Prospective validation of microseminoprotein-ß added to the 4Kscore in predicting high-grade prostate cancer in an international multicentre cohort.

OBJECTIVES: To prospectively evaluate the performance of a pre-specified statistical model based on four kallikrein markers in blood (total prostate-specific antigen [PSA], free PSA, intact PSA, and human kallikrein-related peptidase 2), commercially available as the 4Kscore, in predicting Gleason Grade Group (GG) ≥2 prostate cancer at biopsy in an international multicentre study at three academic medical centres, and whether microseminoprotein-ß (MSP) adds predictive value. PATIENTS AND METHODS: A total of 984 men were prospectively enrolled at three academic centres. The primary outcome was GG ≥2 on prostate biopsy. Three pre-specified statistical models were used: a base model including PSA, age, digital rectal examination and prior negative biopsy; a model that added free PSA to the base model; and the 4Kscore. RESULTS: A total of 947 men were included in the final analysis and 273 (29%) had GG ≥2 on prostate biopsy. The base model area under the receiver operating characteristic curve of 0.775 increased to 0.802 with the addition of free PSA, and to 0.824 for the 4Kscore. Adding MSP to the 4Kscore model yielded an increase (0.014-0.019) in discrimination. In decision-curve analysis of clinical utility, the 4Kscore showed a benefit starting at a 7.5% threshold. CONCLUSION: A prospective multicentre evaluation of a pre-specified model based on four kallikrein markers (4Kscore) with the addition of MSP improves the predictive discrimination for GG ≥2 prostate cancer on biopsy and could be used to inform biopsy decision-making.

Kallikrein markers performance in pretreatment blood to predict early prostate cancer recurrence and metastasis after radical prostatectomy among very high-risk men.

BACKGROUND: To assess whether a prespecified statistical model based on the four kallikrein markers measured in blood-total, free, and intact prostate-specific antigen (PSA), together with human kallikrein-related peptidase 2 (hK2)-or any individual marker measured in pretreatment serum were associated with biochemical recurrence-free (BCR) or metastasis-free survival after radical prostatectomy (RP) in a subgroup of men with very high-risk disease. METHODS: We identified 106 men treated at Mayo Clinic from 2004 to 2008 with pathological Gleason grade group 4 to 5 or seminal vesicle invasion at RP. Univariable and multivariable Cox models were used to test the association between standard predictors (Kattan nomogram and GPSM [Gleason, PSA, seminal vesicle and margin status] score), kallikrein panel, and individual kallikrein markers with the outcomes. RESULTS: BCR and metastasis occurred in 67 and 30 patients, respectively. The median follow-up for patients who did not develop a BCR was 10.3 years (interquartile range = 8.2-11.8). In this high-risk group, neither Kattan risk, GPSM score, or the kallikrein panel model was associated with either outcome. However, after adjusting for Kattan risk and GPSM score, separately, preoperative intact PSA was associated with both outcomes while hK2 was associated with metastasis-free survival. CONCLUSIONS: Conventional risk prediction tools were poor discriminators for risk of adverse outcomes after RP (Kattan risk and GPSM risk) in patients with very high-risk disease. Further studies are needed to define the role of individual kallikrein marker forms in the blood to predict adverse prostate cancer outcomes after RP in this high-risk setting.

Prostate Health Index improves multivariable risk prediction of aggressive prostate cancer.

OBJECTIVE: To examine the use of the Prostate Health Index (PHI) as a continuous variable in multivariable risk assessment for aggressive prostate cancer in a large multicentre US study. MATERIALS AND METHODS: The study population included 728 men, with prostate-specific antigen (PSA) levels of 2-10 ng/mL and a negative digital rectal examination, enrolled in a prospective, multi-site early detection trial. The primary endpoint was aggressive prostate cancer, defined as biopsy Gleason score ≥7. First, we evaluated whether the addition of PHI improves the performance of currently available risk calculators (the Prostate Cancer Prevention Trial [PCPT] and European Randomised Study of Screening for Prostate Cancer [ERSPC] risk calculators). We also designed and internally validated a new PHI-based multivariable predictive model, and created a nomogram. RESULTS: Of 728 men undergoing biopsy, 118 (16.2%) had aggressive prostate cancer. The PHI predicted the risk of aggressive prostate cancer across the spectrum of values. Adding PHI significantly improved the predictive accuracy of the PCPT and ERSPC risk calculators for aggressive disease. A new model was created using age, previous biopsy, prostate volume, PSA and PHI, with an area under the curve of 0.746. The bootstrap-corrected model showed good calibration with observed risk for aggressive prostate cancer and had net benefit on decision-curve analysis. CONCLUSION: Using PHI as part of multivariable risk assessment leads to a significant improvement in the detection of aggressive prostate cancer, potentially reducing harms from unnecessary prostate biopsy and overdiagnosis.

