Estimating the hidden number of scrapie affected holdings in great Britain using a simple, truncated count model allowing for heterogeneity

None of the current surveillance streams monitoring the presence of scrapie in Great Britain provide a comprehensive and unbiased estimate of the prevalence of the disease at the holding level. Previous work to estimate the under-ascertainment adjusted prevalence of scrapie in Great Britain applied multiple-list capture-recapture methods. The enforcement of new control measures on scrapie-affected holdings in 2004 has stopped the overlapping between surveillance sources and, hence, the application of multiple-list capture-recapture models. Alternative methods, still under the capture-recapture methodology, relying on repeated entries in one single list have been suggested in these situations. In this article, we apply one-list capture-recapture approaches to data held on the Scrapie Notifications Database to estimate the undetected population of scrapie-affected holdings with clinical disease in Great Britain for the years 2002, 2003, and 2004. For doing so, we develop a new diagnostic tool for indication of heterogeneity as well as a new understanding of the Zelterman and Chao's lower bound estimators to account for potential unobserved heterogeneity. We demonstrate that the Zelterman estimator can be viewed as a maximum likelihood estimator for a special, locally truncated Poisson likelihood equivalent to a binomial likelihood. This understanding allows the extension of the Zelterman approach by means of logistic regression to include observed heterogeneity in the form of covariates-in case studied here, the holding size and country of origin. Our results confirm the presence of substantial unobserved heterogeneity supporting the application of our two estimators. The total scrapie-affected holding population in Great Britain is around 300 holdings per year. None of the covariates appear to inform the model significantly.

A simple variance formula for population size estimators by conditioning

This note considers the variance estimation for population size estimators based on capture–recapture experiments. Whereas a diversity of estimators of the population size has been suggested, the question of estimating the associated variances is less frequently addressed. This note points out that the technique of conditioning can be applied here successfully which also allows us to identify sources of variation: the variance due to estimation of the model parameters and the binomial variance due to sampling n units from a population of size N. It is applied to estimators typically used in capture–recapture experiments in continuous time including the estimators of Zelterman and Chao and improves upon previously used variance estimators. In addition, knowledge of the variances associated with the estimators by Zelterman and Chao allows the suggestion of a new estimator as the weighted sum of the two. The decomposition of the variance into the two sources allows also a new understanding of how resampling techniques like the Bootstrap could be used appropriately. Finally, the sample size question for capture–recapture experiments is addressed. Since the variance of population size estimators increases with the sample size, it is suggested to use relative measures such as the observed-to-hidden ratio or the completeness of identification proportion for approaching the question of sample size choice.

The extrapolation problem and how population modeling can help

We argue that population modeling can add value to ecological risk assessment by reducing uncertainty when extrapolating from ecotoxicological observations to relevant ecological effects. We review other methods of extrapolation, ranging from application factors to species sensitivity distributions to suborganismal (biomarker and "-omics'') responses to quantitative structure activity relationships and model ecosystems, drawing attention to the limitations of each. We suggest a simple classification of population models and critically examine each model in an extrapolation context. We conclude that population models have the potential for adding value to ecological risk assessment by incorporating better understanding of the links between individual responses and population size and structure and by incorporating greater levels of ecological complexity. A number of issues, however, need to be addressed before such models are likely to become more widely used. In a science context, these involve challenges in parameterization, questions about appropriate levels of complexity, issues concerning how specific or general the models need to be, and the extent to which interactions through competition and trophic relationships can be easily incorporated.

Relating traits to diversification: A simple test

We describe a simple comparative method for determining whether rates of diversification are correlated with continuous traits in species-level phylogenies. This involves comparing traits of species with net speciation rate (number of nodes linking extant species with the root divided by the root to tip evolutionary distance), using a phylogenetically corrected correlation. We use simulations to examine the power of this test. We find that the approach has acceptable power to uncover relationships between speciation and a continuous trait and is robust to background random extinction; however, the power of the approach is reduced when the rate of trait evolution is decreased. The test has low power to relate diversification to traits when extinction rate is correlated with the trait. Clearly, there are inherent limitations in using only data on extant species to infer correlates of extinction; however, this approach is potentially a powerful tool in analyzing correlates of speciation.

