Ian Blazina

Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force.

BACKGROUND Screening can detect prostate cancer at earlier, asymptomatic stages, when treatments might be more effective. PURPOSE To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate cancer. DATA SOURCES MEDLINE (2002 to July 2011) and the Cochrane Library Database (through second quarter of 2011). STUDY SELECTION Randomized trials of prostate-specific antigen-based screening, randomized trials and cohort studies of prostatectomy or radiation therapy versus watchful waiting, and large observational studies of perioperative harms. DATA EXTRACTION Investigators abstracted and checked study details and quality using predefined criteria. DATA SYNTHESIS Of 5 screening trials, the 2 largest and highest-quality studies reported conflicting results. One found that screening was associated with reduced prostate cancer-specific mortality compared with no screening in a subgroup of men aged 55 to 69 years after 9 years (relative risk, 0.80 [95% CI, 0.65 to 0.98]; absolute risk reduction, 0.07 percentage point). The other found no statistically significant effect after 10 years (relative risk, 1.1 [CI, 0.80 to 1.5]). After 3 or 4 screening rounds, 12% to 13% of screened men had false-positive results. Serious infections or urine retention occurred after 0.5% to 1.0% of prostate biopsies. There were 3 randomized trials and 23 cohort studies of treatments. One good-quality trial found that prostatectomy for localized prostate cancer decreased risk for prostate cancer-specific mortality compared with watchful waiting through 13 years of follow-up (relative risk, 0.62 [CI, 0.44 to 0.87]; absolute risk reduction, 6.1%). Benefits seemed to be limited to men younger than 65 years. Treating approximately 3 men with prostatectomy or 7 men with radiation therapy instead of watchful waiting would each result in 1 additional case of erectile dysfunction. Treating approximately 5 men with prostatectomy would result in 1 additional case of urinary incontinence. Prostatectomy was associated with perioperative death (about 0.5%) and cardiovascular events (0.6% to 3%), and radiation therapy was associated with bowel dysfunction. LIMITATIONS Only English-language articles were included. Few studies evaluated newer therapies. CONCLUSION Prostate-specific antigen-based screening results in small or no reduction in prostate cancer-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Screening women for intimate partner violence: A systematic review to update the U.S. Preventive services task force recommendation

BACKGROUND In 2004, the U.S. Preventive Services Task Force determined that evidence was insufficient to support screening women for intimate partner violence (IPV). PURPOSE To review new evidence on the effectiveness of screening and interventions for women in health care settings in reducing IPV and related health outcomes, the diagnostic accuracy of screening instruments, and adverse effects of screening and interventions. DATA SOURCES MEDLINE and PsycINFO (January 2002 to January 2012), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through fourth quarter 2011), Scopus, and reference lists. STUDY SELECTION English-language trials of the effectiveness of screening and interventions, diagnostic accuracy studies of screening instruments, and studies of any design about adverse effects. DATA EXTRACTION Investigators extracted data about study populations, designs, and outcomes and rated study quality by using established criteria. DATA SYNTHESIS A large fair-quality trial of screening versus usual care indicated reduced IPV and improved health outcomes for both groups, but no statistically significant differences between groups. Fifteen fair- and good-quality studies evaluated 13 screening instruments, and six instruments were highly accurate. Four fair- and good-quality trials of counseling reported reduced IPV and improved birth outcomes for pregnant women, reduced IPV for new mothers, and reduced pregnancy coercion and unsafe relationships for women in family-planning clinics. Fourteen studies indicated minimal adverse effects with screening, but some women experienced discomfort, loss of privacy, emotional distress, and concerns about further abuse. LIMITATION Trials were limited by heterogeneity, lack of true control groups, high loss to follow-up, self-reported measures, and lack of accepted reference standards. CONCLUSION Screening instruments accurately identify women experiencing IPV. Screening women for IPV can provide benefits that vary by population, while potential adverse effects have minimal effect on most women. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

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.

