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Original Contribution |

Operating Characteristics of Prostate-Specific Antigen in Men With an Initial PSA Level of 3.0 ng/mL or Lower FREE

Ian M. Thompson, MD; Donna Pauler Ankerst, PhD; Chen Chi, MS; M. Scott Lucia, MD; Phyllis J. Goodman, MS; John J. Crowley, PhD; Howard L. Parnes, MD; Charles A. Coltman, MD
[+] Author Affiliations

Author Affiliations: Department of Urology, University of Texas Health Science Center at San Antonio (Dr Thompson); Fred Hutchinson Cancer Research Center, Seattle, Wash (Dr Ankerst and Mss Chi and Goodman); University of Colorado, Denver (Dr Lucia); Cancer Research and Biostatistics, Seattle (Dr Crowley); National Cancer Institute, National Institutes of Health, Bethesda, Md (Dr Parnes); and Southwest Oncology Group, San Antonio (Dr Coltman).

More Author Information
JAMA. 2005;294(1):66-70. doi:10.1001/jama.294.1.66.
Text Size: A A A
Published online

Context Three fourths of US men older than 50 years have been screened with prostate-specific antigen (PSA) for prostate cancer.

Objective To estimate the receiver operating characteristic (ROC) curve for PSA.

Design, Setting, and Participants Calculation of PSA ROC curves in the placebo group of the Prostate Cancer Prevention Trial, a randomized, prospective study conducted from 1993 to 2003 at 221 US centers. Participants were 18 882 healthy men aged 55 years or older without prostate cancer and with PSA levels less than or equal to 3.0 ng/mL and normal digital rectal examination results, followed up for 7 years with annual PSA measurement and digital rectal examination. If PSA level exceeded 4.0 ng/mL or rectal examination result was abnormal, a prostate biopsy was recommended. After 7 years of study participation, an end-of-study prostate biopsy was recommended in all cancer-free men.

Main Outcome Measures Operating characteristics of PSA for prostate cancer detection, including sensitivity, specificity, and ROC curve.

Results Of 8575 men in the placebo group with at least 1 PSA measurement and digital rectal examination in the same year, 5587 (65.2%) had had at least 1 biopsy; of these, 1225 (21.9%) were diagnosed with prostate cancer. Of 1213 cancers with Gleason grade recorded, 250 (20.6%) were Gleason grade 7 or greater and 57 (4.7%) were Gleason grade 8 or greater. The areas under the ROC curve (AUC) for PSA to discriminate any prostate cancer vs no cancer, Gleason grade 7 or greater cancer vs no or lower-grade cancer, and Gleason grade 8 or greater cancer vs no or lower-grade cancer were 0.678 (95% confidence interval [CI], 0.666-0.689), 0.782 (95% CI, 0.748-0.816), and 0.827 (95% CI, 0.761-0.893), respectively (all P values <.001 for AUC vs 50%). For detecting any prostate cancer, PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4%, 52.6%, 32.2%, and 20.5%, and specificities of 38.9%, 72.5%, 86.7%, and 93.8%, respectively. Age-stratified analyses showed slightly better performance of PSA in men younger than 70 years vs those 70 years or older with AUC values of 0.699 (SD, 0.013) vs 0.663 (SD, 0.013) (P = .03).

Conclusion There is no cutpoint of PSA with simultaneous high sensitivity and high specificity for monitoring healthy men for prostate cancer, but rather a continuum of prostate cancer risk at all values of PSA.

