The Lehmann Model with Time-dependent Covariates

Consider the Lehmann model with time-dependent covariates, which is different from Cox’s model. We find out that (1) the parameter space for β under the Lehmann model is restricted, and the maximum point of the parametric likelihood for β may lie outside the parameter space; (2) for some particular time-dependent covariate, under the standard generalized likelihood the semiparametric maximum likelihood estimator (SMLE) is inconsistent and we propose a modified generalized likelihood which leads to the consistent SMLE.     

Consistency of The MMGLE under the piecewise proportional hazards models with interval-censored data

Wong et al. [(2018), ‘Piece-wise Proportional Hazards Models with Interval-censored Data’, Journal of Statistical Computation and Simulation, 88, 140–155] studied the piecewise proportional hazards (PWPH) model with interval-censored (IC) data under the distribution-free set-up. It is well known that the partial likelihood approach is not applicable for IC data, and Wong et al. (2018) showed that the standard generalised likelihood approach does not work either. They proposed the maximum modified generalised likelihood estimator (MMGLE) and the simulation results suggest that the MMGLE is consistent. We establish the consistency and asymptotically normality of the MMGLE.     

Estimation Under the Lehmann Regression Model with Interval-Censored Data

We consider the estimation problem under the Lehmann model with interval-censored data, but focus on the computational issues. There are two methods for computing the semi-parametric maximum likelihood estimator (SMLE) under the Lehmann model (or called Cox model): the Newton-Raphson (NR) method and the profile likelihood (PL) method. We show that they often do not get close to the SMLE. We propose several approach to overcome the computational difficulty and apply our method to a breast cancer research data set.     

Semiparametric Estimation of a Two-component Mixture Model where One Component is known

Abstract.  We consider a two-component mixture model where one component distribution is known while the mixing proportion and the other component distribution are unknown. These kinds of models were first introduced in biology to study the differences in expression between genes. The various estimation methods proposed till now have all assumed that the unknown distribution belongs to a parametric family. In this paper, we show how this assumption can be relaxed. First, we note that generally the above model is not identifiable, but we show that under moment and symmetry conditions some 'almost everywhere' identifiability results can be obtained. Where such identifiability conditions are fulfilled we propose an estimation method for the unknown parameters which is shown to be strongly consistent under mild conditions. We discuss applications of our method to microarray data analysis and to the training data problem. We compare our method to the parametric approach using simulated data and, finally, we apply our method to real data from microarray experiments.     

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.     

A class of semiparametric transformation models for survival data with a cured proportion

We propose a new class of semiparametric regression models based on a multiplicative frailty assumption with a discrete frailty, which may account for cured subgroup in population. The cure model framework is then recast as a problem with a transformation model. The proposed models can explain a broad range of nonproportional hazards structures along with a cured proportion. An efficient and simple algorithm based on the martingale process is developed to locate the nonparametric maximum likelihood estimator. Unlike existing expectation-maximization based methods, our approach directly maximizes a nonparametric likelihood function, and the calculation of consistent variance estimates is immediate. The proposed method is useful for resolving identifiability features embedded in semiparametric cure models. Simulation studies are presented to demonstrate the finite sample properties of the proposed method. A case study of stage III soft-tissue sarcoma is given as an illustration.     

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.     

Piecewise Cox models with right-censored data

We study a general class of piecewise Cox models. We discuss the computation of the semi-parametric maximum likelihood estimates (SMLE) of the parameters, with right-censored data, and a simplified algorithm for the maximum partial likelihood estimates (MPLE). Our simulation study suggests that the relative efficiency of the PMLE of the parameter to the SMLE ranges from 96% to 99.9%, but the relative efficiency of the existing estimators of the baseline survival function to the SMLE ranges from 3% to 24%. Thus, the SMLE is much better than the existing estimators.     

Semiparametric Mixtures of Generalized Exponential Families

Abstract.  A semiparametric mixture model is characterized by a non-parametric mixing distribution Q (with respect to a parameter θ ) and a structural parameter β common to all components. Much of the literature on mixture models has focused on fixing β and estimating Q . However, this can lead to inconsistent estimation of both Q and the order of the model m . Creating a framework for consistent estimation remains an open problem and is the focus of this article. We formulate a class of generalized exponential family (GEF) models and establish sufficient conditions for the identifiability of finite mixtures formed from a GEF along with sufficient conditions for a nesting structure. Finite identifiability and nesting structure lead to the central result that semiparametric maximum likelihood estimation of Q and β fails. However, consistent estimation is possible if we restrict the class of mixing distributions and employ an information-theoretic approach. This article provides a foundation for inference in semiparametric mixture models, in which GEFs and their structural properties play an instrumental role.     

