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Over the last two decades, awareness of the negative repercussions of flaws in the planning, conduct and reporting of preclinical research involving experimental animals has been growing. Several initiatives have set out to increase transparency and internal validity of preclinical studies, mostly publishing expert consensus and experience. While many of the points raised in these various guidelines are identical or similar, they differ in detail and rigour. Most of them focus on reporting, only few of them cover the planning and conduct of studies. The aim of this systematic review is to identify existing experimental design, conduct, analysis and reporting guidelines relating to preclinical animal research. A systematic search in PubMed, Embase and Web of Science retrieved 13 863 unique results. After screening these on title and abstract, 613 papers entered the full-text assessment stage, from which 60 papers were retained. From these, we extracted unique 58 recommendations on the planning, conduct and reporting of preclinical animal studies. Sample size calculations, adequate statistical methods, concealed and randomised allocation of animals to treatment, blinded outcome assessment and recording of animal flow through the experiment were recommended in more than half of the publications. While we consider these recommendations to be valuable, there is a striking lack of experimental evidence on their importance and relative effect on experiments and effect sizes.

Latent growth modeling approaches, such as growth mixture models, are used to identify meaningful groups or classes of individuals in a larger heterogeneous population. But when applied to multivariate repeated measures computational problems are likely, due to the high dimension of the joint distribution of the random effects in these mixed-effects models. This article proposes a cluster algorithm for multivariate repeated data, using pseudo-likelihood and ideas based on k-means clustering, to reveal homogenous subgroups. The algorithm was demonstrated on an electro-encephalogram dataset set quantifying the effect of psychoactive compounds on the brain activity in rats. peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=lbps20 ispartof: Journal of Biopharmaceutical Statistics vol:26 issue:4 pages:725-741 ispartof: location:England status: published

Objective Within the last years, there has been growing awareness of the negative repercussions of unstandardized planning, conduct and reporting of preclinical and biomedical research. Several initiatives have set the aim of increasing validity and reliability in reporting of studies and publications, and publishers have formed similar groups. Additionally, several groups of experts across the biomedical spectrum have published experience and opinion-based guidelines and guidance on potential standardized reporting. While all these guidelines cover reporting of experiments, an important step prior to this should be rigours planning and conduction of studies. The aim of this systematic review is to identify and harmonize existing experimental design, conduct and analysis guidelines relating to internal validity and reproducibility of preclinical animal research. The review will also identify literature describing risks of bias pertaining to the design, conduct and analysis of preclinical biomedical research. Search strategy PubMed, Embase and Web of Science will be searched systematically to identify guidelines published in English language in peer-reviewed journals before January 2018 (box 1). All articles or systematic reviews in English language that describe or review guidelines on the internal validity and reproducibility of animal studies will be included. Google search for guidelines published on the websites of major funders and professional organisations can be found in (Box 2). Screening and annotation Unique references will be screened in two phases: screening for eligibility based on title and abstract, followed by screening for definitive inclusion based on full text. Screening will be performed in SyRF (http://syrf.org.uk). Each reference will be randomly presented to two independent reviewers. Disagreements between reviewers will be resolved by additional screening of the reference by a third, senior researcher. Data management and reporting All data, including extracted text and guidelines, will be stored in the SyRF platform. Elements of the included guidelines will be identified using a standardized extraction form. Reporting will follow the PRISMA guidelines as far as applicable.

Contains fulltext : 200413.pdf (Publisher’s version ) (Open Access) Background: Microdialysis can be used to measure amino acids in the extracellular space in vivo, based on the principle of diffusion. Variations in experimental set-up result in variations in baseline levels of the compounds measured. Variations may also be due to circadian rhythms. Method: We systematically searched and mapped the literature on all studies reporting baseline microdialysis measurements of histamine and the amino acids asparagine, aspartate, GABA, glutamate, glutamine, glycine, proline and taurine. We fully reviewed the studies describing circadian rhythms for histamine and the selected amino acids. Results: We retrieved 2331 papers describing baseline measurements of one or more of the compounds of interest. We provide a numerical summary and lists of the publications by compound. We retrieved 11 references describing studies on the circadian rhythms of the compounds of interest. Aspartate, glutamate and histamine are generally higher during the dark than during the light phase in nocturnal rodents. For glutamine, no rhythmicity was observed. For GABA, the results were too inconsistent to generalise. For asparagine, glycine, proline and taurine, insufficient data are available. Conclusion: The literature on intracerebral microdialysis measurements of the amino acids is vast, but certain primary studies are still warranted. Future systematic reviews on the individual compounds can shed light on the effects of experimental variations on baseline concentrations.

The drug development process involves identifying a compound and assessing its merit through rigorous pre-clinical and clinical trials. The pre-clinical stage is designed to assess the chemical properties of the new drug, as well as to determine the steps for synthesis and purification. In this stage of drug development, circumstances might dictate the use of alternative endpoints than the originally anticipated clinically relevant endpoint. In this regard, identification and evaluation of surrogate endpoints is of paramount importance. The validation methods make it possible to quantify degrees of association between the clinically relevant endpoint, also termed the true endpoint, and the alternative, surrogate endpoint. In this paper, we adapt the surrogate marker evaluation methodology of Alonso et al. (2003); (2006), developed for the case of two longitudinal outcomes, to the situation where either a longitudinal surrogate and cross sectional true endpoint is recorded, or vice versa. The work is motivated by a preclinical experiment conducted to assess association between corticosterone (CORT), heart rate, and blood pressure in rats, the data from which are then subjected to analysis. It was found that there is a weak relationship between CORT and behavior, and between CORT on the one hand and heart rate and blood pressure on the other hand, but a reasonably high degree of association was registered between heart rate and behavior. Financial support from the IAP research network #P6/03 of the Belgian Government (Belgian Science Policy) is gratefully acknowledged.