A Comparison of Outcomes in Patients with Infrapopliteal Disease Randomised to Vein Bypass or Plain Balloon Angioplasty in the Bypass vs. Angioplasty in Severe Ischaemia of the Leg (BASIL) Trial.

OBJECTIVE: The aim was to compare outcomes in a subgroup of patients with infrapopliteal (IP) disease randomised to infrapopliteal vein bypass (VB) or plain balloon angioplasty (PBA) in the original BASIL trial. METHODS: A comparison of outcomes from patients randomised to VB or PBA undergoing revascularisation for severe limb ischaemia (SLI) because of IP disease with or without femoropopliteal disease. Data were extracted from case report forms from the BASIL trial. The primary outcome was amputation free survival (AFS); secondary outcomes included overall survival (OS), 30 day mortality and morbidity, freedom from arterial re-intervention, immediate technical success, repeat and crossover interventions, length of hospital stay, and quality of revascularisation. RESULTS: A total of 104 patients were identified in the BASIL study with IP disease, 56 randomised to IP VB, and 48 to IP PBA. Groups were similar at baseline except for more chronic kidney disease and non-steroidal anti-inflammatory drug use in the VB group, and more previous surgical arterial intervention and antihypertensive use in the PBA group. There were no statistically significant differences in AFS or OS; however, clinically important trends were apparent in favour of a VB first strategy. Patients allocated to VB demonstrated significantly quicker relief of rest pain when compared with PBA (p = .005), but no significant differences in improved tissue healing. Median length of index hospital admission was significantly greater in the VB than in the PBA group (18 vs. 10 days, p < .0001) but there was no difference between the two groups in median total hospital stay between randomisation and the primary endpoint (VB 43.5 vs. PBA 42 days). CONCLUSIONS: Further randomised trials, like BASIL-2 and BEST-CLI, are required to determine whether patients with severe limb ischaemia who require IP revascularisation and who are suitable for VB should have bypass or endovascular intervention as their primary revascularisation procedure.

Ultrasound bladder wall thickness and detrusor overactivity: a multicentre test accuracy study.

OBJECTIVE: Women with overactive bladder (OAB) often undergo urodynamics before invasive treatments are considered. Ultrasound measurement of bladder wall thickness (BWT) is a less invasive, less expensive and widely available test. It has the potential to diagnose the presence of detrusor overactivity (DO). We aimed to evaluate the accuracy of BWT in the diagnosis of DO. DESIGN: Prospective cohort study. SETTING: Twenty-two UK clinics (university and district general hospitals). METHODS: Consecutive eligible women with OAB symptoms had transvaginal ultrasound to estimate BWT (index test). The reference standard for the diagnosis of DO was urodynamic testing with multichannel subtracted cystometry. MAIN OUTCOME MEASURES: The sensitivity, specificity and likelihood ratios using a BWT threshold of ≥5 mm were used to indicate the presence of DO, and the area under the receiver operating characteristics (ROC) curve to give an overall estimate of BWT accuracy. RESULTS: Between March 2011 and 2013, 644/687 (94%) women recruited had both tests. The mean age was 52.7 years (standard deviation 13.9) and DO was diagnosed in 399/666 (60%) women. BWT had a sensitivity of 43% [95% confidence interval (CI) 38-48%], specificity of 62% (95% CI 55-68%), and likelihood ratios of 1.11 (95% CI 0.92-1.35) and 0.93 (95% CI 0.82-1.06) for positive and negative tests, respectively. The area under the ROC curve was 0.53 (95% CI 0.48-0.57). Extensive sensitivity analyses and subgroup analyses were carried out, but did not alter the interpretation. CONCLUSIONS: BWT is not a good replacement test for urodynamics in women with overactive bladder. TWEETABLE ABSTRACT: Bladder wall thickness is not a good replacement test for urodynamics in women with overactive bladder.

Predicting the chance of live birth for women undergoing IVF: a novel pretreatment counselling tool.

