{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:57:10Z","timestamp":1762865830453,"version":"3.38.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: High-throughput perturbation screens measure the phenotypes of thousands of biological samples under various conditions. The phenotypes measured in the screens are subject to substantial biological and technical variation. At the same time, in order to enable high throughput, it is often impossible to include a large number of replicates, and to randomize their order throughout the screens. Distinguishing true changes in the phenotype from stochastic variation in such experimental designs is extremely challenging, and requires adequate statistical methodology.<\/jats:p><jats:p>Results: We propose a statistical modeling framework that is based on experimental designs with at least two controls profiled throughout the experiment, and a normalization and variance estimation procedure with linear mixed-effects models. We evaluate the framework using three comprehensive screens of Saccharomyces cerevisiae, which involve 4940 single-gene knock-out haploid mutants, 1127 single-gene knock-out diploid mutants and 5798 single-gene overexpression haploid strains. We show that the proposed approach (i) can be used in conjunction with practical experimental designs; (ii) allows extensions to alternative experimental workflows; (iii) enables a sensitive discovery of biologically meaningful changes; and (iv) strongly outperforms the existing noise reduction procedures.<\/jats:p><jats:p>Availability: All experimental datasets are publicly available at www.ionomicshub.org. The R package HTSmix is available at http:\/\/www.stat.purdue.edu\/~ovitek\/HTSmix.html.<\/jats:p><jats:p>Contact: \u00a0ovitek@stat.purdue.edu<\/jats:p><jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btr359","type":"journal-article","created":{"date-parts":[[2011,6,18]],"date-time":"2011-06-18T04:15:07Z","timestamp":1308370507000},"page":"2173-2180","source":"Crossref","is-referenced-by-count":10,"title":["Noise reduction in genome-wide perturbation screens using linear mixed-effect models"],"prefix":"10.1093","volume":"27","author":[{"given":"Danni","family":"Yu","sequence":"first","affiliation":[{"name":"1 Department of Statistics, Purdue University, West Lafayette, IN 47907, USA, 2Department of Plant and Soil Science, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK, 3USDA-ARS Plant Genetics Research Unit, Donald Danforth Plant Science Center, St. Louis, MO 63132, 4Department of Crop and Soil Sciences, Cornell University, Ithaca, NY 14853, USA, 5Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK and 6Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Danku","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, Purdue University, West Lafayette, IN 47907, USA, 2Department of Plant and Soil Science, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK, 3USDA-ARS Plant Genetics Research Unit, Donald Danforth Plant Science Center, St. Louis, MO 63132, 4Department of Crop and Soil Sciences, Cornell University, Ithaca, NY 14853, USA, 5Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK and 6Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Baxter","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, Purdue University, West Lafayette, IN 47907, USA, 2Department of Plant and Soil Science, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK, 3USDA-ARS Plant Genetics Research Unit, Donald Danforth Plant Science Center, St. Louis, MO 63132, 4Department of Crop and Soil Sciences, Cornell University, Ithaca, NY 14853, USA, 5Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK and 6Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sungjin","family":"Kim","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, Purdue University, West Lafayette, IN 47907, USA, 2Department of Plant and Soil Science, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK, 3USDA-ARS Plant Genetics Research Unit, Donald Danforth Plant Science Center, St. Louis, MO 63132, 4Department of Crop and Soil Sciences, Cornell University, Ithaca, NY 14853, USA, 5Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK and 6Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olena K.","family":"Vatamaniuk","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, Purdue University, West Lafayette, IN 47907, USA, 2Department of Plant and Soil Science, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK, 3USDA-ARS Plant Genetics Research Unit, Donald Danforth Plant Science Center, St. Louis, MO 63132, 4Department of Crop and Soil Sciences, Cornell University, Ithaca, NY 14853, USA, 5Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK and 6Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David E.","family":"Salt","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, Purdue University, West Lafayette, IN 47907, USA, 2Department of Plant and Soil Science, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK, 3USDA-ARS Plant Genetics Research Unit, Donald Danforth Plant Science Center, St. Louis, MO 63132, 4Department of Crop and Soil Sciences, Cornell University, Ithaca, NY 14853, USA, 5Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK and 6Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"},{"name":"1 Department of Statistics, Purdue University, West Lafayette, IN 47907, USA, 2Department of Plant and Soil Science, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK, 3USDA-ARS Plant Genetics Research Unit, Donald Danforth Plant Science Center, St. Louis, MO 63132, 4Department of Crop and Soil Sciences, Cornell University, Ithaca, NY 14853, USA, 5Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK and 6Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Vitek","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, Purdue University, West Lafayette, IN 47907, USA, 2Department of Plant and Soil Science, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK, 3USDA-ARS Plant Genetics Research Unit, Donald Danforth Plant Science Center, St. Louis, MO 63132, 