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Are incentive spirometry, intermittent positive pressure breathing, and deep breathing exercises effective in the prevention of postoperative pulmonary complications after upper abdominal surgery? A systematic overview and meta-analysis.

BACKGROUND AND PURPOSE: The purpose of this meta-analysis was to quantitatively assess the conflicting body of literature concerning the efficacy of incentive spirometry (IS), intermittent positive pressure breathing (IPPB), and deep breathing exercises (DBEX) in the prevention of postoperative pulmonary complications in patients undergoing upper abdominal surgery. METHODS: Computerized searches of MEDLINE and the Cumulative Index to Nursing and Allied Health databases were performed for the years 1966 through 1992. Citations were selected based on the following relevance criteria: (1) patients undergoing any type of upper abdominal surgery; (2) any combination of IS, IPPB, and DBEX; (3) an outcome of pulmonary complications; and (4) randomized trials. Review of 116 citations yielded 55 potential trials and 10 review articles. Of these, 14 citations were included in the overview based on relevance criteria requirements. Study validity was assessed by two independent observers, and data were extracted. RESULTS: The common odds ratio (COR) for the occurrence of pulmonary complications for IS versus no physical therapy was 0.44 in favor of IS. The COR for DBEX versus no physical therapy was 0.43 in favor of DBEX. Both findings were statistically significant. The CORs for IS versus IPPB, IS versus DBEX, and IPPB versus DBEX were 0.76 (95% confidence interval [CI] = 0.39-1.4), 0.91 (95% CI = 0.57-1.4), and 0.94 (95% CI = 0.28-3.17), respectively. None of these comparisons reached statistical significance. CONCLUSION AND DISCUSSION: Incentive spirometry and DBEX appear to be more effective than no physical therapy intervention in the prevention of postoperative pulmonary complications. There is no evidence to support a significant difference between any of the three modalities. [Thomas JA, McIntosh JM. Are incentive spirometry, intermittent positive pressure breathing, and deep breathing exercises effective in the prevention of postoperative pulmonary complications after upper abdominal surgery? a systematic overview and meta-analysis.

Abdomen↗

Role of glycopeptides as part of initial empirical treatment of febrile neutropenic patients: a meta-analysis of randomised controlled trials.

We did a meta-analysis of randomised controlled trials studying glycopeptides as part of the initial empirical treatment of febrile neutropenic patients with a beta-lactam and with or without an aminoglycoside. 14 randomised controlled trials that studied 2413 patients were included in the analysis. A better outcome regarding treatment success, without modification of the initial regimen, was accomplished with the inclusion of a glycopeptide in the empirical therapy; this better outcome applied to the full set of studied patients (OR=1.63, 95% CI 1.17-2.28), as well as in three important subsets of patients--those with microbiologically documented infections (2.03, 1.39-2.97), patients with bacteraemia (1.80, 1.23-2.63), and patients with severe neutropenia, defined as a white blood cell count below 100 cells/microL (2.24, 1.15-4.39). However, mortality was not different in the compared groups (0.67, 0.42-1.05). Overall treatment success was not different if a glycopeptide was added to the antimicrobial regimen in the case of continuation of fever 72 hours or more after the start of treatment (1.02, 0.68-1.52). Also, the inclusion of a glycopeptide in the empirical regimen did not lead to a difference regarding time to defervesence. Adverse effects (4.98, 2.91-8.55), including nephrotoxicity (2.10, 1.12-3.95), were more common in the group receiving a glycopeptide as part of the empirical treatment. In conclusion, our meta-analysis suggests that there are good reasons why glycopeptides should not be routinely used as part of the initial empirical treatment of febrile neutropenic patients.

Anti-Bacterial Agents↗

Hawthorn extract for treating chronic heart failure: meta-analysis of randomized trials.

