Tracy L Beil

Screening for Colorectal Cancer: A Targeted, Updated Systematic Review for the U.S. Preventive Services Task Force

Colorectal cancer ranks third in incidence and second in cause of cancer death for both men and women (1). Most cases of colorectal cancer occur in average-risk individuals (those without a family or predisposing medical history), and increasing age, male sex, and black race are associated with increased incidence (2). Black persons have the highest incidence of and mortality rates from colorectal cancer among all racial and ethnic subgroups (37) and nearly double the colorectal cancerrelated mortality rate compared with other ethnic minorities (8). Colorectal cancer screening has been recommended by the U.S. Preventive Services Task Force (USPSTF) and many other organizations for more than 10 years (9). On the basis of evidence from multiple randomized, controlled trials (RCTs), a screening program with repeated annual or biennial guaiac fecal occult blood tests (FOBTs) and endoscopic follow-up of positive test results reduces colorectal cancer mortality; according to a recent update, colorectal cancer mortality was reduced 16% (CI, 10% to 22%) after 12 to 18 years (10). Extrapolating from trial evidence, clinical studies of test accuracy, and other supporting evidence, the USPSTF recognized flexible sigmoidoscopy (with or without FOBTs), colonoscopy, and double-contrast barium enema as other colorectal cancer screening options in 2002 (11, 12). However, because colorectal cancer screening tests have potential harms, limited accessibility, or imperfect acceptability to patients, and no tests could be identified as superior in cost-effectiveness analysis (13), the USPSTF also recommended that choice among recommended methods for colorectal cancer screening to be individualized to patients or practice settings (14). Despite strong recommendations from the USPSTF and many others, serial national surveys document inadequate, slowly improving rates of colorectal cancer screening in the United States (1520). In 2006, 60.8% of adults 50 years of age or older reported recent colorectal screening (20). Disparities in colorectal cancer screening exist, with lower rates of colorectal cancer screening in nonwhite and Hispanic populations (16, 21, 22) and in areas with higher poverty rates (23). To increase the uptake of and benefits from recommended colorectal cancer screening, researchers have sought to improve the accuracy, acceptability, or accessibility of screening by introducing new tests or enhancing existing tests. However, the availability of additional options for colorectal cancer screeningincluding highly sensitive guaiac FOBT; fecal immunochemical testing; fecal DNA testing; and virtual colonoscopy approaches, such as computed tomographic (CT) colonographyhas created uncertainty about what methods should be used for colorectal cancer screening in the general population. To assist the USPSTF in updating its 2002 recommendation for colorectal cancer screening in average-risk adults age 50 years or older, we conducted a targeted systematic review primarily focused on evidence gaps or new evidence since the previous review. This approach updated what the USPSTF judged was the most important evidence for newer colorectal cancer screening tests and community-performed endoscopies, and it was supplemented by a companion decision analysis examining screening program performance and life-years gained by using different colorectal cancer screening tests, test intervals, and starting and stopping ages (24). Methods Under guidance from the USPSTF, this targeted review addressed only the first 3 questions of the full evidence chain in the analytic framework (Figure 1). From our larger report (25), we report here the accuracy (one-time test performance characteristics) and potential harms of newer colorectal cancer screening tests (high-sensitivity FOBTs, fecal immunochemical tests, fecal DNA testing, and CT colonography) in screening populations (key questions 2b and 3b) and the accuracy and harms of screening colonoscopy and flexible sigmoidoscopy in the community setting (key questions 2a and 3a). In the full report, we discuss lack of new data on the mortality benefits of colorectal cancer screening beyond FOBT programs (key question 1); race-, sex-, and age-related issues in colorectal cancer screening; considerations of targeted screening recommendations; and suggested future research. Detailed methods are provided in the Appendix and Appendix Tables 1, 2, and 3 and in the full report (25). Figure 1. Analytic framework and key questions ( KQs ). KQ1: What is the effectiveness of the following screening methods (alone or in combination) in reducing mortality from colorectal cancer? a. Flexible sigmoidoscopy, b. Colonoscopy, c. Computed tomographic (CT) colonography, d. Fecal screening tests: i. High-sensitivity guaiac fecal occult blood test (FOBTs); ii. Fecal immunochemical test; iii. Fecal DNA test. KQ2a: What are the sensitivity and specificity of 1) colonoscopy and 2) flexible sigmoidoscopy when used to screen for colorectal cancer in the community practice setting? KQ2b: What are the test performance characteristics of 1) CT colonography and 2) fecal screening tests (as listed in KQ1d) for colorectal cancer screening, as compared to an acceptable reference standard? KQ3a: What are age-specific rates of harm from colonoscopy and flexible sigmoidoscopy in the community practice setting? KQ3b: What are the adverse effects of newer tests, including 1) CT colonography and 2) fecal screening tests (as listed in KQ1d)? Appendix Table 1. Eligibility Criteria for Studies, by Key Question Appendix Table 2. U.S. Preventive Services Task Force Design-Specific Quality Rating Criteria Appendix Table 3. SAS Code for the Meta-Analysis of Serious Complications Searches and Selection Process In brief, we searched PubMed; Database of Abstracts of Reviews of Effects; Cochrane Database of Systematic Reviews; and the Institute of Medicine, National Institute for Health and Clinical Effectiveness, and Health Technology Assessment databases for recent systematic reviews (19992006) to support our review of all key questions (26). We found 11 existing systematic reviews for newer colorectal cancer screening tests (key question 2b). Using methods detailed in the Appendix, we selected 3 good-quality reviews of CT colonography (27, 28) or fecal DNA testing (29) to locate relevant primary studies; we supplemented these with additional MEDLINE and Cochrane Library searches from January 2006 through January 2008 to locate additional studies published after the end date of the searches. Because there were no good-quality relevant systematic reviews for reports on fecal immunochemical tests (key questions 2b and 3b), we searched MEDLINE and the Cochrane Library (19902008) and from 2000 to 2008 to locate studies of the harms of screening tests (key questions 3a and 3b) since the 2002 report. Abstracts and articles were dual-reviewed against inclusion criteria (Appendix) and required agreement of 2 reviewers. Eligible studies reported on the sensitivity and specificity of colorectal cancer screening tests or on health outcomes. We excluded studies that did not address average-risk populations for colorectal cancer screening, unless an average-risk subgroup was reported. We excluded casecontrol studies of screening accuracy because these may overestimate sensitivity as a design-related source of bias (30), as recently demonstrated for FOBTs (31). To avoid biases related to reference standards, we excluded studies of test accuracy that incompletely applied a valid reference standard or used an inadequate reference standard (32). For CT colonography, we considered only technologies that were compared with colonoscopy in average-risk populations, used a multidetector scanner (27), and reported per-patient sensitivity and specificity. In all, we evaluated 3948 abstracts and 490 full-text articles (Figure 2). Figure 2. Study selection. KQ= key question; SER= standardized evidence review. For list of key questions, see legend for Figure 1. Quality Assessment and Data Abstraction Two investigators critically appraised and quality-rated all eligible studies by using design-specific USPSTF criteria (33) supplemented by other criteria (Appendix). Poor-quality studies were excluded. One investigator abstracted key elements of included studies into standardized evidence tables. A second reviewer verified these data. We resolved disagreements about data abstraction or quality appraisal by consensus. Evidence tables and tables of excluded studies for each key question are available in the full report (25). Data Synthesis and Analysis We report qualitative synthesis of the results for most key questions because of study heterogeneity. The performance of screening tests is preferentially described per person (sensitivity and specificity), supplemented by per-polyp analyses (miss rates). Sensitivity for large adenomas from 2 similar studies of CT colonography screening was combined by using the inverse variance fixed-effects model because no heterogeneity was detected on the basis of the Cochran Q test and the I 2 statistic (34). Because of the stringency of our inclusion criteria for studies to estimate rates of endoscopy harms in the community practice setting (key question 3a), included studies were clinically homogeneous enough to pool. A random-effects logistic model was used to evaluate statistical heterogeneity, estimate pooled rates, and explore potential sources of variation for complications from study-level characteristics (35, 36). Model details and SAS PROC NLMIXED code are provided in the Appendix. Total serious adverse events required hospital admission (for example, perforation, major bleeding, severe abdominal symptoms, and cardiovascular events) or resulted in death. Results of exploratory analyses for potential sources of variation for pooled estimates are discussed in the full report, along with pooled estimates for individual complications, su

Effectiveness of Weight Management Interventions in Children: A Targeted Systematic Review for the USPSTF

CONTEXT: Targeted systematic review to support the updated US Preventive Services Task Force (USPSTF) recommendation on screening for obesity in children and adolescents. OBJECTIVES: To examine the benefits and harms of behavioral and pharmacologic weight-management interventions for overweight and obese children and adolescents. METHODS: Our data sources were Ovid Medline, PsycINFO, the Education Resources Information Center, the Database of Abstracts of Reviews of Effects, the Cochrane databases, reference lists of other reviews and trials, and expert recommendations. After 2 investigators reviewed 2786 abstracts and 369 articles against inclusion/exclusion criteria, we included 15 fair- to good-quality trials in which the effects of treatment on weight, weight-related comorbidities, and harms were evaluated. Studies were quality rated by 2 investigators using established criteria. Investigators abstracted data into standard evidence tables. RESULTS: In the available research, obese (or overweight) children and adolescents aged 4 to 18 years were enrolled, and no studies targeted those younger than 4 years. Comprehensive behavioral interventions of medium-to-high intensity were the most effective behavioral approach with 1.9 to 3.3 kg/m2 difference favoring intervention groups at 12 months. More limited evidence suggests that these improvements can be maintained over the 12 months after the end of treatments and that there are few harms with behavioral interventions. Two medications combined with behavioral interventions resulted in small (0.85 kg/m2 for orlistat) or moderate (2.6 kg/m2 for sibutramine) BMI reduction in obese adolescents on active medication; however, no studies followed weight changes after medication use ended. Potential adverse effects were greater than for behavioral interventions alone and varied in severity. Only 1 medication (orlistat) has been approved by the US Food and Drug Administration for prescription use in those aged ≥12 years. CONCLUSIONS: Over the past several years, research into weight management in obese children and adolescents has improved in quality and quantity. Despite important gaps, available research supports at least short-term benefits of comprehensive medium- to high-intensity behavioral interventions in obese children and adolescents.

