Monica Daeges

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

Statins for Prevention of Cardiovascular Disease in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force

Importance Cardiovascular disease (CVD), the leading cause of mortality and morbidity in the United States, may be potentially preventable with statin therapy. Objective To systematically review benefits and harms of statins for prevention of CVD to inform the US Preventive Services Task Force. Data Sources Ovid MEDLINE (from 1946), Cochrane Central Register of Controlled Trials (from 1991), and Cochrane Database of Systematic Reviews (from 2005) to June 2016. Study Selection Randomized clinical trials of statins vs placebo, fixed-dose vs titrated statins, and higher- vs lower-intensity statins in adults without prior cardiovascular events. Data Extraction and Synthesis One investigator abstracted data, a second checked data for accuracy, and 2 investigators independently assessed study quality using predefined criteria. Data were pooled using random-effects meta-analysis. Main Outcomes and Measures All-cause mortality, CVD-related morbidity or mortality, and harms. Results Nineteen trials (n = 71 344 participants [range, 95-17 802]; mean age, 51-66 years) compared statins vs placebo or no statin. Statin therapy was associated with decreased risk of all-cause mortality (risk ratio [RR], 0.86 [95% CI, 0.80 to 0.93]; I2 = 0%; absolute risk difference [ARD], -0.40% [95% CI, -0.64% to -0.17%]), cardiovascular mortality (RR, 0.69 [95% CI, 0.54 to 0.88]; I2 = 54%; ARD, -0.43% [95% CI, -0.75% to -0.11%]), stroke (RR, 0.71 [95% CI, 0.62 to 0.82]; I2 = 0; ARD, -0.38% [95% CI, -0.53% to -0.23%]), myocardial infarction (RR, 0.64 [95% CI, 0.57 to 0.71]; I2 = 0%; ARD, -0.81% [95% CI, -1.19 to -0.43%]), and composite cardiovascular outcomes (RR, 0.70 [95% CI, 0.63 to 0.78]; I2 = 36%; ARD, -1.39% [95% CI, -1.79 to -0.99%]). Relative benefits appeared consistent in demographic and clinical subgroups, including populations without marked hyperlipidemia (total cholesterol level <200 mg/dL); absolute benefits were higher in subgroups at higher baseline risk. Statins were not associated with increased risk of serious adverse events (RR, 0.99 [95% CI, 0.94 to 1.04]), myalgias (RR, 0.96 [95% CI, 0.79 to 1.16]), or liver-related harms (RR, 1.10 [95% CI, 0.90 to 1.35]). In pooled analysis, statins were not associated with increased risk of diabetes (RR, 1.05 [95% CI, 0.91 to 1.20]), although statistical heterogeneity was present (I2 = 52%), and 1 trial found high-intensity statins associated with increased risk (RR, 1.25 [95% CI, 1.05 to 1.49]). No trial directly compared titrated vs fixed-dose statins, and there were no clear differences based on statin intensity. Conclusions and Relevance In adults at increased CVD risk but without prior CVD events, statin therapy was associated with reduced risk of all-cause and cardiovascular mortality and CVD events, with greater absolute benefits in patients at greater baseline risk.

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

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).

Barriers and facilitators to exchanging health information: a systematic review.

OBJECTIVES We conducted a systematic review of studies assessing facilitators and barriers to use of health information exchange (HIE). METHODS We searched MEDLINE, PsycINFO, CINAHL, and the Cochrane Library databases between January 1990 and February 2015 using terms related to HIE. English-language studies that identified barriers and facilitators of actual HIE were included. Data on study design, risk of bias, setting, geographic location, characteristics of the HIE, perceived barriers and facilitators to use were extracted and confirmed. RESULTS Ten cross-sectional, seven multiple-site case studies, and two before-after studies that included data from several sources (surveys, interviews, focus groups, and observations of users) evaluated perceived barriers and facilitators to HIE use. The most commonly cited barriers to HIE use were incomplete information, inefficient workflow, and reports that the exchanged information that did not meet the needs of users. The review identified several facilitators to use. DISCUSSION Incomplete patient information was consistently mentioned in the studies conducted in the US but not mentioned in the few studies conducted outside of the US that take a collective approach toward healthcare. Individual patients and practices in the US may exercise the right to participate (or not) in HIE which effects the completeness of patient information available to be exchanged. Workflow structure and user roles are key but understudied. CONCLUSIONS We identified several facilitators in the studies that showed promise in promoting electronic health data exchange: obtaining more complete patient information; thoughtful workflow that folds in HIE; and inclusion of users early in implementation.

