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PMID: 21702898 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study

Metagenomic biomarker discovery and explanation.

Genome biology ·Vol. 12 ·No. 6 ·2011-06-24 ·Pages R60

Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C

Abstract

This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.

MeSH Terms
Adult Animals Bacteria/classification Biomarkers Colitis, Ulcerative/microbiology Data Mining Humans Infant Metagenome Metagenomics/methods Mice Mice, Inbred BALB C Mice, Knockout Mucous Membrane/microbiology Sensitivity and Specificity Software Viruses/classification
Chemicals
Biomarkers
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Segata Nicola
Department of Biostatistics, 677 Huntington Avenue, Harvard School of Public Health, Boston, MA 02115, USA.
Izard Jacques
Waldron Levi
Gevers Dirk
Miropolsky Larisa
Garrett Wendy S
Huttenhower Curtis
References (93)
93 references, click to expand
  1. The properties of high-dimensional data spaces: implications for exploring gene and protein expression data.
    Nat Rev Cancer. 2008 Jan;8(1):37-49 PMID: 18097463
  2. Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era.
    Gastroenterology. 2009 May;136(6):2015-31 PMID: 19462507
  3. Galaxy: a web-based genome analysis tool for experimentalists.
    Curr Protoc Mol Biol. 2010 Jan;Chapter 19:Unit 19.10.1-21 PMID: 20069535
  4. Visual and statistical comparison of metagenomes.
    Bioinformatics. 2009 Aug 1;25(15):1849-55 PMID: 19515961
  5. The subsystems approach to genome annotation and its use in the project to annotate 1000 genomes.
    Nucleic Acids Res. 2005 Oct 07;33(17):5691-702 PMID: 16214803
  6. Multivariate Cutoff Level Analysis (MultiCoLA) of large community data sets.
    Nucleic Acids Res. 2010 Aug;38(15):e155 PMID: 20547594
  7. Rarity associated with specific ecological niches in the bacterial world: the 'Synergistes' example.
    Environ Microbiol. 2005 Feb;7(2):213-24 PMID: 15658988
  8. Statistical methods for detecting differentially abundant features in clinical metagenomic samples.
    PLoS Comput Biol. 2009 Apr;5(4):e1000352 PMID: 19360128
  9. An ecological and evolutionary perspective on human-microbe mutualism and disease.
    Nature. 2007 Oct 18;449(7164):811-8 PMID: 17943117
  10. Identifying biologically relevant differences between metagenomic communities.
    Bioinformatics. 2010 Mar 15;26(6):715-21 PMID: 20130030
  11. Exploring the within- and between-class correlation distributions for tumor classification.
    Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6737-42 PMID: 20339085
  12. An obesity-associated gut microbiome with increased capacity for energy harvest.
    Nature. 2006 Dec 21;444(7122):1027-31 PMID: 17183312
  13. Low counts of Faecalibacterium prausnitzii in colitis microbiota.
    Inflamm Bowel Dis. 2009 Aug;15(8):1183-9 PMID: 19235886
  14. Bifidobacterium animalis subsp. lactis fermented milk product reduces inflammation by altering a niche for colitogenic microbes.
    Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):18132-7 PMID: 20921388
  15. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea.
    J Clin Gastroenterol. 2010 May-Jun;44(5):354-60 PMID: 20048681
  16. Survival of Campylobacter jejuni under conditions of atmospheric oxygen tension with the support of Pseudomonas spp.
    Appl Environ Microbiol. 2010 Sep;76(17):5911-7 PMID: 20639377
  17. Microbial community profiling for human microbiome projects: Tools, techniques, and challenges.
    Genome Res. 2009 Jul;19(7):1141-52 PMID: 19383763
  18. Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis.
    Nat Clin Pract Gastroenterol Hepatol. 2006 Jul;3(7):390-407 PMID: 16819502
  19. Biomarkers for infants at risk for necrotizing enterocolitis: clues to prevention?
    Pediatr Res. 2009 May;65(5 Pt 2):91R-97R PMID: 19190533
  20. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system.