Screening for abdominal aortic aneurysm: A best-evidence systematic review for the U.S. Preventive Services Task Force

An abdominal aortic aneurysm (AAA) occurs when the aorta below the renal arteries expands to a maximal diameter of 3.0 cm or greater. Abdominal aortic aneurysms are found in 4% to 8% of older men and 0.5% to 1.5% of older women (1-5). Age, smoking, sex, and family history are the most significant AAA risk factors (1). Aortic aneurysms account for about 15000 deaths in the United States annually; of these, 9000 are AAA-related and the remainder are due to thoracic aortic aneurysms (6, 7). Most AAA deaths occur in men 65 years of age and older (8, 9). Although AAAs may be asymptomatic for years, as many as 1 in 3 eventually rupture if left untreated (10). The prognosis for ruptured AAAs is grim. Since most patients with ruptured AAAs die out of the hospital or before surgery (11), and since the operative mortality rate for emergent AAA repair is high (12), only 10% to 25% of individuals with ruptured AAAs survive until hospital discharge. Ultrasonography of the abdomen is accurate (13, 14) and reliable (15) in detecting AAAs. Survival after elective surgical repair approaches that of the general population (16). Elective AAA repair, however, may result in significant harms, such as operative mortality, myocardial infarction, respiratory and renal failure, and changes in functional status (17, 18). In its 1996 recommendation, the U.S. Preventive Services Task Force (USPSTF) found insufficient evidence to recommend for or against routine AAA screening of asymptomatic adults. The Task Force cited the need for data from population-based screening trials to determine whether the potential benefit from preventing ruptured AAAs justified the potential risks from increased surgery (19). Since 1996, results from 4 population-based randomized, controlled trials of AAA screening have been published (5, 9, 20-24). On the basis of this new evidence, the USPSTF sought to update its 1996 recommendation by reassessing the benefits and harms of population-based AAA screening. This systematic review was performed by investigators from the Oregon Evidence-based Practice Center, Portland, Oregon, in collaboration with the USPSTF and the Agency for Healthcare Research and Quality, Rockville, Maryland. Descriptions of the analytic framework, key questions, literature search, inclusion criteria, data extraction methods, quality rating, and trial flow diagram are provided in the Appendix, Appendix Figures 1 and 2, and the Appendix Table. The evidence review focused on the following key questions: 1a) Does AAA screening, in an asymptomatic average-risk or high-risk population, reduce AAA-related adverse health outcomes? 1b) For individuals who do not have AAAs on initial screening, does periodic repeated screening reduce AAA-related adverse health outcomes? 2) What are the harms associated with AAA screening? 3) For AAAs 3.0 to 5.4 cm detected through screening, does immediate repair or surveillance reduce AAA-related adverse health outcomes? 4) What are the harms associated with repair of AAAs 5.5 cm or greater? 5) What are the harms associated with immediate repair or surveillance of AAAs 3.0 to 5.4 cm? This article focuses only on key questions 1a, 1b, 2, and 4, which are most relevant to determining the net benefit (benefit minus harms) of population-based screening for AAA. Key questions 3 and 5 address management strategies for AAAs 3.0 to 5.4 cm, which are at much lower risk for rupture than larger AAAs (25, 26). Key questions 3 and 5 are reviewed in our full systematic evidence synthesis (available at www.preventiveservices.ahrq.gov). Methods We performed this review on the basis of methods previously established by the USPSTF (27). We initially developed an analytic framework and key questions, in conjunction with USPSTF liaisons, to define the strategy used to perform this systematic review. Since direct evidence regarding population-based screening from randomized, controlled trials was available, we did not explicitly review the accuracy and reliability of ultrasonography in population-based AAA screening. The sensitivity of ultrasound scanning for an AAA is 95%, and the specificity approaches 100%; the examination is safe and reliable (14, 15, 28, 29). Limited ultrasonography for AAA screening can be performed in less than 10 minutes (30). To identify relevant studies, we searched MEDLINE (January 1994 through July 2004), the Cochrane Database of Systematic Reviews (2004, Issue 1), and the Cochrane Controlled Trials Register (January 1994 through May 2004). Literature search strategies are summarized in the Appendix. We identified additional studies from the reference lists of retrieved articles, periodic hand searches of relevant journals, and suggestions from experts. To evaluate the effectiveness of AAA screening (key question 1a), we searched for randomized, controlled trials of population-based screening for AAA. To evaluate the benefit of periodic repeated screening after a normal scan (key question 1b), we identified cohort or follow-up studies of patients without AAAs identified in population screening studies. To evaluate the potential harms associated with AAA screening and treatment (key questions 2 and 4), we examined data from the trials of population screening and searched for other relevant retrospective or prospective cohort studies. Two authors reviewed 271 abstracts and 26 articles using defined inclusion criteria and abstracted relevant information about the population, setting, interventions, and outcomes of each included trial of screening and harms (see the Appendix and Appendix Figure 2 for inclusion criteria and the trial flow diagram). Predefined criteria from the USPSTF were used to assess the internal validity of each population-based screening trial and to assign quality ratings of good, fair, or poor (27). We did not assign quality ratings for studies of repeated screening or harms of screening and treatment. We used published data from the trials of population-based AAA screening to calculate estimates of unadjusted odds ratios (ORs) and 95% CIs for AAA-related mortality and all-cause mortality. We performed meta-analyses to calculate summary estimates for AAA-related mortality and all-cause mortality using the DerSimonian and Laird random-effects model (31). When no heterogeneity is present, the DerSimonian and Laird random-effects estimate is identical to the fixed-effects estimate. We deemed the random-effects model to be more appropriate than a fixed-effects model because the included studies differed in characteristics such as population, starting and stopping ages for screening, outcomes ascertainment, and duration of follow-up (32). We used graphs of trial outcomes and the MantelHaenszel chi-square test to assess heterogeneity. We used RevMan software (Reviewer Manager Version 4.2.2, 2003, The Cochrane Collaboration, Oxford, United Kingdom) to perform all statistical analyses. We modeled the impact of screening on AAA-related mortality over 5 years for 100000 U.S. men age 65 to 74 years. We also examined how the modeled impact of screening would differ in those with a history of smoking and those who had never smoked within this same sample. This article is based on a full evidence synthesis, which is available at www.preventiveservices.ahrq.gov. Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality under a contract to support the work of the U.S. Preventive Services Task Force. Agency staff and Task Force members participated in the initial design of the study and reviewed interim analyses and the final manuscript. The full evidence report was distributed for review to content experts and was revised accordingly. Agency approval was required before this manuscript could be submitted for publication, but the authors are solely responsible for its content and the decision to submit it. Data Synthesis Trial Characteristics We identified 4 randomized, controlled trials that evaluated population-based screening for AAA: the Multicentre Aneurysm Screening Study (MASS) from the United Kingdom (22); the Chichester, United Kingdom, screening study (5, 9, 20); the Viborg County, Denmark, screening study (21); and the Western Australia screening study (23, 33, 34). Table 1 shows the characteristics of the 4 screening trials. All trials identified potential participants age 65 years or older at average risk for AAA through population registries or regional health directories. The 4 trials included more than 125000 total participants. Different stopping ages were used for each trial and ranged from 73 years to 83 years. No data were provided on race or ethnicity. Only the Chichester trial included women. Table 1. Characteristics of Screening Trials for Abdominal Aortic Aneurysm In MASS and in the Chichester and Western Australia trials, participants were excluded before randomization if they resided in nursing homes. In MASS and in the Chichester trial, participants were also excluded before, and without knowledge of, randomization if their primary physician deemed them unfit for elective AAA repair. Participants were then randomly assigned to an intervention group that received an invitation to attend screening or to a control group that received usual care. All control group participants were followed passively and without contact. Across the 4 trials, 63% to 80% of invited participants attended ultrasound scanning. On an intention-to-treat basis, those who were invited to screening but did not attend were also included in the analysis. In MASS and in the Chichester and Viborg County trials, patients with AAAs exceeding a threshold size of 5.0 to 6.0 cm on initial measurement were referred to a vascular surgeon. Patients with smaller AAAs periodically underwent repeated scanning and were referred to a vascular surgeon for AAAs that had expanded to or above the threshold size. In MASS and in the Chichester trial, patients were also referred if the AA

