Tracy Wolff

Aspirin for the Primary Prevention of Cardiovascular Events: An Update of the Evidence for the U.S. Preventive Services Task Force

Cardiovascular disease (CVD) is the leading cause of death in the United States; it is the underlying or contributing cause in approximately 58% of deaths. In 2003, 1 in 3 adults had some form of CVD. In adults age 40 years or older, the lifetime risk for CVD increases to 2 in 3 for men and more than 1 in 2 for women. Mortality data from 2003 showed that CVD was an underlying cause of death in 1 of every 2.7 deaths, accounting for roughly 2.5 million deaths; the mortality rate from CVD was 308.8 per 100000 (1). The epidemiology of CVD events is different for men and women. Men have a higher risk for coronary heart disease and tend to have these events at a younger age than women. Men have a lifetime risk of 49% for a coronary heart disease event after the age of 40 years; for women, the lifetime risk is 32%. The median age for a first myocardial infarction is 65.8 years for men and 70.4 years for women. Women are more likely to die as a result of a myocardial infarction; 38% of women die within 1 year of their first myocardial infarction versus 25% of men. This may in part be because women are likely to be older when they have their first myocardial infarction (1, 2). Although incidence rates of stroke are higher among men than women, more women die of stroke than men because of their longer life expectancy. According to the Framingham data (2), the 10-year risk for initial ischemic stroke at age 55 years is 1.8% for women and 2.4% for men; at age 65 years, the risk increases to 3.9% for women and 5.8% for men. The lifetime risk for ischemic stroke for persons between the ages of 55 and 75 years is greater for women than for men (approximately 17% to 18% for women and 13% to 14% for men). After age 75 years, the risk decreases to 14% for women and 8% for men. In 2002, the U.S. Preventive Services Task Force (USPSTF) strongly recommended that clinicians discuss aspirin with adults who are at increased risk for coronary heart disease (3). The previous USPSTF recommendation for the prophylactic use of aspirin to prevent CVD was based on data from 5 randomized controlled trials (RCTs) that showed a 28% reduction in myocardial infarctions with aspirin use. Only 2 of the 5 studies included women. In 2005, data from the Womens Health Study (4) provided important information about the benefit of aspirin for women. The Womens Health Study was a trial of 39876 women randomly assigned to receive aspirin or placebo and followed for 10 years for cardiovascular events. With the availability of new data on benefits for women, the USPSTF decided to update its previous recommendation by reevaluating the evidence for aspirin use in the primary prevention of CVD, with a focus on sex-specific harms and benefits. This review updates the previous review and focuses on new evidence on the benefits and harms of aspirin for the primary prevention of CVD published since the 2002 USPSTF review and recommendation (3). Analytic Framework and Key Questions In consultation with the USPSTF, we developed an analytic framework (Figure 1). From this analytic framework, we developed the following key questions (KQs): Figure 1. Analytic framework: aspirin to prevent cardiovascular events. CHD = coronary heart disease; CVD = cardiovascular disease; GI = gastrointestinal; KQ = key question. KQ1a. Does aspirin use in women without known cardiovascular disease decrease coronary heart events, strokes, death from coronary heart events or strokes, or all-cause mortality? KQ1b. Does aspirin use in men without known cardiovascular disease decrease coronary heart events, strokes, death from coronary heart events or strokes, or all-cause mortality? KQ2a. Does aspirin use in women increase gastrointestinal bleeding or hemorrhagic strokes? KQ2b. Does aspirin use in men increase gastrointestinal bleeding or hemorrhagic strokes? Methods Data Sources and Searches For evidence on the benefits of aspirin for the primary prevention of CVD events (KQ1), we performed a literature search in PubMed by using the Medical Subject Heading terms aspirin and cardiovascular diseases. For evidence on the harms of aspirin for the primary prevention of CVD events (KQ2), we used the terms aspirin, cardiovascular diseases, gastrointestinal hemorrhage, and cerebral hemorrhage. We searched for studies published between 1 January 2001 and 28 August 2008. We limited our search to English-language studies, human studies, and studies of nonpregnant adults and to the following study types for benefits: RCT, meta-analysis, and systematic review. For evidence on harms, we limited our search to RCTs, casecontrol studies, meta-analyses, and systematic reviews. In addition to the literature search, we looked for other relevant studies in the Cochrane Central Register of Controlled Trials, through the examination of reference lists from included and other important articles, and through consultation with experts. Study Selection Two reviewers independently reviewed the titles, abstracts, and full articles and selected articles on the basis of predefined inclusion criteria. We resolved disagreements on inclusion by consensus or by involving a third reviewer, if necessary. In general, we included studies that evaluated aspirin versus control for the primary prevention of cardiovascular disease events in adults, had a study population of patients without a history of CVD or who were not at very high risk for CVD (such as patients with atrial fibrillation) and was generalizable to the U.S. primary care population, and calculated risk estimates for 1 of the following outcomes: myocardial infarction, stroke, death from myocardial infarction or stroke, or all-cause mortality for benefits and gastrointestinal bleeding, serious bleeding episodes, hemorrhagic stroke, or cerebral hemorrhage for harms. We accepted studies that included patients with a history of CVD or patients who were at very high risk for CVD only if those studies reported separate results for patients without a history of CVD or who were not at very high risk for CVD. Data Extraction and Quality Assessment Two reviewers independently abstracted and quality-rated the included articles. We extracted the following data: geographic location, duration of therapy, proportion of female patients, dosage, control, blinding, outcome adjudication, additional therapies, demographic characteristics, and effect estimates on the previously listed outcomes. We evaluated the quality of the individual studies by using previously published USPSTF criteria on internal and external validity (Appendix Table) (57). We evaluated RCTs on adequacy of randomization; maintenance of similar groups (includes attrition, crossovers, adherence, and contamination); loss to follow-up; equality, reliability, and validity of measurements; clarity of intervention definitions; and appropriateness of outcomes. We evaluated systematic reviews on comprehensiveness of sources considered, search strategy used, explicit selection criteria, standard appraisal of included studies, validity of conclusions, recency, and relevance. We excluded studies of poor quality. We determined generalizability of the study sample to the United States by consensus of 3 reviewers after discussions with the USPSTF on similarities between the health care system in the study country and that of the United States. Considerations about whether a population would be similar to the U.S. population include baseline risk for cardiovascular disease, general health status of the population, and the availability of acute medical care and treatment in a health system with available tertiary care centers. Appendix Table. U.S. Preventive Services Task Force Hierarchy of Research Design and Quality Rating Criteria Data Synthesis We synthesized the studies qualitatively and organized them by key question. We did not synthesize quantitatively because of the availability of a good-quality meta-analysis by Berger and colleagues (8). We discuss the results of this meta-analysis in the Results section. Role of the Funding Source The general work of the USPSTF is supported by the Agency for Healthcare Research and Quality. This specific review did not receive separate funding. Results Our literature search initially identified 726 potentially relevant articles (Figure 2). We excluded most studies because either the sample population comprised only patients at very high risk for CVD or with a history of CVD or the study did not evaluate aspirin for the primary prevention of CVD. We also excluded studies that were duplicates or provided no new information, were not of appropriate study design, or did not report outcomes of interest. We ultimately included 4 studies, which we discuss. The 4 studies provided information on both benefits and harms. Figure 2. Study flow diagram. Key Question 1 Does aspirin use in men and women without known cardiovascular disease decrease coronary heart events, strokes, death from coronary heart events or strokes, or all-cause mortality? New evidence from controlled trials is limited to 1 study in women, the Womens Health Study (4), that reported benefit in the reduction of ischemic strokes with aspirin use. The Womens Health Study was a good-quality, double-blind RCT that evaluated the risks and benefits of aspirin for the primary prevention of cardiovascular disease. The investigators reported a benefit from aspirin use for the reduction of strokes (relative risk [RR], 0.83 [95% CI, 0.69 to 0.99]), specifically ischemic strokes (RR, 0.76 [CI, 0.63 to 0.93]), and no statistically significant benefit in the reduction of combined cardiovascular events, myocardial infarctions, death from CVD, or all-cause mortality. We considered this study to be of good quality because a blinded end point committee of physicians reviewed medical records for all reported end points, analyses were completed by using an intention-to-treat process, and the follow-up rate was high. The investigators did not re

Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Update of the Evidence for the U.S. Preventive Services Task Force

Neural tube defects (NTDs) are among the most common birth defects in the United States (1). It is difficult to estimate disease burden because affected pregnancies are sometimes spontaneously or electively aborted and are underreported on birth certificates (2). The Centers for Disease Control and Prevention estimate that the rates in 2005 for 2 of the most common NTDs, spina bifida and anencephaly, were 17.96 per 100000 live births and 11.11 per 100000 live births, respectively (3). The U.S. Preventive Services Task Force (USPSTF) last issued a recommendation on the use of folic acid in women of childbearing age in 1996. At that time, it recommended that all women planning a pregnancy or capable of conception take a supplement that contained folic acid. They found insufficient evidence to recommend for or against counseling women to increase their dietary folate consumption as an alternative to taking a folic acid supplement. The purpose of this review is to update the evidence on folic acid supplementation in women of childbearing age. The USPSTF decided to focus its new review on folic acid supplementation; therefore, this update does not include a review of the evidence on fortification, counseling to increase dietary intake, or screening for neural tube defects. We include only literature published since 1995 because it is an update of the previous USPSTF review. Figure 1 shows the analytic framework developed for this review, which follows USPSTF methods. The USPSTF developed 2 key questions (KQs) from the analytic framework to guide its consideration of the evidence on folic acid supplementation: Figure 1. Analytic framework for the U.S. Preventive Services Task Force review on folic acid supplementation for the prevention of NTDs. KQ = key question; NTD = neural tube defect. KQ1: Does folic acid supplementation in women of childbearing age reduce the risk for a pregnancy affected by a neural tube defect? KQ2: Does folic acid supplementation in women of childbearing age increase the risk for any harmful outcomes for either the woman or the infant? Methods Data Sources and Searches We performed a systematic search in MEDLINE for English-language articles published between January 1995 and December 2008 by using the terms neural tube defects, folic acid, pregnancy, twinning, and twins. We identified additional studies by searching the Cochrane Central Register of Controlled Trials, having discussions with experts, and hand-searching reference lists from included studies and major review articles and studies. Study Selection Two reviewers independently reviewed the titles and abstracts and selected articles for inclusion on the basis of predetermined inclusion and exclusion criteria. In general, we selected randomized, controlled trials (RCTs); casecontrol studies; cohort studies; and systematic reviews that reported an overall effect on reduction of NTDs or an effect on harms associated with folic acidcontaining supplements and provided new evidence that was not in the 1996 USPSTF report. We excluded studies that did not include new evidence since the 1996 review; did not report outcome data on NTDs or harms associated with folic acid supplementation; did not report on the effect of supplements separate from dietary effects; were letters, editorials, or nonsystematic reviews; were performed in special or high-risk populations; or were performed in a country or population with widespread malnutrition or that was otherwise not generalizable to the United States. The Appendix provides more details on search terms and inclusion and exclusion criteria. We discussed and settled disagreements about inclusion of an article by consensus; if necessary, we involved a third reviewer for disagreements. Data Extraction and Quality Assessment For all citations that met initial eligibility criteria, 2 reviewers reviewed, abstracted, and independently quality-rated the full articles. We ultimately included studies that were rated fair or good on the basis of USPSTF criteria. We achieved consensus about article abstraction data and quality through discussion by the 2 reviewers and resolved disagreements by involving a third reviewer. We extracted data from included studies on the following items: methods; exposure assessment; case ascertainment; selection of participants; dose of folic acid; sample size; size of effect on NTDs, other congenital abnormalities, and twinning; and information on confounders. We used standard USPSTF methodology on internal and external validity to quality-rate the articles for all KQs. We evaluated the quality of RCTs and cohort studies on initial assembly of comparable groups, maintenance of comparable groups, important differential loss to follow-up or overall high loss to follow-up, measurements (equality, reliability, and validity of outcome measurements), clear definition of interventions, and appropriateness of outcomes. We evaluated systematic reviews and meta-analyses on comprehensiveness of sources considered, search strategy, standard appraisal of included studies, validity of conclusions, recency, and relevance. Appendix Table 1 lists more complete criteria and definitions for USPSTF quality ratings. Appendix Table 1. U.S. Preventive Services Task Force Hierarchy of Research Design and Quality Rating Criteria Data Synthesis and Analysis We qualitatively synthesized data from studies included for KQ1 and KQ2 in tabular and narrative format. We organized synthesized evidence by key question. Role of the Funding Source The general work of the USPSTF is supported by the Agency for Healthcare Research and Quality. This specific review did not receive separate funding. Results We identified 1083 articles, of which 4 met our inclusion criteria for benefits and 1 for harms. Figure 2 details the reasons for exclusions. Appendix Tables 2 and 3 discuss studies that initially met inclusion criteria and were abstracted and quality-rated but were ultimately excluded for KQ1 (benefits) and KQ2 (harms), respectively. Figure 2. Study flow diagram. KQ = key question. Appendix Table 2. Studies Excluded After Abstraction and Quality Rating for Key Question 1 (Benefits) Appendix Table 3. Studies Excluded After Abstraction and Quality Rating for Key Question 2 (Harms) Key Question 1 Does folic acid supplementation in women of childbearing age reduce the risk for a pregnancy affected by a neural tube defect? Our literature search to answer this question returned 4 articles that met the inclusion criteria, were published within the search time frame, and were of appropriate methodological quality. The Table lists detailed study characteristics and outcomes. Observational studies on the benefits of folic acid supplementation provide generally consistent evidence that folic acid supplementation in the periconceptional period reduces the risk for neural tube defects in offspring. This evidence was provided by 3 fair- or good-quality cohort, casecontrol, and meta-analytic studies that found statistically significant benefit; a small, fair-quality casecontrol study reported benefit that was not statistically significant. In addition to NTDs, the cohort and meta-analysis found reductions in cardiovascular congenital abnormalities associated with folic acidcontaining multivitamins. Table. Characteristics and Results of Studies Included for Key Questions 1 and 2 The first study, by Czeizel and colleagues (4), recruited a cohort of 6112 women from the Hungarian Preconception Service. Women in the supplementation group received 0.8 mg of folic acid per day beginning 1 month before planned conception. Women who presented at 8 to 12 weeks of gestation with no periconception folic acid supplementation served as control participants and were matched 1-to-1 by age, socioeconomic status, and employment status with 3056 women who received supplements. We rated this study fair quality because women in the supplementation group were more likely than control participants to have congenital abnormalities or a history of congenital abnormalities among family or offspring and because exposure to folic acid supplementation was assessed earlier in the supplementation group than in the control group. One NTD occurred in the supplementation group and 9 in the control group, of 3056 women in each group. Although this difference was statistically significant after adjustment for birth order, chronic maternal disorders, and history of previous fetal death or congenital abnormality, our confidence in the statistical estimates is reduced, given the small number of events. Of note, this study also reported that women who received supplements had infants with significantly fewer cardiovascular congenital abnormalities than did control participants. We found 2 casecontrol studies in the literature search. These studies explored the association between exposure to folic acid supplementation in the periconceptional period and NTD in women residing in 2 areasmost California counties and South Carolina. The Table details the study design. We rated the 1995 casecontrol study by Shaw and colleagues (5) good quality because it accurately ascertained cases, selected case-patients and control participants without obvious biases, had response rates of 88% among both case patients and control participants, applied exposure measurement equally to case-patients and control participants, and explored reporting bias. We rated the 2003 casecontrol study by Thompson and colleagues (6) fair quality because it had a small sample size, differential measurement assessments, and differential response rates among case patients and control participants. Shaw and colleagues (5) reported an odds ratio (OR) of 0.65 (95% CI, 0.45 to 0.94) for any reported use of folic acidcontaining supplements in the 3 months before conception and an OR of 0.60 (CI, 0.46 to 0.79) for supplement use in the 3 months after conception. Thompson and colleagues (6) reported an OR of 0.55

