Manycore high-performance computing in bioinformatics

Mining the increasing amount of genomic data requires having very efficient tools. Increasing the efficiency can be obtained with better algorithms, but one could also take advantage of the hardware itself to reduce the application runtimes. Since a few years, issues with heat dissipation prevent the processors from having higher frequencies. One of the answers to maintain Moore's Law is parallel processing. Grid environments provide tools for effective implementation of coarse grain parallelization. Recently, another kind of hardware has attracted interest: multicore processors. Graphic processing units (GPUs) are a first step towards massively multicore processors. They allow everyone to have some teraflops of cheap computing power in its personal computer. The CUDA library (released in 2007) and the new standard OpenCL (specified in 2008) make programming of such devices very convenient. OpenCL is likely to gain a wide industrial support and to become a standard of choice for parallel programming. In all cases, the best speedups are obtained when combining precise algorithmic studies with a knowledge of the computing architectures. This is especially true with the memory hierarchy: the algorithms have to find a good balance between using large (and slow) global memories and some fast (but small) local memories. In this chapter, we will show how those manycore devices enable more efficient bioinformatics applications. We will first give some insights into architectures and parallelism. Then we will describe recent implementations specifically designed for manycore architectures, including algorithms on sequence alignment and RNA structure prediction. We will conclude with some thoughts about the dissemination of those algorithms and implementations: are they today available on the bookshelf for everyone

Machine learning and data-parallel processing for viral metagenomics

More than 2 million cancer cases around the world each year are caused by viruses. In addition, there are epidemiological indications that other cancer-associated viruses may also exist. However, the identification of highly divergent and yet unknown viruses in human biospecimens is one of the biggest challenges in bio- informatics. Modern-day Next Generation Sequencing (NGS) technologies can be used to directly sequence biospecimens from clinical cohorts with unprecedented speed and depth. These technologies are able to generate billions of bases with rapidly decreasing cost but current bioinformatics tools are inefficient to effectively process these massive datasets. Thus, the objective of this thesis was to facilitate both the detection of highly divergent viruses among generated sequences as well as large-scale analysis of human metagenomic datasets. To re-analyze human sample-derived sequences that were classified as being of “unknown” origin by conventional alignment-based methods, we used a meth- odology based on profile Hidden Markov Models (HMM) which can capture evolutionary changes by using multiple sequence alignments. We thus identified 510 sequences that were classified as distantly related to viruses. Many of these sequences were homologs to large viruses such as Herpesviridae and Mimiviridae but some of them were also related to small circular viruses such as Circoviridae. We found that bioinformatics analysis using viral profile HMM is capable of extending the classification of previously unknown sequences and consequently the detection of viruses in biospecimens from humans. Different organisms use synonymous codons differently to encode the same amino acids. To investigate whether codon usage bias could predict the presence of virus in metagenomic sequencing data originating from human samples, we trained Random Forest and Artificial Neural Networks based on Relative Synonymous Codon Usage (RSCU) frequency. Our analysis showed that machine learning tech- niques based on RSCU could identify putative viral sequences with area under the ROC curve of 0.79 and provide important information for taxonomic classification. For identification of viral genomes among raw metagenomic sequences, we devel- oped the tool ViraMiner, a deep learning-based method which uses Convolutional Neural Networks with two convolutional branches. Using 300 base-pair length sequences, ViraMiner achieved 0.923 area under the ROC curve which is con- siderably improved performance in comparison with previous machine learning methods for virus sequence classification. The proposed architecture, to the best of our knowledge, is the first deep learning tool which can detect viral genomes on raw metagenomic sequences originating from a variety of human samples. To enable large-scale analysis of massive metagenomic sequencing data we used Apache Hadoop and Apache Spark to develop ViraPipe, a scalable parallel bio- informatics pipeline for viral metagenomics. Comparing ViraPipe (executed on 23 nodes) with the sequential pipeline (executed on a single node) was 11 times faster in the metagenome analysis. The new distributed workflow contains several standard bioinformatics tools and can scale to terabytes of data by accessing more computer power from the nodes. To analyze terabytes of RNA-seq data originating from head and neck squamous cell carcinoma samples, we used our parallel bioinformatics pipeline ViraPipe and the most recent version of the HPV sequence database. We detected transcription of HPV viral oncogenes in 92/500 cancers. HPV 16 was the most important HPV type, followed by HPV 33 as the second most common infection. If these cancers are indeed caused by HPV, we estimated that vaccination might prevent about 36 000 head and neck cancer cases in the United States every year. In conclusion, the work in this thesis improves the prospects for biomedical researchers to classify the sequence contents of ultra-deep datasets, conduct large- scale analysis of metagenome studies, and detect presence of viral genomes in human biospecimens. Hopefully, this work will contribute to our understanding of biodiversity of viruses in humans which in turn can help exploring infectious causes of human disease

Machine Learning and Integrative Analysis of Biomedical Big Data.

Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues

Parallelization of dynamic programming recurrences in computational biology

The rapid growth of biosequence databases over the last decade has led to a performance bottleneck in the applications analyzing them. In particular, over the last five years DNA sequencing capacity of next-generation sequencers has been doubling every six months as costs have plummeted. The data produced by these sequencers is overwhelming traditional compute systems. We believe that in the future compute performance, not sequencing, will become the bottleneck in advancing genome science. In this work, we investigate novel computing platforms to accelerate dynamic programming algorithms, which are popular in bioinformatics workloads. We study algorithm-specific hardware architectures that exploit fine-grained parallelism in dynamic programming kernels using field-programmable gate arrays: FPGAs). We advocate a high-level synthesis approach, using the recurrence equation abstraction to represent dynamic programming and polyhedral analysis to exploit parallelism. We suggest a novel technique within the polyhedral model to optimize for throughput by pipelining independent computations on an array. This design technique improves on the state of the art, which builds latency-optimal arrays. We also suggest a method to dynamically switch between a family of designs using FPGA reconfiguration to achieve a significant performance boost. We have used polyhedral methods to parallelize the Nussinov RNA folding algorithm to build a family of accelerators that can trade resources for parallelism and are between 15-130x faster than a modern dual core CPU implementation. A Zuker RNA folding accelerator we built on a single workstation with four Xilinx Virtex 4 FPGAs outperforms 198 3 GHz Intel Core 2 Duo processors. Furthermore, our design running on a single FPGA is an order of magnitude faster than competing implementations on similar-generation FPGAs and graphics processors. Our work is a step toward the goal of automated synthesis of hardware accelerators for dynamic programming algorithms

Extreme Scale De Novo Metagenome Assembly

Metagenome assembly is the process of transforming a set of short, overlapping, and potentially erroneous DNA segments from environmental samples into the accurate representation of the underlying microbiomes's genomes. State-of-the-art tools require big shared memory machines and cannot handle contemporary metagenome datasets that exceed Terabytes in size. In this paper, we introduce the MetaHipMer pipeline, a high-quality and high-performance metagenome assembler that employs an iterative de Bruijn graph approach. MetaHipMer leverages a specialized scaffolding algorithm that produces long scaffolds and accommodates the idiosyncrasies of metagenomes. MetaHipMer is end-to-end parallelized using the Unified Parallel C language and therefore can run seamlessly on shared and distributed-memory systems. Experimental results show that MetaHipMer matches or outperforms the state-of-the-art tools in terms of accuracy. Moreover, MetaHipMer scales efficiently to large concurrencies and is able to assemble previously intractable grand challenge metagenomes. We demonstrate the unprecedented capability of MetaHipMer by computing the first full assembly of the Twitchell Wetlands dataset, consisting of 7.5 billion reads - size 2.6 TBytes.Comment: Accepted to SC1

MammoSapiens: eResearch of the lactation program. Building online facilities for collaborative molecular and evolutionary analysis of lactation and other biological systems from gene sequences and gene expression data.

Delivering bioinformatics power to life science researchers inevitably runs into problems of limited computing resources in the context of exponentially increasing data sources, access time, costs, lack of skills and, rapidly evolving technology and software tools with poorly defined standards. In this context the development of online facilities to best enable collaborative research often needs to be customized to specific project applications in close cooperation with the experimentalist users and, to be concerned with the storage and management of results to allow more consistency and traceability of results on a broad access data mining platform. Here we showcase an Internet based research platform using the PHP/MySQL paradigm for the collaborative, integrative and comparative analysis of lactation related gene sequences and gene expression experiments to support lactation research. We also illustrate how these resources are used, how they enable research by allowing meta-analysis of data and results and, how the bottom-up development of customized eResearch components can lead to the production of more generic functional software tools and eResearch environments for deployment to a larger number of biological researchers working on other bio-systems

MammoSapiens: eResearch of the lactation program.

Delivering bioinformatics power to life science researchers inevitably runs into problems of limited computing resources in the context of exponentially increasing data sources, access time, costs, lack of skills and, rapidly evolving technology and software tools with poorly defined standards. In this context the development of e-facilities to best enable collaborative research often needs to be customized to specific project applications in close cooperation with the experimentalist users and, to be concerned with the storage and management of results to allow more consistency and traceability of e-results on a broad access data mining platform. Here we showcase an internet based eResearch platform using the PHP/MySQL paradigm for the collaborative, integrative and comparative analysis of lactation related gene sequences and gene expression experiments to support lactation research. We also illustrate how these resources are used, how they enable research by allowing meta-analysis of data and results and, how the bottom-up development of customized eResearch components can lead to the production of more generic functional software tools and eResearch environments for deployment to a larger number of biological research users working on other bio-systems.<br /