title: External validation of a multiplex urinary protein panel for the detection of bladder cancer in a multicenter cohort.
abstract: BACKGROUND
  Because of the faltering sensitivity and/or specificity, urine-based assays currently have a limited role in the management of patients with bladder cancer. The aim of this study was to externally validate our previously reported protein biomarker panel from multiple sites in the United States and Europe.
  
  
  METHODS
  This multicenter external validation study included a total of 320 subjects (bladder cancer = 183). The 10 biomarkers (IL8, MMP9, MMP10, SERPINA1, VEGFA, ANG, CA9, APOE, SDC1, and SERPINE1) were measured using commercial ELISA assays in an external laboratory. The diagnostic performance of the biomarker panel was assessed using receiver operator curves (ROC) and descriptive statistical values.
  
  
  RESULTS
  Utilizing the combination of all 10 biomarkers, the area under the ROC for the diagnostic panel was noted to be 0.847 (95% confidence interval, 0.796-0.899), outperforming any single biomarker. The multiplex assay at optimal cutoff value achieved an overall sensitivity of 0.79, specificity of 0.79, positive prediction value of 0.73, and negative prediction value of 0.84 for bladder cancer classification. Sensitivity values of the diagnostic panel for high-grade bladder cancer, low-grade bladder cancer, muscle invasive bladder cancer, and non-muscle invasive bladder cancer were 0.81, 0.90, 0.95, and 0.77, respectively.
  
  
  CONCLUSIONS
  Urinary levels of the biomarker panel enabled discrimination of patients with bladder cancer and controls, and the levels of biomarker subsets were associated with advancing tumor grade and stage.
  
  
  CONCLUSIONS
  If proven to be reliable, urinary diagnostic biomarker assays can detect bladder cancer in a timely manner such that the patient can expect improvements in overall survival and quality of life.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida.
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, The University of Florida, Gainesville, Florida.
authors.forename: Myron
authors.initials: M
authors.lastname: Chang
authors.affiliation: Department of Biostatistics, The University of Florida, Gainesville, Florida.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida.
authors.forename: Karl X
authors.initials: KX
authors.lastname: Chai
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
authors.affiliation: Bladder Cancer Group, Proteomics Unit, Bizkaia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Carbayo
authors.affiliation: Department of Urology, University Hospital Duisburg-Essen, Essen, Germany.
authors.forename: Tibor
authors.initials: T
authors.lastname: Szarvas
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Zwarthoff
authors.affiliation: Department of Urology, University of Miami Miller School of Medicine, Miami, Florida. Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Vinata
authors.initials: V
authors.lastname: Lokeshwar
authors.affiliation: Cancer Epigenetics Group, Research Center Portuguese Oncology Institute, Porto, Portugal. Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.
authors.forename: Carmen
authors.initials: C
authors.lastname: Jeronimo
authors.affiliation: Department of Urology, Mayo Clinic Florida, Jacksonville, Florida.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Parker
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center, Orlando, Florida.
authors.forename: Shanti
authors.initials: S
authors.lastname: Ross
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Torben F
authors.initials: TF
authors.lastname: Orntoft
authors.affiliation: Department of Urology, University Hospital Duisburg-Essen, Essen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Jaeger
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Willemien
authors.initials: W
authors.lastname: Beukers
authors.affiliation: Department of Urology, University of Miami Miller School of Medicine, Miami, Florida. Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Lopez
authors.affiliation: Cancer Epigenetics Group, Research Center Portuguese Oncology Institute, Porto, Portugal. Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.affiliation: Department of Urology, Mayo Clinic Florida, Jacksonville, Florida.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Young
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center, Orlando, Florida. Nonagen Bioscience Corp., Jacksonville, Florida.
authors.forename: Virginia
authors.initials: V
authors.lastname: Urquidi
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center, Orlando, Florida. Nonagen Bioscience Corp., Jacksonville, Florida. Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida.
authors.forename: Steve
authors.initials: S
authors.lastname: Goodison
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center, Orlando, Florida. Nonagen Bioscience Corp., Jacksonville, Florida. University of Hawaii, Honolulu, Hawaii. crosser@cc.hawaii.edu.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Rosser
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000652:urine*; D015331:Cohort Studies; D005060:Europe / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000453:epidemiology / Q000473:pathology / Q000652:urine*; D015203:Reproducibility of Results; D014481:United States / Q000453:epidemiology; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology / Q000473:pathology / Q000652:urine*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor