Some general comparative points on Chao's and Zelterman's estimators of the population size

Two simple and frequently used capture–recapture estimates of the population size are compared: Chao's lower-bound estimate and Zelterman's estimate allowing for contaminated distributions. In the Poisson case it is shown that if there are only counts of ones and twos, the estimator of Zelterman is always bounded above by Chao's estimator. If counts larger than two exist, the estimator of Zelterman is becoming larger than that of Chao's, if only the ratio of the frequencies of counts of twos and ones is small enough. A similar analysis is provided for the binomial case. For a two-component mixture of Poisson distributions the asymptotic bias of both estimators is derived and it is shown that the Zelterman estimator can experience large overestimation bias. A modified Zelterman estimator is suggested and also the bias-corrected version of Chao's estimator is considered. All four estimators are compared in a simulation study.

Revisiting Youden's index as a useful measure of the misclassification error in meta-analysis of diagnostic studies

The paper considers meta-analysis of diagnostic studies that use a continuous Score for classification of study participants into healthy, or diseased groups. Classification is often done on the basis of a threshold or cut-off value, which might vary between Studies. Consequently, conventional meta-analysis methodology focusing solely on separate analysis of sensitivity and specificity might he confounded by a potentially unknown variation of the cut-off Value. To cope with this phenomena it is suggested to use, instead an overall estimate of the misclassification error previously suggested and used as Youden's index and; furthermore, it is argued that this index is less prone to between-study variation of cut-off values. A simple Mantel-Haenszel estimator as a summary measure of the overall misclassification error is suggested, which adjusts for a potential study effect. The measure of the misclassification error based on Youden's index is advantageous in that it easily allows an extension to a likelihood approach, which is then able to cope with unobserved heterogeneity via a nonparametric mixture model. All methods are illustrated at hand of an example on a diagnostic meta-analysis on duplex doppler ultrasound, with angiography as the standard for stroke prevention.

Modelling heterotachy in phylogenetic inference by reversible-jump Markov chain Monte Carlo

The rate at which a given site in a gene sequence alignment evolves over time may vary. This phenomenon-known as heterotachy-can bias or distort phylogenetic trees inferred from models of sequence evolution that assume rates of evolution are constant. Here, we describe a phylogenetic mixture model designed to accommodate heterotachy. The method sums the likelihood of the data at each site over more than one set of branch lengths on the same tree topology. A branch-length set that is best for one site may differ from the branch-length set that is best for some other site, thereby allowing different sites to have different rates of change throughout the tree. Because rate variation may not be present in all branches, we use a reversible-jump Markov chain Monte Carlo algorithm to identify those branches in which reliable amounts of heterotachy occur. We implement the method in combination with our 'pattern-heterogeneity' mixture model, applying it to simulated data and five published datasets. We find that complex evolutionary signals of heterotachy are routinely present over and above variation in the rate or pattern of evolution across sites, that the reversible-jump method requires far fewer parameters than conventional mixture models to describe it, and serves to identify the regions of the tree in which heterotachy is most pronounced. The reversible-jump procedure also removes the need for a posteriori tests of 'significance' such as the Akaike or Bayesian information criterion tests, or Bayes factors. Heterotachy has important consequences for the correct reconstruction of phylogenies as well as for tests of hypotheses that rely on accurate branch-length information. These include molecular clocks, analyses of tempo and mode of evolution, comparative studies and ancestral state reconstruction. The model is available from the authors' website, and can be used for the analysis of both nucleotide and morphological data.

Mechanisms of inverse agonist action at D-2 dopamine receptors

1 Mechanisms of inverse agonist action at the D-2(short) dopamine receptor have been examined. 2 Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [H-3]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. 3 Competition of inverse agonists versus [H-3] NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. K-i values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. K-coupled and K-uncoupled were statistically different for the set of compounds tested ( ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. 4 These observations were supported by simulations of these competition experiments according to the extended ternary complex model. 5 Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [S-35]GTPγ S binding to varying degrees in concentration-response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (-)-sulpiride was unaffected. 6 These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism.