Screening for hypertension in children and adolescents to prevent cardiovascular disease

BACKGROUND AND OBJECTIVE: The prevalence of hypertension is increasing in children, and may persist into adulthood. This systematic review was conducted for the US Preventive Services Task Force recommendation on the effectiveness of screening asymptomatic children and adolescents for hypertension in order to prevent cardiovascular disease. METHODS: Eligible studies were identified from Medline and the Cochrane Library (through July 2012). We included trials and controlled observational studies in asymptomatic children and adolescents on the effectiveness and harms of screening and treatment, as well as accuracy of blood pressure measurement. One author extracted study characteristics and results, which were checked for accuracy by a second author. RESULTS: No studies evaluated the effects of screening for hypertension on health outcomes. Two studies of screening tests for elevated blood pressure reported moderate sensitivities (0.65, 0.72) and specificities (0.75, 0.92). Sensitivities and specificities of child hypertension for the later presence of adult hypertension (7 studies) were wide ranging (0–0.63 and 0.77–1.0, respectively), and associations between child hypertension and carotid intima media thickening and proteinuria in young adults (3 studies) were inconsistent. Seven studies reported that drug interventions effectively lowered blood pressure in adolescents over short follow-up periods. No serious treatment-related adverse effects were reported. CONCLUSIONS: There is no direct evidence that screening for hypertension in children and adolescents reduces adverse cardiovascular outcomes in adults. Additional studies are needed to improve diagnosis and risk stratification of children with elevated blood pressure and to quantify risks and benefits of interventions.

Screening for Type 2 Diabetes Mellitus: A Systematic Review for the U.S. Preventive Services Task Force

