title: Probabilistic (Bayesian) modeling of gene expression in transplant glomerulopathy.
abstract: Transplant glomerulopathy (TG) is associated with rapid decline in glomerular filtration rate and poor outcome. We used low-density arrays with a novel probabilistic analysis to characterize relationships between gene transcripts and the development of TG in allograft recipients. Retrospective review identified TG in 10.8% of 963 core biopsies from 166 patients; patients with stable function were studied for comparison. The biopsies were analyzed for expression of 87 genes related to immune function and fibrosis by using real-time PCR, and a Bayesian model was generated and validated to predict histopathology based on gene expression. A total of 57 individual genes were increased in TG compared with stable function biopsies (P < 0.05). The Bayesian analysis identified critical relationships between ICAM-1, IL-10, CCL3, CD86, VCAM-1, MMP-9, MMP-7, and LAMC2 and allograft pathology. Moreover, Bayesian models predicted TG when derived from either immune function (area under the curve [95% confidence interval] of 0.875 [0.675 to 0.999], P = 0.004) or fibrosis (area under the curve [95% confidence interval] of 0.859 [0.754 to 0.963], P < 0.001) gene networks. Critical pathways in the Bayesian models were also analyzed by using the Fisher exact test and had P values <0.005. This study demonstrates that evaluating quantitative gene expression profiles with Bayesian modeling can identify significant transcriptional associations that have the potential to support the diagnostic capability of allograft histology. This integrated approach has broad implications in the field of transplant diagnostics.
authors.affiliation: Regenerative Medicine Department, Combat Casualty Care, Naval Medical Research Center, Silver Spring, Maryland 20910, USA. eric.elster1@med.navy.mil
authors.forename: Eric A
authors.initials: EA
authors.lastname: Elster
authors.forename: Jason S
authors.initials: JS
authors.lastname: Hawksworth
authors.forename: Orlena
authors.initials: O
authors.lastname: Cheng
authors.forename: David B
authors.initials: DB
authors.lastname: Leeser
authors.forename: Michael
authors.initials: M
authors.lastname: Ring
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Tadaki
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.forename: John S
authors.initials: JS
authors.lastname: Eberhardt
authors.forename: Trevor S
authors.initials: TS
authors.lastname: Brown
authors.forename: Roslyn B
authors.initials: RB
authors.lastname: Mannon
mesh_terms: D000328:Adult; D001499:Bayes Theorem; D015870:Gene Expression; D005919:Glomerular Filtration Rate; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology* / Q000235:genetics; D007678:Kidney Glomerulus / Q000473:pathology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011336:Probability