The Road to Reproducibility in Animal Research

Jilka, Robert L.

doi:10.1002/jbmr.2881

Cited by 28 publications

(18 citation statements)

References 14 publications

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“…Recently, some landmark journals made additional efforts to counter this trend. In an attempt to increase the adherence to ethical use of animals and reporting, some journals have proposed a simplified, and easier to fill, version of the ARRIVE guidelines [ 73 , 74 ], others have developed their own compulsory and comprehensive animal ethics checklist [ 75 ], or organized discussion forums to address these issues [ 76 ]. It is worth noting that reviewers are usually chosen for their expertise in the scientific field of the study, and may lack the information, knowledge (or motivation) to assess whether a study is ethically sound beyond usual superficial statements.…”

Section: Discussionmentioning

confidence: 99%

Impact of Stroke Therapy Academic Industry Roundtable (STAIR) Guidelines on Peri-Anesthesia Care for Rat Models of Stroke: A Meta-Analysis Comparing the Years 2005 and 2015

Thomas

Detilleux

Flecknell³

et al. 2017

PLoS ONE

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Numerous studies using rats in stroke models have failed to translate into successful clinical trials in humans. The Stroke Therapy Academic Industry Roundtable (STAIR) has produced guidelines on the rodent stroke model for preclinical trials in order to promote the successful translation of animal to human studies. These guidelines also underline the importance of anaesthetic and monitoring techniques. The aim of this literature review is to document whether anaesthesia protocols (i.e., choice of agents, mode of ventilation, physiological support and monitoring) have been amended since the publication of the STAIR guidelines in 2009. A number of articles describing the use of a stroke model in adult rats from the years 2005 and 2015 were randomly selected from the PubMed database and analysed for the following parameters: country where the study was performed, strain of rats used, technique of stroke induction, anaesthetic agent for induction and maintenance, mode of intubation and ventilation, monitoring techniques, control of body temperature, vascular accesses, and administration of intravenous fluids and analgesics. For each parameter (stroke, induction, maintenance, monitoring), exact chi-square tests were used to determine whether or not proportions were significantly different across year and p values were corrected for multiple comparisons. An exact p-test was used for each parameter to compare the frequency distribution of each value followed by a Bonferroni test. The level of significant set at < 0.05. Results show that there were very few differences in the anaesthetic and monitoring techniques used between 2005 and 2015. In 2015, significantly more studies were performed in China and significantly fewer studies used isoflurane and nitrous oxide. The most striking finding is that the vast majority of all the studies from both 2005 and 2015 did not report the use of ventilation; measurement of blood gases, end-tidal carbon dioxide concentration, or blood pressure; or administration of intravenous fluids or analgesics. The review of articles published in 2015 showed that the STAIR guidelines appear to have had no effect on the anaesthetic and monitoring techniques in rats undergoing experimental stroke induction, despite the publication of said guidelines in 2009.

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Section: Discussionmentioning

confidence: 99%

Impact of Stroke Therapy Academic Industry Roundtable (STAIR) Guidelines on Peri-Anesthesia Care for Rat Models of Stroke: A Meta-Analysis Comparing the Years 2005 and 2015

Thomas

Detilleux

Flecknell³

et al. 2017

PLoS ONE

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“…Anhedonia, which is the loss of sensitivity to reward and related to depression, was determined by the sucrose preference test (Romano et al, 2015). In light of recently published concerns about reproducibility of animal research (Pusztai et al, 2013; Jilka, 2016) we adopted Noldus video-tracking for all the behavioral assays reported herein. This methodology avoids experimenter bias and increases accuracy of the collected data.…”

Section: Introductionmentioning

confidence: 99%

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

Coronas‐Samano

Baker

Tan

et al. 2016

Front. Aging Neurosci.

