Showing papers on "Funnel plot published in 2015"

Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression

Abstract: Background: The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy). Methods: We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger’s test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables. Results: We illustrate the use of this approach by re-analysing two published Mendelian randomization studies of the causal effect of height on lung function, and the causal effect of blood pressure on coronary artery disease risk. The conservative nature of this approach is illustrated with these examples. Conclusions: An adaption of Egger regression (which we call MR-Egger) can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations. The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation.

Socioeconomic Inequality and Caries A Systematic Review and Meta-Analysis

Abstract: Dental caries is the most prevalent disease worldwide, with the majority of caries lesions being concentrated in few, often disadvantaged social groups. We aimed to systematically assess current evidence for the association between socioeconomic position (SEP) and caries. We included studies investigating the association between social position (determined by own or parental educational or occupational background, or income) and caries prevalence, experience, or incidence. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies. Reported differences between the lowest and highest SEP were assessed and data not missing at random imputed. Random-effects inverse-generic meta-analyses were performed, and subgroup and meta-regression analyses were used to control for possible confounding. Publication bias was assessed via funnel plot analysis and the Egger test. From 5539 screened records, 155 studies with mostly low or moderate quality evaluating a total of 329,798 individuals were included. Studies used various designs, SEP measures, and outcome parameters. Eighty-three studies found at least one measure of caries to be significantly higher in low-SEP compared with high-SEP individuals, while only 3 studies found the opposite. The odds of having any caries lesions or caries experience (decayed missing filled teeth [DMFT]/dmft > 0) were significantly greater in those with low own or parental educational or occupational background or income (between odds ratio [95% confidence interval] = 1.21 [1.03-1.41] and 1.48 [1.34-1.63]. The association between low educational background and having DMFT/dmft > 0 was significantly increased in highly developed countries (R (2) = 1.32 [0.53-2.13]. Publication bias was present but did not significantly affect our estimates. Due to risk of bias in included studies, the available evidence was graded as low or very low. Low SEP is associated with a higher risk of having caries lesions or experience. This association might be stronger in developed countries. Established diagnostic and treatment concepts might not account for the unequal distribution of caries (registered with PROSPERO [CRD42013005947]).

Alcohol-Related Risk of Suicidal Ideation, Suicide Attempt, and Completed Suicide: A Meta-Analysis

Abstract: BACKGROUND: Several original studies have investigated the effect of alcohol use disorder (AUD) on suicidal thought and behavior, but there are serious discrepancies across the studies. Thus, a systematic assessment of the association between AUD and suicide is required. METHODS: We searched PubMed, Web of Science, and Scopus until February 2015. We also searched the Psycinfo web site and journals and contacted authors. We included observational (cohort, case-control, and cross-sectional) studies addressing the association between AUD and suicide. The exposure of interest was AUD. The primary outcomes were suicidal ideation, suicide attempt, and completed suicide. We assessed heterogeneity using Q-test and I2 statistic. We explored publication bias using the Egger's and Begg's tests and funnel plot. We meta-analyzed the data with the random-effects models. For each outcome we calculated the overall odds ratio (OR) or risk ratio (RR) with 95% confidence intervals (CI). RESULTS: We included 31 out of 8548 retrieved studies, with 420,732 participants. There was a significant association between AUD and suicidal ideation (OR=1.86; 95% CI: 1.38, 2.35), suicide attempt (OR=3.13; 95% CI: 2.45, 3.81); and completed suicide (OR=2.59; 95% CI: 1.95, 3.23 and RR=1.74; 95% CI: 1.26, 2.21). There was a significant heterogeneity among the studies, but little concern to the presence of publication bias. CONCLUSIONS: There is sufficient evidence that AUD significantly increases the risk of suicidal ideation, suicide attempt, and completed suicide. Therefore, AUD can be considered an important predictor of suicide and a great source of premature death. Language: en

Statistical methods for dealing with publication bias in meta-analysis.

Abstract: Publication bias is an inevitable problem in the systematic review and meta-analysis. It is also one of the main threats to the validity of meta-analysis. Although several statistical methods have been developed to detect and adjust for the publication bias since the beginning of 1980s, some of them are not well known and are not being used properly in both the statistical and clinical literature. In this paper, we provided a critical and extensive discussion on the methods for dealing with publication bias, including statistical principles, implementation, and software, as well as the advantages and limitations of these methods. We illustrated a practical application of these methods in a meta-analysis of continuous support for women during childbirth. Copyright © 2014 John Wiley & Sons, Ltd.

