proteins respectively, which are to some degree superior to these state-of-the-art competitive models. Conclusions We constructed a comprehensive interactive network based on multi-source data to reduce the noise and errors in the initial PPI, and combined with iterative methods to improve the accuracy of necessary protein prediction, and means that TGSO may be conducive to the future development of essential protein recognition as well.

Background Antifreeze proteins (AFPs) are a group of proteins that inhibit body fluids from growing to ice crystals and thus improve biological antifreeze ability. It is vital to the survival of living organisms in extremely cold environments. However, little research is performed on sequences feature extraction and selection for antifreeze proteins classification in the structure and function prediction, which is of great significance. Results In this paper, to predict the antifreeze proteins, a feature representation of weighted generalized dipeptide composition (W-GDipC) and an ensemble feature selection based on two-stage and multi-regression method (LRMR-Ri) are proposed. Specifically, four feature selection algorithms: Lasso regression, Ridge regression, Maximal information coefficient and Relief are used to select the feature sets, respectively, which is the first stage of LRMR-Ri method. If there exists a common feature subset among the above four sets, it is the optimal subset; otherwise we use Ridge regression to select the optimal subset from the public set pooled by the four sets, which is the second stage of LRMR-Ri. The LRMR-Ri method combined with W-GDipC was performed both on the antifreeze proteins dataset (binary classification), and on the membrane protein dataset (multiple classification). Experimental results show that this method has good performance in support vector machine (SVM), decision tree (DT) and stochastic gradient descent (SGD). The values of ACC, RE and MCC of LRMR-Ri and W-GDipC with antifreeze proteins dataset and SVM classifier have reached as high as 95.56%, 97.06% and 0.9105, respectively, much higher than those of each single method: Lasso, Ridge, Mic and Relief, nearly 13% higher than single Lasso for ACC. Conclusion The experimental results show that the proposed LRMR-Ri and W-GDipC method can significantly improve the accuracy of antifreeze proteins prediction compared with other similar single feature methods. In addition, our method has also achieved good results in the classification and prediction of membrane proteins, which verifies its widely reliability to a certain extent.

BackgroundThe growing researches of molecular biology reveal that complex life phenomena have the ability to demonstrating various types of interactions in the level of genomics. To establish the interactions between genes or proteins and understand the intrinsic mechanisms of biological systems have become an urgent need and study hotspot.ResultsIn order to forecast gene expression data and identify more accurate gene regulatory network, complex-valued version of ordinary differential equation (CVODE) is proposed in this paper. In order to optimize CVODE model, a complex-valued hybrid evolutionary method based on Grammar-guided genetic programming and complex-valued firefly algorithm is presented.ConclusionsWhen tested on three real gene expression datasets fromE.coliand Human Cell, the experiment results suggest that CVODE model could improve 20–50% prediction accuracy of gene expression data, which could also infer more true-positive regulatory relationships and less false-positive regulations than ordinary differential equation.

Background The Damerau-Levenshtein (DL) distance metric has been widely used in the biological science. It tries to identify the similar region of DNA,RNA and protein sequences by transforming one sequence to the another using the substitution, insertion, deletion and transposition operations. Lowrance and Wagner have developed an O(mn) time O(mn) space algorithm to find the minimum cost edit sequence between strings of length m and n, respectively. In our previous research, we have developed algorithms that run in O(mn) time using only O(s∗min{m,n}+m+n) space, where s is the size of the alphabet comprising the strings, to compute the DL distance as well as the corresponding edit sequence. These are so far the fastest and most space efficient algorithms. In this paper, we focus on the development of algorithms whose asymptotic space complexity is linear. Results We develop linear space algorithms to compute the Damerau-Levenshtein (DL) distance between two strings and determine the optimal trace (corresponding edit operations.)Extensive experiments conducted on three computational platforms–Xeon E5 2603, I7-x980 and Xeon E5 2695–show that, our algorithms, in addition to using less space, are much faster than earlier algorithms. Conclusion Besides using less space than the previously known algorithms,significant run-time improvement was seen for our new algorithms on all three of our experimental platforms. On all platforms, our linear-space cache-efficient algorithms reduced run time by as much as 56.4% and 57.4% in respect to compute the DL distance and an optimal edit sequences compared to previous algorithms. Our multi-core algorithms reduced the run time by up to 59.3% compared to the best previously known multi-core algorithms.

