{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:19:19Z","timestamp":1761920359264,"version":"3.37.3"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T00:00:00Z","timestamp":1509062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/about_us\/legal\/notices"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Motivation<\/jats:title><jats:p>A significant difference in the distribution of a feature between two gene sets can provide insight into function or regulation. This statistical setting differs from much of hypothesis testing theory because the genome is often considered to be effectively fixed, finite and entirely known in commonly studied organisms, such as human. The Mann\u2013Whitney U test is commonly employed in this scenario despite the assumptions of the test not being met, leading to unreliable and generally underpowered results. Permutation tests are also commonly employed for this purpose, but are computationally burdensome and are not tractable for obtaining small P values or for multiple comparisons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We present an exact test for the null hypothesis that gene set membership is independent of the quantitative gene feature of interest. We derive an analytic expression for the randomization distribution of the median of the quantitative feature under the null hypothesis. Efficient implementation permits calculation of precise P values of arbitrary magnitude and makes thousands of simultaneous tests of transcriptome-sized gene sets computationally tractable. The flexibility of the hypothesis testing framework presented permits extension to a variety of related tests commonly found in genomics. The exact test is used to identify signatures of translation control and protein function in the human genome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and implementation<\/jats:title><jats:p>The exact test presented here is implemented in R in the package kpmt available on CRAN.<\/jats:p><\/jats:sec><jats:sec><jats:title>Supplementary information<\/jats:title><jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/btx693","type":"journal-article","created":{"date-parts":[[2017,10,26]],"date-time":"2017-10-26T19:11:16Z","timestamp":1509045076000},"page":"971-977","source":"Crossref","is-referenced-by-count":5,"title":["An exact test for comparing a fixed quantitative property between gene sets"],"prefix":"10.1093","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4283-9675","authenticated-orcid":false,"given":"Matthew M","family":"Parks","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA"}]}],"member":"286","published-online":{"date-parts":[[2017,10,27]]},"reference":[{"key":"2023012712572787500_btx693-B1","doi-asserted-by":"crossref","first-page":"475731.","DOI":"10.1155\/2012\/475731","article-title":"Before it gets started: regulating translation at the 5\u2032 UTR","volume":"2012","author":"Araujo","year":"2012","journal-title":"Comp. Funct. Genomics"},{"key":"2023012712572787500_btx693-B2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet"},{"key":"2023012712572787500_btx693-B3","doi-asserted-by":"crossref","first-page":"4015","DOI":"10.1091\/mbc.E14-12-1632","article-title":"Expression, sorting, and segregation of Golgi proteins during germ cell differentiation in the testis","volume":"26","author":"Au","year":"2015","journal-title":"Mol. Biol. Cell"},{"key":"2023012712572787500_btx693-B4","doi-asserted-by":"crossref","first-page":"e1005863.","DOI":"10.1371\/journal.pgen.1005863","article-title":"UPF2-dependent nonsense-mediated mRNA decay pathway is essential for spermatogenesis by selectively eliminating longer 3\u2032UTR transcripts","volume":"12","author":"Bao","year":"2016","journal-title":"PLoS Genet"},{"key":"2023012712572787500_btx693-B5","first-page":"1793","article-title":"The fate of the Golgi apparatus and the endoplasmic reticulum during lens fiber cell differentiation","volume":"36","author":"Bassnett","year":"1995","journal-title":"Invest. Ophthalmol. Vis. Sci"},{"key":"2023012712572787500_btx693-B6","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. B"},{"volume-title":"Proceedings of the Third Berkeley Symposium on Mathematical Statistics and Probability","year":"1956","author":"Birnbaum","key":"2023012712572787500_btx693-B7"},{"key":"2023012712572787500_btx693-B8","doi-asserted-by":"crossref","first-page":"R127.","DOI":"10.1186\/gb-2010-11-12-r127","article-title":"Novel genes exhibit distinct patterns of function acquisition and network integration","volume":"11","author":"Capra","year":"2010","journal-title":"Genome Biol"},{"key":"2023012712572787500_btx693-B9","doi-asserted-by":"crossref","first-page":"e1001366.","DOI":"10.1371\/journal.pgen.1001366","article-title":"Genome