{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T15:14:28Z","timestamp":1777648468538,"version":"3.51.4"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"20","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: Microarray normalization is a fundamental step in removing systematic bias and noise variability caused by technical and experimental artefacts. Several approaches, suitable for large-scale genome arrays, have been proposed and shown to be effective in the reduction of systematic errors. Most of these methodologies are based on specific assumptions that are reasonable for whole-genome arrays, but possibly unsuitable for small microRNA (miRNA) platforms. In this work, we propose a novel normalization (loessM), and we investigate, through simulated and real datasets, the influence that normalizations for two-colour miRNA arrays have on the identification of differentially expressed genes.<\/jats:p><jats:p>Results: We show that normalizations usually applied to large-scale arrays, in several cases, modify the actual structure of miRNA data, leading to large portions of false positives and false negatives. Nevertheless, loessM is able to outperform other techniques in most experimental scenarios. Moreover, when usual assumptions on differential expression distribution are missed, channel effect has a strikingly negative influence on small arrays, bias that cannot be removed by normalizations but rather by an appropriate experimental design. We find that the combination of loessM with eCADS, an experimental design based on biological replicates dye-swap recently proposed for channel-effect reduction, gives better results in most of the experimental conditions in terms of specificity\/sensitivity both on simulated and real data.<\/jats:p><jats:p>Availability: LoessM R function is freely available at http:\/\/gefu.cribi.unipd.it\/papers\/miRNA-simulation\/<\/jats:p><jats:p>Contact: \u00a0chiara.romualdi@unipd.it<\/jats:p><jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btp443","type":"journal-article","created":{"date-parts":[[2009,7,24]],"date-time":"2009-07-24T00:55:41Z","timestamp":1248396941000},"page":"2685-2691","source":"Crossref","is-referenced-by-count":37,"title":["A modified LOESS normalization applied to microRNA arrays: a comparative evaluation"],"prefix":"10.1093","volume":"25","author":[{"given":"Davide","family":"Risso","sequence":"first","affiliation":[{"name":"1 Department of Statistical Sciences, University of Padova, via C. Battisti 241 and 2 Department of Biology, University of Padova, via U. Bassi 58\/B, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Sofia","family":"Massa","sequence":"additional","affiliation":[{"name":"1 Department of Statistical Sciences, University of Padova, via C. Battisti 241 and 2 Department of Biology, University of Padova, via U. Bassi 58\/B, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Chiogna","sequence":"additional","affiliation":[{"name":"1 Department of Statistical Sciences, University of Padova, via C. Battisti 241 and 2 Department of Biology, University of Padova, via U. Bassi 58\/B, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Romualdi","sequence":"additional","affiliation":[{"name":"1 Department of Statistical Sciences, University of Padova, via C. Battisti 241 and 2 Department of Biology, University of Padova, via U. Bassi 58\/B, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,7,23]]},"reference":[{"key":"2023013112131712900_B1","doi-asserted-by":"crossref","first-page":"9226","DOI":"10.1158\/0008-5472.CAN-05-1699","article-title":"Gene expression profiling of human sarcomas: insights into sarcoma biology","volume":"65","author":"Baird","year":"2005","journal-title":"Cancer Res."},{"key":"2023013112131712900_B2","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1117\/1.1486246","article-title":"Simulation of cdna microarrays via a parameterized random signal model","volume":"7","author":"Balagurunathan","year":"2002","journal-title":"J. Biomed. Opt."},{"key":"2023013112131712900_B3","first-page":"57","article-title":"Normalizing DNA microarray data","volume":"4","author":"Bilban","year":"2002","journal-title":"Curr. Issues Mol. Biol."},{"key":"2023013112131712900_B4","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1002\/jcp.20832","article-title":"Identification of differentially expressed microRNAs by microarray: a possible role for microRNA genes in pituitary adenomas","volume":"210","author":"Bottoni","year":"2007","journal-title":"J. Cell Physiol."},{"key":"2023013112131712900_B5","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/ng.2007.30","article-title":"Widespread microRNA repression by Myc contributes to tumorigenesis","volume":"40","author":"Chang","year":"2008","journal-title":"Nat. Genet."},{"key":"2023013112131712900_B6","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/1471-2105-10-61","article-title":"A comparison on effects of normalisations in the detection of differentially expressed genes","volume":"10","author":"Chiogna","year":"2009","journal-title":"BMC Bioinformatics"},{"key":"2023013112131712900_B7","doi-asserted-by":"crossref","first-page":"R44","DOI":"10.1186\/gb-2007-8-3-r44","article-title":"Normalization of two-channel microarrays accounting for experimental design and intensity-dependent relationships","volume":"8","author":"Dabney","year":"2007","journal-title":"Genome Biol."},{"key":"2023013112131712900_B8","first-page":"890","article-title":"A leukemia-enriched cDNA microarray platform identifies new transcripts with relevance to the biology of pediatric acute lymphoblastic leukemia","volume":"90","author":"De Pitta","year":"2005","journal-title":"Haematologica"},{"key":"2023013112131712900_B9","doi-asserted-by":"crossref","first-page":"2772","DOI":"10.1002\/ijc.21698","article-title":"Gene expression profiling identifies potential relevant genes in alveolar rhabdomyosarcoma pathogenesis and discriminates PAX3-FKHR positive and negative tumors","volume":"118","author":"De Pitta","year":"2006","journal-title":"Int. J. Cancer"},{"key":"2023013112131712900_B10","doi-asserted-by":"crossref","first-page":"R60","DOI":"10.1186\/gb-2004-5-8-r60","article-title":"Model selection and efficiency testing for normalization of cDNA microarray data","volume":"5","author":"Futschik","year":"2004","journal-title":"Genome Biol."},{"key":"2023013112131712900_B11","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1093\/bioinformatics\/bti199","article-title":"OLIN: optimized normalization, visualization and quality testing of two-channel microarray data","volume":"21","author":"Futschik","year":"2005","journal-title":"Bioinformatics"},{"key":"2023013112131712900_B12","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2002-3-7-research0033","article-title":"Profound effect of normalization on detection of differentially expressed genes in oligonucleotide microarray data analysis","volume":"3","author":"Hoffmann","year":"2002","journal-title":"Genome Biol."},{"key":"2023013112131712900_B13","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.ygeno.2008.04.002","article-title":"Comparison of normalization methods with microRNA microarray","volume":"92","author":"Hua","year":"2008","journal-title":"Genomics"},{"issue":"Suppl. 1","key":"2023013112131712900_B14","doi-asserted-by":"crossref","first-page":"S96","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96","article-title":"Variance stabilization applied to microarray data calibration and to the quantification of differential expression","volume":"18","author":"Huber","year":"2002","journal-title":"Bioinformatics"},{"key":"2023013112131712900_B15","doi-asserted-by":"crossref","DOI":"10.2202\/1544-6115.1008","article-title":"Parameter estimation for the calibration and variance stabilization of microarray data","volume":"2","author":"Huber","year":"2003","journal-title":"Stat. Appl. Genet. Mol. Biol."},{"key":"2023013112131712900_B16","doi-asserted-by":"crossref","first-page":"3899","DOI":"10.1002\/sim.1548","article-title":"On parametric empirical Bayes methods for comparing multiple groups using replicated gene expression profiles","volume":"22","author":"Kendziorski","year":"2003","journal-title":"Stat. Med."},{"key":"2023013112131712900_B17","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.tig.2003.09.015","article-title":"Fundamentals of cDNA microarray data analysis","volume":"19","author":"Leung","year":"2003","journal-title":"Trends Genet."},{"key":"2023013112131712900_B18","doi-asserted-by":"crossref","first-page":"9740","DOI":"10.1073\/pnas.0403293101","article-title":"An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues","volume":"101","author":"Liu","year":"2004","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023013112131712900_B19","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nature03702","article-title":"MicroRNA expression profiles classify human cancers","volume":"435","author":"Lu","year":"2005","journal-title":"Nature"},{"key":"2023013112131712900_B20","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1038\/sj.onc.1210809","article-title":"Widespread deregulation of microRNA expression in human prostate cancer","volume":"27","author":"Ozen","year":"2008","journal-title":"Oncogene"},{"key":"2023013112131712900_B21","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1038\/nbt1242","article-title":"Performance comparison of one-color and two-color platforms within the microarray quality control (MAQC) project","volume":"24","author":"Patterson","year":"2006","journal-title":"Nat. Biotechnol."},{"key":"2023013112131712900_B22","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1261\/rna.1295509","article-title":"Impact of normalization on miRNA microarray expression profiling","volume":"15","author":"Pradervand","year":"2009","journal-title":"RNA"},{"key":"2023013112131712900_B23","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/35076576","article-title":"Computational analysis of microarray data","volume":"2","author":"Quackenbush","year":"2001","journal-title":"Nat. Rev. Genet."},{"key":"2023013112131712900_B24","doi-asserted-by":"crossref","DOI":"10.2202\/1544-6115.1287","article-title":"A comparison of normalization techniques for microRNA microarray data","volume":"7","author":"Rao","year":"2008","journal-title":"Stat. Appl. Genet. Mol. Biol."},{"key":"2023013112131712900_B25","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1093\/bioinformatics\/btg107","article-title":"Approximate variance-stabilizing transformations for gene-expression microarray data","volume":"19","author":"Rocke","year":"2003","journal-title":"Bioinformatics"},{"key":"2023013112131712900_B26","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1093\/nar\/gkn932","article-title":"Quality assessment and data analysis for microRNA expression arrays","volume":"37","author":"Sarkar","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023013112131712900_B27","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S1046-2023(03)00155-5","article-title":"Normalization of CDNA microarray data","volume":"31","author":"Smyth","year":"2003","journal-title":"Methods"},{"key":"2023013112131712900_B28","doi-asserted-by":"crossref","first-page":"5116","DOI":"10.1073\/pnas.091062498","article-title":"Significance analysis of microarrays applied to the ionizing radiation response","volume":"98","author":"Tusher","year":"2001","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023013112131712900_B29","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1002\/gcc.20415","article-title":"A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas","volume":"46","author":"Wang","year":"2007","journal-title":"Genes Chromosomes Cancer"},{"key":"2023013112131712900_B30","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2002-3-9-research0048","article-title":"A new non-linear normalization method for reducing variability in DNA microarray experiments","volume":"3","author":"Workman","year":"2002","journal-title":"Genome Biol."},{"key":"2023013112131712900_B31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1471-2105-9-25","article-title":"Using generalized procrustes analysis (GPA) for normalization of CDNA microarray data","volume":"9","author":"Xiong","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"2023013112131712900_B32","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1093\/nar\/30.4.e15","article-title":"Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation","volume":"30","author":"Yang","year":"2002","journal-title":"Nucleic Acids Res."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/25\/20\/2685\/48994753\/bioinformatics_25_20_2685.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/25\/20\/2685\/48994753\/bioinformatics_25_20_2685.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T12:27:03Z","timestamp":1710505623000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/25\/20\/2685\/192852"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,7,23]]},"references-count":32,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2009,10,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btp443","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,10,15]]},"published":{"date-parts":[[2009,7,23]]}}}