A Bayesian Framework to Account for Complex Non-Genetic Factors in Gene Expression Levels Greatly Increases Power in eQTL Studies
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{"title"=>"A bayesian framework to account for complex non-genetic factors in gene expression levels greatly increases power in eQTL studies", "type"=>"journal", "authors"=>[{"first_name"=>"Oliver", "last_name"=>"Stegle", "scopus_author_id"=>"57194781099"}, {"first_name"=>"Leopold", "last_name"=>"Parts", "scopus_author_id"=>"57195956429"}, {"first_name"=>"Richard", "last_name"=>"Durbin", "scopus_author_id"=>"7102868950"}, {"first_name"=>"John", "last_name"=>"Winn", "scopus_author_id"=>"15621648700"}], "year"=>2010, "source"=>"PLoS Computational Biology", "identifiers"=>{"sgr"=>"77955505742", "issn"=>"1553734X", "scopus"=>"2-s2.0-77955505742", "pmid"=>"20463871", "pui"=>"359337494", "isbn"=>"10.1371/journal.pcbi.1000770", "doi"=>"10.1371/journal.pcbi.1000770"}, "id"=>"20637b93-adc0-36d4-b575-3245621a3162", "abstract"=>"Gene expression measurements are influenced by a wide range of factors, such as the state of the cell, experimental conditions and variants in the sequence of regulatory regions. To understand the effect of a variable of interest, such as the genotype of a locus, it is important to account for variation that is due to confounding causes. Here, we present VBQTL, a probabilistic approach for mapping expression quantitative trait loci (eQTLs) that jointly models contributions from genotype as well as known and hidden confounding factors. VBQTL is implemented within an efficient and flexible inference framework, making it fast and tractable on large-scale problems. We compare the performance of VBQTL with alternative methods for dealing with confounding variability on eQTL mapping datasets from simulations, yeast, mouse, and human. Employing Bayesian complexity control and joint modelling is shown to result in more precise estimates of the contribution of different confounding factors resulting in additional associations to measured transcript levels compared to alternative approaches. We present a threefold larger collection of cis eQTLs than previously found in a whole-genome eQTL scan of an outbred human population. Altogether, 27% of the tested probes show a significant genetic association in cis, and we validate that the additional eQTLs are likely to be real by replicating them in different sets of individuals. Our method is the next step in the analysis of high-dimensional phenotype data, and its application has revealed insights into genetic regulation of gene expression by demonstrating more abundant cis-acting eQTLs in human than previously shown. Our software is freely available online at http://www.sanger.ac.uk/resources/software/peer/.", "link"=>"http://www.mendeley.com/research/bayesian-framework-account-complex-nongenetic-factors-gene-expression-levels-greatly-increases-power", "reader_count"=>340, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>24, "Researcher"=>100, "Student > Doctoral Student"=>7, "Student > Ph. D. Student"=>126, "Student > Postgraduate"=>12, "Student > Master"=>27, "Other"=>7, "Student > Bachelor"=>16, "Lecturer > Senior Lecturer"=>3, "Professor"=>15}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>24, "Researcher"=>100, "Student > Doctoral Student"=>7, "Student > Ph. D. Student"=>126, "Student > Postgraduate"=>12, "Student > Master"=>27, "Other"=>7, "Student > Bachelor"=>16, "Lecturer > Senior Lecturer"=>3, "Professor"=>15}, "reader_count_by_subject_area"=>{"Unspecified"=>6, "Agricultural and Biological Sciences"=>195, "Arts and Humanities"=>1, "Veterinary Science and Veterinary Medicine"=>1, "Business, Management and Accounting"=>2, "Chemical Engineering"=>1, "Chemistry"=>1, "Computer Science"=>40, "Engineering"=>7, "Biochemistry, Genetics and Molecular Biology"=>42, "Mathematics"=>22, "Medicine and Dentistry"=>11, "Neuroscience"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Physics and Astronomy"=>4, "Psychology"=>1, "Social Sciences"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>4}, "Psychology"=>{"Psychology"=>1}, "Mathematics"=>{"Mathematics"=>22}, "Unspecified"=>{"Unspecified"=>6}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Chemical Engineering"=>{"Chemical Engineering"=>1}, "Arts and Humanities"=>{"Arts and Humanities"=>1}, "Engineering"=>{"Engineering"=>7}, "Chemistry"=>{"Chemistry"=>1}, "Neuroscience"=>{"Neuroscience"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>195}, "Computer Science"=>{"Computer Science"=>40}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>42}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"United States"=>24, "United Kingdom"=>3, "Spain"=>1, "New Zealand"=>1, "Netherlands"=>1, "Austria"=>1, "Korea (South)"=>1, "Belgium"=>1, "Norway"=>1, "Brazil"=>2, "Denmark"=>1, "Mexico"=>1, "Italy"=>1, "France"=>2, "Germany"=>6}, "group_count"=>21}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/850644"], "description"=>"<p>The matrix of measured gene expression levels of genes from individuals is modelled by additive contributions from components and observation noise . Here, the components capture the signal due to primary effect of the genetic state , known factors and hidden factors . Some examples of possible underlying sources of variation are given above the model boxes. The groupings represent some standard genetic association models commonly used.