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  • 1
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    Measures for the degree of overlap of gene signatures and applications to TCGA (2015)
    Oxford University Press
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    Publikationsdatum: 2015-09-16
    Beschreibung: For cancer and many other complex diseases, a large number of gene signatures have been generated. In this study, we use cancer as an example and note that other diseases can be analyzed in a similar manner. For signatures generated in multiple independent studies on the same cancer type and outcome, and for signatures on different cancer types, it is of interest to evaluate their degree of overlap. Many of the existing studies simply count the number (or percentage) of overlapped genes shared by two signatures. Such an approach has serious limitations. In this study, as a demonstrating example, we consider cancer prognosis data under the Cox model. Lasso, which is representative of a large number of regularization methods, is adopted for generating gene signatures. We examine two families of measures for quantifying the degree of overlap. The first family is based on the Cox-Lasso estimates at the optimal tunings, and the second family is based on estimates across the whole solution paths. Within each family, multiple measures, which describe the overlap from different perspectives, are introduced. The analysis of TCGA (The Cancer Genome Atlas) data on five cancer types shows that the degree of overlap varies across measures, cancer types and types of (epi)genetic measurements. More investigations are needed to better describe and understand the overlaps among gene signatures.
    Print ISSN: 1467-5463
    Digitale ISSN: 1477-4054
    Thema: Biologie , Informatik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
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    Optimization of miRNA-seq data preprocessing (2015)
    Oxford University Press
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    Publikationsdatum: 2015-11-20
    Beschreibung: The past two decades of microRNA (miRNA) research has solidified the role of these small non-coding RNAs as key regulators of many biological processes and promising biomarkers for disease. The concurrent development in high-throughput profiling technology has further advanced our understanding of the impact of their dysregulation on a global scale. Currently, next-generation sequencing is the platform of choice for the discovery and quantification of miRNAs. Despite this, there is no clear consensus on how the data should be preprocessed before conducting downstream analyses. Often overlooked, data preprocessing is an essential step in data analysis: the presence of unreliable features and noise can affect the conclusions drawn from downstream analyses. Using a spike-in dilution study, we evaluated the effects of several general-purpose aligners (BWA, Bowtie, Bowtie 2 and Novoalign), and normalization methods (counts-per-million, total count scaling, upper quartile scaling, Trimmed Mean of M, DESeq, linear regression, cyclic loess and quantile) with respect to the final miRNA count data distribution, variance, bias and accuracy of differential expression analysis. We make practical recommendations on the optimal preprocessing methods for the extraction and interpretation of miRNA count data from small RNA-sequencing experiments.
    Print ISSN: 1467-5463
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    Thema: Biologie , Informatik
    Publiziert von Oxford University Press
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  • 3
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    Parameter estimation methods for gene circuit modeling from time-series mRNA data: a comparative study (2015)
    Oxford University Press
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    Publikationsdatum: 2015-11-20
    Beschreibung: Parameter estimation is a challenging computational problem in the reverse engineering of biological systems. Because advances in biotechnology have facilitated wide availability of time-series gene expression data, systematic parameter estimation of gene circuit models from such time-series mRNA data has become an important method for quantitatively dissecting the regulation of gene expression. By focusing on the modeling of gene circuits, we examine here the performance of three types of state-of-the-art parameter estimation methods: population-based methods, online methods and model-decomposition-based methods. Our results show that certain population-based methods are able to generate high-quality parameter solutions. The performance of these methods, however, is heavily dependent on the size of the parameter search space, and their computational requirements substantially increase as the size of the search space increases. In comparison, online methods and model decomposition-based methods are computationally faster alternatives and are less dependent on the size of the search space. Among other things, our results show that a hybrid approach that augments computationally fast methods with local search as a subsequent refinement procedure can substantially increase the quality of their parameter estimates to the level on par with the best solution obtained from the population-based methods while maintaining high computational speed. These suggest that such hybrid methods can be a promising alternative to the more commonly used population-based methods for parameter estimation of gene circuit models when limited prior knowledge about the underlying regulatory mechanisms makes the size of the parameter search space vastly large.
