Bayesian incidence analysis of animal tumorigenicity data

Statistical inference about tumorigenesis should focus on the tumour incidence rate. Unfortunately, in most animal carcinogenicity experiments, tumours are not observable in live animals and censoring of the tumour onset times is informative. In this paper, we propose a Bayesian method for analysing data from such studies. Our approach focuses on the incidence of tumours and accommodates occult tumours and censored onset times without restricting tumour lethality, relying on cause-of-death data, or requiring interim sacrifices. We represent the underlying state of nature by a multistate stochastic process and assume general probit models for the time-specific transition rates. These models allow the incorporation of covariates, historical control data and subjective prior information. The inherent flexibility of this approach facilitates the interpretation of results, particularly when the sample size is small or the data are sparse. We use a Gibbs sampler to estimate the relevant posterior distributions. The methods proposed are applied to data from a US National Toxicology Program carcinogenicity study.     

Analytic expressions for maximum likelihood estimators in a nonparametric model of tumor incidence and death

This research focuses on the estimation of tumor incidence rates from long-term animal studies which incorporate interim sacrifices. A nonparametric stochastic model is described with transition rates between states corresponding to the tumor incidence rate, the overall death rate, and the death rate for tumor-free animals. Exact analytic solutions for the maximum likelihood estimators of the hazard rates are presented, and their application to data from a long-term animal study is illustrated by an example. Unlike many common methods for estimation and comparison of tumor incidence rates among treatment groups, the estimators derived in this paper require no assumptions regarding tumor lethality or treatment lethality. The small sample operating characteristics of these estimators are evaluated using Monte Carlo simulation studies.     

Application of a stochastic model to response assessments in a study of squamous cell carcinoma of the head and neck

This paper discusses the application of a stochastic model in the analysis of response assessments made at various time points in a clinical trial of patients with squamous cell carcinoma of the head and neck. The transition rates and probabilities during treatment administration are derived using maximum likelihood methods. The results are then compared with the standard analyses used in solid tumour studies. Stochastic modelling is considered to complement the standard analyses, provide a holistic approach and better explain the underlying disease process. Copyright © 2012 John Wiley & Sons, Ltd.     

A Likelihood‐Based Analysis for Relaxing the Exclusion Restriction in Randomized Experiments with Noncompliance

The exclusion restriction is usually assumed for identifying causal effects in true or only natural randomized experiments with noncompliance. It requires that the assignment to treatment does not have a direct causal effect on the outcome. Despite its importance, the restriction can often be unrealistic, especially in situations of natural experiments. It is shown that, without the exclusion restriction, the parametric model is identified if the outcome distributions of various compliance statuses are in the same parametric class and that class is a linearly independent set over the field of real numbers. However, the relaxation of the exclusion restriction yields a parametric model that is characterized by the presence of mixtures of distributions. This scenario complicates the likelihood‐based estimation procedures because it implies more than one maximum likelihood point. A two‐step estimation procedure based on detecting the root that is closest to the method of moments estimate of the parameter vector is then proposed and analyzed in detail, under normally distributed outcomes. An economic example with real data concerning returns to schooling concludes the paper.     

ASYMPTOTIC DISTRIBUTIONS OF SEMIPARAMETRIC MAXIMUM LIKELIHOOD ESTIMATORS WITH ESTIMATING EQUATIONS FOR GROUP-CENSORED DATA

Semiparametric maximum likelihood estimation with estimating equations (SMLE) is more flexible than traditional methods; it has fewer restrictions on distributions and regression models. The required information about distribution and regression structures is incorporated in estimating equations of the SMLE to improve the estimation quality of non‐parametric methods. The likelihood of SMLE for censored data involves complicated implicit functions without closed‐form expressions, and the first derivatives of the log‐profile‐likelihood cannot be expressed as summations of independent and identically distributed random variables; it is challenging to derive asymptotic properties of the SMLE for censored data. For group‐censored data, the paper shows that all the implicit functions are well defined and obtains the asymptotic distributions of the SMLE for model parameters and lifetime distributions. With several examples the paper compares the SMLE, the regular non‐parametric likelihood estimation method and the parametric MLEs in terms of their asymptotic efficiencies, and illustrates application of SMLE. Various asymptotic distributions of the likelihood ratio statistics are derived for testing the adequacy of estimating equations and a partial set of parameters equal to some known values.     

