title: Plasma Surfactant Protein-D, Matrix Metalloproteinase-7, and Osteopontin Index Distinguishes Idiopathic Pulmonary Fibrosis from Other Idiopathic Interstitial Pneumonias.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) characterized by abnormal extracellular matrix (ECM) remodeling. We hypothesized that ECM remodeling might result in a plasma profile of proteins specific for IPF that could distinguish patients with IPF from other idiopathic ILDs.
  
  
  
  To identify biomarkers that might assist in distinguishing IPF from non-IPF ILD.
  
  
  
  We developed a panel of 35 ECM, ECM-related, and lung-specific analytes measured in plasma from 86 patients with IPF (derivation cohort) and in 63 patients with IPF (validation cohort). Comparison groups included patients with rheumatoid arthritis-associated ILD (RA-ILD; n = 33), patients with alternative idiopathic ILDs (a-ILD; n = 41), and healthy control subjects (n = 127). Univariable and multivariable logistic regression models identified biomarkers that differentiated patients with IPF from those with a-ILD. Both continuous and diagnostic threshold versions of biomarkers were considered; thresholds were chosen to maximize summed diagnostic sensitivity and specificity in univariate receiver-operating characteristic curve analysis. A diagnostic score was created from the most promising analytes.
  
  
  
  Plasma surfactant protein (SP)-D > 31 ng/ml, matrix metalloproteinase (MMP)-7 > 1.75 ng/ml, and osteopontin > 6 ng/ml each significantly distinguished patients with IPF from patients with a-ILD, both individually and in a combined index. The odds ratio for IPF when at least one analyte in the index exceeded the threshold was 4.4 (95% confidence interval, 2.0-9.7; P = 0.0003). When at least two analytes were elevated, the odds ratio for IPF increased to 5.0 (95% confidence interval, 2.2-11.5; P = 0.0002).
  
  
  
  A biomarker index of SP-D, MMP-7, and osteopontin enhanced diagnostic accuracy in patients with IPF compared with those with non-IPF ILD. Our data suggest that this biomarker index may improve diagnostic confidence in IPF.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Eric S
authors.identifier: 0000-0003-4060-8443
authors.initials: ES
authors.lastname: White
authors.affiliation: 2 Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan.
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.affiliation: 2 Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan.
authors.forename: Susan
authors.initials: S
authors.lastname: Murray
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Rachel
authors.initials: R
authors.lastname: Dyal
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Candace M
authors.initials: CM
authors.lastname: Flaherty
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Flaherty
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
authors.affiliation: 3 Center for International Health Research, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island.
authors.forename: Ling
authors.initials: L
authors.lastname: Cheng
authors.affiliation: 4 Division of Pulmonary and Critical Care and.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Doyle
authors.affiliation: 4 Division of Pulmonary and Critical Care and.
authors.forename: Julian
authors.initials: J
authors.lastname: Villalba
authors.affiliation: 5 Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts; and.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Dellaripa
authors.affiliation: 4 Division of Pulmonary and Critical Care and.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.affiliation: 3 Center for International Health Research, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Kurtis
authors.affiliation: 6 Joan and Sanford Weill Department of Internal Medicine, Weill Cornell Medical College New York, New York.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
mesh_terms: D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D054988:Idiopathic Interstitial Pneumonias / Q000097:blood; D054990:Idiopathic Pulmonary Fibrosis / Q000097:blood*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000097:blood*; D008875:Middle Aged; D053495:Osteopontin / Q000097:blood*; D037663:Pulmonary Surfactant-Associated Protein D / Q000097:blood*; D012372:ROC Curve; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D037663:Pulmonary Surfactant-Associated Protein D; D053495:Osteopontin; D020783:Matrix Metalloproteinase 7
keywords: biomarker; fibrosis; plasma