Bayesian Spatial Analysis for the Evaluation of Breast Cancer Detection Methods

This study investigated the impact of spatial location on the effectiveness of population‐based breast screening in reducing breast cancer mortality compared to other detection methods among Queensland women. The analysis was based on linked population‐based datasets from BreastScreen Queensland and the Queensland Cancer Registry for the period of 1997–2008 for women aged less than 90 years at diagnosis. A Bayesian hierarchical regression modelling approach was adopted and posterior estimation was performed using Markov Chain Monte Carlo techniques. This approach accommodated sparse data resulting from rare outcomes in small geographic areas, while allowing for spatial correlation and demographic influences to be included. A relative survival model was chosen to evaluate the relative excess risk for each breast cancer related factor. Several models were fitted to examine the influence of demographic information, cancer stage, geographic information and detection method on women's relative survival. Overall, the study demonstrated that including the detection method and geographic information when assessing the relative survival of breast cancer patients helped capture unexplained and spatial variability. The study also found evidence of better survival among women with breast cancer diagnosed in a screening program than those detected otherwise, as well as lower risk for those residing in a more urban or socio‐economically advantaged region, even after adjusting for tumour stage, environmental factors and demographics. However, no evidence of dependency between method of detection and geographic location was found. This project provides a sophisticated approach to examining the benefit of a screening program while considering the influence of geographic factors.     

Réduction de la variance dans les sondages en présence d'information auxiliarie: Une approache non paramétrique par splines de régression

The author considers the use of auxiliary information available at population level to improve the estimation of finite population totals. She introduces a new type of model‐assisted estimator based on nonparametric regression splines. The estimator is a weighted linear combination of the study variable with weights calibrated to the B‐splines known population totals. The author shows that the estimator is asymptotically design‐unbiased and consistent under conditions which do not require the superpopulation model to be correct. She proposes a design‐based variance approximation and shows that the anticipated variance is asymptotically equivalent to the Godambe‐Joshi lower bound. She also shows through simulations that the estimator has good properties.     

Selection Strategy for Covariance Structure of Random Effects in Linear Mixed‐effects Models

Linear mixed‐effects models are a powerful tool for modelling longitudinal data and are widely used in practice. For a given set of covariates in a linear mixed‐effects model, selecting the covariance structure of random effects is an important problem. In this paper, we develop a joint likelihood‐based selection criterion. Our criterion is the approximately unbiased estimator of the expected Kullback–Leibler information. This criterion is also asymptotically optimal in the sense that for large samples, estimates based on the covariance matrix selected by the criterion minimize the approximate Kullback–Leibler information. Finite sample performance of the proposed method is assessed by simulation experiments. As an illustration, the criterion is applied to a data set from an AIDS clinical trial.     

Assessing Poisson variation of intestinal tumour multiplicity in mice carrying a Robertsonian translocation

Summary.  Tumour multiplicity is a frequently measured phenotype in animal studies of cancer biology. Poisson variation of this measurement represents a biological and statistical reference point that is usually violated, even in highly controlled experiments, owing to sources of variation in the stochastic process of tumour formation. A recent experiment on murine intestinal tumours presented conditions which seem to generate Poisson-distributed tumour counts. If valid, this would support a claim about mechanisms by which the adenomatous polyposis coli gene is inactivated during tumour initiation. In considering hypothesis testing strategies, model choice and Bayesian approaches, we quantify the positive evidence favouring Poisson variation in this experiment. Statistical techniques used include likelihood ratio testing, the Bayes and Akaike information criteria, negative binomial modelling, reversible jump Markov chain Monte Carlo methods and posterior predictive checking. The posterior approximation that is based on the Bayes information criterion is found to be quite accurate in this small n case-study.     

Fast Inference for Network Models of Infectious Disease Spread

Models of infectious disease over contact networks offer a versatile means of capturing heterogeneity in populations during an epidemic. Highly connected individuals tend to be infected at a higher rate early during an outbreak than those with fewer connections. A powerful approach based on the probability generating function of the individual degree distribution exists for modelling the mean field dynamics of outbreaks in such a population. We develop the same idea in a stochastic context, by proposing a comprehensive model for 1‐week‐ahead incidence counts. Our focus is inferring contact network (and other epidemic) parameters for some common degree distributions, in the case when the network is non‐homogeneous ‘at random’. Our model is initially set within a susceptible–infectious–removed framework, then extended to the susceptible–infectious–removed–susceptible scenario, and we apply this methodology to influenza A data.     

Sample‐size calculations for multi‐group comparison in population pharmacokinetic experiments

This paper describes an approach for calculating sample size for population pharmacokinetic experiments that involve hypothesis testing based on multi‐group comparison detecting the difference in parameters between groups under mixed‐effects modelling. This approach extends what has been described for generalized linear models and nonlinear population pharmacokinetic models that involve only binary covariates to more complex nonlinear population pharmacokinetic models. The structural nonlinear model is linearized around the random effects to obtain the marginal model and the hypothesis testing involving model parameters is based on Wald's test. This approach provides an efficient and fast method for calculating sample size for hypothesis testing in population pharmacokinetic models. The approach can also handle different design problems such as unequal allocation of subjects to groups and unbalanced sampling times between and within groups. The results obtained following application to a one compartment intravenous bolus dose model that involved three different hypotheses under different scenarios showed good agreement between the power obtained from NONMEM simulations and nominal power. Copyright © 2009 John Wiley & Sons, Ltd.     

The Stabilisation of Model Parameter Estimates from Repeated Surveys with Rare Observations

In many surveys, the domains of study are small and the samples that carry information on a domain can be very small indeed. If the survey is conducted repeatedly there is often a high degree of overlap in samples over time. We show how to use the richness of information over time to compensate for the paucity of cross‐sectional information. We propose a model‐based estimator of the population total which makes use of stabilised parameter estimates that combine information from different survey periods that are adjacent in time. The motivating example for this research was the ProdCom survey as implemented in the UK.     

A Quasi‐Score Statistic for Homogeneity Testing against Covariate‐Varying Heterogeneity

In statistical modelling, it is often of interest to evaluate non‐negative quantities that capture heterogeneity in the population such as variances, mixing proportions and dispersion parameters. In instances of covariate‐dependent heterogeneity, the implied homogeneity hypotheses are nonstandard and existing inferential techniques are not applicable. In this paper, we develop a quasi‐score test statistic to evaluate homogeneity against heterogeneity that varies with a covariate profile through a regression model. We establish the limiting null distribution of the proposed test as a functional of mixtures of chi‐square processes. The methodology does not require the full distribution of the data to be entirely specified. Instead, a general estimating function for a finite dimensional component of the model, that is, of interest is assumed but other characteristics of the population are left completely unspecified. We apply the methodology to evaluate the excess zero proportion in zero‐inflated models for count data. Our numerical simulations show that the proposed test can greatly improve efficiency over tests of homogeneity that neglect covariate information under the alternative hypothesis. An empirical application to dental caries indices demonstrates the importance and practical utility of the methodology in detecting excess zeros in the data.     

Limited information likelihood analysis of survey data

Analysts of survey data are often interested in modelling the population process, or superpopulation, that gave rise to a 'target' set of survey variables. An important tool for this is maximum likelihood estimation. A survey is said to provide limited information for such inference if data used in the design of the survey are unavailable to the analyst. In this circumstance, sample inclusion probabilities, which are typically available, provide information which needs to be incorporated into the analysis. We consider the case where these inclusion probabilities can be modelled in terms of a linear combination of the design and target variables, and only sample values of these are available. Strict maximum likelihood estimation of the underlying superpopulation means of these variables appears to be analytically impossible in this case, but an analysis based on approximations to the inclusion probabilities leads to a simple estimator which is a close approximation to the maximum likelihood estimator. In a simulation study, this estimator outperformed several other estimators that are based on approaches suggested in the sampling literature.     

An individual measure of relative survival

Summary.  Relative survival techniques are used to compare survival experience in a study cohort with that expected if background population rates apply. The techniques are especially useful when cause-specific death information is not accurate or not available as they provide a measure of excess mortality in a group of patients with a certain disease. Whereas these methods are based on group comparisons, we present here a transformation approach which instead gives for each individual an outcome measure relative to the appropriate background population. The new outcome measure is easily interpreted and can be analysed by using standard survival analysis techniques. It provides additional information on relative survival and gives new options in regression analysis. For example, one can estimate the proportion of patients who survived longer than a given percentile of the respective general population or compare survival experience of individuals while accounting for the population differences. The regression models for the new outcome measure are different from existing models, thus providing new possibilities in analysing relative survival data. One distinctive feature of our approach is that we adjust for expected survival before modelling. The paper is motivated by a study into the survival of patients after acute myocardial infarction.     

Pseudo‐empirical likelihood ratio confidence intervals for complex surveys

The authors show how an adjusted pseudo‐empirical likelihood ratio statistic that is asymptotically distributed as a chi‐square random variable can be used to construct confidence intervals for a finite population mean or a finite population distribution function from complex survey samples. They consider both non‐stratified and stratified sampling designs, with or without auxiliary information. They examine the behaviour of estimates of the mean and the distribution function at specific points using simulations calling on the Rao‐Sampford method of unequal probability sampling without replacement. They conclude that the pseudo‐empirical likelihood ratio confidence intervals are superior to those based on the normal approximation, whether in terms of coverage probability, tail error rates or average length of the intervals.     

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.     

Bayesian inversion of geoelectrical resistivity data

Summary. Enormous quantities of geoelectrical data are produced daily and often used for large scale reservoir modelling. To interpret these data requires reliable and efficient inversion methods which adequately incorporate prior information and use realistically complex modelling structures. We use models based on random coloured polygonal graphs as a powerful and flexible modelling framework for the layered composition of the Earth and we contrast our approach with earlier methods based on smooth Gaussian fields. We demonstrate how the reconstruction algorithm may be efficiently implemented through the use of multigrid Metropolis–coupled Markov chain Monte Carlo methods and illustrate the method on a set of field data.     

Generalised Linear Models Incorporating Population Level Information: An Empirical Likelihood Based Approach

In many situations information from a sample of individuals can be supplemented by population level information on the relationship between a dependent variable and explanatory variables. Inclusion of the population level information can reduce bias and increase the efficiency of the parameter estimates.Population level information can be incorporated via constraints on functions of the model parameters. In general the constraints are nonlinear making the task of maximum likelihood estimation harder. In this paper we develop an alternative approach exploiting the notion of an empirical likelihood. It is shown that within the framework of generalised linear models, the population level information corresponds to linear constraints, which are comparatively easy to handle. We provide a two-step algorithm that produces parameter estimates using only unconstrained estimation. We also provide computable expressions for the standard errors. We give an application to demographic hazard modelling by combining panel survey data with birth registration data to estimate annual birth probabilities by parity.     

Inference on Polychotomous Responses in Finite Populations

Abstract. A model‐based predictive estimator is proposed for the population proportions of a polychotomous response variable, based on a sample from the population and on auxiliary variables, whose values are known for the entire population. The responses for the non‐sample units are predicted using a multinomial logit model, which is a parametric function of the auxiliary variables. A bootstrap estimator is proposed for the variance of the predictive estimator, its consistency is proved and its small sample performance is compared with that of an analytical estimator. The proposed predictive estimator is compared with other available estimators, including model‐assisted ones, both in a simulation study involving different sampling designs and model mis‐specification, and using real data from an opinion survey. The results indicate that the prediction approach appears to use auxiliary information more efficiently than the model‐assisted approach.     

Estimating rates of population change for a neotropical parrot with ratio,mark-recapture and matrix methods

Robust methods for estimating rates of population change ( u ) are necessary for applied and theoretical goals in conservation and evolutionary biology. Traditionally, u has been calculated from either ratios of population counts (observed u or u obs ), or population models based on projection matrices (asymptotic u or u asy ,). New mark-recapture methods permit calculation of u from mark-resighting information alone (realized u or u rea ), but empirical comparisons with other methods are rare. In this paper, rates of population change were calculated for a population of green-rumped parrotlets ( Forpus passerinus ) that have been studied for more than a decade in central Venezuela. First, a ratio method based on counts of detected birds was used to calculate u obs. Next, a temporal symmetry method based on mark-recapture data (i.e. the u -parameterization introduced by Pradel, 1996) was used to calculate u rea . Finally, a stage-structured matrix model based on state-specific estimates of fecundity, immigration, local survival, and transition rates was used to calculate u asy . Analyses were conducted separately for females and males. Overall values of u from the three methods were consistent and all indicated that the finite rate of population change was not significantly different from 1. Annual values of u from the three methods were also in general agreement for a majority of years. However, u rea from the temporal symmetry method had the greatest precision, and apparently better accuracy than u asy . Unrealistic annual values of u asy could have been due to poor estimates of the transitional probability of becoming a breeder ( é ) or to a mismatch between the actual and the asymptotic stable stage distribution. In this study, the trade-off between biological realism and accuracy was better met by the temporal symmetry than the matrix method. Our results suggest that the temporal symmetry models can be applied with confidence to populations where less information may be available.     

A Sample Selection Model with Skew‐normal Distribution

Non‐random sampling is a source of bias in empirical research. It is common for the outcomes of interest (e.g. wage distribution) to be skewed in the source population. Sometimes, the outcomes are further subjected to sample selection, which is a type of missing data, resulting in partial observability. Thus, methods based on complete cases for skew data are inadequate for the analysis of such data and a general sample selection model is required. Heckman proposed a full maximum likelihood estimation method under the normality assumption for sample selection problems, and parametric and non‐parametric extensions have been proposed. We generalize Heckman selection model to allow for underlying skew‐normal distributions. Finite‐sample performance of the maximum likelihood estimator of the model is studied via simulation. Applications illustrate the strength of the model in capturing spurious skewness in bounded scores, and in modelling data where logarithm transformation could not mitigate the effect of inherent skewness in the outcome variable.     

Bioequivalence and the pharmaceutical industry

Since the early 1990s, average bioequivalence (ABE) studies have served as the international regulatory standard for demonstrating that two formulations of drug product will provide the same therapeutic benefit and safety profile when used in the marketplace. Population (PBE) and individual (IBE) bioequivalence have been the subject of intense international debate since methods for their assessment were proposed in the late 1980s and since their use was proposed in United States Food and Drug Administration guidance in 1997. Guidance has since been proposed and finalized by the Food and Drug Administration for the implementation of such techniques in the pioneer and generic pharmaceutical industries. The current guidance calls for the use of replicate design and of cross‐over studies (cross‐overs with sequences TRTR, RTRT, where T is the test and R is the reference formulation) for selected drug products, and proposes restricted maximum likelihood and method‐of‐moments techniques for parameter estimation. In general, marketplace access will be granted if the products demonstrate ABE based on a restricted maximum likelihood model. Study sponsors have the option of using PBE or IBE if the use of these criteria can be justified to the regulatory authority. Novel and previously proposed SAS^®‐based approaches to the modelling of pharmacokinetic data from replicate design studies will be summarized. Restricted maximum likelihood and method‐of‐moments modelling results are compared and contrasted based on the analysis of data available from previously performed replicate design studies, and practical issues involved in the application of replicate designs to demonstrate ABE are characterized. It is concluded that replicate designs may be used effectively to demonstrate ABE for highly variable drug products. Statisticians should exercise caution in the choice of modelling procedure. Copyright © 2002 John Wiley & Sons, Ltd.     

The use of resighting data to estimate the rate of population growth of the snail kite in Florida

The rate of population growth ( u ) is an important demographic parameter used to assess the viability of a population and to develop management and conservation agendas. We examined the use of resighting data to estimate u for the snail kite population in Florida from 1997-2000. The analyses consisted of (1) a robust design approach that derives an estimate of u from estimates of population size and (2) the Pradel (1996) temporal symmetry (TSM) approach that directly estimates u using an open-population capture-recapture model. Besides resighting data, both approaches required information on the number of unmarked individuals that were sighted during the sampling periods. The point estimates of u differed between the robust design and TSM approaches, but the 95% confidence intervals overlapped substantially. We believe the differences may be the result of sparse data and do not indicate the inappropriateness of either modelling technique. We focused on the results of the robust design because this approach provided estimates for all study years. Variation among these estimates was smaller than levels of variation among ad hoc estimates based on previously reported index statistics. We recommend that u of snail kites be estimated using capture-resighting methods rather than ad hoc counts.