The aim of this meta-analysis was to assess the evidence from rigorous clinical trials of the use of hawthorn extract to treat patients with chronic heart failure. We searched the literature using MEDLINE, EMBASE, the Cochrane Library, CINAHL, CISCOM, and AMED. Experts on and manufacturers of commercial preparations containing hawthorn extract were asked to contribute published and unpublished studies. There were no restrictions about the language of publication. Two reviewers independently performed the screening of studies, selection, validation, data extraction, and the assessment of methodological quality. To be included, studies were required to state that they were randomized, double-blind, and placebo controlled, and used hawthorn extract monopreparations. Thirteen trials met all inclusion criteria. In most of the studies, hawthorn was used as an adjunct to conventional treatment. Eight trials including 632 patients with chronic heart failure (New York Heart Association classes I to III) provided data that were suitable for meta-analysis. For the physiologic outcome of maximal workload, treatment with hawthorn extract was more beneficial than placebo (weighted mean difference, 7 Watt; 95% confidence interval [CI]: 3 to 11 Watt; P < 0.01; n = 310 patients). The pressure-heart rate product also showed a beneficial decrease (weighted mean difference, -20; 95% CI: -32 to -8; n = 264 patients) with hawthorn treatment. Symptoms such as dyspnea and fatigue improved significantly with hawthorn treatment as compared with placebo. Reported adverse events were infrequent, mild, and transient; they included nausea, dizziness, and cardiac and gastrointestinal complaints. In conclusion, these results suggest that there is a significant benefit from hawthorn extract as an adjunctive treatment for chronic heart failure.

Crataegus↗

New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis.

New onset diabetes mellitus (NODM) is a serious complication of transplantation. This meta-analysis evaluates the reported incidence of NODM after solid organ transplantation in patients receiving CNI treatment. Databases from January 1992 to April 2002 were searched. Fifty-six publications providing NODM incidence data were reviewed. Sixteen prospective, randomized comparative studies providing information on incidence of insulin-dependent diabetes mellitus (IDDM) were subjected to meta-analysis. New onset diabetes mellitus was reported in 13.4% of patients after solid organ transplantation, with a higher incidence in patients receiving tacrolimus than cyclosporine (16.6% vs. 9.8%). This trend was observed across renal, liver, heart and lung transplant groups. Meta-analysis of 16 studies included patients receiving either tacrolimus (n=1636) or cyclosporine (n=1407). The incidence of IDDM was significantly higher among tacrolimus-treated patients (10.4% vs. 4.5%, p<0.00001), an effect observed in renal (9.8% vs. 2.7% p<0.00001) and nonrenal (11.1% vs. 6.2%; p<0.003) groups, and among patients receiving equal doses of concomitant medication in both treatment arms (12.0% vs. 3.0%; p<0.00001). The reported incidence of NODM during the past decade was significantly higher among patients receiving tacrolimus than cyclosporine. These data provide a quantitative foundation for studies designed to reduce the rates of NODM following solid organ transplantation.

Calcineurin Inhibitors↗

Does off-pump coronary artery bypass reduce mortality, morbidity, and resource utilization when compared with conventional coronary artery bypass? A meta-analysis of randomized trials.

The authors undertook a meta-analysis of 37 randomized trials (3369 patients) of off-pump coronary artery bypass surgery versus conventional coronary artery bypass surgery. No significant differences were found for 30-day mortality (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.58-1.80), myocardial infarction (OR, 0.77; 95%CI, 0.48-1.26), stroke (OR, 0.68; 95%CI, 0.33-1.40), renal dysfunction, intraaortic balloon pump, wound infection, rethoracotomy, or reintervention. However, off-pump coronary artery bypass surgery significantly decreased atrial fibrillation (OR, 0.58; 95%CI, 0.44-0.77), transfusion (OR, 0.43; 95%CI, 0.29-0.65), inotrope requirements (OR, 0.48; 95%CI, 0.32-0.73), respiratory infections (OR, 0.41; 95%CI, 0.23-0.74), ventilation time (weighted mean difference, -3.4 h; 95%CI, -5.1 to -1.7 h), intensive care unit stay (weighted mean difference, -0.3 days; 95%CI -0.6 to -0.1 days), and hospital stay (weighted mean difference, -1.0 days; 95%CI -1.5 to -0.5 days). Patency and neurocognitive function results were inconclusive. In-hospital and 1-yr direct costs were generally higher for conventional coronary artery bypass surgery versus off-pump coronary artery bypass surgery. Therefore, this meta-analysis demonstrates that mortality, stroke, myocardial infarction, and renal failure were not reduced in off-pump coronary artery bypass surgery surgery; however, selected short-term and mid-term clinical and resource outcomes were improved compared with conventional coronary artery bypass surgery.

Coronary Artery Bypass↗

Meta-analysis and indirect comparisons of levetiracetam with other second-generation antiepileptic drugs in partial epilepsy.

Few comparative clinical trials of newer antiepileptic drugs (AEDs) in patients with refractory partial epilepsy are available. Therefore, meta-analysis is a widely used and useful method for comparing them. Despite the limitations of indirect comparisons, and recognizing that these drugs were tested at different doses, such comparisons can be helpful to physicians making practical treatment decisions. The purposes of this study were to present newer meta-analysis results for add-on levetiracetam compared with placebo and to estimate its efficacy and tolerability compared with other new AEDs (gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide) in a meta-analysis using methods for making indirect comparisons. Randomized placebo-controlled clinical trials of add-on therapy with levetiracetam, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide in patients with refractory partial epilepsy were identified in the Cochrane Library 2002. A fixed-effects model was used to estimate Mantel-Haenszel odds ratios for the responder rate (efficacy measure) and withdrawal rate (mainly tolerability measure) of levetiracetam and other new AEDs versus placebo. Because no head-to-head clinical trials comparing these new AEDs exist, adjusted indirect comparisons were then made between levetiracetam and each other AED using the meta-analysis results. At the doses tested, levetiracetam was more effective in terms of responder rate than gabapentin (odds ratio 2.64 with 95% CI 1.51-4.63) and lamotrigine (odds ratio 1.86 with 95% CI 1.04-3.34) and equally well tolerated. Levetiracetam had a significantly lower withdrawal rate than topiramate (odds ratio 0.52 with 95% CI 0.29-0.93) and oxcarbazepine (odds ratio 0.55 with 95% CI 0.33-0.92), with comparable efficacy. Although levetiracetam did not differ significantly from the other AEDs, numerical trends favoring levetiracetam were obtained in response rate and in withdrawal rate (tiagabine, zonisamide). Indirect comparisons based on meta-analysis suggest that add-on therapy with levetiracetam has a favorable responder and/or withdrawal rate relative to several AEDs in patients with partial epilepsy with doses used in clinical trials. These meta-analyses give only short-term efficacy and safety data. Comparative clinical trials and long-term studies of these agents are needed to confirm these findings.

Anticonvulsants↗

A cross-study contextual analysis of effects from individual-level drinking and group-level drinking factors: a meta-analysis of multiple longitudinal studies from the collaborative alcohol-related longitudinal project.

In contextual (cross-level) analysis within multiple longitudinal general population studies, individual-level drinking behaviors (quantity per typical occasion, frequency of drinking per month and total volume of drinks per month) at final measurement are assessed by three models that simultaneously enter individual- and group-level measures. Two age groups (15-20 and 21-30) are independently assessed. In each model, the Time 1 individual-level drinking behavior and one of three group-level factors are entered. The group-level factors are (1) the percentage of abstainers at Time 1 for each age/sex cohort, (2) the Time 1 group mean for the drinking measure for the age/sex cohort and (3) the mean difference of the age/sex cohort's change in the drinking measure over time. All variables in the model are controlled by variations to exposure in per capita consumption of alcohol during the age/sex cohort's formative years and at Time 2. Meta-analysis assesses the homogeneity of the findings across studies. Models were proposed with the rationale that (1) understanding of individual drinking behavior can be advanced if individual-level data and group-level data are considered in the same models, and (2) integration of these two levels of analyses are, to date, rare. The rationale for using meta-analysis is that findings from the models can be assessed across social contexts with respect to their generalizability. The mean difference model, controlling for individual drinking at Time 1, is the most influential of the group-level models for the younger age group: the degree to which the group changes its drinking pattern is positively related to individual-level drinking behavior at final measurement, over and above the individual's drinking behavior at Time 1, for individual-level frequency of drinking among males (homogeneous among drinkers only). Younger females show more significant relationships for the mean difference females show more significant relationships for the mean difference model. Findings are significant for all relationships examined for the mean difference of the drinking of the group and the individual drinking among the older males and females. Measures of individual-level drinking for all measures at Time 1, controlling for the group-level effects, are significantly related to individual-level drinking at final measurement. The results are homogeneous for quantity (drinkers only) and volume among the young. Findings indicate that characterizations of the drinking for both the individual and the group to which the individual belongs predict measures of drinking practices on the individual level over time.

Adolescent↗

Meta-analysis by combining p-values: simulated linkage studies.

Meta-analysis has been little explored to make an overall assessment of linkage from different studies. In practice, it is likely that published linkage studies will only report p-values. We compared the performance of the widely used Fisher method for combining p-values with that of pooling raw data. More loci were consistently found by pooling raw data. In the absence of further information, combining p-values can provide an overall, but limited, assessment of different linkage studies. However, meta-analysis would be better viewed as a preliminary step toward the goal of analyzing the pooled raw data.

Genetic Linkage↗

Residential magnetic fields and childhood leukemia: a meta-analysis.

OBJECTIVES: This article uses meta-analysis methodology to examine the statistical consistency and importance of random variation among results of epidemiologic studies of residential magnetic field exposure and childhood leukemia. METHODS: A variety of meta-analytic statistical methods were applied to all available studies combined and on sub-groups of studies chosen by exposure characteristics. Sample sizes and fail-safe n's were calculated to determine the robustness of results and the potential role of publication bias. RESULTS: Most studies show elevated but not statistically significant odds ratios. Results for exposures assessed by wire codes, distance, and/or historically reconstructed fields are relatively consistent, homogeneous, and positive, while those for direct magnetic field measurements are consistent, homogeneous, and marginally protective. Several unpublished studies, or a single unpublished study with several hundred subjects, would be needed to nullify the observed data. CONCLUSIONS: The observed results identify a consistent risk that cannot be explained by random variation. The data supporting magnetic fields as the principal risk factor are suggestive but inconsistent. Additional studies using innovative designs that focus on highly exposed children offer the most hope of untangling this issue.

Bias↗

Of apples and oranges, file drawers and garbage: why validity issues in meta-analysis will not go away.

This paper examines how threats to the validity of meta-analysis have been dealt with by clinical researchers employing this approach to literature review. Three validity threats were identified--mixing of dissimilar studies, publication bias, and inclusion of poor quality studies. Approaches to addressing these threats were evaluated for their effectiveness and popularity by surveying 32 published meta-analyses in clinical psychology. Distrust of meta-analysis, however, was found to transcend these validity threats. Other explanations for why this popular research strategy continues to receive widespread criticism were considered. Suggestions were made for how meta-analysis might better address these concerns.

Humans↗

A unification of models for meta-analysis of diagnostic accuracy studies.

Studies of diagnostic accuracy require more sophisticated methods for their meta-analysis than studies of therapeutic interventions. A number of different, and apparently divergent, methods for meta-analysis of diagnostic studies have been proposed, including two alternative approaches that are statistically rigorous and allow for between-study variability: the hierarchical summary receiver operating characteristic (ROC) model (Rutter and Gatsonis, 2001) and bivariate random-effects meta-analysis (van Houwelingen and others, 1993), (van Houwelingen and others, 2002), (Reitsma and others, 2005). We show that these two models are very closely related, and define the circumstances in which they are identical. We discuss the different forms of summary model output suggested by the two approaches, including summary ROC curves, summary points, confidence regions, and prediction regions.

Diagnostic Tests, Routine↗

Meta-analysis combining parallel and cross-over clinical trials. III: The issue of carry-over.

In meta-analysis combining results from parallel and cross-over trials, there is a risk of bias originating from the carry-over effect in cross-over trials. When pooling treatment effects estimated from parallel trials and two-period two-treatment cross-over trials, meta-analytic estimators of treatment effect can be obtained from the combination of parallel trial results either with cross-over trial results based on data of the first period only or with cross-over trial results analysed with data from both periods. Taking data from the first cross-over period protects against carry-over but gives less efficient treatment estimators and may lead to selection bias. This study evaluates in terms of variance reduction and mean square error the cost of calculating meta-analysis estimates with data from the first period instead of data from the two cross-over periods. If the information on cross-over sequence is available, we recommend performing two combined design meta-analyses, one using the first cross-over period data and one based on data from both cross-over periods. To investigate simultaneously the statistical significance of these two estimators as well as the carry-over at meta-analysis level, a method based on a multivariate analysis of the meta-analytic treatment effect and carry-over estimates is proposed.

Blood Pressure↗

Importance of trends in the interpretation of an overall odds ratio in the meta-analysis of clinical trials.

This paper contains a proposition related to the publication of meta-analyses of clinical trials. We consider the situation where the results of a number of trials are summarized by a common or typical odds ratio. We show that stating such an odds ratio as the summary of evidence from a number of trials can be misleading if certain systematic differences between trials exist. In such cases the author should state not just one odds ratio but also its dependence on the relevant characteristics of the trials. In particular, we propose that those reporting a meta-analysis state in advance a (limited) number of variables to be considered for potential interaction with the exposure (risk factor or treatment) of interest. The list might include centre size and the odds in the placebo or control group if such an effect is a priori clinically plausible. The trials should be ordered according to each of these variables and a trend test for the odds ratio should be computed. Apart from a 'genuine' effect, an appreciable interaction could also be indicative of the (multiplicative) odds ratio being an inappropriate measure for the particular meta-analysis. Without any consideration as to the possibility of interaction, the meta-analysis should be considered incomplete. If such an interaction exists, the odds ratio should be stated as a function of the interacting variable, either as a formula or (preferably) in a table stating the odds ratio for a number of different values of the interacting variable, and not as a single summary statistic.

Clinical Trials as Topic↗

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes.

AIMS/HYPOTHESIS: Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PPARGC1A) is a transcriptional co-activator with a central role in energy expenditure and glucose metabolism. Several studies have suggested that the common PPARGC1A polymorphism Gly482Ser may be associated with risk of type 2 diabetes, with conflicting results. To clarify the role of Gly482Ser in type 2 diabetes and related human metabolic phenotypes we genotyped this polymorphism in a case-control study and performed a meta-analysis of relevant published data. MATERIALS AND METHODS: Gly482Ser was genotyped in a type 2 diabetes case-control study (N=1,096) using MassArray technology. A literature search revealed publications that examined Gly482Ser for association with type 2 diabetes and related metabolic phenotypes. Meta-analysis of the current study and relevant published data was undertaken. RESULTS: In the pooled meta-analysis, including data from this study and seven published reports (3,718 cases, 4,818 controls), there was evidence of between-study heterogeneity (p<0.1). In the fixed-effects meta-analysis, the pooled odds ratio for risk of type 2 diabetes per Ser482 allele was 1.07 (95% CI 1.00-1.15, p=0.044). Elimination of one of the studies from the meta-analysis gave a summary odds ratio of 1.11 (95% CI 1.04-1.20, p=0.004), with no between-study heterogeneity (p=0.475). For quantitative metabolic traits in normoglycaemic subjects, we also found significant between-study heterogeneity. However, no significant association was observed between Gly482Ser and BMI, fasting glucose or fasting insulin. CONCLUSIONS/INTERPRETATION: This meta-analysis of data from the current and published studies supports a modest role for the Gly482Ser PPARGC1A variant in type 2 diabetes risk.

Blood Glucose↗

Factors involved in validity measurements of diagnostic tests for approximal caries--a meta-analysis.

In this study, a meta-analysis was performed on published validity parameters of visual inspection, radiographic examination and visual inspection upon fibreoptic transillumination (FOTI) in approximal caries diagnosis. It was the objective to investigate the influence of the diagnostic test, the study design and the validation method on reported validity. Sensitivities and specificities reported in the literature were transformed into D2 values, representing the performance of a diagnostic method above chance, or of the observer using it, in a single parameter. Dz values were neither statistically significantly different between visual inspection, radiographic examination and FOTI nor between 'weak' and 'strong' validation methods (p > 0.05). Dz values obtained from in vivo studies were significantly different from those obtained from in vitro studies (p < 0.05), indicating that study design had a significant impact on the measurement of the validity of the evaluated test for approximal caries diagnosis.