Figures in this Article

One of the most common cancer screening activities in the United States is the measurement of prostate-specific antigen (PSA) levels for the early detection of prostate cancer. In 2001, approximately 75% of men in the United States aged 50 years and older reported that they had previously undergone PSA screening and 54% have reported regular PSA screening.1,2 Prostate cancer screening with PSA has been controversial, as no studies have proven that this strategy reduces mortality from prostate cancer.3 After almost 2 decades of PSA screening in the United States, mortality from prostate cancer has decreased, but it is unknown if the mortality reduction is due to screening or to other factors such as treatment efficacy.46 Of concern relative to a causal interpretation is that prostate cancer mortality rates have declined in countries where PSA screening is uncommon.79 In the United States, regions with different rates of prostate cancer screening and treatment have similar rates of disease-specific mortality.10

A potential explanation for these observations may be due to the characteristics of PSA measurement as a screening test. In general, prostate biopsy has not been recommended unless PSA levels exceed a threshold value, generally 4.0 ng/mL, with slightly lower values recommended recently by some authors.11,12 We have reported that as many as 15% of men with a PSA value less than 4.0 ng/mL have prostate cancer and that 15% of these cancers are high grade.13 With an understanding that the performance characteristics of a screening test play an important role in determining its efficacy and efficiency, we report the receiver operating characteristic (ROC) curve for PSA.

The Prostate Cancer Prevention Trial, conducted from 1993 to 2003 at 221 US centers, randomized 18 882 men aged 55 years or older with a normal digital rectal examination result and PSA level less than or equal to 3.0 ng/mL to receive either finasteride or placebo for 7 years.14 Measurement of PSA levels and digital rectal examination were performed annually. Measurements of PSA levels were performed in a central laboratory using the Tandem E assay (Hybritech; Beckman Coulter Inc, Fullerton, Calif) until 2000, when this was replaced with the Access assay (Beckman Coulter). A prostate biopsy with a minimum of 6 cores was recommended if PSA levels exceeded 4.0 ng/mL or the digital rectal examination result was suspicious for cancer. At the end of 7 years all participants not previously diagnosed with cancer were requested to undergo an end-of-study prostate biopsy within 90 days of the randomization anniversary date. Race was defined because of the greater impact of prostate cancer on African American men; race was self-reported by the participants using categories defined by the National Institutes of Health. All participants provided written informed consent, and the study was approved by the institutional review boards of the participating institutions.

Two groups of participants were analyzed. Verified participants were defined as those who underwent prostate biopsy and had had a PSA measurement and digital rectal examination within 1 year previous to their biopsy. For individuals with multiple biopsies the last biopsy was used; all analyses were repeated using instead the first biopsy and confirmed results. Unverified participants were defined as those without a prostate biopsy over the course of the trial; for this group, the last PSA measurement available with an accompanying digital rectal examination result within the year was used for analysis.

The operating characteristics are summarized in terms of the sensitivity and specificity for cutoff values of PSA and the calculated ROC curve for prostate cancer vs no prostate cancer. To examine the operating characteristics of PSA for detecting more-aggressive, higher-grade disease, the operating characteristics for Gleason grade 7 or greater prostate cancer vs Gleason grade less than 7 or no prostate cancer, and Gleason grade 8 or greater prostate cancer vs Gleason grade less than 8 or no prostate cancer were also calculated. The sensitivity is defined as the proportion of cases with a PSA value exceeding each cutoff value, and the specificity as the proportion of noncases with a PSA value equal to or below each cutoff value. The ROC curve is a plot of 1−specificity vs sensitivity for all cutoff values in the range of PSA levels observed. A test of the null hypothesis that the area under the ROC curve (AUC) is 50% was performed using the Wilcoxon rank sum test.

A confirmatory ROC analysis for prostate cancer vs no prostate cancer was performed by adding unverified participants to biopsy-verified participants and using a verification bias adjustment.15,16 To perform the adjustment, a Markov Chain Monte Carlo algorithm using the covariates age, family history of prostate cancer (0 = no; 1 = yes), current digital rectal examination result (0 = negative or normal; 1 = positive indicating suspicion for cancer), and PSA level was used to estimate the probability of cancer and to impute the missing disease status indicator for each of the unverified participants.17 The algorithm essentially weights the unknown disease statuses for the unverified participants by what was observed for similar verified cases. Similar ROC curves with and without verification bias adjustment indicate a lack of verification bias. The program was executed in the C programming language. P<.05 was used to determine statistical significance.