Omega-3 fatty acids for depression in adults

Abstract: Background Major depressive disorder (MDD) is highly debilitating, difficult to treat, has a high rate of recurrence, and negatively impacts the individual and society as a whole. One emerging potential treatment for MDD is n-3 polyunsaturated fatty acids (n-3PUFAs), also known as omega-3 oils, naturally found in fatty fish, some other seafood, and some nuts and seeds. Various lines of evidence suggest a role for n-3PUFAs in MDD, but the evidence is far from conclusive. Reviews and meta-analyses clearly demonstrate heterogeneity between studies. Investigations of heterogeneity suggest differential effects of n-3PUFAs, depending on severity of depressive symptoms, where no effects of n-3PUFAs are found in studies of individuals with mild depressive symptomology, but possible benefit may be suggested in studies of individuals with more severe depressive symptomology. Objectives To assess the effects of n-3 polyunsaturated fatty acids (also known as omega-3 fatty acids) versus a comparator (e.g. placebo, anti-depressant treatment, standard care, no treatment, wait-list control) for major depressive disorder (MDD) in adults. Search methods We searched the Cochrane Depression, Anxiety and Neurosis Review Group’s Specialised Registers (CCDANCTR) and International Trial Registries over all years to May 2015. We searched the database CINAHL over all years of records to September 2013. Selection criteria We included studies in the review if they: were a randomised controlled trial; provided n-3PUFAs as an intervention; used a comparator; measured depressive symptomology as an outcome; and were conducted in adults with MDD. Primary outcomes were depressive symptomology (continuous data collected using a validated rating scale) and adverse events. Secondary outcomes were depressive symptomology (dichotomous data on remission and response), quality of life, and failure to complete studies. Data collection and analysis We used standard methodological procedures as expected by Cochrane. Main results We found 26 relevant studies: 25 studies involving a total of 1438 participants investigated the impact of n-3PUFA supplementation compared to placebo, and one study involving 40 participants investigated the impact of n-3PUFA supplementation compared to antidepressant treatment. For the placebo comparison, n-3PUFA supplementation results in a small to modest benefit for depressive symptomology, compared to placebo: standardised mean difference (SMD) -0.30 (95% confidence interval (CI) -0.10 to -0.50; 25 studies, 1373 participants, very low quality evidence), but this effect is unlikely to be clinically meaningful (an SMD of 0.30 represents a difference between groups in scores on the HDRS (17-item) of approximately 2.1 points (95% CI 0.7 to 3.5)). The confidence intervals include both a possible clinically important effect and a possible negligible effect, and there is considerable heterogeneity between the studies. Although the numbers of individuals experiencing adverse events were similar in intervention and placebo groups (odds ratio (OR) 1.24, 95% CI 0.95 to 1.62; 19 studies, 1207 participants; very low-quality evidence), the confidence intervals include a significant increase in adverse events with n-3PUFAs as well as a small possible decrease. Rates of remission and response, quality of life, and rates of failure to complete studies were also similar between groups, but confidence intervals are again wide. The evidence on which these results are based is very limited. All studies contributing to our analyses were of direct relevance to our research question, but we rated the quality of the evidence for all outcomes as low to very low. The number of studies and number of participants contributing to all analyses were low, and the majority of studies were small and judged to be at high risk of bias on several measures. Our analyses were also likely to be highly influenced by three large trials. Although we judge these trials to be at low risk of bias, they contribute 26.9% to 82% of data. Our effect size estimates are also imprecise. Funnel plot asymmetry and sensitivity analyses (using fixed-effect models, and only studies judged to be at low risk of selection bias, performance bias or attrition bias) also suggest a likely bias towards a positive finding for n-3PUFAs. There was substantial heterogeneity in analyses of our primary outcome of depressive symptomology. This heterogeneity was not explained by the presence or absence of comorbidities or by the presence or absence of adjunctive therapy. Only one study was available for the antidepressant comparison, involving 40 participants. This study found no differences between treatment with n-3PUFAs and treatment with antidepressants in depressive symptomology (mean difference (MD) -0.70 (95% CI -5.88 to 4.48)), rates of response to treatment or failure to complete. Adverse events were not reported in a manner suitable for analysis, and rates of depression remission and quality of life were not reported. Authors' conclusions At present, we do not have sufficient high quality evidence to determine the effects of n-3PUFAs as a treatment for MDD. Our primary analyses suggest a small-to-modest, non-clinically beneficial effect of n-3PUFAs on depressive symptomology compared to placebo; however the estimate is imprecise, and we judged the quality of the evidence on which this result is based to be low/very low. Sensitivity analyses, funnel plot inspection and comparison of our results with those of large well-conducted trials also suggest that this effect estimate is likely to be biased towards a positive finding for n-3PUFAs, and that the true effect is likely to be smaller. Our data, however, also suggest similar rates of adverse events and numbers failing to complete trials in n-3PUFA and placebo groups, but again our estimates are very imprecise. The one study that directly compares n-3PUFAs and antidepressants in our review finds comparable benefit. More evidence, and more complete evidence, are required, particularly regarding both the potential positive and negative effects of n-3PUFAs for MDD.

Post-stroke depression and lesion location: a systematic review

Abstract: Post-stroke depression (PSD) is a frequent problem in stroke rehabilitation. Several studies have evaluated association between the lesion location and the risk of depression. Different conclusions and contradictory findings have been published. The aim of the present study was to perform a systematic meta-analysis to evaluate the relationship between PSD and lesion location. We researched PubMed, ISI Web of Science, EMBASE, and systematically reviewed available publications reporting investigations on stroke location and risk of PSD. Subgroup analyses were performed according to the time since stroke onset to assessment for PSD or the source of patients. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used for pooled analyses. Heterogeneity was assessed with Cochran's Q test and I (2) test. Begg's funnel plot and Egger's test were used to examine the publication bias. A total of 43 studies involving 5,507 patients suffering from stroke were included in this meta-analysis. The pooled OR with 95 % CI for the overall association of stroke location and depression risk was 0.99 (0.88-1.11). Subgroups analyses highlighted that only studies with subacute post-stroke group (1-6 months) showed a statistical association between right hemisphere stroke and risk of depression (OR = 0.79, 95 % CI 0.66-0.93). This systematic review offered no support for the hypothesis that lesion of the left hemisphere was associated with an increased risk of depression after stroke. We only find significant association between right hemisphere stroke and incidence of depression for studies within subacute post-stroke phase.

