title: Validation of a multiprotein plasma classifier to identify benign lung nodules.
abstract: BACKGROUND
  Indeterminate pulmonary nodules (IPNs) lack clinical or radiographic features of benign etiologies and often undergo invasive procedures unnecessarily, suggesting potential roles for diagnostic adjuncts using molecular biomarkers. The primary objective was to validate a multivariate classifier that identifies likely benign lung nodules by assaying plasma protein expression levels, yielding a range of probability estimates based on high negative predictive values (NPVs) for patients with 8 to 30 mm IPNs.
  
  
  METHODS
  A retrospective, multicenter, case-control study was performed using multiple reaction monitoring mass spectrometry, a classifier comprising five diagnostic and six normalization proteins, and blinded analysis of an independent validation set of plasma samples.
  
  
  RESULTS
  The classifier achieved validation on 141 lung nodule-associated plasma samples based on predefined statistical goals to optimize sensitivity. Using a population based nonsmall-cell lung cancer prevalence estimate of 23% for 8 to 30 mm IPNs, the classifier identified likely benign lung nodules with 90% negative predictive value and 26% positive predictive value, as shown in our prior work, at 92% sensitivity and 20% specificity, with the lower bound of the classifier's performance at 70% sensitivity and 48% specificity. Classifier scores for the overall cohort were statistically independent of patient age, tobacco use, nodule size, and chronic obstructive pulmonary disease diagnosis. The classifier also demonstrated incremental diagnostic performance in combination with a four-parameter clinical model.
  
  
  CONCLUSIONS
  This proteomic classifier provides a range of probability estimates for the likelihood of a benign etiology that may serve as a noninvasive, diagnostic adjunct for clinical assessments of patients with IPNs.
authors.affiliation: *Division of Pulmonary, Allergy, and Critical Care Medicine, Penn Lung Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; †Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York; ‡Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine and §Department of Environmental Medicine, New York University School of Medicine, New York University Langone Medical Center, New York, New York; ‖Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota; ¶Unité de Recherche en Pneumologie, Centre de Recherche de l'Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval; Québec, Canada; ≠Integrated Diagnostics, Seattle, Washington; **Respiratory Institute, Cleveland Clinic, Cleveland, Ohio; ††Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; ‡‡Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington; §§Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Veterans Administration Eastern Colorado Healthcare System, University of Colorado Denver School of Medicine, Denver, Colorado; ‖‖Statistics Consultant, Carlsbad, California; ¶¶Thoracic Program, Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, Tennessee; ≠≠Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville Campus, Nashville, Tennessee.
authors.forename: Anil
authors.initials: A
authors.lastname: Vachani
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.forename: David E
authors.initials: DE
authors.lastname: Midthun
authors.forename: Eric S
authors.initials: ES
authors.lastname: Edell
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Li
authors.forename: Pui-Yee
authors.initials: PY
authors.lastname: Fong
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Hunsucker
authors.forename: Clive
authors.initials: C
authors.lastname: Hayward
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mazzone
authors.forename: David K
authors.initials: DK
authors.lastname: Madtes
authors.forename: York E
authors.initials: YE
authors.lastname: Miller
authors.forename: Michael G
authors.initials: MG
authors.lastname: Walker
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.forename: Paul
authors.initials: P
authors.lastname: Kearney
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Fang
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Massion
mesh_terms: D000368:Aged; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000097:blood*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000145:classification / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D055613:Multiple Pulmonary Nodules / Q000097:blood* / Q000145:classification / Q000175:diagnosis; D040901:Proteomics / Q000379:methods*; D012372:ROC Curve; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor