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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 83,609 bioRxiv papers from 360,279 authors.

Most downloaded bioRxiv papers, all time

in category bioinformatics

7,875 results found. For more information, click each entry to expand.

41: Bayesian Inference for a Generative Model of Transcriptome Profiles from Single-cell RNA Sequencing
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Posted to bioRxiv 30 Mar 2018

Bayesian Inference for a Generative Model of Transcriptome Profiles from Single-cell RNA Sequencing
8,153 downloads bioinformatics

Romain Lopez, Jeffrey Regier, Michael Cole, Michael Jordan, Nir Yosef

Transcriptome profiles of individual cells reflect true and often unexplored biological diversity, but are also affected by noise of biological and technical nature. This raises the need to explicitly model the resulting uncertainty and take it into account in any downstream analysis, such as dimensionality reduction, clustering, and differential expression. Here, we introduce Single-cell Variational Inference (scVI), a scalable framework for probabilistic representation and analysis of gene expression in single cells. Our model uses variational inference and stochastic optimization of deep neural networks to approximate the parameters that govern the distribution of expression values of each gene in every cell, using a non-linear mapping between the observations and a low-dimensional latent space. By doing so, scVI pools information between similar cells or genes while taking nuisance factors of variation such as batch effects and limited sensitivity into account. To evaluate scVI, we conducted a comprehensive comparative analysis to existing methods for distributional modeling and dimensionality reduction, all of which rely on generalized linear models. We first show that scVI scales to over one million cells, whereas competing algorithms can process at most tens of thousands of cells. Next, we show that scVI fits unseen data more closely and can impute missing data more accurately, both indicative of a better generalization capacity. We then utilize scVI to conduct a set of fundamental analysis tasks -- including batch correction, visualization, clustering and differential expression -- and demonstrate its accuracy in comparison to the state-of-the-art tools in each task. scVI is publicly available, and can be readily used as a principled and inclusive solution for multiple tasks of single-cell RNA sequencing data analysis.

42: Performance of neural network basecalling tools for Oxford Nanopore sequencing
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Posted to bioRxiv 07 Feb 2019

Performance of neural network basecalling tools for Oxford Nanopore sequencing
8,133 downloads bioinformatics

Ryan R. Wick, Louise M. Judd, Kathryn E. Holt

Background Basecalling, the computational process of translating raw electrical signal to nucleotide sequence, is of critical importance to the sequencing platforms produced by Oxford Nanopore Technologies (ONT). Here we examine the performance of different basecalling tools, looking at accuracy at the level of bases within individual reads and at majority-rules consensus basecalls in an assembly. We also investigate some additional aspects of basecalling: training using a taxon-specific dataset, using a larger neural network model and improving consensus basecalls in an assembly by additional signal-level analysis with Nanopolish. Results Training basecallers on taxon-specific data results in a significant boost in consensus accuracy, mostly due to the reduction of errors in methylation motifs. A larger neural network is able to improve both read and consensus accuracy, but at a cost to speed. Improving consensus sequences (‘polishing’) with Nanopolish somewhat negates the accuracy differences in basecallers, but prepolish accuracy does have an effect on post-polish accuracy. Conclusions Basecalling accuracy has seen significant improvements over the last two years. The current version of ONT’s Guppy basecaller performs well overall, with good accuracy and fast performance. If higher accuracy is required, users should consider producing a custom model using a larger neural network and/or training data from the same species.

43: Deep Learning and Association Rule Mining for Predicting Drug Response in Cancer. A Personalised Medicine Approach.
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Posted to bioRxiv 19 Aug 2016

Deep Learning and Association Rule Mining for Predicting Drug Response in Cancer. A Personalised Medicine Approach.
8,015 downloads bioinformatics

Konstantinos Vougas, Magdalena Krochmal, Thomas Jackson, Alexander Polyzos, Archimides Aggelopoulos, Ioannis S Pateras, Michael Liontos, Anastasia Varvarigou, Elizabeth O Johnson, Vassilis Georgoulias, Antonia Vlahou, Paul Townsend, Dimitris Thanos, Jiri Bartek, Vassilis G Gorgoulis