Simple sequence repeats reveal uneven distribution of genetic diversity in chloroplast genomes of Brassica oleracea L. and (n=9) wild relatives

Diversity in the chloroplast genome of 171 accessions representing the Brassica 'C' (n = 9) genome, including domesticated and wild B. oleracea and nine inter-fertile related wild species, was investigated using six chloroplast SSR (microsatellite) markers. The lack of diversity detected among 105 cultivated and wild accessions of B. oleracea contrasted starkly with that found within its wild relatives. The vast majority of B. oleracea accessions shared a single haplotype, whereas as many as six haplotypes were detected in two wild species, B. villosa Biv. and B. cretica Lam.. The SSRs proved to be highly polymorphic across haplotypes, with calculated genetic diversity values (H) of 0.23-0.87. In total, 23 different haplotypes were detected in C genome species, with an additional five haplotypes detected in B. rapa L. (A genome n = 10) and another in B. nigra L. (B genome, n = 8). The low chloroplast diversity of B. oleracea is not suggestive of multiple domestication events. The predominant B. oleracea haplotype was also common in B. incana Ten. and present in low frequencies in B. villosa, B. macrocarpa Guss, B. rupestris Raf. and B. cretica. The chloroplast SSRs reveal a wealth of diversity within wild Brassica species that will facilitate further evolutionary and phylogeographic studies of this important crop genus.

A simple and rapid method for preserving RNA of aquatic invertebrates for ecotoxicogenomics

Here we describe a novel, inexpensive and simple method for preserving RNA that reduces handling stress in aquatic invertebrates following ecotoxicogenomic experimentation. The application of the method is based on transcriptomic experiments conducted on Daphnia magna, but may easily be applied on a range of other aquatic organisms of a particular size with e.g. amphipod Gammarus pulex representing an upper size limit. We explain in detail how to apply this new method, named the "Cylindrical Sieve (CS) system", and highlight its advantages and disadvantages.

A novel Bayesian approach to drug design with simple and complex enzymes: Use with lens aldehyde dehydrogenase and the glyoxalase pathway

Purpose: Acquiring details of kinetic parameters of enzymes is crucial to biochemical understanding, drug development, and clinical diagnosis in ocular diseases. The correct design of an experiment is critical to collecting data suitable for analysis, modelling and deriving the correct information. As classical design methods are not targeted to the more complex kinetics being frequently studied, attention is needed to estimate parameters of such models with low variance. Methods: We have developed Bayesian utility functions to minimise kinetic parameter variance involving differentiation of model expressions and matrix inversion. These have been applied to the simple kinetics of the enzymes in the glyoxalase pathway (of importance in posttranslational modification of proteins in cataract), and the complex kinetics of lens aldehyde dehydrogenase (also of relevance to cataract). Results: Our successful application of Bayesian statistics has allowed us to identify a set of rules for designing optimum kinetic experiments iteratively. Most importantly, the distribution of points in the range is critical; it is not simply a matter of even or multiple increases. At least 60 % must be below the KM (or plural if more than one dissociation constant) and 40% above. This choice halves the variance found using a simple even spread across the range.With both the glyoxalase system and lens aldehyde dehydrogenase we have significantly improved the variance of kinetic parameter estimation while reducing the number and costs of experiments. Conclusions: We have developed an optimal and iterative method for selecting features of design such as substrate range, number of measurements and choice of intermediate points. Our novel approach minimises parameter error and costs, and maximises experimental efficiency. It is applicable to many areas of ocular drug design, including receptor-ligand binding and immunoglobulin binding, and should be an important tool in ocular drug discovery.

Inter-simple sequence repeat and aggressiveness analyses revealed high genetic diversity, recombination and long-range dispersal in Fusarium culmorum

Inter-simple sequence repeat (ISSR) analysis and aggressiveness assays were used to investigate genetic variability within a global collection of Fusarium culmorum isolates. A set of four ISSR primers were tested, of which three primers amplified a total of 37 bands out of which 30 (81%) were polymorphic. The intraspecific diversity was high, ranging from four to 28 different ISSR genotypes for F. culmorum depending on the primer. The combined analysis of ISSR data revealed 59 different genotypes clustered into seven distinct clades amongst 75 isolates of F. culmorum examined. All the isolates were assayed to test their aggressiveness on a winter wheat cv. 'Armada'. A significant quantitative variation for aggressiveness was found among the isolates. The ISSR and aggressiveness variation existed on a macro- as well as micro-geographical scale. The data suggested a long-range dispersal of F. culmorum and indicated that this fungus may have been introduced into Canada from Europe. In addition to the high level of intraspecific diversity observed in F. culmorum, the index of multilocus association calculated using ISSR data indicated that reproduction in F. culmorum cannot be exclusively clonal and recombination is likely to occur.

Simple linear asymmetrical complexes of silver(I): NC-Ag-NH3 and Br-Ag-NH3

The compounds Ag(CN)(NH3) and Ag(Br)(NH3) are remarkable in that they form solids containing the simple molecular units NC-Ag-NH3 and Br-Ag-NH3, rather than extended solids, and are the first examples of simple linear asymmetric complexes of silver(I).

Simple general method of generating non-oxo, non-amavadine model octacoordinated vanadium(IV) complexes of some tetradentate ONNO chelating ligands from various oxovanadium(IV/V) compounds and structural characterization of one of them

A simple general route of obtaining very stable octacoordinated non-oxovanadium( IV) complexes of the general formula VL2 (where H2L is a tetradentate ONNO donor) is presented. Six such complexes (1-6) are adequately characterized by elemental analysis, mass spectrometry, and various spectroscopic techniques. One of these compounds (1) has been structurally characterized. The molecule has crystallographic 4 symmetry and has a dodecahedral structure existing in a tetragonal space group P4n2. The non-oxo character and VL2 stoichiometry for all of the complexes are established from analytical and mass spectrometric data. In addition, the non-oxo character is clearly indicated by the complete absence of the strong nu(v=o) band in the 925-1025 cm(-1) region, which is a signature of all oxovanadium species. The complexes are quite stable in open air in the solid state and in solution, a phenomenon rarely observed in non-oxovanadium(IV) or bare vanadium(IV) complexes.

Literacy as a complex activity: deconstructing the simple view of reading

The Rose Review into the teaching of early reading recommended that the conceptual framework incorporated into the National Literacy Strategy Framework for Teaching – the Searchlights model of reading and its development – should be replaced by the Simple View of Reading. In this paper, we demonstrate how these two frameworks relate to each other, and show that nothing has been lost in this transformation from Searchlights to Simple View: on the contrary, much has been gained. That nothing has been lost is demonstrated by consideration of the underlying complexity inherent in each of the two dimensions delineated in the Simple View. That much has been gained is demonstrated by the increased understanding of each dimension that follows from careful scientific investigation of each. The better we understand what is involved in each dimension, the better placed we are to unravel and understand the essential, complex and continual interactions between each dimension which underlie skilled reading. This has clear implications for further improving the early teaching of reading.

Protocol for the PINCER trial: a cluster randomised trial comparing the effectiveness of a pharmacist-led IT-based intervention with simple feedback in reducing rates of clinically important errors in medicines management in general practices

Background: Medication errors are an important cause of morbidity and mortality in primary care. The aims of this study are to determine the effectiveness, cost effectiveness and acceptability of a pharmacist-led information-technology-based complex intervention compared with simple feedback in reducing proportions of patients at risk from potentially hazardous prescribing and medicines management in general (family) practice. Methods: Research subject group: "At-risk" patients registered with computerised general practices in two geographical regions in England. Design: Parallel group pragmatic cluster randomised trial. Interventions: Practices will be randomised to either: (i) Computer-generated feedback; or (ii) Pharmacist-led intervention comprising of computer-generated feedback, educational outreach and dedicated support. Primary outcome measures: The proportion of patients in each practice at six and 12 months post intervention: - with a computer-recorded history of peptic ulcer being prescribed non-selective non-steroidal anti-inflammatory drugs - with a computer-recorded diagnosis of asthma being prescribed beta-blockers - aged 75 years and older receiving long-term prescriptions for angiotensin converting enzyme inhibitors or loop diuretics without a recorded assessment of renal function and electrolytes in the preceding 15 months. Secondary outcome measures; These relate to a number of other examples of potentially hazardous prescribing and medicines management. Economic analysis: An economic evaluation will be done of the cost per error avoided, from the perspective of the UK National Health Service (NHS), comparing the pharmacist-led intervention with simple feedback. Qualitative analysis: A qualitative study will be conducted to explore the views and experiences of health care professionals and NHS managers concerning the interventions, and investigate possible reasons why the interventions prove effective, or conversely prove ineffective. Sample size: 34 practices in each of the two treatment arms would provide at least 80% power (two-tailed alpha of 0.05) to demonstrate a 50% reduction in error rates for each of the three primary outcome measures in the pharmacist-led intervention arm compared with a 11% reduction in the simple feedback arm. Discussion: At the time of submission of this article, 72 general practices have been recruited (36 in each arm of the trial) and the interventions have been delivered. Analysis has not yet been undertaken.

The benefits of providing benefit information: examining the effectiveness of provision of simple benefit statements on people's judgements about a medicine

Three experiments examined the effects of adding information about medication benefits to a short written explanation about a medicine. Participants were presented with a fictitious scenario about visiting the doctor, being prescribed an antibiotic and being given information about the medicine. They were asked to make various judgements relating to the information, the medicine and their intention to take it. Experiment 1 found that information about benefits enhanced the judgements, but did not influence the intention to comply. Experiment 2 compared the relative effectiveness of two different forms of the benefit statement, and found that both were effective in improving judgements, but had no effect on intention to comply. Experiment 3 compared the effectiveness of the two forms of benefit information but participants were told that the medicine was associated with four named side effects. Both types of statement improved ratings of the intention to comply, as well as ratings on the other measures. The experiments provide fairly consistent support for the inclusion of benefit information in medicine information leaflets, particularly to balance concerns about side effects.