    Print ISSN: 1467-5463
    Digitale ISSN: 1477-4054
    Thema: Biologie , Informatik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 4
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    Comparing the evolutionary conservation between human essential genes, human orthologs of mouse essential genes and human housekeeping genes (2015)
    Oxford University Press
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    Publikationsdatum: 2015-11-20
    Beschreibung: Human housekeeping genes are often confused with essential human genes, and several studies regard both types of genes as having the same level of evolutionary conservation. However, this is not necessarily the case. To clarify this, we compared the differences between human housekeeping genes and essential human genes with respect to four aspects: the evolutionary rate (dN/dS), protein sequence identity, single-nucleotide polymorphism (SNP) density and level of linkage disequilibrium (LD). The results showed that housekeeping genes had lower evolutionary rates, higher sequence identities, lower SNP densities and higher levels of LD compared with essential genes. Together, these findings indicate that housekeeping and essential genes are two distinct types of genes, and that housekeeping genes have a higher level of evolutionary conservation. Therefore, we suggest that researchers should pay careful attention to the distinctions between housekeeping genes and essential genes. Moreover, it is still controversial whether we should substitute human orthologs of mouse essential genes for human essential genes. Therefore, we compared the evolutionary features between human orthologs of mouse essential genes and human housekeeping genes and we got inconsistent results in long-term and short-term evolutionary characteristics implying the irrationality of simply replacing human essential genes with human orthologs of mouse essential genes.
    Print ISSN: 1467-5463
    Digitale ISSN: 1477-4054
    Thema: Biologie , Informatik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 5
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    2HiGWAS: a unifying high-dimensional platform to infer the global genetic architecture of trait development (2015)
    Oxford University Press
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    Publikationsdatum: 2015-11-20
    Beschreibung: Whole-genome search of genes is an essential approach to dissecting complex traits, but a marginal one-single-nucleotide polymorphism (SNP)/one-phenotype regression analysis widely used in current genome-wide association studies fails to estimate the net and cumulative effects of SNPs and reveal the developmental pattern of interplay between genes and traits. Here we describe a computational framework, which we refer to as two-side high-dimensional genome-wide association studies (2HiGWAS), to associate an ultrahigh dimension of SNPs with a high dimension of developmental trajectories measured across time and space. The model is implemented with a dual dimension-reduction procedure for both predictors and responses to select a sparse but full set of significant loci from an extremely large pool of SNPs and estimate their net time-varying effects on trait development. The model can not only help geneticists to precisely identify an entire set of genes underlying complex traits but also allow them to elucidate a global picture of how genes control developmental and dynamic processes of trait formation. We investigated the statistical properties of the model via extensive simulation studies. With the increasing availability of GWAS in various organisms, 2HiGWAS will have important implications for genetic studies of developmental compelx traits.
    Print ISSN: 1467-5463
    Digitale ISSN: 1477-4054
    Thema: Biologie , Informatik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 6
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    A comparative study of RNA-seq analysis strategies (2015)
    Oxford University Press
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    Publikationsdatum: 2015-11-20
    Beschreibung: Three principal approaches have been proposed for inferring the set of transcripts expressed in RNA samples using RNA-seq. The simplest approach uses curated annotations, which assumes the transcripts in a sample are a subset of the transcripts listed in a curated database. A more ambitious method involves aligning reads to a reference genome and using the alignments to infer the transcript structures, possibly with the aid of a curated transcript database. The most challenging approach is to assemble reads into putative transcripts de novo without the aid of reference data. We have systematically assessed the properties of these three approaches through a simulation study. We have found that the sensitivity of computational transcript set estimation is severely limited. Computational approaches (both genome-guided and de novo assembly) produce a large number of artefacts, which are assigned large expression estimates and absorb a substantial proportion of the signal when performing expression analysis. The approach using curated annotations shows good expression correlation even when the annotations are incomplete. Furthermore, any incorrect transcripts present in a curated set do not absorb much signal, so it is preferable to have a curation set with high sensitivity than high precision. Software to simulate transcript sets, expression values and sequence reads under a wider range of parameter values and to compare sensitivity, precision and signal-to-noise ratios of different methods is freely available online ( https://github.com/boboppie/RSSS ) and can be expanded by interested parties to include methods other than the exemplars presented in this article.
    Print ISSN: 1467-5463
    Digitale ISSN: 1477-4054
    Thema: Biologie , Informatik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 7
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    Detecting and overcoming systematic bias in high-throughput screening technologies: a comprehensive review of practical issues and methodological solutions (2015)
    Oxford University Press
    Details
    Publikationsdatum: 2015-11-20
    Beschreibung: Significant efforts have been made recently to improve data throughput and data quality in screening technologies related to drug design. The modern pharmaceutical industry relies heavily on high-throughput screening (HTS) and high-content screening (HCS) technologies, which include small molecule, complementary DNA (cDNA) and RNA interference (RNAi) types of screening. Data generated by these screening technologies are subject to several environmental and procedural systematic biases, which introduce errors into the hit identification process. We first review systematic biases typical of HTS and HCS screens. We highlight that study design issues and the way in which data are generated are crucial for providing unbiased screening results. Considering various data sets, including the publicly available ChemBank data, we assess the rates of systematic bias in experimental HTS by using plate-specific and assay-specific error detection tests. We describe main data normalization and correction techniques and introduce a general data preprocessing protocol. This protocol can be recommended for academic and industrial researchers involved in the analysis of current or next-generation HTS data.
    Print ISSN: 1467-5463
    Digitale ISSN: 1477-4054
    Thema: Biologie , Informatik
    Publiziert von Oxford University Press
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  • 8
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    A review of ensemble methods for de novo motif discovery in ChIP-Seq data (2015)
    Oxford University Press
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    Publikationsdatum: 2015-11-20
    Beschreibung: De novo motif discovery is a difficult computational task. Historically, dedicated algorithms always reported a high percentage of false positives. Their performance did not improve considerably even after they adapted to handle large amounts of chromatin immunoprecipitation sequencing (ChIP-Seq) data. Several studies have advocated aggregating complementary algorithms, combining their predictions to increase the accuracy of the results. This led to the development of ensemble methods. To form a better view on modern ensembles, we review all compound tools designed for ChIP-Seq. After a brief introduction to basic algorithms and early ensembles, we describe the most recent tools. We highlight their limitations and strengths by presenting their architecture, the input options and their output. To provide guidance for next-generation sequencing practitioners, we observe the differences and similarities between them. Last but not least, we identify and recommend several features to be implemented by any novel ensemble algorithm.
    Print ISSN: 1467-5463
    Digitale ISSN: 1477-4054
    Thema: Biologie , Informatik
    Publiziert von Oxford University Press
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  • 9
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    Methodological aspects of whole-genome bisulfite sequencing analysis (2015)
    Oxford University Press
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    Publikationsdatum: 2015-05-19
    Beschreibung: The combination of DNA bisulfite treatment with high-throughput sequencing technologies has enabled investigation of genome-wide DNA methylation beyond CpG sites and CpG islands. These technologies have opened new avenues to understand the interplay between epigenetic events, chromatin plasticity and gene regulation. However, the processing, managing and mining of this huge volume of data require specialized computational tools and statistical methods that are yet to be standardized. Here, we describe a complete bisulfite sequencing analysis workflow, including recently developed programs, highlighting each of the crucial analysis steps required, i.e. sequencing quality control, reads alignment, methylation scoring, methylation heterogeneity assessment, genomic features annotation, data visualization and determination of differentially methylated cytosines. Moreover, we discuss the limitations of these technologies and considerations to perform suitable analyses.
    Print ISSN: 1467-5463
    Digitale ISSN: 1477-4054
    Thema: Biologie , Informatik
    Publiziert von Oxford University Press
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  • 10
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    Exploring the function of genetic variants in the non-coding genomic regions: approaches for identifying human regulatory variants affecting gene expression (2015)
    Oxford University Press
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    Publikationsdatum: 2015-05-19
    Beschreibung: Understanding the genetic basis of human traits/diseases and the underlying mechanisms of how these traits/diseases are affected by genetic variations is critical for public health. Current genome-wide functional genomics data uncovered a large number of functional elements in the noncoding regions of human genome, providing new opportunities to study regulatory variants (RVs). RVs play important roles in transcription factor bindings, chromatin states and epigenetic modifications. Here, we systematically review an array of methods currently used to map RVs as well as the computational approaches in annotating and interpreting their regulatory effects, with emphasis on regulatory single-nucleotide polymorphism. We also briefly introduce experimental methods to validate these functional RVs.
    Print ISSN: 1467-5463
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    Thema: Biologie , Informatik
    Publiziert von Oxford University Press
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