Direct parametric inference for the cumulative incidence function

Summary.  In survival data that are collected from phase III clinical trials on breast cancer, a patient may experience more than one event, including recurrence of the original cancer, new primary cancer and death. Radiation oncologists are often interested in comparing patterns of local or regional recurrences alone as first events to identify a subgroup of patients who need to be treated by radiation therapy after surgery. The cumulative incidence function provides estimates of the cumulative probability of locoregional recurrences in the presence of other competing events. A simple version of the Gompertz distribution is proposed to parameterize the cumulative incidence function directly. The model interpretation for the cumulative incidence function is more natural than it is with the usual cause-specific hazard parameterization. Maximum likelihood analysis is used to estimate simultaneously parametric models for cumulative incidence functions of all causes. The parametric cumulative incidence approach is applied to a data set from the National Surgical Adjuvant Breast and Bowel Project and compared with analyses that are based on parametric cause-specific hazard models and nonparametric cumulative incidence estimation.     

Nonparametric estimation of the hazard function by using a model selection method: estimation of cancer deaths in Hiroshima atomic bomb survivors

Summary.  Controversy has intensified regarding the death-rate from cancer that is induced by a dose of radiation. In the models that are usually considered the hazard function is an increasing function of the dose of radiation. Such models can mask local variations. We consider the models of excess relative risk and of absolute risk and propose a nonparametric estimation of the effect of the dose by using a model selection procedure. This estimation deals with stratified data. We approximate the function of the dose by a collection of splines and select the best one according to the Akaike information criterion. In the same way between the models of excess relative risk or excess absolute risk, we choose the model that best fits the data. We propose a bootstrap method for calculating a pointwise confidence interval of the dose function. We apply our method for estimating the solid cancer and leukaemia death hazard functions to Hiroshima.     

Bayesian prediction for small areas using sur models

Sample surveys are usually designed and analyzed to produce estimates for larger areas and/or populations. Nevertheless, sample sizes are often not large enough to give adequate precision for small area estimates of interest. To circumvent such difficulties, borrowing strength from related small areas via modeling becomes essential. In line with this, we propose a hierarchical multivariate Bayes prediction method for small area estimation based on the seemingly unrelated regressions (SUR) model. The performance of the proposed method was evaluated through simulation studies.     

Analysing competing risks data with transformation models

We present a flexible class of marginal models for the cumulative incidence function. The semiparametric transformation model is utilized in a decomposition for the marginal failure probabilities which extends previous work on Farewell's cure model. Novel estimation, inference and prediction procedures are developed, with large sample properties derived from the theory of martingales and U-statistics. A small simulation study demonstrates that the methods are appropriate for practical use. The methods are illustrated with a thorough analysis of a prostate cancer clinical trial. Simple graphical displays are used to check for the goodness of fit.     

The analysis of ratios and cross-product ratios of poisson variates with application to incidence rates

The incidence of most diseases is low enough that in. large populations the number of new cases may be considered a Poisson variate. This paper explores models and methods for analyzing such data Specific cases are the estimation and testing of ratios and the cross-product ratios, both simple and stratified* We assume the Poisson means are exponential functions of the relevant parameters. The resulting sets of sufficient statistics are partitioned into a test statistic and a vector of statistics related to the nuisance parameters . The methods derived are based on the conditional distribution of the test statistic given the other sufficient statistics. The analyses of stratified cross-product ratios are seen to be analogues of the noncentral distribution associated with theanalysis of the common odds ratio in several 2×2 tables. The various methods are illustrated in numerical examples involving incidence rates of cancer in two metropolitan areas adjusting for both age and sex.     