Background Next-generation sequencing technologies revolutionized genomics by producing high-throughput reads at low cost, and this progress has prompted the recent development of de novo assemblers. Multiple assembly methods based on de Bruijn graph have been shown to be efficient for Illumina reads. However, the sequencing errors generated by the sequencer complicate analysis of de novo assembly and influence the quality of downstream genomic researches. Results In this paper, we develop a de Bruijn assembler, called Clover (clustering-oriented de novo assembler), that utilizes a novel k-mer clustering approach from the overlap-layout-consensus concept to deal with the sequencing errors generated by the Illumina platform. We further evaluate Clover’s performance against several de Bruijn graph assemblers (ABySS, SOAPdenovo, SPAdes and Velvet), overlap-layout-consensus assemblers (Bambus2, CABOG and MSR-CA) and string graph assembler (SGA) on three datasets (Staphylococcus aureus, Rhodobacter sphaeroides and human chromosome 14). The results show that Clover achieves a superior assembly quality in terms of corrected N50 and E-size while remaining a significantly competitive in run time except SOAPdenovo. In addition, Clover was involved in the sequencing projects of bacterial genomes Acinetobacter baumannii TYTH-1 and Morganella morganii KT. Conclusions The marvel clustering-based approach of Clover that integrates the flexibility of the overlap-layout-consensus approach and the efficiency of the de Bruijn graph method has high potential on de novo assembly. Now, Clover is freely available as open source software from https://oz.nthu.edu.tw/~d9562563/src.html.

Background Network alignment is an efficient computational framework in the prediction of protein function and phylogenetic relationships in systems biology. However, most of existing alignment methods focus on aligning PPIs based on static network model, which are actually dynamic in real-world systems. The dynamic characteristic of PPI networks is essential for understanding the evolution and regulation mechanism at the molecular level and there is still much room to improve the alignment quality in dynamic networks. Results In this paper, we proposed a novel alignment algorithm, Twadn, to align dynamic PPI networks based on a strategy of time warping. We compare Twadn with the existing dynamic network alignment algorithm DynaMAGNA++ and DynaWAVE and use area under the receiver operating characteristic curve and area under the precision-recall curve as evaluation indicators. The experimental results show that Twadn is superior to DynaMAGNA++ and DynaWAVE. In addition, we use protein interaction network of Drosophila to compare Twadn and the static network alignment algorithm NetCoffee2 and experimental results show that Twadn is able to capture timing information compared to NetCoffee2. Conclusions Twadn is a versatile and efficient alignment tool that can be applied to dynamic network. Hopefully, its application can benefit the research community in the fields of molecular function and evolution.

Background Recognition is an essential function of human beings. Humans easily recognize a person using various inputs such as voice, face, or gesture. In this study, we mainly focus on DL model with multi-modality which has many benefits including noise reduction. We used ResNet-50 for extracting features from dataset with 2D data. Results This study proposes a novel multimodal and multitask model, which can both identify human ID and classify the gender in single step. At the feature level, the extracted features are concatenated as the input for the identification module. Additionally, in our model design, we can change the number of modalities used in a single model. To demonstrate our model, we generate 58 virtual subjects with public ECG, face and fingerprint dataset. Through the test with noisy input, using multimodal is more robust and better than using single modality. Conclusions This paper presents an end-to-end approach for multimodal and multitask learning. The proposed model shows robustness on the spoof attack, which can be significant for bio-authentication device. Through results in this study, we suggest a new perspective for human identification task, which performs better than in previous approaches.

Background The latest works on CRISPR genome editing tools mainly employs deep learning techniques. However, deep learning models lack explainability and they are harder to reproduce. We were motivated to build an accurate genome editing tool using sequence-based features and traditional machine learning that can compete with deep learning models. Results In this paper, we present CRISPRpred(SEQ), a method for sgRNA on-target activity prediction that leverages only traditional machine learning techniques and hand-crafted features extracted from sgRNA sequences. We compare the results of CRISPRpred(SEQ) with that of DeepCRISPR, the current state-of-the-art, which uses a deep learning pipeline. Despite using only traditional machine learning methods, we have been able to beat DeepCRISPR for the three out of four cell lines in the benchmark dataset convincingly (2.174%, 6.905% and 8.119% improvement for the three cell lines). Conclusion CRISPRpred(SEQ) has been able to convincingly beat DeepCRISPR in 3 out of 4 cell lines. We believe that by exploring further, one can design better features only using the sgRNA sequences and can come up with a better method leveraging only traditional machine learning algorithms that can fully beat the deep learning models.

Background Semantic resources such as knowledge bases contains high-quality-structured knowledge and therefore require significant effort from domain experts. Using the resources to reinforce the information retrieval from the unstructured text may further exploit the potentials of such unstructured text resources and their curated knowledge. Results The paper proposes a novel method that uses a deep neural network model adopting the prior knowledge to improve performance in the automated extraction of biological semantic relations from the scientific literature. The model is based on a recurrent neural network combining the attention mechanism with the semantic resources, i.e., UniProt and BioModels. Our method is evaluated on the BioNLP and BioCreative corpus, a set of manually annotated biological text. The experiments demonstrate that the method outperforms the current state-of-the-art models, and the structured semantic information could improve the result of bio-text-mining. Conclusion The experiment results show that our approach can effectively make use of the external prior knowledge information and improve the performance in the protein-protein interaction extraction task. The method should be able to be generalized for other types of data, although it is validated on biomedical texts.

Background Apoptosis, also called programmed cell death, refers to the spontaneous and orderly death of cells controlled by genes in order to maintain a stable internal environment. Identifying the subcellular location of apoptosis proteins is very helpful in understanding the mechanism of apoptosis and designing drugs. Therefore, the subcellular localization of apoptosis proteins has attracted increased attention in computational biology. Effective feature extraction methods play a critical role in predicting the subcellular location of proteins. Results In this paper, we proposed two novel feature extraction methods based on evolutionary information. One of the features obtained the evolutionary information via the transition matrix of the consensus sequence (CTM). And the other utilized the evolutionary information from PSSM based on absolute entropy correlation analysis (AECA-PSSM). After fusing the two kinds of features, linear discriminant analysis (LDA) was used to reduce the dimension of the proposed features. Finally, the support vector machine (SVM) was adopted to predict the protein subcellular locations. The proposed CTM-AECA-PSSM-LDA subcellular location prediction method was evaluated using the CL317 dataset and ZW225 dataset. By jackknife test, the overall accuracy was 99.7% (CL317) and 95.6% (ZW225) respectively. Conclusions The experimental results show that the proposed method which is hopefully to be a complementary tool for the existing methods of subcellular localization, can effectively extract more abundant features of protein sequence and is feasible in predicting the subcellular location of apoptosis proteins.

Background Gene regulatory networks (GRNs) can be inferred from both gene expression data and genetic perturbations. Under different conditions, the gene data of the same gene set may be different from each other, which results in different GRNs. Detecting structural difference between GRNs under different conditions is of great significance for understanding gene functions and biological mechanisms. Results In this paper, we propose a Bayesian Fused algorithm to jointly infer differential structures of GRNs under two different conditions. The algorithm is developed for GRNs modeled with structural equation models (SEMs), which makes it possible to incorporate genetic perturbations into models to improve the inference accuracy, so we name it BFDSEM. Different from the naive approaches that separately infer pair-wise GRNs and identify the difference from the inferred GRNs, we first re-parameterize the two SEMs to form an integrated model that takes full advantage of the two groups of gene data, and then solve the re-parameterized model by developing a novel Bayesian fused prior following the criterion that separate GRNs and differential GRN are both sparse. Conclusions Computer simulations are run on synthetic data to compare BFDSEM to two state-of-the-art joint inference algorithms: FSSEM and ReDNet. The results demonstrate that the performance of BFDSEM is comparable to FSSEM, and is generally better than ReDNet. The BFDSEM algorithm is also applied to a real data set of lung cancer and adjacent normal tissues, the yielded normal GRN and differential GRN are consistent with the reported results in previous literatures. An open-source program implementing BFDSEM is freely available in Additional file 1.