In the United States, approximately 21 million persons received diabetes diagnoses in 2010, and an estimated 8 million cases were undiagnosed; roughly 90% to 95% of them have type 2 diabetes mellitus (1, 2). Prevalence of diabetes among U.S. adults has increased, from approximately 5% in 1995 to 8% in 2010 (3). Diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and blindness; a major cause of heart disease and stroke; and the seventh-leading cause of death in the United States (1). Risk factors for diabetes include obesity, physical inactivity, smoking, and older age (1). Diabetes is more common among certain ethnic and racial minorities (1, 3). Type 2 diabetes is caused by insulin resistance and relative insulin deficiency, resulting in the inability to maintain normoglycemia. Diabetes typically develops slowly (4, 5), although microvascular disease, such as retinopathy and neuropathy, may be present at the time of diagnosis due to vascular damage during the subclinical phase (4, 6). Screening asymptomatic persons (those without signs or symptoms of hyperglycemia and no clinical sequelae) may lead to earlier identification and earlier or more-intensive treatments, potentially improving health outcomes (2). Strategies for screening include routine screening or targeted screening based on the presence of risk factors, such as obesity or hypertension. In 2008, the U.S. Preventive Services Task Force (USPSTF) recommended diabetes screening in asymptomatic adults with sustained blood pressure (BP) (treated or untreated) greater than 135/80 mm Hg (B recommendation). Although direct evidence on benefits and harms of screening was not available, the recommendation was based on the ability of screening to identify persons with diabetes and evidence that more-intensive BP treatment was associated with reduced risk for cardiovascular events, including cardiovascular mortality, in patients with diabetes and hypertension. The USPSTF found insufficient evidence to assess the balance of benefits and harms of screening in adults without elevated BP (I statement). It also found that lifestyle and drug interventions for impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), defined as a hemoglobin A1c level of 5.7% to 6.4% or a fasting blood glucose level between 5.55 and 6.94 mmol/L (100 and 125 mg/dL) (2), were associated with reduced risk for progression to diabetes (714). Other groups also recommend screening persons with risk factors (1520). This article updates previous USPSTF reviews (2123) on diabetes screening in nonpregnant adults. 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. DM = diabetes mellitus; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; KQ = key question; MI = myocardial infarction. 1. Is there direct evidence that screening for type 2 diabetes, IFG, or IGT among asymptomatic adults improves health outcomes? 2. What are the harms of screening for type 2 diabetes, IFG, or IGT? 3. Do interventions for screen-detected or early diabetes, IFG, or IGT provide an incremental benefit in health outcomes compared with no interventions or initiating interventions after clinical diagnosis? 4. What are the harms of interventions for screen-detected or early diabetes, IFG, or IGT? 5. Is there evidence that more-intensive glucose, BP, or lipid control interventions improve health outcomes in adults with type 2 diabetes, IFG, or IGT compared with traditional control? Is there evidence that aspirin use improves health outcomes in these populations compared with nonuse? 6. What are the harms of more-intensive interventions compared with traditional control in adults with type 2 diabetes, IFG, or IGT? 7. Do interventions for IFG or IGT delay or prevent the progression to type 2 diabetes? The full report (24), on which this article is based, provides detailed methods and data for the review, including search strategies, evidence tables, and quality ratings of individual studies (available at www.uspreventiveservicestaskforce.org). The full report includes an additional key question on whether the effects of screening or interventions for screen-detected or early diabetes, IFG, or IGT vary by subgroup; effects of treatments on microvascular outcomes; and evidence on effects of more- versus less-intensive lipid control and aspirin use (24). Data Sources and Searches A research librarian searched the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews and MEDLINE (2007 to October 2014). We supplemented electronic searches by reviewing previous USPSTF reports and reference lists of relevant articles. Study Selection At least 2 reviewers independently evaluated each study to determine inclusion eligibility using predefined inclusion and exclusion criteria (Appendix Figure 2). Because of the limited evidence on treatment of screen-detected diabetes (key question 5), we also included studies of treatment of early diabetes (defined as a pharmacologically untreated hemoglobin A1c level <8.5% or diabetes diagnosis in the past year) that was not specifically screen-detected. Appendix Figure 3 summarizes the selection of literature. Appendix Figure 2. Inclusion and exclusion criteria per KQ. BP = blood pressure; DM = diabetes mellitus; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; KQ = key question; MI = myocardial infarction. Appendix Figure 3. Summary of evidence search and selection. KQ = key question. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. Other sources include previous reports, reference lists of relevant articles, and systematic reviews. An additional 27 publications are included in the full report (23). Some studies have several publications and some are included for more than 1 KQ. 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 abstraction for accuracy. Two investigators independently applied criteria developed by the USPSTF (25) to rate the quality of each study as good, fair, or poor. Discrepancies were resolved through a consensus process. Data Synthesis and Analysis We conducted meta-analyses to calculate risk ratios (RRs) on effects of interventions with the DerSimonianLaird random-effects model using Stata, version 12 (StataCorp). Statistical heterogeneity was assessed using the I 2 statistic (26). When statistical heterogeneity was present, we performed sensitivity analyses using the profile likelihood method because the DerSimonianLaird model results in overly narrow 95% CIs (27). Two studies (2830) that used a 22 factorial design reported no interaction between treatments and were analyzed as a 2-group parallel group trial for the comparison of interest. When studies evaluated several lifestyle strategies, we combined the lifestyle groups. We included all studies in meta-analyses, regardless of event rates. For rare events (incidence <1%), we calculated the Peto odds ratio (31). We stratified results by drug class or lifestyle intervention and performed additional sensitivity analyses based on study quality and presence of outlier trials. 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, based on the quality of studies, precision of estimates, consistency of results, and directness of evidence (25). 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 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. It also 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 Benefits of Screening Two randomized, controlled trials (ADDITION [Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen Detected Diabetes in Primary Care]Cambridge [Cambridge, United Kingdom] trial [n=19226] [32], rated good-quality, and a trial conducted in Ely, United Kingdom [n=4936] [33], rated fair-quality) evaluated effects of diabetes screening versus no screening on mortality (Appendix Table 1). The ongoing ADDITION trial includes sites in Cambridge, the Netherlands, and Denmark on intensive versus standard treatment of screen-detected diabetes; however, only the Cambridge site had a no-screening component (34). Mean age ranged from 51 to 58 years, 36% to 54% of participants were women, and follow-up was 10 years in both studies (32, 33). In ADDITION-Cambridge, persons at high risk for diabetes, based on known risk factors, were randomly assigned in clusters by clinic site to screening or no screening (32). The Ely study randomly enrolled participants (not selected based on high risk for diabetes) to screening or no screening from a single practice site (33). Seventy-eight percent of participants (11737 of 15089) invited to screening had screening in the ADDITION trial (32); 68% of participants in the Ely study were screened (33). Methodological shortcomings in the Ely study included unclear randomization and allocation concealment method

