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.     

Alternating event processes during lifetimes: population dynamics and statistical inference

In the literature studying recurrent event data, a large amount of work has been focused on univariate recurrent event processes where the occurrence of each event is treated as a single point in time. There are many applications, however, in which univariate recurrent events are insufficient to characterize the feature of the process because patients experience nontrivial durations associated with each event. This results in an alternating event process where the disease status of a patient alternates between exacerbations and remissions. In this paper, we consider the dynamics of a chronic disease and its associated exacerbation-remission process over two time scales: calendar time and time-since-onset. In particular, over calendar time, we explore population dynamics and the relationship between incidence, prevalence and duration for such alternating event processes. We provide nonparametric estimation techniques for characteristic quantities of the process. In some settings, exacerbation processes are observed from an onset time until death; to account for the relationship between the survival and alternating event processes, nonparametric approaches are developed for estimating exacerbation process over lifetime. By understanding the population dynamics and within-process structure, the paper provide a new and general way to study alternating event processes.     

Estimation under generalized sampling of cell proportions for contingency tables subject to marginal constraints

Under simple random (multinomial) sampling the problem of estimating cell proportions for a contingency table subject to marginal constraints has been well explored. We briefly review methods that have been considered; then we develop a general method, for more complicated sampling, which reflects the variance structure of the estimated cell proportions. For stratified and cluster sampling we compare our method against earlier methods for the 2×2 table and find it potentially advantageous.     

Bayesiam simultaneous estimation for several multinomial distributions

A Bayesian method is proposed for estimating the cell probabilities of several multinomial distributions. Parameters of different distributions are taken to be a priori exchangeable. The prior specification is based upon mixtures of a hierarchical distribution, referred to as the multivariate “Dirichlet-Dirichlet” distribution. The analysis is facilitated by a multinomial approximation relating to the multinomial-Dirichlet distribution. The posterior estimates depend upon measures of entropy for the various distributions and shrink the individual observed proportions towards values obtained by pooling the data across the distributions. As well as incorporating prior information they are particularly useful when some of the cell frequencies are zero. We use them to investigate a numerical classification of males of various vocations, according to cause of death.     

Estimating progression-free survival in paediatric brain tumour patients when some progression statuses are unknown

In oncology, progression-free survival time, which is defined as the minimum of the times to disease progression or death, often is used to characterize treatment and covariate effects. We are motivated by the desire to estimate the progression time distribution on the basis of data from 780 paediatric patients with choroid plexus tumours, which are a rare brain cancer where disease progression always precedes death. In retrospective data on 674 patients, the times to death or censoring were recorded but progression times were missing. In a prospective study of 106 patients, both times were recorded but there were only 20 non-censored progression times and 10 non-censored survival times. Consequently, estimating the progression time distribution is complicated by the problems that, for most of the patients, either the survival time is known but the progression time is not known, or the survival time is right censored and it is not known whether the patient's disease progressed before censoring. For data with these missingness structures, we formulate a family of Bayesian parametric likelihoods and present methods for estimating the progression time distribution. The underlying idea is that estimating the association between the time to progression and subsequent survival time from patients having complete data provides a basis for utilizing covariates and partial event time data of other patients to infer their missing progression times. We illustrate the methodology by analysing the brain tumour data, and we also present a simulation study.     

Predicting infectious disease outbreak risk via migratory waterfowl vectors

The spread of an emerging infectious disease is a major public health threat. Given the uncertainties associated with vector-borne diseases, in terms of vector dynamics and disease transmission, it is critical to develop statistical models that address how and when such an infectious disease could spread throughout a region such as the USA. This paper considers a spatio-temporal statistical model for how an infectious disease could be carried into the USA by migratory waterfowl vectors during their seasonal migration and, ultimately, the risk of transmission of such a disease to domestic fowl. Modeling spatio-temporal data of this type is inherently difficult given the uncertainty associated with observations, complexity of the dynamics, high dimensionality of the underlying process, and the presence of excessive zeros. In particular, the spatio-temporal dynamics of the waterfowl migration are developed by way of a two-tiered functional temporal and spatial dimension reduction procedure that captures spatial and seasonal trends, as well as regional dynamics. Furthermore, the model relates the migration to a population of poultry farms that are known to be susceptible to such diseases, and is one of the possible avenues toward transmission to domestic poultry and humans. The result is a predictive distribution of those counties containing poultry farms that are at the greatest risk of having the infectious disease infiltrate their flocks assuming that the migratory population was infected. The model naturally fits into the hierarchical Bayesian framework.     