Screening for Carotid Artery Stenosis: An Update of the Evidence for the U.S. Preventive Services Task Force

Cerebrovascular disease is the third leading cause of death in the United States (1). Approximately 500000 people in the United States each year experience a first stroke (1). The mortality rate for cerebrovascular disease has declined by nearly 70% since 1950 (2). Much of the decrease is probably due to reduced cigarette smoking and improved control of hypertension. Carotid artery stenosis (CAS) is pathologic atherosclerotic narrowing of the extracranial carotid arteries. The contribution of CAS to overall stroke burden is difficult to approximate. Eighty-eight percent of strokes are ischemic, and 20% or fewer of these are due to large-artery stenosis (39). A subgroup of patients have large-artery stenosis due to stenosis of the carotid bifurcation or proximal carotid artery that is approachable by carotid endarterectomy; some of these patients are asymptomatic. A clinically important degree of CAS is defined as the percentage of stenosis that corresponds to a substantially increased risk for stroke. Because stroke risk depends on more than the degree of carotid artery narrowing, it is difficult to define categories of CAS that are associated with various risk levels of stroke in asymptomatic people. Most studies of treatment for CAS consider stenosis of 50% or greater or 60% or greater to be clinically important. The most important risk factor is previous cerebrovascular disease. Other risk factors include hemodynamic factors; atrial fibrillation; collateral circulation; patient age (>65 years); male sex; comorbid conditions; and cardiovascular risk factors, such as hypertension, cigarette smoking, clotting mechanisms, and plaque structure (1016). The presence of the strongest reported risk factors, smoking or heart disease, approximately doubles the risk for CAS (14, 15). However, no single risk factor or clinically useful risk model incorporating multiple factors clearly discriminates people who have clinically important CAS from people who do not. Several population-based cohort and cross-sectional studies have examined the prevalence of CAS. These prevalence estimates are based on a positive result on a screening carotid ultrasonography. Estimates of the prevalence of CAS from population-based studies range from 0.5% to 8% (5, 10, 1719). On the basis of population-based studies and the accuracy of ultrasonography, we estimate the actual prevalence of clinically important CAS (60% to 99%) to be approximately 1% or less in the general primary care population and about 1% in persons age 65 years or older. A detailed discussion on the prevalence of CAS is available in a larger report at www.ahrq.gov/clinic/uspscacas.htm (20). Carotid endarterectomy has been proposed as a strategy for reducing the burden of suffering due to stroke, in addition to controlling such risk factors as tobacco use and hypertension. Randomized, controlled trials (RCTs) have shown that carotid endarterectomy effectively reduces stroke among people who have severe CAS and have had a transient ischemic attack or minor stroke. It is not clear, however, whether screening asymptomatic people (those who have never had a transient ischemic attack) to detect CAS and treatment with carotid endarterectomy are effective in reducing stroke. Before carotid endarterectomy, cerebral angiography after ultrasonography may be used to confirm CAS. A small percentage of patients will be harmed by the angiographic procedure itself. In an RCT of carotid endarterectomy in asymptomatic patients, 1.2% of patients who had angiography had a nonfatal stroke. Prospective studies of cerebral angiography have found rates of persistent neurologic complications of 0.1% to 0.5% (2123). Because of the increased risk for stroke, there is disagreement on whether cerebral angiography should be used to confirm a positive ultrasonography screening result. Current practice varies widely: Some surgeons do other confirmatory tests, such as magnetic resonance angiography (MRA) or computed tomographic angiography (CTA), whereas others request angiography before carotid endarterectomy. In 1996, the U.S. Preventive Services Task Force (USPSTF) concluded that evidence was insufficient to recommend for or against screening of asymptomatic persons for CAS by using physical examination or carotid ultrasonography (24). This recommendation was based on new evidence at the time, including data from ACAS (Asymptomatic Carotid Atherosclerosis Study), an RCT involving 1662 persons with asymptomatic stenosis greater than 60%. Results of ACAS suggested that the overall benefit of treatment with carotid endarterectomy depends greatly on the perioperative complications. At that time, information was limited about carotid endarterectomy complications in the general population. Since the previous Task Force review, the largest RCT of carotid endarterectomy versus medical treatment for asymptomatic CAS, the ACST (Asymptomatic Carotid Surgery Trial), and several large studies on actual harms of carotid endarterectomy have been published. This review updates the 1996 USPSTF review of screening for CAS, focusing on duplex ultrasonography as the screening test (with various confirmatory tests) and carotid endarterectomy as the treatment for clinically important CAS. Medical interventions and screening with carotid auscultation were not reviewed in this report. The USPSTF has reviewed screening for several known risk factors of carotid artery stenosis and stroke, including hyperlipidemia, hypertension, aspirin prophylaxis, and smoking. The evidence reports and recommendations are available at the Agency for Healthcare Research and Quality Web site at www.preventiveservices.ahrq.gov . Figure 1 shows the analytic framework for this review, which was developed by following USPSTF methods (25). The USPSTF developed 4 key questions from the analytic framework to guide its consideration of the benefits and harms of screening with ultrasonography for CAS. The key questions were as follows: Figure 1. Analytic framework for screening for carotid artery stenosis ( CAS ). CEA = carotid endarterectomy; KQ = key question. Key question 1: Is there direct evidence that screening adults with duplex ultrasonography for asymptomatic CAS reduces fatal or nonfatal stroke? Key question 2: What is the accuracy and reliability of duplex ultrasonography to detect clinically important CAS? Key question 3: For people with asymptomatic CAS 60% to 99%, does intervention with carotid endarterectomy reduce CAS-related morbidity or mortality? Key question 4: Does screening or carotid endarterectomy for asymptomatic CAS 60% to 99% result in harm? Methods The USPSTF designated key questions 1, 2, and 3 as subsidiary questions for which they requested nonsystematic reviews to assist them in updating their recommendations. Key question 4 was the only key question for which the USPSTF requested a systematic evidence review. Data Sources and Searches We searched MEDLINE for English-language articles published between 1 January 1994 and 2 April 2007 that addressed key questions 1, 2, and 3. We identified additional studies by examining the reference lists of major review articles and by consulting experts. For key question 3, we performed a MEDLINE search for RCTs, systematic reviews, and meta-analyses that compared carotid endarterectomy with medical therapy for asymptomatic people with CAS. We identified 1 in-process RCT by its inclusion in a systematic review, and we included it once it was published. For key question 4, we performed a systematic search of MEDLINE for English-language articles published between 1 January 1994 and 2 April 2007 by using the focused Medical Subject Heading terms endarterectomy, carotid, and outcome and process assessment. We also selected a key study from this search and identified related articles through MEDLINE. Additional studies were identified through a search of the Cochrane database, discussions with experts, and hand-searching of reference lists from major review articles and studies. Study Selection Titles and abstracts of articles retrieved for key questions 1, 2, and 3 were nonsystematically selected and reviewed by 2 reviewers. The process was considered nonsystematic because articles were selected for review and abstracted by 1 reviewer. Articles for key question 1 were selected for inclusion if they were RCTs; compared screened versus nonscreened groups; used ultrasonography, MRA, or CTA as screening methods; reported outcomes of strokes or death in asymptomatic persons; and were performed in a population generalizable to the United States. For key question 2, we included systematic reviews that compared screening tests (ultrasonography, MRA, or CTA) with angiography in asymptomatic persons and were performed in a population generalizable to the United States. Articles for key question 3 were included if they were RCTs of carotid endarterectomy comparing surgical treatment with medical treatment, reported 30-day complication rates (stroke and death) of carotid endarterectomy, included only asymptomatic patients, and were performed in a population generalizable to the United States. For key question 4, three reviewers independently reviewed the abstracts and selected articles from titles and abstracts on the basis of inclusion and exclusion criteria. In general, studies were selected if they were large, multi-institution, prospective studies that reported 30-day mortality or stroke outcomes for asymptomatic patients undergoing carotid endarterectomy. Studies were excluded if they did not report outcomes by symptom status, included patients receiving carotid endarterectomy combined with other major surgeries, were not performed in the United States, included patients with restenosis, or covered patients at extremely high risk. Appendix Table 1 shows detailed search terms and inclusion and exclusion criteria. Abstracts that were chosen by fewer than 3 reviewers were discussed and selected on t

Screening for Syphilis Infection in Pregnant Women: Evidence for the U.S. Preventive Services Task Force Reaffirmation Recommendation Statement