analysis reveals interplay between 5\u2032UTR introns and nuclear mRNA export for secretory and mitochondrial genes","volume":"7","author":"Cenik","year":"2011","journal-title":"PLoS Genet"},{"key":"2023012712572787500_btx693-B10","doi-asserted-by":"crossref","first-page":"R13.","DOI":"10.1186\/gb-2014-15-1-r13","article-title":"Constitutive patterns of gene expression regulated by RNA-binding proteins","volume":"15","author":"Cirillo","year":"2014","journal-title":"Genome Biol"},{"key":"2023012712572787500_btx693-B11","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1101\/gr.131037.111","article-title":"Genome-wide analysis of long noncoding RNA stability","volume":"22","author":"Clark","year":"2012","journal-title":"Genome Res"},{"key":"2023012712572787500_btx693-B12","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1101\/gr.132159.111","article-title":"The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression","volume":"22","author":"Derrien","year":"2012","journal-title":"Genome Res"},{"year":"2017","author":"Divine","key":"2023012712572787500_btx693-B13"},{"key":"2023012712572787500_btx693-B14","doi-asserted-by":"crossref","first-page":"e39.","DOI":"10.1371\/journal.pcbi.0030039","article-title":"Discovering motifs in ranked lists of DNA sequences","volume":"3","author":"Eden","year":"2007","journal-title":"PLoS Comput. Biol"},{"key":"2023012712572787500_btx693-B15","doi-asserted-by":"crossref","first-page":"87","DOI":"10.2307\/2340521","article-title":"On the interpretation of \u03c72 from contingency tables, and the calculation of P","volume":"85","author":"Fisher","year":"1922","journal-title":"J. R. Stat. Soc"},{"key":"2023012712572787500_btx693-B16","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1002\/dvdy.21545","article-title":"Chromatin remodeling during mouse and human embryonic stem cell differentiation","volume":"237","author":"Golob","year":"2008","journal-title":"Dev. Dyn"},{"key":"2023012712572787500_btx693-B17","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/nature09267","article-title":"Mammalian microRNAs predominantly act to decrease target mRNA levels","volume":"466","author":"Guo","year":"2010","journal-title":"Nature"},{"key":"2023012712572787500_btx693-B18","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/biomet\/asr079","article-title":"Conservative hypothesis tests and confidence intervals using importance sampling","volume":"99","author":"Harrison","year":"2012","journal-title":"Biometrika"},{"key":"2023012712572787500_btx693-B19","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1101\/gr.135350.111","article-title":"GENCODE: the reference human genome annotation for The ENCODE Project","volume":"22","author":"Harrow","year":"2012","journal-title":"Genome Res"},{"key":"2023012712572787500_btx693-B20","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.celrep.2013.12.030","article-title":"The earliest transcribed zygotic genes are short, newly evolved, and different across species","volume":"6","author":"Heyn","year":"2014","journal-title":"Cell Rep"},{"key":"2023012712572787500_btx693-B21","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1126\/science.1168978","article-title":"Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling","volume":"324","author":"Ingolia","year":"2009","journal-title":"Science"},{"key":"2023012712572787500_btx693-B22","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.cell.2011.10.002","article-title":"Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes","volume":"147","author":"Ingolia","year":"2011","journal-title":"Cell"},{"key":"2023012712572787500_btx693-B23","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/nature03001","article-title":"Finishing the euchromatic sequence of the human genome","volume":"431","author":"Human Genome Sequencing Consortium","year":"2004","journal-title":"Nature"},{"key":"2023012712572787500_btx693-B24","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.tig.2008.05.006","article-title":"Rapidly regulated genes are intron poor","volume":"24","author":"Jeffares","year":"2008","journal-title":"Trends Genet"},{"key":"2023012712572787500_btx693-B25","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1083\/jcb.120.5.1251","article-title":"Mouse differentiation-specific keratins 1 and 10 require a preexisting keratin scaffold to form a filament network","volume":"120","author":"Kartasova","year":"1993","journal-title":"J. Cell. Biol"},{"key":"2023012712572787500_btx693-B26","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/cbf.1776","article-title":"A unique Golgi apparatus distribution may be a marker for osteogenic differentiation of