BackgroundSystematic Reviews (SRs) of experimental animal studies are not yet common practice, but awareness of the merits of conducting such SRs is steadily increasing. As animal intervention studies differ from randomized clinical trials (RCT) in many aspects, the methodology for SRs of clinical trials needs to be adapted and optimized for animal intervention studies. The Cochrane Collaboration developed a Risk of Bias (RoB) tool to establish consistency and avoid discrepancies in assessing the methodological quality of RCTs. A similar initiative is warranted in the field of animal experimentation.MethodsWe provide an RoB tool for animal intervention studies (SYRCLE’s RoB tool). This tool is based on the Cochrane RoB tool and has been adjusted for aspects of bias that play a specific role in animal intervention studies. To enhance transparency and applicability, we formulated signalling questions to facilitate judgment.ResultsThe resulting RoB tool for animal studies contains 10 entries. These entries are related to selection bias, performance bias, detection bias, attrition bias, reporting bias and other biases. Half these items are in agreement with the items in the Cochrane RoB tool. Most of the variations between the two tools are due to differences in design between RCTs and animal studies. Shortcomings in, or unfamiliarity with, specific aspects of experimental design of animal studies compared to clinical studies also play a role.ConclusionsSYRCLE’s RoB tool is an adapted version of the Cochrane RoB tool. Widespread adoption and implementation of this tool will facilitate and improve critical appraisal of evidence from animal studies. This may subsequently enhance the efficiency of translating animal research into clinical practice and increase awareness of the necessity of improving the methodological quality of animal studies.

Collecting and analysing all available literature before starting an animal experiment is important and it is indispensable when writing a systematic review (SR) of animal research. Writing such review prevents unnecessary duplication of animal studies and thus unnecessary animal use (Reduction). One of the factors currently impeding the production of ‘high-quality’ SRs in laboratory animal science is the fact that searching for all available literature concerning animal experimentation is rather difficult. In order to diminish these difficulties, we developed a search filter for PubMed to detect all publications concerning animal studies. This filter was compared with the method most frequently used, the PubMed Limit: Animals, and validated further by performing two PubMed topic searches. Our filter performs much better than the PubMed limit: it retrieves, on average, 7% more records. Other important advantages of our filter are that it also finds the most recent records and that it is easy to use. All in all, by using our search filter in PubMed, all available literature concerning animal studies on a specific topic can easily be found and assessed, which will help in increasing the scientific quality and thereby the ethical validity of animal experiments.

Systematic reviews are generally regarded by professionals in the field of evidence-based medicine as the highest level of medical evidence, and they are already standard practice for clinical studies. However, they are not yet widely used nor undertaken in the field of animal experimentation, even though there is a lot to be gained from the process. Therefore, a gold standard publication checklist (GSPC) for animal studies is presented in this paper. The items on the checklist have been selected on the basis of a literature analysis and the resulting scientific evidence that these factors are decisive in determining the outcome of animal studies. In order to make future systematic reviews and meta-analyses of animal studies possible, to allow others to replicate and build on work previously published, diminish the number of animals needed in animal experimentation (reduction), improve animal welfare (refinement) and, above all, improve the quality of scientific papers on animal experimentation, this publication checklist needs to be used and followed. We have discussed and optimised this GSPC through feedback from interviews with experts in the field of animal experimentation. From these interviews, it became clear that scientists will adopt this GSPC when journals demand it. The GSPC was compared with the current instructions for authors from nine different journals, selected on the basis that they featured a high number of publications on animal studies. In general, the journals' demands for the description of the animal studies are so limited that it is not possible to repeat the studies, let alone carry out a systematic review. By using the GSPC for animal studies, the quality of scientific papers will be improved. The use of the GSPC and the concomitant improvement in the quality of scientific papers will also contribute to decreased variation and increased standardisation and, as a consequence, a reduction in the numbers of animals used and a more reliable outcome of animal studies. It is of major importance that journal editors become convinced of and adopt these recommendations, because only then will scientists follow these guidelines to the full extent.

Systematic reviews are an important method to support evidencebased decisions in healthcare (research).Although not yet as common as clinical systematic reviews, the number of systematic reviews of animal studies has been increasing steadily in recent years. An important method to promote high-quality systematic reviews is to pre-specify the review methodology in a protocol, before the conduct of the systematic review itself. In contrast to clinical systematic reviews, a standard protocol format for systematic reviews of animal studies is not yet available. Here, we present a protocol format tailored to the preparation, registration and publication of systematic reviews of animal intervention studies (i.e. systematic reviews of animal experiments studying the efficacy and/or safety of interventions intended for use in human patients). In analogy to the Cochrane review protocol, the format helps authors predefine the methodological approach of their systematic review, from research question to data synthesis. We recommend that authors prospectively complete and agree on the protocol, and register and/or publish it to allow feedback on the proposed methodology and to avoid the introduction of bias during the review process. Opportunities for obtaining feedback, and for registration and publication of review protocols are also discussed.

Ischemic preconditioning (IPC) is a potent renoprotective strategy which has not yet been translated successfully into clinical practice, in spite of promising results in animal studies. We performed a unique systematic review and meta-analysis of animal studies to identify factors modifying IPC efficacy in renal ischemia/reperfusion injury (IRI), in order to enhance the design of future (clinical) studies. An electronic literature search for animal studies on IPC in renal IRI yielded fifty-eight studies which met our inclusion criteria. We extracted data for serum creatinine, blood urea nitrogen and histological renal damage, as well as study quality indicators. Meta-analysis showed that IPC reduces serum creatinine (SMD 1.54 [95%CI 1.16, 1.93]), blood urea nitrogen (SMD 1.42 [95% CI 0.97, 1.87]) and histological renal damage (SMD 1.12 [95% CI 0.89, 1.35]) after IRI as compared to controls. Factors influencing IPC efficacy were the window of protection (<24 h = early vs. ≥24 h = late) and animal species (rat vs. mouse). No difference in efficacy between local and remote IPC was observed. In conclusion, our findings show that IPC effectively reduces renal damage after IRI, with higher efficacy in the late window of protection. However, there is a large gap in study data concerning the optimal window of protection, and IPC efficacy may differ per animal species. Moreover, current clinical trials on RIPC may not be optimally designed, and our findings identify a need for further standardization of animal experiments.

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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.