Roger Chou, MD; John L. Gore, MD, MS; David Buckley, MD, MPH; Rongwei Fu, PhD; Katie Gustafson, MD; Jessica C. Griffin, MS; Sara Grusing, BA; Shelley Selph, MD
Disclaimer: The authors of this manuscript are responsible for its content. Statements in the manuscript should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services. The Agency for Healthcare Research and Quality retains a license to display, reproduce, and distribute the data and the report from which this manuscript was derived under the terms of the agency's contract with the author.
Financial Support: By the Agency for Healthcare Research and Quality; U.S. Department of Health and Human Services (contract HHSA290201200014I).
Disclosures: Dr. Chou reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Dr. Gore reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Dr. Fu reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0997.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Requests for Single Reprints: Roger Chou, MD, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, email@example.com.
Current Author Addresses: Drs. Chou, Buckley, Fu, Gustafson, and Selph; Ms. Griffin; and Ms. Grusing: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239.
Dr. Gore: Department of Urology, University of Washington, Box 356510, Seattle, WA 98195.
Author Contributions: Conception and design: R. Chou, J.L. Gore, D. Buckley.
Analysis and interpretation of the data: R. Chou, J.L. Gore, R. Fu, J.C. Griffin, S. Selph.
Drafting of the article: R. Chou, R. Fu, J.C. Griffin.
Critical revision of the article for important intellectual content: R. Chou, J.L. Gore.
Final approval of the article: R. Chou, J.L. Gore, D. Buckley, R. Fu, K. Gustafson, J.C. Griffin, S. Grusing, S. Selph.
Statistical expertise: R. Fu, S. Selph.
Obtaining of funding: R. Chou.
Administrative, technical, or logistic support: R. Chou, J.C. Griffin, S. Grusing.
Collection and assembly of data: R. Chou, J.L. Gore, D. Buckley, K. Gustafson, J.C. Griffin, S. Grusing.
Chou R, Gore JL, Buckley D, Fu R, Gustafson K, Griffin JC, et al. Urinary Biomarkers for Diagnosis of Bladder Cancer: A Systematic Review and Meta-analysis. Ann Intern Med. 2015;163:922-931. doi: 10.7326/M15-0997
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Published: Ann Intern Med. 2015;163(12):922-931.
Published at www.annals.org on 15 December 2015
Urinary biomarkers may be a useful alternative or adjunct to cystoscopy for diagnosis of bladder cancer.
To systematically review the evidence on the accuracy of urinary biomarkers for diagnosis of bladder cancer in adults who have signs or symptoms of the disease or are undergoing surveillance for recurrent disease.
Ovid MEDLINE (January 1990 through June 2015), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists.
57 studies that evaluated the diagnostic accuracy of quantitative or qualitative nuclear matrix protein 22 (NMP22), qualitative or quantitative bladder tumor antigen (BTA), fluorescence in situ hybridization (FISH), fluorescent immunohistochemistry (ImmunoCyt [Scimedx]), and Cxbladder (Pacific Edge Diagnostics USA) using cystoscopy and histopathology as the reference standard met inclusion criteria. Case–control studies were excluded.
Dual extraction and quality assessment of individual studies. Overall strength of evidence (SOE) was also assessed.
Across biomarkers, sensitivities ranged from 0.57 to 0.82 and specificities ranged from 0.74 to 0.88. Positive likelihood ratios ranged from 2.52 to 5.53, and negative likelihood ratios ranged from 0.21 to 0.48 (moderate SOE for quantitative NMP22, qualitative BTA, FISH, and ImmunoCyt; low SOE for others). For some biomarkers, sensitivity was higher for initial diagnosis of bladder cancer than for diagnosis of recurrence. Sensitivity increased with higher tumor stage or grade. Studies that directly compared the accuracy of quantitative NMP22 and qualitative BTA found no differences in diagnostic accuracy (moderate SOE); head-to-head studies of other biomarkers were limited. Urinary biomarkers plus cytologic evaluation were more sensitive than biomarkers alone but missed about 10% of bladder cancer cases.
Restricted to English-language studies; no search for studies published only as abstracts; statistical heterogeneity present in most analyses; few studies for qualitative NMP22, quantitative BTA, and Cxbladder; and methodological shortcomings in almost all studies.
Urinary biomarkers miss a substantial proportion of patients with bladder cancer and are subject to false-positive results in others. Accuracy is poor for low-stage and low-grade tumors.
Agency for Healthcare Research and Quality. (PROSPERO registration number: CRD42014013284)
Summary of evidence search and selection.
* Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews.
† Includes prior reports, reference lists of relevant articles, and systematic reviews.
Appendix Table 1. Biomarker Study Characteristics
Appendix Table 1 — Continued
Sensitivity and specificity of quantitative NMP22.
NMP22 = nuclear matrix protein 22; TN = true-negative; TP = true-positive.
Sensitivity and specificity of qualitative NMP22.
Sensitivity and specificity of qualitative BTA.
BTA = bladder tumor antigen; TN = true-negative; TP = true-positive.
Sensitivity and specificity of quantitative BTA.
Sensitivity and specificity of FISH.
FISH = fluorescence in situ hybridization; TN = true-negative; TP = true-positive.
Sensitivity and specificity of ImmunoCyt.
TN = true-negative; TP = true-positive.
Appendix Table 2. Test Performance of Urinary Biomarkers for Diagnosis of Bladder Cancer
Appendix Table 3. Direct (Within-Study) Comparisons of Diagnostic Accuracy of Urinary Biomarkers for Diagnosis of Bladder Cancer
Appendix Table 4. Sensitivity of Urinary Biomarkers for Bladder Cancer, by Tumor Stage and Grade
Pooled sensitivities of urinary biomarkers.
BTA = bladder tumor antigen; FISH = fluorescence in situ hybridization; NMP22 = nuclear matrix protein 22; TP = true-positive.
Pooled specificities of urinary biomarkers.
BTA = bladder tumor antigen; FISH = fluorescence in situ hybridization; NMP22 = nuclear matrix protein 22; TN = true-negative.
Table 1. Strength-of-Evidence Ratings
Table 2. Posttest Probability of Bladder Cancer With Use of Different Biomarkers
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