A major challenge in cancer treatment is predicting the clinical response to anti-cancer drugs for each individual patient. For complex diseases such as cancer, characterized by high inter-patient variance, the implementation of precision medicine approaches is dependent upon understanding the pathological processes at the molecular level. While the 'omics' era provides unique opportunities to dissect the molecular features of diseases, the ability to utilize it in targeted therapeutic efforts is hindered by both the massive size and diverse nature of the 'omics' data. Recent advances with Deep Learning Neural Networks (DLNNs), suggests that DLNN could be trained on large data sets to efficiently predict therapeutic responses in cancer treatment. We present the application of Association Rule Mining combined with DLNNs for the analysis of high-throughput molecular profiles of 1001 cancer cell lines, in order to extract cancer-specific signatures in the form of easily interpretable rules and use these rules as input to predict pharmacological responses to a large number of anti-cancer drugs. The proposed algorithm outperformed Random Forests (RF) and Bayesian Multitask Multiple Kernel Learning (BMMKL) classification which currently represent the state-of-the-art in drug-response prediction. Moreover, the in silico pipeline presented, introduces a novel strategy for identifying potential therapeutic targets, as well as possible drug combinations with high therapeutic potential. For the first time, we demonstrate that DLNNs trained on a large pharmacogenomics data-set can effectively predict the therapeutic response of specific drugs in different cancer types. These findings serve as a proof of concept for the application of DLNNs to predict therapeutic responsiveness, a milestone in precision medicine.

44: Canu: scalable and accurate long-read assembly via adaptive k-mer weighting and repeat separation
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Posted to bioRxiv 24 Aug 2016

Canu: scalable and accurate long-read assembly via adaptive k-mer weighting and repeat separation
7,978 downloads bioinformatics

Sergey Koren, Brian P Walenz, Konstantin Berlin, Jason R Miller, Nicholas H. Bergman, Adam M Phillippy

Long-read single-molecule sequencing has revolutionized de novo genome assembly and enabled the automated reconstruction of reference-quality genomes. However, given the relatively high error rates of such technologies, efficient and accurate assembly of large repeats and closely related haplotypes remains challenging. We address these issues with Canu, a successor of Celera Assembler that is specifically designed for noisy single-molecule sequences. Canu introduces support for nanopore sequencing, halves depth-of-coverage requirements, and improves assembly continuity while simultaneously reducing runtime by an order of magnitude on large genomes versus Celera Assembler 8.2. These advances result from new overlapping and assembly algorithms, including an adaptive overlapping strategy based on tf-idf weighted MinHash and a sparse assembly graph construction that avoids collapsing diverged repeats and haplotypes. We demonstrate that Canu can reliably assemble complete microbial genomes and near-complete eukaryotic chromosomes using either PacBio or Oxford Nanopore technologies, and achieves a contig NG50 of greater than 21 Mbp on both human and Drosophila melanogaster PacBio datasets. For assembly structures that cannot be linearly represented, Canu provides graph-based assembly outputs in graphical fragment assembly (GFA) format for analysis or integration with complementary phasing and scaffolding techniques. The combination of such highly resolved assembly graphs with long-range scaffolding information promises the complete and automated assembly of complex genomes.

45: De novo Identification of DNA Modifications Enabled by Genome-Guided Nanopore Signal Processing
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Posted to bioRxiv 15 Dec 2016

De novo Identification of DNA Modifications Enabled by Genome-Guided Nanopore Signal Processing
7,910 downloads bioinformatics

Marcus Stoiber, Joshua Quick, Rob Egan, Ji Eun Lee, Susan Celniker, Robert K. Neely, Nicholas Loman, Len A. Pennacchio, James Brown

Advances in nanopore sequencing technology have enabled investigation of the full catalogue of covalent DNA modifications. We present the first algorithm for the identification of modified nucleotides without the need for prior training data along with the open source software implementation, nanoraw. Nanoraw accurately assigns contiguous raw nanopore signal to genomic positions, enabling novel data visualization, and increasing power and accuracy for the discovery of covalently modified bases in native DNA. Ground truth case studies utilizing synthetically methylated DNA show the capacity to identify three distinct methylation marks, 4mC, 5mC, and 6mA, in seven distinct sequence contexts without any changes to the algorithm. We demonstrate quantitative reproducibility simultaneously identifying 5mC and 6mA in native E. coli across biological replicates processed in different labs. Finally we propose a pipeline for the comprehensive discovery of DNA modifications in any genome without a priori knowledge of their chemical identities.

