Can Animal Models of Disease Reliably Inform Human Studies?

H. Bart van der Worp and colleagues discuss the controversies and possibilities of translating the results of animal experiments into human clinical trials

Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia

No single animal model is able to encompass all of the variables known to affect human ischemic stroke. This review highlights the major strengths and weaknesses of the most commonly used animal models of acute ischemic stroke in the context of matching model and experimental aim. Particular emphasis is placed on the relationships between outcome and underlying vascular variability, physiologic control, and use of models of comorbidity. The aim is to provide, for novice and expert alike, an overview of the key controllable determinants of experimental stroke outcome to help ensure the most effective application of animal models to translational research

A systematic review and meta-analysis of erythropoietin in experimental stroke

Erythropoietin (EPO) has shown promise as a neuroprotectant in animal models of ischemic stroke. EPO is thought not only to protect neurons from cell death, but also to promote regeneration after stroke. Here, we report a systematic review and meta-analysis of the efficacy of EPO in animal models of focal cerebral ischemia. Primary outcomes were infarct size and neurobehavioral outcome. Nineteen studies involving 346 animals for infarct size and 425 animals for neurobehavioral outcome met our inclusion criteria. Erythropoietin improved infarct size by 30.0% (95% CI: 21.3 to 38.8) and neurobehavioral outcome by 39.8% (33.7 to 45.9). Studies that randomized to treatment group or that blinded assessment of outcome showed lower efficacy. Erythropoietin was tested in animals with hypertension in no studies reporting infarct size and in 7.5% of the animals reporting neurobehavioral outcome. These findings show efficacy for EPO in experimental stroke, but when the impact of common sources of bias are considered, this efficacy falls, suggesting we may be overestimating its potential benefit. As common human co-morbidities may reduce therapeutic efficacy, broader testing to delineate the range of circumstances in which EPO works best would be beneficial

Randomisation, blinded outcome assessment, and sample size calculation in systematic reviews of animal studies.

a<p>Summarises the data of six systematic reviews of treatment strategies for acute ischemic stroke. There is an overlap of 18 publications between references <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000245#pmed.1000245-Sena1" target="_blank">[16]</a> and <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000245#pmed.1000245-VanderWorp2" target="_blank">[19]</a>.</p><p>ALS, amyotrophic lateral sclerosis; N/A, data not available; RDS, respiratory distress syndrome.</p

Four types of bias threatening internal validity.

<p>Adapted from <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000245#pmed.1000245-Juni1" target="_blank">[12]</a>,<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000245#pmed.1000245-Altman1" target="_blank">[13]</a>.</p