STUDY QUESTION: Which pretreatment patient variables have an effect on live birth rates following assisted conception? SUMMARY ANSWER: The predictors in the final multivariate logistic regression model found to be significantly associated with reduced chances of IVF/ICSI success were increasing age (particularly above 36 years), tubal factor infertility, unexplained infertility and Asian or Black ethnicity. WHAT IS KNOWN ALREADY: The two most widely recognized prediction models for live birth following IVF were developed on data from 1991 to 2007; pre-dating significant changes in clinical practice. These existing IVF outcome prediction models do not incorporate key pretreatment predictors, such as BMI, ethnicity and ovarian reserve, which are readily available now. STUDY DESIGN, SIZE, DURATION: In this cohort study a model to predict live birth was derived using data collected from 9915 women who underwent IVF/ICSI treatment at any CARE (Centres for Assisted Reproduction) clinic from 2008 to 2012. Model validation was performed on data collected from 2723 women who underwent treatment in 2013. The primary outcome for the model was live birth, which was defined as any birth event in which at least one baby was born alive and survived for more than 1 month. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected from 12 fertility clinics within the CARE consortium in the UK. Multivariable logistic regression was used to develop the model. Discriminatory ability was assessed using the area under receiver operating characteristic (AUROC) curve, and calibration was assessed using calibration-in-the-large and the calibration slope test. MAIN RESULTS AND THE ROLE OF CHANCE: The predictors in the final model were female age, BMI, ethnicity, antral follicle count (AFC), previous live birth, previous miscarriage, cause and duration of infertility. Upon assessing predictive ability, the AUROC curve for the final model and validation cohort was (0.62; 95% confidence interval (CI) 0.61-0.63) and (0.62; 95% CI 0.60-0.64) respectively. Calibration-in-the-large showed a systematic over-estimation of the predicted probability of live birth (Intercept (95% CI) = -0.168 (-0.252 to -0.084), P < 0.001). However, the calibration slope test was not significant (slope (95% CI) = 1.129 (0.893-1.365), P = 0.28). Due to the calibration-in-the-large test being significant we recalibrated the final model. The recalibrated model showed a much-improved calibration. LIMITATIONS, REASONS FOR CAUTION: Our model is unable to account for factors such as smoking and alcohol that can affect IVF/ICSI outcome and is somewhat restricted to representing the ethnic distribution and outcomes for the UK population only. We were unable to account for socioeconomic status and it may be that by having 75% of the population paying privately for their treatment, the results cannot be generalized to people of all socioeconomic backgrounds. In addition, patients and clinicians should understand this model is designed for use before treatment begins and does not include variables that become available (oocyte, embryo and endometrial) as treatment progresses. Finally, this model is also limited to use prior to first cycle only. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study to present a novel, up-to-date model encompassing three readily available prognostic factors; female BMI, ovarian reserve and ethnicity, which have not previously been used in prediction models for IVF outcome. Following geographical validation, the model can be used to build a user-friendly interface to aid decision-making for couples and their clinicians. Thereafter, a feasibility study of its implementation could focus on patient acceptability and quality of decision-making. STUDY FUNDING/COMPETING INTEREST: None.

Applicability and feasibility of systematic review for performing evidence-based risk assessment in food and feed safety.

Food and feed safety risk assessment uses multi-parameter models to evaluate the likelihood of adverse events associated with exposure to hazards in human health, plant health, animal health, animal welfare, and the environment. Systematic review and meta-analysis are established methods for answering questions in health care, and can be implemented to minimize biases in food and feed safety risk assessment. However, no methodological frameworks exist for refining risk assessment multi-parameter models into questions suitable for systematic review, and use of meta-analysis to estimate all parameters required by a risk model may not be always feasible. This paper describes novel approaches for determining question suitability and for prioritizing questions for systematic review in this area. Risk assessment questions that aim to estimate a parameter are likely to be suitable for systematic review. Such questions can be structured by their "key elements" [e.g., for intervention questions, the population(s), intervention(s), comparator(s), and outcome(s)]. Prioritization of questions to be addressed by systematic review relies on the likely impact and related uncertainty of individual parameters in the risk model. This approach to planning and prioritizing systematic review seems to have useful implications for producing evidence-based food and feed safety risk assessment.

Outcome in fetal lower urinary tract obstruction: a prospective registry study.