46: Comparison of long-read sequencing technologies in the hybrid assembly of complex bacterial genomes
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Posted to bioRxiv 26 Jan 2019

Comparison of long-read sequencing technologies in the hybrid assembly of complex bacterial genomes
7,561 downloads bioinformatics

Nicola De Maio, Liam P. Shaw, Alasdair Hubbard, Sophie George, Nick Sanderson, Jeremy Swann, Ryan Wick, Manal AbuOun, Emma Stubberfield, Sarah J Hoosdally, Derrick W Crook, Timothy E. A. Peto, Anna E. Sheppard, Mark J. Bailey, Daniel S. Read, Muna F. Anjum, A Sarah Walker, Nicole Stoesser, on behalf of the REHAB consortium

Illumina sequencing allows rapid, cheap and accurate whole genome bacterial analyses, but short reads (<300 bp) do not usually enable complete genome assembly. Long read sequencing greatly assists with resolving complex bacterial genomes, particularly when combined with short-read Illumina data (hybrid assembly); however, it is not clear how different long-read sequencing methods impact on assembly accuracy. Relative automation of the assembly process is also crucial to facilitating high-throughput complete bacterial genome reconstruction, avoiding multiple bespoke filtering and data manipulation steps. In this study, we compared hybrid assemblies for 20 bacterial isolates, including two reference strains, using Illumina sequencing and long reads from either Oxford Nanopore Technologies (ONT) or from SMRT Pacific Biosciences (PacBio) sequencing platforms. We chose isolates from the Enterobacteriaceae family, as these frequently have highly plastic, repetitive genetic structures and complete genome reconstruction for these species is relevant for a precise understanding of the epidemiology of antimicrobial resistance. We de novo assembled genomes using the hybrid assembler Unicycler and compared different read processing strategies. Both strategies facilitate high-quality genome reconstruction. Combining ONT and Illumina reads fully resolved most genomes without additional manual steps, and at a lower cost per isolate in our setting. Automated hybrid assembly is a powerful tool for complete and accurate bacterial genome assembly.

47: Fast and accurate long-read assembly with wtdbg2
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Posted to bioRxiv 26 Jan 2019

Fast and accurate long-read assembly with wtdbg2
7,456 downloads bioinformatics

Jue Ruan, Heng Li

Existing long-read assemblers require tens of thousands of CPU hours to assemble a human genome and are being outpaced by sequencing technologies in terms of both throughput and cost. We developed a novel long-read assembler wtdbg2 that, for human data, is tens of times faster than published tools while achieving comparable contiguity and accuracy. It represents a significant algorithmic advance and paves the way for population-scale long-read assembly in future.

48: TBtools - an integrative toolkit developed for interactive analyses of big biological data
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Posted to bioRxiv 27 Mar 2018

TBtools - an integrative toolkit developed for interactive analyses of big biological data
7,345 downloads bioinformatics

Chengjie Chen, Hao Chen, Yi Zhang, Hannah R. Thomas, Margaret H Frank, Yehua He, Rui Xia

The rapid development of high-throughput sequencing (HTS) techniques has led biology into the big-data era. Data analyses using various bioinformatics tools rely on programming and command-line environments, which are challenging and time-consuming for most wet-lab biologists. Here, we present TBtools (a Toolkit for Biologists integrating various biological data handling tools), a stand-alone software with a user-friendly interface. The toolkit incorporates over 100 functions, which are designed to meet the increasing demand for big-data analyses, ranging from bulk sequence processing to interactive data visualization. A wide variety of graphs can be prepared in TBtools, with a new plotting engine (“JIGplot”) developed to maximum their interactive ability, which allows quick point-and-click modification to almost every graphic feature. TBtools is a platform-independent software that can be run under all operating systems with Java Runtime Environment 1.6 or newer. It is freely available to non-commercial users at <https://github.com/CJ-Chen/TBtools/releases>.

