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[Ginkgo biloba extract in peripheral arterial diseases. Meta-analysis of controlled clinical studies].

In the first part the statistical methods of meta-analysis are discussed. Meta-analysis is considered as a statistical tool for quantitatively summarizing the results of clinical trials with comparable aims (treatments) and designs. Meta-analysis can be based on the significance probabilities or effect values. The last procedure is preferable as it gives an estimate (and confidence interval) for the global effect of the treatment of interest, if homogeneity of the effects between the trials can be assumed. Such a homogeneity can be often achieved by a suitable standardization of the effect variables within the trials. In the second part the methods of meta-analysis are applied to controlled clinical trials with Ginkgo biloba extract EGb 761 in patients with peripheral arterial disease. Included were 5 placebo-controlled clinical trials with similar design and inclusion criteria. In all studies treatment effect was quantified by the increase of walking distance (measured in standardized treadmill exercise). The effect value of EGb 761 treatment was expressed by the standardized mean difference in walking distance increase between EGb 761 and placebo, standardized by the standard deviation. It could be shown that this effect value is homogeneous in all trials. The global effect size was estimated as 0.75. This means that the mean increase in walking distance achieved by EGb 761 is 0.75 times of the standard deviation higher than that achieved by placebo. This value is highly significant different from zero. So the meta-analysis revealed a highly significant therapeutic effect of EGb 761 for the treatment of peripheral arterial disease.

Arteries↗

Neonatal outcome and mode of delivery after epidural analgesia for labour with ropivacaine and bupivacaine: a prospective meta-analysis.

In this prospective meta-analysis, we have evaluated the effect of epidural analgesia with ropivacaine for pain in labour on neonatal outcome and mode of delivery compared with bupivacaine. In six randomized, double-blind studies, 403 labouring women, primigravidae and multiparae, received epidural analgesia with ropivacaine or bupivacaine 2.5 mg ml-1. The drugs were administered as intermittent boluses in four studies and by continuous infusion in two. Apgar scores, neurological and adaptive capacity scores (NACS), degree of motor block and mode of delivery were recorded. The studies were designed prospectively to fit meta-analysis of the pooled results. Results showed similar pain relief and consumption of the two drugs. In the vaginally delivered neonates, NACS scores were approximately equal for both groups at 2 h, but at 24 h there were fewer infants with NACS less than 35 in the ropivacaine compared with the bupivacaine group (2.8% vs 7.6%; P < 0.05). Spontaneous vaginal deliveries occurred more frequently overall with ropivacaine than with bupivacaine (58% vs 49%; P < 0.05) and instrumental deliveries (forceps and vacuum extraction) less frequently (27% vs 40%; P < 0.01), while the frequency of Caesarean section was similar between groups. The intensity of motor block was lower with ropivacaine. There were no significant differences in adverse events.

Adolescent↗

Meta-analysis: the glass eye of evidence-based practice?

Meta-analysis was developed as a technique for combining the results of many different quantitative studies: it is often used to produce quantitative estimates of causal relations and/or association between variables. Meta-analysis is sometimes regarded as a central component of evidence-based practice. We draw attention to an incompatibility in the epistemology and methods of reasoning in quantitative meta-analysis and the epistemology and reasoning implicit in expert practice. We argue that this may be because the common perception of meta-analysis appeals to truth as correspondence; we suggest that rejecting the naive realism that underpins truth as correspondence allows meta-analysis to be understood in terms of truth as coherence. We can then develop an account of meta-analysis that does not depend upon reduction to a mathematical procedure but is an attempt to maximise coherence in beliefs about what works that is consistent with clinical reasoning in expert practice.

Decision Making↗

Bulky DNA adducts and risk of cancer: a meta-analysis.

We present a meta-analysis to test the hypothesis that the presence of a high level of bulky DNA adducts in tissues is associated with an increased risk of cancer in humans. Seven articles were selected that matched the selection criteria, for a total of 691 cancer patients and 632 control subjects. In five studies the cases had lung cancer, in one oral cancer, and in one bladder cancer. Six studies measured adducts in WBCs and one in normal lung tissue around tumor tissue. Six were case-control investigations, and one was a case-control study on lung cancer nested within a cohort. Current smokers showed a statistically significant difference between cases and controls, with cases having 83% higher levels of adducts than controls (95% confidence interval, 0.44-1.22). Results were negative or contradictory in ex-smokers and nonsmokers. This observation was confirmed by sensitivity analyses. Publication bias does not seem to be a problem. Despite some methodological limitations, our meta-analysis shows that current smokers with high levels of adducts have an increased risk of lung and bladder cancers. This conclusion also suggests that similar (aromatic) compounds may be involved in the etiology of both types of cancer.

