Effect of censoring on adjusting for covariates in comparison of survival times

The increase in the variance of the estimate of treatment effect which results from omitting a dichotomous or continuous covariate is quantified as a function of censoring. The efficiency of not adjusting for a covariate is measured by the ratio of the variance obtained with and without adjustment for the covariate. The variance is derived using the Weibull proportional hazards model. Under random censoring, the efficiency of not adjusting for a continuous covariate is an increasing function of the percentage of censored observations.     

Goodness-of-link testing in ordinal regression models

McCullagh (1980) presented a comprehensive review of regression models for ordinal response variables. In these models, the functional relationship between the covariates and the response categories is dependent on the link function. This paper shows that discrimination between links is feasible when the response variable is ordinal. Using the log-gamma distribution of Prentice (1974), a generalized link function is constructed which allows discrimination between the probit, log-log, and complementary log-log links. Sample-size considerations are noted, and examples are presented.     

Likelihood methods for missing covariate data in highly stratified studies

Summary. The paper considers canonical link generalized linear models with stratum-specific nuisance intercepts and missing covariate data. This family includes the conditional logistic regression model. Existing methods for this problem, each of which uses a conditioning argu- ment to eliminate the nuisance intercept, model either the missing covariate data or the missingness process. The paper compares these methods under a common likelihood framework. The semiparametric efficient estimator is identified, and a new estimator, which reduces dependence on the model for the missing covariate, is proposed. A simulation study compares the methods with respect to efficiency and robustness to model misspecification.     

Unmasking the Trend Sought by Jonckheere-Type Tests for Right-Censored Data

Medical and epidemiological studies often involve groups of subjects associated with increasing levels of exposure to a risk factor. Survival of the groups is expected to follow the same order as the level of exposure. Formal tests for this trend fall into the regression framework if one knows what function of exposure to use as a covariate. When unknown, a linear function of exposure level is often used. Jonckheere-type tests for trend have generated continued interest largely because they do not require specification of a covariate. This paper shows that the Jonckheere-type test statistics are special cases of a generalized linear rank statistic with time-dependent covariates which unfortunately depend on the initial group sizes and censoring distributions. Using asymptotic relative efficiency calculations, the Jonckheere tests are compared to standard linear rank tests based on a linear covariate over a spectrum of shapes for the true trend.     

Asymptotic efficiency of a competing risks model: A two-sample case

A generalized Cox regression model is studied for the covariance analysis of competing risks data subject to independent random censoring. The information of the maximum partial likelihood estimates is compared with that of maximum likelihood estimates assuming a log linear hazard function.The method of generalized variance is used to define the efficiency of estimation between the two models. This is then applied to two-sample problems with two exponentially censoring rates. Numerical results are summarized ane presented graphically.The detailed results indicate that the semi-parametric model wrks well for a higher rate of censoring. A method of generalizing the result to type 1 censoring and the efficiency of estimating the coefficient of the covariate are discussecd. A brief account of using the results to help design experiments is also given.     

Covariate handling approaches in combination with dynamic borrowing for hybrid control studies

Borrowing data from external control has been an appealing strategy for evidence synthesis when conducting randomized controlled trials (RCTs). Often named hybrid control trials, they leverage existing control data from clinical trials or potentially real-world data (RWD), enable trial designs to allocate more patients to the novel intervention arm, and improve the efficiency or lower the cost of the primary RCT. Several methods have been established and developed to borrow external control data, among which the propensity score methods and Bayesian dynamic borrowing framework play essential roles. Noticing the unique strengths of propensity score methods and Bayesian hierarchical models, we utilize both methods in a complementary manner to analyze hybrid control studies. In this article, we review methods including covariate adjustments, propensity score matching and weighting in combination with dynamic borrowing and compare the performance of these methods through comprehensive simulations. Different degrees of covariate imbalance and confounding are examined. Our findings suggested that the conventional covariate adjustment in combination with the Bayesian commensurate prior model provides the highest power with good type I error control under the investigated settings. It has desired performance especially under scenarios of different degrees of confounding. To estimate efficacy signals in the exploratory setting, the covariate adjustment method in combination with the Bayesian commensurate prior is recommended.     

Generalized symmetrical partial linear model

In this work, we propose a new model called generalized symmetrical partial linear model, based on the theory of generalized linear models and symmetrical distributions. In our model the response variable follows a symmetrical distribution such a normal, Student-t, power exponential, among others. Following the context of generalized linear models we consider replacing the traditional linear predictors by the more general predictors in whose case one covariate is related with the response variable in a non-parametric fashion, that we do not specified the parametric function. As an example, we could imagine a regression model in which the intercept term is believed to vary in time or geographical location. The backfitting algorithm is used for estimating the parameters of the proposed model. We perform a simulation study for assessing the behavior of the penalized maximum likelihood estimators. We use the quantile residuals for checking the assumption of the model. Finally, we analyzed real data set related with pH rivers in Ireland.     

Properties of Added Variable Plots in Cox's Regression Model

The added variable plot is useful for examining the effect of a covariate in regression models. The plot provides information regarding the inclusion of a covariate, and is useful in identifying influential observations on the parameter estimates. Hall et al. (1996) proposed a plot for Cox's proportional hazards model derived by regarding the Cox model as a generalized linear model. This paper proves and discusses properties of this plot. These properties make the plot a valuable tool in model evaluation. Quantities considered include parameter estimates, residuals, leverage, case influence measures and correspondence to previously proposed residuals and diagnostics.     

