Bioinformatics

Syndicate content
Updated: 11 hours 26 min ago

EPIP: a novel approach for condition-specific enhancer–promoter interaction prediction

Tue, 2019-08-13 02:00
Abstract
Motivation
The identification of enhancer–promoter interactions (EPIs), especially condition-specific ones, is important for the study of gene transcriptional regulation. Existing experimental approaches for EPI identification are still expensive, and available computational methods either do not consider or have low performance in predicting condition-specific EPIs.
Results
We developed a novel computational method called EPIP to reliably predict EPIs, especially condition-specific ones. EPIP is capable of predicting interactions in samples with limited data as well as in samples with abundant data. Tested on more than eight cell lines, EPIP reliably identifies EPIs, with an average area under the receiver operating characteristic curve of 0.95 and an average area under the precision–recall curve of 0.73. Tested on condition-specific EPIPs, EPIP correctly identified 99.26% of them. Compared with two recently developed methods, EPIP outperforms them with a better accuracy.
Availability and implementation
The EPIP tool is freely available at http://www.cs.ucf.edu/˜xiaoman/EPIP/.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

Author Index

Fri, 2019-07-05 02:00
Agar,J. i208
Categories: Bioinformatics, Journals

Learning a mixture of microbial networks using minorization–maximization

Fri, 2019-07-05 02:00
Abstract
Motivation
The interactions among the constituent members of a microbial community play a major role in determining the overall behavior of the community and the abundance levels of its members. These interactions can be modeled using a network whose nodes represent microbial taxa and edges represent pairwise interactions. A microbial network is typically constructed from a sample-taxa count matrix that is obtained by sequencing multiple biological samples and identifying taxa counts. From large-scale microbiome studies, it is evident that microbial community compositions and interactions are impacted by environmental and/or host factors. Thus, it is not unreasonable to expect that a sample-taxa matrix generated as part of a large study involving multiple environmental or clinical parameters can be associated with more than one microbial network. However, to our knowledge, microbial network inference methods proposed thus far assume that the sample-taxa matrix is associated with a single network.
Results
We present a mixture model framework to address the scenario when the sample-taxa matrix is associated with K microbial networks. This count matrix is modeled using a mixture of K Multivariate Poisson Log-Normal distributions and parameters are estimated using a maximum likelihood framework. Our parameter estimation algorithm is based on the minorization–maximization principle combined with gradient ascent and block updates. Synthetic datasets were generated to assess the performance of our approach on absolute count data, compositional data and normalized data. We also addressed the recovery of sparse networks based on an l1-penalty model.
Availability and implementation
MixMPLN is implemented in R and is freely available at https://github.com/sahatava/MixMPLN.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

ISMB/ECCB 2019 Proceedings

Fri, 2019-07-05 02:00
The biennial joint meeting of ISMB (27th Annual Conference on Intelligent Systems for Molecular Biology) and ECCB (18th European Conference on Computational Biology) was held in Basel, Switzerland, July 21–25, 2019. ISMB is the flagship conference of the International Society for Computational Biology and the world’s premier forum for dissemination of scientific research in computational biology and its intersection with other areas. ECCB is similarly a top venue in the field, with a long tradition of publishing and presenting world-class research. This special issue serves as the Proceedings of ISMB/ECCB 2019.
Categories: Bioinformatics, Journals

ShaKer: RNA SHAPE prediction using graph kernel

Fri, 2019-07-05 02:00
Abstract
Summary
SHAPE experiments are used to probe the structure of RNA molecules. We present ShaKer to predict SHAPE data for RNA using a graph-kernel-based machine learning approach that is trained on experimental SHAPE information. While other available methods require a manually curated reference structure, ShaKer predicts reactivity data based on sequence input only and by sampling the ensemble of possible structures. Thus, ShaKer is well placed to enable experiment-driven, transcriptome-wide SHAPE data prediction to enable the study of RNA structuredness and to improve RNA structure and RNA–RNA interaction prediction. For performance evaluation, we use accuracy and accessibility comparing to experimental SHAPE data and competing methods. We can show that Shaker outperforms its competitors and is able to predict high quality SHAPE annotations even when no reference structure is provided.
Availability and implementation
ShaKer is freely available at https://github.com/BackofenLab/ShaKer.
Categories: Bioinformatics, Journals

