Vic Hasselblad

Accuracy of the Papanicolaou Test in Screening for and Follow-up of Cervical Cytologic Abnormalities: A Systematic Review

Since the implementation of widespread screening with the Papanicolaou (Pap) test, rates of cervical cancer in the United States have decreased from 14.2 per 100 000 in 1973 to 7.8 per 100 000 in 1994. Nevertheless, cervical cancer is still the ninth-leading cause of cancer deaths among U.S. women (1). Most of these deaths occur in women who have never had a Pap test, but some occur in women who recently received negative test results. Approximately two thirds of false-negative results are caused by sampling error, and the rest are caused by detection error. Sampling error occurs when abnormal cells are not collected or are not transferred to the Pap slide, and detection error occurs when abnormal cells on the Pap slide are missed or misinterpreted. The most common sampling error is lack of cells from the cervical transformation zone. To reduce sampling error, an endocervical cytobrush and a spatula can be used instead of a cotton swab. However, a recent meta-analysis found that the Pap test did not differ in sensitivity or specificity when different sampling devices were used (2). The Food and Drug Administration (FDA) has approved another potential solution: liquid-based monolayer preparation (ThinPrep, Cytyc Corp., Boxborough, Massachusetts). With this technique, the sample is collected as in the conventional Pap test, but cells are then placed in a fixative solution. The cells are dispersed, collected onto a filter, and transferred to a microscopic slide for interpretation. Because samples are fixed immediately after collection, fewer cellular morphologic artifacts occur. Fewer cells on the slide are obscured because the process reduces the amounts of other sampled material, such as blood and mucus, and deposits cells on the slide in a monolayer. To reduce detection error, some researchers advocate rescreening slides initially reported to be normal. The Clinical Laboratory Improvement Amendments of 1988 mandate rescreening of a 10% random sample of normal slides as a quality assurance measure. Rescreening can also be performed on a higher proportion of slides by using computerized technologies. The FDA has approved two such systems, one that is algorithm-based (AutoPap QC System, TriPath Imaging, Inc., Redmond, Washington), and one that uses neural networks (PAPNET, Neuromedical Systems, Inc., Suffern, New York). PAPNET uses neural network computerized imaging of Papanicolaou smear slides to identify cells or clusters of cells that require review; it then displays up to 128 images per slide that are likely to contain abnormalities. A cytotechnologist reviews these images and decides whether to review the actual slide using light microscopy. AutoPap uses its algorithm-based decision-making technology to identify slides that exceed a certain threshold for the likelihood of abnormal cells. The laboratory can select different thresholds, corresponding to 10%, 15%, or 20% review rates. In contrast to random rescreening, AutoPap selects a sample of slides that is enriched with abnormalities, thereby including most of the slides that contain abnormalities missed by manual screening. Another approach to reducing detection error is improving the sensitivity of the initial screening step. The FDA has recently approved a new method (AutoPap Primary Screening System, TriPath Imaging) for this indication. AutoPap Primary Screening System uses proprietary computerized algorithms to identify slides that exceed a certain threshold for the likelihood of abnormal cells. A cytotechnologist then reviews these slides. The system allows laboratories to concentrate on the 75% of slides that most likely contain abnormal cells while immediately archiving the remainder. Sampling and detection errors are reduced when Pap test screening is repeated frequently. However, cost-effectiveness analyses have concluded that if persons are screened more than every 3 years, cost-effectiveness ratios exceed

Effect of Nesiritide in Patients with Acute Decompensated Heart Failure

50 000 per life-year saved (3, 4). Precise estimates of cytologic test sensitivity and specificity are important because they may be used to determine policy decisions, such as recommendations for optimal frequency of screening, management of mild abnormalities, and use of newer methods. Our primary objective was to systematically review the operating characteristics of conventional and new methods (computer screening and monolayer slide preparation) of Pap testing in the detection of cervical cancer and its precursors. We also evaluated test performance among women with previous cytologic abnormalities. The Agency for Healthcare Research and Quality (AHRQ), under contract to Duke University (Durham, North Carolina), funded the study. An AHRQ-approved advisory panel assisted in the design, conduct, and reporting of this work, and the evidence report on which this manuscript is based was reviewed by an external peer review panel (5). Methods Data Sources Data sources, including MEDLINE (from 1966), EMBASE (from 1980), HealthStar (from 1975), CancerLit (from 1983), and CINAHL (from 1983) were searched through October 1999 by using a strategy developed with a medical librarian (Table 1). Searches were limited to English-language studies in humans. We manually searched newly published relevant journal issues, bibliographies of included studies, and recent systematic reviews (6-9). To locate unpublished studies, we also contacted relevant professional societies and manufacturers of cytologic devices. Table 1. Search Strategy Study Selection We identified studies of conventional Pap testing (with or without manual rescreening), Pap testing using monolayer slide preparation (ThinPrep), Pap testing with primary computer screening (AutoPap or PAPNET), and Pap testing with computer rescreening (AutoPap or PAPNET). Other recently developed methods, the AutoCyte PREP System and the AutoCyte SCREEN system (TriPath Imaging, Inc., Burlington, North Carolina), had not been approved by the FDA at the time of our review and were not evaluated in this study. Study samples included women undergoing Pap testing for primary screening and those undergoing evaluation for previous cytologic abnormalities. The main outcome measures were the sensitivity and specificity of the cytologic test for detecting cases. Cytologic abnormality was defined by one of three thresholds: atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), and high-grade squamous intraepithelial lesions (HSIL). Cases were defined as histologic diagnosis of cervical intraepithelial neoplasia (CIN), grades I to III, or carcinoma. Equivalent categories in other classification schemes (10-14) were also used (Figure). Figure. Map of classification schemes for cervical cytology. We included studies of the conventional Pap test if a reference standard of histologic examination or colposcopy was reasonably concurrent to the cytologic screening test (within 3 months) and if sufficient data were reported to complete all four cells of a 2 2 table. Comparison with such a reference standard provides a more relevant outcome for clinical decision makers because colposcopic or histologic diagnoses form the basis of most clinical management decisions. Only one study of ThinPrep (15) provided enough information to allow us to extract data on sensitivity and specificity compared with a gold standard of histologic examination or colposcopy. We therefore used a separate set of screening criteria for studies of the new methods, based on cytology society guidelines (16, 17) and FDA documents [18]: 1) The study must prospectively compare screening tests or test and reference standard on the same set of patients or slides; 2) if cytologic examination is the reference standard, discordant results from the two study tests must be adjudicated by an independent panel of experienced cytology professionals; 3) at least 50% of patients testing positive for HSIL must be verified by histologic examination or colposcopy; and 4) the study design must allow for separate analyses of sensitivity (or relative true-positive rate) and specificity (or relative false-positive rate). Data based on a cytologic reference standard cannot be integrated with data based on a histologic reference standard (19-23). However, when negative test results are not verified with the reference standard, information about incremental characteristics of test performance may be obtained by directly comparing independently applied conventional and new tests (21). In this case, both tests must be applied independently to all patients, and all positive results on either test must be verified with the reference standard. A relative true-positive rate and a relative false-positive rate, which can be used to determine relative estimates of the performance of the new test, can then be calculated. Two investigators independently screened each study. Differences of opinion were reconciled by consensus. The title and abstract of each citation were screened first, and the full report was screened second. Of the 1193 bibliographic references we reviewed, 761 (approximately 64%) were excluded on the basis of title or abstract. We reviewed the full reports of 346 studies of the conventional Pap test and 86 studies of the new methods (18 on AutoPap, 42 on PAPNET, and 26 on ThinPrep). We developed a numeric quality score to evaluate included citations. Nine members of the studys working group (6 clinicians, 2 economists, and 1 health policy analyst) initially identified more than 12 evaluation criteria on the basis of previously reported criteria (6, 24, 25). We used a consensus process to narrow this list to 7. Blinded to the rest of the group, each participant then independently assigned numerical weights to the criteria. The means of these votes were calculated. Each participant received a copy of his or her responses, depicted graphically in relation to the mean for each criterion, and was requested to confirm or

Interventions used in disease management programmes for patients with chronic illness—which ones work? Meta›analysis of published reports

BACKGROUND Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Pediatric Vesicoureteral Reflux Guidelines Panel Summary Report on the Management of Primary Vesicoureteral Reflux in Children

Abstract Objective: To systematically evaluate the published evidence regarding the characteristics and effectiveness of disease management programmes. Design: Meta-analysis. Data sources:Computerised databases for English language articles during 1987-2001. Study selection: 102 articles evaluating 118 disease management programmes. Main outcome measures: Pooled effect sizes calculated with a random effects model. Results: Patient education was the most commonly used intervention (92/118 programmes), followed by education of healthcare providers (47/118) and provider feedback (32/118). Most programmes (70/118) used more than one intervention. Provider education, feedback, and reminders were associated with significant improvements in provider adherence to guidelines (effect sizes (95% confidence intervals) 0.44 (0.19 to 0.68), 0.61 (0.28 to 0.93), and 0.52 (0.35 to 0.69) respectively) and with significant improvements in patient disease control (effect sizes 0.35 (0.19 to 0.51), 0.17 (0.10 to 0.25), and 0.22 (0.1 to 0.37) respectively). Patient education, reminders, and financial incentives were all associated with improvements in patient disease control (effect sizes 0.24 (0.07 to 0.40), 0.27 (0.17 to 0.36), and 0.40 (0.26 to 0.54) respectively). Conclusions: All studied interventions were associated with improvements in provider adherence to practice guidelines and disease control. The type and number of interventions varied greatly, and future studies should directly compare different types of intervention to find the most effective.

Cardiorenal Interactions: Insights From the ESCAPE Trial

PURPOSE The American Urological Association convened the Pediatric Vesicoureteral Reflux Guidelines Panel to analyze the literature regarding available methods for treating vesicoureteral reflux diagnosed following a urinary tract infection in children and to make practice policy recommendations based on the treatment outcomes data insofar as the data permit. MATERIALS AND METHODS The panel searched the MEDLINE data base for all articles from 1965 to 1994 on vesicoureteral reflux and systematically analyzed outcomes data for 7 treatment alternatives: 1) intermittent antibiotic therapy, 2) bladder training, 3) continuous antibiotic prophylaxis, 4) antibiotic prophylaxis and bladder training, 5) antibiotic prophylaxis, anticholinergics and bladder training, 6) open surgical repair and 7) endoscopic repair. Key outcomes identified were probability of reflux resolution, likelihood of developing pyelonephritis and scarring, and possibility of complications of medical and surgical treatment. RESULTS Available outcomes data on the various treatment alternatives were summarized in tabular form and graphically, and the relative probabilities of possible outcomes were compared for each alternative. Treatment recommendations were based on scientific evidence and expert opinion. The panel concluded that only a few recommendations can be derived purely from scientific evidence of a beneficial effect on health outcomes. CONCLUSIONS For most children the panel recommended continuous antibiotic prophylaxis as initial treatment. Surgery was recommended for children with persistent reflux and other indications, as specified in the document.

Meta-analysis of screening and diagnostic tests.

OBJECTIVES We examined the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) database to understand the impact and pathophysiology of renal dysfunction in patients hospitalized with advanced decompensated heart failure (HF). BACKGROUND Baseline renal insufficiency (RI) (estimated glomerular filtration rate [eGFR] <60 ml/min) and worsening renal function (WRF) (upward arrow serum creatinine [SCr] >or=0.3 mg/dl) during treatment of decompensated HF are associated with adverse outcomes. METHODS We used a Cox proportional hazards model to evaluate the impact of renal function on 6-month outcomes. Renal parameters were correlated with hemodynamic measurements. The impact of a strategy using pulmonary artery catheter (PAC) guidance on WRF and outcomes in patients with baseline RI was compared with treatment based on clinical assessment alone. RESULTS Baseline and discharge RI, but not WRF, were associated with an increased risk of death and death or rehospitalization. Among the hemodynamic parameters measured in patients randomized to the PAC arm (n = 194), only right atrial pressure correlated weakly with baseline SCr (r = 0.165, p = 0.03). There was no correlation between baseline hemodynamics or change in hemodynamics and WRF. A PAC-guided strategy was associated with less average increase in creatinine but did not decrease the incidence of defined WRF during hospitalization or affect renal function after discharge relative to clinical assessment alone. CONCLUSIONS Among patients with advanced decompensated HF, baseline RI impacts outcomes more than WRF. Poor forward flow alone does not appear to account for the development of RI or WRF in these patients. The addition of hemodynamic monitoring to clinical assessment does not prevent WRF or improve renal function after discharge.

Effect of Clinical Decision-Support Systems: A Systematic Review

Screening and diagnostic tests are common in the fields of psychology, medicine, and education. Often there are several competing tests, and decisions must be made about the relative accuracy of those tests. This article describes a general measure that can be used for both continuous and dichotomous outcome measures. It is the standardized distance between the means of the 2 populations. For continuous measures, it is the effect size measure. For dichotomous measures, it is proportional to the logarithm of the odds of the sensitivity plus the logarithm of the odds of the specificity. The measure is easily computed for both kinds of outcomes. Properties of this measure are discussed, and examples are given. Ths use of this measure to compare the average performance of different tests is described.