A primer on network meta-analysis with emphasis on mental health

Abstract: Objective A quantitative synthesis of evidence via standard pair-wise meta-analysis lies on the top of the hierarchy for evaluating the relative effectiveness or safety between two interventions. In most healthcare problems, however, there is a plethora of competing interventions. Network meta-analysis allows to rank competing interventions and evaluate their relative effectiveness even if they have not been compared in an individual trial. The aim of this paper is to explain and discuss the main features of this statistical technique. Methods We present the key assumptions underlying network meta-analysis and the graphical methods to visualise results and information in the network. We used one illustrative example that compared the relative effectiveness of 15 antimanic drugs and placebo in acute mania. Results A network plot allows to visualise how information flows in the network and reveals important information about network geometry. Discrepancies between direct and indirect evidence can be detected using inconsistency plots. Relative effectiveness or safety of competing interventions can be presented in a league table. A contribution plot reveals the contribution of each direct comparison to each network estimate. A comparison-adjusted funnel plot is an extension of simple funnel plot to network meta-analysis. A rank probability matrix can be estimated to present the probabilities of all interventions assuming each rank and can be represented using rankograms and cumulative probability plots. Conclusions Network meta-analysis is very helpful in comparing the relative effectiveness and acceptability of competing treatments. Several issues, however, still need to be addressed when conducting a network meta-analysis for the results to be valid and correctly interpreted.

Association between anxiety and hypertension: a systematic review and meta-analysis of epidemiological studies.

Abstract: Background Epidemiological studies have repeatedly investigated the association between anxiety and hypertension. However, the results have been inconsistent. This study aimed to summarize the current evidence from cross-sectional and prospective studies that evaluated this association. Methods Seven common databases were searched for articles published up to November 2014. Cross-sectional and prospective studies that reported an association between the two conditions in adults were included. Data on prevalence, incidence, unadjusted or adjusted odds ratios or hazard ratios, and 95% confidence intervals (CIs) were extracted or calculated by the authors. The pooled odds ratio was calculated separately for cross-sectional and prospective studies using random-effects models. The Q test and I 2 statistic was used to assess heterogeneity. A funnel plot and modified Egger linear regression test were used to estimate publication bias. Results The search yielded 13 cross-sectional studies (n=151,389), and the final pooled odds ratio was 1.18 (95% CI 1.02–1.37; P Q<0.001; I 2=84.9%). Eight prospective studies with a total sample size of 80,146 and 2,394 hypertension case subjects, and the pooled adjusted hazard ratio was 1.55 (95% CI 1.24–1.94; P Q<0.001; I 2=84.6%). The meta-regression showed that location, diagnostic criteria for anxiety, age, sex, sample size, year of publication, quality, and years of follow-up (for prospective study) were not sources of heterogeneity. Conclusion Our results suggest that there is an association between anxiety and increased risk of hypertension. These results support early detection and management of anxiety in hypertensive patients.

Quantifying the risk of error when interpreting funnel plots

Abstract: Funnel plots are widely used to investigate possible publication bias in meta-analyses. There has, however, been little formal assessment of whether a visual inspection of a funnel plot is sufficient to identify publication bias. Visual assessment of bias in a funnel plot is quantified using two new statistics: the Imbalance and the Asymmetry Distance, both intended to replicate how a funnel plot is typically assessed. A simulation study was performed to assess the performance of these two statistics for identifying publication bias. The two statistics both have high type I error and low statistical power, unless the number of studies in the meta-analysis is very large. These results suggest that visual inspection of a funnel plot is unlikely to lead to a valid assessment of publication bias. In most systematic reviews, visual inspection of a funnel plot may give a misleading impression of the presence or absence of publication bias. Formal statistical tests for bias should generally be preferred.

Healthcare workers' willingness to work during an influenza pandemic: a systematic review and meta-analysis.

Abstract: To estimate the proportion of healthcare workers (HCWs) willing to work during an influenza pandemic and identify associated risk factors, we undertook a systematic review and meta-analysis compliant with PRISMA guidance. Databases and grey literature were searched to April 2013, and records were screened against protocol eligibility criteria. Data extraction and risk of bias assessments were undertaken using a piloted form. Random-effects meta-analyses estimated (i) pooled proportion of HCWs willing to work and (ii) pooled odds ratios of risk factors associated with willingness to work. Heterogeneity was quantified using the I(2) statistic, and publication bias was assessed using funnel plots and Egger's test. Data were synthesized narratively where meta-analyses were not possible. Forty-three studies met our inclusion criteria. Meta-analysis of the proportion of HCWs willing to work was abandoned due to excessive heterogeneity (I(2) = 99.2%). Narrative synthesis showed study estimates ranged from 23.1% to 95.8% willingness to work, depending on context. Meta-analyses of specific factors showed that male HCWs, physicians and nurses, full-time employment, perceived personal safety, awareness of pandemic risk and clinical knowledge of influenza pandemics, role-specific knowledge, pandemic response training, and confidence in personal skills were statistically significantly associated with increased willingness. Childcare obligations were significantly associated with decreased willingness. HCWs' willingness to work during an influenza pandemic was moderately high, albeit highly variable. Numerous risk factors showed a statistically significant association with willingness to work despite significant heterogeneity between studies. None of the included studies were based on appropriate theoretical constructs of population behaviour.