Screening for Syphilis: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

IMPORTANCE Screening for syphilis infection is currently recommended for high-risk individuals, including those with previous syphilis infection, an infected sexual partner, HIV infection, or more than 4 sex partners in the preceding year. OBJECTIVE To update a 2004 systematic review of studies of syphilis screening effectiveness, test accuracy, and screening harms in nonpregnant adults and adolescents. DATA SOURCES Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews through October 2015 and Ovid MEDLINE (January 2004 to October 2015), with updated search through March 2016. STUDY SELECTION English-language trials and observational studies of screening effectiveness, test accuracy, and screening harms in nonpregnant adults and adolescents. DATA EXTRACTION AND SYNTHESIS One investigator abstracted data, a second checked data for accuracy, and 2 investigators independently assessed study quality using predefined criteria. MAIN OUTCOMES AND MEASURES Transmission of disease, including HIV; complications of syphilis; diagnostic accuracy; and harms of screening. RESULTS No evidence was identified regarding the effectiveness of screening on clinical outcomes or the effectiveness of risk assessment instruments; the harms of screening; or the effectiveness of screening in average-risk, nonpregnant adolescents or adults or high-risk individuals other than men who have sex with men (MSM) or men who are HIV positive. Four non-US studies indicated higher rates of syphilis detection with screening every 3 months vs 6 or 12 months for early syphilis in HIV-positive men or MSM. For example, there was an increased proportion of asymptomatic, higher-risk MSM in Australia (n = 6789 consultations) receiving a diagnosis of early syphilis when tested every 3 months vs annually (53% vs 16%, P = .001), but no difference among low-risk MSM. Treponemal and nontreponemal tests were accurate in asymptomatic individuals (sensitivity >85%, specificity >91%) in 3 studies but required confirmatory testing. Reverse sequence testing with an initial automated treponemal test yielded more false reactive test results than with rapid plasma reagin in 2 studies, one with a low-prevalence US population (0.6% vs 0.0%, P = .03) and another in a higher-prevalence Canadian population (0.26% vs 0.13%). CONCLUSIONS AND RELEVANCE Screening HIV-positive men or MSM for syphilis every 3 months is associated with improved syphilis detection. Treponemal or nontreponemal tests are accurate screening tests but require confirmation. Research is needed on the effect of screening on clinical outcomes; effective screening strategies, including reverse sequence screening, in various patient populations; and harms of screening.

Screening for Gonorrhea and Chlamydia: A Systematic Review for the U.S. Preventive Services Task Force

