Miranda Pappas

Screening for Lung Cancer With Low-Dose Computed Tomography: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

BACKGROUND Lung cancer is the leading cause of cancer-related death in the United States. Because early-stage lung cancer is associated with lower mortality than late-stage disease, early detection and treatment may be beneficial. PURPOSE To update the 2004 review of screening for lung cancer for the U.S. Preventive Services Task Force, focusing on screening with low-dose computed tomography (LDCT). DATA SOURCES MEDLINE (2000 to 31 May 2013), the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2012), Scopus, and reference lists. STUDY SELECTION English-language randomized, controlled trials or cohort studies that evaluated LDCT screening for lung cancer. DATA EXTRACTION One reviewer extracted study data about participants, design, analysis, follow-up, and results, and a second reviewer checked extractions. Two reviewers rated study quality using established criteria. DATA SYNTHESIS Four trials reported results of LDCT screening among patients with smoking exposure. One large good-quality trial reported that screening was associated with significant reductions in lung cancer (20%) and all-cause (6.7%) mortality. Three small European trials showed no benefit of screening. Harms included radiation exposure, overdiagnosis, and a high rate of false-positive findings that typically were resolved with further imaging. Smoking cessation was not affected. Incidental findings were common. LIMITATIONS Three trials were underpowered and of insufficient duration to evaluate screening effectiveness. Overdiagnosis, an important harm of screening, is of uncertain magnitude. No studies reported results in women or minority populations. CONCLUSION Strong evidence shows that LDCT screening can reduce lung cancer and all-cause mortality. The harms associated with screening must be balanced with the benefits. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

The U.S. Preventive Services Task Force (USPSTF) recommended in 2005 that women whose family histories are associated with increased risks for clinically significant, or deleterious, mutations in the BRCA1 or BRCA2 gene be referred for genetic counseling and evaluation for mutation testing (1). This recommendation was intended for primary prevention of cancer and applies to women without previous diagnoses of breast or ovarian cancer. Deleterious mutations in the BRCA1 and BRCA2 genes are associated with increased risks for breast, ovarian, fallopian tube, and peritoneal cancer in women and breast cancer in men (2). They are also, to a lesser degree, associated with pancreatic and early-onset prostate cancer, and BRCA2 mutations are associated with melanoma. Mutations in BRCA genes cluster in families exhibiting an autosomal dominant pattern of transmission and account for 5% to 10% of cases of breast cancer overall (3, 4). Specific BRCA mutations, known as founder mutations, occur among certain ethnic groups, including Ashkenazi Jewish (57), black (8), and Hispanic persons (9, 10), and in identified families (1115). Other genes are associated with hereditary susceptibility to breast and ovarian cancer but are not commonly tested, such as PTEN (the Cowden syndrome) and TP53 (the LiFraumeni syndrome) (2, 16). Genetic risk assessment and testing involve determining individual risk for BRCA mutations, followed by selective testing of high-risk persons. Characteristics associated with an increased likelihood ofBRCA mutations (1720) include breast and ovarian cancer in relatives and young age at onset. These and other individual and family characteristics can be used to assess personal mutation risk and the need for referral for additional evaluation. Genetic counseling is the process of identifying and counseling persons at risk for familial or inherited cancer and is recommended before testing (21, 22). Guidelines recommend testing for mutations only when an individual has a personal or family history of cancer suggestive of inherited cancer susceptibility and the results can be adequately interpreted and will aid in management (23). The type of mutation analysis that is required depends on family history. Persons without links to families or groups with known mutations (510, 1214) generally have direct DNA sequencing. For appropriate candidates, interventions to reduce cancer risk include earlier, more frequent, or intensive cancer screening; risk-reducing medications; and risk-reducing surgery, including bilateral mastectomy and salpingo-oophorectomy. This systematic review is an update of a prior review (1, 24, 25) for the USPSTF on the effectiveness and adverse effects of risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. Its purpose is to evaluate and summarize research addressing specific key questions important to the USPSTF as it considers new recommendations for primary care practice. Methods This research is part of a comprehensive systematic review that includes an additional analysis of studies of the prevalence and penetrance of BRCA mutations that is not included in this manuscript (26). We followed a standard protocol consistent with the Agency for Healthcare Research and Quality (AHRQ) methods for systematic reviews (27). On the basis of evidence gaps identified from a prior review (24, 25), the USPSTF and AHRQ determined the key questions for this update by using the methods of the USPSTF (28). Investigators created an analytic framework incorporating the key questions and outlining the patient populations, interventions, outcomes, and potential adverse effects (Appendix Figure 1). A work plan was externally reviewed and modified. Appendix Figure 1. Analytic framework and key questions. KQ = key question; MRI = magnetic resonance imaging. * Clinically significant mutations of the BRCA1 or BRCA2 gene or related syndromes. Testing may be done on the unaffected woman, the relative with cancer, or the relative with the highest risk, as appropriate. No known mutation in relatives and none detected in the patient. Known mutation in relatives but none detected in the patient. Interventions include increased early detection through intensive screening (e.g., earlier and more frequent mammography and breast MRI), risk-reducing medications (tamoxifen and raloxifene), and risk-reducing surgery (mastectomy and salpingo-oophorectomy). The target population includes women without cancer or known BRCA mutations who are seen in clinical settings applicable to U.S. primary care practice, although the ideal candidate for mutation testing could be a male or female relative withcancer. The conditions of interest are mutation carrier status and BRCA-related cancer (predominantly breast, ovarian, fallopian tube, and peritoneal). Although other types of cancer are also considered during familial risk assessment, studies with these cancer outcomes are outside the scope of this review. Data Sources We searched MEDLINE from 2004 to 30 July 2013, the Cochrane Central Register of Controlled Trials and Cochrane Databaseof Systematic Reviews from 2004 through the second quarter of 2013, and Health Technology Assessment during the fourth quarter of 2012 for relevant English-language studies, systematic reviews, and meta-analyses. We manually reviewed reference lists of articles and reviewed citations of key studies by using Scopus. Study Selection Research published in 2004 or later and done in the United States or in populations that receive services and interventions applicable to medical practice in the United States was reviewed. Randomized, controlled trials (RCTs); systematic reviews; prospective and retrospective cohort studies; casecontrol studies; and diagnostic accuracy evaluations were included if they addressed the accuracy of risk assessment methods, outcomes of genetic counseling and testing, and the effectiveness of interventions to reduce BRCA-related cancer and mortality among mutation carriers. Risk assessment methods were included if they were designed to guide referrals to genetic counselors or other genetic specialists and could be used by nonspecialists in genetics in clinical settings (that is, methods that were brief and nontechnical and did not require special training to administer or interpret). Evaluation of comprehensive models used in the practice of genetic counseling was outside the scope of this review, which focuses on primary care practice. Interventions included intensive screening, risk-reducing medications, and risk-reducing surgery. Only risk-reducing medications approved by the U.S. Food and Drug Administration (that is, tamoxifen and raloxifene) were considered, consistent with the scope of the USPSTF. Studies of any design were included if they described potential adverse effects, including inaccurate risk assessment; inappropriate testing; false-positive and false-negative results; false reassurance; incomplete testing; misinterpretation of results; anxiety; cancer-related worry; immediate and long-term harms associated with interventions; and ethical, legal, and social implications. For adverse effects of interventions, studies were included that enrolled women at high risk for BRCA-related cancer regardless of their mutation status. After an initial review of abstracts, we reviewed full-text articles by using additional inclusion criteria. Studies from the prior review that met inclusion criteria for the update were included to build on previous relevant research. Appendix Figure 2 shows the results of the search and selection process. Appendix Figure 2. Summary of evidence search and selection. * Identified from reference lists, hand-searching, suggestions from experts, and other methods. Results are provided in an additional publication (26). Studies that provided data and contributed to the body of evidence were considered to be included. Studies may contribute data to >1 key question. This number includes studies from the prior review as well as studies published since 2004. Data Abstraction and Quality Assessment An investigator abstracted data about the study design and setting; participant characteristics; procedures for data collection; number of participants enrolled and lost to follow-up; methods of exposure and outcome ascertainment; analytic methods, including adjustment for confounders; and outcomes. A second investigator confirmed the accuracy of key data. Two investigators used predefined criteria for RCTs; systematic reviews; and cohort, casecontrol, and diagnostic accuracy studies developed by the USPSTF (28, 29) to rate the quality of studies (good, fair, or poor) and resolved discrepancies by consensus. Quality could not be assessed for many studies with designs that did not have predefined criteria, such as descriptive, cross-sectional, and prepost studies and case series. The applicability of studies was determined using the population, intervention, comparator, outcomes, timing of outcomes measurement, and setting format adapted to this topic (30). Data Synthesis and Analysis Because of heterogeneity across studies, results were not combined in a quantitative meta-analysis. We assessed the aggregate quality of the body of evidence (good, fair, or poor) by using methods that the USPSTF developed on the basis of the number, quality, and size of studies and consistency of results between studies (28). Studies were considered consistent if outcomes were generally in the same direction of effect and ranges of effect sizes were narrow. Role of the Funding Source This research was funded by the AHRQ. Investigators worked with AHRQ staff and USPSTF members to define the scope, analytic framework, and key questions; resolve issues arising during the project; and review the final report to ensure that it met basic methodological standards for systematic reviews. The draft report was reviewed by content experts, USPSTF members, AHR

Harms of Breast Cancer Screening: Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation.

In 2009, the U.S. Preventive Services Task Force (USPSTF) recommended biennial mammography screening for women aged 50 to 74 years (1) on the basis of evidence of benefits and harms (2, 3). The USPSTF concluded that screening decisions for women aged 40 to 49 years should be based on individual considerations and that evidence was insufficient to assess benefits and harms for those aged 75 years or older (1). Although there is general consensus that mammography screening is beneficial for many women, benefits must be weighed against potential harms to determine the net effect of screening on individual women. Determining the balance between benefits and harms is complicated by several important considerations that are unresolved, including defining and quantifying potential harms; the optimal ages at which to begin and end routine screening; the optimal screening intervals; appropriate use of various imaging modalities, including supplemental technologies; values and preferences of women in regards to screening; and how all of these considerations vary depending on a womans risk for breast cancer. This systematic review updates evidence for the USPSTF on the harms of breast cancer screening, including false-positive mammography results, overdiagnosis, anxiety, pain during procedures, and radiation exposure, and how these adverse effects vary by age, risk factor, screening interval, and screening modality. Systematic reviews of the effectiveness of screening (4), performance characteristics of screening methods (5), and the accuracy of breast density determination and use of supplemental screening technologies (6) are provided in additional reports. Methods Scope, Key Questions, and Analytic Framework The USPSTF determined the scope and key questions for this review by using established methods (7, 8). A standard protocol was developed and publicly posted on the USPSTF Web site. A technical report further describes the methods and includes search strategies and additional information (4). Investigators created an analytic framework outlining the key questions, patient populations, interventions, and outcomes reviewed (Appendix Figure 1). Key questions include the harms of routine breast cancer screening and how they differ by age, risk factor, screening interval, and screening modality (mammography [film, digital, or tomosynthesis], magnetic resonance imaging [MRI], and ultrasonography). Harms include false-positive and false-negative mammography results, overdiagnosis, anxiety and other psychological responses, pain during procedures, and radiation exposure. Overdiagnosis refers to women receiving a diagnosis of ductal carcinoma in situ (DCIS) or invasive breast cancer when they have abnormal lesions that are unlikely to become clinically evident during their lifetime in the absence of screening. Overdiagnosed women may be harmed by unnecessary procedures and treatments as well as by the burden of receiving a cancer diagnosis. Appendix Figure 1. Analytic framework and key questions. KQ = key question. * Excludes women with preexisting breast cancer; clinically significant BRCA1 or BRCA2 mutations, Li-Fraumeni syndrome, Cowden syndrome, hereditary diffuse gastric cancer, or other familial breast cancer syndrome; high-risk lesions (ductal carcinoma in situ, lobular carcinoma in situ, atypical ductal hyperplasia, or atypical lobular hyperplasia); or previous large doses of chest radiation (20 Gy) before age 30 y. False-positive and false-negative mammography results, biopsy recommendations due to false-positive mammography results, overdiagnosis and resulting overtreatment, anxiety, pain, and radiation exposure. Family history; breast density; race/ethnicity; menopausal status; current use of menopausal hormone therapy or oral contraceptives; prior benign breast biopsy; and, for women aged >50 y, body mass index. Mammography (film, digital, or tomosynthesis), magnetic resonance imaging, ultrasonography, and clinical breast examination (alone or in combination). The target population for the USPSTF recommendation includes women aged 40 years or older and excludes women with known physical signs or symptoms of breast abnormalities and those at high risk for breast cancer whose surveillance and management are beyond the scope of the USPSTF recommendations for preventive services (preexisting breast cancer or high-risk breast lesions, hereditary genetic syndromes associated with breast cancer, and previous large doses of chest radiation before age 30 years). Risk factors considered in this review are common among women who are not at high risk for breast cancer (9) (described in Appendix Figure 1). Data Sources and Searches A research librarian conducted electronic searches of the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE through December 2014 for relevant studies and systematic reviews. Searches were supplemented by references identified from additional sources, including reference lists and experts. Studies of harms included in the previous systematic review for the USPSTF (2, 3) were also included. Study Selection Two investigators independently evaluated each study to determine eligibility based on prespecified inclusion criteria. Discrepancies were resolved through consensus. We included recently published systematic reviews; randomized, controlled trials (RCTs); and observational studies of prespecified harms. When available, studies providing outcomes specific to age, risk factors, screening intervals, and screening modalities were preferred over studies providing general outcomes. Studies that were most clinically relevant to practice in the United States were selected; relevance was determined by practice setting, population, date of publication, and use of technologies and therapies in current practice. Studies meeting criteria for high quality and with designs ranked higher in the study designbased hierarchy of evidence were emphasized because they are less susceptible to bias (for example, RCTs were chosen over observational studies). Data Extraction and Quality Assessment Details of the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results were abstracted by one investigator and confirmed by another. Two investigators independently applied criteria developed by the USPSTF (7, 8) to rate the quality of each RCT, cohort study, casecontrol study, and systematic review as good, fair, or poor; criteria to rate studies with other designs included in this review are not available. Discrepancies were resolved through consensus. Data Synthesis Studies meeting inclusion criteria were qualitatively synthesized. Most studies in this review had designs for which quality rating criteria are not available, which limited data synthesis. When possible, we assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) by using methods developed by the USPSTF based on the number, quality, and size of studies; consistency of results between studies; and directness of evidence (7, 8). Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. The investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic frameworks, and key questions; resolve issues during the project; and finalize the report. The AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. The AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. The AHRQ performed a final review of the manuscript to ensure that the analysis met methodological standards. The investigators are solely responsible for the content and the decision to submit the manuscript for publication. Results Of the 12004 abstracts identified by searches and other sources, 59 studies met inclusion criteria for key questions in this report, including 10 systematic reviews of 134 studies and 49 additional studies (Appendix Figure 2). Appendix Figure 2. Summary of evidence search and selection. RCT = randomized, controlled trial. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. False-Positive Mammography Results Two new observational studies estimated the cumulative probability of false-positive results after 10 years of screening with film and digital mammography, based on data from the Breast Cancer Surveillance Consortium, a large population-based database in the United States (Appendix Table 1) (10, 11). When screening began at age 40 years, the cumulative probability of receiving at least 1 false-positive mammography result after 10 years was 61% (95% CI, 59% to 63%) with annual screening and 42% (CI, 41% to 43%) with biennial screening (10). Estimates were similar when screening began at age 50 years. The cumulative probability of receiving a biopsy recommendation due to a false-positive mammography result after 10 years of screening was 7% (CI, 6% to 8%) with annual screening versus 5% (CI, 4% to 5%) with biennial screening for women who initiated screening at age 40 years and 9% (CI, 7% to 12%) with annual screening versus 6% (CI, 6% to 7%) with biennial screening for those who began at age 50 years. Appendix Table 1. U.S. Studies of Cumulative False-Positive Mammography and Biopsy Results In a separate analysis, rates of false-positive mammography results were highest among women receiving annual mammography who had extremely dense breasts and either were aged 40 to 49 years (65.5%) or used combination hormone therapy (65.8%) (11). The highest rates of biopsy due to false-positive mammography results were related to similar characteristics and ranged from 12% to 1

Effectiveness of Breast Cancer Screening: Systematic Review and Meta-analysis to Update the 2009 U.S. Preventive Services Task Force Recommendation

