False-positive Screening Tests Research Articles

Risk of Breast Cancer After False-Positive Test Results in Screening Mammography

Screening for disease in healthy people inevitably leads to some false-positive tests in disease-free individuals. Normally, women with false-positive screening tests for breast cancer are referred back to routine screening. However, the long-term outcome for women with false-positive tests is unknown. We used data from a long-standing population-based screening mammography program in Copenhagen, Denmark, to determine the long-term risk of breast cancer in women with false-positive tests. The age-adjusted relative risk (RR) of breast cancer for women with a false-positive test compared with women with only negative tests was estimated with Poisson regression, adjusted for age, and stratified by screening round and technology period. All statistical tests were two-sided. A total of 58 003 women, aged 50-69 years, were included in the analysis. Women with negative tests had an absolute cancer rate of 339/100 000 person-years at risk, whereas women with a false-positive test had an absolute rate of 583/100 000 person-years at risk. The adjusted relative risk of breast cancer after a false-positive test was 1.67 (95% confidence interval [CI] 1.45 to 1.88). The relative risk remained statistically significantly increased 6 or more years after the false-positive test, with point estimates varying between 1.58 and 2.30. When stratified by assessment technology phase and using equal follow-up time, the false-positive group from the mid 1990s had a statistically significantly higher risk of breast cancer (RR = 1.65, 95% CI = 1.22 to 2.24) than the group with negative tests, whereas the false-positive group from the early 2000s was not statistically significantly different from the group testing negative. The implementation of new assessment technology coincided with a decrease in the size of excess risk of breast cancer for women with false-positive screening results. However, it may be beneficial to actively encourage women with false-positive tests to continue to attend regular screening.

Effect of Screening on Ovarian Cancer Mortality

Screening for ovarian cancer with cancer antigen 125 (CA-125) and transvaginal ultrasound has an unknown effect on mortality. To evaluate the effect of screening for ovarian cancer on mortality in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Randomized controlled trial of 78,216 women aged 55 to 74 years assigned to undergo either annual screening (n = 39,105) or usual care (n = 39,111) at 10 screening centers across the United States between November 1993 and July 2001. Intervention The intervention group was offered annual screening with CA-125 for 6 years and transvaginal ultrasound for 4 years. Participants and their health care practitioners received the screening test results and managed evaluation of abnormal results. The usual care group was not offered annual screening with CA-125 for 6 years or transvaginal ultrasound but received their usual medical care. Participants were followed up for a maximum of 13 years (median [range], 12.4 years [10.9-13.0 years]) for cancer diagnoses and death until February 28, 2010. Mortality from ovarian cancer, including primary peritoneal and fallopian tube cancers. Secondary outcomes included ovarian cancer incidence and complications associated with screening examinations and diagnostic procedures. Ovarian cancer was diagnosed in 212 women (5.7 per 10,000 person-years) in the intervention group and 176 (4.7 per 10,000 person-years) in the usual care group (rate ratio [RR], 1.21; 95% confidence interval [CI], 0.99-1.48). There were 118 deaths caused by ovarian cancer (3.1 per 10,000 person-years) in the intervention group and 100 deaths (2.6 per 10,000 person-years) in the usual care group (mortality RR, 1.18; 95% CI, 0.82-1.71). Of 3285 women with false-positive results, 1080 underwent surgical follow-up; of whom, 163 women experienced at least 1 serious complication (15%). There were 2924 deaths due to other causes (excluding ovarian, colorectal, and lung cancer) (76.6 per 10,000 person-years) in the intervention group and 2914 deaths (76.2 per 10,000 person-years) in the usual care group (RR, 1.01; 95% CI, 0.96-1.06). Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. Diagnostic evaluation following a false-positive screening test result was associated with complications. Trial Registration clinicaltrials.gov Identifier: NCT00002540.

Modelling the cumulative risk of a false-positive screening test

Modelling the cumulative risk of a false-positive screening test

Effect of screening on ovarian cancer mortality in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer randomized screening trial.