Optimum designs for parameter estimation in a mixture experiment with two correlated responses

In this paper, we investigate a mixture problem with two responses, which are functions of the mixing proportions, and are correlated with known dispersion matrix. We obtain D- and A-optimal designs for estimating the parameters of the response functions, when none or some of the regression coefficients of the two functions are the same. It is shown that when no prior knowledge about the regression coefficients is available, the D-optimal design is independent of the dispersion matrix, while the A-optimal design depends on it, provided the response functions are of different degree. On the other hand, when some of the regression coefficients are known to be the same for both the functions, the D-optimal design depends on the dispersion matrix when the two response functions are not of the same degree.     

Estimators in capture–recapture studies with two sources

This paper investigates the applications of capture–recapture methods to human populations. Capture–recapture methods are commonly used in estimating the size of wildlife populations but can also be used in epidemiology and social sciences, for estimating prevalence of a particular disease or the size of the homeless population in a certain area. Here we focus on estimating the prevalence of infectious diseases. Several estimators of population size are considered: the Lincoln–Petersen estimator and its modified version, the Chapman estimator, Chao’s lower bound estimator, the Zelterman’s estimator, McKendrick’s moment estimator and the maximum likelihood estimator. In order to evaluate these estimators, they are applied to real, three-source, capture-recapture data. By conditioning on each of the sources of three source data, we have been able to compare the estimators with the true value that they are estimating. The Chapman and Chao estimators were compared in terms of their relative bias. A variance formula derived through conditioning is suggested for Chao’s estimator, and normal 95% confidence intervals are calculated for this and the Chapman estimator. We then compare the coverage of the respective confidence intervals. Furthermore, a simulation study is included to compare Chao’s and Chapman’s estimator. Results indicate that Chao’s estimator is less biased than Chapman’s estimator unless both sources are independent. Chao’s estimator has also the smaller mean squared error. Finally, the implications and limitations of the above methods are discussed, with suggestions for further development. We are grateful to the Medical Research Council for supporting this work.     

A three-state disease model with interval-censored data: Estimation and applications to AIDS and cancer

In presence of interval-censored data, we propose a general three-state disease model with covariates. Such data can arise, for example, in epidemiologic studies of infectious disease where both the times of infection and disease onset are not directly observed, or in cancer studies where the time of disease metastasis is known up to a specified interval. The proposed model allows the distributions of the transition times between states to depend on covariates and the time in the previous state. An estimation procedure for the underlying distributions and the model coefficients is suggested with the EM algorithm. The EMS algorithm (Smoothed EM algorithm) is also considered to obtain smooth estimates of the distributions. The proposed method is illustrated with data from an AIDS study and a study of patients with malignant melanoma.     

Accelerated failure time models for the analysis of competing risks

Competing risks are common in clinical cancer research, as patients are subject to multiple potential failure outcomes, such as death from the cancer itself or from complications arising from the disease. In the analysis of competing risks, several regression methods are available for the evaluation of the relationship between covariates and cause-specific failures, many of which are based on Cox’s proportional hazards model. Although a great deal of research has been conducted on estimating competing risks, less attention has been devoted to linear regression modeling, which is often referred to as the accelerated failure time (AFT) model in survival literature. In this article, we address the use and interpretation of linear regression analysis with regard to the competing risks problem. We introduce two types of AFT modeling framework, where the influence of a covariate can be evaluated in relation to either a cause-specific hazard function, referred to as cause-specific AFT (CS-AFT) modeling in this study, or the cumulative incidence function of a particular failure type, referred to as crude-risk AFT (CR-AFT) modeling. Simulation studies illustrate that, as in hazard-based competing risks analysis, these two models can produce substantially different effects, depending on the relationship between the covariates and both the failure type of principal interest and competing failure types. We apply the AFT methods to data from non-Hodgkin lymphoma patients, where the dataset is characterized by two competing events, disease relapse and death without relapse, and non-proportionality. We demonstrate how the data can be analyzed and interpreted, using linear competing risks regression models.     

Bayesian inference for Poisson and multinomial log-linear models

Categorical data frequently arise in applications in the Social Sciences. In such applications, the class of log-linear models, based on either a Poisson or (product) multinomial response distribution, is a flexible model class for inference and prediction. In this paper we consider the Bayesian analysis of both Poisson and multinomial log-linear models. It is often convenient to model multinomial or product multinomial data as observations of independent Poisson variables. For multinomial data, Lindley (1964) [20] showed that this approach leads to valid Bayesian posterior inferences when the prior density for the Poisson cell means factorises in a particular way. We develop this result to provide a general framework for the analysis of multinomial or product multinomial data using a Poisson log-linear model. Valid finite population inferences are also available, which can be particularly important in modelling social data. We then focus particular attention on multivariate normal prior distributions for the log-linear model parameters. Here, an improper prior distribution for certain Poisson model parameters is required for valid multinomial analysis, and we derive conditions under which the resulting posterior distribution is proper. We also consider the construction of prior distributions across models, and for model parameters, when uncertainty exists about the appropriate form of the model. We present classes of Poisson and multinomial models, invariant under certain natural groups of permutations of the cells. We demonstrate that, if prior belief concerning the model parameters is also invariant, as is the case in a ‘reference’ analysis, then the choice of prior distribution is considerably restricted. The analysis of multivariate categorical data in the form of a contingency table is considered in detail. We illustrate the methods with two examples.     

Modeling restricted mean survival time under general censoring mechanisms

Restricted mean survival time (RMST) is often of great clinical interest in practice. Several existing methods involve explicitly projecting out patient-specific survival curves using parameters estimated through Cox regression. However, it would often be preferable to directly model the restricted mean for convenience and to yield more directly interpretable covariate effects. We propose generalized estimating equation methods to model RMST as a function of baseline covariates. The proposed methods avoid potentially problematic distributional assumptions pertaining to restricted survival time. Unlike existing methods, we allow censoring to depend on both baseline and time-dependent factors. Large sample properties of the proposed estimators are derived and simulation studies are conducted to assess their finite sample performance. We apply the proposed methods to model RMST in the absence of liver transplantation among end-stage liver disease patients. This analysis requires accommodation for dependent censoring since pre-transplant mortality is dependently censored by the receipt of a liver transplant.     

Tobit regression for modeling mean survival time using data subject to multiple sources of censoring

Mean survival time is often of inherent interest in medical and epidemiologic studies. In the presence of censoring and when covariate effects are of interest, Cox regression is the strong default, but mostly due to convenience and familiarity. When survival times are uncensored, covariate effects can be estimated as differences in mean survival through linear regression. Tobit regression can validly be performed through maximum likelihood when the censoring times are fixed (ie, known for each subject, even in cases where the outcome is observed). However, Tobit regression is generally inapplicable when the response is subject to random right censoring. We propose Tobit regression methods based on weighted maximum likelihood which are applicable to survival times subject to both fixed and random censoring times. Under the proposed approach, known right censoring is handled naturally through the Tobit model, with inverse probability of censoring weighting used to overcome random censoring. Essentially, the re‐weighting data are intended to represent those that would have been observed in the absence of random censoring. We develop methods for estimating the Tobit regression parameter, then the population mean survival time. A closed form large‐sample variance estimator is proposed for the regression parameter estimator, with a semiparametric bootstrap standard error estimator derived for the population mean. The proposed methods are easily implementable using standard software. Finite‐sample properties are assessed through simulation. The methods are applied to a large cohort of patients wait‐listed for kidney transplantation.     

Estimation of proportions for multinomial contingency tables subject to marginal constraints

For a two-way table of observed proportions we consider four approaches to the problem of fitting a new set of proportions which-subject to satisfying marginal constraints on row and column totals-corresponds as closely as possible to the original table, The approaches are known to be asymptotically equivalent; but our chief interest is in establishing, at least for the 2x2 table, a hierarchy of preferences under multinomial sampling for moderate sample sizes. Implementation of minimum chi-square is described and recommended.     

A statistical method to convert published response rates into marginal distributions with an example application in psoriasis

Assessment of severity is essential for the management of chronic diseases. Continuous variables like scores obtained from the Hamilton Rating Scale for Depression or the Psoriasis Area and Severity Index (PASI) are standard measures used in clinical trials of depression and psoriasis. In clinical trials of psoriasis, for example, the reduction of PASI from baseline in response to therapy, in particular the proportion of patients achieving at least 75%, 90%, or 100% improvement of disease (PASI 75, PASI 90, or PASI 100), is typically used to evaluate treatment efficacy. However, evaluation of the proportions of patients reaching absolute PASI values (eg, ≤1, ≤2, ≤3, or ≤5) has recently gained greater clinical interest and is increasingly being reported. When relative versus absolute scores are standard, as is the case with the PASI in psoriasis, it is difficult to compare absolute changes using existing published data. Thus, we developed a method to estimate absolute PASI levels from aggregated relative levels. This conversion method is based on a latent 2‐dimensional normal distribution for the absolute score at baseline and at a specific endpoint with a truncation to allow for baseline inclusion criterion. The model was fitted to aggregated results from simulations and from 3 phase III studies that had known absolute PASI proportions. The predictions represented the actual results quite precisely. This model might be applied to other conditions, such as depression, to estimate proportions of patients achieving an absolute low level of disease activity, given absolute values at baseline and proportions of patients achieving relative improvements at a subsequent time point.     

Design issues for studies of infectious diseases

The design of infectious disease studies has received little attention because they are generally viewed as observational studies. That is, epidemic and endemic disease transmission happens and we observe it. We argue here that statistical design often provides useful guidance for such studies with regard to type of data and the size of the data set to be collected. It is shown that data on disease transmission in part of the community enables the estimation of central parameters and it is possible to compute the sample size required to make inferences with a desired precision. We illustrate this for data on disease transmission in a single community of uniformly mixing individuals and for data on outbreak sizes in households. Data on disease transmission is usually incomplete and this creates an identifiability problem for certain parameters of multitype epidemic models. We identify designs that can overcome this problem for the important objective of estimating parameters that help to assess the effectiveness of a vaccine. With disease transmission in animal groups there is greater scope for conducting planned experiments and we explore some possibilities for such experiments. The topic is largely unexplored and numerous open research problems in the area of statistical design of infectious disease data are mentioned.     

Estimating the transmission probability of human immunodeficiency virus in injecting drug users in Thailand

We estimate the transmission probability for the human immunodeficiency virus from seroconversion data of a cohort of injecting drug users (IDUs) in Thailand. The transmission probability model developed accounts for interval censoring and incorporates each IDU's reported frequency of needle sharing and injecting acts. Using maximum likelihood methods, the per needle sharing act transmission probability estimate between infectious and susceptible IDUs is 0.008. The effects of covariates, disease dynamics, mismeasured exposure information and the uncertainty of the disease prevalence on the transmission probability estimate are considered.     

Estimating probability of occurrence of the most likely multinomial event

The problem of estimating the parameters of a multinomial population arises in discrete multivariate analysis. This paper deals with the problem of estimating the probability associated with the most likely multinomial event. We consider several estimates, such as the maximum likelihood estimate and its modifications, and a Bayes estimate. Certain mathematical properties of the estimates are shown. Empirical results are given, showing the relative performance of the estimates with respect to the mean squared error as the loss function.     

Objective Bayesian analysis of counting experiments with correlated sources of background

Searches for faint signals in counting experiments are often encountered in particle physics and astrophysics, as well as in other fields. Many problems can be reduced to the case of a model with independent and Poisson-distributed signal and background. Often several background contributions are present at the same time, possibly correlated. We provide the analytic solution of the statistical inference problem of estimating the signal in the presence of multiple backgrounds, in the framework of objective Bayes statistics. The model can be written in the form of a product of a single Poisson distribution with a multinomial distribution. The first is related to the total number of events, whereas the latter describes the fraction of events coming from each individual source. Correlations among different backgrounds can be included in the inference problem by a suitable choice of the priors.     

Pairwise comparisons for proportions estimated by pooled testing

When estimating the prevalence of a rare trait, pooled testing can confer substantial benefits when compared to individual testing. In addition to screening experiments for infectious diseases in humans, pooled testing has also been exploited in other applications such as drug testing, epidemiological studies involving animal disease, plant disease assessment, and screening for rare genetic mutations. Within a pooled-testing context, we consider situations wherein different strata or treatments are to be compared with the goals of assessing significant and practical differences between strata and ranking strata in terms of prevalence. To achieve these goals, we first present two simultaneous pairwise interval estimation procedures for use with pooled data. Our procedures rely on asymptotic results, so we investigate small-sample behavior and compare the two procedures in terms of simultaneous coverage probability and mean interval length. We then present a unified approach to determine pool sizes which deliver desired coverage properties while taking testing costs and interval precision into account. We illustrate our methods using data from an observational HIV study involving heterosexual males who use intravenous drugs.