Inference for proportional hazard model with propensity score

Since the publication of the seminal paper by Cox (1972), proportional hazard model has become very popular in regression analysis for right censored data. In observational studies, treatment assignment may depend on observed covariates. If these confounding variables are not accounted for properly, the inference based on the Cox proportional hazard model may perform poorly. As shown in Rosenbaum and Rubin (1983), under the strongly ignorable treatment assignment assumption, conditioning on the propensity score yields valid causal effect estimates. Therefore we incorporate the propensity score into the Cox model for causal inference with survival data. We derive the asymptotic property of the maximum partial likelihood estimator when the model is correctly specified. Simulation results show that our method performs quite well for observational data. The approach is applied to a real dataset on the time of readmission of trauma patients. We also derive the asymptotic property of the maximum partial likelihood estimator with a robust variance estimator, when the model is incorrectly specified.     

Missing data mechanisms and their implications on the analysis of categorical data

We review some issues related to the implications of different missing data mechanisms on statistical inference for contingency tables and consider simulation studies to compare the results obtained under such models to those where the units with missing data are disregarded. We confirm that although, in general, analyses under the correct missing at random and missing completely at random models are more efficient even for small sample sizes, there are exceptions where they may not improve the results obtained by ignoring the partially classified data. We show that under the missing not at random (MNAR) model, estimates on the boundary of the parameter space as well as lack of identifiability of the parameters of saturated models may be associated with undesirable asymptotic properties of maximum likelihood estimators and likelihood ratio tests; even in standard cases the bias of the estimators may be low only for very large samples. We also show that the probability of a boundary solution obtained under the correct MNAR model may be large even for large samples and that, consequently, we may not always conclude that a MNAR model is misspecified because the estimate is on the boundary of the parameter space.     

Bayesian item response model: a generalized approach for the abilities' distribution using mixtures

Traditional Item Response Theory models assume the distribution of the abilities of the population in study to be Gaussian. However, this may not always be a reasonable assumption, which motivates the development of more general models. This paper presents a generalized approach for the distribution of the abilities in dichotomous 3-parameter Item Response models. A mixture of normal distributions is considered, allowing for features like skewness, multimodality and heavy tails. A solution is proposed to deal with model identifiability issues without compromising the flexibility and practical interpretation of the model. Inference is carried out under the Bayesian Paradigm through a novel MCMC algorithm. The algorithm is designed in a way to favour good mixing and convergence properties and is also suitable for inference in traditional IRT models. The efficiency and applicability of our methodology is illustrated in simulated and real examples.     

Using Auxiliary Data for Binomial Parameter Estimation with Nonignorable Nonresponse

Nonignorable nonresponse is a nonresponse mechanism that depends on the values of the variable having nonresponse. When an observed data of a binomial distribution suffer missing values from a nonignorable nonresponse mechanism, the binomial distribution parameters become unidentifiable without any other auxiliary information or assumption. To address the problems of non identifiability, existing methods mostly based on the log-linear regression model. In this article, we focus on the model when the nonresponse is nonignorable and we consider to use the auxiliary data to improve identifiability; furthermore, we derive the maximum likelihood estimator (MLE) for the binomial proportion and its associated variance. We present results for an analysis of real-life data from the SARS study in China. Finally, the simulation study shows that the proposed method gives promising results.     

Estimation of treatment effects based on possibly misspecified Cox regression

In randomized clinical trials, a treatment effect on a time-to-event endpoint is often estimated by the Cox proportional hazards model. The maximum partial likelihood estimator does not make sense if the proportional hazard assumption is violated. Xu and O'Quigley (Biostatistics 1:423-439, 2000) proposed an estimating equation, which provides an interpretable estimator for the treatment effect under model misspecification. Namely it provides a consistent estimator for the log-hazard ratio among the treatment groups if the model is correctly specified, and it is interpreted as an average log-hazard ratio over time even if misspecified. However, the method requires the assumption that censoring is independent of treatment group, which is more restricted than that for the maximum partial likelihood estimator and is often violated in practice. In this paper, we propose an alternative estimating equation. Our method provides an estimator of the same property as that of Xu and O'Quigley under the usual assumption for the maximum partial likelihood estimation. We show that our estimator is consistent and asymptotically normal, and derive a consistent estimator of the asymptotic variance. If the proportional hazards assumption holds, the efficiency of the estimator can be improved by applying the covariate adjustment method based on the semiparametric theory proposed by Lu and Tsiatis (Biometrika 95:679-694, 2008).     

Robust Bayesian synthetic likelihood via a semi-parametric approach

Bayesian synthetic likelihood (BSL) is now a well-established method for performing approximate Bayesian parameter estimation for simulation-based models that do not possess a tractable likelihood function. BSL approximates an intractable likelihood function of a carefully chosen summary statistic at a parameter value with a multivariate normal distribution. The mean and covariance matrix of this normal distribution are estimated from independent simulations of the model. Due to the parametric assumption implicit in BSL, it can be preferred to its nonparametric competitor, approximate Bayesian computation, in certain applications where a high-dimensional summary statistic is of interest. However, despite several successful applications of BSL, its widespread use in scientific fields may be hindered by the strong normality assumption. In this paper, we develop a semi-parametric approach to relax this assumption to an extent and maintain the computational advantages of BSL without any additional tuning. We test our new method, semiBSL, on several challenging examples involving simulated and real data and demonstrate that semiBSL can be significantly more robust than BSL and another approach in the literature.     

