{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:10:29Z","timestamp":1753877429305,"version":"3.41.2"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T00:00:00Z","timestamp":1600387200000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1615789","1853556"],"award-info":[{"award-number":["1615789","1853556"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We are motivated by biological studies intended to understand global gene expression fold change. Biologists have generally adopted a fixed cutoff to determine the significance of fold changes in gene expression studies (e.g. by using an observed fold change equal to two as a fixed threshold). Scientists can also use a t-test or a modified differential expression test to assess the significance of fold changes. However, these methods either fail to take advantage of the high dimensionality of gene expression data or fail to test fold change directly. Our research develops a new empirical Bayesian approach to substantially improve the power and accuracy of fold-change detection. Specifically, we more accurately estimate gene-wise error variation in the log of fold change. We then adopt a t-test with adjusted degrees of freedom for significance assessment. We apply our method to a dosage study in Arabidopsis and a Down syndrome study in humans to illustrate the utility of our approach. We also present a simulation study based on real datasets to demonstrate the accuracy of our method relative to error variance estimation and power in fold-change detection. Our developed R package with a detailed user manual is publicly available on GitHub at https:\/\/github.com\/cuiyingbeicheng\/Foldseq.<\/jats:p>","DOI":"10.1093\/nargab\/lqaa072","type":"journal-article","created":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T14:54:29Z","timestamp":1600440869000},"source":"Crossref","is-referenced-by-count":0,"title":["An empirical bayesian approach for testing gene expression fold change and its application in detecting global dosage effects"],"prefix":"10.1093","volume":"2","author":[{"given":"Zhenxing","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowen","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of Missouri at Columbia, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James A","family":"Birchler","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of Missouri at Columbia, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Albizua","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie\u00a0L","family":"Sherman","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaohui S","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1915-5892","authenticated-orcid":false,"given":"Tieming","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of Missouri at Columbia, Columbia, MO 65211, USA"},{"name":"Roche Diagnostics, Santa Clara, CA 95050, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,9,18]]},"reference":[{"key":"2020103008540721400_B1","first-page":"131","article-title":"John Langdon Down (1828-1896)","volume":"8","author":"Van\u00a0Robys","year":"2016","journal-title":"Facts Views Vis. Obgyn."},{"key":"2020103008540721400_B2","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1126\/science.52.1347.388","article-title":"Chromosomal duplication and Mendelian phenomena in Datura mutants","volume":"52","author":"Blakeslee","year":"1920","journal-title":"Science"},{"key":"2020103008540721400_B3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/oxfordjournals.jhered.a103898","article-title":"New Jimson weeds from old chromosomes","volume":"25","author":"Blakeslee","year":"1934","journal-title":"J. Hered."},{"key":"2020103008540721400_B4","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1086\/280023","article-title":"Sex in relation to chromosomes and genes","volume":"59","author":"Bridges","year":"1925","journal-title":"Am. Nat."},{"key":"2020103008540721400_B5","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1105\/tpc.17.00313","article-title":"Reciprocally retained genes in the angiosperm lineage show the hallmarks of dosage balance sensitivity","volume":"29","author":"Tasdighian","year":"2017","journal-title":"Plant Cell"},{"key":"2020103008540721400_B6","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1146\/annurev.arplant.043008.092122","article-title":"Bias in plant gene content following different sorts of duplication: tandem, whole-genome, segmental, or by transposition","volume":"60","author":"Freeling","year":"2009","journal-title":"Annu. Rev. Plant. Biol."},{"key":"2020103008540721400_B7","doi-asserted-by":"crossref","first-page":"e1007267","DOI":"10.1371\/journal.pgen.1007267","article-title":"Preferential retention of genes from one parental genome after polyploidy illustrates the nature and scope of the genomic conflicts induced by hybridization","volume":"14","author":"Emery","year":"2018","journal-title":"PLoS Genet."},{"key":"2020103008540721400_B8","doi-asserted-by":"crossref","first-page":"E11321","DOI":"10.1073\/pnas.1807796115","article-title":"Global impacts of chromosomal imbalance on gene expression in Arabidopsis and other taxa","volume":"115","author":"Hou","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020103008540721400_B9","doi-asserted-by":"crossref","first-page":"e0194581","DOI":"10.1371\/journal.pone.0194581","article-title":"Transcriptome analysis of genetically matched human induced pluripotent stem cells disomic or trisomic for chromosome 21","volume":"13","author":"Gonzales","year":"2018","journal-title":"PLoS One"},{"key":"2020103008540721400_B10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"2020103008540721400_B11","doi-asserted-by":"crossref","first-page":"4288","DOI":"10.1093\/nar\/gks042","article-title":"Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation","volume":"40","author":"McCarthy","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2020103008540721400_B12","doi-asserted-by":"crossref","first-page":"R106","DOI":"10.1186\/gb-2010-11-10-r106","article-title":"Differential expression analysis for sequence count data","volume":"11","author":"Anders","year":"2010","journal-title":"Genome Biol."