5001 Background: Ovarian cancer is among the five leading causes of cancer death in women in the United States. Women diagnosed with early stage disease have significantly improved survival compared to women diagnosed with advanced ovarian cancer. However, the effect on mortality of screening for the early detection of ovarian cancer with CA-125 and transvaginal ultrasound (TVU) is unknown. We evaluated the effect on mortality of screening for ovarian cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Methods: PLCO is a randomized controlled trial involving 10 screening centers across the U.S. that recruited 78,216 women aged 55-74 years. Women were randomized to receive either annual screening(intervention arm; 39,105 participants) or usual care (39,111 participants) between November 1993 and July 2001. Women in the intervention arm were offered annual CA-125 testing for6 years and TVU for 4 years. Participants and their health care providers received the screening test results and managed evaluation of abnormal results. All participants were followed for up to 13 years for cancer diagnoses and death. The primary outcome was ovarian cancer mortality. Secondary outcomes included ovarian cancer incidence and complications associated with screening exams and diagnostic procedures. Results: Ovarian cancer was diagnosed in 212 women in the intervention arm and 176 in the usual care arm, for a rate ratio of 1.21 (95% Confidence Interval (CI) 0.99 – 1.48). There were 118 deaths from ovarian cancer in the intervention arm and 100 in the usual care arm, for a mortality rate ratio of 1.18 (95% CI 0.91-1.54). Of 3,285 women undergoing surgery following a false positive exam, 166 encountered at least one serious complication. Deaths from all other causes (excluding ovarian, colorectal and lung cancer) were 2,924 and 2,914 in the intervention and usual care arms, respectively. Conclusions: Screening simultaneously with CA-125 and TVU did not reduce ovarian cancer mortality in women from the general population, and there was evidence of harm from diagnostic evaluation following a false positive screening test.

Screening for Sudden Cardiac Death in the Young

Sudden cardiac death (SCD) in the young (SCDY) has a devastating impact on families, care providers, and the community and attracts significant public and media attention. Sudden cardiac death is defined as an abrupt and unexpected death due to a cardiovascular cause, typically occurring 1 hour from the onset of symptoms. Depending on the source, “young” is variably defined as those less than 25, 30, 35, or 40 years of age. Estimates of the incidence of SCDY (not including infants) vary broadly from 0.6 to 6.2 per 100 000 persons. 1–3 Sudden infant death syndrome (SIDS) may be related to SCD in some infants. Sudden infant death syndrome is defined as the sudden death of an infant 1 year of age that cannot be explained after a thorough investigation is conducted, including an autopsy, death scene evaluation, and review of the clinical history. The incidence of SIDS ranges from 50 to 100 in 100 000,4 and emerging data suggest that as many as 10% to 15% of SIDS deaths are associated with functional cardiac ion channelopathy gene variants.5 The most common diagnoses that increase risk for SCDY include hypertrophic cardiomyopathy (HCM), coronary artery anomalies of wrong sinus origin, myocarditis, arrhythmogenic right ventricular cardiomyopathy, and ion channelopathies.6 The latter category includes hereditary diseases such as the congenital long-QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome, among other less common channelopathies. These diseases are typically undetected before the SCD event. Estimated prevalence rates of these conditions range from 1 per 500 persons for HCM to 1 per 2500 for the LQTS. SCD related to these diagnoses has been documented in infancy and during competitive athletics. In addition, prescription stimulant use for treatment of attention deficit hyperactivity disorder (ADHD) has been postulated to be a trigger for SCD.7,8 Sudden cardiac death in the young is a critical public health issue. A young life cut short represents a devastating event for families, and is associated with many lost productive years. There is significant dissonance among experts in the field about the best approach to prevent SCDY in the United States. Some experts support the implementation of largescale cardiovascular screening programs in infants, in athletes, or in all children to identify at-risk individuals in an effort to prevent SCDY. Cardiovascular screening for SCDY typically involves the addition of an ECG to the current standard of care of history and physical examination. Echocardiography and genetic testing represent alternative or additional screening modalities. Observational data from the Veneto region of Italy suggest that ECG screening can successfully identify at-risk cardiovascular diseases and dramatically reduce the incidence of SCD in competitive athletes.9,10 Proponents of ECG screening in the United States suggest that it can be effective, feasible, and cost-effective. 11 Critics of ECG screening cite a lack of evidence to support its effectiveness or feasibility in the United States; lack of clinical accuracy; cost implications; and the potential clinical, financial, and emotional consequences of falsepositive screening test results. 12 Cost estimates for a national ECG screening program in the United States for

Receipt of a False Positive Test Result During Routine Screening for Ovarian Cancer: A Teachable Moment?

