Spatial modeling using frequentist approach for disease mapping

In this article, a generalized linear mixed model (GLMM) based on a frequentist approach is employed to examine spatial trend of asthma data. However, the frequentist analysis of GLMM is computationally difficult. On the other hand, the Bayesian analysis of GLMM has been computationally convenient due to the advent of Markov chain Monte Carlo algorithms. Recently developed data cloning (DC) method, which yields to maximum likelihood estimate, provides frequentist approach to complex mixed models and equally computationally convenient method. We use DC to conduct frequentist analysis of spatial models. The advantages of the DC approach are that the answers are independent of the choice of the priors, non-estimable parameters are flagged automatically, and the possibility of improper posterior distributions is completely avoided. We illustrate this approach using a real dataset of asthma visits to hospital in the province of Manitoba, Canada, during 2000–2010. The performance of the DC approach in our application is also studied through a simulation study.     

Hierarchical Bayesian bivariate disease mapping: analysis of children and adults asthma visits to hospital

In spatial epidemiology, detecting areas with high ratio of disease is important as it may lead to identifying risk factors associated with disease. This in turn may lead to further epidemiological investigations into the nature of disease. Disease mapping studies have been widely performed with considering only one disease in the estimated models. Simultaneous modelling of different diseases can also be a valuable tool both from the epidemiological and also from the statistical point of view. In particular, when we have several measurements recorded at each spatial location, one can consider multivariate models in order to handle the dependence among the multivariate components and the spatial dependence between locations. In this paper, spatial models that use multivariate conditionally autoregressive smoothing across the spatial dimension are considered. We study the patterns of incidence ratios and identify areas with consistently high ratio estimates as areas for further investigation. A hierarchical Bayesian approach using Markov chain Monte Carlo techniques is employed to simultaneously examine spatial trends of asthma visits by children and adults to hospital in the province of Manitoba, Canada, during 2000–2010.     

Spatio‐temporal modelling of disease mapping of rates

This paper studies generalized linear mixed models (GLMMs) for the analysis of geographic and temporal variability of disease rates. This class of models adopts spatially correlated random effects and random temporal components. Spatio‐temporal models that use conditional autoregressive smoothing across the spatial dimension and autoregressive smoothing over the temporal dimension are developed. The model also accommodates the interaction between space and time. However, the effect of seasonal factors has not been previously addressed and in some applications (e.g., health conditions), these effects may not be negligible. The authors incorporate the seasonal effects of month and possibly year as part of the proposed model and estimate model parameters through generalized estimating equations. The model provides smoothed maps of disease risk and eliminates the instability of estimates in low‐population areas while maintaining geographic resolution. They illustrate the approach using a monthly data set of the number of asthma presentations made by children to Emergency Departments (EDs) in the province of Alberta, Canada, during the period 2001–2004. The Canadian Journal of Statistics 38: 698–715; 2010 © 2010 Statistical Society of Canada     

Estimating the Relative Density of Snapper in and around a Marine Reserve Using a Log-Linear Mixed-Effects Model

Angling from small recreational fishing boats was used as a sampling method to quantify the relative density of snapper ( Pagrus auratus ) in six areas within the Cape Rodney-Okakari Point Marine Reserve (New Zealand) and four areas adjacent to the reserve. Penalized quasi-likelihood was used to fit a log-linear mixed-effects model having area and date as fixed effects and boat as a random effect. Simulation and first-order bias correction formulae were employed to assess the validity of the estimates of the area effects. The bias correction is known to be unsuitable for general use because it typically over-estimatesbias, and this was observed here. However, it was qualitatively useful for indicating the direction of bias and for indicating when estimators were approximately unbiased. The parameter of primary interest was the ratio of snapper density in the marine reserve versus snapper density outside the reserve, and the estimator of this parameter was first-order asymptotically unbiased. This ratio of snapper densities was estimated to be 11 (±3).     

Spatio-temporal model for crop yield forecasting

This paper proposes a linear mixed model (LMM) with spatial effects, trend, seasonality and outliers for spatio-temporal time series data. A linear trend, dummy variables for seasonality, a binary method for outliers and a multivariate conditional autoregressive (MCAR) model for spatial effects are adopted. A Bayesian method using Gibbs sampling in Markov Chain Monte Carlo is used for parameter estimation. The proposed model is applied to forecast rice and cassava yields, a spatio-temporal data type, in Thailand. The data have been extracted from the Office of Agricultural Economics, Ministry of Agriculture and Cooperatives of Thailand. The proposed model is compared with our previous model, an LMM with MCAR, and a log transformed LMM with MCAR. We found that the proposed model is the most appropriate, using the mean absolute error criterion. It fits the data very well in both the fitting part and the validation part for both rice and cassava. Therefore, it is recommended to be a primary model for forecasting these types of spatio-temporal time series data.     

Bayesian analysis of spatial data using different variance and neighbourhood structures

In disease mapping, the overall goal is to study the incidence or mortality risk caused by a specific disease in a number of geographical regions. It is common to assume that the response variable follows a Poisson distribution, whose average rate can be explained by a group of covariates and a random effect. For this random effect, it is considered conditional autoregressive (CAR) models, which carry information about the neighbourhood relationship between the regions. The focus of this paper was to explore and compare some CAR models proposed in the literature. An application with epidemiological data was conducted to model the risk of death due to Crohn's Disease and Ulcerative Colitis in the State of São Paulo – Brazil. Finally, a simulation study was done to strengthen the results and assess the performance of the models in the presence of various levels of spatial dependence.     

Comparing alternating logistic regressions to other approaches to modelling correlated binary data

Alternating logistic regressions (ALRs) seem to offer some of the advantages of marginal models estimated via generalized estimating equations (GEE) and generalized linear mixed models (GLMMs). Via simulation study we compared ALRs to marginal models estimated via GEE and subject-specific models estimated via GLMMs, with a focus on estimation of the correlation structure in three-level data sets (e.g. students in classes in schools). Data set size and structure, and amount of correlation in the data sets were varied. For simple correlation structures, ALRs performed well. For three-level correlation structures, all approaches, but especially ALRs, had difficulty assigning the correlation to the correct level, though sample sizes used were small. In addition, ALRs and GEEs had trouble attaching correct inference to the mean effects, though this improved as overall sample size improved. ALRs are a valuable addition to the data analyst's toolkit, though care should be taken when modelling data with three-level structures.     

Bayesian joint modeling of correlated counts data with application to adverse birth outcomes

In disease mapping, health outcomes measured at the same spatial locations may be correlated, so one can consider joint modeling the multivariate health outcomes accounting for their dependence. The general approaches often used for joint modeling include shared component models and multivariate models. An alternative way to model the association between two health outcomes, when one outcome can naturally serve as a covariate of the other, is to use ecological regression model. For example, in our application, preterm birth (PTB) can be treated as a predictor for low birth weight (LBW) and vice versa. Therefore, we proposed to blend the ideas from joint modeling and ecological regression methods to jointly model the relative risks for LBW and PTBs over the health districts in Saskatchewan, Canada, in 2000–2010. This approach is helpful when proxy of areal-level contextual factors can be derived based on the outcomes themselves when direct information on risk factors are not readily available. Our results indicate that the proposed approach improves the model fit when compared with the conventional joint modeling methods. Further, we showed that when no strong spatial autocorrelation is present, joint outcome modeling using only independent error terms can still provide a better model fit when compared with the separate modeling.     

A test for the linearity of the nonparametric part of a semiparametric logistic regression model

A semiparametric logistic regression model is proposed in which its nonparametric component is approximated with fixed-knot cubic B-splines. To assess the linearity of the nonparametric component, we construct a penalized likelihood ratio test statistic. When the number of knots is fixed, the null distribution of the test statistic is shown to be asymptotically the distribution of a linear combination of independent chi-squared random variables, each with one degree of freedom. We set the asymptotic null expectation of this test statistic equal to a value to determine the smoothing parameter value. Monte Carlo experiments are conducted to investigate the performance of the proposed test. Its practical use is illustrated with a real-life example.     

Model-cum-design-based estimation of the prevalence rate of a disease in a locality using spatial smoothing

In this article, we study the problem of estimating the prevalence rate of a disease in a geographical area, based on data collected from a sample of locations within this area. If there are several locations with zero incidence of the disease, the usual estimators are not suitable and so we develop a new estimator, together with an unbiased estimator of its variance, which may be appropriately used in such situations. An application of this estimator is illustrated with data from a large-scale survey, which was carried out in the city of Kolkata, India, to estimate the prevalence rate of stroke. We show that spatial modelling may be used to smooth the observed data before applying our proposed estimator. Our computations show that this smoothing helps to reduce the coefficient of variation and such a model-cum-design-based procedure is useful for estimating the prevalence rate. This method may of course be used in other similar situations.     

Statistical disease mapping for heterogeneous neuroimaging studies

Many cancers and neuro‐related diseases display significant phenotypic and genetic heterogeneity across subjects and subpopulations. Characterizing such heterogeneity could transform our understanding of the etiology of these conditions and inspire new approaches to urgently needed prevention, diagnosis, treatment, and prognosis. However, most existing statistical methods face major challenges in delineating such heterogeneity at both the group and individual levels. The aim of this article is to propose a novel statistical disease‐mapping (SDM) framework to address some of these challenges. We develop an efficient estimation method to estimate unknown parameters in SDM and delineate individual and group disease maps. Statistical inference procedures such as hypothesis‐testing problems are also investigated for parameters of interest. Both simulation studies and real data analysis on the ADNI hippocampal surface dataset show that our SDM not only effectively detects diseased regions in each patient but also provides a group disease‐mapping analysis of Alzheimer subgroups.     

A Simulation-based Goodness-of-fit Test for Random Effects in Generalized Linear Mixed Models

Abstract.  The goodness-of-fit of the distribution of random effects in a generalized linear mixed model is assessed using a conditional simulation of the random effects conditional on the observations. Provided that the specified joint model for random effects and observations is correct, the marginal distribution of the simulated random effects coincides with the assumed random effects distribution. In practice, the specified model depends on some unknown parameter which is replaced by an estimate. We obtain a correction for this by deriving the asymptotic distribution of the empirical distribution function obtained from the conditional sample of the random effects. The approach is illustrated by simulation studies and data examples.     

Vector-borne infectious disease mapping with stochastic difference equations: an analysis of dengue disease in Malaysia

Few publications consider the estimation of relative risk for vector-borne infectious diseases. Most of these articles involve exploratory analysis that includes the study of covariates and their effects on disease distribution and the study of geographic information systems to integrate patient-related information. The aim of this paper is to introduce an alternative method of relative risk estimation based on discrete time–space stochastic SIR-SI models (susceptible–infective–recovered for human populations; susceptible–infective for vector populations) for the transmission of vector-borne infectious diseases, particularly dengue disease. First, we describe deterministic compartmental SIR-SI models that are suitable for dengue disease transmission. We then adapt these to develop corresponding discrete time–space stochastic SIR-SI models. Finally, we develop an alternative method of estimating the relative risk for dengue disease mapping based on these models and apply them to analyse dengue data from Malaysia. This new approach offers a better model for estimating the relative risk for dengue disease mapping compared with the other common approaches, because it takes into account the transmission process of the disease while allowing for covariates and spatial correlation between risks in adjacent regions.     

Modelling population-based cancer survival trends using join point models for grouped survival data

Summary.  In the USA cancer as a whole is the second leading cause of death and a major burden to health care; thus medical progress against cancer is a major public health goal. There are many individual studies to suggest that cancer treatment breakthroughs and early diagnosis have significantly improved the prognosis of cancer patients. To understand better the relationship between medical improvements and the survival experience for the patient population at large, it is useful to evaluate cancer survival trends on the population level, e.g. to find out when and how much the cancer survival rates changed. We analyse population-based grouped cancer survival data by incorporating join points into the survival models. A join point survival model facilitates the identification of trends with significant change-points in cancer survival, when related to cancer treatments or interventions. The Bayesian information criterion is used to select the number of join points. The performance of the join point survival models is evaluated with respect to cancer prognosis, join point locations, annual percentage changes in death rates by year of diagnosis and sample sizes through intensive simulation studies. The model is then applied to grouped relative survival data for several major cancer sites from the 'Surveillance, epidemiology and end results' programme of the National Cancer Institute. The change-points in the survival trends for several major cancer sites are identified and the potential driving forces behind such change-points are discussed.     

Joint modelling of longitudinal response and time-to-event data using conditional distributions: a Bayesian perspective

Over the last 20 or more years a lot of clinical applications and methodological development in the area of joint models of longitudinal and time-to-event outcomes have come up. In these studies, patients are followed until an event, such as death, occurs. In most of the work, using subject-specific random-effects as frailty, the dependency of these two processes has been established. In this article, we propose a new joint model that consists of a linear mixed-effects model for longitudinal data and an accelerated failure time model for the time-to-event data. These two sub-models are linked via a latent random process. This model will capture the dependency of the time-to-event on the longitudinal measurements more directly. Using standard priors, a Bayesian method has been developed for estimation. All computations are implemented using OpenBUGS. Our proposed method is evaluated by a simulation study, which compares the conditional model with a joint model with local independence by way of calibration. Data on Duchenne muscular dystrophy (DMD) syndrome and a set of data in AIDS patients have been analysed.     

Analyzing dependence in incidence of diabetes and heart problem using generalized bivariate geometric models with covariates

For analyzing incidence data on diabetes and health problems, the bivariate geometric probability distribution is a natural choice but remained unexplored largely due to lack of models linking covariates with the probabilities of bivariate incidence of correlated outcomes. In this paper, bivariate geometric models are proposed for two correlated incidence outcomes. The extended generalized linear models are developed to take into account covariate dependence of the bivariate probabilities of correlated incidence outcomes for diabetes and heart diseases for the elderly population. The estimation and test procedures are illustrated using the Health and Retirement Study data. Two models are shown in this paper, one based on conditional-marginal approach and the other one based on the joint probability distribution with an association parameter. The joint model with association parameter appears to be a very good choice for analyzing the covariate dependence of the joint incidence of diabetes and heart diseases. Bootstrapping is performed to measure the accuracy of estimates and the results indicate very small bias.     

Goodness-of-fit tests of generalized linear mixed models for repeated ordinal responses

Categorical longitudinal data are frequently applied in a variety of fields, and are commonly fitted by generalized linear mixed models (GLMMs) and generalized estimating equations models. The cumulative logit is one of the useful link functions to deal with the problem involving repeated ordinal responses. To check the adequacy of the GLMMs with cumulative logit link function, two goodness-of-fit tests constructed by the unweighted sum of squared model residuals using numerical integration and bootstrap resampling technique are proposed. The empirical type I error rates and powers of the proposed tests are examined by simulation studies. The ordinal longitudinal studies are utilized to illustrate the application of the two proposed tests.     

Simultaneous modelling of multiple traffic safety performance indicators by using a multivariate generalized linear mixed model

Summary.  Traffic safety in the UK is one of the increasing number of areas where central government sets targets based on 'outcome-focused' performance indicators (PIs). Judgments about such PIs are often based solely on rankings of raw indicators and simple league tables dominate centrally published analyses. There is a considerable statistical literature examining health and education issues which has tended to use the generalized linear mixed model (GLMM) to address variability in the data when drawing inferences about relative performance from headline PIs. This methodology could obviously be applied in contexts such as traffic safety. However, when such models are applied to the fairly crude data sets that are currently available, the interval estimates generated, e.g. in respect of rankings, are often too broad to allow much real differentiation between the traffic safety performance of the units that are being considered. Such results sit uncomfortably with the ethos of 'performance management' and raise the question of whether the inference from such data sets about relative performance can be improved in some way. Motivated by consideration of a set of nine road safety performance indicators measured on English local authorities in the year 2000, the paper considers methods to strengthen the weak inference that is obtained from GLMMs of individual indicators by simultaneous, multivariate modelling of a range of related indicators. The correlation structure between indicators is used to reduce the uncertainty that is associated with rankings of any one of the individual indicators. The results demonstrate that credible intervals can be substantially narrowed by the use of the multivariate GLMM approach and that multivariate modelling of multiple PIs may therefore have considerable potential for introducing more robust and realistic assessments of differential performance in some contexts.     

Relative risk analysis of dengue cases using convolution extended into spatio-temporal model

Dengue Hemmorage Fever (DHF) cases have become a serious problem every year in tropical countries such as Indonesia. Understanding the dynamic spread of the disease is essential in order to find an effective strategy in controlling its spread. In this study, a convolution (Poisson-lognormal) model that integrates both uncorrelated and correlated random effects was developed. A spatial–temporal convolution model to accomodate both spatial and temporal variations of the disease spread dynamics was considered. The model was applied to the DHF cases in the city of Kendari, Indonesia. DHF data for 10 districts during the period 2007–2010 were collected from the health services. The data of rainfall and population density were obtained from the local offices in Kendari. The numerical experiments indicated that both the rainfall and the population density played an important role in the increasing DHF cases in the city of Kendari. The result suggested that DHF cases mostly occured in January, the wet session with high rainfall, and in Kadia, the densest district in the city. As people in the city have high mobility while dengue mosquitoes tend to stay localized in their area, the best intervention is in January and in the district of Kadia.     

Testing for bioequivalence of highly variable drugs from TR‐RT crossover designs with heterogeneous residual variances

Traditional bioavailability studies assess average bioequivalence (ABE) between the test (T) and reference (R) products under the crossover design with TR and RT sequences. With highly variable (HV) drugs whose intrasubject coefficient of variation in pharmacokinetic measures is 30% or greater, assertion of ABE becomes difficult due to the large sample sizes needed to achieve adequate power. In 2011, the FDA adopted a more relaxed, yet complex, ABE criterion and supplied a procedure to assess this criterion exclusively under TRR‐RTR‐RRT and TRTR‐RTRT designs. However, designs with more than 2 periods are not always feasible. This present work investigates how to evaluate HV drugs under TR‐RT designs. A mixed model with heterogeneous residual variances is used to fit data from TR‐RT designs. Under the assumption of zero subject‐by‐formulation interaction, this basic model is comparable to the FDA‐recommended model for TRR‐RTR‐RRT and TRTR‐RTRT designs, suggesting the conceptual plausibility of our approach. To overcome the distributional dependency among summary statistics of model parameters, we develop statistical tests via the generalized pivotal quantity (GPQ). A real‐world data example is given to illustrate the utility of the resulting procedures. Our simulation study identifies a GPQ‐based testing procedure that evaluates HV drugs under practical TR‐RT designs with desirable type I error rate and reasonable power. In comparison to the FDA's approach, this GPQ‐based procedure gives similar performance when the product's intersubject standard deviation is low (≤0.4) and is most useful when practical considerations restrict the crossover design to 2 periods.