49: FMRIPrep: a robust preprocessing pipeline for functional MRI
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Posted to bioRxiv 25 Apr 2018

FMRIPrep: a robust preprocessing pipeline for functional MRI
7,312 downloads bioinformatics

Oscar Esteban, Christopher J. Markiewicz, Ross W. Blair, Craig A. Moodie, A. Ilkay Isik, Asier Erramuzpe, James D. Kent, Mathias Goncalves, Elizabeth DuPre, Madeleine Snyder, Hiroyuki Oya, Satrajit S. Ghosh, Jessey Wright, Joke Durnez, Russell A. Poldrack, Krzysztof J. Gorgolewski

Preprocessing of functional MRI (fMRI) involves numerous steps to clean and standardize data before statistical analysis. Generally, researchers create ad hoc preprocessing workflows for each new dataset, building upon a large inventory of tools available for each step. The complexity of these workflows has snowballed with rapid advances in MR data acquisition and image processing techniques. We introduce fMRIPrep, an analysis-agnostic tool that addresses the challenge of robust and reproducible preprocessing for task-based and resting fMRI data. FMRIPrep automatically adapts a best-in-breed workflow to the idiosyncrasies of virtually any dataset, ensuring high-quality preprocessing with no manual intervention. By introducing visual assessment checkpoints into an iterative integration framework for software-testing, we show that fMRIPrep robustly produces high-quality results on a diverse fMRI data collection comprising participants from 54 different studies in the OpenfMRI repository. We review the distinctive features of fMRIPrep in a qualitative comparison to other preprocessing workflows. We demonstrate that fMRIPrep achieves higher spatial accuracy as it introduces less uncontrolled spatial smoothness than commonly used preprocessing tools. FMRIPrep has the potential to transform fMRI research by equipping neuroscientists with a high-quality, robust, easy-to-use and transparent preprocessing workflow which can help ensure the validity of inference and the interpretability of their results.

50: Inference of CRISPR Edits from Sanger Trace Data
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Posted to bioRxiv 20 Jan 2018

Inference of CRISPR Edits from Sanger Trace Data
7,272 downloads bioinformatics

Tim Hsiau, David Conant, Nicholas Rossi, Travis Maures, Kelsey Waite, Joyce Yang, Sahil Joshi, Reed Kelso, Kevin Holden, Brittany L Enzmann, Rich Stoner

Efficient precision genome editing requires a quick, quantitative, and inexpensive assay of editing outcomes. Here we present ICE (Inference of CRISPR Edits), which enables robust analysis of CRISPR edits using Sanger data. ICE proposes potential outcomes for editing with guide RNAs (gRNAs) and then determines which are supported by the data via regression. Additionally, we develop a score called ICE-D (Discordance) that can provide information on large or unexpected edits. We empirically confirm through over 1,800 edits that the ICE algorithm is robust, reproducible, and can analyze CRISPR experiments within days after transfection. We also confirm that ICE strongly correlates with next-generation sequencing of amplicons (Amp-Seq). The ICE tool is free to use and offers several improvements over current analysis tools. For instance, ICE can analyze individual experiments as well as multiple experiments simultaneously (batch analysis). ICE can also detect a wider variety of outcomes, including multi-guide edits (multiple gRNAs per target) and edits resulting from homology-directed repair (HDR), such as knock-ins and base edits. ICE is a reliable analysis tool that can significantly expedite CRISPR editing workflows. It is available online at [ice.synthego.com][1], and the source code is at [github.com/synthego-open/ice][2] [1]: http://ice.synthego.com [2]: http://github.com/synthego-open/ice

51: Efficient de novo assembly of eleven human genomes using PromethION sequencing and a novel nanopore toolkit
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Posted to bioRxiv 26 Jul 2019

Efficient de novo assembly of eleven human genomes using PromethION sequencing and a novel nanopore toolkit
7,271 downloads bioinformatics

Kishwar Shafin, Trevor Pesout, Ryan Lorig-Roach, Marina Haukness, Hugh E Olsen, Colleen Bosworth, Joel Armstrong, Kristof Tigyi, Nicholas Maurer, Sergey Koren, Fritz J. Sedlazeck, Tobias Marschall, Simon Mayes, Vania Costa, Justin M Zook, Kelvin J Liu, Duncan Kilburn, Melanie Sorensen, Katy M Munson, Mitchell R. Vollger, Evan E. Eichler, Sofie Salama, David Haussler, Richard E. Green, Mark Akeson, Adam Phillippy, Karen H. Miga, Paolo Carnevali, Miten Jain, Benedict Paten

Present workflows for producing human genome assemblies from long-read technologies have cost and production time bottlenecks that prohibit efficient scaling to large cohorts. We demonstrate an optimized PromethION nanopore sequencing method for eleven human genomes. The sequencing, performed on one machine in nine days, achieved an average 63x coverage, 42 Kb read N50, 90% median read identity and 6.5x coverage in 100 Kb+ reads using just three flow cells per sample. To assemble these data we introduce new computational tools: Shasta - a de novo long read assembler, and MarginPolish & HELEN - a suite of nanopore assembly polishing algorithms. On a single commercial compute node Shasta can produce a complete human genome assembly in under six hours, and MarginPolish & HELEN can polish the result in just over a day, achieving 99.9% identity (QV30) for haploid samples from nanopore reads alone. We evaluate assembly performance for diploid, haploid and trio-binned human samples in terms of accuracy, cost, and time and demonstrate improvements relative to current state-of-the-art methods in all areas. We further show that addition of proximity ligation (Hi-C) sequencing yields near chromosome-level scaffolds for all eleven genomes.

52: DeepGS: Predicting phenotypes from genotypes using Deep Learning
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Posted to bioRxiv 31 Dec 2017

DeepGS: Predicting phenotypes from genotypes using Deep Learning
7,174 downloads bioinformatics

Wenlong Ma, Zhixu Qiu, Jie Song, Qian Cheng, Chuang Ma

Motivation: Genomic selection (GS) is a new breeding strategy by which the phenotypes of quantitative traits are usually predicted based on genome-wide markers of genotypes using conventional statistical models. However, the GS prediction models typically make strong assumptions and perform linear regression analysis, limiting their accuracies since they do not capture the complex, non-linear relationships within genotypes, and between genotypes and phenotypes. Results: We present a deep learning method, named DeepGS, to predict phenotypes from geno-types. Using a deep convolutional neural network, DeepGS uses hidden variables that jointly repre-sent features in genotypic markers when making predictions; it also employs convolution, sampling and dropout strategies to reduce the complexity of high-dimensional marker data. We used a large GS dataset to train DeepGS and compare its performance with other methods. In terms of mean normalized discounted cumulative gain value, DeepGS achieves an increase of 27.70%~246.34% over a conventional neural network in selecting top-ranked 1% individuals with high phenotypic values for the eight tested traits. Additionally, compared with the widely used method RR-BLUP, DeepGS still yields a relative improvement ranging from 1.44% to 65.24%. Through extensive simulation experiments, we also demonstrated the effectiveness and robustness of DeepGS for the absent of outlier individuals and subsets of genotypic markers. Finally, we illustrated the complementarity of DeepGS and RR-BLUP with an ensemble learning approach for further improving prediction performance. Availability: DeepGS is provided as an open source R package available at https://github.com/cma2015/DeepGS.

53: A Comparison of Methods: Normalizing High-Throughput RNA Sequencing Data
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Posted to bioRxiv 03 Sep 2015

A Comparison of Methods: Normalizing High-Throughput RNA Sequencing Data
7,074 downloads bioinformatics

Rahul Reddy

As RNA-Seq and other high-throughput sequencing grow in use and remain critical for gene expression studies, technical variability in counts data impedes studies of differential expression studies, data across samples and experiments, or reproducing results. Studies like Dillies et al. (2013) compare several between-lane normalization methods involving scaling factors, while Hansen et al. (2012) and Risso et al. (2014) propose methods that correct for sample-specific bias or use sets of control genes to isolate and remove technical variability. This paper evaluates four normalization methods in terms of reducing intra-group, technical variability and facilitating differential expression analysis or other research where the biological, inter-group variability is of interest. To this end, the four methods were evaluated in differential expression analysis between data from Pickrell et al. (2010) and Montgomery et al. (2010) and between simulated data modeled on these two datasets. Though the between-lane scaling factor methods perform worse on real data sets, they are much stronger for simulated data. We cannot reject the recommendation of Dillies et al. to use TMM and DESeq normalization, but further study of power to detect effects of different size under each normalization method is merited.

