title: The use of molecular analyses in voided urine for the assessment of patients with hematuria.
abstract: BACKGROUND
  Patients presenting with painless hematuria form a large part of the urological patient population. In many cases, especially in younger patients, the cause of hematuria is harmless. Nonetheless, hematuria could be a symptom of malignant disease and hence most patients will be subject to cystoscopy. In this study, we aimed to develop a prediction model based on methylation markers in combination with clinical variables, in order to stratify patients with high risk for bladder cancer.
  
  
  METHODS
  Patients (n=169) presenting with painless hematuria were included. 54 patients were diagnosed with bladder cancer. In the remaining 115 patients, the cause of hematuria was non-malignant. Urine samples were collected prior to cystoscopy. Urine DNA was analyzed for methylation of OSR1, SIM2, OTX1, MEIS1 and ONECUT2. Methylation percentages were calculated and were combined with clinical variables into a logistic regression model.
  
  
  RESULTS
  Logistic regression analysis based on the five methylation markers, age, gender and type of hematuria resulted in an area under the curve (AUC) of 0.88 and an optimism corrected AUC of 0.84 after internal validation by bootstrapping. Using a cut-off value of 0.307 allowed stratification of patients in a low-risk and high-risk group, resulting in a sensitivity of 82% (44/54) and a specificity of 82% (94/115). Most aggressive tumors were found in patients in the high-risk group. The addition of cytology to the prediction model, improved the AUC from 0.88 to 0.89, with a sensitivity and specificity of 85% (39/46) and 87% (80/92), retrospectively.
  
  
  CONCLUSIONS
  This newly developed prediction model could be a helpful tool in risk stratification of patients presenting with painless hematuria. Accurate risk prediction might result in less extensive examination of low risk patients and thereby, reducing patient burden and costs. Further validation in a large prospective patient cohort is necessary to prove the true clinical value of this model.
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Willemien
authors.initials: W
authors.lastname: Beukers
authors.forename: Raju
authors.initials: R
authors.lastname: Kandimalla
authors.forename: Diandra
authors.initials: D
authors.lastname: van Houwelingen
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Kovacic
authors.forename: Jie-Fen D
authors.initials: JF
authors.lastname: Chin
authors.forename: Hester F
authors.initials: HF
authors.lastname: Lingsma
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjot
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Zwarthoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D006417:Hematuria / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology / Q000652:urine*; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D015233:Models, Statistical; D015999:Multivariate Analysis; D018570:Risk Assessment; D001749:Urinary Bladder Neoplasms / Q000150:complications; D014554:Urination; D055815:Young Adult
chemical_list: D015415:Biomarkers