In 2005, on the basis of epidemiologic studies of screening and studies of the diagnostic accuracy of screening tests (13), the U.S. Preventive Services Task Force (USPSTF) recommended screening for gonorrhea in all sexually active or pregnant women at increased risk for infection (4). It recommended against routine screening in low-risk men and nonpregnant women and found insufficient evidence to recommend for or against routine screening in high-risk men and low-risk pregnant women. In 2007, on the basis of studies of the effectiveness of screening, harms, and diagnostic accuracy of screening tests (13), the USPSTF recommended screening for chlamydia in all sexually active or pregnant women younger than 25 years and in older, high-risk women (5). It recommended against routine screening in low-risk women, regardless of pregnancy status, and found insufficient evidence to recommend for or against screening in men. Gonorrhea and chlamydia are the 2 most commonly reported sexually transmitted infections (STIs) in the United States (6). In 2012, totals of 334826 cases of gonorrhea and 1422976 cases of chlamydia were reported to the Centers for Disease Control and Prevention (6). However, the true incidence of gonorrhea and chlamydia is difficult to estimate because most infections are undetected. In women, gonococcal and chlamydial infections are most often asymptomatic but can cause cervicitis and complications of pelvic inflammatory disease (PID), ectopic pregnancy, infertility, and chronic pelvic pain (6, 7). In men, these infections can cause urethritis and epididymitis (6, 8). Most men with gonococcal urethritis are symptomatic, prompting timely treatment that prevents serious complications (9). However, gonococcal infections at extragenital sites, including the pharynx and rectum, and genital chlamydial infections are typically asymptomatic. Gonorrhea and chlamydia can also facilitate HIV transmission in both men and women (6, 10, 11). Infection with either gonorrhea or chlamydia in pregnant women can lead to adverse neonatal outcomes, including preterm birth and transmission of infection to the newborn. Chlamydial infection also causes neonatal ophthalmia and pneumonia in infants. Age is a strong predictor of risk for both gonorrhea and chlamydia, and infection rates are greatest among persons aged 15 to 24 years (6). Although rates are greater for women than men (108.7 cases of gonorrhea per 100000 women vs. 105.8 per 100000 men; 643.3 cases of chlamydia per 100000 women vs. 262.6 per 100000 men), rates have increased more rapidly among men in recent years (6). Other risk factors include having new or multiple sex partners or a partner with an STI, inconsistent condom use, and history of previous or coexisting STIs (1, 2). These risk factors are often used to define persons at increased risk in screening recommendations. Rates differ among population subgroups, and black and Hispanic persons generally have greater rates of infections compared with white persons (6, 12). Men who have sex with men who were tested in STD Surveillance Network clinics in 2012 had median prevalence rates of 16.4% for gonorrhea and 12.0% for chlamydia (6). This systematic review is an update of previous reviews for the USPSTF (13). It focuses on new studies of the effectiveness and adverse effects of gonorrhea and chlamydia screening in asymptomatic men and women, including pregnant women and adolescents, as well as the diagnostic accuracy of screening tests. Methods Methods are further described in a technical report (13). We followed a standard protocol consistent with the Agency for Healthcare Research and Quality (AHRQ) methods for systematic reviews (14). On the basis of evidence gaps identified from previous reviews (13), the USPSTF and AHRQ determined the key questions for this update (15). The investigators created analytic frameworks incorporating the key questions and outlining the patient populations, interventions, outcomes, and potential adverse effects (Supplements 1 and 2). A work plan was externally reviewed and modified but was not registered. Supplement 1. Analytic framework and key questions for screening men and nonpregnant women, including adolescents. Supplement 2. Analytic framework and key questions for screening pregnant women. The target populations were asymptomatic, sexually active men and women, including pregnant women and adolescents. The key questions focused on the effectiveness of screening compared with not screening in preventing adverse health outcomes, effectiveness of different screening strategies, diagnostic accuracy of screening tests, and potential harms of screening. Screening strategies included selective screening of high-risk groups, sampling from various anatomical sites, cotesting for concurrent STIs (including HIV), and using different screening intervals, among others. Outcomes included reduction of complications of infection and transmission or acquisition of disease, including gonorrhea, chlamydia, and HIV. For pregnant women, outcomes also included reduction in maternal complications and adverse pregnancy and infant outcomes. Harms of screening included labeling, anxiety, false-positive and false-negative test results, and other consequences of testing. The efficacy and harms of antibiotic treatments were well-established and were not further evaluated. Data Sources and Searches We searched Ovid MEDLINE (1 January 2004 to 13 June 2014), the Cochrane Central Register of Controlled Trials (May 2014), the Cochrane Database of Systematic Reviews (May 2014), the Health Technology Assessment Database (May 2014), the Database of Abstracts of Reviews of Effects (May 2014), and ClinicalTrials.gov (May 2014) and reviewed reference lists for additional citations (13). Search terms are provided in Supplement 3. Supplement 3. MEDLINE Search Strategies Study Selection Abstracts were selected for full-text review if they included asymptomatic, sexually active men and women, including pregnant women and adolescents; were relevant to a key question; and met additional prespecified inclusion criteria for each key question (13). Although this update was intended to evaluate studies published since the previous USPSTF reviews, the scope, key questions, and inclusion criteria differ across reviews, resulting in the inclusion of older studies that have not been previously reviewed. We included only English-language articles and excluded studies that were published as abstracts only or did not report original data. The selection of studies is summarized in a literature flow diagram Supplement 4. Two reviewers independently evaluated each study to determine inclusion eligibility. Supplement 4. Literature flow diagram. Only randomized, controlled trials (RCTs) and controlled observational studies were included to evaluate the effectiveness of screening, whereas uncontrolled observational studies were also included to determine adverse effects. Studies of screening strategies were included if they adequately described the study population and comparison groups, features of the screening program, and outcome measures. Inclusion criteria were less restrictive for effectiveness studies than diagnostic accuracy studies because the main comparison concerned outcomes related to the overall approach of screening compared with nonscreening rather than the characteristics of the individual tests. Studies of the accuracy of diagnostic tests were included if they evaluated screening tests in asymptomatic participants using technologies and methods that have been cleared by the U.S. Food and Drug Administration (FDA) and are available for clinical practice in the United States. These inclusion criteria reflect the scope of the USPSTF recommendations about technologies and medications. On the basis of these criteria, rectal, pharyngeal, and self-collected vaginal specimens obtained in nonclinical settings and point-of-care or in-house tests were excluded. Tests that were previously cleared and subsequently removed from the U.S. market (such as the ligase chain reaction test) were also excluded (16). Included studies used credible reference standards, adequately described the study population, defined positive test results, and reported performance characteristics of tests (such as sensitivity and specificity) or provided data to calculate them. Data Abstraction and Quality Rating A single investigator abstracted details about study design, patient population, comparison groups, setting, screening method, analysis, follow-up, and results. A second investigator reviewed data abstraction for accuracy. By using prespecified criteria for RCTs, cohort, and diagnostic accuracy studies developed by the USPSTF (14), 2 investigators independently rated the quality of studies (good, fair, or poor) and resolved discrepancies by consensus. Data Synthesis and Analysis Two independent reviewers assessed the internal validity (quality) of the body of evidence for the new studies for each key question using methods developed by the USPSTF, on the basis of the number, quality, and size of studies; consistency of results among studies; and directness of evidence (14, 15). Statistical meta-analysis was not done because of methodological limitations of the studies and heterogeneity in study designs, interventions, populations, and other factors. Studies included in previous reviews were reviewed for consistency with current results; however, lack of studies and differences in scope, key questions, and inclusion criteria limited aggregate synthesis with the updated evidence. Role of the Funding Source This research was funded by 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. AHRQ had no role in study selection, quality assessment, syn

Screening for dyslipidemia in younger adults: A systematic review for the U.S. Preventive services task force

Dyslipidemia affects about 53% of U.S. adults (105.3 million) (1). Although dyslipidemia becomes more prevalent with age, it also affects younger adults. About 36% of adults aged 20 to 29 years and 43% aged 30 to 39 years meet levels recommended by the National Cholesterol Education Program for all lipids (2). Dyslipidemia is associated with cardiovascular disease, the leading cause of death in the United States. In 2010, the prevalence of coronary heart disease (CHD) was 1.2% among those aged 18 to 44 years (3). The number of myocardial infarctions or fatal CHD events annually is estimated at 20000 for men aged 35 to 44 and 5000 for women aged 35 to 44 years (4). In 2011, CHD caused 12% of deaths in persons aged 25 to 44 years (5). Because of the asymptomatic nature of dyslipidemia before signs or symptoms of cardiovascular disease develop, its identification requires screening. Detecting dyslipidemia in younger adults might enable management strategies, including lifestyle modification or medications, to be implemented to reduce the risk for cardiovascular events. Screening may be particularly beneficial in identifying young adults with markedly elevated lipid levels due to unrecognized familial hypercholesterolemia. In 2008, the U.S. Preventive Services Task Force (USPSTF) recommended lipid screening in men aged 20 to 35 years and women aged 20 to 45 years with CHD risk factors (B recommendation) (6). Although the USPSTF found no direct evidence regarding benefits or harms of lipid screening in these age groups, its recommendation was based on data showing that some younger adults with CHD risk factors have lipid levels sufficient to place them at high (>10%) 10-year cardiovascular risk and might benefit from lipid-lowering therapies. The USPSTF made no recommendation for or against lipid screening in men and women in these age groups without CHD risk factors (C recommendation) because of the low likelihood of identifying lipid levels high enough to justify treatment, thus resulting in small expected benefits. Recommendations from other groups vary regarding lipid screening in persons without CHD risk factors. Some guidelines recommend screening starting at age 20 years; others do not recommend screening until age 35 to 40 for men or 40 to 50 for women (710). In general, all guidelines recommend lipid testing in younger adults with CHD, CHD equivalents, or 1 or more CHD risk factors. The 2014 American College of Cardiology and American Heart Association guideline on assessing cardiovascular risk considers it reasonable to evaluate traditional cardiovascular risk factors, including lipids, every 4 to 6 years starting at age 20 (7). The purpose of this report is to update previous USPSTF reviews (1113) on screening for dyslipidemia in adults. It will be used by the USPSTF to update its 2008 recommendation (6). One difference between this update and earlier USPSTF reviews is that it focuses on screening in younger adults (defined as those aged 21 to 39 years). The USPSTF did not re-review evidence on screening for dyslipidemia in older adults because it already strongly recommends screening in men older than 35 years and women older than 45 (A recommendation). In addition, the decision to initiate lipid-lowering therapy with statins is based on a global assessment of cardiovascular risk, not just lipid levels. Therefore, the USPSTF commissioned a separate evidence review on the use of statin therapy for cardiovascular disease prevention in adults aged 40 years or older (14). A separate USPSTF review addresses dyslipidemia screening in persons younger than 21 years (15). Methods Scope of the Review Using established methods (16, 17), the USPSTF determined the scope, key questions, and analytic framework (Figure 1) used to guide this review. A standard protocol was developed and publicly posted on the USPSTF Web site before the review was carried out (www.uspreventiveservicestaskforce.org/Page/Document/final-research-plan98/statin-use-in-adults-preventive-medication1). Figure 1. Analytic framework. Numbers in circles correspond to the key question numbers. CHD = coronary heart disease; CVA = cerebrovascular accident (stroke). Key questions are as follows: 1. What are the benefits of screening for dyslipidemia in asymptomatic adults aged 21 to 39 years on CHD- or cerebrovascular accident (CVA, or stroke)related morbidity or mortality, or on all-cause mortality? 2. What are the harms of screening for dyslipidemia in asymptomatic adults aged 21 to 39 years? 