A meta-analysis of ventriculostomy-associated cerebrospinal fluid infections

Abstract: Ventriculostomy insertion is a common neurosurgical intervention and can be complicated by ventriculostomy-associated cerebrospinal fluid infection (VAI) which is associated with increased morbidity and mortality. This meta-analysis was aimed at determining the pooled incidence rate (number per 1000 catheter-days) of VAI. Relevant studies were identified from MEDLINE and EMBASE and from reference searching of included studies and recent review articles on relevant topics. The Newcastle-Ottawa Scale was used to assess quality and risk of bias. A random effects model was used to pool individual study estimates and 95% confidence intervals (CI) were calculated using the exact Poisson method. Heterogeneity was assessed using the heterogeneity χ2 and I-squared tests. Subgroup analyses were performed and a funnel plot constructed to assess publication bias. There were a total of 35 studies which yielded 752 infections from 66,706 catheter-days of observation. The overall pooled incidence rate of VAI was 11.4 per 1000 catheter days (95% CI 9.3 to 13.5), for high quality studies the rate was 10.6 (95% CI 8.3 to 13) and 13.5 (95% CI 8.9 to 18.1) for low quality studies. Studies which had mean duration of EVD treatment of less than 7 days had a pooled VAI rate of 19.6 per 1000 catheter-days, those with mean duration of 7–10 days had VAI rate of 12.8 per 1000 catheter-days and those with mean duration greater than 10 days had VAI rate of 8 per 1000 catheter-days. There was significant heterogeneity for the primary outcome (p = 0.004, I-squared = 44%) and most subgroups. The funnel plot did not show evidence for publication bias. The incidence rate of VAI is 11.4 per 1000 catheter-days. Further research should focus on analysis of risk factors for VAI and techniques for reducing the rate of VAI.

Breakfast skipping and the risk of type 2 diabetes: a meta-analysis of observational studies

Abstract: Objective Breakfast skipping has been reported to be associated with type 2 diabetes (T2D), but the results are inconsistent. No meta-analyses have applied quantitative techniques to compute summary risk estimates. The present study aimed to conduct a meta-analysis of observational studies summarizing the evidence on the association between breakfast skipping and the risk of T2D. Design Systematic review and meta-analysis. Setting Relevant studies were identified by a search of PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI) and SINOMED up to 9 August 2014. We also reviewed reference lists from retrieved articles. We included studies that reported risk estimates (including relative risks, odds ratios and hazard ratios) with 95 % confidence intervals for the association between breakfast skipping and the risk of T2D. Subjects Eight studies involving 106 935 participants and 7419 patients with T2D were included in the meta-analysis. Results A pooled adjusted relative risk for the association between exposure to breakfast skipping and T2D risk was 1·21 (95 % CI 1·12, 1·31; P=0·984; I 2 =0·0 %) in cohort studies and the pooled OR was 1·15 (95 % CI, 1·05, 1·24; P=0·770; I 2 =0·0 %) in cross-sectional studies. Visual inspection of a funnel plot and Begg’s test indicated no evidence of publication bias. Conclusions Breakfast skipping is associated with a significantly increased risk of T2D. Regular breakfast consumption is potentially important for the prevention of T2D.

Meta-Analysis of the Association Between Whole Grain Intake and Coronary Heart Disease Risk

Abstract: Epidemiologic studies evaluating the association of whole-grain intake with risk for coronary heart disease (CHD) have produced inconsistent results. The aim of this meta-analysis was to summarize the evidence from observed studies regarding the association between whole-grain intake and risk for CHD. Pertinent studies were identified by searching the Web of Knowledge and PubMed up to July 2014. A random-effects model was used to combine the results. Publication bias was estimated using Begg's funnel plot and Egger's regression asymmetry test. Ultimately, fourteen reports of 18 studies (15 cohort studies and 3 case-control studies) involving 14,427 patients with CHD and 400,492 participants were used in this meta-analysis. Pooled results suggested that highest whole-grain intake amount compared with the lowest amount was significantly associated with reduced risk for CHD (summary relative risk 0.787, 95% confidence interval 0.743 to 0.833), with no between-study heterogeneity observed (I 2 = 0%, p = 0.537). The association was significant in cohort studies but not in case-control studies. Inverse associations were also found in the United States and Europe. No publication bias was found. In conclusion, this meta-analysis indicates that higher whole-grain intake has a protective effect against CHD.

Publication bias as a function of study characteristics.

Abstract: Researchers frequently conceptualize publication bias as a bias against publishing nonsignificant results. However, other factors beyond significance levels can contribute to publication bias. Some of these factors include study characteristics, such as the source of funding for the research project, whether the project was single center or multicenter, and prevailing theories at the time of publication. This article examines the relationship between publication bias and 2 study characteristics by breaking down 2 meta-analytic data sets into levels of the relevant study characteristic and assessing publication bias in each level with funnel plots, trim and fill (Duval & Tweedie, 2000a, 2000b), Egger's linear regression (Egger, Smith, Schneider, & Minder, 1997), cumulative meta-analysis (Borenstein, Hedges, Higgins, & Rothstein, 2009), and the Vevea and Hedges (1995) weight-function model. Using the Vevea and Hedges model, we conducted likelihood ratio tests to determine whether information was lost if only 1 pattern of selection was estimated. Results indicate that publication bias can differ over levels of study characteristics, and that developing a model to accommodate this relationship could be advantageous.

