title: Development and validation of a plasma biomarker panel for discerning clinical significance of indeterminate pulmonary nodules.
abstract: BACKGROUND
  The recent findings of the National Lung Screening Trial showed 24.2% of individuals at high risk for lung cancer having one or more indeterminate nodules detected by low-dose computed tomography-based screening, 96.4% of which were eventually confirmed as false positives. These positive scans necessitate additional diagnostic procedures to establish a definitive diagnosis that adds cost and risk to the paradigm. A plasma test able to assign benign versus malignant pathology in high-risk patients would be an invaluable tool to complement low-dose computed tomography-based screening and promote its rapid implementation.
  
  
  METHODS
  We evaluated 17 biomarkers, previously shown to have value in detecting lung cancer, against a discovery cohort, comprising benign (n = 67) cases and lung cancer (n = 69) cases. A Random Forest method based analysis was used to identify the optimal biomarker panel for assigning disease status, which was then validated against a cohort from the Mayo Clinic, comprising patients with benign (n = 61) or malignant (n = 20) indeterminate lung nodules.
  
  
  RESULTS
  Our discovery efforts produced a seven-analyte plasma biomarker panel consisting of interleukin 6 (IL-6), IL-10, IL-1ra, sIL-2Rα, stromal cell-derived factor-1α+β, tumor necrosis factor α, and macrophage inflammatory protein 1 α. The sensitivity and specificity of our panel in our validation cohort is 95.0% and 23.3%, respectively. The validated negative predictive value of our panel was 93.8%.
  
  
  CONCLUSIONS
  We developed a seven-analyte plasma biomarker panel able to identify benign nodules, otherwise deemed indeterminate, with a high degree of accuracy. This panel may have clinical utility in risk-stratifying screen-detected lung nodules, decrease unnecessary follow-up imaging or invasive procedures, and potentially avoid unnecessary morbidity, mortality, and health care costs.
authors.affiliation: Department of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Daly
authors.forename: Daniel
authors.initials: D
authors.lastname: Rinewalt
authors.forename: Cristina
authors.initials: C
authors.lastname: Fhied
authors.forename: Sanjib
authors.initials: S
authors.lastname: Basu
authors.forename: Brett
authors.initials: B
authors.lastname: Mahon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Liptay
authors.forename: Edward
authors.initials: E
authors.lastname: Hong
authors.forename: Gary
authors.initials: G
authors.lastname: Chmielewski
authors.forename: Mark A
authors.initials: MA
authors.lastname: Yoder
authors.forename: Palmi N
authors.initials: PN
authors.lastname: Shah
authors.forename: Eric S
authors.initials: ES
authors.lastname: Edell
authors.forename: Fabien
authors.initials: F
authors.lastname: Maldonado
authors.forename: Aaron O
authors.initials: AO
authors.lastname: Bungum
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Borgia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D054405:Chemokine CCL3 / Q000097:blood; D054377:Chemokine CXCL12 / Q000097:blood; D016207:Cytokines / Q000097:blood*; D005260:Female; D006099:Granuloma / Q000097:blood; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood; D008175:Lung Neoplasms / Q000097:blood* / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D055613:Multiple Pulmonary Nodules / Q000097:blood* / Q000000981:diagnostic imaging / Q000473:pathology; D011014:Pneumonia / Q000097:blood; D011237:Predictive Value of Tests; D012372:ROC Curve; D011859:Radiography; D012141:Respiratory Tract Infections / Q000097:blood; D003074:Solitary Pulmonary Nodule / Q000097:blood* / Q000000981:diagnostic imaging / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D054405:Chemokine CCL3; D054377:Chemokine CXCL12; D016207:Cytokines; C507763:IL1RN protein, human; C508017:IL2RA protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10