3. What is the diagnostic yield of alternative screening strategies (for example, universal vs. risk-based screening) for asymptomatic dyslipidemia in adults aged 21 to 39 years? 4. What are the benefits of dyslipidemia treatment (such as drug or lifestyle interventions) in adults aged 21 to 39 years on CHD- or CVA-related morbidity or mortality, or on all-cause mortality? 5. What are the benefits of delayed versus immediate dyslipidemia treatment in adults aged 21 to 39 years on CHD- or CVA- related morbidity or mortality, or on all-cause mortality? 6. What are the harms of drug treatment of asymptomatic dyslipidemia in adults aged 21 to 39 years? Detailed methods and data for this review, including search strategies and detailed inclusion criteria, are contained in the full USPSTF report (18). The full review also includes 2 contextual questions (not reviewed systematically): 1 on how intermediate outcomes are affected by drug treatment of dyslipidemia in younger adults and the other on how lipid levels change over time in younger adults. Data Sources and Searches We searched the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through May 2016), Ovid MEDLINE (2008 through May 2016) (Appendix Table 1), and reference lists. Searches were limited to English-language articles. We also searched ClinicalTrials.gov for ongoing studies. Appendix Table 1. Search Strategies Study Selection Two reviewers independently evaluated the literature on the basis of predefined criteria (Appendix Table 2). Eligible studies were randomized trials, cohort studies, and casecontrol studies of lipid screening versus no screening, dyslipidemia treatment versus no treatment, and delayed versus immediate dyslipidemia treatment in asymptomatic adults aged 21 to 39 years that evaluated mortality, cardiovascular outcomes (CHD- or CVA-related morbidity or mortality), or harms of screening or treatment. Studies reporting the diagnostic yield (number of true positives per number tested) of lipid screening in adults aged 21 to 39 years also were eligible for inclusion. Studies enrolling older adults were also eligible if the results were reported separately for patients younger than 40 years or if the mean age of the population was less than 40 years. Regarding treatment, both drug therapy and lifestyle interventions (such as exercise and diet changes) were eligible for inclusion. Appendix Table 2. Inclusion and Exclusion Criteria per KQ Studies of individuals with prior cardiovascular events were excluded. The literature selection is summarized in Figure 2. Figure 2. Literature flow diagram. KQ = key question. * Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Data Abstraction and Quality Rating We planned for 1 investigator to abstract details about each articles study design, patient population, setting, screening method, treatment regimen, analysis, follow-up, and results; 1 investigator to review the data abstraction for accuracy; and 2 investigators to independently apply criteria developed by the USPSTF (16) to rate the quality of each study as good, fair, or poor ( Appendix ), with discrepancies resolved through consensus. No studies, however, met the inclusion criteria. Data Synthesis We planned to assess 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 among studies; and directness of evidence (16). No studies, however, met the inclusion criteria. 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. Investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic framework, and key questions; resolve issues arising during the project; and finalize the report. The AHRQ had no role in the study selection, quality assessment, synthesis, or development of conclusions. It 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. Results Screening We identified no studies on the benefits or harms of screening versus no screening for dyslipidemia on cardiovascular outcomes in asymptomatic adults aged 21 to 39 years. Diagnostic Yield of Alternate Screening Strategies We identified no studies on the diagnostic yield of alternative strategies for dyslipidemia screening in asymptomatic adults aged 21 to 39 years. Treatment We identified no studies on benefits or harms of treatment versus no treatment regarding cardiovascular outcomes in adults aged 21 to 39 years. Although 4 trials of statins for primary prevention enrolled patients younger than 40 years, results were not reported separately for this subgroup, which made up a small part of the study populations (1922). One cohort study evaluated the efficacy of statins in patients with familial hypercholesterolemia, but the mean age at enrollment was 44 years (23). We also identified no studies on benefits or harms of delayed versus immediate dyslipidemia treatment in adults aged 21 to 39

