title: Aptamer-based proteomic signature of intensive phase treatment response in pulmonary tuberculosis.
abstract: BACKGROUND
  New drug regimens of greater efficacy and shorter duration are needed for tuberculosis (TB) treatment. The identification of accurate, quantitative, non-culture based markers of treatment response would improve the efficiency of Phase 2 TB drug testing.
  
  
  METHODS
  In an unbiased biomarker discovery approach, we applied a highly multiplexed, aptamer-based, proteomic technology to analyze serum samples collected at baseline and after 8 weeks of treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in a Centers for Disease Control and Prevention (CDC) TB Trials Consortium Phase 2B treatment trial.
  
  
  RESULTS
  We identified protein expression differences associated with 8-week culture status, including Coagulation Factor V, SAA, XPNPEP1, PSME1, IL-11 Rα, HSP70, Galectin-8, α2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. Markers noted to have differential changes between responders and slow-responders included nectin-like protein 2, EphA1 (Ephrin type-A receptor 1), gp130, CNDP1, TGF-b RIII, MRC2, ADAM9, and CDON. A logistic regression model combining markers associated with 8-week culture status revealed an ROC curve with AUC = 0.96, sensitivity = 0.95 and specificity = 0.90. Additional markers showed differential changes between responders and slow-responders (nectin-like protein), or correlated with time-to-culture-conversion (KLRK1).
  
  
  CONCLUSIONS
  Serum proteins involved in the coagulation cascade, neutrophil activity, immunity, inflammation, and tissue remodeling were found to be associated with TB treatment response. A quantitative, non-culture based, five-marker signature predictive of 8-week culture status was identified in this pilot study.
authors.affiliation: Pulmonary and Critical Care Medicine, University of California, San Francisco at San Francisco General Hospital, 1001 Potrero Ave, 5K1, San Francisco, CA 94110, USA. Electronic address: pnahid@ucsf.edu.
authors.forename: Payam
authors.initials: P
authors.lastname: Nahid
authors.affiliation: Centers for Disease Control and Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd., NE, MS E10, Atlanta, GA 30333, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Bliven-Sizemore
authors.affiliation: Pulmonary and Critical Care Medicine, University of California, San Francisco at San Francisco General Hospital, 1001 Potrero Ave, 5K1, San Francisco, CA 94110, USA.
authors.forename: Leah G
authors.initials: LG
authors.lastname: Jarlsberg
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Campus Box 1682, Fort Collins, CO 80523, USA; SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: De Groote
authors.affiliation: Tuberculosis Research Unit, Division of Infectious Diseases, Case Western Reserve University, Cleveland, OH, USA; Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.
authors.forename: John L
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.
authors.forename: Grace
authors.initials: G
authors.lastname: Muzanyi
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Engle
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Weiner
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Janjic
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Sterling
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA. Electronic address: uochsner@somalogic.com.
authors.forename: Urs A
authors.initials: UA
authors.lastname: Ochsner
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D040901:Proteomics / Q000379:methods; D052156:SELEX Aptamer Technique / Q000379:methods; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D015415:Biomarkers
keywords: Biomarkers; Logistic regression model; Multiplex analysis; Proteomics; SOMAscan; Treatment response; Tuberculosis