title: Assessing the clinical impact of prostate-specific antigen assay variability and nonequimolarity: a simulation study based on the population of the United Kingdom.
abstract: 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 can 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.
authors.affiliation: Cancer Research UK Epidemiology Unit, University of Oxford, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom. roddam@cancer.org.uk
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roddam
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Price
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Allen
authors.forename: Anthony Milford
authors.initials: AM
authors.lastname: Ward
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015982:Bias; D001706:Biopsy; D019411:Clinical Laboratory Techniques / Q000592:standards*; D003198:Computer Simulation; D005188:False Negative Reactions; D005189:False Positive Reactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood*; D011470:Prostatic Hyperplasia / Q000097:blood / Q000175:diagnosis*; D011471:Prostatic Neoplasms / Q000097:blood / Q000175:diagnosis*; D012680:Sensitivity and Specificity; D006113:United Kingdom
chemical_list: D017430:Prostate-Specific Antigen