Predicting Mendelian Disease-Causing Non-Synonymous Single Nucleotide Variants in Exome Sequencing Studies
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{"title"=>"Predicting Mendelian Disease-Causing Non-Synonymous Single Nucleotide Variants in Exome Sequencing Studies", "type"=>"journal", "authors"=>[{"first_name"=>"Miao Xin", "last_name"=>"Li", "scopus_author_id"=>"17135391100"}, {"first_name"=>"Johnny S H", "last_name"=>"Kwan", "scopus_author_id"=>"37063349600"}, {"first_name"=>"Su Ying", "last_name"=>"Bao", "scopus_author_id"=>"53663218300"}, {"first_name"=>"Wanling", "last_name"=>"Yang", "scopus_author_id"=>"23101349500"}, {"first_name"=>"Shu Leong", "last_name"=>"Ho", "scopus_author_id"=>"25959633500"}, {"first_name"=>"Yong Qiang", "last_name"=>"Song", "scopus_author_id"=>"55812396800"}, {"first_name"=>"Pak C.", "last_name"=>"Sham", "scopus_author_id"=>"34573429300"}], "year"=>2013, "source"=>"PLoS Genetics", "identifiers"=>{"sgr"=>"84873486397", "doi"=>"10.1371/journal.pgen.1003143", "pui"=>"368295359", "issn"=>"15537390", "pmid"=>"23341771", "isbn"=>"1553-7404", "scopus"=>"2-s2.0-84873486397"}, "id"=>"d7e0db28-4527-3b02-b9c0-b336bb676546", "abstract"=>"Exome sequencing is becoming a standard tool for mapping Mendelian disease-causing (or pathogenic) non-synonymous single nucleotide variants (nsSNVs). Minor allele frequency (MAF) filtering approach and functional prediction methods are commonly used to identify candidate pathogenic mutations in these studies. Combining multiple functional prediction methods may increase accuracy in prediction. Here, we propose to use a logit model to combine multiple prediction methods and compute an unbiased probability of a rare variant being pathogenic. Also, for the first time we assess the predictive power of seven prediction methods (including SIFT, PolyPhen2, CONDEL, and logit) in predicting pathogenic nsSNVs from other rare variants, which reflects the situation after MAF filtering is done in exome-sequencing studies. We found that a logit model combining all or some original prediction methods outperforms other methods examined, but is unable to discriminate between autosomal dominant and autosomal recessive disease mutations. Finally, based on the predictions of the logit model, we estimate that an individual has around 5% of rare nsSNVs that are pathogenic and carries approximately 22 pathogenic derived alleles at least, which if made homozygous by consanguineous marriages may lead to recessive diseases.", "link"=>"http://www.mendeley.com/research/predicting-mendelian-diseasecausing-nonsynonymous-single-nucleotide-variants-exome-sequencing-studie", "reader_count"=>161, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>13, "Researcher"=>45, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>50, "Student > Postgraduate"=>2, "Student > Master"=>20, "Other"=>3, "Student > Bachelor"=>11, "Lecturer > Senior Lecturer"=>1, "Professor"=>10}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>13, "Researcher"=>45, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>50, "Student > Postgraduate"=>2, "Student > Master"=>20, "Other"=>3, "Student > Bachelor"=>11, "Lecturer > Senior Lecturer"=>1, "Professor"=>10}, "reader_count_by_subject_area"=>{"Engineering"=>4, "Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>19, "Mathematics"=>1, "Agricultural and Biological Sciences"=>94, "Medicine and Dentistry"=>21, "Neuroscience"=>2, "Business, Management and Accounting"=>1, "Physics and Astronomy"=>2, "Psychology"=>2, "Computer Science"=>12, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>4}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>21}, "Neuroscience"=>{"Neuroscience"=>2}, "Physics and Astronomy"=>{"Physics and Astronomy"=>2}, "Psychology"=>{"Psychology"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>94}, "Computer Science"=>{"Computer Science"=>12}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>19}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Argentina"=>1, "Hungary"=>1, "United States"=>8, "United Kingdom"=>5, "Spain"=>2, "Netherlands"=>1, "Korea (South)"=>1, "Turkey"=>1, "Denmark"=>2, "Brazil"=>1, "Italy"=>1, "Australia"=>1, "Germany"=>2}, "group_count"=>8}

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Figshare

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  • {"files"=>["https://ndownloader.figshare.com/files/276031", "https://ndownloader.figshare.com/files/276076", "https://ndownloader.figshare.com/files/276116", "https://ndownloader.figshare.com/files/276154"], "description"=>"<div><p>Exome sequencing is becoming a standard tool for mapping Mendelian disease-causing (or pathogenic) non-synonymous single nucleotide variants (nsSNVs). Minor allele frequency (MAF) filtering approach and functional prediction methods are commonly used to identify candidate pathogenic mutations in these studies. Combining multiple functional prediction methods may increase accuracy in prediction. Here, we propose to use a logit model to combine multiple prediction methods and compute an unbiased probability of a rare variant being pathogenic. Also, for the first time we assess the predictive power of seven prediction methods (including SIFT, PolyPhen2, CONDEL, and logit) in predicting pathogenic nsSNVs from other rare variants, which reflects the situation after MAF filtering is done in exome-sequencing studies. We found that a logit model combining all or some original prediction methods outperforms other methods examined, but is unable to discriminate between autosomal dominant and autosomal recessive disease mutations. Finally, based on the predictions of the logit model, we estimate that an individual has around 5% of rare nsSNVs that are pathogenic and carries ∼22 pathogenic derived alleles at least, which if made homozygous by consanguineous marriages may lead to recessive diseases.</p> </div>", "links"=>[], "tags"=>["predicting", "mendelian", "disease-causing", "non-synonymous", "nucleotide", "variants", "exome", "sequencing", "studies"], "article_id"=>114376, "categories"=>["Genetics"], "users"=>["Miao-Xin Li", "Johnny S. H. Kwan", "Su-Ying Bao", "Wanling Yang", "Shu-Leong Ho", "Yong-Qiang Song", "Pak C. Sham"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003143.s001", "https://dx.doi.org/10.1371/journal.pgen.1003143.s002", "https://dx.doi.org/10.1371/journal.pgen.1003143.s003", "https://dx.doi.org/10.1371/journal.pgen.1003143.s004"], "stats"=>{"downloads"=>22, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Predicting_Mendelian_Disease_Causing_Non_Synonymous_Single_Nucleotide_Variants_in_Exome_Sequencing_Studies__/114376", "title"=>"Predicting Mendelian Disease-Causing Non-Synonymous Single Nucleotide Variants in Exome Sequencing Studies", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-01-17 01:12:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/505767"], "description"=>"a<p>Related cases with autosomal dominant spinocerebellar ataxia.</p>b<p>Case with neonatal-onset Crohn's disease.</p>c<p>nsSNVs in which prediction is unavailable due to missing scores.</p>", "links"=>[], "tags"=>["numbers", "nssnvs", "removed", "hard-filtering", "logit", "mendelian-disease", "patients", "in-house", "exome", "sequencing"], "article_id"=>176270, "categories"=>["Genetics"], "users"=>["Miao-Xin Li", "Johnny S. H. Kwan", "Su-Ying Bao", "Wanling Yang", "Shu-Leong Ho", "Yong-Qiang Song", "Pak C. Sham"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003143.t004", "stats"=>{"downloads"=>4, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_numbers_and_proportion_of_nsSNVs_removed_by_hard_filtering_and_functional_prediction_by_the_logit_model_in_3_Mendelian_disease_patients_with_in_house_exome_sequencing_data_/176270", "title"=>"The numbers and proportion of nsSNVs removed by hard-filtering and functional prediction by the logit model in 3 Mendelian-disease patients with in-house exome sequencing data.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-01-17 01:44:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/505863"], "description"=>"a<p>The nsSNVs with missing scores at SIFT and/or MutationTaster were not used in the estimation.</p>b<p>the 95% confidence interval was derived empirically from randomly repeating 10-fold cross-validation 200 times.</p>", "links"=>[], "tags"=>["pathogenic", "nssnvs", "derived", "alleles", "hapmap", "subjects", "sequencing"], "article_id"=>176375, "categories"=>["Genetics"], "users"=>["Miao-Xin Li", "Johnny S. H. Kwan", "Su-Ying Bao", "Wanling Yang", "Shu-Leong Ho", "Yong-Qiang Song", "Pak C. Sham"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003143.t002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_proportion_of_pathogenic_rare_nsSNVs_and_total_load_of_pathogenic_derived_alleles_in_8_HapMap_subjects_with_high_coverage_sequencing_data_/176375", "title"=>"The proportion of pathogenic rare nsSNVs and total load of pathogenic derived alleles in 8 HapMap subjects with high coverage sequencing data.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-01-17 01:46:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/505480"], "description"=>"<p>(a) ROC and (b) PR. AUC is shown next to the name of each method.