In 2009, the U.S. Preventive Services Task Force (USPSTF) recommended biennial mammography screening for women aged 50 to 74 years (1) on the basis of evidence of benefits and harms (2). The USPSTF concluded that screening decisions for women aged 40 to 49 years should be based on individual considerations, and that evidence was insufficient to assess benefits and harms for women aged 75 years or older (1). Mammography screening in the United States is generally opportunistic, unlike many screening programs organized as public health services in other countries. Despite changes in practice guidelines and variation in clinical practices (3), overall screening rates in the United States have remained relatively stable for the past decade (4, 5). Data from the Healthcare Effectiveness Data and Information Set indicate that mammography screening in 2014 in HMOs was performed for 74% of eligible women covered by commercial plans, 72% by Medicare, and 59% by Medicaid (6). This systematic review updates evidence for the USPSTF on the effectiveness of mammography screening in reducing breast cancer mortality, all-cause mortality, and advanced breast cancer for women at average risk; and how effectiveness varies by age, risk factors, screening intervals, and imaging modalities. Systematic reviews of harms of screening (7), performance characteristics of screening methods (8), and accuracy of breast density determination and use of supplemental screening technologies (9) are provided in separate reports. Methods Scope, Key Questions, and Analytic Framework The USPSTF determined the scope and key questions for this review by using established methods (10, 11). A standard protocol was developed and publicly posted on the USPSTF Web site. A technical report further describes the methods and includes search strategies and additional information (7). Investigators created an analytic framework outlining the key questions, patient populations, interventions, and outcomes reviewed (Appendix Figure 1). Key questions include the effectiveness of screening in reducing breast cancer mortality, all-cause mortality, and advanced breast cancer, and how effectiveness differs by age, risk factors, screening intervals, and modalities (mammography [film, digital, tomosynthesis], magnetic resonance imaging [MRI], and ultrasonography). Appendix Figure 1. Analytic framework and key questions. KQ = key question. * Excludes women with preexisting breast cancer; clinically significant BRCA1 or BRCA2 mutations, LiFraumeni syndrome, Cowden syndrome, hereditary diffuse gastric cancer, or other familial breast cancer syndromes; high-risk lesions (ductal carcinoma in situ, lobular carcinoma in situ, atypical ductal hyperplasia, atypical lobular hyperplasia); or previous large doses of chest radiation (20 Gy) before age 30 y. Risk factors include family history; breast density; race/ethnicity; menopausal status; current use of menopausal hormone therapy or oral contraceptives; prior benign breast biopsy; and, for women aged >50 y, body mass index. Morbidity includes physical adverse effects of treatment, quality-of-life measures, and other measures of impairment. Screening modalities include mammography (film, digital, tomosynthesis), magnetic resonance imaging, ultrasonography, and clinical breast examination (alone or in combination). The target population for the USPSTF recommendation includes women aged 40 years or older, and excludes women with known physical signs or symptoms of breast abnormalities and those at high-risk for breast cancer whose surveillance and management are beyond the scope of the USPSTFs recommendations for prevention services (i.e., preexisting breast cancer or high-risk breast lesions, hereditary genetic syndromes associated with breast cancer, or previous large doses of chest radiation before age 30 years). Risk factors considered in this review are common among women who are not at high risk for breast cancer (12) (Appendix Figure 1). Data Sources and Searches A research librarian conducted electronic database searches of the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Ovid MEDLINE to 4 June 2015. Searches were supplemented by references identified from additional sources, including reference lists and experts. Additional unpublished data were provided by the investigators of the Canadian National Breast Screening Study (CNBSS) and Swedish Two-County Trial. Study Selection Two investigators independently evaluated each study to determine inclusion eligibility on the basis of prespecified criteria. Discrepancies were resolved through consensus. We included randomized, controlled trials (RCTs); observational studies of screening cohorts; and systematic reviews that compared outcomes of women exposed to screening versus not screening. For advanced cancer outcomes, studies that reported the incidence of late-stage disease among screened and unscreened populations were included, whereas those reporting comparisons of detection methods that did not capture a womans longitudinal screening experience were not included (e.g., rates of screen-detected vs. nonscreen-detected cancer). Studies providing outcomes specific to age, risk factors, screening intervals, and modalities were preferred over studies providing general outcomes, when available. Studies most clinically relevant to practice in the United States were selected over studies that were less relevant. Relevance was determined by practice setting, population, date of publication, and use of technologies and therapies in current practice. Studies meeting criteria for high quality and those with designs ranked higher in the study designbased hierarchy of evidence were emphasized because they are less susceptible to bias (e.g., RCTs over observational studies). Data Extraction and Quality Assessment Details of the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results were abstracted by one investigator and confirmed by a second. Two investigators independently applied criteria developed by the USPSTF (10, 11) to rate the quality of each study as good, fair, or poor for studies designed as RCTs, cohort studies, casecontrol studies, and systematic reviews; criteria to rate other study designs included in this review are not available. Discrepancies were resolved through consensus. Data Synthesis We conducted several meta-analyses to determine more precise summary estimates when adequate data were reported by trials rated as fair- or good-quality. In each meta-analysis, the number of included trials was counted as the number of discrete data sources contributing to the summary estimate using their most recent results. To determine the appropriateness of meta-analysis, we considered clinical and methodological diversity and assessed statistical heterogeneity. All outcomes were binary (breast cancer mortality, all-cause mortality, and advanced cancer incidence defined by stage and tumor size). We used a random-effects model to combine relative risks (RRs) as the effect measure of the meta-analyses, while incorporating variation among studies. A profile-likelihood model was used to combine studies in the primary analyses (13). We assessed the presence of statistical heterogeneity among the studies by using the standard Cochran chi-square test, and the magnitude of heterogeneity by using the I 2 statistic (14). To account for clinical heterogeneity and obtain clinically meaningful estimates, we stratified the analyses by age group whenever possible (39 to 49 years, 50 to 59 years, 60 to 69 years, 70 to 74 years, and 50 years). We obtained additional age-stratified data for the meta-analysis from the investigators of 3 trials (15, 16) (Tabr L. Personal communication). For breast cancer mortality, we used 2 methods of including cases to help clarify discrepancies between estimates. The long case accrual method counts all breast cancer cases contributing to breast cancer deaths. In this method, the case accrual time is equivalent to or close to the follow-up time. The short case accrual method includes only deaths that occur among cases of breast cancer diagnosed during the screening intervention period, and in some trials, within an additional defined case accrual period. The longest follow-up times available for each trial were selected for inclusion in the initial meta-analyses, and sensitivity analyses were conducted by using results of short case accrual methods. We calculated the absolute rate reduction for 100000 woman-years of follow-up (i.e., 10000 women followed for 10 years) for each age group on the basis of the combined RR and the combined cancer rate of the control group. We estimated combined cancer rates for each age group for controls with a random effects Poisson model using data from the trials. All analyses were performed by using Stata/IC, version 13.1 (StataCorp). We assessed the aggregate internal validity (quality) of the body of evidence for each key question as good, fair, or poor by using methods developed by the USPSTF that are based on the number, quality, and size of studies; consistency of results between studies; and directness of evidence (10, 11). Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. The investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic framework, and key questions; resolve issues during the project; and finalize the report. The AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. The AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. The AHRQ performed a final review of the manuscript to ensure that the

Screening for Vitamin D Deficiency: A Systematic Review for the U.S. Preventive Services Task Force

Vitamin D is obtained through food consumption and synthesis in the skin after ultraviolet (UV) B exposure (1). Researchers have reported associations between low 25-hydroxyvitamin D [25-(OH)D] levels and risk for fractures (26), falls (7, 8), cardiovascular disease (914), colorectal cancer (1320), diabetes (13, 14, 2129), depressed mood (13, 14, 30, 31), cognitive decline (13, 14), and death (13, 32). Vitamin D deficiency is determined by measuring total serum 25-(OH)D concentrations (33). Measuring 25-(OH)D levels is complicated by the presence of multiple assays (34); evidence of intermethod and interlaboratory variability in measurement (3543); and the lack of an internationally recognized, commutable vitamin D reference standard (44). Efforts to increase standardization are in progress (34, 44). There is no consensus on optimal 25-(OH)D concentrations. Although experts generally agree that levels lower than 50 nmol/L (20 ng/mL) are associated with bone health (36, 45), disagreement exists about whether optimal 25-(OH)D levels are higher than this threshold (Table 1). According to NHANES (National Health and Nutrition Examination Survey) data from 2001 to 2006, 33% of the U.S. population was at risk for 25-(OH)D levels below 50 nmol/L (20 ng/mL) (47) and 77% had 25-(OH)D levels below 75 nmol/L (30 ng/mL) (48). Risk factors for low vitamin D levels include darker skin pigmentation (33), low vitamin D intake (4951), little or no UVB exposure (49, 50, 5254), and obesity (4951, 55). Older age (4953), female sex (49, 51, 52), low physical activity (49, 50, 53), low education attainment (48), and low health status (51, 54) were factors also associated with vitamin D deficiency in some studies. Table 1. Summary of Current Opinions About Appropriate 25-(OH)D Level Cutoffs for Defining Vitamin D Deficiency and Associations Between These Cutoffs and Health Outcomes* Vitamin D deficiency is treated by increasing dietary intake of food fortified with vitamin D or oral vitamin D treatment. Two commonly available vitamin D treatments (vitamin D3 [cholecalciferol] and vitamin D2 [ergocalciferol]) are available in several forms (for example, tablet and gel capsule), dosages (for example, 200 to 500000 IU), and dosing regimens (for example, daily, weekly, monthly, or yearly) and can be given in combination with oral calcium (56, 57). Potential harms of vitamin D treatment include hypercalcemia, hyperphosphatemia, suppressed parathyroid hormone levels, and hypercalciuria (46, 58, 59). Although very high levels of vitamin D are associated with other potential harms, these events are rare with typical replacement doses (Table 1). Screening for vitamin D deficiency can identify persons with low levels who might benefit from treatment. This report reviews the current evidence on vitamin D screening in asymptomatic adults to help the U.S. Preventive Services Task Force (USPSTF) develop a recommendation statement. Although the USPSTF has not previously issued recommendations on screening for vitamin D deficiency, it has made recommendations on vitamin D supplementation to prevent adverse health outcomes (for example, falls, fractures, cancer, and cardiovascular disease) in populations not necessarily vitamin Ddeficient (that is, general populations who may or may not have been deficient) (6063). Methods Scope of the Review We developed a review protocol and analytic framework (Appendix Figure 1) that included the following key questions: Appendix Figure 1. Analytic framework. Numbers on figures indicate key questions. For a list of key questions, see the Methods section or Table 2. 1. Is there direct evidence that screening for vitamin D deficiency results in improved health outcomes? 1a. Are there differences in screening efficacy between patient subgroups? 2. What are the harms of screening (for example, risk for procedure, false positives, or false negatives)? 3. Does treatment of vitamin D deficiency using vitamin D lead to improved health outcomes? 3a. Are there differences in efficacy between patient subgroups? 4. What are the adverse effects of treatment of vitamin D deficiency using vitamin D? 4a. Are there differences in adverse effects between patient subgroups? Detailed methods and data for this review are contained in the full report, including search strategies, inclusion criteria, abstraction and quality rating tables, and contextual questions (46). We developed our protocol using a standardized process after gathering input from experts and the public. The analytic framework focuses on direct evidence that screening for vitamin D deficiency improves important health outcomes (for example, death, falls, fractures, functional status, or risk for cancer) versus not screening. Further, the framework details evidence that treatment in persons found to have vitamin D deficiency is associated with improved health outcomes, harms resulting from screening or subsequent treatment, and how effects of screening and treatment vary in subgroups defined by demographic and other factors (for example, body mass index, UV exposure, and institutionalized status). We did not review the accuracy of vitamin D testing because of the lack of an accepted reference standard and studies reporting diagnostic accuracy. For the purposes of this report, the term vitamin Ddeficient refers to populations in which at least 90% of persons have 25-(OH)D levels of 75 nmol/L (30 ng/mL) or less. For studies that did not restrict enrollment to persons with 25-(OH)D levels of 75 nmol/L (30 ng/mL), we used the mean 25-(OH)D level plus the SD multiplied by 1.282 to approximate the 90th percentile to determine whether this level was at or below the 75-nmol/L (30-ng/mL) threshold. Because of uncertainty about what 25-(OH)D level constitutes deficiency, we stratified studies according to whether at least 90% of persons had levels less than 50 nmol/L (<20 ng/mL in this report) or at least 90% had levels less than 75 nmol/L (30 ng/mL) with at least 10% greater than 50 nmol/L (20 ng/mL) (75 nmol/L [30 ng/mL] in this report). Data Sources and Searches A research librarian searched Ovid MEDLINE (1946 through the third week of August 2014), Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (through August 2014). We supplemented our electronic searches by reviewing reference lists of retrieved articles. Study Selection At least 2 reviewers independently evaluated each study to determine inclusion eligibility. For screening studies, we included randomized, controlled trials (RCTs) of screening for vitamin D deficiency versus no screening in healthy, asymptomatic adults (aged 18 years). For studies of the effectiveness of vitamin D treatment, we included RCTs of vitamin D treatment with or without calcium versus placebo or no treatment in vitamin Ddeficient persons that reported health outcomes after at least 8 weeks of treatment. Because the Womens Health Initiative (WHI) is the largest RCT about vitamin D (64), we included data from nested casecontrol studies of WHI participants with known 25-(OH)D status. We included English-language articles only and excluded studies published only as abstracts. We included studies conducted in the United States, Canada, United Kingdom, and other geographic settings generalizable to the United States. We excluded studies that specifically targeted populations with symptoms or conditions associated with vitamin D deficiency (for example, osteoporosis, history of nontraumatic fractures, or history of falls) or with medical conditions that increase a persons risk for deficiency (such as liver, kidney, or malabsorptive disease) because screening and treatment of vitamin D deficiency could be a component of medical management in these conditions. The summary of evidence search and selection is shown in Appendix Figure 2. Appendix Figure 2. Summary of evidence search and selection. 25-(OH)D = 25-hydroxyvitamin D. * Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Identified from reference lists or by hand-searching or suggested by experts. Studies that provided data and contributed to the body of evidence were considered included. Studies may have provided data for more than 1 key question or published article; 27 unique studies were included, and a total of 35 articles were included. Data Abstraction and Quality Rating One investigator abstracted details about the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results. A second investigator reviewed data for accuracy. Two investigators independently applied USPSTF criteria (65) to rate the quality of each study as good, fair, or poor. We resolved discrepancies through a consensus process. We excluded from data synthesis studies rated as poor quality. Those studies had 1 or more fatal flaws, including inadequate randomization or lack of intervention fidelity combined with postrandomization exclusions, high rates of withdrawals, and unclear randomization. Data Synthesis and Analysis We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) using methods developed by the USPSTF on the basis of the number, quality, and size of studies; consistency of results; and directness of evidence (65). We conducted meta-analyses to calculate risk ratios (RRs) using the DerSimonianLaird random-effects model (Review Manager, version 5.2; Cochrane Collaboration). Analyses were based on total follow-up (including time after discontinuation of vitamin D treatment). For falls per person, we calculated incidence rate ratios and assumed equal mean length of follow-up across treatment groups if these data were not reported. For analyses with between-study heterogeneity, we conducted sensitivity analyses using profile likelihood random-effects models (66). Rate ratio analysis and analyses using the profil