Using the structure of genome data in the design of deep neural networks for predicting amyotrophic lateral sclerosis from genotype

Fri, 2019-07-05 02:00
Abstract
Motivation
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by aberrations in the genome. While several disease-causing variants have been identified, a major part of heritability remains unexplained. ALS is believed to have a complex genetic basis where non-additive combinations of variants constitute disease, which cannot be picked up using the linear models employed in classical genotype–phenotype association studies. Deep learning on the other hand is highly promising for identifying such complex relations. We therefore developed a deep-learning based approach for the classification of ALS patients versus healthy individuals from the Dutch cohort of the Project MinE dataset. Based on recent insight that regulatory regions harbor the majority of disease-associated variants, we employ a two-step approach: first promoter regions that are likely associated to ALS are identified, and second individuals are classified based on their genotype in the selected genomic regions. Both steps employ a deep convolutional neural network. The network architecture accounts for the structure of genome data by applying convolution only to parts of the data where this makes sense from a genomics perspective.
Results
Our approach identifies potentially ALS-associated promoter regions, and generally outperforms other classification methods. Test results support the hypothesis that non-additive combinations of variants contribute to ALS. Architectures and protocols developed are tailored toward processing population-scale, whole-genome data. We consider this a relevant first step toward deep learning assisted genotype–phenotype association in whole genome-sized data.
Availability and implementation
Our code will be available on Github, together with a synthetic dataset (https://github.com/byin-cwi/ALS-Deeplearning). The data used in this study is available to bona-fide researchers upon request.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

Multifaceted protein–protein interaction prediction based on Siamese residual RCNN

Fri, 2019-07-05 02:00
Abstract
Motivation
Sequence-based protein–protein interaction (PPI) prediction represents a fundamental computational biology problem. To address this problem, extensive research efforts have been made to extract predefined features from the sequences. Based on these features, statistical algorithms are learned to classify the PPIs. However, such explicit features are usually costly to extract, and typically have limited coverage on the PPI information.
Results
We present an end-to-end framework, PIPR (Protein–Protein Interaction Prediction Based on Siamese Residual RCNN), for PPI predictions using only the protein sequences. PIPR incorporates a deep residual recurrent convolutional neural network in the Siamese architecture, which leverages both robust local features and contextualized information, which are significant for capturing the mutual influence of proteins sequences. PIPR relieves the data pre-processing efforts that are required by other systems, and generalizes well to different application scenarios. Experimental evaluations show that PIPR outperforms various state-of-the-art systems on the binary PPI prediction problem. Moreover, it shows a promising performance on more challenging problems of interaction type prediction and binding affinity estimation, where existing approaches fall short.
Availability and implementation
The implementation is available at https://github.com/muhaochen/seq_ppi.git.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

Weighted elastic net for unsupervised domain adaptation with application to age prediction from DNA methylation data

Fri, 2019-07-05 02:00
Abstract
Motivation
Predictive models are a powerful tool for solving complex problems in computational biology. They are typically designed to predict or classify data coming from the same unknown distribution as the training data. In many real-world settings, however, uncontrolled biological or technical factors can lead to a distribution mismatch between datasets acquired at different times, causing model performance to deteriorate on new data. A common additional obstacle in computational biology is scarce data with many more features than samples. To address these problems, we propose a method for unsupervised domain adaptation that is based on a weighted elastic net. The key idea of our approach is to compare dependencies between inputs in training and test data and to increase the cost of differently behaving features in the elastic net regularization term. In doing so, we encourage the model to assign a higher importance to features that are robust and behave similarly across domains.
Results
We evaluate our method both on simulated data with varying degrees of distribution mismatch and on real data, considering the problem of age prediction based on DNA methylation data across multiple tissues. Compared with a non-adaptive standard model, our approach substantially reduces errors on samples with a mismatched distribution. On real data, we achieve far lower errors on cerebellum samples, a tissue which is not part of the training data and poorly predicted by standard models. Our results demonstrate that unsupervised domain adaptation is possible for applications in computational biology, even with many more features than samples.
Availability and implementation
Source code is available at https://github.com/PfeiferLabTue/wenda.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