Background Identifying different types of cancer based on gene expression data has become hotspot in bioinformatics research. Clustering cancer gene expression data from multiple cancers to their own class is a significance solution. However, the characteristics of high-dimensional and small samples of gene expression data and the noise of the data make data mining and research difficult. Although there are many effective and feasible methods to deal with this problem, the possibility remains that these methods are flawed. Results In this paper, we propose the graph regularized low-rank representation under symmetric and sparse constraints (sgLRR) method in which we introduce graph regularization based on manifold learning and symmetric sparse constraints into the traditional low-rank representation (LRR). For the sgLRR method, by means of symmetric constraint and sparse constraint, the effect of raw data noise on low-rank representation is alleviated. Further, sgLRR method preserves the important intrinsic local geometrical structures of the raw data by introducing graph regularization. We apply this method to cluster multi-cancer samples based on gene expression data, which improves the clustering quality. First, the gene expression data are decomposed by sgLRR method. And, a lowest rank representation matrix is obtained, which is symmetric and sparse. Then, an affinity matrix is constructed to perform the multi-cancer sample clustering by using a spectral clustering algorithm, i.e., normalized cuts (Ncuts). Finally, the multi-cancer samples clustering is completed. Conclusions A series of comparative experiments demonstrate that the sgLRR method based on low rank representation has a great advantage and remarkable performance in the clustering of multi-cancer samples.

Background Subcellular localization prediction of protein is an important component of bioinformatics, which has great importance for drug design and other applications. A multitude of computational tools for proteins subcellular location have been developed in the recent decades, however, existing methods differ in the protein sequence representation techniques and classification algorithms adopted. Results In this paper, we firstly introduce two kinds of protein sequences encoding schemes: dipeptide information with space and Gapped k-mer information. Then, the Gapped k-mer calculation method which is based on quad-tree is also introduced. Conclusions >From the prediction results, this method not only reduces the dimension, but also improves the prediction precision of protein subcellular localization.

Background As the terminal products of cellular regulatory process, functional related metabolites have a close relationship with complex diseases, and are often associated with the same or similar diseases. Therefore, identification of disease related metabolites play a critical role in understanding comprehensively pathogenesis of disease, aiming at improving the clinical medicine. Considering that a large number of metabolic markers of diseases need to be explored, we propose a computational model to identify potential disease-related metabolites based on functional relationships and scores of referred literatures between metabolites. First, obtaining associations between metabolites and diseases from the Human Metabolome database, we calculate the similarities of metabolites based on modified recommendation strategy of collaborative filtering utilizing the similarities between diseases. Next, a disease-associated metabolite network (DMN) is built with similarities between metabolites as weight. To improve the ability of identifying disease-related metabolites, we introduce scores of text mining from the existing database of chemicals and proteins into DMN and build a new disease-associated metabolite network (FLDMN) by fusing functional associations and scores of literatures. Finally, we utilize random walking with restart (RWR) in this network to predict candidate metabolites related to diseases. Results We construct the disease-associated metabolite network and its improved network (FLDMN) with 245 diseases, 587 metabolites and 28,715 disease-metabolite associations. Subsequently, we extract training sets and testing sets from two different versions of the Human Metabolome database and assess the performance of DMN and FLDMN on 19 diseases, respectively. As a result, the average AUC (area under the receiver operating characteristic curve) of DMN is 64.35%. As a further improved network, FLDMN is proven to be successful in predicting potential metabolic signatures for 19 diseases with an average AUC value of 76.03%. Conclusion In this paper, a computational model is proposed for exploring metabolite-disease pairs and has good performance in predicting potential metabolites related to diseases through adequate validation. This result suggests that integrating literature and functional associations can be an effective way to construct disease associated metabolite network for prioritizing candidate diseases-related metabolites.

