{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:21:53Z","timestamp":1778286113642,"version":"3.51.4"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2019,2,19]],"date-time":"2019-02-19T00:00:00Z","timestamp":1550534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Disease","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"publisher","award":["F31 AI131595"],"award-info":[{"award-number":["F31 AI131595"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM129512"],"award-info":[{"award-number":["R01 GM129512"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>The human microbiome is notoriously variable across individuals, with a wide range of \u2018healthy\u2019 microbiomes. Paired and longitudinal studies of the microbiome have become increasingly popular as a way to reduce unmeasured confounding and to increase statistical power by reducing large inter-subject variability. Statistical methods for analyzing such datasets are scarce.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We introduce a paired UniFrac dissimilarity that summarizes within-individual (or within-pair) shifts in microbiome composition and then compares these compositional shifts across individuals (or pairs). This dissimilarity depends on a novel transformation of relative abundances, which we then extend to more than two time points and incorporate into several phylogenetic and non-phylogenetic dissimilarities. The data transformation and resulting dissimilarities may be used in a wide variety of downstream analyses, including ordination analysis and distance-based hypothesis testing. Simulations demonstrate that tests based on these dissimilarities retain appropriate type 1 error and high power. We apply the method in two real datasets.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The R package pldist is available on GitHub at https:\/\/github.com\/aplantin\/pldist.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btz120","type":"journal-article","created":{"date-parts":[[2019,2,18]],"date-time":"2019-02-18T04:25:53Z","timestamp":1550463953000},"page":"3567-3575","source":"Crossref","is-referenced-by-count":21,"title":["pldist: ecological dissimilarities for paired and longitudinal microbiome association analysis"],"prefix":"10.1093","volume":"35","author":[{"given":"Anna M","family":"Plantinga","sequence":"first","affiliation":[{"name":"Department of Mathematics and Statistics, Williams College , Williamstown, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Research, Division of Biomedical Statistics and Informatics , Mayo Clinic, Rochester, MN, USA"},{"name":"Microbiome Program, Center for Individualized Medicine, Mayo Clinic , Rochester, MN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert R","family":"Jenq","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA"},{"name":"Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Biomathematics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center , Seattle, WA, USA"},{"name":"Department of Biostatistics, University of Washington , Seattle, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,2,19]]},"reference":[{"key":"2023013108134000300_btz120-B1","first-page":"32","article-title":"A new method for non-parametric multivariate analysis of variance","volume":"26","author":"Anderson","year":"2001","journal-title":"Austral. Ecol"},{"key":"2023013108134000300_btz120-B2","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/nature09944","article-title":"Enterotypes of the human gut microbiome","volume":"473","author":"Arumugam","year":"2011","journal-title":"Nature"},{"key":"2023013108134000300_btz120-B3","doi-asserted-by":"crossref","first-page":"325","DOI":"10.2307\/1942268","article-title":"An ordination of the upland forest communities of southern Wisconsin","volume":"27","author":"Bray","year":"1957","journal-title":"Ecol. Monogr"},{"key":"2023013108134000300_btz120-B4","doi-asserted-by":"crossref","first-page":"1.","DOI":"10.1186\/1471-2105-12-118","article-title":"Variance adjusted weighted UniFrac: a powerful beta diversity measure for comparing communities based on phylogeny","volume":"12","author":"Chang","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"2023013108134000300_btz120-B5","doi-asserted-by":"crossref","first-page":"e15216.","DOI":"10.1371\/journal.pone.0015216","article-title":"Disordered microbial communities in the upper respiratory tract of cigarette smokers","volume":"5","author":"Charlson","year":"2010","journal-title":"PLoS