The term "teachable moment" (TM) has been used to describe a life transition or event which motivates an individual to change a behavior or presents an opportunity to intervene to prompt behavior change. We examined whether receipt of a false positive ovarian cancer (OC) screening result may represent a TM. 403 women participating in an OC screening program completed questionnaires assessing demographic, clinical, behavioral, and psychosocial information. The TM was operationalized as expressed interest in receiving health-related information. We hypothesized that among women receiving a false positive screening test result, those women who had experienced greater personal perceived risk for OC as well as distress would be more interested in receiving health-related information than women receiving a normal result. Analyses revealed that women receiving a false positive screening result were less interested in receiving health-related information than women receiving a normal screening result. For women receiving a false positive result, expressed interest in receipt of health-related information was only modestly related to distress and related even less to perceptions of OC risk. Our data do not support viewing a false positive OC screening result as a TM. Potential explanations for the current findings as well as recommendations for future research investigating the TM are discussed.

Pathologic findings following false-positive screening tests for ovarian cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial

Pathologic findings following false-positive screening tests for ovarian cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial

Acute Dengue Fever Causes False-Positive Reactivity in OraQuick Rapid HIV-1/2 Antibody Test

To the Editors: The OraQuick ADVANCE Rapid HIV-1/2 Antibody Test, from OraSure Technologies Inc., detects antibodies to HIV-1 and HIV-2 in 20 minutes. This immunoassay can be performed on oral fluid, fingerstick whole blood, venipuncture whole blood, and plasma specimens. The manufacturer reports a sensitivity of 99.3% (95% confidence interval: = 98.4% to 99.7%) and specificity of 99.8% (95% confidence interval: = 99.6% to 99.9%) for use of the test with oral fluid specimens.1 However, false-positive results have been detected, including in test kits close to the expiration date. One study found a false-positive rate of 1.17% in test kits used with ≤1 month remaining until expiration.2 It is noted that these results came from an older version of the OraQuick ADVANCE test kit. Accuracy of both oral and blood HIV screening tests may also be affected by concomitant tropical infections. In sub-Saharan Africa, false-positive HIV enzyme-linked immunosorbent assay (ELISA) results were associated with a diagnosis of human African trypanosomiasis,3 urinary schistosomiasis,4 uncomplicated malaria,5 and visceral leishmaniasis.6 These false-positive results in HIV antibody detection testing have been attributed to polyclonal B-cell activation and/or high concentration of rheumatoid factor-like anti-immunoglobulin antibodies seen in these infections.3-6 In Colombia, 1 study postulated that parasitic proteins similar to the reverse transcriptase could be a possible cause of false positive HIV ELISA tests in patients infected by Trypanosoma cruzi.7 Since December 2008, we have been using the OraQuick test kit on oral fluid as part of a study in the Duke University Hospital Emergency Department to determine whether rapid HIV testing can be effectively offered and accepted as a routine screening test. Recently, a false-positive result occurred in a patient presenting with acute Dengue fever. The patient had just returned to the United States after traveling abroad to the island of Guadeloupe, French West Indies, for 3 weeks where she recalled receiving multiple mosquito bites. She was admitted to Duke University Hospital after presenting to the Emergency Department with acute HIV-like symptoms of recurrent fevers, night sweats, nausea, vomiting, headache, joint aches, and rash. Her initial temperature was 37.3°C, but she reported fevers up to 39.4°C at home. The patient had an erythematous, raised, nonpruritic maculopapular rash on her lower extremities. Upon presentation, her white blood cells was low at 1600 cells × 109/L with an absolute lymphocyte count of 500. Her platelets were low at 88 × 109/L and ultimately dropped to 47 during her hospitalization. Her aspartate aminotransferase was slightly elevated at 77 U/L. In Guadeloupe, she had serologies drawn, which were positive for Dengue. Acute and convalescent serologies drawn at Duke were sent to the North Carolina State Laboratory and also confirmed to be positive. As there are no reports of malaria in Guadeloupe,8 a blood smear was not performed. Her initial and repeat OraQuick oral swabs were positive. The patient denied any recent high-risk behaviors that would place her at risk for acute HIV infection and had tested negative for HIV 2 years ago. As part of our protocol for confirmation of a preliminary reactive test, a Western Blot was performed which was indeterminate with a faint band at p24. Further workup demonstrated a negative serum HIV ELISA and an undetectable HIV viral load. Although both OraQuick tests used had expiration dates ≤1 month from time of use, it is not clear if this was a contributing factor as we were using the newer version of the kit. More likely, the diagnosis of acute Dengue contributed to the false-positive result. There is only one other report documenting HIV-1 false-positive rapid ELISA tests in patients with Dengue fever.9 In this study, false-positive HIV screening tests on sera occurred in 4 of the 9 patients with Dengue, though there was no information on the mechanism by which Dengue infection triggered the false-positive reactivity. Our findings indicate that false positives may occur with rapid HIV assays, particularly in the case of concomitant infections. This may be a greater concern in resource-poor regions where diseases such as Dengue are most prevalent and as rapid HIV tests become more widely used. Alice Mao Chidera Obi-Gwacham Tamsey Hill, DMin Catherine Ryan, MSHSA Arthur Hendricks, MDiv Mehri McKellar, MD Division of Infectious Diseases and Department of Medicine, Duke University Durham, NC

Pathologic findings following false-positive screening tests for ovarian cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial

Objective In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), ovarian cancer screening with transvaginal ultrasound (TVU) and CA-125 produced a large number of false-positive tests. We examined relationships between histopathologic diagnoses, false-positive test group, and participant and screening test characteristics. Methods The PLCO ovarian cancer screening arm included 39,105 women aged 55–74 years assigned to annual CA-125 and TVU. Histopathologic diagnoses from women with false-positive tests and subsequent surgery were reviewed in this analysis: all CA125+ ( n = 121); all CA125+/TVU+ ( n = 46); and a random sample of TVU+ ( n = 373). Demographic and ovarian cancer risk factor data were self-reported. Pathologic diagnoses were abstracted from surgical pathology reports. We compared participant characteristics and pathologic diagnoses by category of false-positive using Pearson χ 2, Fisher's exact, or Wilcoxon–Mann–Whitney tests. Results Women with a false-positive TVU were younger ( P < 0.001), heavier ( P < 0.001), and reported a higher frequency of prior hysterectomy ( P < 0.001). Serous cystadenoma, the most common benign ovarian diagnosis, was more frequent among women with TVU+ compared to CA-125+ and CA-125+/TVU+ ( P < 0.001). Benign non-ovarian findings were commonly associated with all false-positive s, although more frequently with CA-125+ than TVU+ or CA-125+/TVU+ groups ( P = 0.019). Non-ovarian cancers were diagnosed most frequently among CA-125+ ( P < 0.001). Conclusions False-positive ovarian cancer screening tests were associated with a range of histopathologic diagnoses, some of which may be related to patient and screening test characteristics. Further research into the predictors of false-positive ovarian cancer screening tests may aid efforts to reduce false-positive results.

False-positive Human Papillomavirus DNA tests in cervical screening: It is all in a definition

Aim Based on data from randomised controlled trials (RCT) on primary cervical screening, it has been reported that the problem of more frequent false-positive tests in Human Papillomavirus (HPV) DNA screening compared to cytology could be overcome. However, these reports predominantly operated with a narrow definition of a (false-)positive test. The aim of this paper was to illustrate how the narrow definition affected the measured adverse effects of HPV DNA screening compared with cytology screening. Methods In the European RCT data, we measured the impact of the narrow definition of a positive screening test on the published relative positive predictive values (PPV), an indicator of the relative frequency of false-positive screening tests. Results Using the trialists’ definitions of positive screening tests, HPV screening combined with cytology triage had relative PPVs of 0.87 (95% confidence interval (CI): 0.60–1.26) for ⩾CIN3 based on Swedish RCT data, and 0.78 (0.52–1.16) for ⩾CIN2 in the Italian Phase 1 RCT (25–34 years). These PPVs changed to 0.44 (0.30–0.64) and 0.51 (0.33–0.79), respectively, when all positive HPV or cytology screening tests were accounted for. In the Finnish RCT data, HPV screening using the cut-off point of ⩾10 pg/ml had a relative PPV of 0.27 (0.15–0.50) for ⩾CIN3, which changed to 1.84 (0.99–3.41). Conclusion The relative PPV was incorrectly estimated in six out of seven studies. In three of those six studies, the relative PPV changed significantly after inclusion of the previously erroneously excluded false-positive HPV or cytology tests.