Contemporary biological observations have revealed a large variety of mechanisms acting during the expansion of a tumor. However, there are still many qualitative and quantitative aspects of the phenomenon that remain largely unknown. In this context, mathematical and computational modeling appears as an invaluable tool providing the means for conducting in silico experiments, which are cheaper and less tedious than real laboratory experiments.This paper aims at developing an extensible and computationally efficient framework for in silico modeling of tumor growth in a 3-dimensional, inhomogeneous and time-varying chemical environment. The resulting model consists of a set of mathematically derived and algorithmically defined operators, each one addressing the effects of a particular biological mechanism on the state of the system. These operators may be extended or re-adjusted, in case a different set of starting assumptions or a different simulation scenario needs to be considered.In silico modeling provides an alternative means for testing hypotheses and simulating scenarios for which exact biological knowledge remains elusive. However, finer tuning of pertinent methods presupposes qualitative and quantitative enrichment of available biological evidence. Validation in a strict sense would further require comprehensive, case-specific simulations and detailed comparisons with biomedical observations.

BackgroundProtein complex identification from protein-protein interaction (PPI) networks is crucial for understanding cellular organization principles and functional mechanisms. In recent decades, numerous computational methods have been proposed to identify protein complexes. However, most of the current state-of-the-art studies still have some challenges to resolve, including their high false-positives rates, incapability of identifying overlapping complexes, lack of consideration for the inherent organization within protein complexes, and absence of some biological attachment proteins.ResultsIn this paper, to overcome these limitations, we present a protein complex identification method based on an edge weight method and core-attachment structure (EWCA) which consists of a complex core and some sparse attachment proteins. First, we propose a new weighting method to assess the reliability of interactions. Second, we identify protein complex cores by using the structural similarity between a seed and its direct neighbors. Third, we introduce a new method to detect attachment proteins that is able to distinguish and identify peripheral proteins and overlapping proteins. Finally, we bind attachment proteins to their corresponding complex cores to form protein complexes and discard redundant protein complexes. The experimental results indicate that EWCA outperforms existing state-of-the-art methods in terms of both accuracy andp-value. Furthermore, EWCA could identify many more protein complexes with statistical significance. Additionally, EWCA could have better balance accuracy and efficiency than some state-of-the-art methods with high accuracy.ConclusionsIn summary, EWCA has better performance for protein complex identification by a comprehensive comparison with twelve algorithms in terms of different evaluation metrics. The datasets and software are freely available for academic research athttps://github.com/RongquanWang/EWCA.

Background Advances in medical technology have allowed for customized prognosis, diagnosis, and treatment regimens that utilize multiple heterogeneous data sources. Multiple kernel learning (MKL) is well suited for the integration of multiple high throughput data sources. MKL remains to be under-utilized by genomic researchers partly due to the lack of unified guidelines for its use, and benchmark genomic datasets. Results We provide three implementations of MKL in R. These methods are applied to simulated data to illustrate that MKL can select appropriate models. We also apply MKL to combine clinical information with miRNA gene expression data of ovarian cancer study into a single analysis. Lastly, we show that MKL can identify gene sets that are known to play a role in the prognostic prediction of 15 cancer types using gene expression data from The Cancer Genome Atlas, as well as, identify new gene sets for the future research. Conclusion Multiple kernel learning coupled with modern optimization techniques provides a promising learning tool for building predictive models based on multi-source genomic data. MKL also provides an automated scheme for kernel prioritization and parameter tuning. The methods used in the paper are implemented as an R package called RMKL package, which is freely available for download through CRAN at https://CRAN.R-project.org/package=RMKL. Electronic supplementary material The online version of this article (10.1186/s12859-019-2992-1) contains supplementary material, which is available to authorized users.

