Computational solutions for omics data

High-throughput experimental technologies are generating increasingly massive and complex genomic data sets. The sheer enormity and heterogeneity of these data threaten to make the arising problems computationally infeasible. Fortunately, powerful algorithmic techniques lead to software that can answer important biomedical questions in practice. In this Review, we sample the algorithmic landscape, focusing on state-of-the-art techniques, the understanding of which will aid the bench biologist in analysing omics data. We spotlight specific examples that have facilitated and enriched analyses of sequence, transcriptomic and network data sets.National Institutes of Health (U.S.) (Grant GM081871

Searching for improvement

Engineering design can be thought of as a search for the best solutions to engineering problems. To perform an effective search, one must distinguish between competing designs and establish a measure of design quality, or fitness. To compare different designs, their features must be adequately described in a well-defined framework, which can mean separating the creative and analytical parts of the design process. By this we mean that a distinction is drawn between coming up with novel design concepts, or architectures, and the process of detailing or refining existing design architecture. In the case of a given design architecture, one can consider the set of all possible designs that could be created by varying its features. If it were possible to measure the fitness of all designs in this set, then one could identify a fitness landscape and search for the best possible solution for this design architecture. In this Chapter, the significance of the interactions between design features in defining the metaphorical fitness landscape is described. This highlights that the efficiency of a search algorithm is inextricably linked to the problem structure (and hence the landscape). Two approaches, namely, Genetic Algorithms (GA) and Robust Engineering Design (RED) are considered in some detail with reference to a case study on improving the design of cardiovascular stents

NOVEL COMPUTATIONAL METHODS FOR SEQUENCING DATA ANALYSIS: MAPPING, QUERY, AND CLASSIFICATION

Over the past decade, the evolution of next-generation sequencing technology has considerably advanced the genomics research. As a consequence, fast and accurate computational methods are needed for analyzing the large data in different applications. The research presented in this dissertation focuses on three areas: RNA-seq read mapping, large-scale data query, and metagenomics sequence classification. A critical step of RNA-seq data analysis is to map the RNA-seq reads onto a reference genome. This dissertation presents a novel splice alignment tool, MapSplice3. It achieves high read alignment and base mapping yields and is able to detect splice junctions, gene fusions, and circular RNAs comprehensively at the same time. Based on MapSplice3, we further extend a novel lightweight approach called iMapSplice that enables personalized mRNA transcriptional profiling. As huge amount of RNA-seq has been shared through public datasets, it provides invaluable resources for researchers to test hypotheses by reusing existing datasets. To meet the needs of efficiently querying large-scale sequencing data, a novel method, called SeqOthello, has been developed. It is able to efficiently query sequence k-mers against large-scale datasets and finally determines the existence of the given sequence. Metagenomics studies often generate tens of millions of reads to capture the presence of microbial organisms. Thus efficient and accurate algorithms are in high demand. In this dissertation, we introduce MetaOthello, a probabilistic hashing classifier for metagenomic sequences. It supports efficient query of a taxon using its k-mer signatures

Bayesian localization of CNV candidates in WGS data within minutes

Background: Full Bayesian inference for detecting copy number variants (CNV) from whole-genome sequencing (WGS) data is still largely infeasible due to computational demands. A recently introduced approach to perform Forward-Backward Gibbs sampling using dynamic Haar wavelet compression has alleviated issues of convergence and, to some extent, speed. Yet, the problem remains challenging in practice. Results: In this paper, we propose an improved algorithmic framework for this approach. We provide new space-efficient data structures to query sufficient statistics in logarithmic time, based on a linear-Time, in-place transform of the data, which also improves on the compression ratio. We also propose a new approach to efficiently store and update marginal state counts obtained from the Gibbs sampler. Conclusions: Using this approach, we discover several CNV candidates in two rat populations divergently selected for tame and aggressive behavior, consistent with earlier results concerning the domestication syndrome as well as experimental observations. Computationally, we observe a 29.5-fold decrease in memory, an average 5.8-fold speedup, as well as a 191-fold decrease in minor page faults. We also observe that metrics varied greatly in the old implementation, but not the new one. We conjecture that this is due to the better compression scheme. The fully Bayesian segmentation of the entire WGS data set required 3.5 min and 1.24 GB of memory, and can hence be performed on a commodity laptop

Optimizing the Performance of Streaming Numerical Kernels on the IBM Blue Gene/P PowerPC 450 Processor

Several emerging petascale architectures use energy-efficient processors with vectorized computational units and in-order thread processing. On these architectures the sustained performance of streaming numerical kernels, ubiquitous in the solution of partial differential equations, represents a challenge despite the regularity of memory access. Sophisticated optimization techniques are required to fully utilize the Central Processing Unit (CPU). We propose a new method for constructing streaming numerical kernels using a high-level assembly synthesis and optimization framework. We describe an implementation of this method in Python targeting the IBM Blue Gene/P supercomputer's PowerPC 450 core. This paper details the high-level design, construction, simulation, verification, and analysis of these kernels utilizing a subset of the CPU's instruction set. We demonstrate the effectiveness of our approach by implementing several three-dimensional stencil kernels over a variety of cached memory scenarios and analyzing the mechanically scheduled variants, including a 27-point stencil achieving a 1.7x speedup over the best previously published results

Randomized lasso links microbial taxa with aquatic functional groups inferred from flow cytometry