Population-level assessment of risks of pesticides to birds and mammals in the UK

It is generally acknowledged that population-level assessments provide,I better measure of response to toxicants than assessments of individual-level effects. population-level assessments generally require the use of models to integrate potentially complex data about the effects of toxicants on life-history traits, and to provide a relevant measure of ecological impact. Building on excellent earlier reviews we here briefly outline the modelling options in population-level risk assessment. Modelling is used to calculate population endpoints from available data, which is often about Individual life histories, the ways that individuals interact with each other, the environment and other species, and the ways individuals are affected by pesticides. As population endpoints, we recommend the use of population abundance, population growth rate, and the chance of population persistence. We recommend two types of model: simple life-history models distinguishing two life-history stages, juveniles and adults; and spatially-explicit individual-based landscape models. Life-history models are very quick to set up and run, and they provide a great deal or insight. At the other extreme, individual-based landscape models provide the greatest verisimilitude, albeit at the cost of greatly increased complexity. We conclude with a discussion of the cations of the severe problems of parameterising models.

Parametric accelerated failure time models with random effects and an application to kidney transplant survival

Accelerated failure time models with a shared random component are described, and are used to evaluate the effect of explanatory factors and different transplant centres on survival times following kidney transplantation. Different combinations of the distribution of the random effects and baseline hazard function are considered and the fit of such models to the transplant data is critically assessed. A mixture model that combines short- and long-term components of a hazard function is then developed, which provides a more flexible model for the hazard function. The model can incorporate different explanatory variables and random effects in each component. The model is straightforward to fit using standard statistical software, and is shown to be a good fit to the transplant data. Copyright (C) 2004 John Wiley Sons, Ltd.

Investigation of the mechanism of agonist and inverse agonist action at D-2 dopamine receptors

This study investigated, for the D-2 dopamine receptor, the relation between the ability of agonists and inverse agonists to stabilise different states of the receptor and their relative efficacies. K-i values for agonists were determined in competition, versus the binding of the antagonist [H-3]spiperone. Competition data were fitted best by a two-binding site model (with the exception of bromocriptine, for which a one-binding site model provided the best fit) and agonist affinities for the higher (K-h) (G protein-coupled) and lower affinity (K-l) (G protein-uncoupled) sites determined. Ki values for agonists were also determined in competition versus the binding of the agonist [H-3]N-propylnorapomorphine (NPA) to provide a second estimate of K-h,. Maximal agonist effects (E-max) and their potencies (EC50) were determined from concentration-response curves for agonist stimulation of guanosine-5'-O-(3-[S-32] thiotriphosphate) ([S-35]GTPgammaS) binding. The ability of agonists to stabilise the G protein-coupled state of the receptor (K-l/K-h, determined from ligand-binding assays) did not correlate with either of two measures of relative efficacy (relative E-max, Kl/EC50) of agonists determined in [S-35]GTPgammaS-binding assays, when the data for all of the compounds tested were analysed For a subset of compounds, however, there was a relation between K-l/K-h and E-max.. Competition-binding data versus [H-3]spiperone and [H-3]NPA for a range of inverse agonists were fitted best by a one-binding site model. K-i values for the inverse agonists tested were slightly lower in competition versus [H-3]NPA compared to [H-3]spiperone. These data do not provide support for the idea that inverse agonists act by binding preferentially to the ground state of the receptor. (C) 2004 Elsevier Inc. All rights reserved.

Analysis of molecular determinants of affinity and relative efficacy of a series of R- and S-2-(dipropylamino)tetralins at the 5-HT1A serotonin receptor

1 Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT1A serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). 2 Ligand binding studies were used to determine dissociation constants for agonist binding to the 5HT(1A) receptor: (a) K-i values for agonists were determined in competition versus the binding of the agonist [H-3]-8-OH DPAT. Competition data were all fitted best by a one-binding site model. (b) K-i values for agonists were also determined in competition versus the binding of the antagonist [H-3]-NAD-199. Competition data were all fitted best by a two-binding site model, and agonist affinities for the higher (K-h) and lower affinity (K-1) sites were determined. 3 The ability of the agonists to activate the 5-HT1A receptor was determined using stimulation of [S-35]-GTPgammaS binding. Maximal effects of agonists (E-max) and their potencies (EC50) were determined from concentration/response curves for stimulation of [S-35]-GTPgammaS binding. 4 K-1/K-h determined from ligand binding assays correlated with the relative efficacy (relative Em) of agonists determined in [S-35]-GTPgammaS binding assays. There was also a correlation between K-1/K-h and K-1/EC50 for agonists determined from ligand binding and [S-35]-GTPgammaS binding assays. 5 Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of K-1/K-h for predicting the relative efficacy of agonists. British Journal of Pharmacology (2003) 138, 1129-1139. doi: 10. 1038/sj.bjp.705085.