Screening for Depression in Adult Patients in Primary Care Settings: A Systematic Evidence Review

Major depressive disorder (MDD) is common, with an estimated lifetime prevalence of 13.2%. In primary care settings, prevalence estimates of MDD range from 5% to 13% in all adults (1, 2), with lower estimates in those older than 55 years (6% to 9%) (3, 4). Primary care practitioners manage approximately one third to one half of nonelderly adults (5, 6) and almost two thirds of older adults (7) who received treatment for MDD. The severity of depressive symptoms in patients who receive treatment in primary care is equivalent to that of patients treated in psychiatric settings (8). For example, approximately 43% of such primary care patients report some degree of suicidal ideation within the previous week (8, 9). In 2002, the U.S. Preventive Services Task Force (USPSTF) recommended screening adults for depression in clinical practices that have systems to ensure accurate diagnosis, effective treatment, and follow-up. Subsequent reviewers have concluded that screening does not improve health outcomes (10), but care management systems for depressed patients improve depression remission rates (11). Commentators on these divergent reviews have been divided (12, 13). We conducted this systematic review to aid the USPSTF in updating its 2002 recommendation for adult depression screening in primary care. We sought to 1) identify evidence published since the previous review on the benefits of screening for depression in primary care and integrate it with the previously identified evidence and 2) review the evidence in several areas in which evidence was insufficient at the time of the previous review or not was examined by the previous review (14). This includes the benefits of depression treatment in older adults, the harms of depression screening, and the harms of depression treatment with antidepressant medications. Methods Scope of the Review We developed an analytic framework (Appendix Figure 1) and 5 key questions that focused on the evidence that the USPSTF required to update its recommendation by using the USPSTFs methods (15). Appendix Figure 1. Analytic framework and key questions. SSRI = selective serotonin reuptake inhibitor. 1. Is there direct evidence that screening for depression among adults and elderly patients in primary care reduces morbidity and/or mortality? 1a. What is the effect of clinician feedback of screening test results (with or without additional care management support) on depression response and remission in screening-detected depressed patients receiving usual care? 2. What are the adverse effects of screening for depressive disorders in adults and elderly patients in primary care? 3. Is antidepressant and/or psychotherapy treatment of elderly depressed patients effective in improving health outcomes? 4. What are the adverse effects of antidepressant treatment (particularly selective serotonin reuptake inhibitors [SSRIs] and other second-generation drugs) for depression in adults and elderly patients? This article discusses methods and results for key questions 1, 1a, and 4. Detailed methods and results for the remaining key questions are in the full report (16). Data Sources and Searches We used the Database of Abstracts of Reviews of Effects, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE, and PsycINFO to search for relevant systematic reviews, meta-analyses, and primary studies published in English from January 1998 to December 2007. The full report provides the search strategies (16). Study Selection Two investigators reviewed 4088 abstracts published in English and 412 full-text articles (Appendix Figure 2) against key questionspecific inclusion and exclusion criteria (Appendix Table 1). Articles for key questions 1 and 1a were limited to randomized and controlled clinical trials that were conducted in primary care or similar settings. Key question 1 trials compared outcomes in screened and unscreened patients. Trials for key question 1a were required to have used the screening results for care decisions for intervention recipients and not for the control participants. Outcomes for these 2 questions were focused on depression response and remission. Appendix Figure 2. Search results and article flow, by key question. KQ = key question. * Numbers differ slightly from the full report (16) because only articles relevant to the more limited body of literature discussed in this publication are included in this figure. Appendix Table 1. Inclusion and Exclusion Criteria for KQs Discussed We focused our review of harms of treatment (key question 4) on already-synthesized evidence, supplemented by large observational studies. Methods for incorporating systematic reviews and meta-analyses are detailed elsewhere (Appendix Table 2). We examined serious adverse effects associated with antidepressant treatment, including suicide-related events (completed suicide, serious self-harm or attempted suicide, suicidal ideation, or suicidal behavior [usually defined to include suicide attempts, preparatory acts, or nonfatal serious self-harm]), and serious psychiatric events, including hospitalization. For older adults, we also considered evidence of serious medical events (for example, upper gastrointestinal bleeding) that were associated with SSRI and other second-generation antidepressant use. We examined rates of early discontinuation as a proxy for less serious adverse effects, particularly discontinuation due to adverse effects as a measure of tolerability. We focused on second-generation antidepressants (SSRIs in particular) because of their preponderance of use in the United States (17, 18). Appendix Table 2. Use of Existing Systematic Reviews Updated Searching and Study Examination Because of the delay between completion of the systematic review and publication, we repeated our search strategy through February 2009. We reviewed 800 abstracts against inclusion and exclusion criteria, and 21 seemed to meet criteria for this systematic review. After examining results of each of these new studies (as described in the abstracts), we determined that they would be unlikely to change our conclusions. Appendix Table 3 lists these studies. Appendix Table 3. Studies Found in Bridge Search With Possible Inclusion or Exclusion Criteria Data Extraction and Quality Assessment Two investigators rated articles for quality by using design-specific quality criteria on the basis of the USPSTF methods (15). The National Institute for Health and Clinical Excellence (19) criteria (for all study designs) and the Oxman criteria (20) (for systematic reviews) supplemented these methods. One investigator abstracted data from included studies into evidence tables and another verified it. The full review shows complete quality criteria (16). Regulatory reviews provided unique challenges and could not be evaluated by using typical quality criteria. For example, their search approach was different because they can mandate that manufacturers supply requested data. Because of the large number of trials (often in the hundreds) and proprietary information involved, however, they did not provide detailed information about individual trials. Data Synthesis and Analysis Data synthesis was primarily qualitative because of clinical heterogeneity. For cohort studies included for key question 4, we calculated absolute event rates and CIs for suicide-related events on the basis of reported data if this information was not provided. The 95% CIs were calculated on the basis of a Poisson distribution by using the GENMOD procedure (SAS software, version 8.2, SAS Institute, Cary, North Carolina) with the RISK option. Similarly, for the meta-analyses of antidepressant trials included for key question 4, we calculated missing CIs by using the FREQ procedure. Role of Funding Source The Agency for Healthcare Research and Quality funded this work, provided project oversight, and assisted in external review of the draft report but had no role in the design, conduct, or reporting of the review. The authors worked with 4 USPSTF members at key points throughout the review process to develop the analytic framework and key questions and resolve issues about scope and approach. The draft systematic review was reviewed by 6 experts and was revised on the basis of their feedback. Results Key Question 1 Is there direct evidence that screening for depression among adults and elderly patients in primary care reduces morbidity and/or mortality? One fair-quality randomized, controlled trial (RCT) of primary care patients reported mixed results when screened participants were compared with an unscreened usual care group (21) (Table). Concerns about the follow-up sample, however, limit our confidence in the results. At 3-month follow-up, the proportion of people who met criteria for depression, according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised, was similar in the screened (37%) and usual care groups (46%) (P= 0.19), although power to detect a population-level effect was inadequate (n= 218). After the investigators controlled for baseline severity of depression (which differed between the screened and usual care groups in the full randomized sample), the mean reduction in symptom counts derived from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised, was similar for the 2 groups (1.6 in screened patients vs. 1.5 in unscreened patients; P= 0.21). However, among the subset of patients who were depressed at baseline, screened patients were more likely than unscreened patients to be in complete remission at follow-up (1 symptom of depression in 48% of those screened vs. 27% of those not screened; P< 0.05). Only patients from 1 of the 2 study sites were included in the follow-up sample. At this site, only those with a diagnosis of depression at baseline and a random sample of the remaining participants (oversampling those with depressive sympt

Behavioral Counseling to Promote Physical Activity and a Healthful Diet to Prevent Cardiovascular Disease in Adults: A Systematic Review for the U.S. Preventive Services Task Force