OBJECTIVE: To describe influences on decision-making and prognostic variables in the prenatal management of fetal lower urinary tract obstruction (LUTO). METHODS: This was a prospective registry study of pregnant women with a male fetus with LUTO from centers within the British Isles and The Netherlands. Women and/or their clinicians were given the treatment option of either conservative management or vesicoamniotic shunting (VAS). Baseline characteristics of women in the registry, reasons for entry to the registry and pregnancy outcomes were assessed. The main study outcomes were survival to 28 days after delivery, further survival to 2 years and renal function. Logistic regression analysis was used to examine prognostic variables that affected outcome. Results were compared with those of women in a randomized controlled trial (RCT) who were allocated randomly to a treatment option. RESULTS: Forty-five women were registered, of whom 78% (35/45) underwent conservative management. Twenty-seven women entered the registry owing to their clinician's preference for management and 18 because of their own preference. Compared to the conservative-management group of the RCT, a higher proportion of women in the registry opting for conservative management had a normal amniotic fluid volume at diagnosis (P = 0.05) and a diagnosis of LUTO ≥ 24 weeks' gestation (P = 0.003). On multivariable logistic regression analysis, these variables showed a significant association with perinatal survival (P < 0.001). Survival to 28 days after delivery was higher in the conservative-management group, at 69% (24/35), compared to 40% (4/10) in the VAS group (P = 0.02) but this difference had limited statistical significance owing to small study size (relative risk, 0.58 (95% CI, 0.26-1.29); P = 0.14). CONCLUSION: In our prospective registry, the majority of fetuses with LUTO received conservative management, which was associated with better short- and long-term outcomes. A significant proportion of these pregnancies had normal amniotic fluid volume and a gestational age at diagnosis of ≥ 24 weeks, characteristics shown to be associated with improved survival.

S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study.

OBJECTIVE: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC. DESIGN: This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy. METHODS: The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R2D statistic. RESULTS: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5. CONCLUSION: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

Meta-analysis of test accuracy studies using imputation for partial reporting of multiple thresholds.

INTRODUCTION: For tests reporting continuous results, primary studies usually provide test performance at multiple but often different thresholds. This creates missing data when performing a meta-analysis at each threshold. A standard meta-analysis (no imputation [NI]) ignores such missing data. A single imputation (SI) approach was recently proposed to recover missing threshold results. Here, we propose a new method that performs multiple imputation of the missing threshold results using discrete combinations (MIDC). METHODS: The new MIDC method imputes missing threshold results by randomly selecting from the set of all possible discrete combinations which lie between the results for 2 known bounding thresholds. Imputed and observed results are then synthesised at each threshold. This is repeated multiple times, and the multiple pooled results at each threshold are combined using Rubin's rules to give final estimates. We compared the NI, SI, and MIDC approaches via simulation. RESULTS: Both imputation methods outperform the NI method in simulations. There was generally little difference in the SI and MIDC methods, but the latter was noticeably better in terms of estimating the between-study variances and generally gave better coverage, due to slightly larger standard errors of pooled estimates. Given selective reporting of thresholds, the imputation methods also reduced bias in the summary receiver operating characteristic curve. Simulations demonstrate the imputation methods rely on an equal threshold spacing assumption. A real example is presented. CONCLUSIONS: The SI and, in particular, MIDC methods can be used to examine the impact of missing threshold results in meta-analysis of test accuracy studies.

A systematic review of rapid diagnostic tests for the detection of tuberculosis infection.

