A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic
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{"title"=>"A groupwise association test for rare mutations using a weighted sum statistic", "type"=>"journal", "authors"=>[{"first_name"=>"Bo Eskerod", "last_name"=>"Madsen", "scopus_author_id"=>"56212355000"}, {"first_name"=>"Sharon R.", "last_name"=>"Browning", "scopus_author_id"=>"7005801400"}], "year"=>2009, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-61449168010", "sgr"=>"61449168010", "issn"=>"15537390", "doi"=>"10.1371/journal.pgen.1000384", "pmid"=>"19214210", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pui"=>"354253484"}, "id"=>"f380404f-8a58-36c5-a51a-1a65b563ca16", "abstract"=>"Resequencing is an emerging tool for identification of rare disease-associated mutations. Rare mutations are difficult to tag with SNP genotyping, as genotyping studies are designed to detect common variants. However, studies have shown that genetic heterogeneity is a probable scenario for common diseases, in which multiple rare mutations together explain a large proportion of the genetic basis for the disease. Thus, we propose a weighted-sum method to jointly analyse a group of mutations in order to test for groupwise association with disease status. For example, such a group of mutations may result from resequencing a gene. We compare the proposed weighted-sum method to alternative methods and show that it is powerful for identifying disease-associated genes, both on simulated and Encode data. Using the weighted-sum method, a resequencing study can identify a disease-associated gene with an overall population attributable risk (PAR) of 2%, even when each individual mutation has much lower PAR, using 1,000 to 7,000 affected and unaffected individuals, depending on the underlying genetic model. This study thus demonstrates that resequencing studies can identify important genetic associations, provided that specialised analysis methods, such as the weighted-sum method, are used.", "link"=>"http://www.mendeley.com/research/groupwise-association-test-rare-mutations-using-weighted-sum-statistic", "reader_count"=>369, "reader_count_by_academic_status"=>{"Unspecified"=>5, "Professor > Associate Professor"=>40, "Librarian"=>1, "Student > Doctoral Student"=>13, "Researcher"=>111, "Student > Ph. D. Student"=>109, "Student > Postgraduate"=>8, "Student > Master"=>25, "Other"=>20, "Student > Bachelor"=>12, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>23}, "reader_count_by_user_role"=>{"Unspecified"=>5, "Professor > Associate Professor"=>40, "Librarian"=>1, "Student > Doctoral Student"=>13, "Researcher"=>111, "Student > Ph. D. Student"=>109, "Student > Postgraduate"=>8, "Student > Master"=>25, "Other"=>20, "Student > Bachelor"=>12, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>23}, "reader_count_by_subject_area"=>{"Unspecified"=>13, "Agricultural and Biological Sciences"=>179, "Business, Management and Accounting"=>2, "Chemistry"=>2, "Computer Science"=>20, "Engineering"=>4, "Biochemistry, Genetics and Molecular Biology"=>46, "Mathematics"=>38, "Medicine and Dentistry"=>52, "Neuroscience"=>2, "Sports and Recreations"=>1, "Physics and Astronomy"=>3, "Psychology"=>2, "Social Sciences"=>2, "Immunology and Microbiology"=>2, "Linguistics"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>52}, "Social Sciences"=>{"Social Sciences"=>2}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>3}, "Psychology"=>{"Psychology"=>2}, "Mathematics"=>{"Mathematics"=>38}, "Unspecified"=>{"Unspecified"=>13}, "Engineering"=>{"Engineering"=>4}, "Chemistry"=>{"Chemistry"=>2}, "Neuroscience"=>{"Neuroscience"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>179}, "Computer Science"=>{"Computer Science"=>20}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>2}, "Linguistics"=>{"Linguistics"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>46}}, "reader_count_by_country"=>{"Hong Kong"=>1, "United States"=>22, "United Kingdom"=>7, "Malaysia"=>1, "Spain"=>1, "Canada"=>2, "Sweden"=>1, "Austria"=>1, "Korea (South)"=>1, "Norway"=>1, "Denmark"=>1, "Brazil"=>2, "Mexico"=>1, "Australia"=>2, "France"=>2, "Germany"=>2}, "group_count"=>22}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/908258"], "description"=>"<p>The power of the investigated methods is shown for different number of D-variants (disease-risk contributing variants). The power simulations were performed using <i>n<sup>A</sup></i> = <i>n<sup>U</sup></i> = 1000 individuals, 50% D-variants, group PAR of 10% and <i>p<sub>M</sub></i> = 10%. Note that the jump in the power for the CMC method under the Recessive-set model occurs because a low number of variants yields a high allele-frequency of each variant, and the variants are hence not grouped by the CMC method.</p>", "links"=>[], "tags"=>["genetics and genomics/disease models", "genetics and genomics/genetics of disease", "genetics and genomics/medical genetics", "mathematics/statistics", "public health and epidemiology/epidemiology"], "article_id"=>578718, "categories"=>["Mathematics", "Genetics", "Neuroscience"], "users"=>["Bo Eskerod Madsen", "Sharon R. Browning"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000384.g003"], "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Power_versus_number_of_D_variants_/578718", "title"=>"Power versus number of D-variants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-02-13 02:25:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/908420"], "description"=>"<p>The power of the investigated methods is shown for different proportions of D-variants (disease-risk contributing variants). The power simulations were performed using <i>n<sup>A</sup></i> = <i>n<sup>U</sup></i> = 1000 individuals, 50 D-variants, group PAR of 10% and <i>p<sub>M</sub></i> = 10%.</p>", "links"=>[], "tags"=>["genetics and genomics/disease models", "genetics and genomics/genetics of disease", "genetics and genomics/medical genetics", "mathematics/statistics", "public health and epidemiology/epidemiology"], "article_id"=>578874, "categories"=>["Mathematics", "Genetics", "Neuroscience"], "users"=>["Bo Eskerod Madsen", "Sharon R. Browning"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000384.g004"], "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Power_versus_proportion_of_D_variants_/578874", "title"=>"Power versus proportion of D-variants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-02-13 02:27:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/908146"], "description"=>"<p>The power of the investigated methods is shown for different levels of group-PAR. The power simulations were performed using <i>n<sup>A</sup></i> = <i>n<sup>U</sup></i> = 1000 individuals, 50 D-variants, 50 N-variants and <i>p<sub>M</sub></i> = 10%.</p>", "links"=>[], "tags"=>["par"], "article_id"=>578607, "categories"=>["Mathematics", "Genetics", "Neuroscience"], "users"=>["Bo Eskerod Madsen", "Sharon R. Browning"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000384.g002"], "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Power_versus_PAR_of_group_/578607", "title"=>"Power versus PAR of group.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-02-13 02:23:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/908566"], "description"=>"<p>For each Encode region, we test whether rare exonic variants are overrepresented in the African (YRI) population compared to the central European (CEU) population. To mimic studies of rare variants, five different minor allele frequency (MAF) cut-off values (1%–5%) are used; all variants with a MAF over the cut-off value are omitted in the analysis. For each set of variants, the number of tested variants is reported along with the number of variants that are only polymorphic in the YRI population (the first number in the parenthesis), and the number of variants that are only polymorphic in the CEU population (the second number in the parenthesis). Below the number of variants, p-values from the investigated methods are reported. It is seen that the proposed test yields lower p-values than the alternative tests in nearly all cases where the rare variants are significantly overrepresented in the YRI population. The only exception is for the ENm010 region with MAF cut-off at 1%; in that case, the weighted-sum method yields a slightly higher p-value than the CMC and CAST methods.</p>", "links"=>[], "tags"=>["excess", "exonic", "variants", "yri", "compared", "ceu"], "article_id"=>579024, "categories"=>["Mathematics", "Genetics", "Neuroscience"], "users"=>["Bo Eskerod Madsen", "Sharon R. Browning"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000384.t002"], "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tests_for_excess_of_rare_exonic_variants_in_the_YRI_population_compared_to_the_CEU_population_/579024", "title"=>"Tests for excess of rare exonic variants in the YRI population compared to the CEU population.