One"},{"key":"2023013108134000300_btz120-B6","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/978-1-4614-7846-1_16","volume-title":"Topics in Applied Statistics","author":"Chen","year":"2013"},{"key":"2023013108134000300_btz120-B7","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1093\/bioinformatics\/bts342","article-title":"Associating microbiome composition with environmental covariates using generalized UniFrac distances","volume":"28","author":"Chen","year":"2012","journal-title":"Bioinformatics"},{"key":"2023013108134000300_btz120-B8","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/apt.13286","article-title":"Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome","volume":"42","author":"Chumpitazi","year":"2015","journal-title":"Alimentary Pharmacol. Ther"},{"key":"2023013108134000300_btz120-B9","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1023\/A:1023818214614","article-title":"Isometric logratio transformations for compositional data analysis","volume":"35","author":"Egozcue","year":"2003","journal-title":"Math. Geol"},{"key":"2023013108134000300_btz120-B10","doi-asserted-by":"crossref","first-page":"e16384.","DOI":"10.1371\/journal.pone.0016384","article-title":"Analysis of the lung microbiome in the \u201chealthy\u201d smoker and in COPD","volume":"6","author":"Erb-Downward","year":"2011","journal-title":"PLoS One"},{"key":"2023013108134000300_btz120-B11","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.mib.2015.04.004","article-title":"Metagenomics meets time series analysis: unraveling microbial community dynamics","volume":"25","author":"Faust","year":"2015","journal-title":"Curr. Opin. Microbiol"},{"key":"2023013108134000300_btz120-B12","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1016\/S0140-6736(09)60237-3","article-title":"Graft-versus-host disease","volume":"373","author":"Ferrara","year":"2009","journal-title":"Lancet"},{"key":"2023013108134000300_btz120-B13","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/env.966","article-title":"Principal component analysis for compositional data with outliers","volume":"20","author":"Filzmoser","year":"2009","journal-title":"Environmetrics"},{"key":"2023013108134000300_btz120-B14","doi-asserted-by":"crossref","first-page":"531.","DOI":"10.1186\/s13059-014-0531-y","article-title":"Temporal variability is a personalized feature of the human microbiome","volume":"15","author":"Flores","year":"2014","journal-title":"Genome Biol"},{"key":"2023013108134000300_btz120-B15","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1139\/cjm-2015-0821","article-title":"Compositional analysis: a valid approach to analyze microbiome high-throughput sequencing data","volume":"62","author":"Gloor","year":"2016","journal-title":"Can. J. Microbiol"},{"key":"2023013108134000300_btz120-B16","doi-asserted-by":"crossref","first-page":"2224.","DOI":"10.3389\/fmicb.2017.02224","article-title":"Microbiome datasets are compositional: and this is not optional","volume":"8","author":"Gloor","year":"2017","journal-title":"Front. Microbiol"},{"key":"2023013108134000300_btz120-B17","doi-asserted-by":"crossref","first-page":"857","DOI":"10.2307\/2528823","article-title":"A general coefficient of similarity and some of its properties","volume":"27","author":"Gower","year":"1971","journal-title":"Biometrics"},{"key":"2023013108134000300_btz120-B18","doi-asserted-by":"crossref","first-page":"17004.","DOI":"10.1038\/nmicrobiol.2017.4","article-title":"Dynamics of the human gut microbiome in inflammatory bowel disease","volume":"2","author":"Halfvarson","year":"2017","journal-title":"Nat. Microbiol"},{"key":"2023013108134000300_btz120-B19","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.bbmt.2014.01.030","article-title":"Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease","volume":"20","author":"Holler","year":"2014","journal-title":"Biol. Blood Marrow Transplant"},{"key":"2023013108134000300_btz120-B20","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1469-8137.1912.tb05611.x","article-title":"The distribution of the flora in the alpine zone","volume":"11","author":"Jaccard","year":"1912","journal-title":"New Phytol"},{"key":"2023013108134000300_btz120-B21","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.bbmt.2014.12.001","article-title":"National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: i. the 2014 diagnosis and staging working group report","volume":"21","author":"Jagasia","year":"2015","journal-title":"Biol. Blood Marrow Transplant"},{"key":"2023013108134000300_btz120-B22","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nrmicro2859","article-title":"Categorization