title: Classification of usual interstitial pneumonia in patients with interstitial lung disease: assessment of a machine learning approach using high-dimensional transcriptional data.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease that distorts pulmonary architecture, leading to hypoxia, respiratory failure, and death. Diagnosis is difficult because other interstitial lung diseases have similar radiological and histopathological characteristics. A usual interstitial pneumonia pattern is a hallmark of idiopathic pulmonary fibrosis and is essential for its diagnosis. We aimed to develop a molecular test that distinguishes usual interstitial pneumonia from other interstitial lung diseases in surgical lung biopsy samples. The eventual goal of this research is to develop a method to diagnose idiopathic pulmonary fibrosis without the patient having to undergo surgery.
  
  
  METHODS
  We collected surgical lung biopsy samples from patients with various interstitial lung diseases at 11 hospitals in North America. Pathology diagnoses were confirmed by an expert panel. We measured RNA expression levels for 33 297 transcripts on microarrays in all samples. A classifier algorithm was trained on one set of samples and tested in a second set. We subjected a subset of samples to next-generation RNA sequencing (RNAseq) generating expression levels on 55 097 transcripts, and assessed a classifier trained on RNAseq data by cross-validation.
  
  
  RESULTS
  We took 125 surgical lung biopsies from 86 patients. 58 samples were identified by the expert panel as usual interstitial pneumonia, 23 as non-specific interstitial pneumonia, 16 as hypersensitivity pneumonitis, four as sarcoidosis, four as respiratory bronchiolitis, two as organising pneumonia, and 18 as subtypes other than usual interstitial pneumonia. The microarray classifier was trained on 77 samples and was assessed in a test set of 48 samples, for which it had a specificity of 92% (95% CI 81-100) and a sensitivity of 82% (64-95). Based on a subset of 36 samples, the RNAseq classifier had a specificity of 95% (84-100) and a sensitivity of 59% (35-82).
  
  
  CONCLUSIONS
  Our results show that the development of a genomic signature that predicts usual interstitial pneumonia is feasible. These findings are an important first step towards the development of a molecular test that could be applied to bronchoscopy samples, thus avoiding surgery in the diagnosis of idiopathic pulmonary fibrosis.
  
  
  BACKGROUND
  Veracyte.
authors.affiliation: Veracyte, South San Francisco, CA, USA.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Veracyte, South San Francisco, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Diggans
authors.affiliation: Veracyte, South San Francisco, CA, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Pankratz
authors.affiliation: Veracyte, South San Francisco, CA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Veracyte, South San Francisco, CA, USA.
authors.forename: Moraima
authors.initials: M
authors.lastname: Pagan
authors.affiliation: Veracyte, South San Francisco, CA, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Sindy
authors.affiliation: Veracyte, South San Francisco, CA, USA.
authors.forename: Ed
authors.initials: E
authors.lastname: Tom
authors.affiliation: Veracyte, South San Francisco, CA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Veracyte, South San Francisco, CA, USA.
authors.forename: Yoonha
authors.initials: Y
authors.lastname: Choi
authors.affiliation: National Jewish Health, Denver, CO, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Lynch
authors.affiliation: Vanderbilt University, Nashville, TN, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Steele
authors.affiliation: University of Michigan, Ann Arbor, MI, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Flaherty
authors.affiliation: National Jewish Health, Denver, CO, USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.affiliation: Hannibal Clinic, Hannibal, MO, USA.
authors.forename: Humam
authors.initials: H
authors.lastname: Farah
authors.affiliation: Hannibal Clinic, Hannibal, MO, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bukstein
authors.affiliation: Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico.
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, DF, Mexico.
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
authors.affiliation: University of California, San Francisco, CA, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
authors.affiliation: Inova Fairfax Hospital, Falls Church, VA, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Nathan
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Colby
authors.affiliation: University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Myers
authors.affiliation: SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: Anna-Luise A
authors.initials: AL
authors.lastname: Katzenstein
authors.affiliation: University of Washington Medical Center, Seattle, WA, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Raghu
authors.affiliation: Veracyte, South San Francisco, CA, USA. Electronic address: giulia@veracyte.com.
authors.forename: Giulia C
authors.initials: GC
authors.lastname: Kennedy
mesh_terms: D001706:Biopsy; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D054988:Idiopathic Interstitial Pneumonias / Q000175:diagnosis* / Q000473:pathology; D008168:Lung / Q000473:pathology; D000069550:Machine Learning; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity