A Bayesian approach for estimating antiviral efficacy in HIV dynamic models

The study of HIV dynamics is one of the most important developments in recent AIDS research. It has led to a new understanding of the pathogenesis of HIV infection. Although important findings in HIV dynamics have been published in prestigious scientific journals, the statistical methods for parameter estimation and model-fitting used in those papers appear surprisingly crude and have not been studied in more detail. For example, the unidentifiable parameters were simply imputed by mean estimates from previous studies, and important pharmacological/clinical factors were not considered in the modelling. In this paper, a viral dynamic model is developed to evaluate the effect of pharmacokinetic variation, drug resistance and adherence on antiviral responses. In the context of this model, we investigate a Bayesian modelling approach under a non-linear mixed-effects (NLME) model framework. In particular, our modelling strategy allows us to estimate time-varying antiviral efficacy of a regimen during the whole course of a treatment period by incorporating the information of drug exposure and drug susceptibility. Both simulated and real clinical data examples are given to illustrate the proposed approach. The Bayesian approach has great potential to be used in many aspects of viral dynamics modelling since it allow us to fit complex dynamic models and identify all the model parameters. Our results suggest that Bayesian approach for estimating parameters in HIV dynamic models is flexible and powerful.     

A UNIFIED FRAMEWORK FOR MODELLING WILDLIFE POPULATION DYNAMICS†

This paper proposes a unified framework for defining and fitting stochastic, discrete‐time, discrete‐stage population dynamics models. The biological system is described by a state‐space model, where the true but unknown state of the population is modelled by a state process, and this is linked to survey data by an observation process. All sources of uncertainty in the inputs, including uncertainty about model specification, are readily incorporated. The paper shows how the state process can be represented as a generalization of the standard Leslie or Lefkovitch matrix. By dividing the state process into subprocesses, complex models can be constructed from manageable building blocks. The paper illustrates the approach with a model of the British grey seal metapopulation, using sequential importance sampling with kernel smoothing to fit the model.     

A class of models for aggregated traffic volume time series

Summary. The development of time series models for traffic volume data constitutes an important step in constructing automated tools for the management of computing infrastructure resources. We analyse two traffic volume time series: one is the volume of hard disc activity, aggregated into half-hour periods, measured on a workstation, and the other is the volume of Internet requests made to a workstation. Both of these time series exhibit features that are typical of network traffic data, namely strong seasonal components and highly non-Gaussian distributions. For these time series, a particular class of non-linear state space models is proposed, and practical techniques for model fitting and forecasting are demonstrated.     

A non-linear time series approach to modelling asymmetry in stock market indexes

In this paper we analyse the performances of a novel approach to modelling non-linear conditionally heteroscedastic time series characterised by asymmetries in both the conditional mean and variance. This is based on the combination of a TAR model for the conditional mean with a Constrained Changing Parameters Volatility (CPV-C) model for the conditional variance. Empirical results are given for the daily returns of the S&P 500, NASDAQ composite and FTSE 100 stock market indexes.     

Identifiable state‐space models: A case study of the Bay of Fundy sea scallop fishery

State‐space models (SSMs) are now popular tools in fisheries science for providing management advice when faced with noisy survey and commercial fishery data. Such models are often fitted within a Bayesian framework requiring both the specification of prior distributions for model parameters and simulation‐based approaches for inference. Here we present a frequentist framework as a viable alternative and recommend using the Laplace approximation with automatic differentiation, as implemented in the R package Template Model Builder, for fast fitting and reliable inference. Additionally we highlight some identifiability issues associated with SSMs that fisheries scientists should be aware of and demonstrate how our modelling strategy surmounts these problems. Using the Bay of Fundy sea scallop fishery we show that our implementation yields more conservative advice than that of the reference model. The Canadian Journal of Statistics 47: 27–45; 2019 © 2018 Statistical Society of Canada     

Parameter Estimation in Large Dynamic Paired Comparison Experiments

Paired comparison data in which the abilities or merits of the objects being compared may be changing over time can be modelled as a non-linear state space model. When the population of objects being compared is large, likelihood-based analyses can be too computationally cumbersome to carry out regularly. This presents a problem for rating populations of chess players and other large groups which often consist of tens of thousands of competitors. This problem is overcome through a computationally simple non-iterative algorithm for fitting a particular dynamic paired comparison model. The algorithm, which improves over the commonly used algorithm of Elo by incorporating the variability in parameter estimates, can be performed regularly even for large populations of competitors. The method is evaluated on simulated data and is applied to ranking the best chess players of all time, and to ranking the top current tennis-players.     

An approach to non-linear principal components analysis using radially symmetric kernel functions

An approach to non-linear principal components using radially symmetric kernel basis functions is described. The procedure consists of two steps: a projection of the data set to a reduced dimension using a non-linear transformation whose parameters are determined by the solution of a generalized symmetric eigenvector equation. This is achieved by demanding a maximum variance transformation subject to a normalization condition (Hotelling's approach) and can be related to the homogeneity analysis approach of Gifi through the minimization of a loss function. The transformed variables are the principal components whose values define contours, or more generally hypersurfaces, in the data space. The second stage of the procedure defines the fitting surface, the principal surface, in the data space (again as a weighted sum of kernel basis functions) using the definition of self-consistency of Hastie and Stuetzle. The parameters of this principal surface are determined by a singular value decomposition and crossvalidation is used to obtain the kernel bandwidths. The approach is assessed on four data sets.     

Nonlinear mixed effects modelling for estimation of steady state attainment

Assessment of the time needed to attain steady state is a key pharmacokinetic objective during drug development. Traditional approaches for assessing steady state include ANOVA‐based methods for comparing mean plasma concentration values from each sampling day, with either a difference or equivalence test. However, hypothesis‐testing approaches are ill suited for assessment of steady state. This paper presents a nonlinear mixed effects modelling approach for estimation of steady state attainment, based on fitting a simple nonlinear mixed model to observed trough plasma concentrations. The simple nonlinear mixed model is developed and proposed for use under certain pharmacokinetic assumptions. The nonlinear mixed modelling estimation approach is described and illustrated by application to trough data from a multiple dose trial in healthy subjects. The performance of the nonlinear mixed modelling approach is compared to ANOVA‐based approaches by means of simulation techniques. Copyright © 2005 John Wiley & Sons, Ltd.     

An EM-type algorithm for multivariate mixture models

This paper introduces a new approach, based on dependent univariate GLMs, for fitting multivariate mixture models. This approach is a multivariate generalization of the method for univariate mixtures presented by Hinde (1982). Its accuracy and efficiency are compared with direct maximization of the log-likelihood. Using a simulation study, we also compare the efficiency of Monte Carlo and Gaussian quadrature methods for approximating the mixture distribution. The new approach with Gaussian quadrature outperforms the alternative methods considered. The work is motivated by the multivariate mixture models which have been proposed for modelling changes of employment states at an individual level. Similar formulations are of interest for modelling movement between other social and economic states and multivariate mixture models also occur in biostatistics and epidemiology.     

A semi‐parametric approach to fitting a nonlinear mixed PK/PD model with an effect compartment using SAS

Modelling of the relationship between concentration (PK) and response (PD) plays an important role in drug development. The modelling becomes complicated when the drug concentration and response measurements are not taken simultaneously and/or hysteresis occurs between the response and the concentration. A model‐based approach fits a joint pharmacokinetic (PK) and concentration–response (PK/PD) model, including an effect compartment if necessary, to concentration and response data. However, this approach relies on the PK data being well described by a common PK model. We propose an algorithm for a semi‐parametric approach to fitting nonlinear mixed PK/PD models including an effect compartment using linear interpolation and extrapolation for concentration data. This approach is independent of the PK model, and the algorithm can easily be implemented using SAS PROC NLMIXED. Practical issues in programming and computing are also discussed. The properties of this approach are examined using simulations. This approach is used to analyse data from a study of the PK/PD relationship between insulin and glucose levels. Copyright © 2005 John Wiley & Sons, Ltd.     

Reml and best linear unbiased prediction in state space models

This article takes a hierarchical model approach to the estimation of state space models with diffuse initial conditions. An initial state is said to be diffuse when it cannot be assigned a proper prior distribution. In state space models this occurs either when fixed effects are present or when modelling nonstationarity in the state transition equation. Whereas much of the literature views diffuse states as an initialization problem, we follow the approach of Sallas and Harville (1981,1988) and incorporate diffuse initial conditions via noninformative prior distributions into hierarchical linear models. We apply existing results to derive the restricted loglike-lihood and appropriate modifications to the standard Kalman filter and smoother. Our approach results in a better understanding of De Jong's (1991) contributions. This article also shows how to adjust the standard Kalman filter, the fixed inter- val smoother and the state space model forecasting recursions, together with their mean square errors, for he presence of diffuse components. Using a hierarchical model approach it is shown that the estimates obtained are Best Linear Unbiased Predictors (BLUP).     

Applied state space modelling of non-Gaussian time series using integration-based Kalman filtering

The main topic of the paper is on-line filtering for non-Gaussian dynamic (state space) models by approximate computation of the first two posterior moments using efficient numerical integration. Based on approximating the prior of the state vector by a normal density, we prove that the posterior moments of the state vector are related to the posterior moments of the linear predictor in a simple way. For the linear predictor Gauss-Hermite integration is carried out with automatic reparametrization based on an approximate posterior mode filter. We illustrate how further topics in applied state space modelling, such as estimating hyperparameters, computing model likelihoods and predictive residuals, are managed by integration-based Kalman-filtering. The methodology derived in the paper is applied to on-line monitoring of ecological time series and filtering for small count data.     

Modelling daily multivariate pollutant data at multiple sites

Summary. This paper considers the spatiotemporal modelling of four pollutants measured daily at eight monitoring sites in London over a 4-year period. Such multiple-pollutant data sets measured over time at multiple sites within a region of interest are typical. Here, the modelling was carried out to provide the exposure for a study investigating the health effects of air pollution. Alternative objectives include the design problem of the positioning of a new monitoring site, or for regulatory purposes to determine whether environmental standards are being met. In general, analyses are hampered by missing data due, for example, to a particular pollutant not being measured at a site, a monitor being inactive by design (e.g. a 6-day monitoring schedule) or because of an unreliable or faulty monitor. Data of this type are modelled here within a dynamic linear modelling framework, in which the dependences across time, space and pollutants are exploited. Throughout the approach is Bayesian, with implementation via Markov chain Monte Carlo sampling.     

Model-based clustering,classification, and discriminant analysis of data with mixed type

We propose a mixture of latent variables model for the model-based clustering, classification, and discriminant analysis of data comprising variables with mixed type. This approach is a generalization of latent variable analysis, and model fitting is carried out within the expectation-maximization framework. Our approach is outlined and a simulation study conducted to illustrate the effect of sample size and noise on the standard errors and the recovery probabilities for the number of groups. Our modelling methodology is then applied to two real data sets and their clustering and classification performance is discussed. We conclude with discussion and suggestions for future work.     

Bayesian inference for generalized additive mixed models based on Markov random field priors

Most regression problems in practice require flexible semiparametric forms of the predictor for modelling the dependence of responses on covariates. Moreover, it is often necessary to add random effects accounting for overdispersion caused by unobserved heterogeneity or for correlation in longitudinal or spatial data. We present a unified approach for Bayesian inference via Markov chain Monte Carlo simulation in generalized additive and semiparametric mixed models. Different types of covariates, such as the usual covariates with fixed effects, metrical covariates with non-linear effects, unstructured random effects, trend and seasonal components in longitudinal data and spatial covariates, are all treated within the same general framework by assigning appropriate Markov random field priors with different forms and degrees of smoothness. We applied the approach in several case-studies and consulting cases, showing that the methods are also computationally feasible in problems with many covariates and large data sets. In this paper, we choose two typical applications.     

Fully exponential Laplace approximations for the joint modelling of survival and longitudinal data

Summary.  A common objective in longitudinal studies is the joint modelling of a longitudinal response with a time-to-event outcome. Random effects are typically used in the joint modelling framework to explain the interrelationships between these two processes. However, estimation in the presence of random effects involves intractable integrals requiring numerical integration. We propose a new computational approach for fitting such models that is based on the Laplace method for integrals that makes the consideration of high dimensional random-effects structures feasible. Contrary to the standard Laplace approximation, our method requires much fewer repeated measurements per individual to produce reliable results.     

The potential of integrated modelling in conservation biology: A case study of the black‐footed albatross (Phoebastria nigripes)

Conservation biology aims at assessing the status of a population, based on information which is often incomplete. Integrated population modelling based on state‐space models appears to be a powerful and relevant way of combining into a single likelihood several types of information such as capture‐recapture data and population surveys. In this paper, the authors describe the principles of integrated population modelling and they evaluate its performance for conservation biology based on a case study, that of the black‐footed albatross, a northern Pacific albatross species suspected to be impacted by longline fishing     

Disaggregated spatial modelling for areal unit categorical data

Summary.  We consider joint spatial modelling of areal multivariate categorical data assuming a multiway contingency table for the variables, modelled by using a log-linear model, and connected across units by using spatial random effects. With no distinction regarding whether variables are response or explanatory, we do not limit inference to conditional probabilities, as in customary spatial logistic regression. With joint probabilities we can calculate arbitrary marginal and conditional probabilities without having to refit models to investigate different hypotheses. Flexible aggregation allows us to investigate subgroups of interest; flexible conditioning enables not only the study of outcomes given risk factors but also retrospective study of risk factors given outcomes. A benefit of joint spatial modelling is the opportunity to reveal disparities in health in a richer fashion, e.g. across space for any particular group of cells, across groups of cells at a particular location, and, hence, potential space–group interaction. We illustrate with an analysis of birth records for the state of North Carolina and compare with spatial logistic regression.     

A comparison of methods for the fitting of generalized additive models

There are several procedures for fitting generalized additive models, i.e. regression models for an exponential family response where the influence of each single covariates is assumed to have unknown, potentially non-linear shape. Simulated data are used to compare a smoothing parameter optimization approach for selection of smoothness and of covariates, a stepwise approach, a mixed model approach, and a procedure based on boosting techniques. In particular it is investigated how the performance of procedures is linked to amount of information, type of response, total number of covariates, number of influential covariates, and extent of non-linearity. Measures for comparison are prediction performance, identification of influential covariates, and smoothness of fitted functions. One result is that the mixed model approach returns sparse fits with frequently over-smoothed functions, while the functions are less smooth for the boosting approach and variable selection is less strict. The other approaches are in between with respect to these measures. The boosting procedure is seen to perform very well when little information is available and/or when a large number of covariates is to be investigated. It is somewhat surprising that in scenarios with low information the fitting of a linear model, even with stepwise variable selection, has not much advantage over the fitting of an additive model when the true underlying structure is linear. In cases with more information the prediction performance of all procedures is very similar. So, in difficult data situations the boosting approach can be recommended, in others the procedures can be chosen conditional on the aim of the analysis.     

基于风险预期的深市收益率预报研究

在预报股市收益率时考虑到股市风险波动及其结构性变化对股民心理预期的影响,采用状态空间理论将静态风险溢价GARCH-M模型改进为动态风险溢价模型。以中国深圳股市作为算例,研究了2006年1月至2008年8月深市风险的波动及股民风险预期的变化,并据此模拟了深市2008年8月的收益率,结果表明改进模型解释力更强,拟合精度更高,比一般的GARCH-M预报结果更准确。