Bayesian population pharmacokinetic analysis of sirolimus

Objective: It is usual that data collected from routine clinical care is sparse and unable to support the more complex pharmacokinetic (PK) models that may have been reported in previous rich data studies. Informative priors may be a pre-requisite for model development. The aim of this study was to estimate the population PK parameters of sirolimus using a fully Bayesian approach with informative priors. Methods: Informative priors including prior mean and precision of the prior mean were elicited from previous published studies using a meta-analytic technique. Precision of between-subject variability was determined by simulations from a Wishart distribution using MATLAB (version 6.5). Concentration-time data of sirolimus retrospectively collected from kidney transplant patients were analysed using WinBUGS (version 1.3). The candidate models were either one- or two-compartment with first order absorption and first order elimination. Model discrimination was based on computation of the posterior odds supporting the model. Results: A total of 315 concentration-time points were obtained from 25 patients. Most data were clustered at trough concentrations with range of 1.6 to 77 hours post-dose. Using informative priors, either a one- or two-compartment model could be used to describe the data. When a one-compartment model was applied, information was gained from the data for the value of apparent clearance (CL/F = 18.5 L/h), and apparent volume of distribution (V/F = 1406 L) but no information was gained about the absorption rate constant (ka). When a two-compartment model was fitted to the data, the data were informative about CL/F, apparent inter-compartmental clearance, and apparent volume of distribution of the peripheral compartment (13.2 L/h, 20.8 L/h, and 579 L, respectively). The posterior distribution of the volume distribution of central compartment and ka were the same as priors. The posterior odds for the two-compartment model was 8.1, indicating the data supported the two-compartment model. Conclusion: The use of informative priors supported the choice of a more complex and informative model that would otherwise have not been supported by the sparse data.

Ecoregion classification using a bayesian approach and centre-focused clusters

Ecological regions are increasingly used as a spatial unit for planning and environmental management. It is important to define these regions in a scientifically defensible way to justify any decisions made on the basis that they are representative of broad environmental assets. The paper describes a methodology and tool to identify cohesive bioregions. The methodology applies an elicitation process to obtain geographical descriptions for bioregions, each of these is transformed into a Normal density estimate on environmental variables within that region. This prior information is balanced with data classification of environmental datasets using a Bayesian statistical modelling approach to objectively map ecological regions. The method is called model-based clustering as it fits a Normal mixture model to the clusters associated with regions, and it addresses issues of uncertainty in environmental datasets due to overlapping clusters.

Bayesian retrieval of scatterometer wind fields

The retrieval of wind fields from scatterometer observations has traditionally been separated into two phases; local wind vector retrieval and ambiguity removal. Operationally, a forward model relating wind vector to backscatter is inverted, typically using look up tables, to retrieve up to four local wind vector solutions. A heuristic procedure, using numerical weather prediction forecast wind vectors and, often, some neighbourhood comparison is then used to select the correct solution. In this paper we develop a Bayesian method for wind field retrieval, and show how a direct local inverse model, relating backscatter to wind vector, improves the wind vector retrieval accuracy. We compare these results with the operational U.K. Meteorological Office retrievals, our own CMOD4 retrievals and a neural network based local forward model retrieval. We suggest that the neural network based inverse model, which is extremely fast to use, improves upon current forward models when used in a variational data assimilation scheme.

Bayesian invariant measurements of generalisation for discrete distributions

Neural network learning rules can be viewed as statistical estimators. They should be studied in Bayesian framework even if they are not Bayesian estimators. Generalisation should be measured by the divergence between the true distribution and the estimated distribution. Information divergences are invariant measurements of the divergence between two distributions. The posterior average information divergence is used to measure the generalisation ability of a network. The optimal estimators for multinomial distributions with Dirichlet priors are studied in detail. This confirms that the definition is compatible with intuition. The results also show that many commonly used methods can be put under this unified framework, by assume special priors and special divergences.

Bayesian invariant measurements of generalisation for continuous distributions

A family of measurements of generalisation is proposed for estimators of continuous distributions. In particular, they apply to neural network learning rules associated with continuous neural networks. The optimal estimators (learning rules) in this sense are Bayesian decision methods with information divergence as loss function. The Bayesian framework guarantees internal coherence of such measurements, while the information geometric loss function guarantees invariance. The theoretical solution for the optimal estimator is derived by a variational method. It is applied to the family of Gaussian distributions and the implications are discussed. This is one in a series of technical reports on this topic; it generalises the results of ¸iteZhu95:prob.discrete to continuous distributions and serve as a concrete example of a larger picture ¸iteZhu95:generalisation.

Two Bayesian treatments of the n-tuple recognition method

Two probabilistic interpretations of the n-tuple recognition method are put forward in order to allow this technique to be analysed with the same Bayesian methods used in connection with other neural network models. Elementary demonstrations are then given of the use of maximum likelihood and maximum entropy methods for tuning the model parameters and assisting their interpretation. One of the models can be used to illustrate the significance of overlapping n-tuple samples with respect to correlations in the patterns.

A Bayesian formulation of search, control and the exploration/exploitation trade-off

A new approach to optimisation is introduced based on a precise probabilistic statement of what is ideally required of an optimisation method. It is convenient to express the formalism in terms of the control of a stationary environment. This leads to an objective function for the controller which unifies the objectives of exploration and exploitation, thereby providing a quantitative principle for managing this trade-off. This is demonstrated using a variant of the multi-armed bandit problem. This approach opens new possibilities for optimisation algorithms, particularly by using neural network or other adaptive methods for the adaptive controller. It also opens possibilities for deepening understanding of existing methods. The realisation of these possibilities requires research into practical approximations of the exact formalism.

Bayesian invariant measurements of generalisation

The problem of evaluating different learning rules and other statistical estimators is analysed. A new general theory of statistical inference is developed by combining Bayesian decision theory with information geometry. It is coherent and invariant. For each sample a unique ideal estimate exists and is given by an average over the posterior. An optimal estimate within a model is given by a projection of the ideal estimate. The ideal estimate is a sufficient statistic of the posterior, so practical learning rules are functions of the ideal estimator. If the sole purpose of learning is to extract information from the data, the learning rule must also approximate the ideal estimator. This framework is applicable to both Bayesian and non-Bayesian methods, with arbitrary statistical models, and to supervised, unsupervised and reinforcement learning schemes.

An upper bound on the Bayesian error bars for generalized linear regression

In the Bayesian framework, predictions for a regression problem are expressed in terms of a distribution of output values. The mode of this distribution corresponds to the most probable output, while the uncertainty associated with the predictions can conveniently be expressed in terms of error bars. In this paper we consider the evaluation of error bars in the context of the class of generalized linear regression models. We provide insights into the dependence of the error bars on the location of the data points and we derive an upper bound on the true error bars in terms of the contributions from individual data points which are themselves easily evaluated.

Bayesian regression filter and the issue of priors

We propose a Bayesian framework for regression problems, which covers areas which are usually dealt with by function approximation. An online learning algorithm is derived which solves regression problems with a Kalman filter. Its solution always improves with increasing model complexity, without the risk of over-fitting. In the infinite dimension limit it approaches the true Bayesian posterior. The issues of prior selection and over-fitting are also discussed, showing that some of the commonly held beliefs are misleading. The practical implementation is summarised. Simulations using 13 popular publicly available data sets are used to demonstrate the method and highlight important issues concerning the choice of priors.

On the relationship between Bayesian error bars and the input data density

We investigate the dependence of Bayesian error bars on the distribution of data in input space. For generalized linear regression models we derive an upper bound on the error bars which shows that, in the neighbourhood of the data points, the error bars are substantially reduced from their prior values. For regions of high data density we also show that the contribution to the output variance due to the uncertainty in the weights can exhibit an approximate inverse proportionality to the probability density. Empirical results support these conclusions.