Background How can we obtain fast and high-quality clusters in genome scale bio-networks? Graph clustering is a powerful tool applied on bio-networks to solve various biological problems such as protein complexes detection, disease module detection, and gene function prediction. Especially, MCL (Markov Clustering) has been spotlighted due to its superior performance on bio-networks. MCL, however, is skewed towards finding a large number of very small clusters (size 1-3) and fails to detect many larger clusters (size 10+). To resolve this fragmentation problem, MLR-MCL (Multi-level Regularized MCL) has been developed. MLR-MCL still suffers from the fragmentation and, in cases, unrealistically large clusters are generated. Results In this paper, we propose PS-MCL (Parallel Shotgun Coarsened MCL), a parallel graph clustering method outperforming MLR-MCL in terms of running time and cluster quality. PS-MCL adopts an efficient coarsening scheme, called SC (Shotgun Coarsening), to improve graph coarsening in MLR-MCL. SC allows merging multiple nodes at a time, which leads to improvement in quality, time and space usage. Also, PS-MCL parallelizes main operations used in MLR-MCL which includes matrix multiplication. Conclusions Experiments show that PS-MCL dramatically alleviates the fragmentation problem, and outperforms MLR-MCL in quality and running time. We also show that the running time of PS-MCL is effectively reduced with parallelization.

Background Essential proteins are distinctly important for an organism’s survival and development and crucial to disease analysis and drug design as well. Large-scale protein-protein interaction (PPI) data sets exist in Saccharomyces cerevisiae, which provides us with a valuable opportunity to predict identify essential proteins from PPI networks. Many network topology-based computational methods have been designed to detect essential proteins. However, these methods are limited by the completeness of available PPI data. To break out of these restraints, some computational methods have been proposed by integrating PPI networks and multi-source biological data. Despite the progress in the research of multiple data fusion, it is still challenging to improve the prediction accuracy of the computational methods. Results In this paper, we design a novel iterative model for essential proteins prediction, named Randomly Walking in the Heterogeneous Network (RWHN). In RWHN, a weighted protein-protein interaction network and a domain-domain association network are constructed according to the original PPI network and the known protein-domain association network, firstly. And then, we establish a new heterogeneous matrix by combining the two constructed networks with the protein-domain association network. Based on the heterogeneous matrix, a transition probability matrix is established by normalized operation. Finally, an improved PageRank algorithm is adopted on the heterogeneous network for essential proteins prediction. In order to eliminate the influence of the false negative, information on orthologous proteins and the subcellular localization information of proteins are integrated to initialize the score vector of proteins. In RWHN, the topology, conservative and functional features of essential proteins are all taken into account in the prediction process. The experimental results show that RWHN obviously exceeds in predicting essential proteins ten other competing methods. Conclusions We demonstrated that integrating multi-source data into a heterogeneous network can preserve the complex relationship among multiple biological data and improve the prediction accuracy of essential proteins. RWHN, our proposed method, is effective for the prediction of essential proteins.

Background In the era of precision oncology and publicly available datasets, the amount of information available for each patient case has dramatically increased. From clinical variables and PET-CT radiomics measures to DNA-variant and RNA expression profiles, such a wide variety of data presents a multitude of challenges. Large clinical datasets are subject to sparsely and/or inconsistently populated fields. Corresponding sequencing profiles can suffer from the problem of high-dimensionality, where making useful inferences can be difficult without correspondingly large numbers of instances. In this paper we report a novel deployment of machine learning techniques to handle data sparsity and high dimensionality, while evaluating potential biomarkers in the form of unsupervised transformations of RNA data. We apply preprocessing, MICE imputation, and sparse principal component analysis (SPCA) to improve the usability of more than 500 patient cases from the TCGA-HNSC dataset for enhancing future oncological decision support for Head and Neck Squamous Cell Carcinoma (HNSCC). Results Imputation was shown to improve prognostic ability of sparse clinical treatment variables. SPCA transformation of RNA expression variables reduced runtime for RNA-based models, though changes to classifier performance were not significant. Gene ontology enrichment analysis of gene sets associated with individual sparse principal components (SPCs) are also reported, showing that both high- and low-importance SPCs were associated with cell death pathways, though the high-importance gene sets were found to be associated with a wider variety of cancer-related biological processes. Conclusions MICE imputation allowed us to impute missing values for clinically informative features, improving their overall importance for predicting two-year recurrence-free survival by incorporating variance from other clinical variables. Dimensionality reduction of RNA expression profiles via SPCA reduced both computation cost and model training/evaluation time without affecting classifier performance, allowing researchers to obtain experimental results much more quickly. SPCA simultaneously provided a convenient avenue for consideration of biological context via gene ontology enrichment analysis.