},{"key":"2020103008540721400_B13","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1111\/1467-9868.00346","article-title":"A direct approach to false discovery rates","volume":"64","author":"Storey","year":"2002","journal-title":"J. R. Statist. Soc. B"},{"key":"2020103008540721400_B14","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1089\/106652701300099074","article-title":"On differential variability of expression ratios: improving statistical inference about gene expression changes from microarray data","volume":"8","author":"Newton","year":"2001","journal-title":"J. Comput. Biol."},{"key":"2020103008540721400_B15","first-page":"31","article-title":"Replicated microarray data","volume":"12","author":"L\u00f6nnstedt","year":"2002","journal-title":"Stat. Sin."},{"key":"2020103008540721400_B16","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1186\/1471-2105-11-422","article-title":"baySeq: empirical Bayesian methods for identifying differential expression in sequence count data","volume":"11","author":"Hardcastle","year":"2010","journal-title":"BMC Bioinformatics"},{"key":"2020103008540721400_B17","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1093\/biostatistics\/kxs033","article-title":"A new shrinkage estimator for dispersion improves differential expression detection in RNA-seq data","volume":"14","author":"Wu","year":"2013","journal-title":"Biostatistics"},{"key":"2020103008540721400_B18","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"2020103008540721400_B19","doi-asserted-by":"crossref","first-page":"Article3","DOI":"10.2202\/1544-6115.1027","article-title":"Linear models and empirical bayes methods for assessing differential expression in microarray experiments","volume":"3","author":"Smyth","year":"2004","journal-title":"Stat. Appl. Genet. Mol. Biol."},{"key":"2020103008540721400_B20","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1186\/gb-2014-15-2-r29","article-title":"voom: precision weights unlock linear model analysis tools for RNA-seq read counts","volume":"15","author":"Law","year":"2014","journal-title":"Genome Biol."},{"key":"2020103008540721400_B21","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1093\/genetics\/92.4.1211","article-title":"A study of enzyme activities in a dosage series of the long arm of chromosome one in maize","volume":"92","author":"Birchler","year":"1979","journal-title":"Genetics"},{"key":"2020103008540721400_B22","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/genetics\/99.2.247","article-title":"Modulation of protein levels in chromosomal dosage series of maize: the biochemical basis of aneuploid syndromes","volume":"99","author":"Birchler","year":"1981","journal-title":"Genetics"},{"key":"2020103008540721400_B23","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1126\/science.266.5193.1999","article-title":"Trans-acting dosage effects on the expression of model gene systems in maize aneuploids","volume":"266","author":"Guo","year":"1994","journal-title":"Science"},{"key":"2020103008540721400_B24","doi-asserted-by":"crossref","first-page":"7383","DOI":"10.1073\/pnas.1305638110","article-title":"Dosage compensation and inverse effects in triple X metafemales of Drosophila","volume":"110","author":"Sun","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020103008540721400_B25","doi-asserted-by":"crossref","first-page":"16514","DOI":"10.1073\/pnas.1316041110","article-title":"Differential effect of aneuploidy on the X chromosome and genes with sex-biased expression in Drosophila","volume":"110","author":"Sun","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020103008540721400_B26","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1006\/dbio.2001.0262","article-title":"Dosage-dependent gene regulation in multicullular eukaryotes: implications for dosage compensation, aneuploid syndromes, and quantitative traits","volume":"234","author":"Birchler","year":"2001","journal-title":"Dev. Biol."},{"key":"2020103008540721400_B27","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1172\/JCI0215043","article-title":"Transcription factor haploinsufficiency: when half a loaf is not enough","volume":"109","author":"Seidman","year":"2002","journal-title":"J. Clin. Invest."},{"key":"2020103008540721400_B28","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.tig.2004.05.001","article-title":"A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplications","volume":"20","author":"Kondrashov","year":"2004","journal-title":"Trends Genet."},{"key":"2020103008540721400_B29","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s00427-013-0443-y","article-title":"Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation","volume":"223","author":"Boell","year":"2013","journal-title":"Dev. Genes Evol."},{"key":"2020103008540721400_B30","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1126\/science.1136678","article-title":"Relative impact of nucleotide and copy number variation on gene expression phenotypes","volume":"315","author":"Stranger","year":"2007","journal-title":"Science"},{"key":"2020103008540721400_B31","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.cell.2012.10.012","article-title":"Revisiting global gene expression analysis","volume":"151","author":"Lov\u00e9n","year":"2012","journal-title":"Cell"},{"key":"2020103008540721400_B32","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.ygeno.2007.08.005","article-title":"Gene expression profiling in the adult Down syndrome brain","volume":"90","author":"Lockstone","year":"2007","journal-title":"Genomics"},{"key":"2020103008540721400_B33","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1186\/1471-2164-12-229","article-title":"Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes","volume":"12","author":"Vilardell","year":"2011","journal-title":"BMC Genomics"},{"key":"2020103008540721400_B34","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3389\/fgene.2018.00125","article-title":"Integrated quantitative transcriptome maps of human trisomy 21 tissues and cells","volume":"9","author":"Pelleri","year":"2018","journal-title":"Front. Genet."