hDP-MSCs","volume":"29","author":"Kasap","year":"2011","journal-title":"Cell. Biochem. Funct"},{"key":"2023012712572787500_btx693-B27","doi-asserted-by":"crossref","first-page":"e1002841.","DOI":"10.1371\/journal.pgen.1002841","article-title":"Rapid turnover of long noncoding RNAs and the evolution of gene expression","volume":"8","author":"Kutter","year":"2012","journal-title":"PLoS Genet"},{"key":"2023012712572787500_btx693-B28","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/cdd.2017.28","article-title":"Keratins regulate colonic epithelial cell differentiation through the Notch1 signalling pathway","volume":"24","author":"L\u00e4hdeniemi","year":"2017","journal-title":"Cell Death Differ"},{"key":"2023012712572787500_btx693-B29","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1214\/aoms\/1177730491","article-title":"On a test of whether one of two random variables is stochastically larger than the other","volume":"18","author":"Mann","year":"1947","journal-title":"Ann. Math. Stat"},{"key":"2023012712572787500_btx693-B30","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1038\/nprot.2013.092","article-title":"Large-scale gene function analysis with the PANTHER classification system","volume":"8","author":"Mi","year":"2013","journal-title":"Nat. Protoc"},{"key":"2023012712572787500_btx693-B31","doi-asserted-by":"crossref","DOI":"10.1093\/database\/bav003","article-title":"LocSigDB: a database of protein localization signals","author":"Negi","year":"2015","journal-title":"Database (Oxford)"},{"key":"2023012712572787500_btx693-B32","first-page":"209","volume-title":"Proceedings of the Thirty-First Annual SAS Users Group International Conference","author":"O\u2019Brien","year":"2006"},{"key":"2023012712572787500_btx693-B33","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/nar\/27.1.29","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"27","author":"Ogata","year":"1999","journal-title":"Nucleic Acids Res"},{"key":"2023012712572787500_btx693-B34","doi-asserted-by":"crossref","first-page":"e01311.","DOI":"10.7554\/eLife.01311","article-title":"The life cycle of Drosophila orphan genes","volume":"3","author":"Palmieri","year":"2014","journal-title":"elife"},{"key":"2023012712572787500_btx693-B35","doi-asserted-by":"crossref","DOI":"10.2202\/1544-6115.1585","article-title":"Permutation P-values should never be zero: calculating exact P-values when permutations are randomly drawn","volume":"9","author":"Phipson","year":"2010","journal-title":"Stat. Appl. Genet. Mol. Biol"},{"key":"2023012712572787500_btx693-B36","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1242\/jcs.146720","article-title":"Role of cell-cell adhesion complexes in embryonic stem cell biology","volume":"127","author":"Pieters","year":"2014","journal-title":"J. Cell. Sci"},{"key":"2023012712572787500_btx693-B37","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1038\/ng.2343","article-title":"The yak genome and adaptation to life at high altitude","volume":"44","author":"Qiu","year":"2012","journal-title":"Nat. Genet"},{"year":"2013","author":"R Core Team","key":"2023012712572787500_btx693-B38"},{"key":"2023012712572787500_btx693-B39","doi-asserted-by":"crossref","first-page":"e47.","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023012712572787500_btx693-B40","doi-asserted-by":"crossref","first-page":"7200.","DOI":"10.1038\/ncomms8200","article-title":"Translational regulation shapes the molecular landscape of complex disease phenotypes","volume":"6","author":"Schafer","year":"2015","journal-title":"Nat. Commun"},{"key":"2023012712572787500_btx693-B41","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1101\/gr.121210.111","article-title":"Unusually effective microRNA targeting within repeat-rich coding regions of mammalian mRNAs","volume":"21","author":"Schnall-Levin","year":"2011","journal-title":"Genome Res"},{"key":"2023012712572787500_btx693-B42","doi-asserted-by":"crossref","first-page":"574.","DOI":"10.1186\/1471-2164-13-574","article-title":"Comparison of total and cytoplasmic mRNA reveals global regulation by nuclear retention and miRNAs","volume":"13","author":"Solnestam","year":"2012","journal-title":"BMC Genomics"},{"key":"2023012712572787500_btx693-B43","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1101\/gr.156919.113","article-title":"3\u2032 UTR-isoform choice has limited influence on the stability and translational efficiency of most mRNAs in mouse fibroblasts","volume":"23","author":"Spies","year":"2013","journal-title":"Genome Res"},{"key":"2023012712572787500_btx693-B44","doi-asserted-by":"crossref","first-page":"82.","DOI":"10.1186\/s12862-015-0360-y","article-title":"Convergent evolution of cysteine-rich proteins in feathers and