Patient-Centered Outcomes among Lung Cancer Screening Recipients with Computed Tomography: A Systematic Review

Introduction: Lung cancer screening using low-dose computed tomography (LDCT) is now widely recommended for adults who are current or former heavy smokers. It is important to evaluate the impact of screening on patient-centered outcomes. Among current and former smokers eligible for lung cancer screening, we sought to determine the consequences of screening with LDCT, and subsequent results, on patient-centered outcomes such as quality of life, distress, and anxiety. Methods: We searched the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth Quarter 2012), MEDLINE (2000 to May 31, 2013), reference lists of articles, and Scopus for relevant English-language studies and systematic reviews. To evaluate the effect of LDCT screening on patient-centered outcomes, we included only randomized controlled trials (RCTs) involving asymptomatic adults. To evaluate the association of particular results and/or recommendations from a screening LDCT with patient-centered outcomes, we included results from RCTs as well as from cohort studies. Results: A total of 8215 abstracts were reviewed. Five publications from two European RCTs and one publication from a cohort study conducted in the United States met inclusion criteria. The process of LDCT lung cancer screening was associated with short-term psychologic discomfort in many people but did not affect distress, worry, or health-related quality of life. False-positive results were associated with short-term increases in distress that returned to levels that were similar to those among people with negative results. Negative results were associated with short-term decreases in distress. Conclusions: As lung cancer screening is implemented in the general population, it will be important to evaluate its association with patient-centered outcomes. People considering lung cancer screening should be aware of the possibility of distress caused by false-positive results. Clinicians may want to consider tailoring communication strategies that can decrease the distress associated with these results.

Preventing Dental Caries in Children <5 Years: Systematic Review Updating USPSTF Recommendation

BACKGROUND AND OBJECTIVE: Screening and preventive interventions by primary care providers could improve outcomes related to early childhood caries. The objective of this study was to update the 2004 US Preventive Services Task Force systematic review on prevention of caries in children younger than 5 years of age. METHODS: Searching Medline and the Cochrane Library (through March 2013) and reference lists, we included trials and controlled observational studies on the effectiveness and harms of screening and treatments. One author extracted study characteristics and results, which were checked for accuracy by a second author. Two authors independently assessed study quality. RESULTS: No study evaluated effects of screening by primary care providers on clinical outcomes. One good-quality cohort study found pediatrician examination associated with a sensitivity of 0.76 for identifying a child with cavities. No new trials evaluated oral fluoride supplementation. Three new randomized trials were consistent with previous studies in finding fluoride varnish more effective than no varnish (reduction in caries increment 18% to 59%). Three trials of xylitol were inconclusive regarding effects on caries. New observational studies were consistent with previous evidence showing an association between early childhood fluoride use and enamel fluorosis. Evidence on the accuracy of risk prediction instruments in primary care settings is not available. CONCLUSIONS: There is no direct evidence that screening by primary care clinicians reduces early childhood caries. Evidence previously reviewed by the US Preventive Services Task Force found oral fluoride supplementation effective at reducing caries incidence, and new evidence supports the effectiveness of fluoride varnish in higher-risk children.