54: LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis
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Posted to bioRxiv 03 May 2016

LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis
7,031 downloads bioinformatics

Jie Zheng, A Mesut Erzurumluoglu, Benjamin L. Elsworth, Laurence Howe, Philip C Haycock, Gibran Hemani, Katherine Tansey, Charles Laurin, Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium, Beate Pourcain, Nicole M. Warrington, HK Finucane, Alkes L Price, Brendan K. Bulik-Sullivan, Verneri Anttila, Lavinia Paternoster, Tom Gaunt, David M Evans, Benjamin M. Neale

Motivation: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously. Results: In this manuscript, we describe LD Hub - a centralized database of summary-level GWAS results for 177 diseases/traits from different publicly available resources/consortia and a web interface that automates the LD score regression analysis pipeline. To demonstrate functionality and validate our software, we replicated previously reported LD score regression analyses of 49 traits/diseases using LD Hub; and estimated SNP heritability and the genetic correlation across the different phenotypes. We also present new results obtained by uploading a recent atopic dermatitis GWAS meta-analysis to examine the genetic correlation between the condition and other potentially related traits. In response to the growing availability of publicly accessible GWAS summary-level results data, our database and the accompanying web interface will ensure maximal uptake of the LD score regression methodology, provide a useful database for the public dissemination of GWAS results, and provide a method for easily screening hundreds of traits for overlapping genetic aetiologies. Availability and implementation: The web interface and instructions for using LD Hub are available at http://ldsc.broadinstitute.org/

55: Using Deep Learning to Annotate the Protein Universe
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Posted to bioRxiv 03 May 2019

Using Deep Learning to Annotate the Protein Universe
6,991 downloads bioinformatics

Maxwell Bileschi, David Belanger, Drew Bryant, Theo Sanderson, Brandon Carter, D. Sculley, Mark A. DePristo, Lucy Colwell

Understanding the relationship between amino acid sequence and protein function is a long-standing problem in molecular biology with far-reaching scientific implications. Despite six decades of progress, state-of-the-art techniques cannot annotate 1/3 of microbial protein sequences, hampering our ability to exploit sequences collected from diverse organisms. In this paper, we explore an alternative methodology based on deep learning that learns the relationship between unaligned amino acid sequences and their functional annotations across all 17929 families of the Pfam database. Using the Pfam seed sequences we establish rigorous benchmark assessments that use both random and clustered data splits to control for potentially confounding sequence similarities between train and test sequences. Using Pfam full, we report convolutional networks that are significantly more accurate and computationally efficient than BLASTp, while learning sequence features such as structural disorder and transmembrane helices. Our model co-locates sequences from unseen families in embedding space, allowing sequences from novel families to be accurately annotated. These results suggest deep learning models will be a core component of future protein function prediction tools.

56: STAR-Fusion: Fast and Accurate Fusion Transcript Detection from RNA-Seq
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Posted to bioRxiv 24 Mar 2017

STAR-Fusion: Fast and Accurate Fusion Transcript Detection from RNA-Seq
6,813 downloads bioinformatics

Brian J. Haas, Alex Dobin, Nicolas Stransky, Bo Li, Xiao Yang, Timothy Tickle, Asma Bankapur, Carrie Ganote, Thomas G. Doak, Nathalie Pochet, Jing Sun, Catherine J. Wu, Thomas R. Gingeras, Aviv Regev

