Exam (elaborations) Explore Bristol Research0097

Reporting animal research: Explanation and Elaboration for the ARRIVE guidelines 2019 Nathalie Percie du Sert1 , Amrita Ahluwalia2 , Sabina Alam3 , Marc T. Avey4 , Monya Baker5 , William J. Browne6 , Alejandra Clark7 , Innes C. Cuthill6 , Ulrich Dirnagl8 , Michael Emerson9 , Paul Garner10, Stephen T. Holgate11, David W. Howells12 , Viki Hurst1 , Natasha A. Karp13, Katie Lidster1 , Catriona J. MacCallum14, Malcolm Macleod15, Esther J Pearl1 , Ole Petersen16, Frances Rawle17, Penny Reynolds18, Kieron Rooney19, Emily S. Sena 15, Shai D. Silberberg20, Thomas Steckler21, Hanno Würbel22 1. NC3Rs, UK 2. Queen Mary University of London, UK 3. Taylor & Francis Group, UK 4. ICF, USA 5. Nature, USA 6. University of Bristol, UK 7. PLOS ONE, UK 8. Universitätsmedizin Berlin, Germany 9. Imperial College London, UK 10.Liverpool School of Tropical Medicine, UK 11.University of Southampton, UK 12.University of Tasmania, Australia 13.Data Sciences & Quantitative Biology, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, UK 14.Hindawi Ltd, UK 15.Centre for Clinical Brain Sciences, University of Edinburgh, UK 16.Cardiff University, UK 17.Medical Research Council, UK 18.University of Florida, USA 19.University of Sydney, Australia 20.National Institute of Neurological Disorders and Stroke, USA 21.Janssen Pharmaceutica NV, Belgium 22.University of Bern, Switzerland Abstract Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting are vital to this process; it allows readers to assess the reliability of the findings, and repeat or build upon the work of other researchers. The NC3Rs developed the ARRIVE guidelines in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of the ARRIVE guidelines on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This Explanation and Elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2019, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature. under a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use bioRxiv preprint doi: 2 Introduction Transparent and accurate reporting is essential to improve the reproducibility of scientific research; it enables others to scrutinise the methodological rigour of the studies, assess how reliable the findings are, and repeat or build upon the work. However, evidence shows that the majority of publications fail to include key information and there is significant scope to improve the reporting of studies involving animal research [1-4]. To that end, the NC3Rs published the ARRIVE guidelines in 2010. The guidelines are a checklist of information to include in a manuscript to ensure that publications contain enough information to add to the knowledge base [5]. The guidelines have received widespread endorsement from the scientific community and are currently recommended by more than a thousand journals, with further endorsement from research funders, universities and learned societies worldwide. Studies measuring the impact of ARRIVE on the quality of reporting have produced mixed results [6-11] and there is evidence that in vivo scientists are not sufficiently aware of the importance of reporting the information covered in the guidelines, and fail to appreciate the relevance to their work or their research field [12]. As a new international working group – the authors of this publication, we have revised the guidelines to update them and facilitate their uptake; the ARRIVE guidelines 2019 are published alongside this paper [13]. We have updated the recommendations in line with current best practice, reorganised the information and classified the items into two sets. The ARRIVE Essential 10 constitute the minimum reporting requirement and the Recommended Set provides further context to the study described. The two sets help authors, journal staff, editors and reviewers use the guidelines in practice, and allow a pragmatic implementation with an initial focus on the most critical issues. Once the Essential 10 are consistently reported in manuscripts, items from the Recommended Set can be added to journal requirements over time until all 21 items are routinely reported in all manuscripts. Full methodology for the revision and the allocation of items into sets is described in the accompanying publication [13]. A key aspect of the revision was to develop this Explanation and Elaboration document to provide background and rationale for each of the 21 items of ARRIVE 2019. Here we present additional guidance for each item and subitem, explain the importance of reporting this information in manuscripts that describe animal research, elaborate on what to report, and provide supporting evidence. Each subitem is also illustrated with examples of good reporting from the published literature. Box 1: Glossary Bias: Introduction of a systematic error in the estimated effect of an intervention, caused by inadequacies in the design, conduct, or analysis of an experiment. Effect size: Quantitative measure that estimates the magnitude of differences between groups, or relationships between variables. Experimental unit: Biological entity subjected to an intervention independently of all other units, such that it is possible to assign any two experimental units to different treatment groups. External validity: Extent to which the results of an animal experiment provide a correct basis for generalisations to other populations of animals (including humans) and/or other environmental conditions. False positive: Statistically significant result obtained by chance when the effect being investigated does not exist. False negative: Non-statistically significant result obtained when the effect being investigated genuinely exists. Independent variable of interest: Factor that a researcher manipulates within a controlled environment in order to test its impact on the outcome measured. Also known as: predictor variable, factor of interest. Internal validity: Refers to the rigour of the study design and statistical analysis to isolate cause and effect, and attribute the effect observed to manipulation of the independent variable of interest. In an experiment with high internal validity, sources of bias and chance observations are minimised. In an experiment with low internal validity, the effect may be caused by bias, chance and other nuisance variables rather than the independent variable(s) of interest. under a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use bioRxiv preprint doi: 3 Null and alternative hypotheses: The null hypothesis (H0) refers to the postulate that the response being measured is unaffected by the experimental manipulation being tested. The alternative hypothesis (H1) refers to the postulate that manipulating the independent variable of interest has an effect on the response measured. Nuisance variable: Sources of variability or conditions that could potentially bias results. Also known as: confounding factor, confounding variable Outcome measure: Any variable recorded during a study to assess the effects of a treatment or experimental intervention. Also known as: dependent variable, response variable Power: Probability that a test of significance will detect an effect (i.e. a deviation from the null hypothesis), if an effect exists (i.e. true positive result). Sample size: Number of experimental units per group, also referred to as N number. Definitions adapted from [14, 15] and placed in the context of animal research. 1. ARRIVE Essential 10 The ARRIVE Essential 10 (Box 2) constitute the minimum reporting requirement, to ensure that reviewers and readers can assess the reliability of the findings presented. There is no ranking within the set, items are presented in a logical order. Box 2: ARRIVE Essential 10 1. Study design 2. Sample size 3. Inclusion and exclusion criteria 4. Randomisation 5. Blinding 6. Outcome measures 7. Statistical methods 8. Experimental animals 9. Experimental procedures 10. Results Item 1. Study design For each experiment, provide brief details of study design including: 1a. The groups being compared, including control groups. If no control group has been used, the rationale should be stated. Explanation The choice of control or comparator group is dependent on the experimental objective. Negative controls are used to determine if a difference between groups is caused by the intervention (e.g. wild-type animals vs genetically modified animals, placebo vs active treatment, sham surgery vs surgical intervention). Positive controls can be used to support the interpretation of negative results or determine if an expected effect is detectable. It may not be necessary to include a separate control with no active treatment if, for example, the experiment aims to compare a treatment administered by different methods (e.g. intraperitoneal administration vs. oral gavage), or animals that are used as their own control in a longitudinal study. A pilot study, such as one designed to test the feasibility of a procedure might also not require a control group. under a CC0 license. author/funder. This article is a US Government wor