BACKGROUND Poor diet and lack of physical activity can worsen cardiovascular health, yet most Americans do not meet diet and physical activity recommendations. PURPOSE To assist the U.S. Preventive Services Task Force in updating its previous recommendations by systematically reviewing trials of physical activity or dietary counseling to prevent cardiovascular disease. DATA SOURCES MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials (2001 to January 2010), experts, and existing systematic reviews. STUDY SELECTION Two investigators independently reviewed 13 562 abstracts and 481 articles against a set of a priori inclusion criteria and critically appraised each study by using design-specific quality criteria. DATA EXTRACTION AND ANALYSIS Data from 73 studies (109 articles) were abstracted by one reviewer and checked by a second reviewer. Random-effects meta-analyses were conducted for multiple intermediate health and behavioral outcomes. DATA SYNTHESIS Long-term observational follow-up of intensive sodium reduction counseling showed a decrease in the incidence of cardiovascular disease; however, other direct evidence for reduction in disease morbidity is lacking. High-intensity dietary counseling, with or without physical activity counseling, resulted in changes of -0.3 to -0.7 kg/m(2) in body mass index (adiposity), -1.5 mm Hg (95% CI, -0.9 to -2.1 mm Hg) in systolic blood pressure, -0.7 mm Hg (CI, -0.6 to -0.9 mm Hg) in diastolic pressure, -0.17 mmol/L (CI, -0.09 to -0.25 mmol/L) (-6.56 mg/dL [CI, -3.47 to -9.65 mg/dL]) in total cholesterol level, and -0.13 mmol/L (CI, -0.06 to -0.21 mmol/L) (-5.02 mg/dL [CI, -2.32 to -8.11 mg/dL]) in low-density lipoprotein cholesterol level. Medium- and high-intensity counseling resulted in moderate to large changes in self-reported dietary and physical activity behaviors. LIMITATIONS Meta-analyses for some outcomes had large statistical heterogeneity or evidence for publication bias. Only 11 trials followed outcomes beyond 12 months. CONCLUSION Counseling to improve diet or increase physical activity changed health behaviors and was associated with small improvements in adiposity, blood pressure, and lipid levels. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Screening for Hereditary Hemochromatosis: A Systematic Review for the U.S. Preventive Services Task Force

The U.S. Preventive Services Task Force (USPSTF) has not previously considered screening for hereditary hemochromatosis for a recommendation as a clinical preventive service for primary care clinicians. We examined key questions to assess hemochromatosis penetrance in C282Y homozygotes (key question 1), address health outcomes of therapeutic phlebotomy (key question 2), and examine the possibility of targeted genetic screening (key question 3). Key questions for this focused systematic review were limited to addressing critical evidence gaps in order for the USPSTF to recommend screening (1, 2), and were applied using strict and consistent definitions of disease, which are described in more detail below. Background Condition Definition Hemochromatosis was originally thought to be a rare idiopathic disorder characterized by end-stage disease (cirrhosis, diabetes, and bronzed skin) but is now recognized as having a hereditary component due to an autosomal recessive inherited disorder of iron metabolism (3). In hemochromatosis, body iron accumulates and can lead to iron overload (4). In iron overload, excess iron is deposited in the liver, pancreas, heart, joints, and endocrine glands, resulting in tissue damage that can lead to disease conditions (such as cirrhosis, diabetes, heart failure, arthropathy, and impotence) (46). Iron overload can be primary (as in hereditary hemochromatosis) or secondary (for example, due to anemias with inefficient erythropoiesis or repeated blood transfusions) (7). In 1996, 2 base-pair alterations, termed C282Y and H63D, of the HFE gene on the region of HLA-A on chromosome 6 were identified in hereditary hemochromatosis (8). C282Y homozygosity is now recognized as the most common genotype in hereditary hemochromatosis (9). Estimates are that 82% to 90% of cases of hereditary hemochromatosis among white persons occur in C282Y/C282Y homozygotes (10). The other 10% to 18% of cases appear to be due to environmental factors or other genotypes. While other HFE-related and nonHFE-related genetic mutations are associated with hereditary hemochromatosis in a small number of cases (4), other genotypes do not appear to be as strongly associated with hereditary hemochromatosis (3, 9). HFE mutations are fairly common in the United States, with 1 in 10 white persons heterozygous for the HFE C282Y mutation (carriers) and 4.4 homozygotes per 1000 (4, 6). The frequency of C282Y homozygosity is much lower among Hispanic persons (0.27 in 1000), Asian Americans (<0.001 per 1000), Pacific Islanders (0.12 per 1000), and black persons (0.14 per 1000) (11). The availability of genotyping has permitted identifying persons who have the susceptible genotype but have little or no evidence of disease. Thus, individuals homozygous for the C282Y genotype can be characterized in 1 of 4 general stages: genetic predisposition without any other abnormality; iron overload without symptoms; iron overload with early symptoms; and iron overload with organ damage, especially cirrhosis (4). Clinically recognized hereditary hemochromatosis is twice as common in males and occurs predominantly in white populations (12). While the natural history is not well understood, the condition appears to have a long latent period, with wide individual variation in biochemical expression (13). This is because iron accumulation and disease expression are modified by environmental factors, such as blood loss from menstruation or donation, alcohol intake, diet, and comorbid disease (for example, viral hepatitis) (14, 15). If symptomatic organ involvement develops, it generally occurs in mid-life with nonspecific signs and symptoms (such as unexplained fatigue, joint pain, and abdominal pain) (14). Age of onset is delayed in females (16), perhaps because of blood loss through menstruation (3). The liver is the first target organ thought to be affected by iron accumulation (17) and is central to both diagnosis and prognosis (13). While a clinical diagnosis is based on serum iron studies and clinical evaluation, documented iron overload relies on 1 of 2 methods: quantitative phlebotomy with calculation of the amount of iron removed, or liver biopsy with determination of quantitative hepatic iron (18). Although liver biopsy was once essential to the diagnosis, it is currently used more as a prognostic tool (19). While hepatic iron concentration greater than 283 mol/g (reference range, 0 to 35 mol/g) is associated with cirrhosis in C282Y homozygotes (20), many patients with much higher levels do not have cirrhosis (13). Even in the absence of systemic iron overload, iron accumulates when the liver is inflamed or cirrhosed because of other causes (such as alcoholic steatohepatitis, transfusion and chronic hemolytic disorders, or chronic viral hepatitis) (21). Cirrhosis is a late-stage disease development and has been reported to shorten life expectancy (2225). Cirrhosis is also a risk factor for hepatocellular carcinoma (13) and typically occurs between the ages of 40 and 60 years (6). Cirrhosis prevention would be a major goal of screening and treatment (26). Prevalence and Burden of Disease Estimates of the general population prevalence of hemochromatosis vary because of the long preclinical period and lack of a consistent case definition. The prevalence of cases of hemochromatosis defined biochemically (elevated serum iron indices) will be higher than the prevalence of cases based on documented iron overload, with or without clinical signs and symptoms. The prevalence will be lowest for cases based on diagnosed disease (cirrhosis, diabetes) (27). Experts have recommended defining iron overload as distinct from hemochromatosis (4), and this provides an objective, although not universally accepted, standard for early disease based on documented increases in body iron stores (27). On the basis of clinically diagnosed hemochromatosis or hemochromatosis-compatible disease, 79850 hemochromatosis-associated hospitalizations (2.3 per 100000 residents) were projected in the United States over 18 years (1979 to 1997), although annual rates could not be reliably calculated (28). Of 29 million deaths from 1979 to 1992, 4858 (0.017%) were consistent with hemochromatosis as an underlying cause (12). Age-adjusted mortality rates for hemochromatosis-consistent deaths increased from 1.2 per million in 1979 to 1.8 per million in 1992. These rates were about twice as high in males as in females and in white persons as in nonwhite persons. Both of these estimates of the burden of disease suggest a disease prevalence much lower than the prevalence of associated genetic mutations, which has fueled the debate about disease penetrance. While these statistics are probably underestimates, primarily because of underdiagnosis (29), the extent of this underestimation is not clear. The prevalence of hemochromatosis-attributable morbid conditions (such as cirrhosis, diabetes, arthralgias, and fatigue or other symptoms) has been proposed as an estimate of the burden due to undiagnosed disease, particularly since diagnosis may commonly be delayed as a result of the nonspecific nature of hemochromatosis-related signs and symptoms (30). Since these signs and symptoms are also prevalent and nonspecific, however, relevant evidence must establish their prevalence due to iron overload, or their excess prevalence in association with iron overload compared with controls. In a previous study, 297 middle-aged patients with previously undetected hereditary hemochromatosis (homozygous for C282Y) had a higher prevalence of diagnosed osteoarthritis, knee symptoms, hypothyroidism, and use of antihypertensive or thyroid replacement medications than sex- and age-specific controls (31). However, general health, mental health, and 52 other questionnaire-based and clinical examinationbased measures of cardiovascular, respiratory, and liver diseases were not statistically different between case-patients and controls. In another cross-sectional comparison of 124 C282Y screening-detected adult homozygotes with 22394 wild-type/wild-type genotypic controls, common symptoms (chronic fatigue, joint symptoms, impotence, and limited general health) and signs (diabetes) were no more frequent in C282Y homozygotes than controls (32). While the relative risk for physician-diagnosed liver problems or hepatitis was increased (relative risk, 2.1 [95% CI, 1.1 to 4.0]), the proportion of C282Y homozygotes with liver problems was modest (10%). Similarly, in the Hemochromatosis and Iron Overload Screening (HEIRS) study, C282Y homozygotes had an increased odds of self-reported liver disease (odds ratio, 3.28 [CI, 1.49 to 7.22]) compared with wild-type controls. Almost one fourth, however, were not identified by screening (11). Clearly, the prevalence of hemochromatosis-attributable morbid conditions is not a simple, reliable way to estimate the disease burden associated with hemochromatosis. Rationale for Population Screening Screening for hemochromatosis or iron overload is theoretically attractive and has been widely discussed over the past 10 to 15 years, with renewed interest and a focus on hereditary hemochromatosis since the discovery of the HFE mutations (4, 3336). Although hereditary hemochromatosis appears to be ideal for population screening (7, 16, 3739) and for a new paradigm for genetics and public health (34), inadequacies in the evidence supporting genetic screening for hereditary hemochromatosis have precluded widespread support for population-based screening (4, 9, 34, 40). Aims of Focused Systematic Review This review addresses 2 major uncertainties in the evidence: How much disease is actually caused by HFE mutations? and Does therapeutic phlebotomy treatment, initiated through earlier identification of those with hereditary hemochromatosis, lead to better outcomes? We also considered evidence for high-risk (as opposed to general population) screening. Methods We focused on hereditary HFE-associ

Screening adults aged 50 years or older for hearing loss: a review of the evidence for the U.S. preventive services task force.

BACKGROUND Hearing loss is common in older adults. Screening could identify untreated hearing loss and lead to interventions to improve hearing-related function and quality of life. PURPOSE To update the 1996 U.S. Preventive Services Task Force evidence review on screening for hearing loss in primary care settings in adults aged 50 years or older. DATA SOURCES MEDLINE (1950 and July 2010) and the Cochrane Library (through the second quarter of 2010). STUDY SELECTION Randomized trials, controlled observational studies, and studies on diagnostic accuracy were selected. DATA EXTRACTION Investigators abstracted details about the patient population, study design, data analysis, follow-up, and results and assessed quality by using predefined criteria. DATA SYNTHESIS Evidence on benefits and harms of screening for and treatments of hearing loss was synthesized qualitatively. One large (2305 participants) randomized trial found that screening for hearing loss was associated with increased hearing aid use at 1 year, but screening was not associated with improvements in hearing-related function. Good-quality evidence suggests that common screening tests can help identify patients at higher risk for hearing loss. One good-quality randomized trial found that immediate hearing aids were effective compared with wait-list control in improving hearing-related quality of life in patients with mild or moderate hearing loss and severe hearing-related handicap. We did not find direct evidence on harms of screening or treatments with hearing aids. LIMITATION Non-English-language studies were excluded, and studies of diagnostic accuracy in high-prevalence specialty settings were included. CONCLUSION Additional research is needed to understand the effects of screening for hearing loss compared with no screening on health outcomes and to confirm benefits of treatment under conditions likely to be encountered in most primary care settings. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Screening for primary open-angle glaucoma in the primary care setting: an update for the US preventive services task force.

PURPOSE Primary open-angle glaucoma (POAG) is a leading cause of blindness and vision-related disability. This review examines the effectiveness of screening for and treatment of early POAG in asymptomatic persons. METHODS We identified studies of glaucoma screening and treatment from MEDLINE, the Cochrane Library, and glaucoma experts. Two reviewers abstracted relevant studies and graded articles according to US Preventive Services Task Force criteria. RESULTS No randomized, controlled trials of population screening for POAG have been reported. Two randomized controlled trials compared the efficacy of treatment to lower intraocular pressure with no treatment for persons who have early primary open-angle glaucoma. In a Swedish trial, treatment reduced progression at 5 years from 62% without treatment to 45% with treatment (absolute risk reduction [ARR] 17%, number needed to treat 5.8, P = .007). In a US trial of patients with early POAG and normal intraocular pressure, progression at 5 years was observed in 39% of those without treatment and 33% of those with treatment (P = .21). The benefit of delaying progression of visual field loss on vision-related function in patients with early POAG is unclear. The principal harm of treatment is loss of visual acuity resulting from an increased risk of cataract formation. CONCLUSIONS Treatment to lower intraocular pressure may delay progression of visual field deficits in some asymptomatic individuals with early POAG. Further studies of population screening are needed to show that early recognition and treatment of glaucoma in asymptomatic patients are effective in improving vision-specific functional outcomes and health-related quality of life.

Challenges in Synthesizing and Interpreting the Evidence From a Systematic Review of Multifactorial Interventions to Prevent Functional Decline in Older Adults

A systematic review of multifactorial assessment and management interventions to prevent functional decline in older adults was undertaken for the U.S. Preventive Services Task Force. It was not possible to determine net benefit because of heterogeneity of studies, including how older adults were selected and their risk of functional decline; the broad spectrum and multifactorial nature of interventions evaluated; the suboptimal and inconsistent use of outcomes measured; and the inconsistent and inadequate reporting of data that might allow comparison of populations, interventions, and outcomes between studies. This review process illustrated the complexities encountered when synthesizing and interpreting the evidence in geriatric research and methods of reviewing complex interventions and multiple interrelated health outcomes. This article summarizes the review findings, focusing on methodological challenges, and offers suggestions to researchers on the design, reporting, and analysis of trials that would help address these challenges and allow for better interpretation of evidence in the future.

Interventions to Prevent Falls in Older Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Importance Falls are the most common cause of injury-related morbidity and mortality among older adults. Objective To systematically review literature on the effectiveness and harms of fall prevention interventions in community-dwelling older adults to inform the US Preventive Services Task Force. Data Sources MEDLINE, PubMed, Cumulative Index for Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials for relevant English-language literature published through August 2016, with ongoing surveillance through February 7, 2018. Study Selection Randomized clinical trials of interventions to prevent falls in community-dwelling adults 65 years and older. Data Extraction and Synthesis Independent critical appraisal and data abstraction by 2 reviewers. Random-effects meta-analyses using the method of DerSimonian and Laird. Main Outcomes and Measures Number of falls (number of unexpected events in which a person comes to rest on the ground, floor, or lower level), people experiencing 1 or more falls, injurious falls, people experiencing injurious falls, fractures, people experiencing fractures, mortality, hospitalizations, institutionalizations, changes in disability, and treatment harms. Results Sixty-two randomized clinical trials (N = 35 058) examining 7 fall prevention intervention types were identified. This article focused on the 3 most commonly studied intervention types: multifactorial (customized interventions based on initial comprehensive individualized falls risk assessment) (26 trials [n = 15 506]), exercise (21 trials [n = 7297]), and vitamin D supplementation (7 trials [n = 7531]). Multifactorial intervention trials were associated with a reduction in falls (incidence rate ratio [IRR], 0.79 [95% CI, 0.68-0.91]) but were not associated with a reduction in other fall-related morbidity and mortality outcomes. Exercise trials were associated with statistically significant reductions in people experiencing a fall (relative risk, 0.89 [95% 13 CI, 0.81-0.97]) and injurious falls (IRR, 0.81 [95% CI, 0.73-0.90]) and with a statistically nonsignificant reduction in falls (IRR, 0.87 [95% CI, 0.75-1.00]) but showed no association with mortality. Few exercise trials reported fall-related fractures. Seven heterogeneous trials of vitamin D formulations (with or without calcium) showed mixed results. One trial of annual high-dose cholecalciferol (500 000 IU), which has not been replicated, showed an increase in falls, people experiencing a fall, and injuries, while 1 trial of calcitriol showed a reduction in falls and people experiencing a fall; the remaining 5 trials showed no significant difference in falls, people experiencing a fall, or injuries. Harms of multifactorial and exercise trials were rarely reported but generally included minor musculoskeletal injuries. Conclusions and Relevance Multifactorial and exercise interventions were associated with fall-related benefit, but evidence was most consistent across multiple fall-related outcomes for exercise. Vitamin D supplementation interventions had mixed results, with a high dose being associated with higher rates of fall-related outcomes.