Early infancy microbial and metabolic alterations affect risk of childhood asthma

Science Translational Medicine

Volumn 7, Issue 307, 2015, Pages

  Arrieta, Marie Claire ^a,b   Stiemsma, Leah T ^b,c   Dimitriu, Pedro A ^b   Thorson, Lisa ^a   Russell, Shannon ^a,b   Yurist Doutsch, Sophie ^a,b   Kuzeljevic, Boris ^c   Gold, Matthew J ^b   Britton, Heidi M ^a   Lefebvre, Diana L ^d   Subbarao, Padmaja ^e,f   Mandhane, Piush ^g   Becker, Allan ^h   McNagny, Kelly M ^b   Sears, Malcolm R ^d   Kollmann, Tobias ^b,c   Mohn, William W ^b   Turvey, Stuart E ^b,c   Finlay, B Brett ^a,b  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^b UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^c UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^d MCMASTER UNIVERSITY   (Canada)

^e UNIVERSITY OF TORONTO   (Canada)

^f HOSPITAL FOR SICK CHILDREN   (Canada)

^g UNIVERSITY OF ALBERTA   (Canada)

^h UNIVERSITY OF MANITOBA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ACETIC ACID; PROBIOTIC AGENT;

ALLERGIC DISEASE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ASTHMA; CHILD; CONTROLLED STUDY; DYSBIOSIS; EXPERIMENTAL ASTHMA; FAECALIBACTERIUM; FEMALE; GERMFREE MOUSE; HUMAN; INCIDENCE; INFANCY; INFANT; INOCULATION; INTESTINE FLORA; LACHNOSPIRACEAE; LONGITUDINAL STUDY; MAJOR CLINICAL STUDY; MALE; METABOLISM; MOUSE; NEWBORN; NONHUMAN; PATHOGENESIS; POPULATION ABUNDANCE; PRESCHOOL CHILD; PREVALENCE; PRIORITY JOURNAL; PROGENY; PROSPECTIVE STUDY; RESPIRATORY TRACT INFLAMMATION; RISK ASSESSMENT; ROTHIA; TAXON; VEILLONELLA; ANIMAL; COMPUTER PROGRAM; FECES; METABOLOME; MICROBIOLOGY; MICROFLORA; PHENOTYPE; PNEUMONIA; RISK FACTOR;

ANIMALS; ASTHMA; CHILD; FECES; GASTROINTESTINAL MICROBIOME; HUMANS; INFANT; METABOLOME; MICE; MICROBIOTA; PHENOTYPE; PNEUMONIA; RISK FACTORS; SOFTWARE;

EID: 84942874856     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aab2271     Document Type: Article

References (68)

1. I. Asher, N. Pearce, Global burden of asthma among children. Int. J. Tuberc. Lung Dis. 18, 1269-1278 (2014).
2. S. T. Holgate, Innate and adaptive immune responses in asthma. Nat. Med. 18, 673-683 (2012).
3. D. Graham-Rowe, Lifestyle: When allergies go west. Nature 479, S2-S4 (2011).
4. F. D. Martinez, D. Vercelli, Asthma. Lancet 382, 1360-1372 (2013).
5. M. C. Arrieta, L. T. Stiemsma, N. Amenyogbe, E. M. Brown, B. Finlay, The intestinal microbiome in early life: Health and disease. Front. Immunol. 5, 427 (2014).
6. J. R. Hunt, R. Martinelli, V. C. Adams, G. A. Rook, L. R. Brunet, Intragastric administration of Mycobacterium vaccae inhibits severe pulmonary allergic inflammation in a mouse model. Clin. Exp. Allergy 35, 685-690 (2005).
7. P. Forsythe, M. D. Inman, J. Bienenstock, Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice. Am. J. Respir. Crit. Care Med. 175, 561-569 (2007).
8. K. Atarashi, T. Tanoue, T. Shima, A. Imaoka, T. Kuwahara, Y. Momose, G. Cheng, S. Yamasaki, T. Saito, Y. Ohba, T. Taniguchi, K. Takeda, S. Hori, I. I. Ivanov, Y. Umesaki, K. Itoh, K. Honda, Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337-341 (2011).
9. A. Shreiner, G. B. Huffnagle, M. C. Noverr, The "microflora hypothesis" of allergic disease. Adv. Exp. Med. Biol. 635, 113-134 (2008).
10. I. C. Arnold, N. Dehzad, S. Reuter, H. Martin, B. Becher, C. Taube, A. Muller, Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J. Clin. Invest. 121, 3088-3093 (2011).
11. S. L. Russell, M. J. Gold, B. P. Willing, L. Thorson, K. M. McNagny, B. B. Finlay, Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 4, 158-164 (2013).
12. J. Cahenzli, Y. Koller, M. Wyss, M. B. Geuking, K. D. McCoy, Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 14, 559-570 (2013).
13. A. Trompette, E. S. Gollwitzer, K. Yadava, A. K. Sichelstiel, N. Sprenger, C. Ngom-Bru, C. Blanchard, T. Junt, L. P. Nicod, N. L. Harris, B. J. Marsland, Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159-166 (2014).
14. N. Arpaia, C. Campbell, X. Fan, S. Dikiy, J. van der Veeken, P. deRoos, H. Liu, J. R. Cross, K. Pfeffer, P. J. Coffer, A. Y. Rudensky, Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451-455 (2013).
15. B. S. Samuel, A. Shaito, T. Motoike, F. E. Rey, F. Backhed, J. K. Manchester, R. E. Hammer, S. C. Williams, J. Crowley, M. Yanagisawa, J. I. Gordon, Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. U.S.A. 105, 16767-16772 (2008).
16. A. Sandin, L. Braback, E. Norin, B. Bjorksten, Faecal short chain fatty acid pattern and allergy in early childhood. Acta Paediatr. 98, 823-827 (2009).
17. E. J. Saude, C. D. Skappak, S. Regush, K. Cook, A. Ben-Zvi, A. Becker, R. Moqbel, B. D. Sykes, B. H. Rowe, D. J. Adamko, Metabolomic profiling of asthma: Diagnostic utility of urine nuclear magnetic resonance spectroscopy. J. Allergy Clin. Immunol. 127, 757-764 (2011).
18. E. J. Saude, I. P. Obiefuna, R. L. Somorjai, F. Ajamian, C. Skappak, T. Ahmad, B. K. Dolenko, B. D. Sykes, R. Moqbel, D. J. Adamko, Metabolomic biomarkers in a model of asthma exacerbation: Urine nuclear magnetic resonance. Am. J. Respir. Crit. Care Med. 179, 25-34 (2009).
19. J. A. Castro-Rodriguez, C. J. Holberg, A. L. Wright, F. D. Martinez, A clinical index to define risk of asthma in young children with recurrent wheezing. Am. J. Respir. Crit. Care Med. 162, 1403-1406 (2000).
20. J. A. Castro-Rodriguez, L. Cifuentes, C. E. Rodriguez-Martinez, The asthma predictive index remains a useful tool to predict asthma in young children with recurrent wheeze in clinical practice. J. Allergy Clin. Immunol. 127, 1082-1083 (2011).
21. L. Hoskin-Parr, A. Teyhan, A. Blocker, A. J. Henderson, Antibiotic exposure in the first two years of life and development of asthma and other allergic diseases by 7.5 yr: A dosedependent relationship. Pediatr. Allergy Immunol. 24, 762-771 (2013).
22. M. B. Azad, T. Konya, H. Maughan, D. S. Guttman, C. J. Field, R. S. Chari, M. R. Sears, A. B. Becker, J. A. Scott, A. L. Kozyrskyj; on behalf of the CHILD Study Investigators, Gut microbiota of healthy Canadian infants: Profiles by mode of delivery and infant diet at 4 months. CMAJ 185, 385-394 (2013).
23. S. Tanaka, T. Kobayashi, P. Songjinda, A. Tateyama, M. Tsubouchi, C. Kiyohara, T. Shirakawa, K. Sonomoto, J. Nakayama, Influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota. FEMS Immunol. Med. Microbiol. 56, 80-87 (2009).
24. T. Yatsunenko, F. E. Rey, M. J. Manary, I. Trehan, M. G. Dominguez-Bello, M. Contreras, M. Magris, G. Hidalgo, R. N. Baldassano, A. P. Anokhin, A. C. Heath, B. Warner, J. Reeder, J. Kuczynski, J. G. Caporaso, C. A. Lozupone, C. Lauber, J. C. Clemente, D. Knights, R. Knight, J. I. Gordon, Human gut microbiome viewed across age and geography. Nature 486, 222-227 (2012).
25. T. R. Abrahamsson, H. E. Jakobsson, A. F. Andersson, B. Bjorksten, L. Engstrand, M. C. Jenmalm, Low gut microbiota diversity in early infancy precedes asthma at school age. Clin. Exp. Allergy 44, 842-850 (2014).
26. E. Holmes, J. V. Li, T. Athanasiou, H. Ashrafian, J. K. Nicholson, Understanding the role of gut microbiome-host metabolic signal disruption in health and disease. Trends Microbiol. 19, 349-359 (2011).
27. S. L. Russell, M. J. Gold, M. Hartmann, B. P. Willing, L. Thorson, M. Wlodarska, N. Gill, M. R. Blanchet, W. W. Mohn, K. M. McNagny, B. B. Finlay, Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 13, 440-447 (2012).
28. T. Olszak, D. An, S. Zeissig, M. P. Vera, J. Richter, A. Franke, J. N. Glickman, R. Siebert, R. M. Baron, D. L. Kasper, R. S. Blumberg, Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489-493 (2012).
29. C. Huttenhower, D. Gevers, R. Knight, S. Abubucker, J. H. Badger, A. T. Chinwalla, H. H. Creasy, A. M. Earl, M. G. FitzGerald, R. S. Fulton, M. G. Giglio, K. Hallsworth-Pepin, E. A. Lobos, R. Madupu, V. Magrini, J. C. Martin, M. Mitreva, D. M. Muzny, E. J. Sodergren, J. Versalovic, A.M.Wollam, K. C.Worley, J. R. Wortman, S. K. Young, Q. D. Zeng, K. M. Aagaard, O. O. Abolude, E. Allen-Vercoe, E. J. Alm, L. Alvarado, G. L. Andersen, S. Anderson, E. Appelbaum, H. M. Arachchi, G. Armitage, C. A. Arze, T. Ayvaz, C. C. Baker, L. Begg, T. Belachew, V. Bhonagiri, M. Bihan, M. J. Blaser, T. Bloom, V. Bonazzi, J. P. Brooks, G. A. Buck, C. J. Buhay, D. A. Busam, J. L. Campbell, S. R. Canon, B. L. Cantarel, P. S. G. Chain, I. M. A. Chen, L. Chen, S. Chhibba, K. Chu, D. M. Ciulla, J. C. Clemente, S. W. Clifton, S. Conlan, J. Crabtree, M. A. Cutting, N. J. Davidovics, C. C. Davis, T. Z. DeSantis, C. Deal, K. D. Delehaunty, F. E. Dewhirst, E. Deych, Y. Ding, D. J. Dooling, S. P. Dugan, W. M. Dunne, A. S. Durkin, R. C. Edgar, R. L. Erlich, C. N. Farmer, R. M. Farrell, K. Faust, M. Feldgarden, V. M. Felix, S. Fisher, A. A. Fodor, L. J. Forney, L. Foster, V. Di