OBJECTIVES: To evaluate the effectiveness of available rapid diagnostic tests to identify tuberculosis (TB) infection. DATA SOURCES: Electronic databases were searched from 1975 to August 2003 for tests for active TB and to March 2004 for tests for latent tuberculosis infection (LTBI). REVIEW METHODS: Studies were selected and evaluated that (1) tested for LTBI, (2) compared tuberculin skin test (TST) and interferon-gamma assays based on ESAT-6 and CFP-10 antigens and (3) provided information on TB exposure or bacille Calmette-Guerin (BCG) vaccination or HIV status. For each test comparison, the sensitivity, specificity and 95% confidence intervals (CIs) were calculated. Sources of heterogeneity were investigated by adding covariates to the standard regression model. The authors examined whether interferon-gamma assays were more strongly associated with high versus low TB exposure than TST. Odds ratios (ORs) were calculated for the association between test results and exposures from each study along with their 95% CIs. Within each study, the OR value for one test was divided by that for another to produce a ratio of OR (ROR). RESULTS: A total of 212 studies were included, providing 368 data sets. A further 19 studies assessing fully automated liquid culture were included. Overall, nucleic acid amplification test (NAAT) accuracy was far superior when applied to respiratory samples as opposed to other body fluids. The better quality in-house studies, were, for pulmonary TB, much better at ruling out TB than the commercial tests (higher sensitivity), but were less good at ruling it in (lower specificity), but it is not possible to recommend any one over another owing to a lack of direct test comparisons. The specificity of NAAT tests was high when applied to body fluids, for example for TB meningitis and pleural TB, but sensitivity was poor, indicating that these tests cannot be used reliably to rule out TB. High specificity estimates suggest that NAAT tests should be the first-line test for ruling in TB meningitis, but that they need to be combined with the result of other tests in order to rule out disease. Evidence for NAAT tests in other forms of TB and for phage-based tests is significantly less prolific than for those above and further research is needed to establish accuracy. There is no evidence to support the use of adenosine deaminase (ADA) tests for diagnosis of pulmonary TB; however, there is considerable evidence to support their use for diagnosis of pleural TB and to a slightly lesser extent for TB meningitis. Anti-TB antibody test performance was universally poor, regardless of type of TB. Fully automated liquid culture methods were superior to culture on solid media, in terms of their speed and their precision. In total, 13 studies were included. Assays based on RD1 specific antigens, ESAT-6 or CFP-10, correlate better with intensity of exposure, and therefore are more likely than TST/purified protein derivative (PPD)-based assays to detect LTBI accurately. An additional advantage is that they are more likely to be independent of BCG vaccination status and HIV status. CONCLUSIONS: The NAAT tests provide a reliable way of increasing the specificity of diagnosis (ruling in disease) but sensitivity is too poor to rule out disease, especially in smear-negative (paucibacillary) disease where clinical diagnosis is equivocal and where the clinical need is greatest. For extra-pulmonary TB, clinical judgement has both poor sensitivity and specificity. For pleural TB and TB meningitis, adenosine deaminase tests have high sensitivity but limited specificity. NAATs have high specificity and could be used alongside ADA (or interferon-gamma) to increase sensitivity for ruling out disease and NAAT for high specificity to rule it in. All studies from low-prevalence countries strongly suggest that the RD1 antigen-based assays are more accurate than TST- and PPD-based assays for diagnosis of LTBI. If their superior diagnostic capability is found to hold up in routine clinical practice, they could confer several advantages on TB control programmes. Further research for active TB needs to establish diagnostic accuracy in a wide spectrum of patients, against an appropriate reference test, and avoiding the major sources of bias. For LTBI, research needs to address different epidemiological and clinical settings, to evaluate the performance of the main existing commercial assays in head-to-head comparison in both developed and developing countries, and to assess the role of adding more TB-specific antigens to try to improve diagnostic sensitivity.

The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation.