Statistical compression of protein sequences and inference of marginal probability landscapes over competing alignments using finite state models and Dirichlet priors

Fri, 2019-07-05 02:00
Abstract
The information criterion of minimum message length (MML) provides a powerful statistical framework for inductive reasoning from observed data. We apply MML to the problem of protein sequence comparison using finite state models with Dirichlet distributions. The resulting framework allows us to supersede the ad hoc cost functions commonly used in the field, by systematically addressing the problem of arbitrariness in alignment parameters, and the disconnect between substitution scores and gap costs. Furthermore, our framework enables the generation of marginal probability landscapes over all possible alignment hypotheses, with potential to facilitate the users to simultaneously rationalize and assess competing alignment relationships between protein sequences, beyond simply reporting a single (best) alignment. We demonstrate the performance of our program on benchmarks containing distantly related protein sequences.
Availability and implementation
The open-source program supporting this work is available from: http://lcb.infotech.monash.edu.au/seqmmligner.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

MCS2: minimal coordinated supports for fast enumeration of minimal cut sets in metabolic networks

Fri, 2019-07-05 02:00
Abstract
Motivation
Constraint-based modeling of metabolic networks helps researchers gain insight into the metabolic processes of many organisms, both prokaryotic and eukaryotic. Minimal cut sets (MCSs) are minimal sets of reactions whose inhibition blocks a target reaction in a metabolic network. Most approaches for finding the MCSs in constrained-based models require, either as an intermediate step or as a byproduct of the calculation, the computation of the set of elementary flux modes (EFMs), a convex basis for the valid flux vectors in the network. Recently, Ballerstein et al. proposed a method for computing the MCSs of a network without first computing its EFMs, by creating a dual network whose EFMs are a superset of the MCSs of the original network. However, their dual network is always larger than the original network and depends on the target reaction. Here we propose the construction of a different dual network, which is typically smaller than the original network and is independent of the target reaction, for the same purpose. We prove the correctness of our approach, minimal coordinated support (MCS2), and describe how it can be modified to compute the few smallest MCSs for a given target reaction.
Results
We compare MCS2 to the method of Ballerstein et al. and two other existing methods. We show that MCS2 succeeds in calculating the full set of MCSs in many models where other approaches cannot finish within a reasonable amount of time. Thus, in addition to its theoretical novelty, our approach provides a practical advantage over existing methods.
Availability and implementation
MCS2 is freely available at https://github.com/RezaMash/MCS under the GNU 3.0 license.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

TADA: phylogenetic augmentation of microbiome samples enhances phenotype classification

Fri, 2019-07-05 02:00
Abstract
Motivation
Learning associations of traits with the microbial composition of a set of samples is a fundamental goal in microbiome studies. Recently, machine learning methods have been explored for this goal, with some promise. However, in comparison to other fields, microbiome data are high-dimensional and not abundant; leading to a high-dimensional low-sample-size under-determined system. Moreover, microbiome data are often unbalanced and biased. Given such training data, machine learning methods often fail to perform a classification task with sufficient accuracy. Lack of signal is especially problematic when classes are represented in an unbalanced way in the training data; with some classes under-represented. The presence of inter-correlations among subsets of observations further compounds these issues. As a result, machine learning methods have had only limited success in predicting many traits from microbiome. Data augmentation consists of building synthetic samples and adding them to the training data and is a technique that has proved helpful for many machine learning tasks.
Results
In this paper, we propose a new data augmentation technique for classifying phenotypes based on the microbiome. Our algorithm, called TADA, uses available data and a statistical generative model to create new samples augmenting existing ones, addressing issues of low-sample-size. In generating new samples, TADA takes into account phylogenetic relationships between microbial species. On two real datasets, we show that adding these synthetic samples to the training set improves the accuracy of downstream classification, especially when the training data have an unbalanced representation of classes.
Availability and implementation
TADA is available at https://github.com/tada-alg/TADA.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