Behavioral Interventions and Counseling to Prevent Child Abuse and Neglect: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

BACKGROUND In 2004, the U.S. Preventive Services Task Force determined that evidence was insufficient to recommend behavioral interventions and counseling to prevent child abuse and neglect. PURPOSE To review new evidence on the effectiveness of behavioral interventions and counseling in health care settings for reducing child abuse and neglect and related health outcomes, as well as adverse effects of interventions. DATA SOURCES MEDLINE and PsycINFO (January 2002 to June 2012), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the second quarter of 2012), Scopus, and reference lists. STUDY SELECTION English-language trials of the effectiveness of behavioral interventions and counseling and studies of any design about adverse effects. DATA EXTRACTION Investigators extracted data about study populations, designs, and outcomes and rated study quality using established criteria. DATA SYNTHESIS Eleven fair-quality randomized trials of interventions and no studies of adverse effects met inclusion criteria. A trial of risk assessment and interventions for abuse and neglect in pediatric clinics for families with children aged 5 years or younger indicated reduced physical assault, Child Protective Services (CPS) reports, nonadherence to medical care, and immunization delay among screened children. Ten trials of early childhood home visitation reported reduced CPS reports, emergency department visits, hospitalizations, and self-reports of abuse and improved adherence to immunizations and well-child care, although results were inconsistent. LIMITATION Trials were limited by heterogeneity, low adherence, high loss to follow-up, and lack of standardized measures. CONCLUSION Risk assessment and behavioral interventions in pediatric clinics reduced abuse and neglect outcomes for young children. Early childhood home visitation also reduced abuse and neglect, but results were inconsistent. Additional research on interventions to prevent child abuse and neglect is needed. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Routine iron supplementation and screening for iron deficiency anemia in pregnancy: A systematic review for the U.S. preventive services task force