Syphilis is caused by the spirochete Treponema pallidum and manifests as a systemic infectious process. Syphilis may be transmitted vertically, usually through the placenta; the risk for fetal infection increases with gestational age. Vertical transmission may also occasionally occur during delivery if maternal genital lesions are present (1). The consequences of fetal syphilis include prematurity, low birthweight, nonimmune hydrops, and intrauterine death (2). Associated conditions and risk factors for syphilis among reproductive-age women in the United States include substance abuse, limited access to health care, poverty, African-American ethnicity, and lack of regular prenatal care (3, 4). In addition, rates of primary and secondary syphilis are highest among individuals 25 to 29 years of age (5). Rates of syphilis among women have increased since 2004. Between 2005 and 2006, rates increased among women by 11.1% (from 0.9 to 1.0 cases per 100000 persons) (5). In the United States, the number of babies born with syphilis has consistently decreased, from 4410 cases in 1991 to 353 cases (8.8 cases per 100000 live births) in 2004 (4). However, the rate of congenital syphilis increased between 2005 and 2006 by 3.7% (from 8.2 to 8.5 cases per 100000 live births) (3). Although the overall rate of congenital syphilis has decreased significantly since the onset of the syphilis elimination plan in 1996, this recent increase is cause for concern, given that congenital syphilis is preventable (5). In 2004, the U.S. Preventive Services Task Force (USPSTF) strongly recommended that clinicians screen all pregnant women for syphilis infection (6, 7). Our purpose is to provide information for the USPSTF to update, and reaffirm, its 2004 recommendation. As a basis for this reaffirmation, the USPSTF asked us to do a targeted literature search to find new and substantial evidence on the benefits and harms of screening for syphilis in pregnancy and the harms of treatment with penicillin. Topics that undergo a reaffirmation update have already undergone a previous systematic USPSTF review; in addition, these topics represent standards of care that are well established, evidence-based, and in current medical practice (8). The USPSTF performs reaffirmation updates for topics that remain a Task Force priority, that are within the scope of review of the USPSTF, and for which the USPSTF has a convincing reason to keep the recommendation current (8). The USPSTF requested that this reaffirmation update address the following primary key questions: Does screening for syphilis in pregnancy reduce the prevalence of congenital syphilis in neonates? Are there harms of screening for syphilis or harms of treatment with penicillin in pregnancy to women or neonates? The USPSTF determined that for this update it was not necessary to review the accuracy of screening tests or the effectiveness of treatment in neonates and in pregnant women. The accuracy of rapid plasma reagin (RPR) and Venereal Disease Research Laboratory (VDRL) screening tests and penicillin treatment are well established. The USPSTF is, however, interested in any potential harms of these screening tests, as well as potential harms of penicillin treatment in neonates and pregnant women, as indicated in the key questions above. Methods Data Sources and Searches We performed literature searches on the benefits and harms of screening for syphilis infection in pregnant women, as well as the harms of penicillin treatment for this infection in pregnant women and in neonates. We limited our searches to the period of 1 January 2003 through 31 July 2008 and used the search terms penicillin, pregnancy, infant, newborn, fetus, adverse effect, allergic reaction, harm, mass screening, rapid plasma reagin, VDRL antigen, pregnancy complications, Treponema pallidum, and syphilis. We limited our initial searches to English-language articles that were indexed in the PubMed core clinical journal subset (formerly known as the Abridged Index Medicus). We supplemented these searches by reviewing reference lists of important articles and recent reviews and by taking suggestions from experts. Study Selection We selected studies that provided evidence on the benefits of screening for syphilis in pregnancy in the reduction of incidence of congenital syphilis; the harms of screening, specifically focusing on false-positive and false-negative results; and the harms of treatment, primarily allergic reactions and fetal harms. For evidence on benefits, we selected studies that included pregnant women. For evidence on false-positive and false-negative results, we included studies in pregnant and nonpregnant adults who were screened with RPR or VDRL and used treponemal-specific tests as the gold standard. We excluded studies that reported only results for newer rapid tests and did not report results on RPR and VDRL, which are considered the standard of care in the United States. For evidence on allergic reactions to penicillin, we selected studies that included pregnant and nonpregnant adults. We excluded studies in high-risk or special populations and studies in populations not generalizable to the United States. We determined generalizability of study sample to the United States by consensus of 2 reviewers after discussions with the USPSTF on similarities between the health care system in the study country and that of the United States. Considerations about whether a population would be