4Department of Crop and Soil Sciences, Cornell University, Ithaca, NY 14853, USA, 5Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK and 6Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"},{"name":"1 Department of Statistics, Purdue University, West Lafayette, IN 47907, USA, 2Department of Plant and Soil Science, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK, 3USDA-ARS Plant Genetics Research Unit, Donald Danforth Plant Science Center, St. Louis, MO 63132, 4Department of Crop and Soil Sciences, Cornell University, Ithaca, NY 14853, USA, 5Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3UU, UK and 6Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2011,6,17]]},"reference":[{"key":"2023012511515084100_B1","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1139\/O09-045","article-title":"Novel role for the Saccharomyces cerevisiae oligopeptide transporter Opt2 in drug detoxification","volume":"87","author":"Aouida","year":"2009","journal-title":"Biochem. Cell Biol."},{"key":"2023012511515084100_B2","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1752-0509-3-80","article-title":"Knowledge based identification of essential signaling from genome-scale siRNA experiments","volume":"3","author":"Bankhead","year":"2009","journal-title":"BMC Syst. Biol."},{"key":"2023012511515084100_B3","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/nmeth.1534","article-title":"Quantitative analysis of fitness and genetic interactions in yeast on a genome scale","volume":"7","author":"Baryshnikova","year":"2010","journal-title":"Nat. Methods"},{"key":"2023012511515084100_B4","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.pbi.2009.05.002","article-title":"Ionomics: studying the social network of mineral nutrients","volume":"12","author":"Baxter","year":"2009","journal-title":"Curr. Opin. Plant Biol."},{"key":"2023012511515084100_B5","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."},{"key":"2023012511515084100_B6","doi-asserted-by":"crossref","first-page":"618","DOI":"10.2174\/138620707782507340","article-title":"Yeast genomics and drug target identification","volume":"10","author":"Bharucha","year":"2007","journal-title":"Comb. Chem. High Throughput Screen"},{"key":"2023012511515084100_B7","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/nmeth.1351","article-title":"Statistical methods for analysis of high-throughput rna interference screens","volume":"6","author":"Birmingham","year":"2009","journal-title":"Nat. Methods"},{"key":"2023012511515084100_B8","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/bioinformatics\/19.2.185","article-title":"A comparison of normalization methods for high density oligonucleotide array data based on variance and bias","volume":"19","author":"Bolstad","year":"2003","journal-title":"Bioinformatics"},{"key":"2023012511515084100_B9","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nrg2085","article-title":"Exploring genetic interactions and networks with yeast","volume":"8","author":"Boone","year":"2007","journal-title":"Nat. Rev. Genet."},{"key":"2023012511515084100_B10","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/nrg2364","article-title":"The art and design of genetic screens: RNA interference","volume":"9","author":"Boutros","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"2023012511515084100_B11","doi-asserted-by":"crossref","first-page":"R66","DOI":"10.1186\/gb-2006-7-7-r66","article-title":"Analysis of cell-based RNAi screens","volume":"7","author":"Boutros","year":"2006","journal-title":"Genome Biol."},{"key":"2023012511515084100_B12","doi-asserted-by":"crossref","first-page":"R63","DOI":"10.1186\/gb-2006-7-7-r63","article-title":"A strategy for extracting and analyzing large-scale quantitative epistatic interaction data","volume":"7","author":"Collins","year":"2006","journal-title":"Genome Biol."},{"key":"2023012511515084100_B13","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1039\/B803529F","article-title":"A high-throughput method for Saccharomyces cerevisiae (yeast) ionomics","volume":"24","author":"Danku","year":"2009","journal-title":"J. Anal. At. Spectrom."},{"key":"2023012511515084100_B14","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1093\/bioinformatics\/18.11.1438","article-title":"Comparison of microarray designs for class comparison and class discovery","volume":"18","author":"Dobbin","year":"2002","journal-title":"Bioinformatics"},{"key":"2023012511515084100_B15","first-page":"1","article-title":"Microarrays, Empirical Bayes, and the two-groups model","volume":"23","author":"Efron","year":"2008","journal-title":"Stat. Sci."},{"key":"2023012511515084100_B16","doi-asserted-by":"crossref","first-page":"R77","DOI":"10.1186\/gb-2005-6-9-r77","article-title":"Characterization of the yeast ionome: a genome-wide analysis of nutrient mineral and trace element homeostasis in saccharomyces cerevisiae","volume":"6","author":"Eide","year":"2005","journal-title":"Genome Biol."},{"key":"2023012511515084100_B17","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/35088500","article-title":"The art and design of genetic screens: yeast","volume":"2","author":"Forsburg","year":"2001","journal-title":"Nat. Rev. Genet."},{"key":"2023012511515084100_B18","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/nrg2633","article-title":"Applying mass spectrometry-based proteomics to genetics, genomics and network biology","volume":"10","author":"Gstaiger","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"2023012511515084100_B19","first-page":"404","volume-title":"Understanding Robust and Exploratory Data Analysis","author":"Hoaglin","year":"1983"},{"key":"2023012511515084100_B20","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1101\/gr.071852.107","article-title":"Protein networks in disease","volume":"18","author":"Ideker","year":"2008","journal-title":"Genome Res."