Received on January 5, 2004
Accepted on February 27, 2004

Cancer Diagnostics

Assessing the Clinical Impact of Prostate-Specific Antigen Assay Variability and Nonequimolarity: Simulation Study based on the Population of the United Kingdom

¹ Cancer Research UK Epidemiology Unit, University of Oxford, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom
² Diagnostics Division, Bayer HealthCare, Bayer House, Strawberry Hill, Newbury, Berks, and Department of Clinical Biochemistry, University of Oxford, Oxford, United Kingdom
³ 19 Kerwin Drive, Dore, Sheffield, United Kingdom

^* To whom correspondence should be addressed. E-mail: andrew.roddam{at}cancer.org.uk.

Background: Prostate-specific antigen (PSA) is the most widely used serum biomarker to differentiate between malignant and benign prostate disease. Assays that measure PSA can be biased and/or nonequimolar and hence report significantly different PSA values for samples with the same nominal amount. This report investigates the effects of biased and nonequimolar assays on the decision to recommend a patient for a prostate biopsy based on age-specific PSA values.

Methods: A simulation model, calibrated to the distribution of PSA values in the United Kingdom, was developed to estimate the effects of bias, nonequimolarity, and analytical imprecision in terms of the rates of men who are recommended to have a biopsy on the basis of their assay-reported PSA values when their true PSA values are below the threshold (false positives) or vice versa (false negatives).

Results: False recommendation rates for a calibrated equimolar assay are 0.5-0.9% for analytical imprecision between 5% and 10%. Positive bias leads to significant increases in false positives and significant decreases in false negatives, whereas negative bias has the opposite effect. False-positive rates for nonequimolar assays increase from 0.5% to 13% in the worst-case scenario, whereas false-negative rates are almost always 0%.

Conclusions: Biased and nonequimolar assays have major detrimental effects on both false-negative and false-positive rates for recommending biopsy. PSA assays should therefore be calibrated to the International Standards and be unbiased and equimolar in response to minimize the likelihood of incorrect clinical decisions, which are potentially detrimental for both patient and healthcare provider.