comparable to a U.S. population include the general health status of the population, the availability of prenatal care, and the availability of trained delivery attendants. We specifically excluded studies in populations with high HIV rates, because these studies are thought not to be generalizable to the United States. To determine whether prenatal screening reduces the prevalence of congenital syphilis in neonates, we included randomized, controlled trials; meta-analyses; and systematic reviews. In addition, we included large ecologic studies and cohort studies that reported the effect of the implementation of widespread screening programs. We included these types of studies because the original evidence on the effectiveness of syphilis screening in pregnancy was from ecologic studies that showed that rates of congenital syphilis were reduced after widespread screening and treatment. To determine the harms of syphilis screening and penicillin treatment, we included randomized, controlled trials; meta-analyses; systematic reviews; cohort studies; casecontrol studies; and large case series. We excluded editorials, narrative reviews, case studies, and guideline reports. At the abstract and full article review stage, 2 reviewers independently evaluated all articles according to predetermined exclusion criteria. Any article selected by at least 1 reviewer at the abstract stage was advanced to the full article stage of the review. We resolved differences of opinion at the full article stage by consensus and involved a third reviewer if necessary. Data Extraction We extracted information from each included study on its design, selection criteria, demographic characteristics, and clinical outcomes. Quality Appraisal We provided narrative descriptions of key methodological deficiencies of included studies that constrain the quality and generalizability of the evidence. Data Synthesis We synthesized the evidence from included studies in a narrative format. Role of the Funding Source The work conducted by the USPSTF is supported by the Agency for Healthcare Research and Quality. This review did not receive separate funding. Results We identified 141 potentially relevant studies. We most commonly excluded studies because they were not on syphilis screening or treatment, were not an appropriate study type, or had no information on relevant health outcomes. After we excluded studies on the basis of predetermined criteria (Figure), 5 studies remained (Table)1 study of the benefits of screening and 4 studies of the harms of screening and treatment. Figure. Study flow diagram. KQ = key question; STD = sexually transmitted disease. Table. New Studies on the Benefits of Screening and Harms of Screening and Treatment for Syphilis in Pregnancy Key Question 1 Does screening for syphilis in pregnancy reduce the incidence of congenital syphilis in neonates? We found 1 study in a non-U.S. population (9) that provided information on the benefits of screening for syphilis in pregnancy and met our inclusion criteria; we did not find any new studies in U.S. populations. The 1 study we found evaluated the effect of implementing a free, routine syphilis screening program for pregnant women in a region of China. A total of 418871 pregnant women who were treated at 61 hospitals in the Shenzhen region of China from 2003 to 2005 were offered free syphilis screening. Ninety-four percent of eligible women were screened. Syphilis was diagnosed in 2019 women over the 3 years of the study, of whom 92% received timely treatment, 3% received delayed treatment, 3% declined treatment, and 2% were lost to follow-up. Of the 1402 women who had syphilis and chose to continue their pregnancy, 86 (6%) had pregnancies that ended in fetal demise or stillbirth. Ninety-two live-born infants with congenital syphilis were reported in the 3 years of the study. Most (83%) of these cases were in babies born to women who received no prenatal care. Eight percent occurred in babies born to women who received late prenatal care, and 5% occurred in babies born to women who declined treatment. The incidence of congenital syphilis decreased after the implementation of this screening program: At the beginning of the study, the incidence rate was 54 cases per 100000 pregnant women; the rate decreased to 22 cases per 100000 pregnant women after initiation of the program. The study investigators report that loss to follow-up was an important limitation because many migratory women changed cont

Reconsidering the Approach to Prevention Recommendations for Older Adults

The U.S. Preventive Services Task Force (USPSTF) bases its recommendations on an evidence-based model of clinical prevention that focuses on specific diseases, well-defined preventive interventions, and evidence of improved health outcomes. Applying this model to prevention for very old patients has been problematic for several reasons: Many geriatric disorders have multiple risk factors, interventions, and expected outcomes; older adults are not often represented in clinical trials; and important outcomes may not be measured and reported in ways that are conducive to evidence synthesis and interpretation. In 2005, the USPSTF convened a geriatrics workgroup to refine USPSTF methodology and processes to better address the preventive needs of older adults. The USPSTF has begun to apply these new approaches to the review and recommendation on interventions to prevent falls in older adults.