Modelling the cumulative risk of a false-positive screening test

The goal of a screening test is to reduce morbidity and mortality through the early detection of disease; but the benefits of screening must be weighed against potential harms, such as false-positive (FP) results, which may lead to increased healthcare costs, patient anxiety, and other adverse outcomes associated with diagnostic follow-up procedures. Accurate estimation of the cumulative risk of an FP test after multiple screening rounds is important for program evaluation and goal setting, as well as informing individuals undergoing screening what they should expect from testing over time. Estimation of the cumulative FP risk is complicated by the existence of censoring and possible dependence of the censoring time on the event history. Current statistical methods for estimating the cumulative FP risk from censored data follow two distinct approaches, either conditioning on the number of screening tests observed or marginalizing over this random variable. We review these current methods, identify their limitations and possibly unrealistic assumptions, and propose simple extensions to address some of these limitations. We discuss areas where additional extensions may be useful. We illustrate methods for estimating the cumulative FP recall risk of screening mammography and investigate the appropriateness of modelling assumptions using 13 years of data collected by the Breast Cancer Surveillance Consortium (BCSC). In the BCSC data we found evidence of violations of modelling assumptions of both classes of statistical methods. The estimated risk of an FP recall after 10 screening mammograms varied between 58% and 77% depending on the approach used, with an estimate of 63% based on what we feel are the most reasonable modelling assumptions.

US Preventive Services Task Force and Breast Cancer Screening

THE US PREVENTIVE SERVICES TASK FORCE (USPSTF) was established more than 2 decades ago as an independent panel of experts in primary care and preventive care with the mandate to conduct rigorous, unbiased assessments of the scientific evidence for the effectiveness of clinical preventive services. The task force uses state-of-the-art methods and explicit criteria for assessing the available evidence and issues recommendations for prevention interventions along with the strength of evidence supporting those recommendations, thereby enabling research on prevention to be translated into clinical practice. Using their usual rigorous methods, including a commissioned systematic review of recent studies and modeling studies of various screening strategies, the USPSTF recently updated the 2002 recommendation statement on screening for breast cancer. Based on thorough evaluation of the available evidence of benefits and harms, the 2009 recommendation statement was updated as follows: the USPSTF recommended “against routine screening mammography in women aged 40 to 49 years,” but emphasized that “the decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take patient context into account, including the patient’s values regarding specific benefits and harms.” The task force also recommended biennial screening mammography for women aged 50 to 74 years, extending the recommendation beyond the 2002 statement to include women aged 70 to 74 years, but concluded that the current evidence is insufficient to assess additional benefits and harms of screening mammography for women aged 75 years and older. In addition, the task force concluded that the current evidence is insufficient to assess additional benefits and harms of clinical breast examination beyond screening mammography in women aged 40 years or older and also recommended against teaching women how to perform breast self-examination. Despite careful assessment of the science behind the updated guidelines, the USPSTF recommendation statement for breast cancer screening, particularly the recommendation regarding routine mammography screening for women aged 40 to 49 years, immediately generated controversy among physicians, disagreement from professional associations such as the American Cancer Society and the American College of Radiology, and outrage from some breast cancer survivors and advocacy groups. The term “routine” apparently was a key word meant to clarify the recommendation, but the meaning was lost or misinterpreted by many. Among other issues, there were concerns that the guidelines would result in insurers denying coverage for mammography screening for some patients and allegations that the guidelines were politically motivated, held up as an example of the health care rationing that purportedly will occur after health system reform is enacted. Perhaps the various reactions of the public and concerns about the task force can be better understood by considering that the issue of screening for breast cancer enters “the murky area between mathematics and psychology.” A person’s beliefs and behaviors do not necessarily follow scientific evidence, especially if the perception is that life is at stake. In this issue of JAMA, 4 Commentaries provide insights into important aspects of the USPSTF recommendations and the implications for physicians and patients. Woolf, a former member of the USPSTF and an author of the 2002 recommendations, describes the misperceptions about the task force and clarifies the misinterpretations of the breast cancer screening guidelines yet cautions that “the mammography controversy, now 2 decades old, is not going away.” Woloshin and Schwartz discuss the importance of understanding the benefits and harms of mammography screening for breast cancer, including false-positive screening tests and overdiagnosis, and provide a useful quantitative summary of key data points that could help foster understanding and aid in decision making about mammography screening. Murphy, a physician-scientist and breast cancer survivor, acknowledges the limitations of mammography as a screening test but emphasizes the strong desire of women to achieve an early diagnosis of breast cancer and high-