MOLI: multi-omics late integration with deep neural networks for drug response prediction

Fri, 2019-07-05 02:00
Abstract
Motivation
Historically, gene expression has been shown to be the most informative data for drug response prediction. Recent evidence suggests that integrating additional omics can improve the prediction accuracy which raises the question of how to integrate the additional omics. Regardless of the integration strategy, clinical utility and translatability are crucial. Thus, we reasoned a multi-omics approach combined with clinical datasets would improve drug response prediction and clinical relevance.
Results
We propose MOLI, a multi-omics late integration method based on deep neural networks. MOLI takes somatic mutation, copy number aberration and gene expression data as input, and integrates them for drug response prediction. MOLI uses type-specific encoding sub-networks to learn features for each omics type, concatenates them into one representation and optimizes this representation via a combined cost function consisting of a triplet loss and a binary cross-entropy loss. The former makes the representations of responder samples more similar to each other and different from the non-responders, and the latter makes this representation predictive of the response values. We validate MOLI on in vitro and in vivo datasets for five chemotherapy agents and two targeted therapeutics. Compared to state-of-the-art single-omics and early integration multi-omics methods, MOLI achieves higher prediction accuracy in external validations. Moreover, a significant improvement in MOLI’s performance is observed for targeted drugs when training on a pan-drug input, i.e. using all the drugs with the same target compared to training only on drug-specific inputs. MOLI’s high predictive power suggests it may have utility in precision oncology.
Availability and implementation
https://github.com/hosseinshn/MOLI.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

DIFFUSE: predicting isoform functions from sequences and expression profiles via deep learning

Fri, 2019-07-05 02:00
Abstract
Motivation
Alternative splicing generates multiple isoforms from a single gene, greatly increasing the functional diversity of a genome. Although gene functions have been well studied, little is known about the specific functions of isoforms, making accurate prediction of isoform functions highly desirable. However, the existing approaches to predicting isoform functions are far from satisfactory due to at least two reasons: (i) unlike genes, isoform-level functional annotations are scarce. (ii) The information of isoform functions is concealed in various types of data including isoform sequences, co-expression relationship among isoforms, etc.
Results
In this study, we present a novel approach, DIFFUSE (Deep learning-based prediction of IsoForm FUnctions from Sequences and Expression), to predict isoform functions. To integrate various types of data, our approach adopts a hybrid framework by first using a deep neural network (DNN) to predict the functions of isoforms from their genomic sequences and then refining the prediction using a conditional random field (CRF) based on co-expression relationship. To overcome the lack of isoform-level ground truth labels, we further propose an iterative semi-supervised learning algorithm to train both the DNN and CRF together. Our extensive computational experiments demonstrate that DIFFUSE could effectively predict the functions of isoforms and genes. It achieves an average area under the receiver operating characteristics curve of 0.840 and area under the precision–recall curve of 0.581 over 4184 GO functional categories, which are significantly higher than the state-of-the-art methods. We further validate the prediction results by analyzing the correlation between functional similarity, sequence similarity, expression similarity and structural similarity, as well as the consistency between the predicted functions and some well-studied functional features of isoform sequences.
Availability and implementation
https://github.com/haochenucr/DIFFUSE.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