Small-Study Effects in Meta-Analysis

Abstract: This chapter describes small-study effects in meta-analysis and how the issues they raise may be addressed. “Small-study effects” is a generic term for the phenomenon that smaller studies sometimes show different, often larger, treatment effects than large ones. This notion was coined by Sterne et al. [55]. One possible, probably the most well-known, reason is publication bias. This is said to occur when the chance of a smaller study being published is increased if it shows a stronger effect [3, 41, 52]. This can happen for a number of reasons, for example authors may be more likely to submit studies with “significant” results for publication or journals may be more likely to publish smaller studies if they have “significant” results. If this occurs, it in turn biases the results of meta-analyses and systematic reviews. There are a number of other possible reasons for small-study effects. One is selective reporting of the most favourable outcomes, known as outcome selection bias or outcome reporting bias [8, 9, 18, 61]. Another possible cause of small-study effects is clinical heterogeneity between patients in large and small studies; e.g., patients in smaller studies may have been selected so that a favourable outcome of the experimental treatment may be expected. In the case of a binary outcome, also a mathematical artefact arises from the fact that for the odds ratio or the risk ratio, the variance of the treatment effect estimate is not independent of the estimate itself [47]. This problem will be discussed in Sect. 5.2.2. Lastly, it can never be ruled out that small-study effects result from mere coincidence [42]. Empirical studies have established evidence for these and other kinds of bias [19, 42, 53]. There is a vast range of tests for small-study effects [4, 20, 24, 38, 43, 48], most of them based on a funnel plot which will be introduced in Sect. 5.1.1.

Association of Histologic Regression in Primary Melanoma With Sentinel Lymph Node Status: A Systematic Review and Meta-analysis

Abstract: Importance The prognostic significance of regression in primary melanoma has been debated for many years. There is no consensus regarding the need for sentinel lymph node (SLN) biopsy when regression is present within the primary tumor. Objective To review the evidence that regression may affect SLN status. Data Sources A systematic review was performed by searching in MEDLINE, Scopus, and the Cochrane Library from January 1, 1990, through June 2014. Study Selection All studies that reported an odds ratio (OR) or data on expected and observed cases of SLN positivity and histologic regression were included. Data Extraction and Synthesis Primary random-effects meta-analyses were used to summarize ORs of SLN positivity and histologic regression. Heterogeneity was assessed using the χ 2 test and I 2 statistic. To assess the potential bias of small studies, we used funnel plots, the Begg rank correlation test, and the Egger weighted linear regression test. The methodologic quality of the studies was assessed according to the Strengthening of Reporting of Observational studies in Epidemiology (STROBE) checklist, and 2 different meta-analyses were performed based on those criteria. Main Outcomes and Measures Summary ORs of histologic regression of primary melanoma and SLN status. Results Of the 1509 citations found in the search, 94 articles were reviewed, and 14 studies comprising 10 098 patients were included in the analysis. In the combined 14 studies, patients with regression had a lower likelihood to have SLN positivity (OR, 0.56; 95% CI, 0.41-0.77) than patients without regression. On the basis of study quality, we found that patients with regression enrolled in high-quality studies had a lower likelihood to have SLN positivity (OR, 0.48; 95% CI, 0.32-0.72) compared with results of low-quality studies (OR, 0.73; 95% CI, 0.53-1.00). Examination of the funnel plot did not provide evidence of publication bias. Conclusions and Relevance The results of this analysis showed that the risk of SLN positivity was significantly lower in patients with histologic regression compared with those without. Regression may be used in these cases to make a selection of which patients should be the most appropriate for this procedure.

Efficacy of thermotherapy to treat cutaneous leishmaniasis : a meta-analysis of controlled clinical trials

Abstract: Introduction The efficacy of thermotherapy for the treatment of cutaneous leishmaniasis presents diverse results with low statistical power. Objective To evaluate the efficacy of thermotherapy to treat cutaneous leishmaniasis. Methods A meta-analysis of controlled clinical trials in 12 databases based on the implementation of a research protocol with inclusion and exclusion criteria and an assessment of methodological quality. The reproducibility and completeness were guaranteed in the information search and extraction. Heterogeneity, sensitivity and publication bias were assessed by graphical methods (Galbraith, L'Abble, funnel plot, Egger plot, and influence plot) and analytical methods (DerSimonian-Laird, Begg and Egger). Random-effects forest plots were constructed, and a cumulative meta-analysis was performed. Results Eight studies were included with 622 patients who underwent thermotherapy, with an efficacy of 73.2% (95% confidence interval (CI) = 69.6-76.7%), and with 667 patients who underwent systemic treatment, with an efficacy of 70.6% (95% CI=67.1-74.1%). Heterogeneity between studies, good sensitivity for the combined measure, and no publication bias were observed. The relative risk for comparison of the efficacy of treatment was 1.02 (95%CI=0.91, 1.15), showing that the effectiveness of thermotherapy is equal to that of pentavalent antimonial drugs. Conclusion Due to its efficacy, greater safety and lower cost, thermotherapy should be the first treatment option for cutaneous leishmaniasis in areas where the prevalence of the mucocutaneous form is low and in patients with contraindications to systemic treatment, such as kidney, liver and heart diseases, as well as in pregnant women, infants, and patients with human immunodeficiency virus infection/acquired immune deficiency syndrome.

A systematic review and meta-analysis of the effect of short birth interval on infant mortality in Ethiopia.