OBJECTIVES: To assess whether open angle glaucoma (OAG) screening meets the UK National Screening Committee criteria, to compare screening strategies with case finding, to estimate test parameters, to model estimates of cost and cost-effectiveness, and to identify areas for future research. DATA SOURCES: Major electronic databases were searched up to December 2005. REVIEW METHODS: Screening strategies were developed by wide consultation. Markov submodels were developed to represent screening strategies. Parameter estimates were determined by systematic reviews of epidemiology, economic evaluations of screening, and effectiveness (test accuracy, screening and treatment). Tailored highly sensitive electronic searches were undertaken. RESULTS: Most potential screening tests reviewed had an estimated specificity of 85% or higher. No test was clearly most accurate, with only a few, heterogeneous studies for each test. No randomised controlled trials (RCTs) of screening were identified. Based on two treatment RCTs, early treatment reduces the risk of progression. Extrapolating from this, and assuming accelerated progression with advancing disease severity, without treatment the mean time to blindness in at least one eye was approximately 23 years, compared to 35 years with treatment. Prevalence would have to be about 3-4% in 40 year olds with a screening interval of 10 years to approach cost-effectiveness. It is predicted that screening might be cost-effective in a 50-year-old cohort at a prevalence of 4% with a 10-year screening interval. General population screening at any age, thus, appears not to be cost-effective. Selective screening of groups with higher prevalence (family history, black ethnicity) might be worthwhile, although this would only cover 6% of the population. Extension to include other at-risk cohorts (e.g. myopia and diabetes) would include 37% of the general population, but the prevalence is then too low for screening to be considered cost-effective. Screening using a test with initial automated classification followed by assessment by a specialised optometrist, for test positives, was more cost-effective than initial specialised optometric assessment. The cost-effectiveness of the screening programme was highly sensitive to the perspective on costs (NHS or societal). In the base-case model, the NHS costs of visual impairment were estimated as 669 pounds. If annual societal costs were 8800 pounds, then screening might be considered cost-effective for a 40-year-old cohort with 1% OAG prevalence assuming a willingness to pay of 30,000 pounds per quality-adjusted life-year. Of lesser importance were changes to estimates of attendance for sight tests, incidence of OAG, rate of progression and utility values for each stage of OAG severity. Cost-effectiveness was not particularly sensitive to the accuracy of screening tests within the ranges observed. However, a highly specific test is required to reduce large numbers of false-positive referrals. The findings that population screening is unlikely to be cost-effective are based on an economic model whose parameter estimates have considerable uncertainty. In particular, if rate of progression and/or costs of visual impairment are higher than estimated then screening could be cost-effective. CONCLUSIONS: While population screening is not cost-effective, the targeted screening of high-risk groups may be. Procedures for identifying those at risk, for quality assuring the programme, as well as adequate service provision for those screened positive would all be needed. Glaucoma detection can be improved by increasing attendance for eye examination, and improving the performance of current testing by either refining practice or adding in a technology-based first assessment, the latter being the more cost-effective option. This has implications for any future organisational changes in community eye-care services. Further research should aim to develop and provide quality data to populate the economic model, by conducting a feasibility study of interventions to improve detection, by obtaining further data on costs of blindness, risk of progression and health outcomes, and by conducting an RCT of interventions to improve the uptake of glaucoma testing.

WITHDRAWN: Vaccines for preventing anthrax.

BACKGROUND: Anthrax is a potentially fatal bacterial disease with cutaneous, inhalation, and gastrointestinal forms. Three anthrax vaccines are commercially available, but their comparative effectiveness and safety is not clear. OBJECTIVES: To assess the effectiveness and safety of vaccines against human anthrax in relation to adverse effects and disease incidence. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group Specialized Register (March 2004), CENTRAL (The Cochrane Library Issue 3, 2005), MEDLINE (1966 to September 2005), EMBASE (1988 to September 2005), Science Citation Index (1981 to September 2005), the U.S. National Institutes of Health (NIH; September 2005), and the reference lists of articles. We contacted the UK Ministry of Defence, US Department of Defense, and individual researchers in the field. SELECTION CRITERIA: Prospective randomized, quasi-randomized, and cluster randomized controlled trials comparing anthrax vaccines with placebo, other (non-anthrax) vaccines, or no intervention. DATA COLLECTION AND ANALYSIS: Six reviewers independently assessed trial methodological quality and extracted data. Adverse effects data was collected from the trials. MAIN RESULTS: Two trials involving 16,052 people met the inclusion criteria. Both trials had methodological limitations. Compared to placebo, vaccination was associated with a reduced risk of contracting anthrax (Relative Risk 0.16; 95% confidence interval 0.07 to 0.35). In the one trial reporting adverse effects, the killed vaccine was associated with a higher incidence of adverse effects compared to the placebo (Peto odds ratio 5.15; 95% confidence interval 2.28 to 11.61). Just over 5% of participants in the vaccine group reported adverse effects. The effectiveness of the vaccine does not appear to be influenced by the route of inoculation (scarifaction compared to needless injection - odds ratio 1.61; 95% confidence interval 0.39 to 6.75). AUTHORS' CONCLUSIONS: Killed anthrax vaccines appear to be effective in reducing the risk of contracting anthrax with low rate of adverse effects. Further research should be carried out on the short and long term safety effects of available vaccines and if possible their effectiveness.