of the gut microbiota: enterotypes or gradients?","volume":"10","author":"Jeffery","year":"2012","journal-title":"Nat. Rev. Microbiol"},{"key":"2023013108134000300_btz120-B23","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.bbmt.2015.04.016","article-title":"Intestinal blautia is associated with reduced death from graft-versus-host disease","volume":"21","author":"Jenq","year":"2015","journal-title":"Biol. Blood Marrow Transplant"},{"key":"2023013108134000300_btz120-B24","doi-asserted-by":"crossref","first-page":"459.","DOI":"10.3389\/fmicb.2016.00459","article-title":"Characterization of the gut microbiome using 16S or shotgun metagenomics","volume":"7","author":"Jovel","year":"2016","journal-title":"Front. Microbiol"},{"key":"2023013108134000300_btz120-B25","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.chom.2014.09.013","article-title":"Rethinking \u201centerotypes\u201d","volume":"16","author":"Knights","year":"2014","journal-title":"Cell Host Microbe"},{"key":"2023013108134000300_btz120-B26","doi-asserted-by":"crossref","first-page":"45.","DOI":"10.1186\/s40168-017-0262-x","article-title":"A powerful microbiome-based association test and a microbial taxa discovery framework for comprehensive association mapping","volume":"5","author":"Koh","year":"2017","journal-title":"Microbiome"},{"key":"2023013108134000300_btz120-B27","doi-asserted-by":"crossref","first-page":"210.","DOI":"10.1186\/s12864-018-4599-8","article-title":"A highly adaptive microbiome-based association test for survival traits","volume":"19","author":"Koh","year":"2018","journal-title":"BMC Genomics"},{"key":"2023013108134000300_btz120-B28","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1101\/gr.131029.111","article-title":"Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis","volume":"22","author":"Kong","year":"2012","journal-title":"Genome Res"},{"key":"2023013108134000300_btz120-B29","doi-asserted-by":"crossref","first-page":"e1002863.","DOI":"10.1371\/journal.pcbi.1002863","article-title":"A guide to enterotypes across the human body: meta-analysis of microbial community structures in human microbiome datasets","volume":"9","author":"Koren","year":"2013","journal-title":"PLoS Comput. Biol"},{"key":"2023013108134000300_btz120-B30","first-page":"57","author":"Kulczy\u0144ski","year":"1928"},{"key":"2023013108134000300_btz120-B31","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.chom.2015.09.008","article-title":"Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn\u2019s disease","volume":"18","author":"Lewis","year":"2015","journal-title":"Cell Host Microbe"},{"key":"2023013108134000300_btz120-B32","doi-asserted-by":"crossref","first-page":"8228","DOI":"10.1128\/AEM.71.12.8228-8235.2005","article-title":"UniFrac: a new phylogenetic method for comparing microbial communities","volume":"71","author":"Lozupone","year":"2005","journal-title":"Appl. Environ. Microbiol"},{"key":"2023013108134000300_btz120-B33","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1128\/AEM.01996-06","article-title":"Quantitative and qualitative \u03b2 diversity measures lead to different insights into factors that structure microbial communities","volume":"73","author":"Lozupone","year":"2007","journal-title":"Appl. Environ. Microbiol"},{"key":"2023013108134000300_btz120-B34","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s40778-014-0002-0","article-title":"The microbiome and graft versus host disease","volume":"1","author":"Mathewson","year":"2015","journal-title":"Curr. Stem Cell Rep"},{"key":"2023013108134000300_btz120-B35","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1097\/GME.0000000000001037","article-title":"Associations between improvement in genitourinary symptoms of menopause and changes in the vaginal ecosystem","volume":"25","author":"Mitchell","year":"2018","journal-title":"Menopause"},{"key":"2023013108134000300_btz120-B36","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1126\/science.1198719","article-title":"Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans","volume":"332","author":"Muegge","year":"2011","journal-title":"Science"},{"key":"2023013108134000300_btz120-B37","doi-asserted-by":"crossref","first-page":"17.","DOI":"10.1186\/s40168-017-0239-9","article-title":"MiRKAT-S: a community-level test of association between the microbiota and survival times","volume":"5","author":"Plantinga","year":"2017","journal-title":"Microbiome"},{"key":"2023013108134000300_btz120-B38","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nature11450","article-title":"A