Background Avian influenza virus can directly cross species barriers and infect humans with high fatality. As antigen novelty for human host, the public health is being challenged seriously. The pandemic risk of avian influenza viruses should be analyzed and a prediction model should be constructed for virology applications. Results The 178 signature positions in 11 viral proteins were firstly screened as features by the scores of five amino acid factors and their random forest rankings. The Supporting Vector Machine algorithm achieved well performance. The most important amino acid factor (Factor 5) and the minimal range of signature positions (63 amino acid residues) were also explored. Moreover, human-origin avian influenza viruses with three or four genome segments from human virus had pandemic risk with high probability. Conclusion Using machine learning methods, the present paper scores the amino acid mutations and predicts pandemic risk with well performance. Although long evolution distances between avian and human viruses suggest that avian influenza virus in nature still need time to fix among human host, it should be notable that there are high pandemic risks for H7N9 and H9N2 avian viruses. Electronic supplementary material The online version of this article (10.1186/s12859-019-2770-0) contains supplementary material, which is available to authorized users.

Intra-tumor heterogeneity is known to contribute to cancer complexity and drug resistance. Understanding the number of distinct subclones and the evolutionary relationships between them is scientifically and clinically very important and still a challenging problem. In this paper, we present BAMSE (BAyesian Model Selection for tumor Evolution), a new probabilistic method for inferring subclonal history and lineage tree reconstruction of heterogeneous tumor samples. BAMSE uses somatic mutation read counts as input and can leverage multiple tumor samples accurately and efficiently. In the first step, possible clusterings of mutations into subclones are scored and a user defined number are selected for further analysis. In the next step, for each of these candidates, a list of trees describing the evolutionary relationships between the subclones is generated. These trees are sorted by their posterior probability. The posterior probability is calculated using a Bayesian model that integrates prior belief about the number of subclones, the composition of the tumor and the process of subclonal evolution. BAMSE also takes the sequencing error into account. We benchmarked BAMSE against state of the art software using simulated datasets. In this work we developed a flexible and fast software to reconstruct the history of a tumor’s subclonal evolution using somatic mutation read counts across multiple samples. BAMSE software is implemented in Python and is available open source under GNU GLPv3 at https://github.com/HoseinT/BAMSE .

Background Gene networks in living cells can change depending on various conditions such as caused by different environments, tissue types, disease states, and development stages. Identifying the differential changes in gene networks is very important to understand molecular basis of various biological process. While existing algorithms can be used to infer two gene networks separately from gene expression data under two different conditions, and then to identify network changes, such an approach does not exploit the similarity between two gene networks, and it is thus suboptimal. A desirable approach would be clearly to infer two gene networks jointly, which can yield improved estimates of network changes. Results In this paper, we developed a proximal gradient algorithm for differential network (ProGAdNet) inference, that jointly infers two gene networks under different conditions and then identifies changes in the network structure. Computer simulations demonstrated that our ProGAdNet outperformed existing algorithms in terms of inference accuracy, and was much faster than a similar approach for joint inference of gene networks. Gene expression data of breast tumors and normal tissues in the TCGA database were analyzed with our ProGAdNet, and revealed that 268 genes were involved in the changed network edges. Gene set enrichment analysis identified a significant number of gene sets related to breast cancer or other types of cancer that are enriched in this set of 268 genes. Network analysis of the kidney cancer data in the TCGA database with ProGAdNet also identified a set of genes involved in network changes, and the majority of the top genes identified have been reported in the literature to be implicated in kidney cancer. These results corroborated that the gene sets identified by ProGAdNet were very informative about the cancer disease status. A software package implementing the ProGAdNet, computer simulations, and real data analysis is available as Additional file 1. Conclusion With its superior performance over existing algorithms, ProGAdNet provides a valuable tool for finding changes in gene networks, which may aid the discovery of gene-gene interactions changed under different conditions. Electronic supplementary material The online version of this article (10.1186/s12859-019-2749-x) contains supplementary material, which is available to authorized users.