Primary care REFerral for EchocaRdiogram (REFER) in heart failure: a diagnostic accuracy study.

BACKGROUND: Symptoms of breathlessness, fatigue, and ankle swelling are common in general practice but deciding which patients are likely to have heart failure is challenging. AIM: To evaluate the performance of a clinical decision rule (CDR), with or without N-Terminal pro-B type natriuretic peptide (NT-proBNP) assay, for identifying heart failure. DESIGN AND SETTING: Prospective, observational, diagnostic validation study of patients aged >55 years, presenting with shortness of breath, lethargy, or ankle oedema, from 28 general practices in England. METHOD: The outcome was test performance of the CDR and natriuretic peptide test in determining a diagnosis of heart failure. The reference standard was an expert consensus panel of three cardiologists. RESULTS: Three hundred and four participants were recruited, with 104 (34.2%; 95% confidence interval [CI] = 28.9 to 39.8) having a confirmed diagnosis of heart failure. The CDR+NT-proBNP had a sensitivity of 90.4% (95% CI = 83.0 to 95.3) and specificity 45.5% (95% CI = 38.5 to 52.7). NT-proBNP level alone with a cut-off <400 pg/ml had sensitivity 76.9% (95% CI = 67.6 to 84.6) and specificity 91.5% (95% CI = 86.7 to 95.0). At the lower cut-off of NT-proBNP <125 pg/ml, sensitivity was 94.2% (95% CI = 87.9 to 97.9) and specificity 49.0% (95% CI = 41.9 to 56.1). CONCLUSION: At the low threshold of NT-proBNP <125 pg/ml, natriuretic peptide testing alone was better than a validated CDR+NT-proBNP in determining which patients presenting with symptoms went on to have a diagnosis of heart failure. The higher NT-proBNP threshold of 400 pg/ml may mean more than one in five patients with heart failure are not appropriately referred. Guideline natriuretic peptide thresholds may need to be revised.

Erratum to: Methods for evaluating medical tests and biomarkers.

[This corrects the article DOI: 10.1186/s41512-016-0001-y.].

Pharmacological interventions for non-ulcer dyspepsia.

BACKGROUND: The commonest cause of upper gastrointestinal symptoms is non-ulcer dyspepsia (NUD) and yet the pathophysiology of this condition has been poorly characterised and the optimum treatment is uncertain. It is estimated that pound450 million is spent on dyspepsia drugs in the UK each year. OBJECTIVES: This review aims to determine the effectiveness of six classes of drugs (antacids, histamine H(2) antagonists, proton pump inhibitors, prokinetics, mucosal protecting agents and antimuscarinics) in the improvement of either the individual or global dyspepsia symptom scores and also quality of life scores patients with non-ulcer dyspepsia. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2005), MEDLINE (1966 to January 2006), EMBASE (1988 to January 2006), CINAHL (1982 to January 2006), SIGLE, and reference lists of articles. We also contacted experts in the field and pharmaceutical companies. Trials were located through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and text words, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and pharmaceutical companies. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing drugs of any of the six groups with each other or with placebo for non-ulcer dyspepsia (NUD). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility, trial quality and extracted data. MAIN RESULTS: We included 73 trials: prokinetics (19 trials with dichotomous outcomes evaluating 3178 participants; relative risk reduction (RRR) 33%; 95% confidence intervals (CI) 18% to 45%), H(2)RAs (12 trials evaluating 2,183 participants; RRR 23%; 95% CI 8% to 35%) and PPIs (10 trials evaluating 3,347 participants; RRR 13%; 95% CI 4% to 20%) were significantly more effective than placebo. Bismuth salts (six trials evaluating 311 participants; RRR 40%; 95% CI -3 to 65%) were superior to placebo but this was of marginal statistical significance. Antacids (one trial evaluating 109 participants; RRR -2%; 95% CI -36% to 24%) and sucralfate (two trials evaluating 246 participants; RRR 29%; 95% CI -40% to 64%) were not statistically significantly superior to placebo. A funnel plot suggested that the prokinetic results could be due to publication bias or other small study effects. AUTHORS' CONCLUSIONS: There is evidence that anti-secretory therapy may be effective in NUD. The trials evaluating prokinetic therapy are difficult to interpret as the meta-analysis result could have been due to publication bias. The effect of these drugs is likely to be small and many patients will need to take them on a long-term basis so economic analyses would be helpful and ideally the therapies assessed need to be inexpensive and well tolerated.