},{"key":"2023012511515084100_B21","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/nmeth0709-476","article-title":"Rnaicut: automated detection of significant genes from functional genomic screens","volume":"6","author":"Kaplow","year":"2009","journal-title":"Nat. Methods"},{"key":"2023012511515084100_B22","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1574-6968.2008.01214.x","article-title":"The PMR1 protein, the major yeast Ca2+-ATPase in the Golgi, regulates intracellular levels of the cadmium ion","volume":"285","author":"Lauer J\u00f9nior","year":"2008","journal-title":"FEMS Microbiol. Lett."},{"key":"2023012511515084100_B23","doi-asserted-by":"crossref","first-page":"e161","DOI":"10.1371\/journal.pgen.0030161","article-title":"Capturing heterogeneity in gene expression studies by surrogate variable analysis","volume":"3","author":"Leek","year":"2007","journal-title":"PLoS Genet."},{"key":"2023012511515084100_B24","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/nrg2825","article-title":"Tackling the widespread and critical impact of batch effects in high-throughput data","volume":"11","author":"Leek","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"2023012511515084100_B25","first-page":"1014","article-title":"Newton-Raphson and EM algorithms for linear mixed-effects models for repeated-measures data","volume":"83","author":"Lindstrom","year":"1988","journal-title":"J. Am. Stat. Assoc."},{"key":"2023012511515084100_B26","doi-asserted-by":"crossref","first-page":"11763","DOI":"10.1074\/jbc.272.18.11763","article-title":"Negative control of heavy metal uptake by the Saccharomyces cerevisiae BSD2 gene","volume":"272","author":"Liu","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2023012511515084100_B27","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nbt1186","article-title":"Statistical practice in high-throughput screening data analysis","volume":"24","author":"Malo","year":"2006","journal-title":"Nat. Biotechnol."},{"key":"2023012511515084100_B28","doi-asserted-by":"crossref","first-page":"e1000655","DOI":"10.1371\/journal.pcbi.1000655","article-title":"How to understand the cell by breaking it: network analysis of gene perturbation screens","volume":"6","author":"Markowetz","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"2023012511515084100_B29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2105-8-S6-S5","article-title":"Inferring cellular networks \u2013 a review","volume":"8","author":"Markowetz","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"2023012511515084100_B30","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1093\/bioinformatics\/btp014","article-title":"RNAither, an automated pipeline for the statistical analysis of high-throughput RNAi screens","volume":"25","author":"Rieber","year":"2009","journal-title":"Bioinformatics"},{"key":"2023012511515084100_B31","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/0092-8674(89)90410-8","article-title":"The yeast secretory pathway is perturbed by mutations in PMR1, a member of a Ca2+ ATPase family","volume":"58","author":"Rudolph","year":"1989","journal-title":"Cell"},{"key":"2023012511515084100_B32","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1146\/annurev.arplant.59.032607.092942","article-title":"Ionomics and the study of the plant ionome","volume":"59","author":"Salt","year":"2008","journal-title":"Annu. Rev. Plant Biol."},{"issue":"Iss. 1","key":"2023012511515084100_B33","article-title":"Linear models and empirical Bayes methods for assessing differential expression in microarray experiments","volume":"3","author":"Smyth","year":"2004","journal-title":"Statistical Applications in Genetics and Molecular Biology"},{"key":"2023012511515084100_B34","article-title":"Bioinformatics and Computational Biology Solutions Using R and Bioconductor","volume-title":"Limma: linear models for microarray data","author":"Smyth","year":"2005"},{"key":"2023012511515084100_B35","first-page":"448","article-title":"A survey of sampling from contaminated distributions","volume-title":"Contributions to probability and statistics: Essays in honor of Harold Hotelling","author":"Tukey","year":"1960"},{"key":"2023012511515084100_B36","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1177\/1087057108323125","article-title":"An analysis of normalization methods for Drosophila RNAi genomic screens and development of a robust validation scheme","volume":"13","author":"Wiles","year":"2008","journal-title":"J. Biomol. Screen"},{"key":"2023012511515084100_B37","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1089\/106652701753307520","article-title":"Assessing gene significance from cDNA microarray expression data via mixed models","volume":"8","author":"Wolfinger","year":"2001","journal-title":"J. Comput. Biol."},{"key":"2023012511515084100_B38","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."},{"key":"2023012511515084100_B39","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/bioinformatics\/btp082","article-title":"Determination of sample size in genome-scale rnai screens","volume":"25","author":"Zhang","year":"2009","journal-title":"Bioinformatics"},{"key":"2023012511515084100_B40","doi-asserted-by":"crossref","first-page":"4667","DOI":"10.1093\/nar\/gkn435","article-title":"Hit selection with false discovery rate control in genome-scale RNAi screens","volume":"36","author":"Zhang","year":"2008","journal-title":"Nucleic Acids Res."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/27\/16\/2173\/48865255\/bioinformatics_27_16_2173.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/27\/16\/2173\/48865255\/bioinformatics_27_16_2173.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T09:41:54Z","timestamp":1741254114000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/27\/16\/2173\/253813"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,6,17]]},"references-count":40,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2011,8,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btr359","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"type":"electronic","value":"1367-4811"},{"type":"print","value":"1367-4803"}],"subject":[],"published-other":{"date-parts":[[2011,8,15]]},"published":{"date-parts":[[2011,6,17]]}}}