Motivation: Fusion genes created by genomic rearrangements can be potent drivers of tumorigenesis. However, accurate identification of functionally fusion genes from genomic sequencing requires whole genome sequencing, since exonic sequencing alone is often insufficient. Transcriptome sequencing provides a direct, highly effective alternative for capturing molecular evidence of expressed fusions in the precision medicine pipeline, but current methods tend to be inefficient or insufficiently accurate, lacking in sensitivity or predicting large numbers of false positives. Here, we describe STAR-Fusion, a method that is both fast and accurate in identifying fusion transcripts from RNA-Seq data. Results: We benchmarked STAR-Fusion's fusion detection accuracy using both simulated and genuine Illumina paired-end RNA-Seq data, and show that it has superior performance compared to popular alternative fusion detection methods. Availability and implementation: STAR-Fusion is implemented in Perl, freely available as open source software at http://star-fusion.github.io, and supported on Linux.

57: Graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells
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Posted to bioRxiv 25 Oct 2017

Graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells
6,762 downloads bioinformatics

F. Alexander Wolf, Fiona Hamey, Mireya Plass, Jordi Solana, Joakim S. Dahlin, Berthold Göttgens, Rajewsky Nikolaus, LM Simon, Fabian J Theis

Single-cell RNA-seq allows quantification of biological heterogeneity across both discrete cell types and continuous cell differentiation transitions. We present approximate graph abstraction (AGA), an algorithm that reconciles the computational analysis strategies of clustering and trajectory inference by explaining cell-to-cell variation both in terms of discrete and continuous latent variables (https://github.com/theislab/graph_abstraction). This enables to generate cellular maps of differentiation manifolds with complex topologies --- efficiently and robustly across different datasets. Approximate graph abstraction quantifies the connectivity of partitions of a neighborhood graph of single cells, thereby generating a much simpler abstracted graph whose nodes label the partitions. Together with a random walk-based distance measure, this generates a topology preserving map of single cells --- a partial coordinatization of data useful for exploring and explaining its variation. We use the abstracted graph to assess which subsets of data are better explained by discrete clusters than by a continuous variable, to trace gene expression changes along aggregated single-cell paths through data and to infer abstracted trees that best explain the global topology of data. We demonstrate the power of the method by reconstructing differentiation processes with high numbers of branchings from single-cell gene expression datasets and by identifying biological trajectories from single-cell imaging data using a deep-learning based distance metric. Along with the method, we introduce measures for the connectivity of graph partitions, generalize random-walk based distance measures to disconnected graphs and introduce a path-based measure for topological similarity between graphs. Graph abstraction is computationally efficient and provides speedups of at least 30 times when compared to algorithms for the inference of lineage trees.

58: Fast, sensitive, and accurate integration of single cell data with Harmony
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Posted to bioRxiv 04 Nov 2018

Fast, sensitive, and accurate integration of single cell data with Harmony
6,758 downloads bioinformatics

Ilya Korsunsky, Jean Fan, Kamil Slowikowski, Fan Zhang, Kevin Wei, Yuriy Baglaenko, Michael Brenner, Po-Ru Loh, Soumya Raychaudhuri

The rapidly emerging diversity of single cell RNAseq datasets allows us to characterize the transcriptional behavior of cell types across a wide variety of biological and clinical conditions. With this comprehensive breadth comes a major analytical challenge. The same cell type across tissues, from different donors, or in different disease states, may appear to express different genes. A joint analysis of multiple datasets requires the integration of cells across diverse conditions. This is particularly challenging when datasets are assayed with different technologies in which real biological differences are interspersed with technical differences. We present Harmony, an algorithm that projects cells into a shared embedding in which cells group by cell type rather than dataset-specific conditions. Unlike available single-cell integration methods, Harmony can simultaneously account for multiple experimental and biological factors. We develop objective metrics to evaluate the quality of data integration. In four separate analyses, we demonstrate the superior performance of Harmony to four single-cell-specific integration algorithms. Moreover, we show that Harmony requires dramatically fewer computational resources. It is the only available algorithm that makes the integration of ~1 million cells feasible on a personal computer. We demonstrate that Harmony identifies both broad populations and fine-grained subpopulations of PBMCs from datasets with large experimental differences. In a meta-analysis of 14,746 cells from 5 studies of human pancreatic islet cells, Harmony accounts for variation among technologies and donors to successfully align several rare subpopulations. In the resulting integrated embedding, we identify a previously unidentified population of potentially dysfunctional alpha islet cells, enriched for genes active in the Endoplasmic Reticulum (ER) stress response. The abundance of these alpha cells correlates across donors with the proportion of dysfunctional beta cells also enriched in ER stress response genes. Harmony is a fast and flexible general purpose integration algorithm that enables the identification of shared fine-grained subpopulations across a variety of experimental and biological conditions.

59: Critical Assessment of Metagenome Interpretation − a benchmark of computational metagenomics software
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Posted to bioRxiv 09 Jan 2017

Critical Assessment of Metagenome Interpretation − a benchmark of computational metagenomics software
6,711 downloads bioinformatics

Alexander Sczyrba, Peter Hofmann, Peter Belmann, David Koslicki, Stefan Janssen, Johannes Dröge, Ivan Gregor, Stephan Majda, Jessika Fiedler, Eik Dahms, Andreas Bremges, Adrian Fritz, Ruben Garrido-Oter, Tue Sparholt Jørgensen, Nicole Shapiro, Philip D Blood, Alexey Gurevich, Yang Bai, Dmitrij Turaev, Matthew Z DeMaere, Rayan Chikhi, Niranjan Nagarajan, Christopher Quince, Fernando Meyer, Monika Balvoit, Lars Hestbjerg Hansen, Søren J. Sørensen, Burton K H Chia, Bertrand Denis, Jeff L Froula, Zhong Wang, Robert Egan, Dongwan Don Kang, Jeffrey J Cook, Charles Deltel, Michael Beckstette, Claire Lemaitre, Pierre Peterlongo, Guillaume Rizk, Dominique Lavenier, Yu-Wei Wu, Steven W. Singer, Chirag Jain, Marc Strous, Heiner Klingenberg, Peter Meinicke, Michael Barton, Thomas Lingner, Hsin-Hung Lin, Yu-Chieh Liao, Genivaldo Gueiros Z. Silva, Daniel A. Cuevas, Robert A. Edwards, Surya Saha, Vitor C. Piro, Bernhard Y. Renard, Mihai Pop, Hans-Peter Klenk, Markus Göker, Nikos C. Kyrpides, Tanja Woyke, Julia A. Vorholt, Paul Schulze-Lefert, Edward M Rubin, Aaron E. Darling, Thomas Rattei, Alice C. McHardy

In metagenome analysis, computational methods for assembly, taxonomic profiling and binning are key components facilitating downstream biological data interpretation. However, a lack of consensus about benchmarking datasets and evaluation metrics complicates proper performance assessment. The Critical Assessment of Metagenome Interpretation (CAMI) challenge has engaged the global developer community to benchmark their programs on datasets of unprecedented complexity and realism. Benchmark metagenomes were generated from ~700 newly sequenced microorganisms and ~600 novel viruses and plasmids, including genomes with varying degrees of relatedness to each other and to publicly available ones and representing common experimental setups. Across all datasets, assembly and genome binning programs performed well for species represented by individual genomes, while performance was substantially affected by the presence of related strains. Taxonomic profiling and binning programs were proficient at high taxonomic ranks, with a notable performance decrease below the family level. Parameter settings substantially impacted performances, underscoring the importance of program reproducibility. While highlighting current challenges in computational metagenomics, the CAMI results provide a roadmap for software selection to answer specific research questions.

60: Identification of transcriptional signatures for cell types from single-cell RNA-Seq
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Posted to bioRxiv 01 Feb 2018

Identification of transcriptional signatures for cell types from single-cell RNA-Seq
6,685 downloads bioinformatics

Vasilis Ntranos, Lynn Yi, Páll Melsted, Lior Pachter

Single-cell RNA-Seq makes it possible to characterize the transcriptomes of cell types and identify their transcriptional signatures via differential analysis. We present a fast and accurate method for discriminating cell types that takes advantage of the large numbers of cells that are assayed. When applied to transcript compatibility counts obtained via pseudoalignment, our approach provides a quantification-free analysis of 3' single-cell RNA-Seq that can identify previously undetectable marker genes.

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