Criteria for assigning laboratory measurands to models for analytical performance specifications defined in the 1st EFLM Strategic Conference.

This paper, prepared by the EFLM Task and Finish Group on Allocation of laboratory tests to different models for performance specifications (TFG-DM), is dealing with criteria for allocating measurands to the different models for analytical performance specifications (APS) recognized in the 1st EFLM Strategic Conference Consensus Statement. Model 1, based on the effect of APS on clinical outcome, is the model of choice for measurands that have a central role in the decision-making of a specific disease or clinical situation and where cut-off/decision limits are established for either diagnosing, screening or monitoring. Total cholesterol, glucose, HbA1c, serum albumin and cardiac troponins represent practical examples. Model 2 is based on components of biological variation and should be applied to measurands that do not have a central role in a specific disease or clinical situation, but where the concentration of the measurand is in a steady state. This is best achieved for measurands under strict homeostatic control in order to preserve their concentrations in the body fluid of interest, but it can also be applied to other measurands that are in a steady state in biological fluids. In this case, it is expected that the "noise" produced by the measurement procedure will not significantly alter the signal provided by the concentration of the measurand. This model especially applies to electrolytes and minerals in blood plasma (sodium, potassium, chloride, bicarbonate, calcium, magnesium, inorganic phosphate) and to creatinine, cystatin C, uric acid and total protein in plasma. Model 3, based on state-of-the-art of the measurement, should be used for all the measurands that cannot be included in models 1 or 2.

Multiple calibrator measurements improve accuracy and stability estimates of automated assays.

OBJECTIVES: The effects of combining multiple calibrations on assay accuracy (bias) and measurement of calibration stability were investigated for total triiodothyronine (TT3), vitamin B12 and luteinizing hormone (LH) using Beckman Coulter's Access 2 analyzer. METHODS: Three calibration procedures (CC1, CC2 and CC3) combined 12, 34 and 56 calibrator measurements over 1, 2, and 3 days. Bias was calculated between target values and average measured value over 3 consecutive days after calibration. Using regression analysis of calibrator measurements versus measurement date, calibration stability was determined as the maximum number of days before a calibrator measurement exceeded 5% tolerance limits. RESULTS: Competitive assays (TT3, vitamin B12) had positive time regression slopes, while sandwich assay (LH) had a negative slope. Bias values for TT3 were -2.49%, 1.49%, and -0.50% using CC1, CC2 and CC3 respectively, with calibrator stability of 32, 20, and 30 days. Bias values for vitamin B12 were 2.44%, 0.91%, and -0.50%, with calibrator stability of 4, 9, and 12 days. Bias values for LH were 2.26%, 1.44% and -0.29% with calibrator stability of >43, 39 and 36 days. Measured stability was more consistent across calibration procedures using percent change rather than difference from target: 26 days for TT3, 12 days for B12 and 31 days for LH. CONCLUSIONS: Averaging over multiple calibrations produced smaller bias, consistent with improved accuracy. Time regression slopes in percent change were unaffected by number of calibration measurements but calibrator stability measured from the target value was highly affected by the calibrator value at time zero.

The cistrome and gene signature of androgen receptor splice variants in castration resistant prostate cancer cells.