Abstract: Introduction Even though Ethiopia has been celebrating the achievements of MDG 4, still one in every 17 Ethiopian children dies before their first birthday. This is the biggest of the African regional average. Short birth interval is inconsistently reported as a risk factor by limited and independent studies in Ethiopia. Therefore, the purpose of this meta-analysis was to determine the pooled effect size of the preceding birth interval length on infant mortality. Methods Studies were accessed through the electronic web-based search mechanism from PUBMED, Advanced Google Scholar, WHO databases and journals: PLOS ONE, and BMC, using independent and combinations of key terms. Comprehensive meta-analysis version 2 was used to analyze the data. An I2 test was used to assess heterogeneity. Funnel plot and statistical significance by Egger’s test of the intercept was used to check publication bias. The final estimate was determined in the form of odds ratio by applying Duval and Tweedie’s trim and fill analysis in the Random-effects model. Results 872 studies were identified on the reviewed topic. During screening, forty-five studies were found to be relevant for data abstraction. However, only five studies fulfilled the inclusion criteria and were included in the analysis. In all of the studies included in the analysis, the preceding birth interval had a significant association with under-one mortality. The final pooled estimate in the form of the odds ratio for infant mortality with a preceding birth interval of less than 24 months was found to be 2.03 (95% CI: 1.52, 2.70, random effect (five studies, n=43,909), I2=70%, P<0.05). Conclusion In Ethiopia, promoting the length of birth interval to at least two years lowered under-one mortality by 50% (95% CI: 35%, 63%).

Assessing the methodological quality of systematic reviews

Abstract: Dear Sirs, We read with interest the paper by Ho et al,1 which used the AMSTAR tool to assess the methodological quality of systematic reviews (SRs) on chronic obstructive pulmonary disease (COPD). As staff at the Cochrane Airways Group with the responsibility of producing high-quality SRs for airway conditions, including COPD, we are always happy to hear how we could improve. However, there are some methodological issues within the study. The abstract states that the methodological quality of the reviews was disappointing and emphasises the more negative findings, neglecting the positive results (e.g., a priori design in 67% SRs, comprehensive literature search in 97% and scientific quality assessed and documented in 85%). The authors did not complete the AMSTAR ratings in duplicate; yet, duplicate data extraction is a mark of a good SR. Our experience with this tool is that the discussion between two or more people helps reach a fair judgement.2 It would have been helpful to see the AMSTAR ratings per review so that the work could be replicated and evaluated. We noted the lack of discussion about the choice to limit the study to SRs that include a meta-analysis. Choosing not to perform a meta-analysis when there is a lot of heterogeneity between studies is a valid decision. The authors highlighted that non-English databases were searched infrequently. This is not an AMSTAR criterion; have the authors suggested that this be incorporated in any update of the tool? Cochrane does not require that non-English language databases be searched and this is usually done only when we expect that this will yield additional relevant trials. We agree that multilingual SR teams are advantageous and we would be grateful if people who wish to translate the trial reports for inclusion in Cochrane reviews contact us. We take the authors’ point about being clearer about reviewers’ support, and making a statement about publication bias in the results section as well as the methods section when there are too few studies to permit a funnel plot. As highlighted in the paper, the quality of SRs has improved significantly in recent years through the development of methods and improved implementation.3,4 It would have been helpful to highlight this important point in the conclusions and abstract.

Detecting and visualizing outliers in provider profiling via funnel plots and mixed effect models

Abstract: In this work we propose the use of a graphical diagnostic tool (the funnel plot) to detect outliers among hospitals that treat patients affected by Acute Myocardial Infarction (AMI). We consider an application to data on AMI hospitalizations recorded in the administrative databases of our regional district. The outcome of interest is the in-hospital mortality, a variable indicating if the patient has been discharged dead or alive. We then compare the results obtained by graphical diagnostic tools with those arising from fitting parametric mixed effects models to the same data.

Impact of Corticosteroids on Mortality in Patients with Acute Respiratory Distress Syndrome: A Systematic Review and Meta-analysis.

Abstract: OBJECTIVE The impact of corticosteroids on acute respiratory distress syndrome (ARDS) mortality remains controversial following the publication of numerous trials, observational studies and meta-analyses. An updated meta-analysis is warranted, as a few original studies on this topic have been published since the last meta-analysis. METHODS We searched for eligible articles using four databases. In particular, we included full-length original articles providing sufficient data for evaluating the impact of corticosteroid treatment on adult ARDS mortality in the form of odds ratios. A fixed model with the confidence interval method was used. An assessment of publication bias and sensitivity analyses were also conducted. RESULTS We included 11 of 185 articles. The pooled odds ratio for corticosteroids with respect to all-cause mortality involving 949 patients was 0.77 [95% confidence interval (CI): 0.58-1.03, p=0.079] with strong heterogeneity(I2=70%, p<0.001). The results of the sensitivity analysis, Begg-Kendall test (τ=0.53, p=0.024)and funnel plot consistently suggested the existence of strong publication bias. After six potentially unpublished cohorts were filled using Duval's trim and fill method, the pooled odds ratio shifted to 1.11 (95% CI0.86-1.44, p=0.427). In addition, the sensitivity analyses suggested that corticosteroid treatment has a different impact on mortality depending on the comorbidities and trigger events. CONCLUSION We were unable to confirm, based on the data of published studies, the favorable impact of corticosteroid therapy on mortality in overall ARDS cases. Published articles exhibit strong publication bias,and previous meta-analyses may be affected by this publication bias. Further research focusing on pathophysiology- or trigger event-specific ARDS is anticipated.