The competing risks Cox model with auxiliary case covariates under weaker missing-at-random cause of failure

In the analysis of time-to-event data with multiple causes using a competing risks Cox model, often the cause of failure is unknown for some of the cases. The probability of a missing cause is typically assumed to be independent of the cause given the time of the event and covariates measured before the event occurred. In practice, however, the underlying missing-at-random assumption does not necessarily hold. Motivated by colorectal cancer molecular pathological epidemiology analysis, we develop a method to conduct valid analysis when additional auxiliary variables are available for cases only. We consider a weaker missing-at-random assumption, with missing pattern depending on the observed quantities, which include the auxiliary covariates. We use an informative likelihood approach that will yield consistent estimates even when the underlying model for missing cause of failure is misspecified. The superiority of our method over naive methods in finite samples is demonstrated by simulation study results. We illustrate the use of our method in an analysis of colorectal cancer data from the Nurses’ Health Study cohort, where, apparently, the traditional missing-at-random assumption fails to hold.     

Statistical Inference and Applications of Mixture of Varying Coefficient Models

In this paper, we consider a new mixture of varying coefficient models, in which each mixture component follows a varying coefficient model and the mixing proportions and dispersion parameters are also allowed to be unknown smooth functions. We systematically study the identifiability, estimation and inference for the new mixture model. The proposed new mixture model is rather general, encompassing many mixture models as its special cases such as mixtures of linear regression models, mixtures of generalized linear models, mixtures of partially linear models and mixtures of generalized additive models, some of which are new mixture models by themselves and have not been investigated before. The new mixture of varying coefficient model is shown to be identifiable under mild conditions. We develop a local likelihood procedure and a modified expectation–maximization algorithm for the estimation of the unknown non‐parametric functions. Asymptotic normality is established for the proposed estimator. A generalized likelihood ratio test is further developed for testing whether some of the unknown functions are constants. We derive the asymptotic distribution of the proposed generalized likelihood ratio test statistics and prove that the Wilks phenomenon holds. The proposed methodology is illustrated by Monte Carlo simulations and an analysis of a CO₂‐GDP data set.     

Conditional inference in linear versus nonlinear models for binary time series

The modelling of discrete such as binary time series, unlike the continuous time series, is not easy. This is due to the fact that there is no unique way to model the correlation structure of the repeated binary data. Some models may also provide a complicated correlation structure with narrow ranges for the correlations. In this paper, we consider a nonlinear dynamic binary time series model that provides a correlation structure which is easy to interpret and the correlations under this model satisfy the full?1 to 1 range. For the estimation of the parameters of this nonlinear model, we use a conditional generalized quasilikelihood (CGQL) approach which provides the same estimates as those of the well-known maximum likelihood approach. Furthermore, we consider a competitive linear dynamic binary time series model and examine the performance of the CGQL approach through a simulation study in estimating the parameters of this linear model. The model mis-specification effects on estimation as well as forecasting are also examined through simulations.     

Consistency of the Semi-parametric MLE in Linear Regression Models with Interval-censored Data

Abstract.  Consider the model Y = β ^' X + ε . Let F ₀ be the unknown cumulative distribution function of the random variable ε . Consistency of the semi-parametric Maximum likelihood estimator of ( β , F ₀), denoted by     , has not been established under any interval censorship (IC) model. We prove in this paper that     is consistent under the mixed case IC model and some mild assumptions.     

Improved precision in the analysis of randomized trials with survival outcomes,without assuming proportional hazards

We present a new estimator of the restricted mean survival time in randomized trials where there is right censoring that may depend on treatment and baseline variables. The proposed estimator leverages prognostic baseline variables to obtain equal or better asymptotic precision compared to traditional estimators. Under regularity conditions and random censoring within strata of treatment and baseline variables, the proposed estimator has the following features: (i) it is interpretable under violations of the proportional hazards assumption; (ii) it is consistent and at least as precise as the Kaplan–Meier and inverse probability weighted estimators, under identifiability conditions; (iii) it remains consistent under violations of independent censoring (unlike the Kaplan–Meier estimator) when either the censoring or survival distributions, conditional on covariates, are estimated consistently; and (iv) it achieves the nonparametric efficiency bound when both of these distributions are consistently estimated. We illustrate the performance of our method using simulations based on resampling data from a completed, phase 3 randomized clinical trial of a new surgical treatment for stroke; the proposed estimator achieves a 12% gain in relative efficiency compared to the Kaplan–Meier estimator. The proposed estimator has potential advantages over existing approaches for randomized trials with time-to-event outcomes, since existing methods either rely on model assumptions that are untenable in many applications, or lack some of the efficiency and consistency properties (i)–(iv). We focus on estimation of the restricted mean survival time, but our methods may be adapted to estimate any treatment effect measure defined as a smooth contrast between the survival curves for each study arm. We provide R code to implement the estimator.