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Insufficient advances in the development of effective therapeutic treatments of sporadic Alzheimer's Disease (sAD) to date are largely due to the lack of sAD-relevant animal models. While the vast majority of models do recapitulate AD's hallmarks of plaques and tangles by virtue of tau and/or beta amyloid overexpression, these models do not reflect the fact that in sAD (unlike familial AD) these genes are not risk factors per se and that other mechanisms like oxidative stress, metabolic dysregulation and inflammation play key roles in AD etiology. Here we characterize and propose the Fus1 KO mice that lack a mitochondrial protein Fus1/Tusc2 as a new sAD model. To establish sAD relevance, we assessed sAD related deficits in Fus1 KO and WT adult mice of 4–5 months old, the equivalent human age when the earliest cognitive and olfactory sAD symptoms arise. Fus1 KO mice showed oxidative stress (increased levels of ROS, decreased levels of PRDX1), disruption of metabolic homeostasis (decreased levels of ACC2, increased phosphorylation of AMPK), autophagy (decreased levels of LC3-II), PKC (decreased levels of RACK1) and calcium signaling (decreased levels of Calb2) in the olfactory bulb and/or hippocampus. Mice were behaviorally tested using objective and accurate video tracking (Noldus), in which Fus1 KO mice showed clear deficits in olfactory memory (decreased habituation/cross-habituation in the short and long term), olfactory guided navigation memory (inability to reduce their latency to find the hidden cookie), spatial memory (learning impairments on finding the platform in the Morris water maze) and showed more sleep time during the diurnal cycle. Fus1 KO mice did not show clear deficits in olfactory perception (cross-habituation), association memory (passive avoidance) or in species-typical behavior (nest building) and no increased anxiety (open field, light-dark box) or depression/anhedonia (sucrose preference) at this relatively young age. These neurobehavioral deficits of the Fus1 KO mice at this relatively young age are highly relevant to sAD, making them suitable for effective research on pharmacological targets in the context of early intervention of sAD.

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“…Lack of rigor and reproducibility in research has been well documented and is the subject of initiatives at the National Institutes of Health . This problem is probably most important in preclinical studies, including studies of animal disease models, highlighting the value of harmonization of reagents and assay protocols, quality control systems, and consensus best practices for experimental design, data analysis, and reporting . The registration of clinical trials via ClinicalTrials.gov and their subsequent publication may contribute to reducing publication bias for clinical studies.…”

Section: How To Approach Mbmamentioning

confidence: 99%

“…11 This problem is probably most important in preclinical studies, including studies of animal disease models, highlighting the value of harmonization of reagents and assay protocols, quality control systems, and consensus best practices for experimental design, data analysis, and reporting. [12][13][14][15] The registration of clinical trials via ClinicalTrials.…”

Section: Illustrative Applications: Reference 21mentioning

confidence: 99%

Model‐Based Meta‐Analysis: Optimizing Research, Development, and Utilization of Therapeutics Using the Totality of Evidence

Upreti

Venkatakrishnan

2019

Clin Pharma and Therapeutics

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Model‐based meta‐analysis (MBMA) is a valuable component of the quantitative pharmacology toolkit for model‐informed drug discovery and development. It enables principled decision making with a totality of evidence mindset through integration of internal and external data across multiple dimensions (e.g., targets/mechanisms, molecules/drugs, doses/regimens, diseases/indications, populations, endpoints, and clinical trial designs). MBMA distinguishes itself from traditional meta‐analysis by infusing pharmacologic plausibility into the statistical rigor that typifies meta‐analytic data integration. This is possible through mechanism‐informed formulation of pharmacologically inspired cause–effect and dose‐response relationships, time course of treatment effects, and interrelationships between proximal and distal outcomes of modulation of disease biology and pathophysiology. In this review, we offer a question‐based approach to enhance appreciation of the value of MBMA across the continuum from drug discovery and translational research through clinical development, comparative effectiveness research, and postapproval optimization of therapeutics using illustrative examples across therapeutic areas.

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The Road to Reproducibility in Animal Research

Cited by 28 publications

References 14 publications

Impact of Stroke Therapy Academic Industry Roundtable (STAIR) Guidelines on Peri-Anesthesia Care for Rat Models of Stroke: A Meta-Analysis Comparing the Years 2005 and 2015

Impact of Stroke Therapy Academic Industry Roundtable (STAIR) Guidelines on Peri-Anesthesia Care for Rat Models of Stroke: A Meta-Analysis Comparing the Years 2005 and 2015

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

Model‐Based Meta‐Analysis: Optimizing Research, Development, and Utilization of Therapeutics Using the Totality of Evidence

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