hair","volume":"15","author":"Strasser","year":"2015","journal-title":"BMC Evol. Biol"},{"key":"2023012712572787500_btx693-B45","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.molcel.2013.09.018","article-title":"The translational landscape of the mammalian cell cycle","volume":"52","author":"Stumpf","year":"2013","journal-title":"Mol. Cell"},{"key":"2023012712572787500_btx693-B46","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nature11083","article-title":"A unifying model for mTORC1-mediated regulation of mRNA translation","volume":"485","author":"Thoreen","year":"2012","journal-title":"Nature"},{"key":"2023012712572787500_btx693-B47","doi-asserted-by":"crossref","first-page":"e1005288.","DOI":"10.1371\/journal.ppat.1005288","article-title":"The transcription and translation landscapes during human cytomegalovirus infection reveal novel host-pathogen interactions","volume":"11","author":"Tirosh","year":"2015","journal-title":"PLoS Pathog"},{"key":"2023012712572787500_btx693-B48","doi-asserted-by":"crossref","first-page":"e1001070.","DOI":"10.1371\/journal.pgen.1001070","article-title":"The transcriptomes of two heritable cell types illuminate the circuit governing their differentiation","volume":"6","author":"Tuch","year":"2010","journal-title":"PLoS Genet"},{"key":"2023012712572787500_btx693-B49","doi-asserted-by":"crossref","first-page":"170","DOI":"10.3102\/10769986023002170","article-title":"The Kruska\u2013Wallis test and stochastic homogeneity","volume":"23","author":"Vargha","year":"1998","journal-title":"J. Educ. Behav. Stat"},{"key":"2023012712572787500_btx693-B50","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1101\/gr.165035.113","article-title":"Evolutionary dynamics and tissue specificity of human long noncoding RNAs in six mammals","volume":"24","author":"Washietl","year":"2014","journal-title":"Genome Res"},{"key":"2023012712572787500_btx693-B51","doi-asserted-by":"crossref","DOI":"10.18637\/jss.v040.i01","article-title":"The split-apply-combine strategy for data analysis","volume":"40","author":"Wickham","year":"2011","journal-title":"J. Stat. Softw"},{"key":"2023012712572787500_btx693-B52","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1126\/science.1257522","article-title":"Targeting and plasticity of mitochondrial proteins revealed by proximity-specific ribosome profiling","volume":"346","author":"Williams","year":"2014","journal-title":"Science (New York, N.Y.)"},{"key":"2023012712572787500_btx693-B53","doi-asserted-by":"crossref","first-page":"R14","DOI":"10.1186\/gb-2010-11-2-r14","article-title":"Gene ontology analysis for RNA-seq: accounting for selection bias","volume":"11","author":"Young","year":"2010","journal-title":"Genome Biol"},{"key":"2023012712572787500_btx693-B54","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1093\/gbe\/evs020","article-title":"Identification and properties of 1,119 candidate lincRNA loci in the Drosophila melanogaster genome","volume":"4","author":"Young","year":"2012","journal-title":"Genome Biol. Evol"},{"key":"2023012712572787500_btx693-B55","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1038\/cdd.2014.79","article-title":"p53-directed translational control can shape and expand the universe of p53 target genes","volume":"21","author":"Zaccara","year":"2014","journal-title":"Cell Death Differ"},{"key":"2023012712572787500_btx693-B56","doi-asserted-by":"crossref","first-page":"16219","DOI":"10.1073\/pnas.1408886111","article-title":"A circadian gene expression atlas in mammals: implications for biology and medicine","volume":"111","author":"Zhang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023012712572787500_btx693-B57","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1741-7007-11-23","article-title":"Frequency of intron loss correlates with processed pseudogene abundance: a novel strategy to test the reverse transcriptase model of intron loss","volume":"11","author":"Zhu","year":"2013","journal-title":"BMC Biol"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/34\/6\/971\/48914568\/bioinformatics_34_6_971.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/34\/6\/971\/48914568\/bioinformatics_34_6_971.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T02:09:49Z","timestamp":1719540589000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/34\/6\/971\/4569006"}},"subtitle":[],"editor":[{"given":"Ziv","family":"Bar-Joseph","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2017,10,27]]},"references-count":57,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018,3,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btx693","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2018,3,15]]},"published":{"date-parts":[[2017,10,27]]}}}