Empirical likelihood based variable selection

Information criteria form an important class of model/variable selection methods in statistical analysis. Parametric likelihood is a crucial part of these methods. In some applications such as the generalized linear models, the models are only specified by a set of estimating functions. To overcome the non-availability of well defined likelihood function, the information criteria under empirical likelihood are introduced. Under this setup, we successfully solve the existence problem of the profile empirical likelihood due to the over constraint in variable selection problems. The asymptotic properties of the new method are investigated. The new method is shown to be consistent at selecting the variables under mild conditions. Simulation studies find that the proposed method has comparable performance to the parametric information criteria when a suitable parametric model is available, and is superior when the parametric model assumption is violated. A real data set is also used to illustrate the usefulness of the new method.     

Generalised quasi‐likelihood inference in a semi‐parametric binary dynamic mixed logit model

There exists a recent study where dynamic mixed‐effects regression models for count data have been extended to a semi‐parametric context. However, when one deals with other discrete data such as binary responses, the results based on count data models are not directly applicable. In this paper, we therefore begin with existing binary dynamic mixed models and generalise them to the semi‐parametric context. For inference, we use a new semi‐parametric conditional quasi‐likelihood (SCQL) approach for the estimation of the non‐parametric function involved in the semi‐parametric model, and a semi‐parametric generalised quasi‐likelihood (SGQL) approach for the estimation of the main regression, dynamic dependence and random effects variance parameters. A semi‐parametric maximum likelihood (SML) approach is also used as a comparison to the SGQL approach. The properties of the estimators are examined both asymptotically and empirically. More specifically, the consistency of the estimators is established and finite sample performances of the estimators are examined through an intensive simulation study.     

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.     

On estimating a transformation correlation coefficient

We consider a semiparametric and a parametric transformation-to-normality model for bivariate data. After an unstructured or structured monotone transformation of the measurement scales, the measurements are assumed to have a bivariate normal distribution with correlation coefficient ρ, here termed the 'transformation correlation coefficient'. Under the semiparametric model with unstructured transformation, the principle of invariance leads to basing inference on the marginal ranks. The resulting rank-based likelihood function of ρis maximized via a Monte Carlo procedure. Under the parametric model, we consider Box-Cox type transformations and maximize the likelihood of ρalong with the nuisance parameters. Efficiencies of competing methods are reported, both theoretically and by simulations. The methods are illustrated on a real-data example.     

Flexible estimates of tumour incidence for intermediately lethal tumours in a typical long-term animal bioassay

The estimation of the incidence of tumours in an animal carcinogenicity study is complicated by the occult nature of the tumours involved (i.e. tumours are not observable before an animal's death). Also, the lethality of tumours is generally unknown, making the tumour incidence function non-identifiable without interim sacrifices, cause-of-death data or modelling assumptions. Although Kaplan–Meier curves for overall survival are typically displayed, obtaining analogous plots for tumour incidence generally requires fairly elaborate model fitting. We present a case-study of tetrafluoroethylene to illustrate a simple method for estimating the incidence of tumours as a function of more easily estimable components. One of the components, tumour prevalence, is modelled by using a generalized additive model, which leads to estimates that are more flexible than those derived under the usual parametric models. A multiplicative assumption for tumour lethality allows for the incorporation of concomitant information, such as the size of tumours. Our approach requires only terminal sacrifice data although additional sacrifice data are easily accommodated. Simulations are used to illustrate the estimator proposed and to evaluate its properties. The method also yields a simple summary measure of tumour lethality, which can be helpful in interpreting the results of a study.     

