Lori A. Bastian

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

Efficacy of Dialectical Behavior Therapy in Women Veterans With Borderline Personality Disorder

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

Effect of Clinical Decision-Support Systems: A Systematic Review

Twenty women veterans who met criteria for borderline personality disorder (BPD) were randomly assigned to Dialectical Behavior Therapy (DBT) or to treatment as usual (TAU) for 6 months. Compared with patients in TAU, those in DBT reported significantly greater decreases in suicidal ideation, hopelessness, depression, and anger expression. In addition, only patients in DBT demonstrated significant decreases in number of parasuicidal acts, anger experienced but not expressed, and dissociation, and a strong trend on number of hospitalizations, although treatment group differences were not statistically significant on these variables. Patients in both conditions reported significant decreases in depressive symptoms and in number of BPD criterion behavior patterns, but no decrease in anxiety. Results of this pilot study suggest that DBT can be provided effectively independent of the treatments developer, and that larger efficacy and effectiveness studies are warranted.

Vascular Risk Factors for Incident Alzheimer Disease and Vascular Dementia: The Cache County Study

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.

Depressive symptoms, menopausal status, and climacteric symptoms in women at midlife.

Vascular risk factors for Alzheimer disease (AD) and vascular dementia (VaD) have been evaluated; however, few studies have compared risks by dementia subtypes and sex. We evaluated relationships between cardiovascular risk factors (hypertension, high cholesterol, diabetes mellitus, and obesity), events (stroke, coronary artery bypass graft surgery, and myocardial infarction), and subsequent risk of AD and VaD by sex in a community-based cohort of 3264 Cache County residents aged 65 or older. Cardiovascular history was ascertained by self-report or proxy-report in detailed interviews. AD and VaD were diagnosed using standard criteria. Estimates from discrete-time survival models showed no association between self-reported history of hypertension and high cholesterol and AD after adjustments. Hypertension increased the risk of VaD [adjusted hazard ratio (aHR) 2.42, 95% confidence interval (CI) 0.95-7.44]. Obesity increased the risk of AD in females (aHR 2.23, 95% CI 1.09-4.30) but not males. Diabetes increased the risk of VaD in females after adjustments (aHR 3.33, 95% CI 1.03-9.78) but not males. The risk of VaD after stroke was increased in females (aHR 16.90, 95% CI 5.58-49.03) and males (aHR 10.95, 95% CI 2.48-44.78). The results indicate that vascular factors increase risks for AD and VaD differentially by sex. Future studies should focus on specific causal pathways for each of these factors with regard to sex to determine if sex differences in the prevalence of vascular factors have an influence on sex differences in dementia risk.

Insomnia And The Eye Of The Beholder: Are There Clinical Markers Of Objective Sleep Disturbances Among Adults With And Without Insomnia Complaints?

Objective Previous studies have found increased rates of depression in women aged 45 to 54 years, but the factors that influence these rates are not understood. It was assessed whether higher rates of depressive symptoms were associated with menopausal status, climacteric symptoms, and use of hormone replacement therapy. Design Cross-sectional survey. Setting Community sample. Methods Data are from 581 women ages 45 to 54 years who were interviewed by telephone between October 1998 and February 1999. Measures Depression was measured with the abbreviated CES-D, a depressive symptoms screening measure. Women’s reported perception of menopausal stage, frequency of periods in the preceding 12 months, and history of oophorectomy were used to classify their menopausal status into four categories: (1) no indication of menopause; (2) close to menopause; (3) had begun menopause; and (4) had completed menopause. Results There were 168 women (28.9%) who reported a high level (≥10) of depressive symptoms when the abbreviated CES-D was used. In a logistic-regression analysis, significant factors associated with increased depressive symptoms included physical inactivity, inadequate income, use of estrogen/progesterone combination, and presence of climacteric symptoms (trouble sleeping, mood swings, or memory problems). Menopausal status was not associated with depressive symptoms. Conclusions In this sample of women age 45 to 54 years, climacteric symptoms but not menopausal status were associated with higher rates of depressive symptoms.

