title: Validation study of a noninvasive urine test for diagnosis and prognosis assessment of bladder cancer: evidence for improved models.
abstract: OBJECTIVE
  We validated the performance of our previously reported test for bladder cancer based on urine gene expression patterns using an independent cohort. We also ascertained whether alternative models could achieve better accuracy.
  
  
  METHODS
  Gene expression patterns of the previously reported 48 genes, including the 12 + 2 genes of the signature, were analyzed by TaqMan® arrays in an independent set of 207 urine samples. We pooled all samples analyzed to date to obtain a larger training set of 404 and used it to search for putative improved new models.
  
  
  RESULTS
  Our 12 + 2 gene expression signature had overall 80% sensitivity with 86% specificity (AUC 0.914) to discriminate between bladder cancer and control samples. It had 75% sensitivity and 75% specificity (AUC 0.83) to predict tumor aggressiveness in the validation set of urine samples. After grouping all samples 3 new signatures for diagnosis containing 2, 5 and 10 genes, respectively, and 1 containing 6 genes for prognosis were designed. Diagnostic performance of the 2, 5, 10 and 12-gene signatures was maintained or improved in the enlarged sample set (AUC 0.913, 0.941, 0.949 and 0.944, respectively). Performance to predict aggressiveness was also improved in the 14 and 6-gene signatures (AUC 0.855 and 0.906, respectively).
  
  
  CONCLUSIONS
  This validation study confirms the accuracy of the 12 + 2 gene signature as a noninvasive tool for assessing bladder cancer. We present improved models with fewer genes that must be validated in future studies.
authors.affiliation: Laboratory and Department of Urology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain. Electronic address: lmengual@clinic.ub.es.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Mengual
authors.affiliation: Laboratory and Department of Urology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Ribal
authors.affiliation: Plataforma de Bioinformática, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lozano
authors.affiliation: Laboratory and Department of Urology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Ingelmo-Torres
authors.affiliation: Laboratory and Department of Urology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Moisés
authors.initials: M
authors.lastname: Burset
authors.affiliation: Pathology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Pedro Luís
authors.initials: PL
authors.lastname: Fernández
authors.affiliation: Laboratory and Department of Urology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcaraz
mesh_terms: D014408:Biomarkers, Tumor / Q000652:urine*; D006801:Humans; D011379:Prognosis; D059467:Transcriptome; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000652:urine
chemical_list: D014408:Biomarkers, Tumor
keywords: CIS; Cq; HG; LG; LOOCV; MIBC; NMIBC; PCR; SN; SP; UCC; biological markers; carcinoma; carcinoma in situ; cycle quantification; gene expression; high grade; leave-one-out cross validation; low grade; muscle invasive bladder cancer; nonMIBC; polymerase chain reaction; sensitivity; specificity; urinary bladder; urothelial cell carcinoma; urothelium