Francesco, J. Friedman, D. C. Friedrich, C. C. Fronick, L. L. Fulton, H. Y. Gao, N. Garcia, G. Giannoukos, C. Giblin, M. Y. Giovanni, J. M. Goldberg, J. Goll, A. Gonzalez, A. Griggs, S. Gujja, S. K. Haake, B. J. Haas, H. A. Hamilton, E. L. Harris, T. A. Hepburn, B. Herter, D. E. Hoffmann, M. E. Holder, C. Howarth, K. H. Huang, S. M. Huse, J. Izard, J. K. Jansson, H. Y. Jiang, C. Jordan, V. Joshi, J. A. Katancik, W. A. Keitel, S. T. Kelley, C. Kells, N. B. King, D. Knights, H. D. H. Kong, O. Koren, S. Koren, K. C. Kota, C. L. Kovar, N. C. Kyrpides, P. S. La Rosa, S. L. Lee, K. P. Lemon, N. Lennon, C. M. Lewis, L. Lewis, R. E. Ley, K. Li, K. Liolios, B. Liu, Y. Liu, C. C. Lo, C. A. Lozupone, R. D. Lunsford, T. Madden, A. A. Mahurkar, P. J. Mannon, E. R. Mardis, V. M. Markowitz, K. Mavromatis, J. M. McCorrison, D. McDonald, J. McEwen, A. L. McGuire, P. McInnes, T. Mehta, K. A. Mihindukulasuriya, J. R. Miller, P. J. Minx, I. Newsham, C. Nusbaum, M. O'Laughlin, J. Orvis, I. Pagani, K. Palaniappan, S. M. Patel, M. Pearson, J. Peterson, M. Podar, C. Pohl, K. S. Pollard, M. Pop, M. E. Priest, L. M. Proctor, X. Qin, J. Raes, J. Ravel, J. G. Reid, M. Rho, R. Rhodes, K. P. Riehle, M. C. Rivera, B. Rodriguez-Mueller, Y. H. Rogers, M. C. Ross, C. Russ, R. K. Sanka, P. Sankar, J. F. Sathirapongsasuti, J. A. Schloss, P. D. Schloss, T. M. Schmidt, M. Scholz, L. Schriml, A. M. Schubert, N. Segata, J. A. Segre, W. D. Shannon, R. R. Sharp, T. J. Sharpton, N. Shenoy, N. U. Sheth, G. A. Simone, I. Singh, C. S. Smillie, J. D. Sobel, D. D. Sommer, P. Spicer, G. G. Sutton, S. M. Sykes, D. G. Tabbaa, M. Thiagarajan, C. M. Tomlinson, M. Torralba, T. J. Treangen, R. M. Truty, T. A. Vishnivetskaya, J. Walker, L. Wang, Z. Y. Wang, D. V. Ward, W. Warren, M. A. Watson, C. Wellington, K. A. Wetterstrand, J. R. White, K. Wilczek-Boney, Y. Q.Wu, K. M. Wylie, T. Wylie, C. Yandava, L. Ye, Y. Z. Ye, S. Yooseph, B. P. Youmans, L. Zhang, Y. J. Zhou, Y. M. Zhu, L. Zoloth, J. D. Zucker, B. W. Birren, R. A. Gibbs, S. K. Highlander, B. A. Methe, K. E. Nelson, J. F. Petrosino, G. M. Weinstock, R. K. Wilson, O. White; Human Microbiome Project Consortium, Structure, function and diversity of the healthy human microbiome. Nature 486, 207-214 (2012).
30. T. De Smedt, B. Pajak, E. Muraille, L. Lespagnard, E. Heinen, P. De Baetselier, J. Urbain, O. Leo, M. Moser, Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J. Exp. Med. 184, 1413-1424 (1996).
31. C. Chassin, M. Kocur, J. Pott, C. U. Duerr, D. Gutle, M. Lotz, M. W. Hornef, miR-146a mediates protective innate immune tolerance in the neonate intestine. Cell Host Microbe 8, 358-368 (2010).
32. M. Fallani, D. Young, J. Scott, E. Norin, S. Amarri, R. Adam, M. Aguilera, S. Khanna, A. Gil, C. A. Edwards, J. Doré; Other members of the INFABIO Team, Intestinal microbiota of 6-weekold infants across Europe: Geographic influence beyond delivery mode, breast-feeding, and antibiotics. J. Pediatr. Gastroenterol. Nutr. 51, 77-84 (2010).
33. E. Jimenez, B. Sanchez, A. Farina, A. Margolles, J. M. Rodriguez, Characterization of the bile and gall bladder microbiota of healthy pigs. Microbiologyopen 3, 937-949 (2014).
34. M. Rogosa, The genus Veillonella. I. General cultural, ecological, and biochemical considerations. J. Bacteriol. 87, 162-170 (1964).
35. N. A. Cornick, N. S. Jensen, D. A. Stahl, P. A. Hartman, M. J. Allison, Lachnospira pectinoschiza sp. nov., an anaerobic pectinophile from the pig intestine. Int. J. Syst. Bacteriol. 44, 87-93 (1994).
36. M. Lopez-Siles, T. M. Khan, S. H. Duncan, H. J. Harmsen, L. J. Garcia-Gil, H. J. Flint, Cultured representatives of two major phylogroups of human colonic Faecalibacterium prausnitzii can utilize pectin, uronic acids, and host-derived substrates for growth. Appl. Environ. Microbiol. 78, 420-428 (2012).
37. M. Manise, G. Holtappels, K. Van Crombruggen, F. Schleich, C. Bachert, R. Louis, Sputum IgE and cytokines in asthma: Relationship with sputum cellular profile. PLOS One 8, e58388 (2013).
38. M. Marini, E. Vittori, J. Hollemborg, S. Mattoli, Expression of the potent inflammatory cytokines, granulocyte-macrophage-colony-stimulating factor and interleukin-6 and interleukin-8, in bronchial epithelial cells of patients with asthma. J. Allergy Clin. Immunol. 89, 1001-1009 (1992).
39. J. C. Virchow Jr., C. Kroegel, C. Walker, H. Matthys, Inflammatory determinants of asthma severity: Mediator and cellular changes in bronchoalveolar lavage fluid of patients with severe asthma. J. Allergy Clin. Immunol. 98, S27-S33 (1996).
40. T. J. Moraes, D. L. Lefebvre, R. Chooniedass, A. B. Becker, J. R. Brook, J. Denburg, K. T. HayGlass, R. G. Hegele, T. R. Kollmann, J. Macri, P. J. Mandhane, J. A. Scott, P. Subbarao, T. K. Takaro, S. E. Turvey, J. D. Duncan, M. R. Sears, A. D. Befus; the CHILD Study Investigators, The Canadian Healthy Infant Longitudinal Development birth cohort study: Biological samples and biobanking. Paediatr. Perinat. Epidemiol. 29, 84-92 (2015).
41. T. K. Takaro, J. A. Scott, R. W. Allen, S. S. Anand, A. B. Becker, A. D. Befus, M. Brauer, J. Duncan, D. L. Lefebvre, W. Lou, P. J. Mandhane, K. E. McLean, G. Miller, H. Sbihi, H. Shu, P. Subbarao, S. E. Turvey, A. J. Wheeler, L. Zeng, M. R. Sears, J. R. Brook; the CHILD Study Investigators, The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study: Assessment of environmental exposures. J. Expo. Sci. Environ. Epidemiol. 10.1038/jes.2015.7 (2015).
42. P. Subbarao, S. S. Anand, A. B. Becker, A. D. Befus, M. Brauer, J. R. Brook, J. A. Denburg, K. T. HayGlass, M. S. Kobor, T. R. Kollmann, A. L. Kozyrskyj, W. Y. Lou, P. J. Mandhane, G. E. Miller, T. J. Moraes, P. D. Pare, J. A. Scott, T. K. Takaro, S. E. Turvey, J. M. Duncan, D. L. Lefebvre, M. R. Sears; CHILD Study Investigators, The Canadian Healthy Infant Longitudinal Development (CHILD) study: Examining developmental origins of allergy and asthma. Thorax 70, 998-1000 (2015).
43. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee, Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 351, 1225-1232 (1998).
44. A. K. Bartram, M. D. Lynch, J. C. Stearns, G. Moreno-Hagelsieb, J. D. Neufeld, Generation of multimillion-sequence 16S rRNA gene libraries from complex microbial communities by assembling paired-end illumina reads. Appl. Environ. Microbiol. 77, 3846-3852 (2011).
45. P. D. Schloss, S. L. Westcott, T. Ryabin, J. R. Hall, M. Hartmann, E. B. Hollister, R. A. Lesniewski, B. B. Oakley, D. H. Parks, C. J. Robinson, J. W. Sahl, B. Stres, G. G. Thallinger, D. J. Van Horn, C. F. Weber, Introducing mothur: Open-source, platform-independent, communitysupported software for describing and comparing microbial communities. Appl. Environ. Microbiol. 75, 7537-7541 (2009).
46. M. Hartmann, C. G. Howes, D. VanInsberghe, H. Yu, D. Bachar, R. Christen, R. Henrik Nilsson, S. J. Hallam, W. W. Mohn, Significant and persistent impact of timber harvesting on soil microbial communities in Northern coniferous forests. ISME J. 6, 2199-2218 (2012).