},{"key":"2020103008540721400_B35","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.clinbiochem.2004.12.014","article-title":"Ontogenetic changes in serum S100B in Down syndrome patients","volume":"38","author":"Netto","year":"2005","journal-title":"Clin. Biochem."},{"key":"2020103008540721400_B36","doi-asserted-by":"crossref","DOI":"10.1155\/2010\/153657","article-title":"Effects of S100B on serotonergic plasticity and neuroinflammation in the hippocampus in down syndrome and Alzheimer\u2019s disease: studies in an S100B overexpressing mouse model","volume":"2010","author":"Shapiro","year":"2010","journal-title":"Cardiovas. Psychiatry Neurol."},{"key":"2020103008540721400_B37","doi-asserted-by":"crossref","first-page":"e22126","DOI":"10.1371\/journal.pone.0022126","article-title":"S100B and APP promote a gliocentric shift and impaired neurogenesis in down syndrome neural progenitors","volume":"6","author":"Lu","year":"2011","journal-title":"PLoS One"},{"key":"2020103008540721400_B38","first-page":"362839","article-title":"\u03b2-Secretases, Alzheimer\u2019s disease, and down syndrome","volume":"2012","author":"Webb","year":"2012","journal-title":"Curr.\u00a0Gerontol. Geriatr.\u00a0Res."},{"key":"2020103008540721400_B39","doi-asserted-by":"crossref","first-page":"2330","DOI":"10.1093\/hmg\/dds052","article-title":"OLIG2 over-expression impairs proliferation of human Down syndrome neural progenitors","volume":"21","author":"Lu","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"2020103008540721400_B40","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.stem.2019.04.014","article-title":"OLIG2 drives abnormal neurodevelopmental phenotypes in human iPSC-Based organoid and chimeric mouse models of down syndrome","volume":"24","author":"Xu","year":"2019","journal-title":"Cell Stem Cell"},{"key":"2020103008540721400_B41","doi-asserted-by":"crossref","first-page":"e74115","DOI":"10.1371\/journal.pone.0074115","article-title":"The expression pattern of EVA1C, a novel slit receptor, is consistent with an axon guidance role in the mouse nervous system","volume":"8","author":"James","year":"2013","journal-title":"PLoS One"},{"key":"2020103008540721400_B42","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1096\/fj.05-5632com","article-title":"BACE2, as a novel APP \u03b8-secretase, is not responsible for the pathogenesis of Alzheimer\u2019s disease in Down syndrome","volume":"20","author":"Sun","year":"2006","journal-title":"FASEB J."},{"key":"2020103008540721400_B43","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1046\/j.1471-4159.2002.00908.x","article-title":"A non-amyloidogenic function of BACE-2 in the secretory pathway","volume":"81","author":"Fluhrer","year":"2002","journal-title":"J. Neurochem."},{"key":"2020103008540721400_B44","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/j.1601-183X.2009.00538.x","article-title":"Characterization of a mouse model overexpressing beta-site APP-cleaving enzyme 2 reveals a new role for BACE2","volume":"9","author":"Azkona","year":"2010","journal-title":"Genes Brain Behavior"},{"key":"2020103008540721400_B45","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Sherman","year":"2009","journal-title":"Nat. Protoc."},{"key":"2020103008540721400_B46","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology","volume":"25","author":"Ashburner","year":"2018","journal-title":"Nat. Genet."},{"key":"2020103008540721400_B47","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1080\/19336918.2016.1269998","article-title":"Contactin-2\/TAG-1, active on the front line for three decades","volume":"11","author":"Masuda","year":"2017","journal-title":"Cell Adh. Migr."},{"key":"2020103008540721400_B48","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1242\/dev.128.20.3963","article-title":"RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons","volume":"128","author":"Enomoto","year":"2001","journal-title":"Development"},{"key":"2020103008540721400_B49","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/nature07456","article-title":"Neuroligins and neurexins link synaptic function to cognitive disease","volume":"455","author":"S\u00fcdhof","year":"2008","journal-title":"Nature"},{"key":"2020103008540721400_B50","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1083\/jcb.151.5.985","article-title":"\u03b2IV spectrin, a new spectrin localized at axon initial segments and nodes of ranvier in the central and peripheral nervous system","volume":"151","author":"Berghs","year":"2000","journal-title":"J. Cell Biol."},{"key":"2020103008540721400_B51","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1016\/j.ajhg.2018.04.012","article-title":"\u03b2IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy","volume":"102","author":"Wang","year":"2018","journal-title":"Am. J. Hum. Genet."}],"container-title":["NAR Genomics and Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/nargab\/article-pdf\/2\/3\/lqaa072\/34054898\/lqaa072.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/nargab\/article-pdf\/2\/3\/lqaa072\/34054898\/lqaa072.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T04:14:48Z","timestamp":1668831288000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nargab\/article\/doi\/10.1093\/nargab\/lqaa072\/5908375"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,1]]},"references-count":51,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/nargab\/lqaa072","relation":{},"ISSN":["2631-9268"],"issn-type":[{"type":"electronic","value":"2631-9268"}],"subject":[],"published-other":{"date-parts":[[2020,9,1]]},"published":{"date-parts":[[2020,9,1]]},"article-number":"lqaa072"}}