    Cell. 2007 Oct 5;131(1):33-45 PMID: 17923086
  21. Salivary transcriptomic biomarkers for detection of resectable pancreatic cancer.
    Gastroenterology. 2010 Mar;138(3):949-57.e1-7 PMID: 19931263
  22. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities.
    Appl Environ Microbiol. 2009 Dec;75(23):7537-41 PMID: 19801464
  23. Environmental distribution of prokaryotic taxa.
    BMC Microbiol. 2010 Mar 22;10:85 PMID: 20307274
  24. Community structure and metabolism through reconstruction of microbial genomes from the environment.
    Nature. 2004 Mar 4;428(6978):37-43 PMID: 14961025
  25. False discovery rate, sensitivity and sample size for microarray studies.
    Bioinformatics. 2005 Jul 1;21(13):3017-24 PMID: 15840707
  26. Diversity of human vaginal bacterial communities and associations with clinically defined bacterial vaginosis.
    Appl Environ Microbiol. 2008 Aug;74(15):4898-909 PMID: 18487399
  27. Incorporating prior knowledge to facilitate discoveries in a genome-wide association study on age-related macular degeneration.
    BMC Res Notes. 2010 Jan 28;3:26 PMID: 20181037
  28. The metagenomics RAST server - a public resource for the automatic phylogenetic and functional analysis of metagenomes.
    BMC Bioinformatics. 2008 Sep 19;9:386 PMID: 18803844
  29. Treatment of ulcerative colitis using fecal bacteriotherapy.
    J Clin Gastroenterol. 2003 Jul;37(1):42-7 PMID: 12811208
  30. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis.
    Cell Host Microbe. 2010 Sep 16;8(3):292-300 PMID: 20833380
  31. Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons.
    Genome Res. 2011 Mar;21(3):494-504 PMID: 21212162
  32. Identification of the uncultured bacillus of Whipple's disease.
    N Engl J Med. 1992 Jul 30;327(5):293-301 PMID: 1377787
  33. National Institute of Allergy and Infectious Diseases bioinformatics resource centers: new assets for pathogen informatics.
    Infect Immun. 2007 Jul;75(7):3212-9 PMID: 17420237
  34. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy.
    Appl Environ Microbiol. 2007 Aug;73(16):5261-7 PMID: 17586664
  35. A primer on metagenomics.
    PLoS Comput Biol. 2010 Feb 26;6(2):e1000667 PMID: 20195499
  36. [Immunoproliferative small intestinal disease associated with Campylobacter jejuni].
    Med Mal Infect. 2005 Jun;35 Suppl 2:S56-8 PMID: 15978389
  37. Metagenomics: the role of the microbiome in cardiovascular diseases.
    Curr Opin Lipidol. 2006 Apr;17(2):157-61 PMID: 16531752
  38. SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB.
    Nucleic Acids Res. 2007;35(21):7188-96 PMID: 17947321
  39. Host specificity in marine sponge-associated bacteria, and potential implications for marine microbial diversity.
    Environ Microbiol. 2004 Feb;6(2):121-30 PMID: 14756877
  40. Galaxy: a comprehensive approach for supporting accessible, reproducible, and transparent computational research in the life sciences.
    Genome Biol. 2010;11(8):R86 PMID: 20738864
  41. A genomic perspective on protein families.
    Science. 1997 Oct 24;278(5338):631-7 PMID: 9381173
  42. Microbial diversity in the deep sea and the underexplored "rare biosphere".
    Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12115-20 PMID: 16880384
  43. Specified species in gingival crevicular fluid predict bacterial diversity.
    PLoS One. 2010 Oct 25;5(10):e13589 PMID: 21049043
  44. Oral cavity as natural reservoir for intestinal lactobacilli.
    Syst Appl Microbiol. 2006 Jan;29(1):69-76 PMID: 16423658
  45. Successful treatment of fulminant Clostridium difficile infection with fecal bacteriotherapy.
    Ann Intern Med. 2008 Apr 15;148(8):632-3 PMID: 18413636
  46. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome.