Prediction of mRNA subcellular localization using deep recurrent neural networks

Fri, 2019-07-05 02:00
Abstract
Motivation
Messenger RNA subcellular localization mechanisms play a crucial role in post-transcriptional gene regulation. This trafficking is mediated by trans-acting RNA-binding proteins interacting with cis-regulatory elements called zipcodes. While new sequencing-based technologies allow the high-throughput identification of RNAs localized to specific subcellular compartments, the precise mechanisms at play, and their dependency on specific sequence elements, remain poorly understood.
Results
We introduce RNATracker, a novel deep neural network built to predict, from their sequence alone, the distributions of mRNA transcripts over a predefined set of subcellular compartments. RNATracker integrates several state-of-the-art deep learning techniques (e.g. CNN, LSTM and attention layers) and can make use of both sequence and secondary structure information. We report on a variety of evaluations showing RNATracker’s strong predictive power, which is significantly superior to a variety of baseline predictors. Despite its complexity, several aspects of the model can be isolated to yield valuable, testable mechanistic hypotheses, and to locate candidate zipcode sequences within transcripts.
Availability and implementation
Code and data can be accessed at https://www.github.com/HarveyYan/RNATracker.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

PRISM: methylation pattern-based, reference-free inference of subclonal makeup

Fri, 2019-07-05 02:00
Abstract
Motivation
Characterizing cancer subclones is crucial for the ultimate conquest of cancer. Thus, a number of bioinformatic tools have been developed to infer heterogeneous tumor populations based on genomic signatures such as mutations and copy number variations. Despite accumulating evidence for the significance of global DNA methylation reprogramming in certain cancer types including myeloid malignancies, none of the bioinformatic tools are designed to exploit subclonally reprogrammed methylation patterns to reveal constituent populations of a tumor. In accordance with the notion of global methylation reprogramming, our preliminary observations on acute myeloid leukemia (AML) samples implied the existence of subclonally occurring focal methylation aberrance throughout the genome.
Results
We present PRISM, a tool for inferring the composition of epigenetically distinct subclones of a tumor solely from methylation patterns obtained by reduced representation bisulfite sequencing. PRISM adopts DNA methyltransferase 1-like hidden Markov model-based in silico proofreading for the correction of erroneous methylation patterns. With error-corrected methylation patterns, PRISM focuses on a short individual genomic region harboring dichotomous patterns that can be split into fully methylated and unmethylated patterns. Frequencies of such two patterns form a sufficient statistic for subclonal abundance. A set of statistics collected from each genomic region is modeled with a beta-binomial mixture. Fitting the mixture with expectation-maximization algorithm finally provides inferred composition of subclones. Applying PRISM for two AML samples, we demonstrate that PRISM could infer the evolutionary history of malignant samples from an epigenetic point of view.
Availability and implementation
PRISM is freely available on GitHub (https://github.com/dohlee/prism).
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

Inference of clonal selection in cancer populations using single-cell sequencing data

Fri, 2019-07-05 02:00
Abstract
Summary
Intra-tumor heterogeneity is one of the major factors influencing cancer progression and treatment outcome. However, evolutionary dynamics of cancer clone populations remain poorly understood. Quantification of clonal selection and inference of fitness landscapes of tumors is a key step to understanding evolutionary mechanisms driving cancer. These problems could be addressed using single-cell sequencing (scSeq), which provides an unprecedented insight into intra-tumor heterogeneity allowing to study and quantify selective advantages of individual clones. Here, we present Single Cell Inference of FItness Landscape (SCIFIL), a computational tool for inference of fitness landscapes of heterogeneous cancer clone populations from scSeq data. SCIFIL allows to estimate maximum likelihood fitnesses of clone variants, measure their selective advantages and order of appearance by fitting an evolutionary model into the tumor phylogeny. We demonstrate the accuracy our approach, and show how it could be applied to experimental tumor data to study clonal selection and infer evolutionary history. SCIFIL can be used to provide new insight into the evolutionary dynamics of cancer.
Availability and implementation
Its source code is available at https://github.com/compbel/SCIFIL.
Categories: Bioinformatics, Journals

scOrange—a tool for hands-on training of concepts from single-cell data analytics

Fri, 2019-07-05 02:00
Abstract
Motivation
Single-cell RNA sequencing allows us to simultaneously profile the transcriptomes of thousands of cells and to indulge in exploring cell diversity, development and discovery of new molecular mechanisms. Analysis of scRNA data involves a combination of non-trivial steps from statistics, data visualization, bioinformatics and machine learning. Training molecular biologists in single-cell data analysis and empowering them to review and analyze their data can be challenging, both because of the complexity of the methods and the steep learning curve.
Results
We propose a workshop-style training in single-cell data analytics that relies on an explorative data analysis toolbox and a hands-on teaching style. The training relies on scOrange, a newly developed extension of a data mining framework that features workflow design through visual programming and interactive visualizations. Workshops with scOrange can proceed much faster than similar training methods that rely on computer programming and analysis through scripting in R or Python, allowing the trainer to cover more ground in the same time-frame. We here review the design principles of the scOrange toolbox that support such workshops and propose a syllabus for the course. We also provide examples of data analysis workflows that instructors can use during the training.
Availability and implementation
scOrange is an open-source software. The software, documentation and an emerging set of educational videos are available at http://singlecell.biolab.si.
Categories: Bioinformatics, Journals

Reconstructing signaling pathways using regular language constrained paths

Fri, 2019-07-05 02:00
Abstract
Motivation
High-quality curation of the proteins and interactions in signaling pathways is slow and painstaking. As a result, many experimentally detected interactions are not annotated to any pathways. A natural question that arises is whether or not it is possible to automatically leverage existing pathway annotations to identify new interactions for inclusion in a given pathway.
Results
We present RegLinker, an algorithm that achieves this purpose by computing multiple short paths from pathway receptors to transcription factors within a background interaction network. The key idea underlying RegLinker is the use of regular language constraints to control the number of non-pathway interactions that are present in the computed paths. We systematically evaluate RegLinker and five alternative approaches against a comprehensive set of 15 signaling pathways and demonstrate that RegLinker recovers withheld pathway proteins and interactions with the best precision and recall. We used RegLinker to propose new extensions to the pathways. We discuss the literature that supports the inclusion of these proteins in the pathways. These results show the broad potential of automated analysis to attenuate difficulties of traditional manual inquiry.
Availability and implementation
https://github.com/Murali-group/RegLinker.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals

hicGAN infers super resolution Hi-C data with generative adversarial networks

Fri, 2019-07-05 02:00
Abstract
Motivation
Hi-C is a genome-wide technology for investigating 3D chromatin conformation by measuring physical contacts between pairs of genomic regions. The resolution of Hi-C data directly impacts the effectiveness and accuracy of downstream analysis such as identifying topologically associating domains (TADs) and meaningful chromatin loops. High resolution Hi-C data are valuable resources which implicate the relationship between 3D genome conformation and function, especially linking distal regulatory elements to their target genes. However, high resolution Hi-C data across various tissues and cell types are not always available due to the high sequencing cost. It is therefore indispensable to develop computational approaches for enhancing the resolution of Hi-C data.
Results
We proposed hicGAN, an open-sourced framework, for inferring high resolution Hi-C data from low resolution Hi-C data with generative adversarial networks (GANs). To the best of our knowledge, this is the first study to apply GANs to 3D genome analysis. We demonstrate that hicGAN effectively enhances the resolution of low resolution Hi-C data by generating matrices that are highly consistent with the original high resolution Hi-C matrices. A typical scenario of usage for our approach is to enhance low resolution Hi-C data in new cell types, especially where the high resolution Hi-C data are not available. Our study not only presents a novel approach for enhancing Hi-C data resolution, but also provides fascinating insights into disclosing complex mechanism underlying the formation of chromatin contacts.
Availability and implementation
We release hicGAN as an open-sourced software at https://github.com/kimmo1019/hicGAN.
Supplementary information
Supplementary dataSupplementary data are available at Bioinformatics online.
Categories: Bioinformatics, Journals