Eradication of Helicobacter pylori for non-ulcer dyspepsia.

BACKGROUND: Helicobacter pylori (H pylori) is the main cause of peptic ulcer disease. The role of H pylori in non-ulcer dyspepsia is less clear. OBJECTIVES: To determine the effect of H pylori eradication on dyspepsia symptoms in patients with non-ulcer dyspepsia. SEARCH STRATEGY: Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and with pharmaceutical companies. SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing drugs to eradicate H pylori with placebo or other drugs known not to eradicate H pylori for patients with non-ulcer dyspepsia. DATA COLLECTION AND ANALYSIS: Data were collected on individual and global dyspeptic symptom scores, quality of life measures and adverse effects. Dyspepsia outcomes were dichotomised into minimal/resolved versus same/worse symptoms. MAIN RESULTS: Twenty one randomised controlled trials were included in the systematic review. Eighteen trials compared antisecretory dual or triple therapy with placebo antibiotics +/- antisecretory therapy, and evaluated dyspepsia at 3-12 months. Seventeen of these trials gave results as dichotomous outcomes evaluating 3566 patients and there was no significant heterogeneity between the studies. There was a 10% relative risk reduction in the H pylori eradication group (95% CI = 6% to 14%) compared to placebo. The number needed to treat to cure one case of dyspepsia = 14 (95% CI = 10 to 25). A further three trials compared Bismuth based H pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H pylori eradication was more effective than either H2 receptor antagonists or sucralfate in treating non-ulcer dyspepsia. AUTHORS' CONCLUSIONS: H pylori eradication therapy has a small but statistically significant effect in H pylori positive non-ulcer dyspepsia. An economic model suggests this modest benefit may still be cost-effective but more research is needed.

HIV and male circumcision--a systematic review with assessment of the quality of studies.

This Cochrane systematic review assesses the evidence for an interventional effect of male circumcision in preventing acquisition of HIV-1 and HIV-2 by men through heterosexual intercourse. The review includes a comprehensive assessment of the quality of all 37 included observational studies. Studies in high-risk populations consisted of four cohort studies, 12 cross-sectional studies, and three case-control studies; general population studies consisted of one cohort study, 16 cross-sectional studies, and one case-control study. There is evidence of methodological heterogeneity between studies, and statistical heterogeneity was highly significant for both general population cross-sectional studies (chi(2)=132.34; degrees of freedom [df]=15; p<0.00001) and high-risk cross-sectional studies (chi(2)=29.70; df=10; p=0.001). Study quality was very variable and no studies measured the same set of potential confounding variables. Therefore, conducting a meta-analysis was inappropriate. Detailed quality assessment of observational studies can provide a useful visual aid to interpreting findings. Although most studies show an association between male circumcision and prevention of HIV, these results may be limited by confounding, which is unlikely to be adjusted for.

A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.

