title: Identification of biomarkers for tuberculosis susceptibility via integrated analysis of gene expression and longitudinal clinical data.
abstract: Tuberculosis (TB) is an infectious disease caused by the bacteria Mycobacterium tuberculosis (Mtb) that affects millions of people worldwide. The majority of individuals who are exposed to Mtb develop latent infections, in which an immunological response to Mtb antigens is present but there is no clinical evidence of disease. Because currently available tests cannot differentiate latent individuals who are at low risk from those who are highly susceptible to developing active disease, there is considerable interest in the identification of diagnostic biomarkers that can predict reactivation of latent TB. We present results from our analysis of a controlled longitudinal experiment in which a group of rhesus macaques were exposed to a low dose of Mtb to study their progression to latent infection or active disease. Subsets of the animals were then euthanized at scheduled time points, and granulomas taken from their lungs were assayed for gene expression using microarrays. The clinical profiles associated with the animals following Mtb exposure revealed considerable variability, and we developed models for the disease trajectory for each subject using a Bayesian hierarchical B-spline approach. Disease severity estimates were derived from these fitted curves and included as covariates in linear models to identify genes significantly associated with disease progression. Our results demonstrate that the incorporation of clinical data increases the value of information extracted from the expression profiles and contributes to the identification of predictive biomarkers for TB susceptibility.
authors.affiliation: Mathematics Department, Tulane University New Orleans, LA, USA.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Covington, LA, USA.
authors.forename: Smriti
authors.initials: S
authors.lastname: Mehra
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Covington, LA, USA.
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Golden
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Covington, LA, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kaushal
authors.affiliation: Mathematics Department, Tulane University New Orleans, LA, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Lacey
keywords: Bayesian hierarchical B-splines; TB biomarkers; TB susceptibility; clinico-genomic models; integrated analysis
references.citation: Front Immunol. 2013 Oct 04;4:312
references.pmid: 24109479
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Biostatistics. 2008 Oct;9(4):686-99
references.pmid: 18349036
references.citation: J Infect Dis. 2013 Apr;207(7):1115-27
references.pmid: 23255564
references.citation: PLoS One. 2010 Aug 31;5(8):e12266
references.pmid: 20824205
references.citation: Mucosal Immunol. 2013 Sep;6(5):972-84
references.pmid: 23299616
references.citation: Mediterr J Hematol Infect Dis. 2013 Nov 16;5(1):e2013070
references.pmid: 24363885
references.citation: Nucleic Acids Res. 2009 Jan;37(1):1-13
references.pmid: 19033363
references.citation: Nat Rev Immunol. 2011 May;11(5):343-54
references.pmid: 21475309
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8431-6
references.pmid: 15152076
references.citation: Nat Rev Microbiol. 2009 Dec;7(12):845-55
references.pmid: 19855401
references.citation: PLoS One. 2013 Sep 16;8(9):e73230
references.pmid: 24066041
references.citation: Stat Appl Genet Mol Biol. 2004;3:Article3
references.pmid: 16646809
references.citation: J Med Primatol. 2011 Aug;40(4):233-43
references.pmid: 21781131
references.citation: Nature. 2010 Aug 19;466(7309):973-7
references.pmid: 20725040
references.citation: Tuberculosis (Edinb). 2012 Mar;92 Suppl 1:S17-20
references.pmid: 22441153
references.citation: Infect Immun. 2003 Oct;71(10):5831-44
references.pmid: 14500505
references.citation: Bioinformatics. 2006 Jul 15;22(14):e184-90
references.pmid: 16873470
references.citation: PLoS One. 2009 Dec 29;4(12):e8459
references.pmid: 20041183
references.citation: J Infect Dis. 2010 Jun 1;201(11):1743-52
references.pmid: 20394526
references.citation: J Clin Invest. 2013 Feb;123(2):712-26
references.pmid: 23281399
references.citation: PLoS One. 2011;6(10):e25803
references.pmid: 21991356
references.citation: Lancet. 2010 May 29;375(9729):1920-37
references.pmid: 20488517