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-02-13 02:30:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/449050", "https://ndownloader.figshare.com/files/449076", "https://ndownloader.figshare.com/files/449105", "https://ndownloader.figshare.com/files/449134", "https://ndownloader.figshare.com/files/449162", "https://ndownloader.figshare.com/files/449198"], "description"=>"<div><p>Resequencing is an emerging tool for identification of rare disease-associated mutations. Rare mutations are difficult to tag with SNP genotyping, as genotyping studies are designed to detect common variants. However, studies have shown that genetic heterogeneity is a probable scenario for common diseases, in which multiple rare mutations together explain a large proportion of the genetic basis for the disease. Thus, we propose a weighted-sum method to jointly analyse a group of mutations in order to test for groupwise association with disease status. For example, such a group of mutations may result from resequencing a gene. We compare the proposed weighted-sum method to alternative methods and show that it is powerful for identifying disease-associated genes, both on simulated and Encode data. Using the weighted-sum method, a resequencing study can identify a disease-associated gene with an overall population attributable risk (PAR) of 2%, even when each individual mutation has much lower PAR, using 1,000 to 7,000 affected and unaffected individuals, depending on the underlying genetic model. This study thus demonstrates that resequencing studies can identify important genetic associations, provided that specialised analysis methods, such as the weighted-sum method, are used.</p></div>", "links"=>[], "tags"=>["groupwise", "mutations", "weighted", "statistic"], "article_id"=>148508, "categories"=>["Mathematics", "Genetics", "Neuroscience"], "users"=>["Bo Eskerod Madsen", "Sharon R. Browning"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000384.s001", "https://dx.doi.org/10.1371/journal.pgen.1000384.s002", "https://dx.doi.org/10.1371/journal.pgen.1000384.s003", "https://dx.doi.org/10.1371/journal.pgen.1000384.s004", "https://dx.doi.org/10.1371/journal.pgen.1000384.s005", "https://dx.doi.org/10.1371/journal.pgen.1000384.s006"], "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Groupwise_Association_Test_for_Rare_Mutations_Using_a_Weighted_Sum_Statistic/148508", "title"=>"A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-02-13 02:21:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/908100"], "description"=>"<p>Model descriptions and examples of predisposing genotypes are shown for the genetic models used. Lines symbolise haplotypes and dots symbolise disease-risk mutations.</p>", "links"=>[], "tags"=>["genetics and genomics/disease models", "genetics and genomics/genetics of disease", "genetics and genomics/medical genetics", "mathematics/statistics", "public health and epidemiology/epidemiology"], "article_id"=>578551, "categories"=>["Mathematics", "Genetics", "Neuroscience"], "users"=>["Bo Eskerod Madsen", "Sharon R. Browning"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000384.g001"], "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genetic_models_/578551", "title"=>"Genetic models.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-02-13 02:22:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/908529"], "description"=>"<p>The power (in %) of the weighted-sum method is shown for different numbers of individuals <i>n</i> = <i>n<sup>A</sup></i> = <i>n<sup>U</sup></i>, and different levels of group PAR (in %). Combinations with at least 80% power are shown in bold. The power simulations were performed using 50 D-variants, 50 N-variants and <i>p<sub>M</sub></i> = 10%.</p>", "links"=>[], "tags"=>["individuals", "disease-associated"], "article_id"=>578994, "categories"=>["Mathematics", "Genetics", "Neuroscience"], "users"=>["Bo Eskerod Madsen", "Sharon R. Browning"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000384.t001"], "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Number_of_individuals_needed_to_identify_a_disease_associated_group_/578994", "title"=>"Number of individuals needed to identify a disease-associated group.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-02-13 02:29:54"}

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