47. T. Z. DeSantis, P. Hugenholtz, N. Larsen, M. Rojas, E. L. Brodie, K. Keller, T. Huber, D. Dalevi, P. Hu, and G. L. Andersen, Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl. Environ. Microbiol. 72, 5069-5072 (2006).
48. M. G. Langille, J. Zaneveld, J. G. Caporaso, D. McDonald, D. Knights, J. A. Reyes, J. C. Clemente, D. E. Burkepile, R. L. Vega Thurber, R. Knight, R. G. Beiko, C. Huttenhower, Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat. Biotechnol. 31, 814-821 (2013).
49. D. H. Parks, G. W. Tyson, P. Hugenholtz, R. G. Beiko, STAMP: Statistical analysis of taxonomic and functional profiles. Bioinformatics 30, 3123-3124 (2014).
50. M. I. Love, W. Huber, S. Anders, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
51. Y. Benjamini, Y. Hochberg, Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B Stat. Methodol. 57, 289-300 (1995).
52. J. M. Campbell, G. C. Fahey Jr., B. W. Wolf, Selected indigestible oligosaccharides affect large bowel mass, cecal and fecal short-chain fatty acids, pH and microflora in rats. J. Nutr. 127, 130-136 (1997).
53. A. M. Evans, C. D. DeHaven, T. Barrett, M. Mitchell, E. Milgram, Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Anal. Chem. 81, 6656-6667 (2009).
54. C. D. Dehaven, A. M. Evans, H. Dai, K. A. Lawton, Organization of GC/MS and LC/MS metabolomics data into chemical libraries. J. Cheminform. 2, 9 (2010).
55. M. I. Smith, T. Yatsunenko, M. J. Manary, I. Trehan, R. Mkakosya, J. Cheng, A. L. Kau, S. S. Rich, P. Concannon, J. C. Mychaleckyj, J. Liu, E. Houpt, J. V. Li, E. Holmes, J. Nicholson, D. Knights, L. K. Ursell, R. Knight, J. I. Gordon, Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 339, 548-554 (2013).
56. M. R. Blanchet, S. Maltby, D. J. Haddon, H. Merkens, L. Zbytnuik, K. M. McNagny, CD34 facilitates the development of allergic asthma. Blood 110, 2005-2012 (2007).
57. D. Zamar, B. McNeney, J. Graham, elrm: Software implementing exact-like inference for logistic regression models. J. Stat. Softw. 21, 1-18 (2007).
58. M. Plummer, N. Best, K. Cowles, K. Vines, CODA: Convergence diagnosis and output analysis for MCMC. R News 6, 7-11 (2006).
59. R Development Core Team, R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, Vienna, 2014).
60. P. J. McMurdie, S. Holmes, phyloseq: An R package for reproducible interactive analysis and graphics of microbiome census data. PLOS One 8, e61217 (2013).
61. H. Wickham, ggplot2: Elegant Graphics for Data Analysis (Springer-Verlag, New York, 2009).
62. H. Wickham, The split-apply-combine strategy for data analysis. J. Stat. Softw. 40, 1-29 (2011).
63. E. Neuwirth, RColorBrewer: ColorBrewer palettes (2011).
64. J. Oksanen, F. G. Blanchet, R. Kindt, P. Legendre, P. R. Minchin, R. B. O'Hara, G. L. Simpson, P. Solymos, M. Henry, H. Stevens, H. Wagner, vegan: Community ecology package (2013).
65. K. Pollard, H. N. Gilbert, Y. Ge, S. Taylor, S. Dudoit, Multiple testing procedures: R multtest package and applications to genomics, in Bioinformatics and Computational Biology Solutions Using R and Bioconductor (Springer, New York, 2005).
66. A. Ploner, Heatplus: Heatmaps with row and/or column covariates and colored clusters (2012).
67. J. Xia, N. Psychogios, N. Young, D. S. Wishart, MetaboAnalyst: A web server for metabolomic data analysis and interpretation. Nucleic Acids Res. 37, W652-W660 (2009).
68. J. Xia, R. Mandal, I. V. Sinelnikov, D. Broadhurst, D. S. Wishart, MetaboAnalyst 2.0-A comprehensive server for metabolomic data analysis. Nucleic Acids Res. 40, W127-W133 (2012).