Dental Caries↗

Efficacy and tolerability of trimetazidine in stable angina: a meta-analysis of randomized, double-blind, controlled trials.

OBJECTIVE: The objective of this meta-analysis was to evaluate the efficacy and tolerance of the metabolic agent trimetazidine (TMZ), both in monotherapy and in combination with other antianginal agents, in the treatment of stable angina pectoris. A search of literature published between 1985 and 2001 was performed on computerized databases (MEDLINE and EMBASE). METHODS: Only double-blind, randomized, controlled trials were included in this meta-analysis. Patients had to be treated for at least 2 weeks. Four parameters were selected, one clinical parameter (number of weekly angina attacks) and three ergometric parameters (time to 1 mm ST-segment depression, total work and exercise duration at peak exercise). They were evaluated at baseline and at the end of the treatment period.The quality of the trials was assessed on specific methodological criteria. Standard statistical methods, pooled odds ratio and 95% confidence intervals for subjective symptoms and pooled z and P for objective symptoms, were used. RESULTS: Twelve clinical studies meeting our criteria were analyzed. Results showed that TMZ significantly reduced the number of weekly angina attacks in coronary patients and improved time to 1 mm segment depression and total work at peak exercise, while exercise duration at peak exercise showed a trend toward improvement (P = 0.09). CONCLUSION: This meta-analysis confirms the efficacy of TMZ in the treatment of stable angina, compared with placebo or conventional antianginal agent, as well as in monotherapy or in combination with conventional antianginal agents. TMZ is well tolerated in monotherapy as well as in combination.

Aged↗

Investigating patient exclusion bias in meta-analysis.

BACKGROUND: Trial investigators frequently exclude patients from trial analyses which may bias estimates of the effect of treatment. Combining these estimates in a meta-analysis could aggregate any such biases. METHODS: To investigate how excluding patients from trials can affect the results of both trials and meta-analyses, we used 14 meta-analyses of individual patient data (IPD) that addressed therapeutic questions in cancer. These included 133 randomized controlled trials (RCT) and 21 905 patients. We explored whether exclusions were related to trial characteristics and categorized the reasons for exclusions. For each RCT and meta-analysis, we compared results of an intention-to-treat analysis of all randomized patients with an analysis based on those patients included in the investigators' analysis. RESULTS: In all, 92 trials (69%) excluded between 0.3 and 38% of patients randomized. Trials excluding patients tended to be older and larger than those that did not. Most patients were excluded because of ineligibility or protocol violations. Exclusions varied substantially by meta-analysis, more patients tending to be excluded from the treatment arm. Comparing trial analyses there was no clear indication that exclusion of patients altered the results more in favour of either treatment or control. However, comparing meta-analysis results, there was a tendency for those based on 'included' patients to favour the research treatment (P = 0.03). Inconsistency of trial results was often increased as a result of the investigators' exclusions. CONCLUSIONS: Trials, systematic reviews, and meta-analyses may be prone to bias associated with post-randomization exclusion of patients. Wherever possible, the level of such exclusions should be taken into account when assessing the potential for bias in trials, systematic reviews, and meta-analyses. Ideally, trials, systematic reviews, and meta-analyses should be based on all randomized patients.

Bias↗

Implications of direct and indirect range restriction for meta-analysis methods and findings.

Range restriction in most data sets is indirect, but the meta-analysis methods used to date have applied the correction for direct range restriction to data in which range restriction is indirect. The authors show that this results in substantial undercorrections for the effects of range restriction, and they present meta-analysis methods for making accurate corrections when range restriction is indirect. Applying these methods to a well-known large-sample empirical database, the authors estimate that previous meta-analyses have underestimated the correlation between general mental ability and job performance by about 25%, indicating that this is potentially an important methodological issue in meta-analysis in general.

Cognition↗