BackgroundThe DerSimonian and Laird approach (DL) is widely used for random effects meta-analysis, but this often results in inappropriate type I error rates. The method described by Hartung, Knapp, Sidik and Jonkman (HKSJ) is known to perform better when trials of similar size are combined. However evidence in realistic situations, where one trial might be much larger than the other trials, is lacking. We aimed to evaluate the relative performance of the DL and HKSJ methods when studies of different sizes are combined and to develop a simple method to convert DL results to HKSJ results.MethodsWe evaluated the performance of the HKSJ versus DL approach in simulated meta-analyses of 2–20 trials with varying sample sizes and between-study heterogeneity, and allowing trials to have various sizes, e.g. 25% of the trials being 10-times larger than the smaller trials. We also compared the number of “positive” (statistically significant at p < 0.05) findings using empirical data of recent meta-analyses with > = 3 studies of interventions from the Cochrane Database of Systematic Reviews.ResultsThe simulations showed that the HKSJ method consistently resulted in more adequate error rates than the DL method. When the significance level was 5%, the HKSJ error rates at most doubled, whereas for DL they could be over 30%. DL, and, far less so, HKSJ had more inflated error rates when the combined studies had unequal sizes and between-study heterogeneity. The empirical data from 689 meta-analyses showed that 25.1% of the significant findings for the DL method were non-significant with the HKSJ method. DL results can be easily converted into HKSJ results.ConclusionsOur simulations showed that the HKSJ method consistently results in more adequate error rates than the DL method, especially when the number of studies is small, and can easily be applied routinely in meta-analyses. Even with the HKSJ method, extra caution is needed when there are = <5 studies of very unequal sizes.

ObjectivesEvaluating the variation in the strength of the effect across studies is a key feature of meta-analyses. This variability is reflected by measures like τ2 or I2, but their clinical interpretation is not straightforward. A prediction interval is less complicated: it presents the expected range of true effects in similar studies. We aimed to show the advantages of having the prediction interval routinely reported in meta-analyses.DesignWe show how the prediction interval can help understand the uncertainty about whether an intervention works or not. To evaluate the implications of using this interval to interpret the results, we selected the first meta-analysis per intervention review of the Cochrane Database of Systematic Reviews Issues 2009–2013 with a dichotomous (n=2009) or continuous (n=1254) outcome, and generated 95% prediction intervals for them.ResultsIn 72.4% of 479 statistically significant (random-effects p<0.05) meta-analyses in the Cochrane Database 2009–2013 with heterogeneity (I2>0), the 95% prediction interval suggested that the intervention effect could be null or even be in the opposite direction. In 20.3% of those 479 meta-analyses, the prediction interval showed that the effect could be completely opposite to the point estimate of the meta-analysis. We demonstrate also how the prediction interval can be used to calculate the probability that a new trial will show a negative effect and to improve the calculations of the power of a new trial.ConclusionsThe prediction interval reflects the variation in treatment effects over different settings, including what effect is to be expected in future patients, such as the patients that a clinician is interested to treat. Prediction intervals should be routinely reported to allow more informative inferences in meta-analyses.

Introduction and hypothesisPelvic organ prolapse (POP) is a common condition with multifactorial etiology. The purpose of this systematic review was to provide an overview of literature on risk factors for POP and POP recurrence.MethodsPubMed and Embase were searched with “pelvic organ prolapse” combined with “recurrence” and combined with “risk factors,” with Medical Subject Headings and Thesaurus terms and text words variations until 4 August 2014, without language or publication date restrictions. Only cohort or cross-sectional studies carried out in western developed countries containing multivariate analyses and with a definition of POP based on anatomical references were included. POP recurrence had to be defined as anatomical recurrence after native tissue repair without mesh. Follow-up after surgery should have been at least 1 year. Articles were excluded if POP was not a separate entity or if it was unclear whether the outcome was primary POP or recurrence.ResultsPubMed and Embase revealed 2,988 and 4,449 articles respectively. After preselection, 534 articles were independently evaluated by two researchers, of which 15 met the selection criteria. In 10 articles on primary POP, 30 risk factors were investigated. Parity, vaginal delivery, age, and body mass index (BMI) were significantly associated in at least two articles. In 5 articles on POP recurrence, 29 risk factors were investigated. Only preoperative stage was significantly associated in at least two articles.ConclusionParity, vaginal delivery, age, and BMI are risk factors for POP and preoperative stage is a risk factor for POP recurrence.

Heterogeneity between small studies is larger than between larger studies. The large imprecision with which τ is estimated in a typical small-studies' meta-analysis is another reason for concern, and sensitivity analyses are recommended.

Background. Immunization of healthy volunteers by bites from Plasmodium falciparum–infected mosquitoes during chloroquine chemoprophylaxis (hereafter, chemoprophylaxis and sporozoites [CPS] immunization) induces sterile protection against malaria. CPS-induced protection is mediated by immunity against pre-erythrocytic stages, presumably at least partially by cytotoxic cellular responses. We therefore aimed to investigate the association of CPS-induced cytotoxic T-cell markers with protection.Methods. In a double-blind randomized controlled trial, we performed dose titration of CPS immunization followed by homologous challenge infection in 29 subjects. Immune responses were assessed by in vitro restimulation of peripheral blood mononuclear cells and flow cytometry.Results. Dose-dependent complete protection was obtained in 4 of 5 volunteers after immunization with bites from 45 P. falciparum–infected mosquitoes, in 8 of 9 volunteers with bites from 30, and in 5 of 10 volunteers with bites from 15 (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.5–17). Completely protected subjects had significantly higher proportions of CD4 T cells expressing the degranulation marker CD107a (OR, 8.4; 95% CI, 1.5–123; P = .011) and CD8 cells producing granzyme B (OR, 11; 95% CI, 1.9–212; P = .004) after P. falciparum restimulation.Conclusions. These data underline the efficiency of CPS immunization to induce sterile protection and support a possible role for cytotoxic CD4 and CD8 T-cell responses in pre-erythrocytic immunity.Clinical Trials Registration. NCT01218893.

Meta-analyses are increasingly used for synthesis of evidence from biomedical research, and often include an assessment of publication bias based on visual or analytical detection of asymmetry in funnel plots. We studied the influence of different normalisation approaches, sample size and intervention effects on funnel plot asymmetry, using empirical datasets and illustrative simulations. We found that funnel plots of the Standardized Mean Difference (SMD) plotted against the standard error (SE) are susceptible to distortion, leading to overestimation of the existence and extent of publication bias. Distortion was more severe when the primary studies had a small sample size and when an intervention effect was present. We show that using the Normalised Mean Difference measure as effect size (when possible), or plotting the SMD against a sample size-based precision estimate, are more reliable alternatives. We conclude that funnel plots using the SMD in combination with the SE are unsuitable for publication bias assessments and can lead to false-positive results.

In research aimed at improving human health care, animal studies still play a crucial role, despite political and scientific efforts to reduce preclinical experimentation in laboratory animals. In animal studies, the results and their interpretation are not always straightforward, as no single study is executed perfectly in all steps. There are several possible sources of bias, and many animal studies are replicates of studies conducted previously. Use of meta-analysis to combine the results of studies may lead to more reliable conclusions and a reduction of unnecessary duplication of animal studies. In addition, due to the more exploratory nature of animal studies as compared to clinical trials, meta-analyses of animal studies have greater potential in exploring possible sources of heterogeneity.There is an abundance of literature on how to perform meta-analyses on clinical data. Animal studies, however, differ from clinical studies in some aspects, such as the diversity of animal species studied, experimental design, and study characteristics. In this paper, we will discuss the main principles and practices for meta-analyses of experimental animal studies.

trialregister.nl NTR1866.