A multiplex immunoassay for the non-invasive detection of bladder cancer

The Youden Index is a frequently used summary measure of the ROC (Receiver Operating Characteristic) curve. It both, measures the effectiveness of a diagnostic marker and enables the selection of an optimal threshold value (cutoff point) for the marker. In this paper we compare several estimation procedures for the Youden Index and its associated cutoff point. These are based on (1) normal assumptions; (2) transformations to normality; (3) the empirical distribution function; (4) kernel smoothing. These are compared in terms of bias and root mean square error in a large variety of scenarios by means of an extensive simulation study. We find that the empirical method which is the most commonly used has the overall worst performance. In the estimation of the Youden Index the kernel is generally the best unless the data can be well transformed to achieve normality whereas in estimation of the optimal threshold value results are more variable.

A combination of methods is used for diagnosis of bladder cancer because no single procedure detects all malignancies. Urine tests are frequently part of an evaluation, but have either been nonspecific for cancer or required specialized analysis at a laboratory. To investigate whether a point-of-care proteomic test that measures the nuclear matrix protein NMP22 in voided urine could enhance detection of malignancy in patients with risk factors or symptoms of bladder cancer. Twenty-three academic, private practice, and veterans' facilities in 10 states prospectively enrolled consecutive patients from September 2001 to May 2002. Participants included 1331 patients at elevated risk for bladder cancer due to factors such as history of smoking or symptoms including hematuria and dysuria. Patients at risk for malignancy of the urinary tract provided a voided urine sample for analysis of NMP22 protein and cytology prior to cystoscopy. The diagnosis of bladder cancer, based on cystoscopy with biopsy, was accepted as the reference standard. The performance of the NMP22 test was compared with voided urine cytology as an aid to cancer detection. Testing for the NMP22 tumor marker was conducted in a blinded manner. Bladder cancer was diagnosed in 79 patients. The NMP22 assay was positive in 44 of 79 patients with cancer (sensitivity, 55.7%; 95% confidence interval [CI], 44.1%-66.7%), whereas cytology test results were positive in 12 of 76 patients (sensitivity, 15.8%; 95% CI, 7.6%-24.0%). The specificity of the NMP22 assay was 85.7% (95% CI, 83.8%-87.6%) compared with 99.2% (95% CI, 98.7%-99.7%) for cytology. The proteomic marker detected 4 cancers that were not visualized during initial endoscopy, including 3 that were muscle invasive and 1 carcinoma in situ. The noninvasive point-of-care assay for elevated urinary NMP22 protein can increase the accuracy of cystoscopy, with test results available during the patient visit.

There is a plethora of published cancer biomarkers but the reality is that very few, if any, new circulating cancer biomarkers have entered the clinic in the last 30 years. I here try to explain this apparent oxymoron by classifying circulating cancer biomarkers into three categories: fraudulent reports (rare); true discoveries of biomarkers, that then fail to meet the demands of the clinic; and false discoveries, which represent artifactual biomarkers. I further provide examples of combinations of some known cancer biomarkers that can perform well in niche clinical applications, despite individually being not useful.