Active Mothers Postpartum A Randomized Controlled Weight-Loss Intervention Trial

Previous findings suggest that some who report insomnia sleep well, whereas some noncomplaining individuals sleep rather poorly. This study was conducted to determine if mood, anxiety, and sleep-related beliefs might relate to perceived sleep disturbance. Thirty-two women and 32 men (aged 40-79 years) with primary insomnia and an aged-matched sample of 61 normal sleepers (31 women, 30 men) completed 6 nocturnal sleep recordings, as well as the Beck Depression Inventory (BDI), the Trait portion of the State-Trait Anxiety Inventory (STAI-2), and the Dysfunctional Beliefs and Attitudes About Sleep Questionnaire. Sleep and interview data were used to subdivide the majority of the sample (n = 108) into objective normal sleepers and subjective insomnia sufferers who seemingly slept well and subjective normal sleepers and objective insomnia sufferers who slept poorly. The 2 subjective subgroups showed the most marked differences on most of the psychometric measures. The findings suggest that the psychological factors scrutinized in this study may mediate sleep satisfaction and/or predict objective sleep difficulties.

Hormone replacement therapy and reduced cognitive decline in older women: The Cache County Study

BACKGROUND Pregnancy may contribute to overweight and obesity. PURPOSE The primary objective of Active Mothers Postpartum was to promote a reduction in BMI through 24-months postpartum via sustainable lifestyle changes. DESIGN Behavioral intervention RCT to enhance postpartum weight loss. SETTING/PARTICIPANTS A total of 450 overweight or obese women, enrolled 6-weeks postpartum, were recruited through obstetrics clinics and community posters in the Durham NC area. INTERVENTION Intervention participants were offered eight healthy-eating classes, ten physical-activity classes, and six telephone-counseling sessions over 9 months. MAIN OUTCOME MEASURES Changes from baseline (6-weeks postpartum) to 1-month post-intervention (12-months postpartum) in: (1) diet (caloric intake, calories from fat, intake of certain foods); (2) physical activity (self-reported physical activity, television time); and (3) weight (collected 2004-2007, analyzed 2007-2008). RESULTS Mean weight loss was 0.90 kg (+/-5.1 kg) in the intervention group and 0.36 kg (+/-4.9 kg) in the control group; this difference was not significant. There were also no significant group differences in improvement of diet or increased physical activity. In secondary analyses, there was a positive bivariate relationship between classes attended and weight loss (p=0.01). CONCLUSIONS There were no significant differences among the arms in diet, physical activity, or weight change. Home-based interventions via mail, telephone, or Internet/e-mail may be more feasible and successful in this population. The postpartum period is an important phase in womens lives with regard to weight retention, but engaging them during this busy period remains a challenge. TRIAL REGISTRATION NCT00212251.

Toward a VA Women's Health Research Agenda: setting evidence-based priorities to improve the health and health care of women veterans.

Objective: To examine the association between postmenopausal hormone replacement therapy (HRT) and the trajectory of global cognitive change with age. Methods: The Modified Mini-Mental State Examination (MMSE) was administered to a population sample of 2,073 nondemented, community-dwelling female residents of Cache County, UT, aged 65 and older. Current and past HRT and other medications at a baseline interview and at follow-up 3 years later were assessed. Between interviews, a telephone Women’s Health Questionnaire was administered to assess initial exposure, duration, and recency of HRT. Generalized estimating equation marginal models were used to evaluate the cross-sectional and longitudinal relations of HRT and modified MMSE score. Also assessed were effects with multivitamins and calcium supplements as exposures likely to reflect a “healthy lifestyle” among HRT users. Model covariates included the presence of APOE ε4 alleles, age, education, concurrent depression, several chronic diseases, and self-perceived general health. Results: Age, lower education, depression, and APOE ε4 were all associated with lower baseline modified MMSE scores. With these covariates in the model, lifetime HRT use was associated with better baseline modified MMSE scores and a slower rate of decline. Stratification by APOE genotype did not alter these effects. Apparent benefits with HRT were attenuated but remained significant after elimination of scores from participants with incident dementia. A significant interaction between age and HRT indicated the strongest effects in women aged 85 and older. Measures of age at initial use of HRT, duration, and recency of exposure did not improve the models. No effects were seen with the “healthy lifestyle” control exposures. Conclusions: In a population cohort of older women, lifetime HRT exposure was associated with improved global cognition and attenuated decline over a 3-year interval. Improvements were greatest in the oldest old.

Smoking Cessation Interventions for Patients with Depression: A Systematic Review and Meta-analysis

The expansion of women in the military is reshaping the veteran population, with women now constituting the fastest growing segment of eligible VA health care users. In recognition of the changing demographics and special health care needs of women, the VA Office of Research & Development recently sponsored the first national VA Women’s Health Research Agenda-setting conference to map research priorities to the needs of women veterans and position VA as a national leader in Women’s Health Research. This paper summarizes the process and outcomes of this effort, outlining VA’s research priorities for biomedical, clinical, rehabilitation, and health services research.