Iron deficiency is the most common pathologic cause of anemia in pregnancy. Increased risk during pregnancy is due to increased maternal iron needs and demands from the growing fetus and placenta; increased erythrocyte mass; and, in the third trimester, expanded maternal blood volume (15). Definitions of iron deficiency anemia (IDA) in pregnant women may be imprecise given pregnancy-associated physiologic changes and variable definitions in population subgroups (1, 2). Physiologic anemia, or dilutional anemia of pregnancy, is common in healthy pregnant women due to blood volume expansion to support the growing fetus and is associated with a modest decrease in hemoglobin levels. Iron deficiency occurs when the level of stored iron becomes depleted. Iron deficiency anemia occurs when iron levels are sufficiently depleted to produce anemia (1, 6). Serum ferritin is useful in diagnosing iron deficiency in pregnant women, who can have an elevated serum transferrin level in the absence of iron deficiency. As an acute-phase reactant, serum ferritin can be elevated in inflammatory conditions and may be of limited usefulness when concentrations decrease late in pregnancy (7). Overall prevalence of iron deficiency in pregnant women in the United States is near 18%, with anemia in 5% of pregnant women and rates of iron deficiency increasing across trimesters from 6.9% to 14.3% to 28.4% (5). Risk factors for iron deficiency or IDA in pregnant women include an iron-deficient diet, gastrointestinal issues affecting absorption, or a short pregnancy interval (8). Pregnant women with clinically significant iron deficiency or IDA may present with fatigue, weakness, pallor, tachycardia, and shortness of breath (9). Maternal iron requirements average 1000 mg/d (10). Because many pregnant women lack sufficient iron stores, iron supplementation may be included in prenatal care. Primary prevention for average-risk populations includes adequate intake of dietary iron and oral, low-dose (30 mg/d) iron supplements early in pregnancy (11). Suggested prophylaxis for IDA in high-risk populations is 60 to 100 mg of elemental iron daily (12). The association between iron status and negative outcomes for women and their infants is inconclusive. Although many older observational studies, including uncontrolled and cross-sectional studies, have shown an association between various measures of iron status and negative perinatal outcomes, such as low birthweight (1315), premature birth (1318), and perinatal death (14), more rigorous trial evidence is inconsistent. Screening for IDA may lead to earlier identification and earlier treatment, which may prevent serious negative health outcomes. The U.S. Preventive Services Task Force (USPSTF) last reviewed evidence on prenatal screening for IDA in 2006 and recommended routine screening (B recommendation) on the basis of fair-quality evidence (19). There was insufficient evidence (no studies) on the accuracy of screening in asymptomatic pregnant women but fair-quality evidence that treating asymptomatic IDA in pregnancy results in moderate health benefits. Evidence was also insufficient to recommend for or against routine iron supplementation for nonanemic pregnant women (I statement). This review was commissioned by the USPSTF to update the prior recommendations (19). We examined evidence from U.S.-relevant populations on the effectiveness of routine supplementation and screening for IDA in pregnancy. Methods Methods are described in detail in a technical report (20). On the basis of evidence gaps identified from prior reviews (21, 22), and in consultation with the USPSTF (23), we developed key questions and analytic frameworks for routine supplementation (Appendix Figure 1) and screening (Appendix Figure 2) for IDA during pregnancy. Key questions were as follows. Appendix Figure 1. Analytic framework for routine iron supplementation in pregnant women. KQ = key question. Appendix Figure 2. Analytic framework for screening for iron deficiency anemia in pregnant women. KQ = key question. Supplementation 1. What are the benefits of routine iron supplementation in pregnant women on maternal and infant health outcomes? 2. What are the harms of routine iron supplementation in pregnant women? Screening 1. What are the benefits of screening asymptomatic pregnant women for iron deficiency anemia on maternal and infant health outcomes? 2. What are the harms of screening for iron deficiency anemia in pregnant women? 3. What are the benefits of treatment for iron deficiency anemia in pregnant women on maternal and infant health outcomes? 4. What are the harms of iron treatment in pregnant women? 5. What is the association between a change in maternal iron status (including changes in ferritin or hemoglobin level) and improvement in newborn and peripartum outcomes in U.S.-relevant populations? Data Sources We searched the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE (1996 to August 2014) (Appendix Table 1). We also searched reference lists of relevant systematic reviews to identify studies published before 1996, the year that the prior reviews concluded. Appendix Table 1. Search Strategies Study Selection Abstracts were selected for full-text review if they included asymptomatic pregnant women receiving screening or supplementation for IDA, were relevant to a key question, and met predefined inclusion criteria (20). For the screening framework, key questions focused on the effectiveness of screening compared with not screening in preventing adverse health outcomes and reducing the incidence of complications, as well as the association of improvements in intermediate and clinical health outcomes with harms (including infant harms). Health outcomes included long- or short-term maternal and infant morbidity (including birth outcomes), infant mortality, and maternal quality of life (including postpartum depression) resulting from screening, supplementation, or treatment and related harms. Intermediate outcomes included iron status based on hematologic indices, including ferritin levels. Additional outcomes included the relationship between a change in maternal iron status and maternal and infant health outcomes. We focused on studies using iron supplementation and treatment regimens commonly used in clinical practice in the United States and those conducted in countries with high or very high human development based on the United Nations Human Development Index (24). We included only English-language articles and excluded studies published as abstracts or without original data. Two reviewers independently evaluated each study to determine inclusion eligibility. We included randomized, controlled trials; nonrandomized, controlled trials; and cohort studies for all key questions. When good- and fair-quality studies were available, poor-quality studies were excluded. The selection of studies is summarized in Figure 1 . Figure 1. Summary of evidence search and selection. KQ = key question. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. Prior reports, reference lists of relevant articles, and systematic reviews. Some studies are included for >1 KQ. Poor-quality studies were excluded because good- and fair-quality evidence was available. Data Abstraction and Quality Rating One investigator abstracted details about study design, patient population, setting, screening method, analysis, follow-up, and results. A second investigator reviewed the data abstraction for accuracy. Using predefined criteria developed by the USPSTF (23), 2 investigators rated the quality of studies (good, fair, or poor) (23) and resolved discrepancies by consensus. Data Synthesis and Analysis 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 among studies; and directness of evidence (23). Meta-analysis was performed when studies were available that used comparable dosages, durations, and timing of outcome assessment. We conducted meta-analyses using the MantelHaenszel random- or fixed-effects models in Review Manager, version 5.2 (Cochrane Collaboration), to calculate risk ratios of the effects of routine iron supplementation on incidence of preterm delivery, low birthweight, and maternal IDA and iron deficiency at term. Statistical heterogeneity was assessed using the I 2 statistic. Due to methodological shortcomings in the studies and differences across studies in design, interventions (timing and dosing), patient populations, and other factors, meta-analysis was not attempted for all outcome measures. 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 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 Effectiveness of Routine Iron Supplementation in Pregnancy We identified a total of 12 good-quality (2527) and fair-quality (2836) trials comparing the effects of routine prenatal iron supplementation versus no supplementation (37, 38). Studies were conducted in the United States, Iran, Hong Ko

Screening for HIV: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

BACKGROUND A 2005 U.S. Preventive Services Task Force (USPSTF) review found good evidence that HIV screening is accurate and that antiretroviral therapy (ART) for immunologically advanced disease is associated with substantial clinical benefits, but insufficient evidence to determine the effects on transmission or in less immunologically advanced disease. PURPOSE To update the 2005 USPSTF review on benefits and harms of HIV screening in adolescents and adults, focusing on research gaps identified in the prior review. DATA SOURCES MEDLINE (2004 to June 2012) and the Cochrane Library (through the second quarter of 2012). STUDY SELECTION Randomized trials and observational studies that compared HIV screening strategies and reported clinical outcomes, evaluated the effects of starting ART at different CD4 cell count thresholds and long-term harms, or reported the effects of interventions on transmission risk. DATA EXTRACTION 2 authors abstracted and checked study details and quality using predefined criteria. DATA SYNTHESIS No study directly evaluated the effects on clinical outcomes of screening versus no screening for HIV infection. A randomized trial and a subgroup analysis from a randomized trial found that ART initiation at CD4 counts less than 0.250 × 109 cells/L was associated with a higher risk for death or AIDS-defining events than initiation at CD4 counts greater than 0.350 × 109 cells/L (hazard ratios, 1.7 [95% CI, 1.1 to 2.5] and 5.3 [CI, 1.3 to 9.6]). Large, fair-quality cohort studies also consistently found that ART initiation at CD4 counts of 0.350 to 0.500 × 109 cells/L was associated with lower risk for death or AIDS-defining events than delayed initiation. New evidence from good-quality cohorts with longer-term follow-up confirms a previously observed small increased risk for cardiovascular events associated with certain antiretrovirals. Strong evidence from 1 good-quality randomized trial and 7 observational studies found that ART was associated with a 10- to 20-fold reduction in risk for sexual transmission of HIV. LIMITATIONS Only English-language articles were included. Observational studies were included. Studies done in resource-poor or high-prevalence settings were included but might have limited applicability to general screening in the United States. CONCLUSION Previous studies have shown that HIV screening is accurate, targeted screening misses a substantial proportion of cases, and treatments are effective in patients with advanced immunodeficiency. New evidence indicates that ART reduces risk for AIDS-defining events and death in persons with less advanced immunodeficiency and reduces sexual transmission of HIV. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Screening and Routine Supplementation for Iron Deficiency Anemia: A Systematic Review

BACKGROUND AND OBJECTIVES: Supplementation and screening for iron-deficiency anemia (IDA) in young children may improve growth and development outcomes. The goal of this study was to review the evidence regarding the benefits and harms of screening and routine supplementation for IDA for the US Preventive Services Task Force. METHODS: We searched Medline and Cochrane databases (1996–August 2014), as well as reference lists of relevant systematic reviews. We included trials and controlled observational studies regarding the effectiveness and harms of routine iron supplementation and screening in children ages 6 to 24 months conducted in developed countries. One author extracted data, which were checked for accuracy by a second author. Dual quality assessment was performed. RESULTS: No studies of iron supplementation in young children reported on the diagnosis of neurodevelopmental delay. Five of 6 trials sparsely reporting various growth outcomes found no clear benefit of supplementation. After 3 to 12 months, Bayley Scales of Infant Development scores were not significantly different in 2 trials. Ten trials assessing iron supplementation in children reported inconsistent findings for hematologic measures. Evidence regarding the harms of supplementation was limited but did not indicate significant differences. No studies assessed the benefits or harms of screening or the association between improvement in impaired iron status and clinical outcomes. Studies may have been underpowered, and control factors varied and could have confounded results. CONCLUSIONS: Although some evidence on supplementation for IDA in young children indicates improvements in hematologic values, evidence on clinical outcomes is lacking. No randomized controlled screening studies are available.

Screening for Hepatitis B Virus Infection in Adolescents and Adults: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

In 2008, an estimated 704000 persons in the United States were chronically infected with hepatitis B virus (HBV) (1). Potential long-term sequelae of chronic HBV infection include cirrhosis, hepatic decompensation, and hepatocellular carcinoma (2). In 2010, deaths associated with HBV infection were estimated at 0.5 per 100000 persons (3). In the United States, persons born in countries with a prevalence of HBV infection of 2% or greater account for 47% to 95% of chronically infected persons (47). Persons at high risk for HBV infection include household contacts or sexual partners of persons with HBV infection, men who have sex with men, injection drug users, and HIV-positive persons. The number of reported acute cases of HBV infection in the United States decreased from more than 20000 annually in the mid-1980s to 2890 in 2011 (the actual number of new cases is estimated at 6.5 times the number of reported cases) (3). Globally, incidence of HBV infection has markedly decreased, particularly among younger persons, after the implementation of universal vaccination programs (1, 8). Screening for HBV infection could identify chronically infected persons who might benefit from antiviral therapies, surveillance to diagnose hepatocellular carcinoma, or interventions to reduce behaviors associated with progression of liver disease (for example, alcohol use) or transmission and to identify persons without HBV immunity who could benefit from vaccination (9). However, in 2004, the U.S. Preventive Services Task Force (USPSTF) recommended against screening asymptomatic persons for HBV infection (D recommendation) on the basis of a lack of evidence that screening improves clinical outcomes and the low prevalence of HBV infection in the general population (10). Other groups recommend screening high-risk persons (7, 9). The purpose of this report is to review the current evidence on screening for HBV infection in asymptomatic adolescents and adults, excluding pregnant women. This report differs from the previous USPSTF review (11) by including additional key questions on the benefits and harms of antiviral treatment and the association between improvements in intermediate outcomes after antiviral therapy and subsequent clinical outcomes. 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. HBeAg = hepatitis B e antigen; HBV = hepatitis B virus; KQ = key question. * The full report (12) addresses this KQ. 1. What are the benefits of screening for HBV infection versus no screening in asymptomatic adolescents and adults on morbidity, mortality, and disease transmission? 2. What are the harms of screening for HBV infection? 3. How well do different screening strategies identify persons with HBV infection? 4. In persons without evidence of HBV immunity, how effective is HBV vaccination at improving clinical outcomes? 5. How effective is antiviral treatment at improving intermediate outcomes? 6. How effective is antiviral treatment at improving health outcomes? 7. What are the harms associated with antiviral treatment for HBV infection? 8. Are improvements in intermediate outcomes after antiviral therapy associated with improvements in health outcomes? The full report (12) contains detailed methods and data, including search strategies, inclusion criteria, abstraction and quality rating tables, an additional key question on the effects of behavior change counseling and education, and results related to biochemical and composite intermediate outcomes. The protocol was developed by using a standardized process with input from experts and the public. The analytic framework focuses on direct evidence that screening for HBV infection improves important health outcomes versus not screening and the chain of indirect evidence linking screening to improved health outcomes. Links in the chain of indirect evidence include the yield and performance of testing strategies for identifying persons with HBV infection and benefits and harms from subsequent treatments. We did not re-review the accuracy of HBV serologic testing, which the USPSTF previously determined to be accurate (sensitivity and specificity >98%) (13). We also did not evaluate prenatal screening, which the USPSTF is not currently addressing. Data Sources and Searches A research librarian searched MEDLINE (1946 through January 2014), the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and PsycINFO. We supplemented 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, we included randomized trials and observational studies that compared different screening strategies in asymptomatic adults without known abnormal liver enzyme levels. We also reported clinical outcomes or the sensitivity and number needed to screen (NNS) to identify 1 HBV-infected person or provided the data to calculate these variables. For treatment, we included placebo-controlled trials of vaccination of adolescents and adults without known immunity to HBV and relevant systematic reviews. For antiviral therapy, we included trials of monotherapy with a medication approved by the U.S. Food and Drug Administration versus placebo or no treatment or first-line antiviral therapies (entecavir, tenofovir, or pegylated interferon-2a) (9) versus other approved therapies (adefovir, nonpegylated interferon, lamivudine, or telbivudine) that reported clinical outcomes (mortality, cirrhosis, hepatic decompensation, hepatocellular carcinoma, need for transplantation, or disease transmission), intermediate outcomes (histologic, virologic, or serologic), or harms (withdrawals due to adverse events, serious adverse events, or overall adverse events). We included trials of interferon-2a (not approved for HBV infection) that reported clinical outcomes because evidence for interferon-2b and pegylated interferon was limited. For the association between achieving an intermediate outcome after antiviral treatment and subsequent clinical outcomes, we included cohort studies that reported adjusted risk estimates. We included only English-language articles and excluded studies published only as abstracts. We excluded trials of persons who did not respond to prior antiviral therapy or those who had virologic relapse and did not evaluate drug resistance as an outcome. We excluded studies of patients co-infected with HIV or hepatitis C virus, transplant recipients, and patients receiving hemodialysis. We excluded systematic reviews of antiviral therapies unless we were unable to abstract the primary studies because they were in a foreign language. Appendix Figure 2 shows the summary of evidence search and selection. Appendix Figure 2. Summary of evidence search and selection. * Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Reference lists of relevant articles. Some studies are included for >1 key question. The full report (12) addresses this key question. 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 criteria developed by the USPSTF (14, 15) to rate the quality of each study as good, fair, or poor. Discrepancies were resolved through consensus. Data Synthesis and Analysis We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) on the basis of the number, quality, and size of studies; consistency of results; and directness of evidence (14, 15). For antiviral therapy and vaccination, we conducted meta-analyses to calculate relative risks using the DerSimonianLaird random-effects model (Review Manager, version 5.2, Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Primary analyses for antiviral therapy were based on total follow-up (including events after discontinuation of treatment), although we conducted sensitivity analyses of events during antiviral therapy. For harms, we analyzed events that occurred during antiviral therapy. For all analyses, we stratified results by antiviral drug. Statistical heterogeneity was assessed by using the I 2 statistic (16). We did additional analyses in which trials were stratified by study quality, duration of follow-up (shorter or longer than 1 year), hepatitis B e antigen (HBeAg) status, and inclusion of patients with cirrhosis. 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 the scope, analytic framework, and key questions. The AHRQ had no role in study selection, quality assessment, or synthesis. Staff from the AHRQ provided project oversight; reviewed the report to ensure that the analysis met methodological standards; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. The investigators are solely responsible for the content and the decision to submit the manuscript for publication. Results No study compared clinical outcomes or harms in persons screened for HBV infection versus those not screened (the first 2 key questions). Yield of Risk-Based Screening Methods One fair-quality cross-sectional study (n= 6194) done in a French clinic for sexually transmitted infections found that targeted screening of persons born in countries with a prevalence of chronic HBV infection of 2% or greater, men, and unemployed persons identified 98% (48 of 49) of infections while testing approximately two