Modelling Survival Events with Longitudinal Covariates Measured with Error

In survival analysis, time-dependent covariates are usually present as longitudinal data collected periodically and measured with error. The longitudinal data can be assumed to follow a linear mixed effect model and Cox regression models may be used for modelling of survival events. The hazard rate of survival times depends on the underlying time-dependent covariate measured with error, which may be described by random effects. Most existing methods proposed for such models assume a parametric distribution assumption on the random effects and specify a normally distributed error term for the linear mixed effect model. These assumptions may not be always valid in practice. In this article, we propose a new likelihood method for Cox regression models with error-contaminated time-dependent covariates. The proposed method does not require any parametric distribution assumption on random effects and random errors. Asymptotic properties for parameter estimators are provided. Simulation results show that under certain situations the proposed methods are more efficient than the existing methods.     

Empirical likelihood confidence intervals for the mean of a population containing many zero values

If a population contains many zero values and the sample size is not very large, the traditional normal approximation‐based confidence intervals for the population mean may have poor coverage probabilities. This problem is substantially reduced by constructing parametric likelihood ratio intervals when an appropriate mixture model can be found. In the context of survey sampling, however, there is a general preference for making minimal assumptions about the population under study. The authors have therefore investigated the coverage properties of nonparametric empirical likelihood confidence intervals for the population mean. They show that under a variety of hypothetical populations, these intervals often outperformed parametric likelihood intervals by having more balanced coverage rates and larger lower bounds. The authors illustrate their methodology using data from the Canadian Labour Force Survey for the year 2000.     

BAYESIAN HIDDEN MARKOV MODELS FOR LONGITUDINAL COUNTS

This paper describes a Bayesian approach to modelling carcinogenity in animal studies where the data consist of counts of the number of tumours present over time. It compares two autoregressive hidden Markov models. One of them models the transitions between three latent states: an inactive transient state, a multiplying state for increasing counts and a reducing state for decreasing counts. The second model introduces a fourth tied state to describe non‐zero observations that are neither increasing nor decreasing. Both these models can model the length of stay upon entry of a state. A discrete constant hazards waiting time distribution is used to model the time to onset of tumour growth. Our models describe between‐animal‐variability by a single hierarchy of random effects and the within‐animal variation by first‐order serial dependence. They can be extended to higher‐order serial dependence and multi‐level hierarchies. Analysis of data from animal experiments comparing the influence of two genes leads to conclusions that differ from those of Dunson (2000). The observed data likelihood defines an information criterion to assess the predictive properties of the three‐ and four‐state models. The deviance information criterion is appropriately defined for discrete parameters.     

Semi-parametric modelling and likelihood estimation with estimating equations

This paper proposes a semi-parametric modelling and estimating method for analysing censored survival data. The proposed method uses the empirical likelihood function to describe the information in data, and formulates estimating equations to incorporate knowledge of the underlying distribution and regression structure. The method is more flexible than the traditional methods such as the parametric maximum likelihood estimation (MLE), Cox's (1972) proportional hazards model, accelerated life test model, quasi-likelihood (Wedderburn, 1974) and generalized estimating equations (Liang & Zeger, 1986). This paper shows the existence and uniqueness of the proposed semi-parametric maximum likelihood estimates (SMLE) with estimating equations. The method is validated with known cases studied in the literature. Several finite sample simulation and large sample efficiency studies indicate that when the sample size is larger than 100 the SMLE is compatible with the parametric MLE; and in all case studies, the SMLE is about 15% better than the parametric MLE with a mis-specified underlying distribution.     