Cumulative Incidence of False-Positive Results in Repeated, Multimodal Cancer Screening

Multiple cancer screening tests have been advocated for the general population; however, clinicians and patients are not always well-informed of screening burdens. We sought to determine the cumulative risk of a false-positive screening result and the resulting risk of a diagnostic procedure for an individual participating in a multimodal cancer screening program. Data were analyzed from the intervention arm of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomized controlled trial to determine the effects of prostate, lung, colorectal, and ovarian cancer screening on disease-specific mortality. The 68,436 participants, aged 55 to 74 years, were randomized to screening or usual care. Women received serial serum tests to detect cancer antigen 125 (CA-125), transvaginal sonograms, posteroanterior-view chest radiographs, and flexible sigmoidoscopies. Men received serial chest radiographs, flexible sigmoidoscopies, digital rectal examinations, and serum prostate-specific antigen tests. Fourteen screening examinations for each sex were possible during the 3-year screening period. After 14 tests, the cumulative risk of having at least 1 false-positive screening test is 60.4% (95% CI, 59.8%-61.0%) for men, and 48.8% (95% CI, 48.1%-49.4%) for women. The cumulative risk after 14 tests of undergoing an invasive diagnostic procedure prompted by a false-positive test is 28.5% (CI, 27.8%-29.3%) for men and 22.1% (95% CI, 21.4%-22.7%) for women. For an individual in a multimodal cancer screening trial, the risk of a false-positive finding is about 50% or greater by the 14th test. Physicians should educate patients about the likelihood of false positives and resulting diagnostic interventions when counseling about cancer screening.

Reducing ovarian cancer mortality through screening: Is it possible, and can we afford it?

ObjectiveOvarian cancer is a leading cause of cancer-related deaths among women. Given the low prevalence of this disease, the effectiveness of screening strategies has not been established. We wished to estimate the clinical impact and cost-effectiveness of potential screening strategies for ovarian cancer using population-specific data. MethodsA Markov state transition model to simulate the natural history of ovarian cancer in a cohort of women age 20 to 100. Age-specific incidence and mortality rates were obtained from SEER. Base-case characteristics of a potential screening test were sensitivity 85%, specificity 95%, and cost $50. Outcome measures were mortality reduction, lifetime number of false positive screening tests, positive predictive value, years of life saved (YLS), lifetime costs in US dollars, and incremental cost-effectiveness ratios (ICER, in cost/YLS). ResultsModel-predicted lifetime risk of ovarian cancer (1.38%), lifetime risk of death from ovarian cancer (0.95%), and stage distribution (stage I-19%; stage II-7%; stage III, IV, or unstaged — 74%) closely approximated SEER data. Annual screening resulted in 43% reduction in ovarian cancer mortality, with ICER of $73,469/YLS (base case) and $36,025/YLS (high-risk population) compared to no screening. In the base case, the average lifetime number of false positive tests is 1.06. Cost-effectiveness of screening is most sensitive to test frequency, specificity and cost. ConclusionsAnnual screening for ovarian cancer has the potential to be cost effective, particularly in high-risk populations. Clinically acceptable positive predictive values are achieved if specificity exceeds 99%. Mortality reduction above 50% may not be achievable without screening intervals less than 12 months.