</p>", "links"=>[], "tags"=>["pr", "curves", "methods", "evaluated", "domrec", "dataset", "3-fold"], "article_id"=>175992, "categories"=>["Genetics"], "users"=>["Miao-Xin Li", "Johnny S. H. Kwan", "Su-Ying Bao", "Wanling Yang", "Shu-Leong Ho", "Yong-Qiang Song", "Pak C. Sham"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003143.g004", "stats"=>{"downloads"=>4, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ROC_and_PR_curves_of_prediction_methods_evaluated_on_the_DomRec_dataset_using_a_3_fold_cross_validation_/175992", "title"=>"ROC and PR curves of prediction methods evaluated on the DomRec dataset using a 3-fold cross-validation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-17 01:39:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/505903"], "description"=>"<p>Theoretical inbreeding coefficient (<i>F</i>) and corresponding number of homozygous pathogenic variants in the children of various relationships, given that on average each individual carries 22 pathogenic derived alleles.</p>", "links"=>[], "tags"=>["inbreeding", "coefficient", "corresponding", "homozygous", "pathogenic", "variants", "children", "carries", "22", "derived"], "article_id"=>176409, "categories"=>["Genetics"], "users"=>["Miao-Xin Li", "Johnny S. H. Kwan", "Su-Ying Bao", "Wanling Yang", "Shu-Leong Ho", "Yong-Qiang Song", "Pak C. Sham"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003143.t003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Theoretical_inbreeding_coefficient_F_and_corresponding_number_of_homozygous_pathogenic_variants_in_the_children_of_various_relationships_given_that_on_average_each_individual_carries_22_pathogenic_derived_alleles_/176409", "title"=>"Theoretical inbreeding coefficient (<i>F</i>) and corresponding number of homozygous pathogenic variants in the children of various relationships, given that on average each individual carries 22 pathogenic derived alleles.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-01-17 01:46:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/505643"], "description"=>"<p>The white dashed lines indicate the estimated range of the prior (5%). We assume that there is no difference in prediction scores from the three methods for the same variant. The <i>α</i>, <i>β</i><sub>SIFT</sub>, <i>β</i><sub>Polyphen2</sub> and <i>β</i><sub>MutationTaster</sub> in a selected sample evaluated in the ExoVar dataset are used in the calculation of posteriors (See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003143#pgen.1003143.e002\" target=\"_blank\">Eq. 2</a> and <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003143#pgen.1003143.e003\" target=\"_blank\">3</a> in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003143#s4\" target=\"_blank\">Materials and Methods</a>) and take the values of −3.53, 1.64, 1.48, and 2.47 respectively. The prior and posterior are equivalent to the quantity <i>P</i><sub>disease</sub> in an individual genome in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003143#pgen.1003143.e003\" target=\"_blank\">Eq. 3</a> and P(<i>Y</i> = 1|<i>X</i>) in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003143#pgen.1003143.e002\" target=\"_blank\">Eq. 2</a> respectively.</p>", "links"=>[], "tags"=>["posterior", "probabilities", "nssnv", "scores"], "article_id"=>176155, "categories"=>["Genetics"], "users"=>["Miao-Xin Li", "Johnny S. H. Kwan", "Su-Ying Bao", "Wanling Yang", "Shu-Leong Ho", "Yong-Qiang Song", "Pak C. Sham"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003143.g005", "stats"=>{"downloads"=>3, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_relationship_between_prior_and_posterior_probabilities_of_a_rare_nsSNV_being_pathogenic_given_the_prediction_scores_from_SIFT_PolyPhen2_and_MutationTaster_/176155", "title"=>"The relationship between prior and posterior probabilities of a rare nsSNV being pathogenic, given the prediction scores from SIFT, PolyPhen2, and MutationTaster.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-17 01:42:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/505397"], "description"=>"<p>(a) ROC and (b) PR. AUC is shown next to the name of each method.</p>", "links"=>[], "tags"=>["pr", "curves", "methods", "evaluated", "humvar", "dataset", "10-fold"], "article_id"=>175901, "categories"=>["Genetics"], "users"=>["Miao-Xin Li", "Johnny S. H. Kwan", "Su-Ying Bao", "Wanling Yang", "Shu-Leong Ho", "Yong-Qiang Song", "Pak C. Sham"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003143.g003", "stats"=>{"downloads"=>1, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ROC_and_PR_curves_of_prediction_methods_evaluated_on_the_HumVar_dataset_using_a_10_fold_cross_validation_/175901", "title"=>"ROC and PR curves of prediction methods evaluated on the HumVar dataset using a 10-fold cross-validation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-17 01:38:21"}

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Relative Metric

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