Longitudinal Blood Transcriptomic Changes Predict Lung Function Decline in patients with Idiopathic Pulmonary Fibrosis

Rationale: Molecular markers of disease progression in idiopathic pulmonary fibrosis are needed. Objective: Derive and validate a blood transcriptomic predictor of forced vital capacity (FVC) decline. Methods: A training cohort (n=74) of IPF patients was stratified according to the presence of progressive disease, defined as ≥10% relative decline in FVC over 12 months. Baseline to 4-month within-patient changes in gene expression were correlated with categorical FVC decline. Genes predictive of FVC decline were identified by two-group comparison with false discovery rate <5% followed by logistic LASSO regression and 10-Fold Cross-Validation for gene list prioritization. Independent validation cohorts with differing transcriptome assay platforms and blood transcriptome sampling times from UChicago (n=27), UPMC (n=35), and Imperial (n=24) underwent receiver operating characteristic with area under the curve (AUC) analyses for validation. Results: A longitudinally-derived FVC-gene predictor accurately discriminated most patients with stable and progressive IPF across four independent IPF cohorts with variable transcriptomic assay platforms and sampling times. The FVC-gene predictorand demonstrated sensitivity and specificity of 74.3% and 82.4% in the combined replication cohort. The likelihood ratio, LR+ and LR- were 4.11 and 0.32, respectively. TGF-beta was the highest-ranking canonical pathway by Gene Set Enrichment Analysis. An approach using longitudinal gene expression changes approach dramatically reduced within-group variation compared to cross-sectional expression for improved prediction modeling. Conclusions: This novel FVC-gene predictor developed from short-term longitudinal gene expression changes successfully discriminates most patients with high likelihood of one-year 10% FVC decline. This tool may better reflect disease activity and prove useful for predictive enrichment of clinical trial populations. Study populations were collected from the University of Chicago Medical Center and was approved by the institutional review board (IRB#14163) and informed consent was provided by all study subjects. All patients with IPF met American Thoracic Society/European Respiratory Society (ATS/ERS) diagnosis criteria. Demographic information, clinical characteristics, and pulmonary function tests were collected from all patients with IPF. Spirometry testing, including forced vital capacity percent predicted (FVC% predicted), diffusion capacity for carbon monoxide percent predicted (DLCO % predicted) as well as lung volumes by plethysmography were obtained per ATS guidelines. The prognosis of IPF subjects was dichotomously categorized as FVC stable (FVC-S) or FVC decline (FVC-D) defined by < or ≥10% reduction in FVC% predicted from the baseline to over 2 years of follow-up. PBMC samples were analyzed.