title: Use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury.
abstract: OBJECTIVE
  Multiple single biomarkers have been associated with poor outcomes in acute lung injury; however, no single biomarker has sufficient discriminating power to clearly indicate prognosis. Using both derivation and replication cohorts, we tested novel risk reclassification methods to determine whether measurement of multiple plasma biomarkers at the time of acute lung injury diagnosis would improve mortality prediction in acute lung injury.
  
  
  METHODS
  Analysis of plasma biomarker levels and prospectively collected clinical data from patients enrolled in two randomized controlled trials of ventilator therapy for acute lung injury.
  
  
  METHODS
  Intensive care units of university hospitals participating in the National Institutes of Health Acute Respiratory Distress Syndrome Network.
  
  
  METHODS
  Subjects enrolled in a trial of lower tidal volume ventilation (derivation cohort) and subjects enrolled in a trial of higher vs. lower positive end-expiratory pressure (replication cohort).
  
  
  METHODS
  None.
  
  
  RESULTS
  The plasma biomarkers were intercellular adhesion molecule-1, von Willebrand factor, interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D. In the derivation cohort (n = 547), adding data on these biomarkers to clinical predictors (Acute Physiology and Chronic Health Evaluation III score) at the time of study enrollment improved the accuracy of risk prediction, as reflected by a net reclassification improvement of 22% (95% confidence interval 13% to 32%; p < .001). In the replication cohort (n = 500), the net reclassification improvement was 17% (95% confidence interval 7% to 26%; p < .001). A reduced set of three biomarkers (interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D) had nearly equivalent prognostic value in both cohorts.
  
  
  CONCLUSIONS
  When combined with clinical data, plasma biomarkers measured at the onset of acute lung injury can improve the accuracy of risk prediction. Combining three or more biomarkers may be useful for selecting a high-risk acute lung injury population for enrollment in clinical trials of novel therapies.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143-0111, USA. carolyn.calfee@ucsf.edu
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Calfee
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.forename: David V
authors.initials: DV
authors.lastname: Glidden
authors.forename: Mark D
authors.initials: MD
authors.lastname: Eisner
authors.forename: Polly E
authors.initials: PE
authors.lastname: Parsons
authors.forename: B Taylor
authors.initials: BT
authors.lastname: Thompson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D055371:Acute Lung Injury / Q000097:blood / Q000175:diagnosis* / Q000401:mortality / Q000628:therapy; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D011175:Positive-Pressure Respiration; D011237:Predictive Value of Tests; D011379:Prognosis; D037663:Pulmonary Surfactant-Associated Protein D / Q000097:blood; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D012121:Respiration, Artificial; D018570:Risk Assessment; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D015415:Biomarkers; D016209:Interleukin-8; D037663:Pulmonary Surfactant-Associated Protein D; D047888:Receptors, Tumor Necrosis Factor, Type I; D014841:von Willebrand Factor; D018799:Intercellular Adhesion Molecule-1