Benefits and Harms of Prostate-Specific Antigen Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force

Prostate cancer is the most common nonskin cancer in men in the United States, and prostate cancer screening has increased in recent years. In 2002, the U.S. Preventive Services Task Force concluded that evidence was insufficient to recommend for or against screening for prostate cancer with prostate-specific antigen (PSA) testing. To examine new evidence on benefits and harms of screening asymptomatic men for prostate cancer with PSA. English-language articles identified in PubMed and the Cochrane Library (search dates, January 2002 to July 2007), reference lists of retrieved articles, and expert suggestions. Randomized, controlled trials and meta-analyses of PSA screening and cross-sectional and cohort studies of screening harms and of the natural history of screening-detected cancer were selected to answer the following questions: Does screening for prostate cancer with PSA, as a single-threshold test or as a function of multiple tests over time, decrease morbidity or mortality? What are the magnitude and nature of harms associated with prostate cancer screening, other than overtreatment? What is the natural history of PSA-detected, nonpalpable, localized prostate cancer? Studies were reviewed, abstracted, and rated for quality by using predefined U.S. Preventive Services Task Force criteria. No good-quality randomized, controlled trials of screening for prostate cancer have been completed. In 1 cross-sectional and 2 prospective cohort studies of fair to good quality, false-positive PSA screening results caused psychological adverse effects for up to 1 year after the test. The natural history of PSA-detected prostate cancer is poorly understood. Few eligible studies were identified. Long-term adverse effects of false-positive PSA screening test results are unknown. Prostate-specific antigen screening is associated with psychological harms, and its potential benefits remain uncertain.

Screening for Chronic Obstructive Pulmonary Disease Using Spirometry: U.S. Preventive Services Task Force Recommendation Statement

New U.S. Preventive Services Task Force (USPSTF) recommendation about screening for chronic obstructive pulmonary disease (COPD) using spirometry. The USPSTF weighed the benefits (prevention of > or =1 exacerbation and improvement in respiratory-related health status measures) and harms (time and effort required by both patients and the health care system, false-positive screening tests, and adverse effects of subsequent unnecessary therapy) of COPD screening identified in the accompanying review of the evidence. The USPSTF did not consider the financial costs of spirometry testing or COPD therapies. Do not screen adults for COPD using spirometry. (Grade D recommendation).

Potential effects of decreased cervical cancer screening participation after HPV vaccination: An example from the U.S.

A concern with widespread implementation of HPV vaccination programs is that women may mistakenly decide that they do not need to be screened any longer, and thus be less likely to participate in cervical cancer screening, because they view themselves to be at low-risk of developing cervical cancer. We hypothesized that non-participation in screening among vaccinated young women in the 5 years following vaccination may result in missed CIN 2–3 cases that could progress to cancer. For instance, if 50% fewer women 26–30 years old, who were vaccinated, participate in screening in the United States over a 5 year time horizon, there would be approximately 4 women (per 1000) with missed CIN 2–3. On the other hand, non-participation will reduce the number of false-positive screening test results, as non-participation would avoid approximately 27 false-positive test results, with a decrease in follow-up procedures and costs. These results highlight the importance of educating women to ensure continued screening, as well as the need to consider new approaches to screening in the era of vaccination.

Serum PAPP-A Levels at 10–14 Weeks of Gestation Are Altered in Women After Assisted Conception

The most sensitive and specific first-trimester Down syndrome screening test employs a combination of maternal age, nuchal translucency (NT) thickness, fβhCG, and PAPP-A. First trimester NT measurements do not differ significantly between pregnancies resulting from assisted reproductive technology (ART) and those resulting from spontaneous conception, but maternal blood levels of free beta human chorionic gonadotropin (fβhCG) are higher following in vitro fertilization-embryo transfer (IVF-ET), and levels of pregnancy-associated plasma protein-A (PAPP-A) are lower. Whether or not this results in a higher rate of false positive screening test results is controversial. The investigators compared the screen-positive rates of the first trimester Down syndrome screening test in women with singleton ART pregnancies to those of women whose pregnancies resulted from spontaneous conception. Participants included 130 women who were pregnant after IVF-ET (group 1); 54 who conceived after intracytoplasmic sperm injection (ISCI; group 2); and 914 control women who conceived spontaneously. Fetal NT thickness was estimated at 10–14 weeks’ gestation. Women who conceived via ICSI were 2.8 times as more likely to be screen positive than control women. Although ovarian stimulation in group 1 and group 2 women was associated with significantly lower PAPP-A levels than were present in the control group, women who conceived via IVF-ET were not more likely to be screen positive than control women. Levels of PAPP-A declined significantly as the number of retrieved oocytes or transferred embryos increased, but the levels of other markers were not affected. When a single embryo was transferred, or when ART conception occurred without ovarian stimulation, marker levels were similar to those following spontaneous conception. Although ICSI appears to be associated with a higher rate of false positive first trimester screening test results than that in spontaneously conceived pregnancies, women who conceive by other ART methods are not at increased risk.

Urine Pregnancy Testing in Two Women with Cancer

Questions1. What are the most striking clinical and laboratory findingsin these patients?2. Why is it important to assess pregnancy status?3. What are some of the causes of false-positive serum andurine pregnancy tests?4. How would you rule out human or technical error as a possiblecause of a false-positive or -negative urine pregnancy test?5. What can cause discordances between urine and serum hCGtest results?6. What is the most likely diagnosis for these patients?7. What is the clinical significance of a false-positive urinepregnancy test?8. Are serum hCG tests unaffected by factors that can causefalse-positive test results?Possible Answers1. The most striking laboratory findings in both of thesepatients was a positive urine pregnancy test in patients who,based on their medical history (data not shown), were not ex-pected to have a positive urine hCG pregnancy test.2. Determination of pregnancy status is important in thework-up of a woman presenting with vaginal bleeding or lowerabdominal pain. Women with these symptoms should bescreened for pregnancy using a urine pregnancy test, especiallyprior to undergoing an x-ray procedure. Clinical decisions re-garding additional diagnostic testing should be based on the re-sults of the urine pregnancy test and knowledge of thoseconditions that can cause false-positive screening tests for humanchorionic gonadotropin (hCG) in urine and serum, includingthe presence of serum human anti-mouse antibodies (HAMA)and diseases (eg, colon or cervical cancer) associated with excre-tion of hCG into the urine.3. A number of preanalytical conditions, other than preg-nancy, including trophoblastic disease and certain non-trophoblastic neoplasms (eg, testicular tumors, prostate cancer,breast cancer, and lung cancer), can cause elevated serum levelsof hCG that are then excreted into the urine.

Health Perceptions in Patients Who Undergo Screening and Workup for Prostate Cancer

False-positive screening tests may induce persistent psychological distress. This study was designed to determine whether a positive screening test with negative biopsy findings for prostate cancer is associated with worsened mental health during short-term follow-up. We conducted a cross-sectional telephone survey of two groups of men approximately 2 months after testing: group 1, 109 men with an abnormal prostate-specific antigen level or digital rectal examination findings but with negative biopsy findings for prostate cancer; and group 2, 101 age-matched primary care patients with PSA screening levels in the reference range (less than 4 ng/mL). Primary outcomes included state anxiety and prostate cancer-related worry. Secondary outcomes included Medical Outcomes Study Short Form 36-item Health Survey subscales and sexual function items. Multivariate regression techniques were used to adjust for differences in baseline covariates. Group 1 patients were more worried than group 2 patients about getting prostate cancer (mean worry 3.9 versus 4.5, P = 0.0001, using a 5-point scale, with 1 indicating extreme worry and 5 no worry). Group 1 patients also perceived their risk of prostate cancer to be significantly greater than that of controls (P = 0.001). No significant differences were found across state anxiety or Medical Outcomes Study Short Form 36-item Health Survey subscales. Sexual bother was greater for group 1 patients, with 19% reporting that sexual function was a moderate to big problem compared with 10% of group 2 patients (P = 0.0001). Men with abnormal prostate cancer screening tests report increased cancer-related worry and more problems with sexual function, despite having a negative biopsy result. Effective counseling interventions are needed before prostate cancer screening and during follow-up.