Polynomial Spline Estimation for a Generalized Additive Coefficient Model

Abstract.  We study a semiparametric generalized additive coefficient model (GACM), in which linear predictors in the conventional generalized linear models are generalized to unknown functions depending on certain covariates, and approximate the non-parametric functions by using polynomial spline. The asymptotic expansion with optimal rates of convergence for the estimators of the non-parametric part is established. Semiparametric generalized likelihood ratio test is also proposed to check if a non-parametric coefficient can be simplified as a parametric one. A conditional bootstrap version is suggested to approximate the distribution of the test under the null hypothesis. Extensive Monte Carlo simulation studies are conducted to examine the finite sample performance of the proposed methods. We further apply the proposed model and methods to a data set from a human visceral Leishmaniasis study conducted in Brazil from 1994 to 1997. Numerical results outperform the traditional generalized linear model and the proposed GACM is preferable.     

Infant mortality model for lifetime data

In this paper we introduce a parametric model for handling lifetime data where an early lifetime can be related to the infant-mortality failure or to the wear processes but we do not know which risk is responsible for the failure. The maximum likelihood approach and the sampling-based approach are used to get the inferences of interest. Some special cases of the proposed model are studied via Monte Carlo methods for size and power of hypothesis tests. To illustrate the proposed methodology, we introduce an example consisting of a real data set.     

Semi-parametric extended Poisson process models for count data

A general framework for the analysis of count data (with covariates) is proposed using formulations for the transition rates of a state-dependent birth process. The form for the transition rates incorporates covariates proportionally, with the residual distribution determined from a smooth non-parametric state-dependent form. Computation of the resulting probabilities is discussed, leading to model estimation using a penalized likelihood function. Two data sets are used as illustrative examples, one representing underdispersed Poisson-like data and the other overdispersed binomial-like data.     

Conditional Akaike Information Criteria for a Class of Poisson Mixture Models with Random Effects

Focusing on the model selection problems in the family of Poisson mixture models (including the Poisson mixture regression model with random effects and zero‐inflated Poisson regression model with random effects), the current paper derives two conditional Akaike information criteria. The criteria are the unbiased estimators of the conditional Akaike information based on the conditional log‐likelihood and the conditional Akaike information based on the joint log‐likelihood, respectively. The derivation is free from the specific parametric assumptions about the conditional mean of the true data‐generating model and applies to different types of estimation methods. Additionally, the derivation is not based on the asymptotic argument. Simulations show that the proposed criteria have promising estimation accuracy. In addition, it is found that the criterion based on the conditional log‐likelihood demonstrates good model selection performance under different scenarios. Two sets of real data are used to illustrate the proposed method.     

Statistical Inference in Partially Linear Varying-Coefficient Models with Missing Responses at Random

This article considers statistical inference for partially linear varying-coefficient models when the responses are missing at random. We propose a profile least-squares estimator for the parametric component with complete-case data and show that the resulting estimator is asymptotically normal. To avoid to estimate the asymptotic covariance in establishing confidence region of the parametric component with the normal-approximation method, we define an empirical likelihood based statistic and show that its limiting distribution is chi-squared distribution. Then, the confidence regions of the parametric component with asymptotically correct coverage probabilities can be constructed by the result. To check the validity of the linear constraints on the parametric component, we construct a modified generalized likelihood ratio test statistic and demonstrate that it follows asymptotically chi-squared distribution under the null hypothesis. Then, we extend the generalized likelihood ratio technique to the context of missing data. Finally, some simulations are conducted to illustrate the proposed methods.     

Asymptotic properties of the estimators of the semi-parametric spatial regression model

Spatial data and non parametric methods arise frequently in studies of different areas and it is a common practice to analyze such data with semi-parametric spatial autoregressive (SPSAR) models. We propose the estimations of SPSAR models based on maximum likelihood estimation (MLE) and kernel estimation. The estimation of spatial regression coefficient ρ was done by optimizing the concentrated log-likelihood function with respect to ρ. Furthermore, under appropriate conditions, we derive the limiting distributions of our estimators for both the parametric and non parametric components in the model.