Biomarkers, Tumor↗

Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis.

We performed a meta-analysis of all 87 published studies linking intratumoral microvessel density (MVD), reflecting angiogenesis, to relapse-free survival (RFS) and overall survival (OS). With median MVD as cutoff, MVD impact was measured by risk ratio (RR) between the two survival distributions. Seventeen studies did not mention survival data or fit inclusion criteria. Twenty-two were multiple publications of the same series, leaving 43 independent studies (8936 patients). MVD was assessed by immunohistochemistry, using antibodies against factor VIII (27 studies; n = 5262), CD31 (10 studies; n = 2296), or CD34 (8 studies; n = 1726). MVD might be a better prognostic factor when assessed by CD31 or CD34 versus factor VIII (P = 0.11). For RFS, statistical calculations were performed in 25 studies (6501 patients). High MVD significantly predicted poor survival [RR = 1.54 for RFS and OS with the same 95% confidence interval (CI), 1.29-1.84]. Twenty-two studies analyzed separately lymph node-negative patients (n = 3580), for whom predictors of poor survival are requested. This latter meta-analysis included 15 studies for RFS (2727 patients) and 11 for OS (1926 patients). High MVD significantly predicted poor survival [RR = 1.99 for RFS (95% CI, 1.33-2.98) and RR = 1.54 for OS (95% CI, 1.01-2.33)]. Between-study variations could result from patient selection criteria, techniques to stain and count microvessels, and cutoff selection. MVD was a significant although weak prognostic factor in women with breast cancer. Standardization of MVD assessment is needed.

ADP-ribosyl Cyclase↗

Qualitative assessment of studies included in a meta-analysis: DES and the risk of pregnancy loss.

Meta-analysis, the qualitative and quantitative integration of available research information, is increasingly used in clinical research. This report examines the qualitative elements of meta-analysis through critical review of two published examples that assessed the effect of diethylstilboestrol (DES) on miscarriage and neonatal mortality, respectively. Our subjective review showed the internal validity of three of five trials aggregated in the former meta-analysis to be severely compromised. The remaining two trials (data from which were aggregated in the latter meta-analysis), while internally valid, studied different clinical populations. Therefore, pooling of their results may have been clinically inappropriate. In conclusion, meta-analysis involves substantial elements of subjective judgment. Qualitative assessment of studies is of pivotal importance, because the validity of any summary estimate of effect hinges on both the methodologic quality and the combinability of the aggregated studies.

Abortion, Spontaneous↗

Laparoscopic versus open appendectomy in children: a meta-analysis.

OBJECTIVE: This study aims to use meta-analysis to compare laparoscopic and open appendectomy in a pediatric population. SUMMARY BACKGROUND DATA: Meta-analysis is a statistical tool that can be used to evaluate the literature in both qualitative and quantitative ways, accounting for variations in characteristics that can influence overall estimate of outcomes of interest. Meta-analysis of laparoscopic versus open appendectomy in a pediatric population has not previously been performed. METHODS: Comparative studies published between 1992 and 2004 of laparoscopic versus open appendectomy in children were included. Endpoints were postoperative pyrexia, ileus, wound infection, intra-abdominal abscess formation, operative time, and postoperative hospital stay. RESULTS: Twenty-three studies including 6477 children (43% laparoscopic, 57% open) were included. Wound infection was significantly reduced with laparoscopic versus open appendectomy (1.5% versus 5%; odds ratio [OR] = 0.45, 95% confidence interval [CI], 0.27-0.75), as was ileus (1.3% versus 2.8%; OR = 0.5, 95% CI, 0.29-0.86). Intra-abdominal abscess formation was more common following laparoscopic surgery, although this was not statistically significant. Subgroup analysis of randomized trials did not reveal significant difference between the 2 techniques in any of the 4 complications. Operative time was not significantly longer in the laparoscopic group, and postoperative stay was significantly shorter (weighted mean difference, -0.48; 95% CI, -0.65 to -0.31). Sensitivity analysis identified lowest heterogeneity when only randomized studies were considered, followed by prospective, recent, and finally large studies. CONCLUSIONS: The results of this meta-analysis suggest that laparoscopic appendectomy in children reduces complications. However, we also see the need for further high-quality randomized trials comparing the 2 techniques, matched not only for age and sex but also for obesity and severity of appendicitis.

Appendectomy↗

The design and analysis of paired cluster randomized trials: an application of meta-analysis techniques.

The statistical issues in clinical trials where clusters, communities or groups rather than individuals are randomized are often not fully appreciated. In this paper we discuss the design and analysis of trials in which pairs of clusters are randomized in the context of one recent trial, the British Family Heart Study. Both sample size calculations and the analysis strategy need to take account of the between-cluster component of variance. The analysis can be considered as a random effects meta-analysis across cluster pairs, and can usefully be presented as such. Techniques developed in the context of meta-analysis can then be used in the analysis, for example using a profile likelihood method to derive a confidence interval for the overall treatment effect which takes into account the variability in the estimate of the between-cluster variance. The methods presented here are contrasted with previously published methods for cluster randomized trials.

Adult↗

Strengths and limitations of meta-analysis: larger studies may be more reliable.

Meta-analysis of randomized controlled trials combines information from independent studies that address a similar question to provide more reliable estimates of treatment effects. At the present time, the methodology and usefulness of meta-analysis is under scrutiny. In the first part of this paper, we summarize the limitations of meta-analysis and make suggestions for improvements. In the second part, we illustrate strengths and limitations using examples of meta-analyses and subsequent large trials that address the same question. We develop the hypothesis that the size of the meta-analysis may be a useful measure of reliability. Small meta-analyses (i.e., those with less than 200 outcome events) may only be useful for summarizing the available information and generating hypotheses for future research. The results of small meta-analyses should be regarded with caution, even if the p value shows extreme statistical significance. Larger meta-analyses (i.e., those with several hundred events) are likely to be more reliable and may be clinically useful. Well-conducted meta-analyses of large trials using individual patient data may provide the best estimates of treatment effects in the cohort overall and in clinically important subgroups.

Bias↗

Meta-analysis in psychiatric genetics.

The article reviews literature on methods for meta-analysis of genetic linkage and association studies, and summarizes and comments on specific meta-analysis findings for psychiatric disorders. The Genome Scan Meta-Analysis and Multiple Scan Probability methods assess the evidence for linkage across studies. Multiple Scan Probability analysis suggested linkage of two chromosomal regions (13q and 22q) to schizophrenia and bipolar disorder, whereas Genome Scan Meta-Analysis on a larger sample identified at least 10 schizophrenia linkage regions, but none for bipolar disorder. Meta-analyses of pooled ORs support association of schizophrenia to the Ser311Cys polymorphism in DRD2 and the T102C polymorphism in HTR2A, and of attention deficit hyperactivity disorder to the 48-bp repeat in DRD4. The 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) may contribute to the risk of bipolar disorder, suicidal behavior, and neuroticism, but association to the lifetime risk of major depression has not been shown. Meta-analyses support linkage of schizophrenia to regions where replicable associations to candidate genes have been identified through positional cloning methods. There are additional supported regions where susceptibility genes are likely to be identified. Linkage meta-analysis has had less clear success for bipolar disorder based on a smaller dataset. Meta-analysis can guide the prioritization of regions for study, but proof of association requires biological confirmation of hypotheses about gene actions. Elucidation of causal mechanisms will require more comprehensive study of sequence variation in candidate genes, better statistical and meta-analytic methods to take all variation into account, and biological strategies for testing etiologic hypotheses.

Adolescent↗

Systematic reviews of medical evidence: the use of meta-analysis in obstetrics and gynecology.