High-nucleic-acid (HNA) and low-nucleic-acid (LNA) bacteria are two operational groups identified by flow cytometry (FCM) in aquatic systems. A number of reports have shown that HNA cell density correlates strongly with heterotrophic production, while LNA cell density does not. However, which taxa are specifically associated with these groups, and by extension, productivity has remained elusive. Here, we addressed this knowledge gap by using a machine learning-based variable selection approach that integrated FCM and 16S rRNA gene sequencing data collected from 14 freshwater lakes spanning a broad range in physicochemical conditions. There was a strong association between bacterial heterotrophic production and HNA absolute cell abundances (R-2 = 0.65), but not with the more abundant LNA cells. This solidifies findings, mainly from marine systems, that HNA and LNA bacteria could be considered separate functional groups, the former contributing a disproportionately large share of carbon cycling. Taxa selected by the models could predict HNA and LNA absolute cell abundances at all taxonomic levels. Selected operational taxonomic units (OTUs) ranged from low to high relative abundance and were mostly lake system specific (89.5% to 99.2%). A subset of selected OTUs was associated with both LNA and HNA groups (12.5% to 33.3%), suggesting either phenotypic plasticity or within-OTU genetic and physiological heterogeneity. These findings may lead to the identification of system-specific putative ecological indicators for heterotrophic productivity. Generally, our approach allows for the association of OTUs with specific functional groups in diverse ecosystems in order to improve our understanding of (microbial) biodiversity-ecosystem functioning relationships. IMPORTANCE A major goal in microbial ecology is to understand how microbial community structure influences ecosystem functioning. Various methods to directly associate bacterial taxa to functional groups in the environment are being developed. In this study, we applied machine learning methods to relate taxonomic data obtained from marker gene surveys to functional groups identified by flow cytometry. This allowed us to identify the taxa that are associated with heterotrophic productivity in freshwater lakes and indicated that the key contributors were highly system specific, regularly rare members of the community, and that some could possibly switch between being low and high contributors. Our approach provides a promising framework to identify taxa that contribute to ecosystem functioning and can be further developed to explore microbial contributions beyond heterotrophic production

Characterization and identification of hidden rare variants in the human genome

BackgroundBy examining the genotype calls generated by the 1000 Genomes Project we discovered that the human reference genome GRCh37 contains almost 20,000 loci in which the reference allele has never been observed in healthy individuals and around 70,000 loci in which it has been observed only in the heterozygous state.ResultsWe show that a large fraction of this rare reference allele (RRA) loci belongs to coding, functional and regulatory elements of the genome and could be linked to rare Mendelian disorders as well as cancer. We also demonstrate that classical germline and somatic variant calling tools are not capable to recognize the rare allele when present in these loci. To overcome such limitations, we developed a novel tool, named RAREVATOR, that is able to identify and call the rare allele in these genomic positions. By using a small cancer dataset we compared our tool with two state-of-the-art callers and we found that RAREVATOR identified more than 1,500 germline and 22 somatic RRA variants missed by the two methods and which belong to significantly mutated pathways.ConclusionsThese results show that, to date, the investigation of around 100,000 loci of the human genome has been missed by re-sequencing experiments based on the GRCh37 assembly and that our tool can fill the gap left by other methods. Moreover, the investigation of the latest version of the human reference genome, GRCh38, showed that although the GRC corrected almost all insertions and a small part of SNVs and deletions, a large number of functionally relevant RRAs still remain unchanged. For this reason, also future resequencing experiments, based on GRCh38, will benefit from RAREVATOR analysis results. RAREVATOR is freely available at http://sourceforge.net/projects/rarevator

Techniques of design optimisation for algorithms implemented in software

The overarching objective of this thesis was to develop tools for parallelising, optimising, and implementing algorithms on parallel architectures, in particular General Purpose Graphics Processors (GPGPUs). Two projects were chosen from different application areas in which GPGPUs are used: a defence application involving image compression, and a modelling application in bioinformatics (computational immunology). Each project had its own specific objectives, as well as supporting the overall research goal. The defence / image compression project was carried out in collaboration with the Jet Propulsion Laboratories. The specific questions were: to what extent an algorithm designed for bit-serial for the lossless compression of hyperspectral images on-board unmanned vehicles (UAVs) in hardware could be parallelised, whether GPGPUs could be used to implement that algorithm, and whether a software implementation with or without GPGPU acceleration could match the throughput of a dedicated hardware (FPGA) implementation. The dependencies within the algorithm were analysed, and the algorithm parallelised. The algorithm was implemented in software for GPGPU, and optimised. During the optimisation process, profiling revealed less than optimal device utilisation, but no further optimisations resulted in an improvement in speed. The design had hit a local-maximum of performance. Analysis of the arithmetic intensity and data-flow exposed flaws in the standard optimisation metric of kernel occupancy used for GPU optimisation. Redesigning the implementation with revised criteria (fused kernels, lower occupancy, and greater data locality) led to a new implementation with 10x higher throughput. GPGPUs were shown to be viable for on-board implementation of the CCSDS lossless hyperspectral image compression algorithm, exceeding the performance of the hardware reference implementation, and providing sufficient throughput for the next generation of image sensor as well. The second project was carried out in collaboration with biologists at the University of Arizona and involved modelling a complex biological system – VDJ recombination involved in the formation of T-cell receptors (TCRs). Generation of immune receptors (T cell receptor and antibodies) by VDJ recombination is an enormously complex process, which can theoretically synthesize greater than 1018 variants. Originally thought to be a random process, the underlying mechanisms clearly have a non-random nature that preferentially creates a small subset of immune receptors in many individuals. Understanding this bias is a longstanding problem in the field of immunology. Modelling the process of VDJ recombination to determine the number of ways each immune receptor can be synthesized, previously thought to be untenable, is a key first step in determining how this special population is made. The computational tools developed in this thesis have allowed immunologists for the first time to comprehensively test and invalidate a longstanding theory (convergent recombination) for how this special population is created, while generating the data needed to develop novel hypothesis