Smoking Behaviors among Patients Receiving Computed Tomography for Lung Cancer Screening. Systematic Review in Support of the U.S. Preventive Services Task Force

RATIONALE Lung cancer screening using low-dose computed tomography (LDCT) is now widely recommended for adults who are current or former heavy smokers. It is important to evaluate the impact of screening on smoking abstinence rates. OBJECTIVE Among current and former smokers eligible for lung cancer screening, we sought to determine the consequence of screening with LDCT, as well as subsequent results, on smoking cessation and relapse rates. EVIDENCE REVIEW We searched the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter, 2012), MEDLINE (2000 to May 31, 2013), reference lists of papers, and Scopus for relevant English-language studies and systematic reviews. To evaluate the effect of LDCT screening on smoking abstinence, we included only randomized controlled trials (RCTs) involving asymptomatic adults. To evaluate the association of particular results and/or recommendations from a screening CT with smoking behaviors, we included results from RCTs as well as cohort studies. MEASUREMENTS AND MAIN RESULTS A total of 8,215 abstracts were reviewed. Three publications from two European RCTs and five publications from three cohort studies conducted in the United States met inclusion criteria. The process of LDCT lung cancer screening did not influence smoking behaviors. LDCT recipients with results concerning for lung cancer had higher abstinence rates than those with scans without such findings. This association may have a dose-response relationship in terms of the number of abnormal CT scans as well as the seriousness of the finding. CONCLUSIONS Limited evidence suggests LDCT lung cancer screening itself does not influence smoking behaviors, but positive results are associated with increased abstinence. As lung cancer screening is implemented in the general population, it is very important to evaluate its association with smoking behaviors to maximize its potential as a teachable moment to encourage long-term abstinence. Clinicians should consider tailoring LDCT result communication to emphasize the importance of smoking abstinence.

Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

Hepatocellular carcinoma (HCC) is the most common primary malignant neoplasm of the liver, usually developing in persons with chronic liver disease. Worldwide, it is the fifth most common type of cancer and the third most common cause of death from cancer (1). There were 25000 deaths attributed to liver and intrahepatic bile duct cancer in the United States in 2011 (2). Common causes of HCC are hepatitis C virus infection, hepatitis B virus infection, and alcohol abuse, although a substantial proportion of cases have no identifiable cause (35). Imaging modalities for HCC include ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Although CT and MRI provide higher-resolution images than ultrasonography, they are also more costly and, in the case of CT, are associated with radiation exposure (5). Because HCC is typically a hypervascular lesion, CT and MRI are performed with arterial-enhancing contrast agents. Microbubble-enhanced ultrasonography can also be performed, although agents are not yet approved by the U.S. Food and Drug Administration for this purpose, and microbubbles are present in the liver for only a limited duration (6). Other technical, patient, and tumor factors may also affect test performance (712). This article reviews the test performance of ultrasonography, MRI, and CT for detection of HCC and for evaluation of focal liver lesions. This was conducted as part of a larger review commissioned by the Agency for Healthcare Research and Quality (AHRQ) on HCC imaging (13). Supplement. Original Version (PDF) Methods Scope of the Review The protocol was developed by using a standardized process with input from experts and the public and was registered in the PROSPERO database (CRD42014007016) (14). The review protocol included key questions on the comparative test performance of imaging for detection of HCC and for evaluation of focal liver lesions. Detailed methods and data for the review, including search strategies, inclusion criteria, and abstraction and quality ratings tables, are available in the full report, which also includes further key questions, full sensitivity and subgroup analyses, and an additional imaging modality (positron emission tomography) (13). Data Sources and Searches A research librarian searched multiple electronic databases, including MEDLINE (1998 to December 2013 for the full report; the update search for the review in this article was performed in December 2014), the Cochrane Library, and Scopus. Additional studies were identified by reviewing reference lists and from peer review suggestions. Study Selection Two investigators independently evaluated each study at the title/abstract and full-text article stages to determine inclusion eligibility (Appendix Table 1). We included studies on the test performance of ultrasonography, CT, or MRI against a reference standard for detection of HCC in surveillance or nonsurveillance settings (for example, imaging performed in patients undergoing treatment for liver disease or in whom HCC was previously diagnosed) or for further evaluation of focal liver lesions. Reference standards were histopathologic examination based on explanted liver or nonexplant histologic specimens, imaging plus clinical follow-up (for example, lesion growth), or a combination of these. Appendix Table 1. Inclusion and Exclusion Criteria We selected studies of ultrasonography (with or without contrast) and contrast-enhanced CT and MRI that met minimum technical criteria (non-multidetector or multidetector spiral CT, or 1.5- or 3.0-T MRI) (7). We excluded studies published before 1998 and those in which imaging began before 1995, unless the imaging methods met minimum technical criteria; studies of MRI with contrast agents no longer commercially produced (for example, superparamagnetic iron oxide [ferumoxides or ferucarbotran] or mangafodipir); and studies of CT arterial portography, CT hepatic angiography, and intraoperative ultrasonography. We included studies of ultrasonography microbubble contrast agents because they are commercially available and commonly used outside the United States, and efforts to obtain approval from the U.S. Food and Drug Administration are ongoing (1517). We excluded studies of diagnostic accuracy for non-HCC malignant lesions, including liver metastases. We included studies that reported results for HCC and cholangiocarcinoma together if cholangiocarcinoma lesions comprised less than 10% of the total. Studies on the accuracy of imaging for distinguishing HCC from a specific type of liver lesion (such as hemangioma or pseudolesion) and on the accuracy of imaging tests used in combination are addressed in the full report (13). We excluded studies published only as conference abstracts and included only English-language articles. The literature flow diagram is shown in Appendix Figure 1. Appendix Figure 1. Summary of evidence search and selection. * Studies of positron emission tomography; effects on clinical decisions, clinical outcomes, or staging; and accuracy for distinguishing hepatocellular carcinoma lesions from another specific type of liver lesion are addressed in the full report (13). Data Abstraction and Quality Rating One investigator abstracted details on the study design, dates of imaging and publication, patient population, country, sample size, imaging method and associated technical factors (Appendix Table 2), and results. Two investigators independently applied the approach recommended in the AHRQ Methods Guide for Medical Test Reviews to assess risk of bias as high, moderate, or low (18, 19). Appendix Table 2. Technical Factors Abstracted, by Imaging Modality Data Synthesis We conducted meta-analysis with a bivariate logistic mixed random-effects model that incorporated the correlation between sensitivity and specificity, using SAS software, version 9.3 (SAS Institute) (20). We assumed bivariate normal distributions for sensitivity and specificity. Statistical heterogeneity was measured with the random-effect variance (2). We calculated positive and negative likelihood ratios by using the summarized sensitivity and specificity (21, 22). We analyzed data separately for each imaging modality; ultrasonography with and without contrast were also analyzed separately. We also separately analyzed studies in which imaging was performed for detection of HCC and for evaluation of focal liver lesions; studies on HCC detection were further stratified by setting (surveillance or nonsurveillance). We separately analyzed test performance by using patients with HCC or by using HCC lesions (one patient can have multiple lesions) as the unit of analysis. Other sensitivity and subgroup analyses were conducted on the reference standard, factors related to risk of bias, country, technical factors (Appendix Table 2), tumor factors (such as HCC lesion size or degree of tumor differentiation), and patient characteristics (for example, severity of underlying liver disease, underlying cause of liver disease, and body mass index). We performed separate analyses on the subset of studies that directly compared 2 or more imaging modalities or techniques in the same population against a common reference standard (23). We used the same bivariate logistic mixed-effects model as described above, with an added indicator variable for imaging modalities. We also performed meta-analyses for within-study comparisons on lesion size, degree of tumor differentiation, and (when data were available) technical factors. We graded the strength of each body of evidence as high, moderate, low, or insufficient on the basis of the aggregate risk of bias, consistency, precision, and directness (24). Role of the Funding Source This research was funded by the AHRQ Effective Health Care Program. Investigators worked with AHRQ staff to develop and refine the review protocol. The AHRQ staff had no role in conducting the review, and the investigators are solely responsible for the content of the manuscript and the decision to submit for publication. Results Of the 5202 citations identified at the title and abstract level, 890 articles seemed to meet inclusion criteria and were selected for further full-text review. After full-text review, 241 studies (Appendix Table 3) met inclusion criteria for the key questions and imaging modalities addressed in this review (Appendix Figure 1). Appendix Table 3. References to Articles That Met the Inclusion Criteria Appendix Table 3Continued. Appendix Table 3Continued. Sixty-eight studies evaluated ultrasonography (Appendix Table 3), 131 evaluated CT (25153), and 125 evaluated MRI (Appendix Table 3). Almost all studies reported sensitivity, but specificity was available in only 139 studies. We rated 5 studies as having low risk of bias (56, 99, 128, 132, 154), 199 as having moderate risk of bias, and 89 as having high risk of bias (13). One hundred twenty-five studies avoided use of a casecontrol design, 160 used blinded design, and 75 were prospective. More studies were conducted in Asia (190 studies) than in Australia, Canada, the United States, or Europe (95 studies in total for these regions). In 166 studies, imaging began in or after 2003 (13). Twenty-eight studies evaluated CT using methods that met minimum technical specifications (8-row multidetector CT; contrast rate 3 mL/s; at least arterial, portal venous, and delayed-phase imaging; delayed-phase imaging performed >120 s after administration of contrast; and enhanced imaging section thickness 5 mm), and 67 studies evaluated MRI using methods that met minimum technical specifications (1.5- or 3.0-T MRI; at least arterial, portal venous, and delayed-phase imaging; delayed-phase imaging performed >120 s after administration of contrast; and enhanced imaging section thickness 5 mm). Seventy-three MRI studies evaluated use of hepatic-specific contrast (for example, gadoxetic acid or gadobenate). Forty-seven ultrasonography studies evaluated use of

Outcomes From Health Information Exchange: Systematic Review and Future Research Needs

Background Health information exchange (HIE), the electronic sharing of clinical information across the boundaries of health care organizations, has been promoted to improve the efficiency, cost-effectiveness, quality, and safety of health care delivery. Objective To systematically review the available research on HIE outcomes and analyze future research needs. Methods Data sources included citations from selected databases from January 1990 to February 2015. We included English-language studies of HIE in clinical or public health settings in any country. Data were extracted using dual review with adjudication of disagreements. Results We identified 34 studies on outcomes of HIE. No studies reported on clinical outcomes (eg, mortality and morbidity) or identified harms. Low-quality evidence generally finds that HIE reduces duplicative laboratory and radiology testing, emergency department costs, hospital admissions (less so for readmissions), and improves public health reporting, ambulatory quality of care, and disability claims processing. Most clinicians attributed positive changes in care coordination, communication, and knowledge about patients to HIE. Conclusions Although the evidence supports benefits of HIE in reducing the use of specific resources and improving the quality of care, the full impact of HIE on clinical outcomes and potential harms are inadequately studied. Future studies must address comprehensive questions, use more rigorous designs, and employ a standard for describing types of HIE. Trial Registration PROSPERO Registry No CRD42014013285; http://www.crd.york.ac.uk/PROSPERO/ display_record.asp?ID=CRD42014013285 (Archived by WebCite at http://www.webcitation.org/6dZhqDM8t).