Health Information Exchange Use (1990-2015): A Systematic Review

Background: In June 2014, the Office of the National Coordinator for Health Information Technology published a 10-year roadmap for the United States to achieve interoperability of electronic health records (EHR) by 2024. A key component of this strategy is the promotion of nationwide health information exchange (HIE). The 2009 Health Information Technology for Economic and Clinical Health (HITECH) Act provided significant investments to achieve HIE. Objective: We conducted a systematic literature review to describe the use of HIE through 2015. Methods: We searched MEDLINE, PsycINFO, CINAHL, and Cochrane databases (1990 – 2015); reference lists; and tables of contents of journals not indexed in the databases searched. We extracted data describing study design, setting, geographic location, characteristics of HIE implementation, analysis, follow-up, and results. Study quality was dual-rated using pre-specified criteria and discrepancies resolved through consensus. Results: We identified 58 studies describing either level of use or primary uses of HIE. These were a mix of surveys, retrospective database analyses, descriptions of audit logs, and focus groups. Settings ranged from community-wide to multinational. Results suggest that HIE use has risen substantially over time, with 82% of non-federal hospitals exchanging information (2015), 38% of physician practices (2013), and 17-23% of long-term care facilities (2013). Statewide efforts, originally funded by HITECH, varied widely, with a small number of states providing the bulk of the data. Characteristics of greater use include the presence of an EHR, larger practice size, and larger market share of the health-system. Conclusions: Use of HIE in the United States is growing but is still limited. Opportunities remain for expansion. Characteristics of successful implementations may provide a path forward.