Meta-analyses of data from human studies are invaluable resources in the life sciences and the methods to conduct these are well documented. Similarly there are a number of benefits in conducting meta-analyses on data from animal studies; they can be used to inform clinical trial design, or to try and explain discrepancies between preclinical and clinical trial results. However there are inherit differences between animal and human studies and so applying the same techniques for the meta-analysis of preclinical data is not straightforward. For example preclinical studies are frequently small and there is often substantial heterogeneity between studies. This may have an impact on both the method of calculating an effect size and the method of pooling data. Here we describe a practical guide for the meta-analysis of data from animal studies including methods used to explore sources of heterogeneity.

The reliability of experimental findings depends on the rigour of experimental design. Here we show limited reporting of measures to reduce the risk of bias in a random sample of life sciences publications, significantly lower reporting of randomisation in work published in journals of high impact, and very limited reporting of measures to reduce the risk of bias in publications from leading United Kingdom institutions. Ascertainment of differences between institutions might serve both as a measure of research quality and as a tool for institutional efforts to improve research quality.

The prevalence, associations, and natural history of pain in multiple sclerosis (MS) are poorly understood. The objective of this work was to study the prevalence of pain syndromes in MS both cross-sectionally, and longitudinally during the MS disease course. We systematically identified prospective studies detailing pain prevalence in definite MS. We used pooled prevalence estimates, explored heterogeneity using meta-regression, and analysed prevalence during the disease course using both estimates at disease milestones and longitudinal studies. Twenty-eight articles (7101 subjects) describing overall pain, or pain syndromes, met inclusion criteria. Pooled overall pain prevalence (17 studies, 5319 subjects) was 63% (95% confidence interval [CI] 55-70%). Marked heterogeneity in this estimate was not significantly explained by selected study design variables (use of outpatient sample, timeframe prior to study over which pain was assessed) or sample demographic variables (mean Expanded Disability Status Scale, mean disease duration, proportion of female sex, and proportion with progressive MS). We quantified prevalence of headache (43%; 95% CI 33-52%), neuropathic extremity pain (26%; 95% CI 7-53%), back pain (20%; 95% CI 13-28%), painful spasms (15%; 95% CI 8.5-23%), Lhermitte sign (16%; 95% CI 10-25%), and trigeminal neuralgia (3.8%; 95% CI 2-6%) in included studies. Prevalence of pain at MS disease milestones (prior to onset, at onset, and at relapse) and during longitudinal follow-up was poorly described. Pain is common in MS, as are specific pain syndromes. The clinical associations and natural history of pain in MS require clarification. Future study could be enhanced by standardised study design.

EAE has proven to be a valuable model in elucidating pathogenesis as well as identifying candidate therapies for multiple sclerosis. However, there is an inconsistent application of measures to limit bias that could be addressed by adopting methodological best practice in study design. Our analysis provides an estimate of sample size required for different levels of power in future studies and suggests a number of interventions for which there are substantial animal data supporting efficacy.

Pain can significantly decrease the quality of life of patients with advanced cancer. Current treatment strategies often provide inadequate analgesia and unacceptable side effects. Animal models of bone cancer pain are used in the development of novel pharmacological approaches. Here we conducted a systematic review and meta-analysis of publications describing in vivo modelling of bone cancer pain in which behavioural, general health, macroscopic, histological, biochemical, or electrophysiological outcomes were reported and compared to appropriate controls. In all, 150 publications met our inclusion criteria, describing 38 different models of bone cancer pain. Reported methodological quality was low; only 31% of publications reported blinded assessment of outcome, and 11% reported random allocation to group. No publication reported a sample size calculation. Studies that reported measures to reduce bias reported smaller differences in behavioural outcomes between tumour-bearing and control animals, and studies that presented a statement regarding a conflict of interest reported larger differences in behavioural outcomes. Larger differences in behavioural outcomes were reported in female animals, when cancer cells were injected into either the tibia or femur, and when MatLyLu prostate or Lewis Lung cancer cells were used. Mechanical-evoked pain behaviours were most commonly reported; however, the largest difference was observed in spontaneous pain behaviours. In the spinal cord astrocyte activation and increased levels of Substance P receptor internalisation, c-Fos, dynorphin, tumor necrosis factor-α and interleukin-1β have been reported in bone cancer pain models, suggesting several potential therapeutic targets. However, the translational impact of animal models on clinical pain research could be enhanced by improving methodological quality.

Background There are reports of developmental and reproductive health effects associated with the widely used biocide triclosan. Objective Apply the Navigation Guide systematic review methodology to answer the question: Does exposure to triclosan have adverse effects on human development or reproduction? Methods We applied the first 3 steps of the Navigation Guide methodology: 1) Specify a study question, 2) Select the evidence, and 3) Rate quality and strength of the evidence. We developed a protocol, conducted a comprehensive search of the literature, and identified relevant studies using pre-specified criteria. We assessed the number and type of all relevant studies. We evaluated each included study for risk of bias and rated the quality and strength of the evidence for the selected outcomes. We conducted a meta-analysis on a subset of suitable data. Results We found 4,282 potentially relevant records, and 81 records met our inclusion criteria. Of the more than 100 endpoints identified by our search, we focused our evaluation on hormone concentration outcomes, which had the largest human and non-human mammalian data set. Three human studies and 8 studies conducted in rats reported thyroxine levels as outcomes. The rat data were amenable to meta-analysis. Because only one of the human thyroxine studies quantified exposure, we did not conduct a meta-analysis of the human data. Through meta-analysis of the data for rats, we estimated for prenatal exposure a 0.09% (95% CI: −0.20, 0.02) reduction in thyroxine concentration per mg triclosan/kg-bw in fetal and young rats compared to control. For postnatal exposure we estimated a 0.31% (95% CI: −0.38, −0.23) reduction in thyroxine per mg triclosan/kg-bw, also compared to control. Overall we found low to moderate risk of bias across the human studies and moderate to high risk of bias across the non-human studies, and assigned a “moderate/low” quality rating to the body of evidence for human thyroid hormone alterations and a “moderate” quality rating to the body of evidence for non-human thyroid hormone alterations. Conclusion Based on this application of the Navigation Guide systematic review methodology, we concluded that there was “sufficient” non-human evidence and “inadequate” human evidence of an association between triclosan exposure and thyroxine concentrations, and consequently, triclosan is “possibly toxic” to reproductive and developmental health. Thyroid hormone disruption is an upstream indicator of developmental toxicity. Additional endpoints may be identified as being of equal or greater concern as other data are developed or evaluated.

Background:Malignant glioma is an aggressive tumour commonly associated with a dismal outcome despite optimal surgical and radio-chemotherapy. Since 2005 temozolomide has been established as first-line chemotherapy. We investigate the role of in vivo glioma models in predicting clinical efficacy.Methods:We searched three online databases to systematically identify publications testing temozolomide in animal models of glioma. Median survival and number of animals treated were extracted and quality was assessed using a 12-point scale; random effects meta-analysis was used to estimate efficacy. We analysed the impact of study design and quality and looked for evidence of publication bias.Results:We identified 60 publications using temozolomide in models of glioma, comprising 2443 animals. Temozolomide prolonged survival by a factor of 1.88 (95% CI 1.74–2.03) and reduced tumour volume by 50.4% (41.8–58.9) compared with untreated controls. Study design characteristics accounted for a significant proportion of between-study heterogeneity, and there was evidence of a significant publication bias.Conclusion:These data reflect those from clinical trials in that temozolomide improves survival and reduces tumour volume, even after accounting for publication bias. Experimental in vivo glioma studies of temozolomide differ from those of other glioma therapies in their consistent efficacy and successful translation into clinical medicine.

Rationale:In regenerative therapy for ischemic heart disease, use of both autologous and allogeneic stem cells has been investigated. Autologous cell can be applied without immunosuppression, but availability is restricted, and cells have been exposed to risk factors and aging. Allogeneic cell therapy enables preoperative production of potent cell lines and immediate availability of cell products, allowing off-the-shelf therapy. It is unknown which cell source is preferred with regard to improving cardiac function.Objective: We performed a meta-analysis of preclinical data of cell therapy for ischemic heart disease. Methods and Results:We conducted a systematic literature search to identify publications describing controlled preclinical trials of unmodified stem cell therapy in large animal models of myocardial ischemia. Data from 82 studies involving 1415 animals showed a significant improvement in mean left ventricular ejection fraction in treated compared with control animals (8.3%, 95% confidence interval, 7.1-9.5; P<0.001). Meta-regression revealed a similar difference in left ventricular ejection fraction in autologous (8.8%, 95% confidence interval, 7.3-10.3; n=981) and allogeneic (7.3%, 95% confidence interval, 4.4-10.2, n=331; P=0.3) cell therapies. Conclusions: Autologous and allogeneic cell therapy for ischemic heart disease show a similar improvement in