Open AccessA robust data-driven genomic signature for idiopathic pulmonary fibrosis with applications for translational model selection
Author(s) -
Ron Ammar,
Pitchumani Sivakumar,
Gábor Járai,
John Ryan Thompson
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0215565
Subject(s) - gene signature , idiopathic pulmonary fibrosis , transcriptome , feature selection , computational biology , pulmonary fibrosis , biomarker , microarray analysis techniques , biomarker discovery , signature (topology) , bleomycin , bioinformatics , medicine , gene expression , computer science , biology , gene , fibrosis , proteomics , lung , pathology , artificial intelligence , genetics , mathematics , geometry , chemotherapy
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease affecting ~5 million people globally. We have constructed an accurate model of IPF disease status using elastic net regularized regression on clinical gene expression data. Leveraging whole transcriptome microarray data from 230 IPF and 89 control samples from Yang et al . (2013), sourced from the Lung Tissue Research Consortium (LTRC) and National Jewish Health (NJH) cohorts, we identify an IPF gene expression signature. We performed optimal feature selection to reduce the number of transcripts required by our model to a parsimonious set of 15. This signature enables our model to accurately separate IPF patients from controls. Our model outperforms existing published models when tested with multiple independent clinical cohorts. Our study underscores the utility of elastic nets for gene signature/panel selection which can be used for the construction of a multianalyte biomarker of disease. We also filter the gene sets used for model input to construct a model reliant on secreted proteins. Using this approach, we identify the preclinical bleomycin rat model that is most congruent with human disease at day 21 post-bleomycin administration, contrasting with earlier timepoints suggested by other studies.