Demographic models and the management of endangered species: a case study of the critically endangered Seychelles magpie robin

1. Demographic models are assuming an important role in management decisions for endangered species. Elasticity analysis and scope for management analysis are two such applications. Elasticity analysis determines the vital rates that have the greatest impact on population growth. Scope for management analysis examines the effects that feasible management might have on vital rates and population growth. Both methods target management in an attempt to maximize population growth. 2. The Seychelles magpie robin Copsychus sechellarum is a critically endangered island endemic, the population of which underwent significant growth in the early 1990s following the implementation of a recovery programme. We examined how the formal use of elasticity and scope for management analyses might have shaped management in the recovery programme, and assessed their effectiveness by comparison with the actual population growth achieved. 3. The magpie robin population doubled from about 25 birds in 1990 to more than 50 by 1995. A simple two-stage demographic model showed that this growth was driven primarily by a significant increase in the annual survival probability of first-year birds and an increase in the birth rate. Neither the annual survival probability of adults nor the probability of a female breeding at age 1 changed significantly over time. 4. Elasticity analysis showed that the annual survival probability of adults had the greatest impact on population growth. There was some scope to use management to increase survival, but because survival rates were already high (> 0.9) this had a negligible effect on population growth. Scope for management analysis showed that significant population growth could have been achieved by targeting management measures at the birth rate and survival probability of first-year birds, although predicted growth rates were lower than those achieved by the recovery programme when all management measures were in place (i.e. 1992-95). 5. Synthesis and applications. We argue that scope for management analysis can provide a useful basis for management but will inevitably be limited to some extent by a lack of data, as our study shows. This means that identifying perceived ecological problems and designing management to alleviate them must be an important component of endangered species management. The corollary of this is that it will not be possible or wise to consider only management options for which there is a demonstrable ecological benefit. Given these constraints, we see little role for elasticity analysis because, when data are available, a scope for management analysis will always be of greater practical value and, when data are lacking, precautionary management demands that as many perceived ecological problems as possible are tackled.

Mechanisms of inverse agonist action at D-2 dopamine receptors

1 Mechanisms of inverse agonist action at the D-2(short) dopamine receptor have been examined. 2 Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [H-3]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. 3 Competition of inverse agonists versus [H-3] NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. K-i values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. K-coupled and K-uncoupled were statistically different for the set of compounds tested ( ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. 4 These observations were supported by simulations of these competition experiments according to the extended ternary complex model. 5 Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [S-35]GTPγ S binding to varying degrees in concentration-response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (-)-sulpiride was unaffected. 6 These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism.

Determining feature relevance for the grouping of motor unit action potentials through generative topographic mapping

The study of motor unit action potential (MUAP) activity from electrornyographic signals is an important stage on neurological investigations that aim to understand the state of the neuromuscular system. In this context, the identification and clustering of MUAPs that exhibit common characteristics, and the assessment of which data features are most relevant for the definition of such cluster structure are central issues. In this paper, we propose the application of an unsupervised Feature Relevance Determination (FRD) method to the analysis of experimental MUAPs obtained from healthy human subjects. In contrast to approaches that require the knowledge of a priori information from the data, this FRD method is embedded on a constrained mixture model, known as Generative Topographic Mapping, which simultaneously performs clustering and visualization of MUAPs. The experimental results of the analysis of a data set consisting of MUAPs measured from the surface of the First Dorsal Interosseous, a hand muscle, indicate that the MUAP features corresponding to the hyperpolarization period in the physisiological process of generation of muscle fibre action potentials are consistently estimated as the most relevant and, therefore, as those that should be paid preferential attention for the interpretation of the MUAP groupings.

Probability density estimation with tunable kernels using orthogonal forward regression

A generalized or tunable-kernel model is proposed for probability density function estimation based on an orthogonal forward regression procedure. Each stage of the density estimation process determines a tunable kernel, namely, its center vector and diagonal covariance matrix, by minimizing a leave-one-out test criterion. The kernel mixing weights of the constructed sparse density estimate are finally updated using the multiplicative nonnegative quadratic programming algorithm to ensure the nonnegative and unity constraints, and this weight-updating process additionally has the desired ability to further reduce the model size. The proposed tunable-kernel model has advantages, in terms of model generalization capability and model sparsity, over the standard fixed-kernel model that restricts kernel centers to the training data points and employs a single common kernel variance for every kernel. On the other hand, it does not optimize all the model parameters together and thus avoids the problems of high-dimensional ill-conditioned nonlinear optimization associated with the conventional finite mixture model. Several examples are included to demonstrate the ability of the proposed novel tunable-kernel model to effectively construct a very compact density estimate accurately.

Fast northward energy transfer in the Atlantic due to Agulhas rings

The adiabatic transit time of wave energy radiated by an Agulhas ring released in the South Atlantic Ocean to the North Atlantic Ocean is investigated in a two-layer ocean model. Of particular interest is the arrival time of baroclinic energy in the northern part of the Atlantic, because it is related to variations in the meridional overturning circulation. The influence of the Mid-Atlantic Ridge is also studied, because it allows for the conversion from barotropic to baroclinic wave energy and the generation of topographic waves. Barotropic energy from the ring is present in the northern part of the model basin within 10 days. From that time, the barotropic energy keeps rising to attain a maximum 500 days after initiation. This is independent of the presence or absence of a ridge in the model basin. Without a ridge in the model, the travel time of the baroclinic signal is 1300 days. This time is similar to the transit time of the ring from the eastern to the western coast of the model basin. In the presence of the ridge, the baroclinic signal arrives in the northern part of the model basin after approximately 10 days, which is the same time scale as that of the barotropic signal. It is apparent that the ridge can facilitate the energy conversion from barotropic to baroclinic waves and the slow baroclinic adjustment can be bypassed. The meridional overturning circulation, parameterized in two ways as either a purely barotropic or a purely baroclinic phenomenon, also responds after 1300 days. The ring temporarily increases the overturning strength. Th presence of the ridge does not alter the time scales.

Assessing and understanding the impact of stratospheric dynamics and variability on the earth system

Advances in weather and climate research have demonstrated the role of the stratosphere in the Earth system across a wide range of temporal and spatial scales. Stratospheric ozone loss has been identified as a key driver of Southern Hemisphere tropospheric circulation trends, affecting ocean currents and carbon uptake, sea ice, and possibly even the Antarctic ice sheets. Stratospheric variability has also been shown to affect short term and seasonal forecasts, connecting the tropics and midlatitudes and guiding storm track dynamics. The two-way interactions between the stratosphere and the Earth system have motivated the World Climate Research Programme's (WCRP) Stratospheric Processes and Their Role in Climate (SPARC) DynVar activity to investigate the impact of stratospheric dynamics and variability on climate. This assessment will be made possible by two new multi-model datasets. First, roughly 10 models with a well resolved stratosphere are participating in the Coupled Model Intercomparison Project 5 (CMIP5), providing the first multi-model ensemble of climate simulations coupled from the stratopause to the sea floor. Second, the Stratosphere Historical Forecasting Project (SHFP) of WCRP's Climate Variability and predictability (CLIVAR) program is forming a multi-model set of seasonal hindcasts with stratosphere resolving models, revealing the impact of both stratospheric initial conditions and dynamics on intraseasonal prediction. The CMIP5 and SHFP model-data sets will offer an unprecedented opportunity to understand the role of the stratosphere in the natural and forced variability of the Earth system and to determine whether incorporating knowledge of the middle atmosphere improves seasonal forecasts and climate projections. Capsule New modeling efforts will provide unprecedented opportunities to harness our knowledge of the stratosphere to improve weather and climate prediction.

Estimation of the friction velocity in stably stratified boundary-layer flows over hills

A method is suggested for the calculation of the friction velocity for stable turbulent boundary-layer flow over hills. The method is tested using a continuous upstream mean velocity profile compatible with the propagation of gravity waves, and is incorporated into the linear model of Hunt, Leibovich and Richards with the modification proposed by Hunt, Richards and Brighton to include the effects of stability, and the reformulated solution of Weng for the near-surface region. Those theoretical results are compared with results from simulations using a non-hydrostatic microscale-mesoscale two-dimensional numerical model, and with field observations for different values of stability. These comparisons show a considerable improvement in the behaviour of the theoretical model when the friction velocity is calculated using the method proposed here, leading to a consistent variation of the boundary-layer structure with stability, and better agreement with observational and numerical data.