Genetic Association Studies of Copy-Number Variation: Should Assignment of Copy Number States Precede Testing?
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{"title"=>"Genetic association studies of copy-number variation: Should assignment of copy number states precede testing?", "type"=>"journal", "authors"=>[{"first_name"=>"Patrick", "last_name"=>"Breheny", "scopus_author_id"=>"6504669360"}, {"first_name"=>"Prabhakar", "last_name"=>"Chalise", "scopus_author_id"=>"36672556800"}, {"first_name"=>"Anthony", "last_name"=>"Batzler", "scopus_author_id"=>"15122001800"}, {"first_name"=>"Liewei", "last_name"=>"Wang", "scopus_author_id"=>"7409176720"}, {"first_name"=>"Brooke L.", "last_name"=>"Fridley", "scopus_author_id"=>"16039265400"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84859512085", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203", "pmid"=>"22493684", "pui"=>"364590402", "doi"=>"10.1371/journal.pone.0034262", "scopus"=>"2-s2.0-84859512085"}, "id"=>"f15ddc52-1392-3465-9195-a1e1ca1c6a5a", "abstract"=>"Recently, structural variation in the genome has been implicated in many complex diseases. Using genomewide single nucleotide polymorphism (SNP) arrays, researchers are able to investigate the impact not only of SNP variation, but also of copy-number variants (CNVs) on the phenotype. The most common analytic approach involves estimating, at the level of the individual genome, the underlying number of copies present at each location. Once this is completed, tests are performed to determine the association between copy number state and phenotype. An alternative approach is to carry out association testing first, between phenotype and raw intensities from the SNP array at the level of the individual marker, and then aggregate neighboring test results to identify CNVs associated with the phenotype. Here, we explore the strengths and weaknesses of these two approaches using both simulations and real data from a pharmacogenomic study of the chemotherapeutic agent gemcitabine. Our results indicate that pooled marker-level testing is capable of offering a dramatic increase in power (> 12-fold) over CNV-level testing, particularly for small CNVs. However, CNV-level testing is superior when CNVs are large and rare; understanding these tradeoffs is an important consideration in conducting association studies of structural variation.", "link"=>"http://www.mendeley.com/research/genetic-association-studies-copynumber-variation-assignment-copy-number-states-precede-testing", "reader_count"=>23, "reader_count_by_academic_status"=>{"Researcher"=>9, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Master"=>3, "Other"=>1}, "reader_count_by_user_role"=>{"Researcher"=>9, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Master"=>3, "Other"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>19, "Medicine and Dentistry"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>19}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}}, "reader_count_by_country"=>{"Sweden"=>1, "Brazil"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/657313"], "description"=>"<p>The shaded region denotes a region of significant elevation, as detected by the methods described in “Marker-level testing”. The top of the plot contains annotations describing the results of the CNV-level analysis in three distinct regions. is the mean adjusted IC50 for cell lines with a called CNV in that region; is the mean adjusted IC50 for cell lines without a called CNV in that region.</p>", "links"=>[], "tags"=>["gemcitabine", "marker-level"], "article_id"=>327802, "categories"=>["Mathematics", "Biological Sciences", "Genetics"], "users"=>["Patrick Breheny", "Prabhakar Chalise", "Anthony Batzler", "Liewei Wang", "Brooke L. Fridley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034262.g005", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Plot_of_from_Gemcitabine_marker_level_tests_as_a_function_of_position_along_the_chromosome_/327802", "title"=>"Plot of from Gemcitabine marker-level tests as a function of position along the chromosome.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 06:49:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/657432"], "description"=>"<p>Continuous outcome, 10,000 replications per cell, CNV size = 30 markers).</p>", "links"=>[], "tags"=>["cnv-calling"], "article_id"=>327925, "categories"=>["Mathematics", "Biological Sciences", "Genetics"], "users"=>["Patrick Breheny", "Prabhakar Chalise", "Anthony Batzler", "Liewei Wang", "Brooke L. Fridley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034262.t001", "stats"=>{"downloads"=>5, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_CNV_calling_threshold_on_the_power_to_detect_a_CNV_/327925", "title"=>"Effect of CNV-calling threshold () on the power to detect a CNV.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-20 06:50:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/657372"], "description"=>"<p>number of CNV calls in that region. If , no association test was carried out, hence the blank entries. For the marker-level tests, a FWER of 0.01–0.05 means that controlling the FWER at the level, we obtain a segmentation in this region, but that if we control the FWER at the level, we do not.</p>", "links"=>[], "tags"=>["cnv-level", "marker-level", "gemcitabine"], "article_id"=>327857, "categories"=>["Mathematics", "Biological Sciences", "Genetics"], "users"=>["Patrick Breheny", "Prabhakar Chalise", "Anthony Batzler", "Liewei Wang", "Brooke L. Fridley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034262.t003", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_CNV_level_and_marker_level_tests_for_the_Gemcitabine_data_/327857", "title"=>"Comparison of CNV-level and marker-level tests for the Gemcitabine data.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-20 06:49:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/657075"], "description"=>"<p>The gray region denotes the estimated boundary of the CNV. The points in the gray region have a mean LRR of −0.98; the surrounding points have a mean of −0.11.</p>", "links"=>[], "tags"=>["lrr", "putative", "cnv", "chromosome", "gemcitabine"], "article_id"=>327554, "categories"=>["Mathematics", "Biological Sciences", "Genetics"], "users"=>["Patrick Breheny", "Prabhakar Chalise", "Anthony Batzler", "Liewei Wang", "Brooke L. Fridley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034262.g001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Example_of_LRR_data_for_a_putative_CNV_on_Chromosome_3_for_a_cell_line_in_the_gemcitabine_study_/327554", "title"=>"Example of LRR data for a putative CNV on Chromosome 3 for a cell line in the gemcitabine study.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 06:48:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/657246"], "description"=>"<p>The CNV-level testing approach uses a false positive CNV call rate of 0.01; the marker-level approach uses the probit transformation. The lower dashed line represents the type I error rate, while the upper dashed line represents the “oracle” power that would be possible if the true CNV status were known, with no measurement error.</p>", "links"=>[], "tags"=>["cnv"], "article_id"=>327737, "categories"=>["Mathematics", "Biological Sciences", "Genetics"], "users"=>["Patrick Breheny", "Prabhakar Chalise", "Anthony Batzler", "Liewei Wang", "Brooke L. Fridley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034262.g004", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Power_as_a_function_of_method_and_CNV_size_/327737", "title"=>"Power as a function of method and CNV size.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 06:49:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/657407"], "description"=>"<p>Continuous outcome, 10,000 replications per cell, CNV size = 30 markers. “Power” here refers to the probability that a segment in which low -values have aggregated can be separated from the test results from surrounding markers. The “no pooling” analysis (which implements a Bonferroni correction to maintain the correct overall type I error rate) is included to illustrate the power gained by pooling information across nearby markers.</p>", "links"=>[], "tags"=>["transformations", "cbs"], "article_id"=>327895, "categories"=>["Mathematics", "Biological Sciences", "Genetics"], "users"=>["Patrick Breheny", "Prabhakar Chalise", "Anthony Batzler", "Liewei Wang", "Brooke L. Fridley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034262.t002", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_various_transformations_of_value_prior_to_application_of_CBS_on_the_power_to_detect_a_CNV_/327895", "title"=>"Effect of various transformations of -value prior to application of CBS on the power to detect a CNV.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-20 06:50:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/657177"], "description"=>"<p><i>Top:</i> Marker-level tests at three markers for the gemcitabine study. The phenotype (IC50, a continuous outcome described in “Gemcitabine pharmacogenomic study”) is plotted as a function of LRR, along with the regression line. The -values for the three -tests are, respectively, from left to right. 0.25, 0.0008, and 0.0008, respectively, from left to right. <i>Bottom:</i> Plot of from the marker-level tests as a function of position along the chromosome. The three tests from the top part of the figure are plotted in red.</p>", "links"=>[], "tags"=>["marker-level"], "article_id"=>327670, "categories"=>["Mathematics", "Biological Sciences", "Genetics"], "users"=>["Patrick Breheny", "Prabhakar Chalise", "Anthony Batzler", "Liewei Wang", "Brooke L. Fridley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034262.g003", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Illustration_of_marker_level_testing_/327670", "title"=>"Illustration of marker-level testing.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 06:48:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/657127"], "description"=>"<p><i>Left:</i> The noise, randomly drawn from among the observed measurement errors for a single subject. <i>Middle:</i> The spiked-in signal. <i>Right:</i> The resulting simulated data, which looks qualitatively similar to the real CNV in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034262#pone-0034262-g001\" target=\"_blank\">Figure 1</a>.</p>", "links"=>[], "tags"=>["lrr", "simulated"], "article_id"=>327617, "categories"=>["Mathematics", "Biological Sciences", "Genetics"], "users"=>["Patrick Breheny", "Prabhakar Chalise", "Anthony Batzler", "Liewei Wang", "Brooke L. Fridley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034262.g002", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Example_of_LRR_data_for_a_simulated_CNV_/327617", "title"=>"Example of LRR data for a simulated CNV.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 06:48:41"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2012-01-01T00:00:00Z", "end_date"=>"2012-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Molecular biology", "average_usage"=>[324, 551, 679, 782, 879, 971, 1064, 1154, 1245, 1328, 1406, 1476, 1541, 1617, 1683, 1754, 1818, 1893, 1962, 2025, 2092, 2164, 2227, 2294, 2355]}, {"subject_area"=>"/Medicine and health sciences/Pharmacology", "average_usage"=>[314, 554, 687, 796, 891, 983, 1075, 1170, 1261, 1340, 1422, 1504, 1574, 1647, 1715, 1786, 1848, 1919, 1990, 2053, 2115, 2197, 2258, 2333, 2395]}, {"subject_area"=>"/Physical sciences/Mathematics", "average_usage"=>[325, 522, 627, 718, 804, 884, 969, 1052, 1131, 1207, 1277, 1346, 1415, 1478, 1542, 1605, 1663, 1723, 1776, 1839, 1895, 1955, 2008, 2066, 2123]}]}
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