Of 9459 men randomized to the placebo group of the study, 8575 had a PSA value and digital rectal examination result available for analysis; characteristics of these participants are shown in Table 1. Of these 8575 participants, 5587 (65.2%) had at least 1 biopsy performed during the 7 years of the study, with a respective PSA and digital rectal examination result available. The participants who were verified were more likely to be older, to have a family history of prostate cancer, and to be white than those who did not undergo a biopsy (P<.001). Of the participants who underwent biopsy, 1225 (21.9%) had prostate cancer (Table 1). Of 1213 cancers with Gleason grade recorded, 250 (20.6%) were Gleason grade 7 or greater and 57 (4.7%) were Gleason grade 8 or greater.

Table Graphic Jump LocationTable 1. Characteristics of Participant Population

Prostate-specific antigen values and digital rectal examination results for placebo group participants who did and did not undergo prostate biopsy are shown in Table 2. Participants who did not undergo prostate biopsy were more likely to have PSA values less than or equal to 4.0 ng/mL and negative digital rectal examination results (P<.001).

Table Graphic Jump LocationTable 2. Prostate-Specific Antigen (PSA) Values and DRE Results Used in Calculation of the Receiver Operating Characteristic Curve

The performance characteristics of PSA for detecting prostate cancer of any grade, Gleason grade 7 or greater, and Gleason grade 8 or greater are shown in the Figure and Table 3. For detecting any grade of cancer, the ROC curve for verified participants only (AUC, 0.682; 95% CI, 0.664-0.699) is nearly identical to that corrected for verification bias (AUC, 0.678; 95% confidence interval, 0.666-0.689), so results are shown only after verification bias adjustment. Although the AUC is significantly better than 50% (P<.001), a clear-cut decision rule for prostate biopsy based on PSA values would be challenging to derive from these data. On one hand, the commonly used cutoff value of 4.1 ng/mL would have a 6.2% false-positive rate (1−specificity) but would detect only 20.5% of cancer cases (sensitivity). To improve cancer detection, the cutoff could be lowered to 1.1 ng/mL, thus detecting 83.4% of cancer cases, but would subject 61.1% of men without cancer to prostate biopsy. The recently recommended cutoff of 2.6 ng/mL would detect only 40.5% of cancer cases. Scanning the first 3 columns of Table 3 shows that there is no single cutoff that would simultaneously yield both high sensitivity and high specificity.

Figure. Receiver Operating Characteristic Curve for Prostate-Specific Antigen (PSA)
Graphic Jump Location

AUC indicates area under the receiver operating characteristic curve.

Table Graphic Jump LocationTable 3. Sensitivity and Specificity for Prostate Cancer and High-Grade Disease, by Cutpoints of Prostate-Specific Antigen (PSA) and by Age*

The operating characteristics of PSA measurement improve for detection of higher-grade disease, as shown in the Figure and Table 3. The AUCs for Gleason grade 7 or greater and Gleason grade 8 or greater cancer are 0.782 (95% confidence interval, 0.748-0.816) and 0.827 (95% confidence interval, 0.761-0.893), respectively. For each PSA cutoff value, the test is more sensitive for higher-grade disease (Table 3). The standard cutoff of 4.1 ng/mL detects 50.9% of highest-grade (Gleason grade ≥8) disease. Lowering the cutoff to 1.6 ng/mL would increase sensitivity for highest-grade disease to 90% at the expense of decreasing the specificity to 53.5%. To examine the impact of age on PSA performance, men younger than 70 years (n = 2956) were compared with men aged 70 years and older (n = 2631). For the younger than 70 years vs 70 years and older age ranges, PSA measurement performed slightly better for younger men with AUC values of 0.699 (SD, 0.013) and 0.663 (SD, 0.013), respectively (P = .03). Sensitivity and specificity for PSA measurement in these 2 age ranges are provided in Table 3. The AUC for PSA measurement in men with normal digital rectal examination results was 0.684 (SD, 0.010) vs 0.662 (SD, 0.024) for men with abnormal results (P = .38).

The Prostate Cancer Prevention Trial provides the first large-scale opportunity to evaluate the operating characteristics of PSA measurement in a prospective-screening setting. The ability to do so results from a unique aspect of the trial—the protocol recommendation for universal verification by prostate biopsy for all men at the end of the study, regardless of PSA levels and digital rectal examination findings. Previous studies have retrospectively estimated sensitivity and specificity.18 Other prospective screening studies have generally performed a prostate biopsy only in those men with PSA levels above 4.0 ng/mL and consequently have been subject to verification bias. Punglia et al16 attempted to correct for verification bias, but the conditions necessary for verification bias adjustment were not strictly satisfied since the study protocol did not require prostate biopsy in men with negative test results.

It is important to recognize the unique nature of this study population. At enrollment, all participants had PSA values of 3.0 ng/mL or less and were older than 54 years (mean age, 62 years), an age similar to that of participants in previous screening studies.19 The participants in the current trial anticipated semiannual visits and annual examinations for 7 years of study. By selecting a healthier, more compliant population, with generally low initial PSA values, these criteria could affect generalizability of the estimates of performance characteristics of PSA measurement to the general population.

The high frequency of cancer in men with PSA levels less than 4.0 ng/mL, previously reported from the Prostate Cancer Prevention Trial, implies that the use of PSA measurement for early detection of prostate cancer may result in delayed detection with the common 4.0 ng/mL cutoff.13 However, test performance may differ in men who have not had previous screening or who have clinically important disease.20 We found sensitivity to increase within the subset of higher-grade cases. Among men with Gleason grade 8 and higher, the sensitivity of the standard PSA cutoff of 4.1 ng/mL was 50.9%, considerably greater than the 20.5% sensitivity observed among all cases. By comparison, Gann et al18 found a 73% sensitivity for PSA measurement among symptomatic cancer cases diagnosed within the 4 years following their serum draw. Cases in the series by Gann et al had never undergone clinical PSA testing, whereas all participants in the current study had PSA levels less than or equal to 3.0 ng/mL and a negative digital rectal examination result at study enrollment. Because of repeated screening, cases in our series were more likely to be diagnosed at an early stage in their disease progression.

This analysis of the operating characteristics of PSA measurement may help explain several observations regarding PSA screening and trends in prostate cancer diagnosis and mortality in the United States since 1985. That many prostate cancers, including high-grade tumors, are missed at low levels of PSA could explain the discrepancy between the rate of PSA screening and the change in prostate cancer mortality over the past 15 years of intensive PSA screening. The delay in diagnosis of high-grade tumors until PSA levels exceed current threshold “normal” values could also explain why there is a 35% risk of subsequent treatment after radical prostatectomy, presumably due to disease recurrence.21 However, lowering the threshold would have 2 consequences: increased biopsy rates and the possibility of increased detection and treatment of biologically inconsequential cancers. Currently, men in the United States have a 17.3% lifetime risk of prostate cancer diagnosis, while the lifetime risk of prostate cancer death is 3%.22 An inherent property of all screening tests is that they disproportionately enhance the detection of slower-growing cancers, because more-aggressive tumors have a greater likelihood of becoming clinically apparent between screenings.23 While lowering the PSA threshold is likely to increase the detection of such aggressive cancers at an earlier stage, the unavoidable tradeoff is the increased detection of biologically inconsequential cancers.

The implications of this analysis are substantial. Prior to clinical use of biomarkers or other tests for cancer screening, properly designed validation studies are essential. A multistep process for validation is currently used by the Early Detection Research Network of the National Cancer Institute.24 While prostate cancer is not unique, it has a variable natural history, ranging from markedly aggressive to indolent. Consideration should be given to the development of biomarkers that incorporate disease prognosis. Finally, it will be a challenge to the medical community to change the long-held notion that there is a “normal” PSA level. Patients and health care professionals must be reeducated that there is a continuum of risk and no clearly defined PSA cutpoint at which to recommend biopsy. It will be the patient, in concert with his health care professional, who will ultimately have to weigh the sensitivity- specificity tradeoffs in combination with the uncertain natural history of the disease to determine whether further evaluation with a prostate biopsy is appropriate.

Corresponding Author: Ian M. Thompson, MD, Department of Urology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (thompsoni@uthscsa.edu).

Author Contributions: Drs Thompson, Ankerst, and Crowley and Mss Chi and Goodman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Thompson, Ankerst, Goodman; Parnes, Coltman.

Acquisition of data: Thompson, Lucia, Goodman, Crowley.

Analysis and interpretation of data: Ankerst, Chi, Lucia, Goodman, Crowley.

Drafting of the manuscript: Thompson, Ankerst, Coltman.

Critical revision of the manuscript for important intellectual content: Thompson, Ankerst, Chi, Lucia, Goodman, Crowley, Parnes.

Statistical analysis: Ankerst, Chi, Goodman.

Obtained funding: Coltman.

Administrative, technical, or material support: Thompson, Coltman.

Study supervision: Thompson, Ankerst, Goodman, Crowley.

Financial Disclosures: None reported.

Funding/Support: This study was supported in part by Public Health Service grants CA 37429, CA 35178, CA 45808, and CA 86402 from the National Cancer Institute.

Role of the Sponsor: The National Cancer Institute sponsored the conduct of the Prostate Cancer Prevention Trial, including collection of primary participant information (PSA measurement and analysis, pathologic evaluation, follow-up of participants, and initial data analysis), but had no role in the data analysis or the decision to publish.

Acknowledgment: We thank Ruth Etzioni, PhD, and Ross Prentice, PhD, of the Fred Hutchinson Cancer Research Center, Seattle, Wash, for their assistance with development of the manuscript.

Reprint Requests: Southwest Oncology Group Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.

Weir HK, Thun MJ, Hankey BF.  et al.  Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control.  J Natl Cancer Inst. 2003;95:1276-1299
PubMed   |  Link to Article
Sirovich BE, Schwartz LM, Woloshin S. Screening men for prostate and colorectal cancer in the United States: does practice reflect the evidence?  JAMA. 2003;289:1414-1420
PubMed   |  Link to Article
Brawley OW. Prostate cancer screening: clinical applications and challenges.  Urol Oncol. 2004;22:353-357
PubMed   |  Link to Article
Feuer EJ, Mariotto A, Merrill R. Modeling the impact of the decline in distant stage disease on prostate carcinoma mortality rates.  Cancer. 2002;95:870-880
PubMed   |  Link to Article
Clegg LX, Li FP, Hankey BF, Chu K, Edwards BK. Cancer survival among US whites and minorities: a SEER (Surveillance, Epidemiology, and End Results) Program population-based study.  Arch Intern Med. 2002;162:1985-1993
PubMed   |  Link to Article
Etzioni R, Legler JM, Feuer EJ, Merrill RM, Cronin KA, Hankey BF. Cancer surveillance series: interpreting trends in prostate cancer, III: quantifying the link between population prostate-specific antigen testing and recent declines in prostate cancer mortality.  J Natl Cancer Inst. 1999;91:1033-1039
PubMed   |  Link to Article
Oliver SE, May MT, Gunnell D. International trends in prostate-cancer mortality in the “PSA ERA.”  Int J Cancer. 2001;92:893-898
PubMed   |  Link to Article
Oliver SE, Gunnell D, Donovan JL. Comparison of trends in prostate-cancer mortality in England and Wales and the USA.  Lancet. 2000;355:1788-1789
PubMed   |  Link to Article
Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality, I: international comparisons.  BJU Int. 2002;90:162-173
PubMed   |  Link to Article
Lu-Yao G, Albertsen PC, Stanford JL, Stukel TA, Walker-Corkery ES, Barry MJ. Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut.  BMJ. 2002;325:740
PubMed   |  Link to Article
Antenor JA, Ham M, Roehl K, Nadler RB, Catalona WJ. Relationship between initial prostate specific antigen level and subsequent prostate cancer detection in a longitudinal screening study.  J Urol. 2004;172:90-93
PubMed   |  Link to Article
Krumholtz JS, Carvalhal GF, Ramos CG.  et al.  Prostate-specific antigen cutoff of 2.6 ng/mL for prostate cancer screening is associated with favorable pathologic tumor features.  Urology. 2002;60:469-473
PubMed   |  Link to Article
Thompson IM, Pauler DK, Goodman PJ.  et al.  Prevalence of prostate cancer among men with a prostate-specific antigen level <4.0 ng per milliliter.  N Engl J Med. 2004;350:2239-2246
PubMed   |  Link to Article
Thompson IM, Goodman PJ, Tangen CM.  et al.  The influence of finasteride on the development of prostate cancer.  N Engl J Med. 2003;349:211-220
PubMed   |  Link to Article
Begg CB, Greenes RA. Assessment of diagnostic tests when disease verification is subject to selection bias.  Biometrics. 1983;39:207-215
PubMed   |  Link to Article
Punglia RS, D’Amico AV, Catalona WJ, Roehl KA, Kuntz KM. Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen.  N Engl J Med. 2003;349:335-342
PubMed   |  Link to Article
Gelfand AE, Smith AF. Sampling-based approaches to calculating marginal densities.  J Am Stat Assoc. 1990;85:398-409
Link to Article
Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer.  JAMA. 1995;273:289-294
PubMed   |  Link to Article
Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen–based screening.  JAMA. 1993;270:948-954
PubMed   |  Link to Article
Etzioni R, Cha R, Feuer EJ, Davidov O. Asymptomatic incidence and duration of prostate cancer.  Am J Epidemiol. 1998;148:775-785
PubMed   |  Link to Article
Lu-Yao GL, Potosky AL, Albertsen PC, Wasson JH, Barry MJ, Wennberg JE. Follow-up prostate cancer treatments after radical prostatectomy: a population-based study.  J Natl Cancer Inst. 1996;88:166-173
PubMed   |  Link to Article
American Cancer Society.  Cancer Facts and Figures, 2004 . Atlanta, Ga: American Cancer Society; 2004. Available at: http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf. Accessibility verified May 31, 2005
Prorok PC, Kramer BS, Gohegan JK. Screening theory and study design: the basics. In: Kramer BS, Gohagan JK, Prorok PC, eds. Cancer Screening, Theory and Practice. New York, NY: Marcel Dekker Inc; 1999:29-53
Sullivan Pepe M, Etzioni R, Feng Z.  et al.  Phases of biomarker development for early detection of cancer.  J Natl Cancer Inst. 2001;93:1054-1061
PubMed   |  Link to Article

Figures

Figure. Receiver Operating Characteristic Curve for Prostate-Specific Antigen (PSA)
Graphic Jump Location

AUC indicates area under the receiver operating characteristic curve.

Tables

Table Graphic Jump LocationTable 1. Characteristics of Participant Population
Table Graphic Jump LocationTable 2. Prostate-Specific Antigen (PSA) Values and DRE Results Used in Calculation of the Receiver Operating Characteristic Curve
Table Graphic Jump LocationTable 3. Sensitivity and Specificity for Prostate Cancer and High-Grade Disease, by Cutpoints of Prostate-Specific Antigen (PSA) and by Age*

References

Weir HK, Thun MJ, Hankey BF.  et al.  Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control.  J Natl Cancer Inst. 2003;95:1276-1299
PubMed   |  Link to Article
Sirovich BE, Schwartz LM, Woloshin S. Screening men for prostate and colorectal cancer in the United States: does practice reflect the evidence?  JAMA. 2003;289:1414-1420
PubMed   |  Link to Article
Brawley OW. Prostate cancer screening: clinical applications and challenges.  Urol Oncol. 2004;22:353-357
PubMed   |  Link to Article
Feuer EJ, Mariotto A, Merrill R. Modeling the impact of the decline in distant stage disease on prostate carcinoma mortality rates.  Cancer. 2002;95:870-880
PubMed   |  Link to Article
Clegg LX, Li FP, Hankey BF, Chu K, Edwards BK. Cancer survival among US whites and minorities: a SEER (Surveillance, Epidemiology, and End Results) Program population-based study.  Arch Intern Med. 2002;162:1985-1993
PubMed   |  Link to Article
Etzioni R, Legler JM, Feuer EJ, Merrill RM, Cronin KA, Hankey BF. Cancer surveillance series: interpreting trends in prostate cancer, III: quantifying the link between population prostate-specific antigen testing and recent declines in prostate cancer mortality.  J Natl Cancer Inst. 1999;91:1033-1039
PubMed   |  Link to Article
Oliver SE, May MT, Gunnell D. International trends in prostate-cancer mortality in the “PSA ERA.”  Int J Cancer. 2001;92:893-898
PubMed   |  Link to Article
Oliver SE, Gunnell D, Donovan JL. Comparison of trends in prostate-cancer mortality in England and Wales and the USA.  Lancet. 2000;355:1788-1789
PubMed   |  Link to Article
Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality, I: international comparisons.  BJU Int. 2002;90:162-173
PubMed   |  Link to Article
Lu-Yao G, Albertsen PC, Stanford JL, Stukel TA, Walker-Corkery ES, Barry MJ. Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut.  BMJ. 2002;325:740
PubMed   |  Link to Article
Antenor JA, Ham M, Roehl K, Nadler RB, Catalona WJ. Relationship between initial prostate specific antigen level and subsequent prostate cancer detection in a longitudinal screening study.  J Urol. 2004;172:90-93
PubMed   |  Link to Article
Krumholtz JS, Carvalhal GF, Ramos CG.  et al.  Prostate-specific antigen cutoff of 2.6 ng/mL for prostate cancer screening is associated with favorable pathologic tumor features.  Urology. 2002;60:469-473
PubMed   |  Link to Article
Thompson IM, Pauler DK, Goodman PJ.  et al.  Prevalence of prostate cancer among men with a prostate-specific antigen level <4.0 ng per milliliter.  N Engl J Med. 2004;350:2239-2246
PubMed   |  Link to Article
Thompson IM, Goodman PJ, Tangen CM.  et al.  The influence of finasteride on the development of prostate cancer.  N Engl J Med. 2003;349:211-220
PubMed   |  Link to Article
Begg CB, Greenes RA. Assessment of diagnostic tests when disease verification is subject to selection bias.  Biometrics. 1983;39:207-215
PubMed   |  Link to Article
Punglia RS, D’Amico AV, Catalona WJ, Roehl KA, Kuntz KM. Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen.  N Engl J Med. 2003;349:335-342
PubMed   |  Link to Article
Gelfand AE, Smith AF. Sampling-based approaches to calculating marginal densities.  J Am Stat Assoc. 1990;85:398-409
Link to Article
Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer.  JAMA. 1995;273:289-294
PubMed   |  Link to Article
Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen–based screening.  JAMA. 1993;270:948-954
PubMed   |  Link to Article
Etzioni R, Cha R, Feuer EJ, Davidov O. Asymptomatic incidence and duration of prostate cancer.  Am J Epidemiol. 1998;148:775-785
PubMed   |  Link to Article
Lu-Yao GL, Potosky AL, Albertsen PC, Wasson JH, Barry MJ, Wennberg JE. Follow-up prostate cancer treatments after radical prostatectomy: a population-based study.  J Natl Cancer Inst. 1996;88:166-173
PubMed   |  Link to Article
American Cancer Society.  Cancer Facts and Figures, 2004 . Atlanta, Ga: American Cancer Society; 2004. Available at: http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf. Accessibility verified May 31, 2005
Prorok PC, Kramer BS, Gohegan JK. Screening theory and study design: the basics. In: Kramer BS, Gohagan JK, Prorok PC, eds. Cancer Screening, Theory and Practice. New York, NY: Marcel Dekker Inc; 1999:29-53
Sullivan Pepe M, Etzioni R, Feng Z.  et al.  Phases of biomarker development for early detection of cancer.  J Natl Cancer Inst. 2001;93:1054-1061
PubMed   |  Link to Article

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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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