    Cell Host Microbe. 2008 Apr 17;3(4):213-23 PMID: 18407065
  47. Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases.
    Cell Host Microbe. 2008 Jun 12;3(6):417-27 PMID: 18541218
  48. A core gut microbiome in obese and lean twins.
    Nature. 2009 Jan 22;457(7228):480-4 PMID: 19043404
  49. Reshaping the gut microbiome with bacterial transplantation and antibiotic intake.
    Genome Res. 2010 Oct;20(10):1411-9 PMID: 20736229
  50. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach.
    Gut. 2006 Feb;55(2):205-11 PMID: 16188921
  51. The COG database: new developments in phylogenetic classification of proteins from complete genomes.
    Nucleic Acids Res. 2001 Jan 1;29(1):22-8 PMID: 11125040
  52. Metascardovia criceti Gen. Nov., Sp. Nov., from hamster dental plaque.
    Microbiol Immunol. 2007;51(8):747-54 PMID: 17704637
  53. Accuracy and quality of massively parallel DNA pyrosequencing.
    Genome Biol. 2007;8(7):R143 PMID: 17659080
  54. Marine microbial diversity: can it be determined?
    Trends Microbiol. 2006 Jun;14(6):257-63 PMID: 16679014
  55. A high-throughput DNA sequence aligner for microbial ecology studies.
    PLoS One. 2009 Dec 14;4(12):e8230 PMID: 20011594
  56. Inclusion of a priori information in genome-wide association analysis.
    Genet Epidemiol. 2009;33 Suppl 1:S74-80 PMID: 19924705
  57. Comparative metagenomics of microbial communities.
    Science. 2005 Apr 22;308(5721):554-7 PMID: 15845853
  58. Over-optimism in bioinformatics research.
    Bioinformatics. 2010 Feb 1;26(3):437-9 PMID: 19942585
  59. Comparative metagenomics revealed commonly enriched gene sets in human gut microbiomes.
    DNA Res. 2007 Aug 31;14(4):169-81 PMID: 17916580
  60. Mouse models for the study of Crohn's disease.
    Trends Mol Med. 2003 May;9(5):218-22 PMID: 12763527
  61. Probiotics and gastrointestinal disease: successes, problems and future prospects.
    Gut Pathog. 2009 Nov 23;1(1):19 PMID: 19930635
  62. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.
    Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14691-6 PMID: 20679230
  63. Substantial alterations of the cutaneous bacterial biota in psoriatic lesions.
    PLoS One. 2008 Jul 23;3(7):e2719 PMID: 18648509
  64. Intestinal mucosal barrier function in health and disease.
    Nat Rev Immunol. 2009 Nov;9(11):799-809 PMID: 19855405
  65. The human microbiome project.
    Nature. 2007 Oct 18;449(7164):804-10 PMID: 17943116
  66. Use of proteomic patterns in serum to identify ovarian cancer.
    Lancet. 2002 Feb 16;359(9306):572-7 PMID: 11867112
  67. Comparison of multiple metagenomes using phylogenetic networks based on ecological indices.
    ISME J. 2010 Oct;4(10):1236-42 PMID: 20428222
  68. A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis.
    J Immunol. 1998 Nov 15;161(10):5733-44 PMID: 9820555
  69. METAREP: JCVI metagenomics reports--an open source tool for high-performance comparative metagenomics.
    Bioinformatics. 2010 Oct 15;26(20):2631-2 PMID: 20798169
  70. UniFrac: a new phylogenetic method for comparing microbial communities.
    Appl Environ Microbiol. 2005 Dec;71(12):8228-35 PMID: 16332807
  71. Human colonic microbiota associated with diet, obesity and weight loss.
    Int J Obes (Lond). 2008 Nov;32(11):1720-4 PMID: 18779823
  72. MEGAN analysis of metagenomic data.
    Genome Res. 2007 Mar;17(3):377-86 PMID: 17255551
  73. Bacterial community variation in human body habitats across space and time.
    Science. 2009 Dec 18;326(5960):1694-7 PMID: 19892944
  74. Using prior knowledge and genome-wide association to identify pathways involved in multiple sclerosis.
    Genome Med. 2009 Jun 29;1(6):65 PMID: 19566917
  75. Development of colonic adenocarcinomas in a mouse model of ulcerative colitis.
    Inflamm Bowel Dis. 1998 Aug;4(3):196-202 PMID: 9741021
  76. Significance analysis of microarrays applied to the ionizing radiation response.
    Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21 PMID: 11309499
  77. False-positive selection identified by ML-based methods: examples from the Sig1 gene of the diatom Thalassiosira weissflogii and the tax gene of a human T-cell lymphotropic virus.
    Mol Biol Evol. 2004 May;21(5):914-21 PMID: 15014169
  78. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice.
    Sci Transl Med. 2009 Nov 11;1(6):6ra14 PMID: 20368178
  79. Ecological and evolutionary forces shaping microbial diversity in the human intestine.
    Cell. 2006 Feb 24;124(4):837-48 PMID: 16497592
  80. High-throughput gene mapping in Caenorhabditis elegans.
    Genome Res. 2002 Jul;12(7):1100-5 PMID: 12097347
  81. Functional metagenomic profiling of nine biomes.
    Nature. 2008 Apr 3;452(7187):629-32 PMID: 18337718
  82. The clinical value of salivary biomarkers for periodontal disease.
    Periodontol 2000. 2009;51:25-37 PMID: 19878467
  83. The Ribosomal Database Project: improved alignments and new tools for rRNA analysis.
    Nucleic Acids Res. 2009 Jan;37(Database issue):D141-5 PMID: 19004872
  84. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.
    Science. 1999 Oct 15;286(5439):531-7 PMID: 10521349
  85. Mouse models of inflammatory bowel disease.
    Adv Drug Deliv Rev. 2007 Sep 30;59(11):1073-83 PMID: 17825455
  86. The NIH Human Microbiome Project.
    Genome Res. 2009 Dec;19(12):2317-23 PMID: 19819907
  87. Linear models and empirical bayes methods for assessing differential expression in microarray experiments.
    Stat Appl Genet Mol Biol. 2004;3:Article3 PMID: 16646809
  88. Metagenomics: Facts and Artifacts, and Computational Challenges*
    J Comput Sci Technol. 2009 Jan;25(1):71-81 PMID: 20648230
  89. 2020 visions.
    Nature. 2010 Jan 7;463(7277):26-32 PMID: 20054379
  90. ShotgunFunctionalizeR: an R-package for functional comparison of metagenomes.
    Bioinformatics. 2009 Oct 15;25(20):2737-8 PMID: 19696045
  91. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome.
    Clin Cancer Res. 2008 Aug 15;14(16):5198-208 PMID: 18698038
  92. The 'rare biosphere': a reality check.
    Nat Methods. 2009 Sep;6(9):636-7 PMID: 19718016
  93. Exploring the diversity of the bifidobacterial population in the human intestinal tract.
    Appl Environ Microbiol. 2009 Mar;75(6):1534-45 PMID: 19168652
Article Info
Journal
Genome biology
Abbr.
Genome Biol
ISSN
1474-760X
DOI
10.1186/gb-2011-12-6-r60
Published
2011-06-24
Epub
2011-00-24
Pages
R60
Language
English
Region
England
NLM ID
100960660
PMCID
PMC3218848
Subset
IM
Grants
NIAID NIH HHS · AI078942 · United States
NIAID NIH HHS · K08 AI078942 · United States
NHGRI NIH HHS · R01 HG005969 · United States
NIDCR NIH HHS · R21 DE017106 · United States
NIDCR NIH HHS · DE017106 · United States
NIDCR NIH HHS · R21 DE017106-02 · United States
NHGRI NIH HHS · 1R01HG005969 · United States
External Links
PubMed source DOI: 10.1186/gb-2011-12-6-r60 PMC Full Text View journal details
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