Background The large biological databases such as GenBank contain vast numbers of records, the content of which is substantively based on external resources, including published literature. Manual curation is used to establish whether the literature and the records are indeed consistent. We explore in this paper an automated method for assessing the consistency of biological assertions, to assist biocurators, which we call BARC, Biocuration tool for Assessment of Relation Consistency. In this method a biological assertion is represented as a relation between two objects (for example, a gene and a disease); we then use our novel set-based relevance algorithm SaBRA to retrieve pertinent literature, and apply a classifier to estimate the likelihood that this relation (assertion) is correct. Results Our experiments on assessing gene–disease relations and protein–protein interactions using the PubMed Central collection show that BARC can be effective at assisting curators to perform data cleansing. Specifically, the results obtained showed that BARC substantially outperforms the best baselines, with an improvement of F-measure of 3.5% and 13%, respectively, on gene-disease relations and protein-protein interactions. We have additionally carried out a feature analysis that showed that all feature types are informative, as are all fields of the documents. Conclusions BARC provides a clear benefit for the biocuration community, as there are no prior automated tools for identifying inconsistent assertions in large-scale biological databases.

Background Bacterial surfaces are complex systems, constructed from membranes, peptidoglycan and, importantly, proteins. The proteins play crucial roles as critical regulators of how the bacterium interacts with and survive in its environment. A full catalog of the motifs in protein families and their relative conservation grade is a prerequisite to target the protein-protein interaction that bacterial surface protein makes to host proteins. Results In this paper, we propose a greedy approach to identify conserved motifs in large sequence families iteratively. Each iteration discovers a motif de novo and masks all occurrences of that motif. Remaining unmasked sequences are subjected to the next round of motif detection until no more significant motifs can be found. We demonstrate the utility of the method through the construction of a proteome-wide motif repository for Group A Streptococcus (GAS), a significant human pathogen. GAS produce numerous surface proteins that interact with over 100 human plasma proteins, helping the bacteria to evade the host immune response. We used the repository to find that proteins part of the bacterial surface has motif architectures that differ from intracellular proteins. Conclusions We elucidate that the M protein, a coiled-coil homodimer that extends over 500 A from the cell wall, has a motif architecture that differs between various GAS strains. As the M protein is known to bind a variety of different plasma proteins, the results indicate that the different motif architectures are responsible for the quantitative differences of plasma proteins that various strains bind. The speed and applicability of the method enable its application to all major human pathogens. Electronic supplementary material The online version of this article (10.1186/s12859-019-2686-8) contains supplementary material, which is available to authorized users.

Background Cryo-electron tomography (cryo-ET) enables the 3D visualization of cellular organization in near-native state which plays important roles in the field of structural cell biology. However, due to the low signal-to-noise ratio (SNR), large volume and high content complexity within cells, it remains difficult and time-consuming to localize and identify different components in cellular cryo-ET. To automatically localize and recognize in situ cellular structures of interest captured by cryo-ET, we proposed a simple yet effective automatic image analysis approach based on Faster-RCNN. Results Our experimental results were validated using in situ cyro-ET-imaged mitochondria data. Our experimental results show that our algorithm can accurately localize and identify important cellular structures on both the 2D tilt images and the reconstructed 2D slices of cryo-ET. When ran on the mitochondria cryo-ET dataset, our algorithm achieved Average Precision >0.95. Moreover, our study demonstrated that our customized pre-processing steps can further improve the robustness of our model performance. Conclusions In this paper, we proposed an automatic Cryo-ET image analysis algorithm for localization and identification of different structure of interest in cells, which is the first Faster-RCNN based method for localizing an cellular organelle in Cryo-ET images and demonstrated the high accuracy and robustness of detection and classification tasks of intracellular mitochondria. Furthermore, our approach can be easily applied to detection tasks of other cellular structures as well.