title: A noninvasive multianalyte urine-based diagnostic assay for urothelial cancer of the bladder in the evaluation of hematuria.
abstract: OBJECTIVE
  To test whether a noninvasive urine-based multianalyte diagnostic readout assay that uses protein and DNA biomarkers can risk stratify patients with hematuria into those who are or are not likely to have bladder cancer and those who should receive standard care.
  
  
  METHODS
  This prospective, observational, multicenter, single-assessment study was conducted between June 12, 2009, and April 15, 2011. Eligible patients presented with hematuria and as part of their evaluation underwent cystoscopy. Urine samples were analyzed for the presence of mutant FGFR3 and quantified matrix metalloproteinase 2 and the hypermethylation of TWIST1 and NID2. A patient's chance of having (positive predictive value [PPV]) or not having (negative predictive value [NPV]) cancer was determined by FGFR3 alone or by all 4 biomarkers, respectively.
  
  
  RESULTS
  Cystoscopy/biopsy diagnosed 690 of 748 patients as negative and 58 as positive for bladder cancer. Of 21 patients identified by FGFR3 as highly likely to have cancer, 20 were also positive by cystoscopy/biopsy, resulting in a PPV of 95.2% (20 of 21), with specificity of 99.9% (689 of 690). The 4-marker combination identified 395 patients as having a low likelihood of cancer. Of these, 56.2% (388 of 690) also had negative biopsy/cystoscopy findings, resulting in an NPV of 98.2% (388 of 395). In total, 416 of the 748 patients with hematuria (55.6%) were identified with extremely high NPV and PPV to have or not have bladder cancer.
  
  
  CONCLUSIONS
  This multianalyte assay accurately stratified patients with high confidence into those who likely do or do not have bladder cancer. This test was developed to enhance and not to eliminate referrals for urologic evaluation.
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN 55905, USA. karnes.r@mayo.edu
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.forename: Cecilia A
authors.initials: CA
authors.lastname: Fernandez
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Shuber
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000652:urine; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules / Q000652:urine; D019175:DNA Methylation; D005260:Female; D006417:Hematuria / Q000652:urine*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000652:urine; D008875:Middle Aged; D009687:Nuclear Proteins / Q000652:urine; D011237:Predictive Value of Tests; D011446:Prospective Studies; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000652:urine; D012680:Sensitivity and Specificity; D051879:Twist-Related Protein 1 / Q000652:urine; D016482:Urinalysis / Q000379:methods*; D001749:Urinary Bladder Neoplasms / Q000652:urine*
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; C114729:NID2 protein, human; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D020778:Matrix Metalloproteinase 2