Benefits of Smoking Cessation for Longevity

BACKGROUND Despite increasing emphasis on the role of clinical decision-support systems (CDSSs) for improving care and reducing costs, evidence to support widespread use is lacking. PURPOSE To evaluate the effect of CDSSs on clinical outcomes, health care processes, workload and efficiency, patient satisfaction, cost, and provider use and implementation. DATA SOURCES MEDLINE, CINAHL, PsycINFO, and Web of Science through January 2011. STUDY SELECTION Investigators independently screened reports to identify randomized trials published in English of electronic CDSSs that were implemented in clinical settings; used by providers to aid decision making at the point of care; and reported clinical, health care process, workload, relationship-centered, economic, or provider use outcomes. DATA EXTRACTION Investigators extracted data about study design, participant characteristics, interventions, outcomes, and quality. DATA SYNTHESIS 148 randomized, controlled trials were included. A total of 128 (86%) assessed health care process measures, 29 (20%) assessed clinical outcomes, and 22 (15%) measured costs. Both commercially and locally developed CDSSs improved health care process measures related to performing preventive services (n= 25; odds ratio [OR], 1.42 [95% CI, 1.27 to 1.58]), ordering clinical studies (n= 20; OR, 1.72 [CI, 1.47 to 2.00]), and prescribing therapies (n= 46; OR, 1.57 [CI, 1.35 to 1.82]). Few studies measured potential unintended consequences or adverse effects. LIMITATIONS Studies were heterogeneous in interventions, populations, settings, and outcomes. Publication bias and selective reporting cannot be excluded. CONCLUSION Both commercially and locally developed CDSSs are effective at improving health care process measures across diverse settings, but evidence for clinical, economic, workload, and efficiency outcomes remains sparse. This review expands knowledge in the field by demonstrating the benefits of CDSSs outside of experienced academic centers. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Clinical Outcomes of Therapeutic Agents That Block the Platelet Glycoprotein IIb/IIIa Integrin in Ischemic Heart Disease

OBJECTIVES This study determined the life extension obtained from stopping smoking at various ages. METHODS We estimated the relation between smoking and mortality among 877,243 respondents to the Cancer Prevention Study II. These estimates were applied to the 1990 US census population to examine the longevity benefits of smoking cessation. RESULTS Life expectancy among smokers who quit at age 35 exceeded that of continuing smokers by 6.9 to 8.5 years for men and 6.1 to 7.7 years for women. Smokers who quit at younger ages realized greater life extensions. However, even those who quit much later in life gained some benefits: among smokers who quit at age 65 years, men gained 1.4 to 2.0 years of life, and women gained 2.7 to 3.7 years. CONCLUSIONS Stopping smoking as early as possible is important, but cessation at any age provides meaningful life extensions.

Single-Therapy Androgen Suppression in Men with Advanced Prostate Cancer: A Systematic Review and Meta-Analysis

BACKGROUND Several platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been evaluated in clinical trials. We conducted a systematic overview (meta-analysis) to assess the effect of these compounds on death, myocardial infarction (MI), and revascularization. METHODS AND RESULTS ORs were calculated for 16 randomized, controlled trials of GP IIb/IIIa inhibitors. An empirical Bayesian random-effects model combined the outcomes of 32 135 patients. There was a significant mortality reduction by GP IIb/IIIa inhibitors at 48 to 96 hours, with an OR of 0.70 (95% CI, 0. 51 to 0.96; P<0.03), equivalent to a reduction of 1 death per 1000 patients treated. Mortality benefits at 30 days (OR, 0.87; 95% CI, 0. 74 to 1.02; P=0.08) and 6 months (OR, 0.97; 95% CI, 0.86 to 1.10; P=0.67) were not statistically significant. For the combined end point of death or MI, there was a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors at each time point. The 30-day OR was 0.76 (95% CI, 0.66 to 0.87), or 20 fewer events per 1000 patients treated. For the composite end point of death, MI, or revascularization, there was also a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors. At 30 days, the OR was 0.77 (95% CI, 0.68 to 0.86), or 30 fewer events per 1000 patients treated. The risk differences for death, death or MI, and composite outcomes were similar at 6 months, indicating a sustained absolute improvement. Similar benefit was seen when trials were subgrouped by therapeutic indication (percutaneous intervention versus acute coronary syndromes). CONCLUSIONS Application of this new therapeutic class to clinical practice promises substantial benefit for both indications.