statistics

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Developments in the Collection of Statistical Information on the Number of Animals used in Experiments and other Scientific Purposes in the European Union

Ursula G. Sauer and Roman Kolar

In 1999, the European Commission presented its second report on the numbers of laboratory animals used in the European Union (EU). The plausibility of the data and the usefulness of the format of the registration tables remain questionable, for reasons previously discussed in connection with the Commission’s first statistical report. In addition, it is impossible to derive sound information on trends in animal use in the EU and its Member States from the second statistical report. The European Commission and the Member States have agreed on new tables to be used for future statistics on the use of experimental animals in the EU. These new tables have been significantly extended and improved. Several categories of little relevance have been revised, and ambiguous expressions have been clarified. However, several problems either persist or have been newly created. Moreover, some important data (i.e. categories for pain and distress, as well as for several specific purposes of use; the origin of some animal species; types of institutions; and the use of genetically engineered animals) are still not required. Nevertheless, these are highly relevant to animal welfare and must be regarded as indispensable for a well-aimed application of the statistics to set priorities concerning the Three Rs.
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In Vitro Phototoxicity Testing: Development and Validation of a New Concentration Response Analysis Software and Biostatistical Analyses Related to the Use of Various Prediction Models

Björn Peters and Hermann-Georg Holzhütter

As demonstrated in several validation studies, the dermal phototoxic potential of chemicals in humans can be effectively assessed by in vitro methods. The core of these methods is to monitor dose-response curves of a chemical in the absence and presence of light, to quantify the difference between these two curves by appropriate measures (either the photo-irritancy factor [PIF], or the mean photo effect [MPE]), and to use these measures as predictors of in vivo phototoxicity. We present new concentration-response analysis software for in vitro phototoxicity testing, which runs on current personal computers, and takes into account all the limitations identified when using a former program. We also demonstrate the validity and robustness of this new software by applying it retrospectively to all data available from two phases of the EU/COLIPA validation trial for the 3T3 neutral red update in vitro phototoxicity test. Some frequently raised questions pertaining to the use of prediction models in phototoxicity testing are addressed, including: the necessity of using prediction models based on a cut-off; whether it is justifiable to use sharp prediction cut-off values; whether there is a biostatistical justification for the highest concentration of the test chemical; and whether repeated testing of a chemical is required.
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Selected Biostatistical Aspects of the Validation of In Vitro Toxicological Assays

Ludwig A. Hothorn

An overview is presented on selected biostatistical aspects of the validation of in vitro toxicological assays. Primarily, the statistical analysis of single assays is discussed. Several approaches are compared for the possible non-monotonic dose-response relationship with a priori unknown shapes. The use of confidence intervals instead of p values for toxicologically appropriate decision making is explained. New methods for demonstrating interlaboratory similarity for dose-response designs are discussed. For validation, the inappropriateness of the concordance coefficient is shown, and sensitivity and specificity, as well as predictive values, are proposed as alternatives. The problem of the missing gold standard is highlighted.
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Statistics of Interlaboratory In Vitro Toxicological Studies

Ludwig A. Hothorn

Interlaboratory studies are common in toxicology, particularly for the introduction of alternative assays. Numerous papers are available on the statistical analysis of interlaboratory studies, but these deal primarily with the case of a replicated single sample studied in several laboratories. This approach can be used for some assays, but for the majority, the results will be unsatisfactory, i.e. involving great variability between both the dose groups and the laboratories. However, the primary objective of toxicological assays is to achieve similarity between the sizes of effects, rather than to determine absolute values. In the parametric model, the sizes of effects are the studentised differences from the negative control or, for the commonly used dose–response designs, the similarity of the slopes of the dose–response curves. Standard approaches for the estimation of intralaboratory and interlaboratory variability, including Mandel plots, are introduced, and new approaches are presented for demonstrating similarity of effect sizes, with or without assuming a dose–response model. One approach is based on a modification of the parallel-line assay, the other is based on a modification of the interaction contrasts of the analysis of variance. SAS programs are given for all approaches, and real data from an interlaboratory immunotoxicological study are analysed as a demonstration.
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An Analysis of the Home Office Statistics of Scientific Procedures on Living Animals, Great Britain 2004

Michelle Hudson and Nirmala Bhogal

The 2004 Statistics of Scientific Procedures on Living Animals were released by the Home Office in December 2005. They indicate that, for the third year running, there has been a significant increase in the number of laboratory animal procedures undertaken in Great Britain, and that increasing numbers of animals are involved. The overall trends in the use of toxicological and non-toxicological procedures involving animals are described. Particular emphasis is placed on the production and use of genetically modified animals, the production of biological materials, and acute toxicity testing. The use of non-human primates and dogs is also discussed. The implications of these latest statistics are consider
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Why do the Numbers of Laboratory Animal Procedures Conducted Continue to Rise? An Analysis of the Home Office Statistics of Scientific Procedures on Living Animals: Great Britain 2005

Michelle Hudson

The publication of the Statistics of Scientific Procedures on Living Animals: Great Britain 2005 once again provides evidence that the levels of animal experimentation in Great Britain are rising, the underlying reason for this being the continued and increasing reliance on genetically modified animals as model systems. There has been a gradual increase in fundamental research, as applied toxicological studies have declined. Of particular concern is the impact that the forthcoming REACH legislation will have and the apparent lack of urgency in facing up to this challenge. The major issues arising from the Statistics are discussed, including the increases in rabbit and primate procedures. The potential of newly validated and emerging techniques to counteract these worrying trends are also considered.
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Estimates for Worldwide Laboratory Animal Use in 2005

Katy Taylor, Nicky Gordon, Gill Langley and Wendy Higgins

Animal experimentation continues to generate public and political concern worldwide. Relatively few countries collate and publish animal use statistics, yet this is a first and essential step toward public accountability and an informed debate, as well as being important for effective policy-making and regulation. The implementation of the Three Rs (replacement, reduction and refinement of animal experiments) should be expected to result in a decline in animal use, but without regular, accurate statistics, this cannot be monitored. Recent estimates of worldwide annual laboratory animal use are imprecise and
unsubstantiated, ranging from 28–100 million. We collated data for 37 countries that publish national statistics, and standardised these against the definitions of ‘animals’, ‘purposes’ and ‘experiments’ used in European Union Directive 86/609/EEC. We developed and applied a statistical model, based on publication rates, for a further 142 countries. This yielded our most conservative estimate of global animal use: 58.3 million animals in 179 countries. However, this figure excludes several uses and forms of animals that are included in the statistics of some countries. With the data available, albeit for only a few countries, we also produced, by extrapolation, a more comprehensive global estimate that includes animals killed for the provision of tissues, animals used to maintain genetically-modified strains, and animals bred for laboratory use but killed as surplus to requirements. For a number of reasons that are explained, this more-comprehensive
figure of 115.3 million animals is still likely to be an underestimate.
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The Home Office Statistics for 2007 — Mutant Mice and Fishy Tales

Michelle Hudson

The publication of the Statistics of Scientific Procedures on Living Animals Great Britain 2007 earlier this year, revealed once again that animal experimentation is on the up. This can mainly be attributed to the continuing use of genetically modified mice and an increased interest in investigations and tests involving fish. Here, some of the general trends are described, developments of interest are discussed, and the implications of the statistics are explored.
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The FRAME Reduction Steering Committee: Reflections on a Decade Devoted to Reducing Animal Use in Biomedical Science

Michelle Hudson and Bryan Howard

Established in 1998, the FRAME Reduction Committee (FRC) (now the FRAME Reduction Steering Committee [FRSC]) has continued to pursue its aim of reducing the number of animals used in biomedical science. Through its expertise in statistics, experimental design, animal welfare and research on alternatives, it has contributed to raising awareness of the need for reduction and the means of achieving and demonstrating it. In recognising the need for training of scientists to appreciate and understand the concept of reduction, the FRSC has organised dedicated workshops and training schools. Some of the Committee’s major achievements are described, and, bearing in mind the current year-on-year increases in the number of scientific procedures on animals, its future activities are outlined.
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