OBJECTIVE: To review the technique of meta-analysis and its uses and limitations in obstetrics and gynecology. DATA SOURCES: We reviewed four major journals in obstetrics and gynecology (American Journal of Obstetrics and Gynecology, Fertility and Sterility, Journal of Reproductive Medicine, and Obstetrics & Gynecology). METHODS OF STUDY SELECTION: Journals were reviewed to determine frequency of meta-analysis as a method of systematic review in obstetrics and gynecology. We also summarized objectives and scientific guidelines for performing a meta-analysis. TABULATION, INTEGRATION, AND RESULTS: Meta-analysis is used with increased frequency in obstetrics and gynecology as a way of systematically reviewing medical evidence. This technique is an attempt to improve on traditional methods of narrative review by an expert and as a framework for evidence-based medicine and developing practice guidelines. By combining data from replicate studies, a meta-analysis can increase statistical power, more precisely estimate the typical effect size of treatment or risk factor, and attempt to resolve controversies in the medical literature. Meta-analysis is a retrospective look at data already collected and is therefore subject to the biases of all retrospective studies. CONCLUSIONS: The technique of meta-analysis requires all the scientific rigor of a randomized clinical trial with careful attention to study design, including a formal protocol for literature search strategies, quality assessment of candidate studies, specific inclusion and exclusion criteria, issues of sampling and publication bias, statistical tests of homogeneity, and sensitivity analysis.

Evidence-Based Medicine↗

Quantifying heterogeneity in a meta-analysis.

The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity.

Albumins↗

Haplotype analysis of VDR gene polymorphisms: a meta-analysis.

INTRODUCTION: Although many studies have addressed the relationship between multiple individual polymorphisms in the vitamin D receptor (VDR) gene and bone health, few have analyzed this data in terms of haplotypes. We performed a meta-analysis of studies with data on the BsmI, ApaI, and TaqI polymorphisms in order to (a) estimate haplotype frequencies, (b) determine linkage disequilibrium (LD), and (c) estimate the magnitude of the association between haplotypes and osteoporosis/bone mineral density (BMD). METHODS: Haplotypes were inferred using the expectation-maximization algorithm (EM); log-linear models were used to determine association with osteoporosis; and regression analysis with variance components was used to determine association with BMD. RESULTS: Our results indicate that the most common haplotype for the VDR gene, regardless of ethnicity, is baT, followed by BAt and bAT in Caucasians, and bAT and BaT in Asians. This indicates strong LD between the BsmI and TaqI polymorphisms. We demonstrate a gain in power when considering the haplotypes rather than the individual polymorphisms separately, i.e., although BsmI, ApaI, and TaqI were not significantly associated with osteoporosis on their own, the haplotypes Bat and BAt were significantly associated, with an OR of approximately 4. CONCLUSION: We have applied haplotype analysis to the VDR polymorphisms and bone measures. We also highlight a number of methodologic issues, including linkage disequilibrium, the robustness of the EM algorithm in this context, and the potential for exploring effect modification.

Bone Density↗

A meta-analysis of the relationship of child sexual abuse to HIV risk behavior among women.

OBJECTIVE: This study is a meta-analysis of the literature exploring the relationship between child sexual abuse (CSA) and HIV risk behavior among women. Four outcome variables were tested: unprotected sex; sex with multiple partners; sex trading; and adult sexual revictimization. METHOD: Forty-six studies met the inclusion criteria and were included in the analysis, and separate meta-analyses were performed for each of the four dependent variables described above. RESULTS: Using the correlation coefficient r as an effect size estimate, results indicate an average effect size of .05 for the unprotected sex meta-analysis (N = 16 studies), .13 for the sex with multiple partners meta-analysis (N = 23 studies), .12 for the sex trading meta-analysis (N = 23 studies), and .17 for the adult sexual revictimization meta-analysis (N = 21 studies). We conducted a test of three potential moderator variables (source of sample, definition of CSA based on type of contact, and definition of CSA based on maximum age of victim). Results did not support the hypothesis that these three variables explain a significant amount of variability in effect sizes with one exception: Studies that define CSA more broadly to include adolescent victims (e.g., victims up to 17 years of age) had larger and more homogenous effect sizes for the sex trading meta-analysis than those that defined CSA as having occurred at younger ages. CONCLUSIONS: These findings suggest a small positive relationship between CSA and subsequent HIV risk behavior among women that varies as a function of how CSA and HIV risk behavior are operationalized.

Adult↗

The Impact of Nutritional Status on Oral Health Outcomes and Management in Older Adults: A Systematic Review and Meta-Analysis.

OBJECTIVE: This systematic review and meta-analysis evaluated the relationship between nutritional status and the oral health of older adults (aged 75&#x2009;years or older). The PECO focus question was, 'What is the occurrence, association and impact of nutritional state on the oral health outcomes and its management in older adults?' METHODS: A comprehensive literature search was performed across MEDLINE (PubMed), Embase and the Cochrane Library. Publications up to April 2025 were considered, yielding 3324 records for initial screening. Quality assessment of the included studies predominantly revealed a low to moderate risk of bias. RESULTS: Eighty-three studies were included for data analysis. Meta-analyses demonstrated that older adults at risk of malnutrition had fewer teeth (SMD&#x2009;=&#x2009;-0.29; 95% CI: -0.46, -0.11; p&#x2009;=&#x2009;0.002). Those with <&#x2009;20 teeth and who were not rehabilitated with dentures were more likely to be malnourished (OR&#x2009;=&#x2009;4.00; 95% CI: 1.21, 13.18; p&#x2009;=&#x2009;0.02). Malnutrition was associated with self-reported chewing problems (OR&#x2009;=&#x2009;2.38; 95% CI: 1.74, 3.26; p&#x2009;<&#x2009;0.0001), swallowing problems (OR&#x2009;=&#x2009;3.18; 95% CI: 2.20, 4.61; p&#x2009;<&#x2009;0.0001) or dry mouth (OR&#x2009;=&#x2009;2.35; 95% CI: 1.91, 2.88; p&#x2009;<&#x2009;0.0001). Conversely, those with oral pain showed lower odds of malnutrition risk (OR&#x2009;=&#x2009;0.68; 95% CI: 0.52, 0.89; p&#x2009;=&#x2009;0.005). CONCLUSIONS: Fewer teeth, existing chewing or swallowing problems, dry mouth and the absence of removable dentures where needed, were associated with malnutrition in care-dependent older adults. The current lack of longitudinal studies and proof of causality for malnutrition affecting oral health outcomes underscores the need for further research to better clarify the complex relationship between oral health and nutrition in older populations. TRIAL REGISTRATION: PROSPERO Registration: CRD420251003549.

Humans↗

Meta-analysis for descriptive research.

Although nurses have begun to use meta-analysis, a review of the nursing literature demonstrates that its use has not been maximized. Meta-analysis can be employed to synthesize descriptive as well as experimental research, yet attention in nursing has focused almost exclusively on meta-analysis techniques for, and meta-analytic studies of, experimental research. Furthermore, nursing literature has emphasized use of the effect size index (d) rather than the correlation index (r); the latter may, in some cases, be the more suitable metric, particularly with meta-analysis of correlational studies. An argument is made for the value of meta-analysis as a technique for integrating descriptive research, and an overview of different meta-analytic approaches to data analysis using the correlational index with descriptive research is provided.

Humans↗

Meta-analysis: formulating, evaluating, combining, and reporting.

Meta-analysis involves combining summary information from related but independent studies. The objectives of a meta-analysis include increasing power to detect an overall treatment effect, estimation of the degree of benefit associated with a particular study treatment, assessment of the amount of variability between studies, or identification of study characteristics associated with particularly effective treatments. This article presents a tutorial on meta-analysis intended for anyone with a mathematical statistics background. Search strategies and review methods of the literature are discussed. Emphasis is focused on analytic methods for estimation of the parameters of interest. Three modes of inference are discussed: maximum likelihood; restricted maximum likelihood, and Bayesian. Finally, software for performing inference using restricted maximum likelihood and fully Bayesian methods are demonstrated. Methods are illustrated using two examples: an evaluation of mortality from prophylactic use of lidocaine after a heart attack, and a comparison of length of hospital stay for stroke patients under two different management protocols.

Anti-Arrhythmia Agents↗

Meta-analysis for dermatologists.

Meta-analysis is a relatively new statistical technique that is attracting a great deal of attention in the medical and social science literature. This technique is discussed in terms of its tenants, advantages, rudiments, and controversies.

Dermatology↗