Hierarchical Bayes estimation in small area estimation using cross-sectional and time-series data

Bayesian methods have been extensively used in small area estimation. A linear model incorporating autocorrelated random effects and sampling errors was previously proposed in small area estimation using both cross-sectional and time-series data in the Bayesian paradigm. There are, however, many situations that we have time-related counts or proportions in small area estimation; for example, monthly dataset on the number of incidence in small areas. This article considers hierarchical Bayes generalized linear models for a unified analysis of both discrete and continuous data with incorporating cross-sectional and time-series data. The performance of the proposed approach is evaluated through several simulation studies and also by a real dataset.     

Spatio-temporal modelling using B-spline for disease mapping: analysis of childhood cancer trends

To examine childhood cancer diagnoses in the province of Alberta, Canada during 1983–2004, we construct a generalized additive mixed model for the analysis of geographic and temporal variability of cancer ratios. In this model, spatially correlated random effects and temporal components are adopted. The interaction between space and time is also accommodated. Spatio-temporal models that use conditional autoregressive smoothing across the spatial dimension and B-spline over the temporal dimension are considered. We study the patterns of incidence ratios over time and identify areas with consistently high ratio estimates as areas for potential further investigation. We apply the method of penalized quasi-likelihood to estimate the model parameters. We illustrate this approach using a yearly data set of childhood cancer diagnoses in the province of Alberta, Canada during 1983–2004.     

Local Linear Estimation for Time-Dependent Coefficients in Cox's Regression Models

This article develops a local partial likelihood technique to estimate the time-dependent coefficients in Cox's regression model. The basic idea is a simple extension of the local linear fitting technique used in the scatterplot smoothing. The coefficients are estimated locally based on the partial likelihood in a window around each time point. Multiple time-dependent covariates are incorporated in the local partial likelihood procedure. The procedure is useful as a diagnostic tool and can be used in uncovering time-dependencies or departure from the proportional hazards model. The programming involved in the local partial likelihood estimation is relatively simple and it can be modified with few efforts from the existing programs for the proportional hazards model. The asymptotic properties of the resulting estimator are established and compared with those from the local constant fitting. A consistent estimator of the asymptotic variance is also proposed. The approach is illustrated by a real data set from the study of gastric cancer patients and a simulation study is also presented.     

The use of power transformations in small area estimation

Sample surveys are usually designed and analysed to produce estimates for larger areas. Nevertheless, sample sizes are often not large enough to give adequate precision for small area estimates of interest. To overcome such difficulties, borrowing strength from related small areas via modelling becomes essential. In line with this, we propose components of variance models with power transformations for small area estimation. This paper reports the results of a study aimed at incorporating the power transformation in small area estimation for improving the quality of small area predictions. The proposed methods are demonstrated on satellite data in conjunction with survey data to estimate mean acreage under a specified crop for counties in Iowa.     

Methods for Quantitative Risk Assessment Using Occupational Studies

Although carcinogenic risk assessment is frequently based on animal bioassay data, occupational studies are generally considered the best source of data for quantitative risk estimation. The model selected for use with occupational study data is required to extrapolate on age, exposure level, and temporal exposure pattern. Relative and absolute risk models are examined, as are alternatives for the definition of a dose (exposure) variable. The models express disease incidence as a function of the chosen exposure variable and convert incidence into estimates of lifetime risk. In this form, predictions of the models can be compared. The methods are illustrated using three examples: arsenic exposure and respiratory cancer, leukemia associated with benzene exposure, and asbestos-induced mesothelioma.     

Accelerated hazards mixture cure model

We propose a new cure model for survival data with a surviving or cure fraction. The new model is a mixture cure model where the covariate effects on the proportion of cure and the distribution of the failure time of uncured patients are separately modeled. Unlike the existing mixture cure models, the new model allows covariate effects on the failure time distribution of uncured patients to be negligible at time zero and to increase as time goes by. Such a model is particularly useful in some cancer treatments when the treat effect increases gradually from zero, and the existing models usually cannot handle this situation properly. We develop a rank based semiparametric estimation method to obtain the maximum likelihood estimates of the parameters in the model. We compare it with existing models and methods via a simulation study, and apply the model to a breast cancer data set. The numerical studies show that the new model provides a useful addition to the cure model literature.     

Semiparametric estimation of employment duration models

There are a variety of economic areas, such as studies of employment duration and of the durability of capital goods, in which data on important variables typically are censored. The standard techinques for estimating a model from censored data require the distributions of unobservable random components of the model to be specified a priori up to a finite set of parameters, and misspecification of these distributions usually leads to inconsistent parameter estimates. However, economic theory rarely gives guidance about distributions and the standard estimation techniques do not provide convenient methods for identifying distributions from censored data. Recently, several distribution-free or semiparametric methods for estimating censored regression models have been developed. This paper presents the results of using two such methods to estimate a model of employment duration. The paper reports the operating characteristics of the semiparametric estimators and compares the semiparametric estimates with those obtained from a standard parametric model.     

A Bayesian predictive inference for small area means incorporating covariates and sampling weights

The main goal in small area estimation is to use models to ‘borrow strength’ from the ensemble because the direct estimates of small area parameters are generally unreliable. However, model-based estimates from the small areas do not usually match the value of the single estimate for the large area. Benchmarking is done by applying a constraint, internally or externally, to ensure that the ‘total’ of the small areas matches the ‘grand total’. This is particularly useful because it is difficult to check model assumptions owing to the sparseness of the data. We use a Bayesian nested error regression model, which incorporates unit-level covariates and sampling weights, to develop a method to internally benchmark the finite population means of small areas. We use two examples to illustrate our method. We also perform a simulation study to further assess the properties of our method.     

Unconstrained parametrizations for variance-covariance matrices

The estimation of variance-covariance matrices through optimization of an objective function, such as a log-likelihood function, is usually a difficult numerical problem. Since the estimates should be positive semi-definite matrices, we must use constrained optimization, or employ a parametrization that enforces this condition. We describe here five different parametrizations for variance-covariance matrices that ensure positive definiteness, thus leaving the estimation problem unconstrained. We compare the parametrizations based on their computational efficiency and statistical interpretability. The results described here are particularly useful in maximum likelihood and restricted maximum likelihood estimation in linear and non-linear mixed-effects models, but are also applicable to other areas of statistics.     

The analysis of incomplete data using stochastic covariates

In the development of many diseases there are often associated random variables which continuously reflect the progress of a subject towards the final expression of the disease (failure). At any given time these processes, which we call stochastic covariates, may provide information about the current hazard and the remaining time to failure. Likewise, in situations when the specific times of key prior events are not known, such as the time of onset of an occult tumour or the time of infection with HIV-1, it may be possible to identify a stochastic covariate which reveals, indirectly, when the event of interest occurred. The analysis of carcinogenicity trials which involve occult tumours is usually based on the time of death or sacrifice and an indicator of tumour presence for each animal in the experiment. However, the size of an occult tumour observed at the endpoint represents data concerning tumour development which may convey additional information concerning both the tumour incidence rate and the rate of death to which tumour-bearing animals are subject. We develop a stochastic model for tumour growth and suggest different ways in which the effect of this growth on the hazard of failure might be modelled. Using a combined model for tumour growth and additive competing risks of death, we show that if this tumour size information is used, assumptions concerning tumour lethality, the context of observation or multiple sacrifice times are no longer necessary in order to estimate the tumour incidence rate. Parametric estimation based on the method of maximum likelihood is outlined and is applied to simulated data from the combined model. The results of this limited study confirm that use of the stochastic covariate tumour size results in more precise estimation of the incidence rate for occult tumours.     

Multilevel modelling of the geographical distributions of diseases

Multilevel modelling is used on problems arising from the analysis of spatially distributed health data. We use three applications to demonstrate the use of multilevel modelling in this area. The first concerns small area all-cause mortality rates from Glasgow where spatial autocorrelation between residuals is examined. The second analysis is of prostate cancer cases in Scottish counties where we use a range of models to examine whether the incidence is higher in more rural areas. The third develops a multiple-cause model in which deaths from cancer and cardiovascular disease in Glasgow are examined simultaneously in a spatial model. We discuss some of the issues surrounding the use of complex spatial models and the potential for future developments.     

Modelling forces of infection by using monotone local polynomials

Summary. On the basis of serological data from prevalence studies of rubella, mumps and hepatitis A, the paper describes a flexible local maximum likelihood method for the estimation of the rate at which susceptible individuals acquire infection at different ages. In contrast with parametric models that have been used before in the literature, the local polynomial likelihood method allows this age-dependent force of infection to be modelled without making any assumptions about the parametric structure. Moreover, this method allows for simultaneous nonparametric estimation of age-specific incidence and prevalence. Unconstrained models may lead to negative estimates for the force of infection at certain ages. To overcome this problem and to guarantee maximal flexibility, the local smoother can be constrained to be monotone. It turns out that different parametric and nonparametric estimates of the force of infection can exhibit considerably different qualitative features like location and the number of maxima, emphasizing the importance of a well-chosen flexible statistical model.     

Updating small area population estimates in England and Wales

"Population estimates have important implications for resource allocation within government and commerce, and are often assumed to be without error. Currently, central government provides annual population estimates for all the local and health authority districts in Britain, but estimates are needed for smaller areas, typically for electoral wards and postal sectors. Small area estimates are provided by some local authorities and commercial organizations, using different methods; the accuracy of these estimates is modelled here within a multilevel framework. Certain characteristics of the small area and of the method of estimation are included as explanatory variables. Results show that the method of estimation used is of great importance."     

Small area estimation strategies for large population surveys: a comparison of design and model-based methods

Small area estimation (SAE) concerns with how to reliably estimate population quantities of interest when some areas or domains have very limited samples. This is an important issue in large population surveys, because the geographical areas or groups with only small samples or even no samples are often of interest to researchers and policy-makers. For example, large population health surveys, such as Behavioural Risk Factor Surveillance System and Ohio Mecaid Assessment Survey (OMAS), are regularly conducted for monitoring insurance coverage and healthcare utilization. Classic approaches usually provide accurate estimators at the state level or large geographical region level, but they fail to provide reliable estimators for many rural counties where the samples are sparse. Moreover, a systematic evaluation of the performances of the SAE methods in real-world setting is lacking in the literature. In this paper, we propose a Bayesian hierarchical model with constraints on the parameter space and show that it provides superior estimators for county-level adult uninsured rates in Ohio based on the 2012 OMAS data. Furthermore, we perform extensive simulation studies to compare our methods with a collection of common SAE strategies, including direct estimators, synthetic estimators, composite estimators, and Datta GS, Ghosh M, Steorts R, Maples J.'s [Bayesian benchmarking with applications to small area estimation. Test 2011;20(3):574–588] Bayesian hierarchical model-based estimators. To set a fair basis for comparison, we generate our simulation data with characteristics mimicking the real OMAS data, so that neither model-based nor design-based strategies use the true model specification. The estimators based on our proposed model are shown to outperform other estimators for small areas in both simulation study and real data analysis.     

Smooth Semi‐nonparametric Analysis for Mixture Cure Models and Its Application to Breast Cancer

Mixture cure models are widely used when a proportion of patients are cured. The proportional hazards mixture cure model and the accelerated failure time mixture cure model are the most popular models in practice. Usually the expectation–maximisation (EM) algorithm is applied to both models for parameter estimation. Bootstrap methods are used for variance estimation. In this paper we propose a smooth semi‐nonparametric (SNP) approach in which maximum likelihood is applied directly to mixture cure models for parameter estimation. The variance can be estimated by the inverse of the second derivative of the SNP likelihood. A comprehensive simulation study indicates good performance of the proposed method. We investigate stage effects in breast cancer by applying the proposed method to breast cancer data from the South Carolina Cancer Registry.