title: Blinded Validation of Breath Biomarkers of Lung Cancer, a Potential Ancillary to Chest CT Screening.
abstract: BACKGROUND
  Breath volatile organic compounds (VOCs) have been reported as biomarkers of lung cancer, but it is not known if biomarkers identified in one group can identify disease in a separate independent cohort. Also, it is not known if combining breath biomarkers with chest CT has the potential to improve the sensitivity and specificity of lung cancer screening.
  
  
  METHODS
  Model-building phase (unblinded): Breath VOCs were analyzed with gas chromatography mass spectrometry in 82 asymptomatic smokers having screening chest CT, 84 symptomatic high-risk subjects with a tissue diagnosis, 100 without a tissue diagnosis, and 35 healthy subjects. Multiple Monte Carlo simulations identified breath VOC mass ions with greater than random diagnostic accuracy for lung cancer, and these were combined in a multivariate predictive algorithm. Model-testing phase (blinded validation): We analyzed breath VOCs in an independent cohort of similar subjects (n = 70, 51, 75 and 19 respectively). The algorithm predicted discriminant function (DF) values in blinded replicate breath VOC samples analyzed independently at two laboratories (A and B). Outcome modeling: We modeled the expected effects of combining breath biomarkers with chest CT on the sensitivity and specificity of lung cancer screening.
  
  
  RESULTS
  Unblinded model-building phase. The algorithm identified lung cancer with sensitivity 74.0%, specificity 70.7% and C-statistic 0.78. Blinded model-testing phase: The algorithm identified lung cancer at Laboratory A with sensitivity 68.0%, specificity 68.4%, C-statistic 0.71; and at Laboratory B with sensitivity 70.1%, specificity 68.0%, C-statistic 0.70, with linear correlation between replicates (r = 0.88). In a projected outcome model, breath biomarkers increased the sensitivity, specificity, and positive and negative predictive values of chest CT for lung cancer when the tests were combined in series or parallel.
  
  
  CONCLUSIONS
  Breath VOC mass ion biomarkers identified lung cancer in a separate independent cohort, in a blinded replicated study. Combining breath biomarkers with chest CT could potentially improve the sensitivity and specificity of lung cancer screening.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00639067.
authors.affiliation: Breath Research Laboratory, Menssana Research Inc, 211 Warren St, Newark, NJ, 07103, United States of America.|Department of Medicine, New York Medical College, Valhalla, NY, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Phillips
authors.affiliation: Christiana Care Health System, Newark, DE, United States of America.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Bauer
authors.affiliation: Breath Research Laboratory, Menssana Research Inc, 211 Warren St, Newark, NJ, 07103, United States of America.
authors.forename: Renee N
authors.initials: RN
authors.lastname: Cataneo
authors.affiliation: Schmitt & Associates, 211 Warren Street, Newark, NJ, 07103, United States of America.
authors.forename: Cassie
authors.initials: C
authors.lastname: Lebauer
authors.affiliation: Breath Research Laboratory, Menssana Research Inc, 211 Warren St, Newark, NJ, 07103, United States of America.
authors.forename: Mayur
authors.initials: M
authors.lastname: Mundada
authors.affiliation: New York University Langone Medical Center, New York, NY, United States of America.
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: University of Florida Health Cancer Center at Orlando Health, Orlando, FL, United States of America.
authors.forename: Naren
authors.initials: N
authors.lastname: Ramakrishna
authors.affiliation: New York University Langone Medical Center, New York, NY, United States of America.
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.affiliation: Swedish Cancer Institute, 1101 Madison Suite 900, Seattle, WA, 98104, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Vallières
mesh_terms: D000368:Aged; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000032:analysis; D001944:Breath Tests; D015331:Cohort Studies; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D009010:Monte Carlo Method; D012680:Sensitivity and Specificity; D055549:Volatile Organic Compounds / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; D055549:Volatile Organic Compounds