</p>", "links"=>[], "tags"=>["additive", "sources"], "article_id"=>521106, "categories"=>["Mathematics", "Genetics", "Computational Biology"], "users"=>["Oliver Stegle", "Leopold Parts", "Richard Durbin", "John Winn"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000770.g001", "stats"=>{"downloads"=>7, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_General_additive_model_for_sources_of_gene_expression_variability_/521106", "title"=>"General additive model for sources of gene expression variability.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-06 00:18:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/850700"], "description"=>"<p>(<b>a</b>) The Bayesian network for the model of gene expression variation used in VBQTL (see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000770#s2\" target=\"_blank\">Methods</a>). The full model combines genetic (green), known factor (blue) and hidden factor (red) models to explain the observed gene expression levels . The solid rectangles indicate that contained variables are duplicated for each gene probe (), SNP () or factor () respectively. A similar rectangle for individuals () is omitted in this representation. The dashed rectangle indicates that the variable switches the contained part of the graph on or off representing the existence or lack of an association. Nodes with thick outlines (, and ) are observed. (<b>b</b>)–(<b>e</b>) Update cycle of the known factors model introduced in Section Inference. The red outline highlights the parts of the model that change in a step, and the thick blue arrows illustrate the flow of information. Details of these updates are discussed in the text.</p>", "links"=>[], "tags"=>["inference"], "article_id"=>521158, "categories"=>["Mathematics", "Genetics", "Computational Biology"], "users"=>["Oliver Stegle", "Leopold Parts", "Richard Durbin", "John Winn"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000770.g002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bayesian_network_and_outline_of_the_inference_schedule_for_VBQTL_/521158", "title"=>"Bayesian network and outline of the inference schedule for VBQTL.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-06 00:19:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/423083", "https://ndownloader.figshare.com/files/423231", "https://ndownloader.figshare.com/files/423296", "https://ndownloader.figshare.com/files/423337", "https://ndownloader.figshare.com/files/423373", "https://ndownloader.figshare.com/files/423400", "https://ndownloader.figshare.com/files/423427", "https://ndownloader.figshare.com/files/423456", "https://ndownloader.figshare.com/files/423489", "https://ndownloader.figshare.com/files/423519", "https://ndownloader.figshare.com/files/423552", "https://ndownloader.figshare.com/files/423581", "https://ndownloader.figshare.com/files/423607"], "description"=>"<div><p>Gene expression measurements are influenced by a wide range of factors, such as the state of the cell, experimental conditions and variants in the sequence of regulatory regions. To understand the effect of a variable of interest, such as the genotype of a locus, it is important to account for variation that is due to confounding causes. Here, we present VBQTL, a probabilistic approach for mapping expression quantitative trait loci (eQTLs) that jointly models contributions from genotype as well as known and hidden confounding factors. VBQTL is implemented within an efficient and flexible inference framework, making it fast and tractable on large-scale problems. We compare the performance of VBQTL with alternative methods for dealing with confounding variability on eQTL mapping datasets from simulations, yeast, mouse, and human. Employing Bayesian complexity control and joint modelling is shown to result in more precise estimates of the contribution of different confounding factors resulting in additional associations to measured transcript levels compared to alternative approaches. We present a threefold larger collection of <em>cis</em> eQTLs than previously found in a whole-genome eQTL scan of an outbred human population. Altogether, 27% of the tested probes show a significant genetic association in <em>cis</em>, and we validate that the additional eQTLs are likely to be real by replicating them in different sets of individuals. Our method is the next step in the analysis of high-dimensional phenotype data, and its application has revealed insights into genetic regulation of gene expression by demonstrating more abundant <em>cis</em>-acting eQTLs in human than previously shown. Our software is freely available online at <a href=\"http://www.sanger.ac.uk/resources/software/peer/\">http://www.sanger.ac.uk/resources/software/peer/</a>.</p></div>", "links"=>[], "tags"=>["bayesian", "non-genetic", "factors", "levels", "increases", "eqtl", "studies"], "article_id"=>143560, "categories"=>["Mathematics", "Genetics", "Biological Sciences"], "users"=>["Oliver Stegle", "Leopold Parts", "Richard Durbin", "John Winn"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1000770.s001", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s002", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s003", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s004", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s005", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s006", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s007", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s008", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s009", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s010", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s011", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s012", "https://dx.doi.org/10.1371/journal.pcbi.1000770.s013"], "stats"=>{"downloads"=>23, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Bayesian_Framework_to_Account_for_Complex_Non_Genetic_Factors_in_Gene_Expression_Levels_Greatly_Increases_Power_in_eQTL_Studies/143560", "title"=>"A Bayesian Framework to Account for Complex Non-Genetic Factors in Gene Expression Levels Greatly Increases Power in eQTL Studies", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-05-06 00:59:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/850774"], "description"=>"<p>(<b>a</b>) Mean-squared error in estimating only the hidden factor contribution. Methods that do not explicitly retain the genetic factors explain them away as hidden global factors, resulting in high error comparable to not accounting for hidden factors at all (Standard). (<b>b</b>) Mean-squared error in estimating the contribution from hidden and genetic factors. (<b>c</b>) Sensitivity of recovering immediate SNP associations. (<b>d</b>) Sensitivity of recovering downstream associations. Seven hidden factors and three transcription factor effects were simulated. For eQTL sensitivity, standard eQTL finding on simulated data (Standard) and same data without the hidden effects (Ideal) are included as comparisons. PCAsig and SVA identified a constant number of hidden components (marked with a diamond shape), thus only a single result (dashed line) is given.</p>", "links"=>[], "tags"=>["recovering", "simulated", "eqtls", "bayesian", "non-bayesian"], "article_id"=>521226, "categories"=>["Mathematics", "Genetics", "Computational Biology"], "users"=>["Oliver Stegle", "Leopold Parts", "Richard Durbin", "John Winn"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000770.g003", "stats"=>{"downloads"=>4, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sensitivity_of_recovering_simulated_hidden_factor_effects_and_eQTLs_for_Bayesian_and_non_Bayesian_methods_/521226", "title"=>"Sensitivity of recovering simulated hidden factor effects and eQTLs for Bayesian and non-Bayesian methods.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-06 00:20:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/850915"], "description"=>"<p>Fraction of tested genes with a <i>cis</i> association in individual chromosomes and overall false discovery rate for the HapMap CEU population (FPR = ).</p>", "links"=>[], "tags"=>["tested", "genes", "chromosomes", "hapmap", "ceu"], "article_id"=>521370, "categories"=>["Mathematics", "Genetics", "Computational Biology"], "users"=>["Oliver Stegle", "Leopold Parts", "Richard Durbin", "John Winn"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000770.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fraction_of_tested_genes_with_a_cis_association_in_individual_chromosomes_and_overall_false_discovery_rate_for_the_HapMap_CEU_population_FPR__/521370", "title"=>"Fraction of tested genes with a <i>cis</i> association in individual chromosomes and overall false discovery rate for the HapMap CEU population (FPR = ).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-06 00:22:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/850837"], "description"=>"<p>Significance-testing based methods (PCAsig, SVA) identified the same number of factors for a wide range of cutoff values (), thus only a single count is given (dashed lines), together with the number of factors found (diamond shape). Other methods were applied with a maximum number of , , and hidden factors.</p>", "links"=>[], "tags"=>["probes", "eqtl", "factors", "published"], "article_id"=>521293, "categories"=>["Mathematics", "Genetics", "Computational Biology"], "users"=>["Oliver Stegle", "Leopold Parts", "Richard Durbin", "John Winn"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000770.g004", "stats"=>{"downloads"=>6, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Number_of_probes_with_an_eQTL_found_as_a_function_of_maximum_number_of_hidden_factors_for_three_previously_published_datasets_/521293", "title"=>"Number of probes with an eQTL found as a function of maximum number of hidden factors for three previously published datasets.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-06 00:21:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/850975"], "description"=>"<p>(<b>a,b,d,e</b>) Venn diagrams depicting overlap of probes with a standard eQTL or VBeQTL in the CEU population and probes with an eQTL in other populations. (<b>c,f</b>) Standard and VBeQTL location and strength relative to the transcription start site.</p>", "links"=>[], "tags"=>["vbeqtls"], "article_id"=>521437, "categories"=>["Mathematics", "Genetics", "Computational Biology"], "users"=>["Oliver Stegle", "Leopold Parts", "Richard Durbin", "John Winn"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000770.g006", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Validation_of_VBeQTLs_by_comparison_to_standard_eQTLs_/521437", "title"=>"Validation of VBeQTLs by comparison to standard eQTLs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-06 00:23:57"}

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