Second-generation antidepressants for preventing seasonal affective disorder in adults

Abstract: Background Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occurs during autumn or winter and remits in spring. The prevalence of SAD ranges from 1.5% to 9%, depending on latitude. The predictable seasonal aspect of SAD provides a promising opportunity for prevention. This review - one of four reviews on efficacy and safety of interventions to prevent SAD - focuses on second-generation antidepressants (SGAs). Objectives To assess the efficacy and safety of second-generation antidepressants (in comparison with other SGAs, placebo, light therapy, melatonin or agomelatine, psychological therapies or lifestyle interventions) in preventing SAD and improving patient-centred outcomes among adults with a history of SAD. Search methods A search of the Specialised Register of the Cochrane Depression, Anxiety and Neuorosis Review Group (CCDANCTR) included all years to 11 August 2015. The CCDANCTR contains reports of randomised controlled trials derived from EMBASE (1974 to date), MEDLINE (1950 to date), PsycINFO (1967 to date) and the Cochrane Central Register of Controlled Trials (CENTRAL). Furthermore, we searched the Cumulative Index to Nursing and Allied Health Literature, Web of Knowledge, The Cochrane Library and the Allied and Complementary Medicine Database (to 26 May 2014). We also conducted a grey literature search and handsearched the reference lists of included studies and pertinent review articles. Selection criteria For efficacy, we included randomised controlled trials on adults with a history of winter-type SAD who were free of symptoms at the beginning of the study. For adverse events, we planned to include non-randomised studies. Eligible studies compared an SGA versus another SGA, placebo, light therapy, psychological therapy, melatonin, agomelatine or lifestyle changes. We also intended to compare SGAs in combination with any of the comparator interventions versus the same comparator intervention as monotherapy. Data collection and analysis Two review authors screened abstracts and full-text publications and assigned risk of bias ratings based on the Cochrane 'Risk of bias' tool. We resolved disagreements by consensus or by consultation with a third party. Two review authors independently extracted data and assessed risk of bias of included studies. When data were sufficient, we conducted random-effects (Mantel-Haenszel) meta-analyses. We assessed statistical heterogeneity by calculating the Chi2 statistic and the Cochran Q. We used the I2 statistic to estimate the magnitude of heterogeneity and examined potential sources of heterogeneity using sensitivity analysis or analysis of subgroups. We assessed publication bias by using funnel plots. However, given the small number of component studies in our meta-analyses, these tests have low sensitivity to detect publication bias. We rated the strength of the evidence using the system developed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group. Main results We identified 2986 citations after de-duplication of search results and excluded 2895 records during title and abstract reviews. We assessed 91 full-text papers for inclusion in the review, of which four publications (on three RCTs) providing data from 1100 people met eligibility criteria for this review. All three RCTs had methodological limitations due to high attrition rates. Overall moderate-quality evidence indicates that bupropion XL is an efficacious intervention for prevention of recurrence of depressive episodes in patients with a history of SAD (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.44 to 0.72; three RCTs, 1100 participants). However, bupropion XL leads to greater risk of headaches (moderate-quality evidence), insomnia and nausea (both low-quality evidence) when compared with placebo. Numbers needed to treat for additional beneficial outcomes (NNTBs) vary by baseline risks. For a population with a yearly recurrence rate of 30%, the NNTB is 8 (95% CI 6 to 12). For populations with yearly recurrence rates of 40% and 50%, NNTBs are 6 (95% CI 5 to 9) and 5 (95% CI 4 to 7), respectively. We could find no studies on other SGAs and no studies comparing SGAs with other interventions of interest such as light therapy, psychological therapies, melatonin or agomelatine. Authors' conclusions Available evidence indicates that bupropion XL is an effective intervention for prevention of recurrence of SAD. Nevertheless, even in a high-risk population, four of five patients will not benefit from preventive treatment with bupropion XL and will be at risk for harm. Clinicians need to discuss with patients advantages and disadvantages of preventive SGA treatment and might want to consider offering other potentially efficacious interventions, which might confer lower risk of adverse events. Given the lack of comparative evidence, the decision for or against initiating preventive treatment of SAD and the treatment selected should be strongly based on patient preferences. Future researchers need to assess the effectiveness and risk of harms of SGAs other than bupropion for prevention of SAD. Investigators also need to compare benefits and harms of pharmacological and non-pharmacological interventions.

Venlafaxine in management of hot flashes in women with breast cancer: a systematic review and meta-analysis

Abstract: Toxicity due to treatment causes a negative impact on quality of life in breast cancer survivors. Hot flash symptoms, described as intense sensations of heat, sweating and flushing occur in more than 50 % of breast cancer patients taking tamoxifen. We hypothesized that venlafaxine, a selective-norepinephrine reuptake inhibitor drug, was effective for reducing patient-reported hot flash scores among women treated for breast cancer compared to other non-hormonal treatments. We searched Medline, Scopus, and Cochrane Central Register of Controlled Trials from inception till May 2015 for venlafaxine (75 mg once daily or greater) with non-hormonal comparators for the treatment of hot flashes in female breast cancer patients. The primary outcome was hot flash score (derived from patient-reported hot flash severity and frequency) in randomized controlled trials. Standardized mean differences (SMD) were calculated for each study due to variation in the outcome measures. Heterogeneity was determined using I (2) statistics, and publication bias was assessed using a contour funnel plot and Egger's tests. Pooled analyses demonstrated that venlafaxine significantly reduced hot flash scores compared to the trial comparators (overall SMD 2.06; 95% confidence interval (CI) [0.40, 3.72]). There was significant heterogeneity among these studies (I (2) = 98.7%, P < 0.001). Asymmetry in the contour funnel plot suggests the presence of publication bias and a trend towards small study effects (Egger's test, P = 0.096). Venlafaxine is efficacious in managing hot flashes among women with breast cancer. This review highlights methodological issues that arise from eligible trials and recommends a collaborative approach in survivorship studies.

Meta- analysis and meta-regression analysis of the associations between sex and the operative outcomes of carotid endarterectomy

Abstract: Subgroup analyses from randomized controlled trials (RCT) of carotid endarterectomy (CEA) for both symptomatic and asymptomatic carotid stenosis suggest less benefit in women compared to men, due partly to higher age-independent peri-operative risk. However, a meta-analysis of case series and databases focussing on CEA-related gender differences has never been investigated. A systematic review of all available publications (including case series, databases and RCTs) reporting data on the association between sex and procedural risk of stroke and/or death following CEA from 1980 to 2015 was investigated. Pooled Peto odds ratios of the procedural risk of stroke and/or death were obtained by Mantel-Haenszel random-effects meta-analysis. The I2 statistic was used as a measure of heterogeneity. Potential publication bias was assessed with the Egger test and represented graphically with Begg funnel plots of the natural log of the OR versus its standard error. Additional sensitivity analyses were undertaken to evaluate the potential effect of key assumptions and study-level factors on the overall results. Meta-regression models were formed to explore potential heterogeneity as a result of potential risk factors or confounders on outcomes. A tria sequential analysis (TSA) was performed with the aim to maintain an over- all 5 % risk of type I error, being the standard in most meta- analyses and systematic reviews. 58 articles reported combined stroke and mortality rates within 30 days of treatment. In the unselected overall meta-analysis, the incidence of stroke and death in the male and female groups differed significantly (Peto OR, 1,162; 95 % CI, 1.067-1.266; P = .001), revealing a worse outcome for female patients. Moderate heterogeneity among the studies was identified (I2 = 36 %), and the possibility of publication bias was low (P = .03). In sensitivity analyses the meta-analysis of case series with gender aspects as a secondary outcome showed a significantly increased risk for 30-day stroke and death in women compared to men (Peto OR, 1.390; 95 % CI, 1.148-1.684; P = .001), In contrast, meta-analysis of databases (Peto OR, 1.025; 95 % CI, 0.958-1.097; P = .474) and case series with gender related outcomes as a primary aim (Peto OR, 1.202; 95 % CI, 0.925-1.561; P = .168) demonstrated no increase in operative risk of stroke and death in women compared to men. Metanalyses of case series and databases dealing with CEA reveal inconsistent results regarding gender differences related to CEA-procedure and should not be transferred into clinical practice.

Statins use and the risk of all and subtype hematological malignancies: a meta‐analysis of observational studies

Abstract: In order to quantify the association between use of statins and the risk of all hematological malignancies and of subtypes, we performed a meta-analysis of observational studies. We achieved a MEDLINE/EMBASE comprehensive search for studies published up to August 2014 investigating the association between use of statins and the risk of hematological malignancies, including Hodgkin- and non-Hodgkin lymphoma, leukemia, and myeloma. Fixed- and random-effect models were fitted to estimate the summary relative risk (RR) based on adjusted study-specific results. Between-study heterogeneity was assessed using the Q and I2 statistics and the sources of heterogeneity were investigated using Deeks' test. Moreover, an influence analysis was performed. Finally, publication bias was evaluated using funnel plot and Egger's regression asymmetry test. Fourteen studies (10 case–control and four cohort studies) contributed to the analysis. Statin use, compared to nonuse of statins, was negatively associated with all hematological malignancies taken together (summary RR 0.86; 95% CI: 0.77–0.96), with leukemia (0.83; 0.74–0.92), and non-Hodgkin lymphoma (0.81; 0.68 to 0.96), but it was not related to the risk of myeloma (0.89; 0.53–1.51). Long-term users of statins showed a statistically significant reduction in the risk of all hematological malignancies taken together (0.78; 0.71–0.87). Statistically significant between-studies heterogeneity was observed for all outcome except for leukemia. Heterogeneity was caused by differences confounding-adjustment level of the included studies only for Myeloma. No significant evidence of publication bias was found.

Effects of stem cell transplantation on cognitive decline in animal models of Alzheimer's disease: A systematic review and meta-analysis.

Abstract: Alzheimer’s disease (AD), an irreversible progressive neurodegenerative disease, causes characteristic cognitive impairment, and no curative treatments are currently available. Stem cell transplantation offers a powerful tool for the treatment of AD. We conducted a systematic review and meta-analysis of data from controlled studies to study the impact of stem cell biology and experimental design on learning and memory function following stem cell transplantation in animal models of AD. A total of 58 eligible controlled studies were included by searching PubMed, EMBASE, and Web of Science up to April 13, 2015. Meta-analysis showed that stem cell transplantation could promote both learning and memory recovery. Stratified meta-analysis was used to explore the influence of the potential factors on the estimated effect size, and meta-regression analyses were undertaken to explore the sources of heterogeneity for learning and memory function. Publication bias was assessed using funnel plots and Egger’s test. The present review reinforces the evidence supporting stem cell transplantation in experimental AD. However, it highlights areas that require well-designed and well-reported animal studies.