OBJECTIVES: To review how heterogeneity has been examined in systematic reviews of diagnostic test accuracy studies. DATA SOURCES: Centre for Reviews and Dissemination's Database of Abstracts of Reviews of Effects (DARE). REVIEW METHODS: Systematic reviews that evaluated a diagnostic or screening test by including studies that compared a test with a reference test were identified from DARE. Reviews for which structured abstracts had been written up to December 2002 were screened for inclusion. Data extraction was undertaken using standardised data extraction forms. RESULTS: A total of 189 systematic reviews met the inclusion criteria. The median number of studies included was 18. Meta-analyses have a higher number with a median of 22 studies compared with 11 for narrative reviews. Graphical plots to demonstrate the spread in study results were provided in 56% of meta-analyses; in 79% these were plots of sensitivity and specificity in the receiver operating characteristic (ROC) space. Statistical tests to identify heterogeneity were used in 32% of reviews: 41% of meta-analyses and 9% of reviews using narrative syntheses. The chi-squared test and Fisher's exact test to assess heterogeneity in individual aspects of test performance were the most common. In contrast, only 16% of meta-analyses used correlation coefficients to test for a threshold effect. A narrative synthesis was used in 30% of reviews. Of the meta-analyses, 52% carried out statistical pooling alone, 18% conducted only summary receiver operator characteristic (SROC) analyses and 30% used both methods of statistical synthesis. For those undertaking SROC analyses, the main differences between the models used were the weights chosen for the regression models, although in 42% of cases the use of, or choice of, weight was not provided. The proportion of reviews using statistical pooling alone has declined from 67% in 1995 to 42% in 2001, with a corresponding increase in the use of SROC methods, from 33% to 58%. However, two-thirds of those using SROC methods also carried out statistical pooling rather than presenting only SROC models. Reviews using SROC analyses also tended to present their results as some combination of sensitivity and specificity rather than using alternative, perhaps less clinically meaningful, means of data presentation such as diagnostic odds ratios. Three-quarters of meta-analyses attempted to investigate statistically possible sources of variation, using subgroup analysis or regression analysis. The impact of clinical or socio-demographic variables was investigated in 74% of these reviews and test- or threshold-related variables in 79%. At least one quality-related variable was investigated in 63% of reviews. Within this subset, the most commonly considered variables were the use of blinding, sample size, the reference test used and the avoidance of verification bias. CONCLUSIONS: The emphasis on pooling individual aspects of diagnostic test performance and the under-use of statistical tests and graphical approaches to identify heterogeneity perhaps reflect the uncertainty in the most appropriate methods to use and also greater familiarity with more traditional indices of test accuracy. This indicates the difficulty and complexity of carrying out such reviews. In these cases it is strongly suggested that meta-analyses are carried out with the involvement of a statistician familiar with the field. Further methodological work on the statistical methods available for combining diagnostic test accuracy studies is needed, as are sufficiently large, prospectively designed primary studies of diagnostic test accuracy comparing two or more tests for the same target disorder. Use of individual patient data meta-analysis in diagnostic test accuracy reviews should be explored to allow heterogeneity to be considered in more detail.

Indirect comparisons of competing interventions.

OBJECTIVES: To survey the frequency of use of indirect comparisons in systematic reviews and evaluate the methods used in their analysis and interpretation. Also to identify alternative statistical approaches for the analysis of indirect comparisons, to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within reviews. DATA SOURCES: Electronic databases. REVIEW METHODS: The Database of Abstracts of Reviews of Effects (DARE) was searched for systematic reviews involving meta-analysis of randomised controlled trials (RCTs) that reported both direct and indirect comparisons, or indirect comparisons alone. A systematic review of MEDLINE and other databases was carried out to identify published methods for analysing indirect comparisons. Study designs were created using data from the International Stroke Trial. Random samples of patients receiving aspirin, heparin or placebo in 16 centres were used to create meta-analyses, with half of the trials comparing aspirin and placebo and half heparin and placebo. Methods for indirect comparisons were used to estimate the contrast between aspirin and heparin. The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results. Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken. RESULTS: Of the reviews identified through DARE, 31/327 (9.5%) included indirect comparisons. A further five reviews including indirect comparisons were identified through electronic searching. Few reviews carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest. Few methodological papers were identified. Some valid approaches for aggregate data that could be applied using standard software were found: the adjusted indirect comparison, meta-regression and, for binary data only, multiple logistic regression (fixed effect models only). Simulation studies showed that the naive method is liable to bias and also produces over-precise answers. Several methods provide correct answers if strong but unverifiable assumptions are fulfilled. Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly randomised comparisons. Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies, but the direction of such discrepancy is unpredictable. CONCLUSIONS: Direct evidence from good-quality RCTs should be used wherever possible. Without this evidence, it may be necessary to look for indirect comparisons from RCTs. However, the results may be susceptible to bias. When making indirect comparisons within a systematic review, an adjusted indirect comparison method should ideally be used employing the random effects model. If both direct and indirect comparisons are possible within a review, it is recommended that these be done separately before considering whether to pool data. There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect. Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons. Research into how evidence from indirect comparisons compares to that from non-randomised studies may also be warranted. Investigations using individual patient data from a meta-analysis of several RCTs using different protocols and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful.