Abstract
PURPOSE: Cxbladder (Cxb) tests combine genomic biomarkers in urine with phenotypic and clinical data to classify hematuria patients into those at low/high probability of urothelial carcinoma (UC). Cxbladder Resolve (CxbR) is designed for use after Cxb Triage (CxbT) and Detect (CxbD), where CxbT-positive tests reflex to CxbD and CxbD-positive to CxbR to identify patients at high probability of high-impact tumors (HIT; high grade Ta, Tis or T1-T3). This study validated the diagnostic performance of CxbR in identifying HIT, and validated the algorithm of Cxb tests to segregate high-impact from low-impact tumors. MATERIALS AND METHODS: CxbR was developed in 863 hematuria patients in 3 studies in United States, Australia and New Zealand. CxbR, separately and combined with other Cxb tests, was validated in a prospective, observational U.S. study in 548 hematuria patients. All UC diagnoses were confirmed by histopathology. RESULTS: In the development data set, CxbR sensitivity was 92.4% (95% CI 83.3-96.7) and specificity 93.8% (95% CI 86.8-97.2) for identifying HIT within the high priority category. During external validation, sequential Cxb tests correctly ruled out 87.6% of patients from further workup (negative predictive value 99.4%); 100% of HIT were correctly identified (specificity 96.3%), and 3 low-grade tumors were missed. In both studies, all patients with HIT were correctly assigned to prioritized evaluation. CONCLUSIONS: CxbR has high sensitivity and specificity, correctly identifying all HIT. Sequential Cxb tests accurately segregate patients with a low vs high probability of HIT, focusing resources on those patients, with a diagnostic yield 4.8-fold higher than American Urological Association guideline stratification.