Evidence for the Reaffirmation of the U.S. Preventive Services Task Force Recommendation on Screening for High Blood Pressure

Hypertension is usually defined in adults as systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher (1). Data from NHANES III (Third National Health and Nutrition Examination Survey) suggest that an estimated 43 million U.S. adults older than 25 years have hypertension and that hypertension is more common in African American and elderly persons than in other groups. In the United States, hypertension is responsible for 35% of myocardial infarctions and strokes, 49% of episodes of heart failure, and 24% of premature deaths. Additional complications of hypertension include end-stage renal disease, retinopathy, and aortic aneurysm (24). In 2006, the U.S. Preventive Services Task Force (USPSTF) decided to reexamine the evidence in order to reaffirm its 2003 recommendation on screening for high blood pressure (or hypertension). The Task Force issues a reaffirmation update for a topic that the USPSTF decides to keep current because the topic is one of its priorities, is within its scope, and is a topic for which there is a compelling reason to make a recommendation. Topics in this category are well-established evidence-based standards of current medical practice. The USPSTF decided to perform a reaffirmation update because the evidence base on hypertension is strong and only large, high-quality studies would overturn such a recommendation. Such recommendations would previously have been an A or D recommendation. Therefore, we performed a literature search for new, substantial evidence that would be sufficient to change the 2003 recommendation. Methods The USPSTF developed 2 key questions to be addressed: 1) What are the benefits of screening for high blood pressure in adults? 2) What are the harms of screening and/or early treatment of high blood pressure? To determine whether the benefits of screening for hypertension continue to outweigh the harms, the USPSTF included new information on the adverse effects of drug therapy for early hypertension as part of the question on harms. Data Sources and Searches We performed nonsystematic literature searches of PubMed and the Cochrane Library. We used the following search terms: hypertension, mass screening, adverse effects, and false positive results. We limited the searches to English-language studies of adult humans (age >18 years) that were published in core clinical journals between 1 October 2001 and 31 March 2006. Core clinical journals are a subset of 120 English-language journals defined by the National Library of Medicine; it was previously known as the Abridged Index Medicus. We also checked reference lists of systematic reviews and other studies for possibly relevant studies. Study Selection We included studies on benefits and harms of screening and treatment of early hypertension. We understood early hypertension to be blood pressure elevation that screening could reasonably identify. We defined early hypertension as prehypertension (systolic blood pressure of 120 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg), hypertension detected through screening, or untreated or newly diagnosed mild to moderate hypertension (systolic blood pressure of 140 to 180 mm Hg or diastolic blood pressure of 90 to 110 mm Hg, when information was not given about how hypertension was detected). We excluded studies in very high-risk or special populations, including patients with preexisting cardiovascular disease. We included studies of nonpregnant adults older than 18 years. We included studies from the United States and from countries with patient populations that are generalizable to the United States. For the literature on benefits, we included meta-analyses; systematic reviews; and randomized, controlled trials. For harms, we included meta-analyses; systematic reviews; randomized, controlled trials; cohorts; casecontrol studies; and case series of large, multisite databases. We excluded editorials, case reports, nonsystematic reviews, and guideline reports. Data Extraction No studies were included for data abstraction on the benefits or harms of screening. For harms of early treatment, 2 reviewers abstracted information on sample size, entry criteria, demographic characteristics, comorbid conditions, study design, treatment group allocation, reports of adverse effects of drug therapy, and quality-of-life outcomes. Data Synthesis and Analysis Data from the included studies were synthesized qualitatively in tabular and narrative formats. Role of the Funding Source The work of the USPSTF is supported by the Agency for Healthcare Research and Quality. No separate funding was used specifically for this study. Results The search returned 378 potentially relevant titles, which we entered into a reference database. A total of 341 studies were excluded after title review, 19 studies were excluded after abstract review, and 13 were excluded after full article review. We excluded 253 studies that were not on hypertension, 62 that included a high-risk population, 31 that did not meet study design criteria, 12 that were not from a U.S. population, 8 that were not done in adults, and 7 that had no relevant outcomes. No new studies on the benefits or harms of screening for high blood pressure met our inclusion criteria. Five studies evaluated the harms of early treatment of hypertension and met our inclusion criteria (Table); these are discussed below. Table. Studies on the Harms of Early Treatment of High Blood Pressure Three studies presented data on adverse effects related to antihypertensive drugs. These studies compared outcomes from treatment of one type of drug versus another type of drug or placebo. In general, they were multicenter studies in the United States, Canada, and United Kingdom; included a predominantly white, male patient sample; and excluded persons with multiple comorbid conditions or manifest cardiovascular disease. In addition, 2 studies examined the effects of antihypertensive medications on quality of life. In these 2 studies, participants with untreated hypertension were randomly allocated to different treatment regimens (the second study also included a placebo group) and followed for effects on quality of life: sexual dysfunction in one study, and symptom distress in the other study. The study on sexual dysfunction included men 40 to 49 years of age, and the study on symptom distress included men and women 50 years of age or older. In 1 study that gathered data on adverse effects, White and colleagues studied the effect of bedtime dosing on early-morning blood pressure in 261 persons who were randomly allocated to 10 weeks of extended-release diltiazem or ramipril (5). Adverse effects were reported in 50% of the diltiazem group and 40% of the ramipril group. Serious adverse effects were uncommon, and 2 of the 3 reported events were probably not related to the drug: 1 event occurred during placebo run-in, and 1 was associated with infection. The most common reasons for withdrawal from the study were lower-extremity edema associated with diltiazem (3%) and cough associated with ramipril (2%). Headache was commonly reported in both groups. The main finding of the study was that diltiazem at bedtime reduced early-morning blood pressure to a greater extent than ramipril. Julius and colleagues compared candesartan with placebo in participants with systolic blood pressure of 130 to 139 mm Hg and diastolic blood pressure of 89 mm Hg or less (6). Serious adverse effects were uncommon, occurring in 3.5% of candesartan recipients and 5.9% of placebo recipients. However, other, less serious adverse effects were very common, occurring in approximately 89% of participants in both the candesartan and placebo groups. Commonly reported adverse effects in the candesartan group were headache (22%), upper respiratory infection (14%), nasopharyngitis (10%), and dizziness (10%). A third study evaluated the effectiveness in reducing clinic-measured and ambulatory blood pressure of 4 antihypertensive agents (doxazosin, amlodipine, enalapril, and bendrofluazide) in 204 persons with diastolic blood pressure of 95 to 110 mm Hg (7). The authors reported that clinic-measured and ambulatory blood pressure decreased in all groups, with no significant differences among them; the authors did not report data that allowed us to determine the statistical significance of this comparison. Adverse effects were very common and did not statistically significantly differ among treatment groups (overall rate, 74% [range among groups, 68% to 81%]). Serious adverse effects were uncommon (overall rate, 11% [range, 6% to 14%]), and the rate of withdrawals due to adverse events was 11%. The most commonly reported adverse effect was headache (overall rate, 20% [range, 16% to 25%]). In 1 study with quality-of-life outcomes, Fogari and colleagues followed 160 married men 40 to 49 years of age with newly diagnosed hypertension (diastolic blood pressure of 95 to 110 mm Hg) who had never been treated for hypertension and had no symptoms of sexual dysfunction (8). One hundred twenty men were randomly assigned to receive an angiotensin II receptor antagonist (valsartan) or a -blocker (carvedilol) for 16 weeks, and, after a placebo washout period, were crossed over to the alternative regimen for another 16 weeks; 40 men were randomly assigned to receive placebo. Results indicated that carvedilol caused a decline in sexual function (the rate of sexual intercourse decreased by 50%, and 13.5% of patients experienced sexual dysfunction). Valsartan produced a temporary and nonstatistically significant decline in sexual function, and function improved with ongoing treatment: By 16 weeks, the rate of sexual intercourse had increased by 19%. The 2 drugs did not differ in control of blood pressure. The other study with quality-of-life outcomes evaluated symptom distress associated with a calcium-channel blocker (amlodipine) and an aldosterone receptor antagonist (eplerenone)

Developing recommendations for evidence-based clinical preventive services for diverse populations: Methods of the u.s. Preventive services task force

The U.S. Preventive Services Task Force (USPSTF) works to improve the health of all Americans by making evidence-based recommendations about clinical preventive services, such as screening, counseling, and use of preventive medications (1). To achieve this goal, we pay particular attention to how our recommendations can be most effectively applied to specific segments of the U.S. population with patterns of disease or the effectiveness of a preventive service that may differ from the general population. These specific populations may be identified by demographic characteristics (for example, age, race/ethnicity, or sex) or other factors (for example, biology, behavior, or heredity). In this article, we outline the principles and considerations that guide the development of our recommendations for specific U.S. populations. We discuss 3 recent recommendations as examples: the 2015 recommendation on screening for abnormal blood glucose and type 2 diabetes (2); the 2016 recommendation on screening for breast cancer (3); and the recommendation on screening for prostate cancer, which is currently in progress (4). A more comprehensive list of recommendations that includes considerations for specific populations is provided in the Table. Table. Selected Examples of USPSTF Recommendation Statements That Incorporate Evidence on Specific Populations Developing Research Plans and Conducting the Evidence Review to Include Diverse Populations We consider diverse populations starting with the first step in our processdevelopment of the research plan. This plan defines the types of evidence that will be gathered and reviewed by the Evidence-based Practice Center (EPC) team and used by the USPSTF to develop the recommendation. The research plan routinely includes a means to identify evidence on whether specific segments of the U.S. population may be disproportionately affected by a condition or susceptible to variation in the effectiveness of the preventive service. In consultation with the USPSTF, the EPC investigators have developed a comprehensive approach to incorporating the evidence for diverse populations throughout all phases of the systematic review process, including determination of the scope of the topic, data abstraction and critical appraisal, data analysis and synthesis, and reporting and interpretation of the evidence (13). Additional input about subpopulations comes from outside review and public comment on the draft research plan to further refine our process. For example, the draft and final research plans on screening for prostate cancer (Supplement 1) highlight additional clarifications from the USPSTF on consideration of African American men and men with family history of prostate cancer, which were added in response to public comments. Supplement. Supplementary Material The research plan guides the systematic evidence review conducted by the EPC team, and the resulting evidence report routinely includes information on the epidemiology across all relevant populations (for example, incidence, prevalence, and mortality). Supplement 2 shows the draft and final research plans for the 2015 recommendation on screening for abnormal blood glucose and type 2 diabetes. The analytic framework depicts the intent to review literature and consider variation in benefits and harms by risk status (high vs. average) and to examine additional variability by age, sex, and race/ethnicity at each stage in the framework. The subsequent systematic evidence review revealed the higher prevalence of diabetes and younger age at disease onset in African Americans, American Indians or Alaskan Natives, Asian Americans, Hispanics or Latinos, and Native Hawaiians or Pacific Islanders than in white populations. Obesity was identified as the defining factor in the high-risk group, for which screening and treatment showed a benefit, but the evidence also showed that Asian Americans had an increased risk for diabetes at a lower body mass index (14). The review revealed limited data on the effectiveness of screening or interventions specific to these racial/ethnic subpopulations. Using the Evidence to Develop Recommendations Relevant to Specific Populations The USPSTF uses the systematic evidence review to develop a recommendation and follows a rubric for assigning grades based on the magnitude of net benefit anticipated for the preventive service (that is, benefits minus harms) and the certainty of that estimate. When a decision to issue a recommendation for specific segments of the population is being made, the ability to clearly and easily identify the factors that define the specific population is important (for example, age, easily measured risk factors, or self-identified race/ethnicity). Although many features may distinguish a specific population under consideration, the final decision to issue a separate graded recommendation for that population is primarily based on whether a difference in magnitude of net benefit can be confidently identified. Evidence That Supports Differences in Magnitude of Net Benefit Sometimes a robust evidence base across different segments of the population allows for determination of corresponding differences in magnitude of net benefit, such as the evidence on mammography screening for breast cancer. Multiple randomized, controlled trials show the effectiveness of screening in women aged 40 to 74 years, with evidence of smaller net benefit at younger ages. The USPSTF issued a grade B recommendation for women aged 50 to 74 years and a grade C recommendation for those aged 40 to 49 years. Both grades favor screening, with grade B signifying moderate net benefit and C indicating a small net benefit. Variability in Quality or Volume of Evidence Supporting a Difference in Magnitude of Net Benefit Sometimes evidence supports a difference in the net benefit of a preventive service for a particular segment of the population, but the quality or volume of the direct evidence is not sufficiently robust to formulate a separate recommendation. For example, a specific population may be studied in randomized, controlled trials, but the highest evidentiary standard is lacking (for example, subgroup hypotheses were not specified a priori, the trial did not have sufficient power to find an effect in the subgroup, or trial results were not analyzed for statistical heterogeneity among subgroups). In this case, the USPSTF may call attention to a clearly identifiable group for whom the net benefit may differ from that of the average population, even if a separate recommendation is not issued. In the breast cancer screening recommendation, modeling studies suggest that women in their 40s with a mother, sister, or daughter with breast cancer have a risk similar to that of average-risk women in their 50s. We singled out family history as a factor that might lead a woman to consider screening in her 40s at the beginning of the grade C recommendation for women in their 40s, and we called attention to this in the Summary of Recommendations and Evidence section. Despite the higher risk and theoretically increased likelihood of benefit from earlier mammography screening in women with a family history of breast cancer, the absence of studies directly testing the efficacy of such screening prevented us from issuing a separate recommendation. Differences in Disease Epidemiology and the Question of Difference in Magnitude of Net Benefit We often have evidence of differences in the epidemiology of disease patterns between populations (for example, differences in incidence, mortality, or competing risks). Although this evidence may be important to communicate to patients and clinicians, differences in epidemiology alone usually do not allow us to make a separate, population-specific recommendation. When assessing the need for a separate, population-specific recommendation, we consider whether the preventive service could reasonably be expected to result in a difference in magnitude of net benefit in the specific population based on this epidemiology. In the absence of this evidence, the recommendation for the general population may reasonably be assumed to apply to that specific population in most cases. For example, African American women have higher rates of breast cancer mortality but the extent to which differences in screening efficacy contribute to this outcome is unclear. In fact, some evidence suggests that less breast cancer treatment is an important contributor to the higher mortality rates in these women. Our recommendation statement called attention to this fact and the importance of screening African American women, but we did not issue a separate recommendation because it is unclear whether more intensive or earlier screening in these women will affect mortality rates. The recommendation statement called for more research to address this question. Younger or older age at disease onset in a particular population may suggest that initiating the preventive service at a different age is indicated. Most screening trials provide little direct evidence on the optimal age for screening initiation or periodicity; therefore, at times we have used modeling to address these questions. Mathematical modeling may help estimate the effects of earlier or more frequent use of a preventive service in a population segment with an underlying disease epidemiology that differs from that of the general population. Differences in Certainty of the Evidence The USPSTF often reviews evidence of a preventive service that has been studied in one population and considers whether the potential of net benefit can be extrapolated to another segment of the population. This extrapolation may decrease the certainty of the effectiveness of the preventive service in that population segment, thereby resulting in a different recommendation grade. One example is screening for abdominal aortic aneurysm (8); studies were primarily conducted in male smokers, so we extra

Update on the Methods of the U.S. Preventive Services Task Force: Methods for Understanding Certainty and Net Benefit When Making Recommendations

Since the 1980s, the U.S. Preventive Services Task Force (USPSTF) has developed and used rigorous methods to make evidence-based recommendations about preventive services to promote health and well-being for all Americans. Recommendations are based on the evidence of magnitude of net benefit (benefits minus harms). Expert opinion is not substituted when evidence is lacking. Evidence gaps are common. Few preventive services are supported by high-quality studies that directly and comprehensively determine the overall magnitude of benefits and harms in the same study. When assessing the body of evidence, studies may not have been conducted in primary care settings, studies may not have sufficiently included populations of interest, and long-term outcomes may not have been directly assessed. When direct evidence is not available, the USPSTF uses the methodologies of applicability to determine whether evidence can be generalized to an asymptomatic primary care population; coherence to link bodies of evidence and create an indirect evidence pathway; extrapolation to make inferences across the indirect evidence pathway, extend evidence to populations not specifically studied, consider service delivery intervals, and infer long-term outcomes; and conceptual bounding to set theoretical lower or upper limits for plausible benefits or harms. The USPSTF extends the evidence only so far as to maintain at least moderate certainty that its findings are preserved. This manuscript details with examples of how the USPSTF uses these methods to make recommendations that truly reflect the evidence.

Update on the Methods of the U.S. Preventive Services Task Force: Linking Intermediate Outcomes and Health Outcomes in Prevention

The U.S. Preventive Services Task Force (USPSTF) is an independent body of experts who make evidence-based recommendations about clinical preventive services using a transparent and objective process. Developing recommendations on a clinical preventive service requires evidence of its effect on health outcomes. Health outcomes are symptoms, functional levels, and conditions that affect a patients quantity or quality of life and are measured by assessments of physical or psychologic well-being. Intermediate outcomes are pathologic, physiologic, psychologic, social, or behavioral measures related to a preventive service. Given the frequent lack of evidence on health outcomes, the USPSTF uses evidence on intermediate outcomes when appropriate. The ultimate goal is to determine precisely a consistent relationship between the direction and magnitude of change in an intermediate outcome with a predictable resultant direction and magnitude of change in the health outcomes. The USPSTF reviewed its historical use of intermediate outcomes, reviewed methods of other evidence-based guideline-making bodies, consulted with other experts, and reviewed scientific literature. Most important were the established criteria for causation, tenets of evidence-based medicine, and consistency with its current standards. Studies that follow participants over time following early treatment, stratify patients according to treatment response, and adjust for important confounders can provide useful information about the association between intermediate and health outcomes. However, such studies remain susceptible to residual confounding. The USPSTF will exercise great caution when making a recommendation that depends on the evidence linking intermediate and health outcomes because of inherent evidence limitations.

Challenges in Developing U.S. Preventive Services Task Force Child Health Recommendations

The U.S. Preventive Services Task Force (USPSTF) uses an objective evidence-based approach to develop recommendations. As part of this process, the USPSTF also identifies important research gaps in scientific evidence. In March 2016, the USPSTF convened an expert panel to discuss its portfolio of child and adolescent recommendations and identify unique methodologic issues when evaluating evidence regarding children and adolescents. The panel identified key domains of challenges, including measuring patient-centered health outcomes; identifying intermediate outcomes predictive of important health outcomes; evaluating the long time horizon needed to assess the balance of benefits and harms; understanding trajectories of growth and development that result in unique windows of time when expected benefits or harms of a preventive service can vary; and considering the perspectives of other individuals who might be affected by the delivery of a preventive service to a child or adolescent. Although the expert panel expressed an interest in being able to make more recommendations for or against preventive services for children and adolescents, it also reinforced the importance of ensuring recommendations were based on sound and sufficient evidence to ensure greatest benefit and minimize unnecessary harms. Accordingly, the need to highlight areas with insufficient evidence is as important as making recommendations. Having identified these key challenges, the USPSTF and other organizations issuing guidelines have an opportunity to advance their methods of evidence synthesis and identified evidence gaps represent important opportunities for researchers and policy makers.