ABSTRACT
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.
Subject(s)
Disease Models, Animal , Meta-Analysis as Topic , Research Design , Animals , HumansABSTRACT
BACKGROUND: The development of therapeutics is often characterized by promising animal research that fails to translate into clinical efficacy; this holds for the development of gene therapy in glioma. We tested the hypothesis that this is because of limitations in the internal and external validity of studies reporting the use of gene therapy in experimental glioma. METHOD: We systematically identified studies testing gene therapy in rodent glioma models by searching three online databases. The number of animals treated and median survival were extracted and studies graded using a quality checklist. We calculated median survival ratios and used random effects meta-analysis to estimate efficacy. We explored effects of study design and quality and searched for evidence of publication bias. RESULTS: We identified 193 publications using gene therapy in experimental glioma, including 6,366 animals. Overall, gene therapy improved median survival by a factor of 1.60 (95% CI 1.53-1.67). Study quality was low and the type of gene therapy did not account for differences in outcome. Study design characteristics accounted for a significant proportion of between-study heterogeneity. We observed similar findings in a data subset limited to the most common gene therapy. CONCLUSION: As the dysregulation of key molecular pathways is characteristic of gliomas, gene therapy remains a promising treatment for glioma. Nevertheless, we have identified areas for improvement in conduct and reporting of studies, and we provide a basis for sample size calculations. Further work should focus on genes of interest in paradigms recapitulating human disease. This might improve the translation of such therapies into the clinic.
ABSTRACT
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.
