SUMMARY: PyHMMER provides Python integration of the popular profile Hidden Markov Model software HMMER via Cython bindings. This allows the annotation of protein sequences with profile HMMs and building new ones directly with Python. PyHMMER increases flexibility of use, allowing creating queries directly from Python code, launching searches, and obtaining results without I/O, or accessing previously unavailable statistics like uncorrected P-values. A new parallelization model greatly improves performance when running multithreaded searches, while producing the exact same results as HMMER. AVAILABILITY AND IMPLEMENTATION: PyHMMER supports all modern Python versions (Python 3.6+) and similar platforms as HMMER (x86 or PowerPC UNIX systems). Pre-compiled packages are released via PyPI (https://pypi.org/project/pyhmmer/) and Bioconda (https://anaconda.org/bioconda/pyhmmer). The PyHMMER source code is available under the terms of the open-source MIT licence and hosted on GitHub (https://github.com/althonos/pyhmmer); its documentation is available on ReadTheDocs (https://pyhmmer.readthedocs.io).

MOTIVATION: Data on bioactivities of drug-like chemicals are rapidly accumulating in public repositories, creating new opportunities for research in computational systems pharmacology. However, integrative analysis of these data sets is difficult due to prevailing ambiguity between chemical names and identifiers and a lack of cross-references between databases. RESULTS: To address this challenge, we have developed CART, a Chemical Annotation Retrieval Toolkit. As a key functionality, it matches an input list of chemical names into a comprehensive reference space to assign unambiguous chemical identifiers. In this unified space, bioactivity annotations can be easily retrieved from databases covering a wide variety of chemical effects on biological systems. Subsequently, CART can determine annotations enriched in the input set of chemicals and display these in tabular format and interactive network visualizations, thereby facilitating integrative analysis of chemical bioactivity data. AVAILABILITY AND IMPLEMENTATION: CART is available as a Galaxy web service (cart.embl.de). Source code and an easy-to-install command line tool can also be obtained from the web site. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

UNLABELLED: MOCAT2 is a software pipeline for metagenomic sequence assembly and gene prediction with novel features for taxonomic and functional abundance profiling. The automated generation and efficient annotation of non-redundant reference catalogs by propagating pre-computed assignments from 18 databases covering various functional categories allows for fast and comprehensive functional characterization of metagenomes. AVAILABILITY AND IMPLEMENTATION: MOCAT2 is implemented in Perl 5 and Python 2.7, designed for 64-bit UNIX systems and offers support for high-performance computer usage via LSF, PBS or SGE queuing systems; source code is freely available under the GPL3 license at http://mocat.embl.de CONTACT: : [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

We present Oqtans, an open-source workbench for quantitative transcriptome analysis, that is integrated in Galaxy. Its distinguishing features include customizable computational workflows and a modular pipeline architecture that facilitates comparative assessment of tool and data quality. Oqtans integrates an assortment of machine learning-powered tools into Galaxy, which show superior or equal performance to state-of-the-art tools. Implemented tools comprise a complete transcriptome analysis workflow: short-read alignment, transcript identification/quantification and differential expression analysis. Oqtans and Galaxy facilitate persistent storage, data exchange and documentation of intermediate results and analysis workflows. We illustrate how Oqtans aids the interpretation of data from different experiments in easy to understand use cases. Users can easily create their own workflows and extend Oqtans by integrating specific tools. Oqtans is available as (i) a cloud machine image with a demo instance at cloud.oqtans.org, (ii) a public Galaxy instance at galaxy.cbio.mskcc.org, (iii) a git repository containing all installed software (oqtans.org/git); most of which is also available from (iv) the Galaxy Toolshed and (v) a share string to use along with Galaxy CloudMan.

The current revolution in sequencing technologies allows us to obtain a much more detailed picture of transcriptomes via deep RNA Sequencing (RNA-Seq). In considering the full complement of RNA transcripts that comprise the transcriptome, two important analytical questions emerge: what is the abundance of RNA transcripts and which genes or transcripts are differentially expressed. In parallel with developing sequencing technologies, data analysis software is also constantly updated to improve accuracy and sensitivity while minimizing run times. The abundance of software programs, however, can be prohibitive and confusing for researchers evaluating RNA-Seq analysis pipelines. We present an open-source workbench, Oqtans , that can be integrated into the Galaxy framework that enables researchers to set up a computational pipeline for quantitative transcriptome analysis. Its distinguishing features include a modular pipeline architecture, which facilitates comparative assessment of tool and data quality. Within Oqtans , the Galaxy ’s workflow architecture enables direct comparison of several tools. Furthermore, it is straightforward to compare the performance of different programs and parameter settings on the same data and choose the best suited for the task. Oqtans analysis pipelines are easy to set up, modify, and (re-)use without significant computational skill. Oqtans integrates more than twenty sophisticated tools that perform very well compared to the state-of-the-art for transcript identification, quantification and differential expression analysis. The toolsuite contains several tools developed in the Rätsch Laboratory, but the majority of the tools were developed by other groups. In particular, we provide tools for read alignment (bwa, STAR, TopHat, PALMapper, …), transcript prediction (cufflinks, Trinity, Scripture, …) and quantitative analyses (DESeq2, edgeR, rDiff, rQuant, …). In addition, we provide tools for alignment filtering (RNA-geeq toolbox), GFF file processing (GFF toolbox) and tools for predictive sequence analysis (EasySVM, ASP, ARTS, …). See http://oqtans.org/tools for more details on included tools. Oqtans is integrated into the publicly available Galaxy server http://galaxy.cbio.mskcc.org which is maintained by the Rätsch Laboratory. It is also available as source code in a public GitHub repository http://bioweb.me/oqtans/git and as a machine image (managed by Galaxy CloudMan) for the Amazon Web Service cloud environment (instructions available at http://oqtans.org ). Oqtans sets a new standard in terms of reproducibility and builds upon Galaxy’s features to facilitate persistent storage, exchange and documentation of intermediate results and analysis workflows. Support: [email protected] Contact: [email protected] Details: http://oqtans.org Public Computing Server: http://galaxy.cbio.mskcc.org oqtans Demo Server: http://cloud.oqtans.org oqtans Amazon Machine Image: ami-65376a0c License: GPL http://www.gnu.org/licenses/gpl.html

We present a novel regularization-based Multitask Learning (MTL) formulation for Structured Output (SO) prediction for the case of hierarchical task relations. Structured output learning often results in difficult inference problems and requires large amounts of training data to obtain accurate models. We propose to use MTL to exploit information available for related structured output learning tasks by means of hierarchical regularization. Due to the combination of example sets, the cost of training models for structured output prediction can easily become infeasible for real world applications. We thus propose an efficient algorithm based on bundle methods to solve the optimization problems resulting from MTL structured output learning. We demonstrate the performance of our approach on gene finding problems from the application domain of computational biology. We show that 1) our proposed solver achieves much faster convergence than previous methods and 2) that the Hierarchical SO-MTL approach clearly outperforms considered non-MTL methods.

BACKGROUND: Alternative splicing (AS) is a process which generates several distinct mRNA isoforms from the same gene by splicing different portions out of the precursor transcript. Due to the (patho-)physiological importance of AS, a complete inventory of AS is of great interest. While this is in reach for human and mammalian model organisms, our knowledge of AS in plants has remained more incomplete. Experimental approaches for monitoring AS are either based on transcript sequencing or rely on hybridization to DNA microarrays. Among the microarray platforms facilitating the discovery of AS events, tiling arrays are well-suited for identifying intron retention, the most prevalent type of AS in plants. However, analyzing tiling array data is challenging, because of high noise levels and limited probe coverage. RESULTS: In this work, we present a novel method to detect intron retentions (IR) and exon skips (ES) from tiling arrays. While statistical tests have typically been proposed for this purpose, our method instead utilizes support vector machines (SVMs) which are appreciated for their accuracy and robustness to noise. Existing EST and cDNA sequences served for supervised training and evaluation. Analyzing a large collection of publicly available microarray and sequence data for the model plant A. thaliana, we demonstrated that our method is more accurate than existing approaches. The method was applied in a genome-wide screen which resulted in the discovery of 1,355 IR events. A comparison of these IR events to the TAIR annotation and a large set of short-read RNA-seq data showed that 830 of the predicted IR events are novel and that 525 events (39%) overlap with either the TAIR annotation or the IR events inferred from the RNA-seq data. CONCLUSIONS: The method developed in this work expands the scarce repertoire of analysis tools for the identification of alternative mRNA splicing from whole-genome tiling arrays. Our predictions are highly enriched with known AS events and complement the A. thaliana genome annotation with respect to AS. Since all predicted AS events can be precisely attributed to experimental conditions, our work provides a basis for follow-up studies focused on the elucidation of the regulatory mechanisms underlying tissue-specific and stress-dependent AS in plants.

The current revolution in sequencing technologies allows us to obtain a much more detailed picture of transcriptomes via RNA-Sequencing. We have developed the first integrative online platform, oqtans, for quantitatively analyzing RNA-Seq experiments. Our approach of providing a self-contained machine image with the accessible, transparent Galaxy framework [ 1 ] minimizes the risk of using a third-party web service for data analysis. These services often disappear a few years after publication and render results irreproducible [ 2 ]. With oqtans, bioinformatics becomes reproducible by providing analysis building blocks for a customized workflow of read mapping, transcript reconstruction and quantitation as well as differential expression analysis. Oqtans includes a comprehensive machine-learning-powered toolsuite developed by the authors for NGS data analysis. PALMapper is a short-read mapper which efficiently computes both unspliced and spliced alignments at high accuracy by taking advantage of base quality information and computational splice site predictions [ 3 ]. mTIM is a transcript reconstruction method, which exploits features derived from RNA-seq read alignments and from computational splice site predictions to infer the exon-intron structure of the corresponding transcripts. rQuant is based on quadratic programming. It simultaneously estimates biases inherent in library preparation, sequencing, and read mapping, and accurately determines the abundances of given transcripts [ 4 ]. rDiff is a set of statistical test techniques that determine significant differences between two RNA-seq experiments to find differentially expressed regions with or without knowledge of transcripts. We compare predictions to the published annotation at the intron and transcript levels. The performance of read aligners is shown in Fig. 1A from D. melanogaster data , and transcript segmentation tools in Fig. 1B, on C. elegans . Our tools, PALMapper and mTIM, outperform TopHat [ 5 ] and Cufflinks [ 6 ]. Oqtans is available free and open-source, from http://oqtans.org as a virtual machine for cloud computing environments, and ready to use on our public compute cluster at http://bioweb.me/mlb-galaxy . A) Accuracy (F-score) of intron predictions in 3-day-old adults of D. melanogaster with aligners PALMapper (green) and TopHat (blue). B) Accuracy of intron predictions with the same aligners and transcript predictions with mTIM (green) and Cufflinks (blue) on C. elegans RNA-seq transcriptome data.

Combinatorial therapy is a promising strategy for combating complex disorders due to improved efficacy and reduced side effects. However, screening new drug combinations exhaustively is impractical considering all possible combinations between drugs. Here, we present a novel computational approach to predict drug combinations by integrating molecular and pharmacological data. Specifically, drugs are represented by a set of their properties, such as their targets or indications. By integrating several of these features, we show that feature patterns enriched in approved drug combinations are not only predictive for new drug combinations but also provide insights into mechanisms underlying combinatorial therapy. Further analysis confirmed that among our top ranked predictions of effective combinations, 69% are supported by literature, while the others represent novel potential drug combinations. We believe that our proposed approach can help to limit the search space of drug combinations and provide a new way to effectively utilize existing drugs for new purposes.

An increasingly large number of novel genomes is being sequenced and the task of automatic genome annotation has never been more important.The current revolution in sequencing technologies also allows us to obtain a detailed picture of the whole complement of expressed RNA transcripts.We have developed a novel de novo gene finding system mGene.ngsthat combines the benefits of accurate ab initio gene finding with the rich information obtained in RNA sequencing (RNA-seq) experiments.The system is based on the recently developed accurate gene finding system mGene [1], which employs state-of-the-art prediction techniques and which has been shown to perform very well compared to established gene finding systems [2].In contrast to many HMM-based gene finders, mGene has the conceptual advantage of being very flexible in terms of incorporating heterogeneous input data.The employed inference techniques can exploit the transcriptome information already at the learning stage to appropriately adapt to the relevance of the different evidences.We show that these advantages can be translated into more accurate gene predictions.Moreover, we developed extensions of mGene.ngs to predict and quantify alternative RNA transcripts.To provide de novo genome annotations based on RNA-seq experiments, we first construct a preliminary, highly specific gene set for genes that are well-covered with RNA-seq reads.In a second step, we train predictors for genomic signals on the preliminary gene set.In the third step we train mGene.ngs,using the preliminary gene models while taking advantage of the RNA-seq read coverage and genomic signal predictions.