metagenome-wide association study of gut microbiota in type 2 diabetes","volume":"490","author":"Qin","year":"2012","journal-title":"Nature"},{"key":"2023013108134000300_btz120-B39","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1126\/science.aan3706","article-title":"Gut microbiome influences efficacy of pd-1\u2013based immunotherapy against epithelial tumors","volume":"359","author":"Routy","year":"2018","journal-title":"Science"},{"key":"2023013108134000300_btz120-B40","doi-asserted-by":"crossref","first-page":"e21887.","DOI":"10.7554\/eLife.21887","article-title":"A phylogenetic transform enhances analysis of compositional microbiota data","volume":"6","author":"Silverman","year":"2017","journal-title":"Elife"},{"key":"2023013108134000300_btz120-B41","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1093\/bioinformatics\/btw311","article-title":"PERMANOVA-S: association test for microbial community composition that accommodates confounders and multiple distances","volume":"32","author":"Tang","year":"2016","journal-title":"Bioinformatics"},{"key":"2023013108134000300_btz120-B42","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/nature07540","article-title":"A core gut microbiome in obese and lean twins","volume":"457","author":"Turnbaugh","year":"2009","journal-title":"Nature"},{"key":"2023013108134000300_btz120-B43","doi-asserted-by":"crossref","first-page":"e105706","DOI":"10.1371\/journal.pone.0105706","article-title":"Complete suppression of the gut microbiome prevents acute graft-versus-host disease following allogeneic bone marrow transplantation","volume":"9","author":"Vossen","year":"2014","journal-title":"PLoS One"},{"key":"2023013108134000300_btz120-B44","doi-asserted-by":"crossref","first-page":"27.","DOI":"10.1186\/s40168-017-0237-y","article-title":"Normalization and microbial differential abundance strategies depend upon data characteristics","volume":"5","author":"Weiss","year":"2017","journal-title":"Microbiome"},{"key":"2023013108134000300_btz120-B45","doi-asserted-by":"crossref","first-page":"56.","DOI":"10.1186\/s13073-016-0302-3","article-title":"An adaptive association test for microbiome data","volume":"8","author":"Wu","year":"2016","journal-title":"Genome Med"},{"key":"2023013108134000300_btz120-B46","doi-asserted-by":"crossref","first-page":"222.","DOI":"10.1038\/nature11053","article-title":"Human gut microbiome viewed across age and geography","volume":"486","author":"Yatsunenko","year":"2012","journal-title":"Nature"},{"key":"2023013108134000300_btz120-B47","doi-asserted-by":"crossref","first-page":"509","DOI":"10.3389\/fmicb.2018.00509","article-title":"Variance component selection with applications to microbiome taxonomic data","volume":"9","author":"Zhai","year":"2018","journal-title":"Frontiers in Microbiology"},{"key":"2023013108134000300_btz120-B48","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/gepi.22030","article-title":"A small-sample multivariate kernel machine test for microbiome association studies","volume":"41","author":"Zhan","year":"2017","journal-title":"Genet. Epidemiol"},{"key":"2023013108134000300_btz120-B49","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1002\/gepi.22160","article-title":"A small-sample kernel association test for correlated data with application to microbiome association studies","volume":"42","author":"Zhan","year":"2018","journal-title":"Genet. Epidemiol"},{"key":"2023013108134000300_btz120-B50","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.ajhg.2015.04.003","article-title":"Testing in microbiome-profiling studies with MiRKAT, the microbiome regression-based kernel association test","volume":"96","author":"Zhao","year":"2015","journal-title":"Am. J. Hum. Genet"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/19\/3567\/48975895\/bioinformatics_35_19_3567.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/19\/3567\/48975895\/bioinformatics_35_19_3567.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T14:47:57Z","timestamp":1675176477000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/35\/19\/3567\/5341424"}},"subtitle":[],"editor":[{"given":"Bonnie","family":"Berger","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2019,2,19]]},"references-count":50,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2019,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz120","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,10,1]]},"published":{"date-parts":[[2019,2,19]]}}}