PURPOSE: Spliced variant forms of androgen receptor were recently identified in castration resistant prostate cancer cell lines and clinical samples. We identified the cistrome and gene signature of androgen receptor splice variants in castration resistant prostate cancer cell lines and determined the clinical significance of androgen receptor splice variant regulated genes. MATERIALS AND METHODS: The castration resistant prostate cancer cell line 22Rv1, which expresses full-length androgen receptor and androgen receptor splice variants endogenously, was used as the research model. We established 22Rv1-ARFL(-)/ARV(+) and 22Rv1-ARFL(-)/ARV(-) through RNA interference. Chromatin immunoprecipitation coupled with next generation sequencing and microarray techniques were used to identify the cistrome and gene expression profiles of androgen receptor splice variants in the absence of androgen. RESULTS: Androgen receptor splice variant binding sites were identified in 22Rv1-ARFL(-)/ARV(+). A gene set was regulated uniquely by androgen receptor splice variants but not by full-length androgen receptor in the absence of androgen. Integrated analysis revealed that some genes were directly modulated by androgen receptor splice variants. Unsupervised clustering analysis showed that the androgen receptor splice variant gene signature differentiated benign from malignant prostate tissue as well as localized prostate cancer from metastatic castration resistant prostate cancer specimens. Some genes that were modulated uniquely by androgen receptor splice variants also correlated with histological grade and biochemical failure. CONCLUSIONS: Androgen receptor splice variants can bind to DNA independent of full-length androgen receptor in the absence of androgen and modulate a unique set of genes that is not regulated by full-length androgen receptor. The androgen receptor splice variant gene signature correlates with disease progression. It distinguishes primary cancer from castration resistant prostate cancer specimens and benign from malignant prostate specimens.

The prostate health index selectively identifies clinically significant prostate cancer.

PURPOSE: The Prostate Health Index (phi) is a new test combining total, free and [-2]proPSA into a single score. It was recently approved by the FDA and is now commercially available in the U.S., Europe and Australia. We investigate whether phi improves specificity for detecting clinically significant prostate cancer and can help reduce prostate cancer over diagnosis. MATERIALS AND METHODS: From a multicenter prospective trial we identified 658 men age 50 years or older with prostate specific antigen 4 to 10 ng/ml and normal digital rectal examination who underwent prostate biopsy. In this population we compared the performance of prostate specific antigen, % free prostate specific antigen, [-2]proPSA and phi to predict biopsy results and, specifically, the presence of clinically significant prostate cancer using multiple criteria. RESULTS: The Prostate Health Index was significantly higher in men with Gleason 7 or greater and "Epstein significant" cancer. On receiver operating characteristic analysis phi had the highest AUC for overall prostate cancer (AUCs phi 0.708, percent free prostate specific antigen 0.648, [-2]proPSA 0.550 and prostate specific antigen 0.516), Gleason 7 or greater (AUCs phi 0.707, percent free prostate specific antigen 0.661, [-2]proPSA 0.558, prostate specific antigen 0.551) and significant prostate cancer (AUCs phi 0.698, percent free prostate specific antigen 0.654, [-2]proPSA 0.550, prostate specific antigen 0.549). At the 90% sensitivity cut point for phi (a score less than 28.6) 30.1% of patients could have been spared an unnecessary biopsy for benign disease or insignificant prostate cancer compared to 21.7% using percent free prostate specific antigen. CONCLUSIONS: The new phi test outperforms its individual components of total, free and [-2]proPSA for the identification of clinically significant prostate cancer. Phi may be useful as part of a multivariable approach to reduce prostate biopsies and over diagnosis.

Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in ß cells and mice.

BACKGROUND & AIMS: New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer. METHODS: Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls). RESULTS: Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not. CONCLUSIONS: Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in ß cells and mice.

Prospective multicenter evaluation of the Beckman Coulter Prostate Health Index using WHO calibration.

PURPOSE: Reported prostate specific antigen values may differ substantially among assays using Hybritech® or WHO standardization. The Beckman Coulter® Prostate Health Index and [-2]proPSA are newly approved serum markers associated with prostate cancer risk and aggressiveness. We studied the influence of assay standardization on these markers. MATERIALS AND METHODS: Prostate specific antigen, percent free prostate specific antigen and [-2]proPSA were measured using Hybritech calibration in 892 men from a prospective, multicenter study undergoing prostate biopsy. We calculated the Prostate Health Index using the equation, ([-2]proPSA/free prostate specific antigen) × PSA. Index performance characteristics for prostate cancer detection were then determined using recalculated WHO calibration prostate specific antigen values. RESULTS: The median Prostate Health Index was significantly higher in men with prostate cancer than in those with negative biopsies using WHO values (47.4 vs 39.8, p <0.001). The index offered improved discrimination of prostate cancer detection on biopsy (AUC 0.704) compared to percent free or total prostate specific antigen using the WHO calibration. CONCLUSIONS: The Prostate Health Index can be calculated using Hybritech or WHO standardized assays. It significantly improved prediction of the biopsy outcome over that of percent free or prostate specific antigen alone.

Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population.

PURPOSE: Patients with locally advanced prostate cancer after radical prostatectomy are candidates for secondary therapy. However, this higher risk population is heterogeneous. Many cases do not metastasize even when conservatively managed. Given the limited specificity of pathological features to predict metastasis, newer risk prediction models are needed. We report a validation study of a genomic classifier that predicts metastasis after radical prostatectomy in a high risk population. MATERIALS AND METHODS: A case-cohort design was used to sample 1,010 patients after radical prostatectomy at high risk for recurrence who were treated from 2000 to 2006. Patients had preoperative prostate specific antigen greater than 20 ng/ml, Gleason 8 or greater, pT3b or a Mayo Clinic nomogram score of 10 or greater. Patients with metastasis at diagnosis or any prior treatment for prostate cancer were excluded from analysis. A 20% random sampling created a subcohort that included all patients with metastasis. We generated 22-marker genomic classifier scores for 219 patients with available genomic data. ROC and decision curves, competing risk and weighted regression models were used to assess genomic classifier performance. RESULTS: The genomic classifier AUC was 0.79 for predicting 5-year metastasis after radical prostatectomy. Decision curves showed that the genomic classifier net benefit exceeded that of clinical only models. The genomic classifier was the predominant predictor of metastasis on multivariable analysis. The cumulative incidence of metastasis 5 years after radical prostatectomy was 2.4%, 6.0% and 22.5% in patients with low (60%), intermediate (21%) and high (19%) genomic classifier scores, respectively (p<0.001). CONCLUSIONS: Results indicate that genomic information from the primary tumor can identify patients with adverse pathological features who are most at risk for metastasis and potentially lethal prostate cancer.

Protocol and standard operating procedures for common use in a worldwide multicenter study on reference values.

The reference intervals (RIs) given in laboratory reports have an important role in aiding clinicians in interpreting test results in reference to values of healthy populations. In this report, we present a proposed protocol and standard operating procedures (SOPs) for common use in conducting multicenter RI studies on a national or international scale. The protocols and consensus on their contents were refined through discussions in recent C-RIDL meetings. The protocol describes in detail (1) the scheme and organization of the study, (2) the target population, inclusion/exclusion criteria, ethnicity, and sample size, (3) health status questionnaire, (4) target analytes, (5) blood collection, (6) sample processing and storage, (7) assays, (8) cross-check testing, (9) ethics, (10) data analyses, and (11) reporting of results. In addition, the protocol proposes the common measurement of a panel of sera when no standard materials exist for harmonization of test results. It also describes the requirements of the central laboratory, including the method of cross-check testing between the central laboratory of each country and local laboratories. This protocol and the SOPs remain largely exploratory and may require a reevaluation from the practical point of view after their implementation in the ongoing worldwide study. The paper is mainly intended to be a basis for discussion in the scientific community.

Category-specific uncertainty modeling in clinical laboratory measurement processes.

BACKGROUND: A statement of measurement uncertainty describes the quality of a clinical assay analysis result, and uncertainty models of clinical assays can be used to evaluate and optimize laboratory protocols designed to minimize the measurement uncertainty associated with an assay. In this study, we propose a methodology to lend systematic structure to the uncertainty modeling process. METHODS: Clinical laboratory assays are typically classified based on the chemical reaction involved, and therefore, based on the assay analysis methodology. We use this fact to demonstrate that uncertainty models for assays within the same category are structurally identical in all respects except for the values of certain model parameters. This is accomplished by building uncertainty models for assays belonging to two categories--substrate assays based on optical absorbance analysis of endpoint reactions, and ion selective electrode (ISE) assays based on potentiometric measurements of electromotive force. RESULTS: Uncertainty models for the substrate assays and the ISE assays are built, and for each category, a general mathematical framework for the uncertainty model is developed. The parameters of the general framework that vary from assay to assay for each category are identified and listed. CONCLUSIONS: Estimates of measurement uncertainty from the models were compared with estimates of uncertainty from quality control data from the clinical laboratory. We demonstrate that building a general modeling framework for each assay category and plugging in parameter values for each assay is sufficient to generate uncertainty models for an assay within a given category.

Utility of a panel of sera for the alignment of test results in the worldwide multicenter study on reference values.

BACKGROUND: In a planned International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) worldwide study on reference intervals (RIs), a common panel of serum samples is to be measured by laboratories from different countries, and test results are to be compared through conversion using linear regression analysis. This report presents a validation study that was conducted in collaboration with four laboratories. METHODS: A panel composed of 80 sera was prepared from healthy individuals, and 45 commonly tested analytes (general chemistry, tumor markers, and hormones) were measured on two occasions 1 week apart in each laboratory. Reduced major-axis linear regression was used to convert reference limits (LL and UL). Precision was expressed as a ratio of the standard error of converted LL or UL to the standard deviation (SD) comprising RI (approx. 1/4 of the RI width corresponding to between-individual SD). The allowable and optimal levels of error for the SD ratio (SDR) were set as ≤0.250 and ≤0.125, respectively, in analogy to the common method of setting limits for analytical bias based on between-individual SD. RESULTS: The values for the calculated SDRs depended upon the distribution patterns of test results: skewness toward higher values makes SDRLL lower and SDRUL higher. However, the CV of the regression line slope, CV(b), is less affected by skewness. The average of SDRLL and SDRUL (aveSDR) correlates closely with CV(b) (r=0.995). The aveSDRs of ≤0.25 and ≤0.125 corresponds approximately to CV(b) values of ≤11% and ≤5.5%, respectively. For all results (i.e., n=80), conversion was allowable (optimal) in 98% (89%) of the analytes, as judged by CV(b). Resampling studies using random subsets of data with a data size (n) of 70 to 20 revealed that SDRs and CV(b) gradually increase with reduction of n, especially with n ≤30. CONCLUSIONS: CV(b) is a robust estimator for judging the convertibility of reference values among laboratories, even with a skewed distribution. Assuming 40 sera to be a practical size for the panel, reference values of 89% (80%) of analytes examined were made comparable by regression analysis with the allowable (optimal) level of precision.

Defining acceptable limits for the metrological traceability of specific measurands.

Although manufacturers are compelled by the European IVD Directive, 98/79/EC, to have traceability of the values assigned to their calibrators if suitable higher order reference materials and/or procedures are available, there is still no equivalence of results for many measurands determined in clinical laboratories. The adoption of assays with metrological traceable results will have a significant impact on laboratory medicine in that results will be equivalent across different laboratories and different analytical platforms. The IFCC WG on Allowable Errors for Traceable Results has been formed to define acceptable limits for metrological traceability chains for specific measurands in order to promote the equivalence of patient results. These limits are being developed based on biological variation for the specific measurands. Preliminary investigations have shown that for some measurands, it is possible for manufacturers to assign values to assay calibrators with a measurement uncertainty that allows the laboratory enough combined uncertainty for their routine measurements. However, for other measurands, e.g., plasma sodium, current assays are too imprecise to fulfil limits based on biological variation. Although an alternative approach based on probability theory is being investigated, the most desirable approach would be for industry to improve measurement methods so that they meet clinical requirements.

Candidate serum biomarkers for prostate adenocarcinoma identified by mRNA differences in prostate tissue and verified with protein measurements in tissue and blood.

BACKGROUND: Improved tests are needed for detection and management of prostate cancer. We hypothesized that differential gene expression in prostate tissue could help identify candidate blood biomarkers for prostate cancer and that blood from men with advanced prostate disease could be used to verify the biomarkers presence in circulation. METHODS: We identified candidate markers using mRNA expression patterns from laser-capture microdissected prostate tissue and confirmed tissue expression using immunohistochemistry (IHC) for the subset of candidates having commercial antisera. We analyzed tissue extracts with tandem mass spectrometry (MS/MS) and measured blood concentrations using immunoassays and MS/MS of trypsin-digested, immunoextracted peptides. RESULTS: We selected 35 novel candidate prostate adenocarcinoma biomarkers. For all 13 markers having commercial antisera for IHC, tissue expression was confirmed; 6 showed statistical discrimination between nondiseased and malignant tissue, and only 5 were detected in tissue extracts by MS/MS. Sixteen of the 35 candidate markers were successfully assayed in blood. Four of 8 biomarkers measured by ELISA and 3 of 10 measured by targeted MS showed statistically significant increases in blood concentrations of advanced prostate cancer cases, compared with controls. CONCLUSIONS: Seven novel biomarkers identified by gene expression profiles in prostate tissue were shown to have statistically significant increased concentrations in blood from men with advanced prostate adenocarcinoma compared with controls: apolipoprotein C1, asporin, cartilage oligomeric matrix protein, chemokine (C-X-C motif) ligand 11 (CXCL11), CXCL9, coagulation factor V, and proprotein convertase subtilisin/kexin 6.

Distribution and associations of [-2]proenzyme-prostate specific antigen in community dwelling black and white men.

PURPOSE: We provide cross-sectional normative data on [-2]proenzyme-prostate specific antigen from the Olmsted County Study of Urinary Symptoms and Health Status among Men, and the Flint Men's Health Study. We also describe associations with clinical urological measures and the risk of prostate cancer diagnosis. MATERIALS AND METHODS: Measurements of [-2]proenzyme-prostate specific antigen were obtained from 420 white men from Olmsted County, Minnesota, and 328 black men from Genesee County, Michigan. Cross-sectional associations between [-2]proenzyme-prostate specific antigen and prostate enlargement/elevated prostate specific antigen were assessed. Cox proportional hazard models were used to assess associations between [-2]proenzyme-prostate specific antigen and the incident diagnosis of prostate cancer. RESULTS: Baseline [-2]proenzyme-prostate specific antigen was slightly higher in black men at a median of 6.3 pg/ml (25th, 75th percentiles 4.1, 8.9) than in white men at a median of 5.6 pg/ml (25th, 75th percentiles 3.9, 7.7, respectively, p = 0.01). Baseline [-2]proenzyme-prostate specific antigen was highly predictive of biopsy confirmed prostate cancer in the Olmsted County Study cohort. Relative to men in the [-2]proenzyme-prostate specific antigen lower quartile those in the upper quartile were at almost eightfold increased risk for prostate cancer (HR 7.8, 95% CI 2.2-27.8) after adjusting for age and baseline prostate specific antigen. CONCLUSIONS: In these cohorts of community dwelling black and white men [-2]proenzyme-prostate specific antigen was much lower than in previous studies. These data suggest that [-2]proenzyme-prostate specific antigen may help identify prostate cancer in men with serum prostate specific antigen in an indeterminate range, although the reference ranges for white and black men may differ slightly.

Benign prostate specific antigen distribution and associations with urological outcomes in community dwelling black and white men.

PURPOSE: We describe cross-sectional associations of benign prostate specific antigen with clinical urological measures and examined the risk of future urological outcomes in 2 population based cohorts of black and white men, respectively. MATERIALS AND METHODS: Two population based cohort studies were established to characterize the natural history of and risk factors for prostate disease progression in white and black male residents of Olmsted County, Minnesota, and Genesee County, Michigan, respectively. RESULTS: The benign prostate specific antigen distribution was similar in black men at a median of 32.9 pg/ml (25th, 75th percentiles 17.3, 68.0) and white men at a median of 32.2 pg/ml (25th, 75th percentiles 16.6, 68.9, respectively). However, it was much lower than in previous reports. For Olmsted County men in the upper quartile of benign prostate specific antigen there was a fifteenfold increased risk of prostate cancer (HR 14.6, 95% CI 3.1-68.6) and a twofold higher risk of treatment for benign prostatic hyperplasia (HR 2.2, 95% CI 1.2-4.2) after adjusting for age. After additional adjustment for baseline prostate specific antigen the association between benign prostate specific antigen and prostate cancer risk was attenuated but remained almost ninefold higher for men in the upper quartile of benign prostate specific antigen (HR 8.7, 95% CI 1.8-42.4). The twofold higher risk of treatment for benign prostatic hyperplasia also remained after adjusting for baseline prostate specific antigen for men in the upper benign prostate specific antigen quartile (HR 1.9, 95% CI 0.9-4.0). CONCLUSIONS: Results suggest that increased benign prostate specific antigen may help identify men with prostate cancer and those at risk for benign prostatic hyperplasia treatment.

Application of mathematical models of system uncertainty to evaluate the utility of assay calibration protocols.

BACKGROUND: Laboratory protocols used to calibrate commercial clinical chemistry systems affect test result quality. Mathematical models of system uncertainty can be developed using performance parameters provided by the manufacturer for various subsystems. These models can be used to evaluate protocols for specific laboratory operations. METHODS: A mathematical model was developed to estimate the uncertainty inherent in the Roche Diagnostics P-Modular system, and included uncertainties associated with the sample and reagent pipettes, spectrometer and the calibration process. The model was then used to evaluate various alternate calibration protocols: calibration based on mean of replicate measurements (n=1-6) and calibration based on conditional acceptance when the following quality control specimen was within one standard deviation of target. The effect of calibrator concentrations on assay measurement uncertainty was also studied, and calibrator concentrations that minimize uncertainty at a specific concentration were identified. RESULTS: The simulation model produced uncertainty estimates of 3.5% for the serum cholesterol assay and identified sample pipette (40%) and spectrometer (21%) as the largest contributors to measurement uncertainty. Each additional replicate calibrator measurements result in diminishing reductions in measurement uncertainty, with maximum reductions (19%) achieved with five replicate measurements. The conditional acceptance of calibration only when the control was within 1s resulted in an 18% reduction. CONCLUSIONS: The model can be used to evaluate the utility of laboratory protocols and establish realistic assay performance targets. The model also can help instrument manufacturers and laboratorians identify major contributors to assay measurement uncertainty, which helps improve performance in future assay systems.

Associations between longitudinal changes in serum estrogen, testosterone, and bioavailable testosterone and changes in benign urologic outcomes.

Some men have rapid increases in benign prostatic enlargement and lower urinary tract symptoms (LUTS), and it is not clear how sex steroid hormones contribute to the rates of change in these urologic outcomes. Therefore, the authors conducted a population-based cohort study of 648 men residing in Olmsted County, Minnesota, from 1990 to 2007, to examine associations between baseline sex steroid hormones, the rate of change in these hormones, and the rates of change in LUTS, maximum urinary flow rate, and prostate volume. Annual changes in hormone levels and urologic outcomes were calculated using mixed-effects regression models. Associations between hormone variables and rates of change in urologic outcomes were assessed with linear regression models. Higher baseline estradiol levels and rapid declines in estradiol over time were associated with rapid increases in LUTS and rapid decreases in maximum flow rate. Lower baseline bioavailable testosterone levels and more rapid declines in bioavailable testosterone were associated with more rapid increases in prostate volume. These results suggest that both absolute sex steroid hormone levels and the rates at which the levels change may be important in the development of urologic conditions in aging men.

A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range.

PURPOSE: Prostate specific antigen and free prostate specific antigen have limited specificity to detect clinically significant, curable prostate cancer, leading to unnecessary biopsy, and detection and treatment of some indolent tumors. Specificity to detect clinically significant prostate cancer may be improved by [-2]pro-prostate specific antigen. We evaluated [-2]pro-prostate specific antigen, free prostate specific antigen and prostate specific antigen using the formula, ([-2]pro-prostate specific antigen/free prostate specific antigen × prostate specific antigen(1/2)) to enhance specificity to detect overall and high grade prostate cancer. MATERIALS AND METHODS: We enrolled 892 men with no history of prostate cancer, normal rectal examination, prostate specific antigen 2 to 10 ng/ml and 6-core or greater prostate biopsy in a prospective multi-institutional trial. We examined the relationship of serum prostate specific antigen, free-to-total prostate specific antigen and the prostate health index with biopsy results. Primary end points were specificity and AUC using the prostate health index to detect overall and Gleason 7 or greater prostate cancer on biopsy compared with those of free-to-total prostate specific antigen. RESULTS: In the 2 to 10 ng/ml prostate specific antigen range at 80% to 95% sensitivity the specificity and AUC (0.703) of the prostate health index exceeded those of prostate specific antigen and free-to-total prostate specific antigen. An increasing prostate health index was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason score greater than or equal to 4 + 3 = 7 disease on biopsy. The AUC of the index exceeded that of free-to-total prostate specific antigen (0.724 vs 0.670) to discriminate prostate cancer with Gleason 4 or greater + 3 from lower grade disease or negative biopsy. Prostate health index results were not associated with age and prostate volume. CONCLUSIONS: The prostate health index may be useful in prostate cancer screening to decrease unnecessary biopsy in men 50 years old or older with prostate specific antigen 2 to 10 ng/ml and negative digital rectal examination with minimal loss in sensitivity.