On Confounding, Prediction and Efficiency in the Analysis of Longitudinal and Cross-sectional Clustered Data

Abstract.  In the analysis of clustered and/or longitudinal data, it is usually desirable to ignore covariate information for other cluster members as well as future covariate information when predicting outcome for a given subject at a given time. This can be accomplished through con-ditional mean models which merely condition on the considered subject's covariate history at each time. Pepe & Anderson (Commun. Stat. Simul. Comput. 23, 1994 , 939) have shown that ordinary generalized estimating equations may yield biased estimates for the parameters in such models, but that valid inferences can be guaranteed by using a diagonal working covariance matrix in the equations. In this paper, we provide insight into the nature of this problem by uncovering substantive data-generating mechanisms under which such biases will result. We then propose a class of asymptotically unbiased estimators for the parameters indexing the suggested conditional mean models. In addition, we provide a representation for the efficient estimator in our class, which attains the semi-parametric efficiency bound under the model, along with an efficient algorithm for calculating it. This algorithm is easy to apply and may realize major efficiency improvements as demonstrated through simulation studies. The results suggest ways to improve the efficiency of inverse-probability-of-treatment estimators which adjust for time-varying confounding, and are used to estimate the effect of discontinuing highly active anti-retroviral therapy (HAART) on viral load in HIV-infected patients.     

Closure of the class of binary generalized linear models in some non-standard settings

This paper considers fitting generalized linear models to binary data in nonstandard settings such as case–control samples, studies with misclassified responses and misspecified models. We develop simple methods for fitting models to case–control data and show that a closure property holds for generalized linear models in the nonstandard settings, i.e. if the responses follow a generalized linear model in the population of interest, then so will the observed response in the non-standard setting, but with a modified link function. These results imply that we can analyse data and study problems in the non-standard settings by using classical generalized linear model methods such as the iteratively reweighted least squares algorithm. Example data illustrate the results.     

Ordered Regressions

There are often situations where two or more regression functions are ordered over a range of covariate values. In this paper, we develop efficient constrained estimation and testing procedures for such models. Specifically, necessary and sufficient conditions for ordering generalized linear regressions are given and shown to unify previous results obtained for simple linear regression, for polynomial regression and in the analysis of covariance models. We show that estimating the parameters of ordered linear regressions requires either quadratic programming or semi‐infinite programming, depending on the shape of the covariate space. A distance‐type test for order is proposed. Simulations demonstrate that the proposed methodology improves the mean square error and power compared with the usual, unconstrained, estimation and testing procedures. Improvements are often substantial. The methodology is extended to order generalized linear models where convex semi‐infinite programming plays a role. The methodology is motivated by, and applied to, a hearing loss study.     

Cox Regression with Incomplete Covariate Measurements using the EM-algorithm

Ibrahim (1990) used the EM-algorithm to obtain maximum likelihood estimates of the regression parameters in generalized linear models with partially missing covariates. The technique was termed EM by the method of weights. In this paper, we generalize this technique to Cox regression analysis with missing values in the covariates. We specify a full model letting the unobserved covariate values be random and then maximize the observed likelihood. The asymptotic covariance matrix is estimated by the inverse information matrix. The missing data are allowed to be missing at random but also the non-ignorable non-response situation may in principle be considered. Simulation studies indicate that the proposed method is more efficient than the method suggested by Paik & Tsai (1997). We apply the procedure to a clinical trials example with six covariates with three of them having missing values.     

A study of regression calibration in a partially observed stratified Cox model

Regression calibration is a simple method for estimating regression models when covariate data are missing for some study subjects. It consists in replacing an unobserved covariate by an estimator of its conditional expectation given available covariates. Regression calibration has recently been investigated in various regression models such as the linear, generalized linear, and proportional hazards models. The aim of this paper is to investigate the appropriateness of this method for estimating the stratified Cox regression model with missing values of the covariate defining the strata. Despite its practical relevance, this problem has not yet been discussed in the literature. Asymptotic distribution theory is developed for the regression calibration estimator in this setting. A simulation study is also conducted to investigate the properties of this estimator.     

Modeling longitudinal binomial responses: implications from two dueling paradigms

The generalized estimating equations (GEEs) and generalized linear mixed-effects model (GLMM) are the two most popular paradigms to extend models for cross-sectional data to a longitudinal setting. Although the two approaches yield well-interpreted models for continuous outcomes, it is quite a different story when applied to binomial responses. We discuss major modeling differences between the GEE- and GLMM-derived models by presenting new results regarding the model-driven differences. Our results show that GLMM induces some artifacts in the marginal models at assessment times, making it inappropriate when applied to such responses from real study data. The different interpretations of parameters resulting from the conceptual difference between the two modeling approaches also carry quite significant implications and ramifications with respect to data and power analyses. Although a special case involving a scale difference in parameters between GEE and GLMM has been noted in the literature, its implications in real data analysis has not been thoroughly addressed. Further, this special case has a very limited covariate structure and does not apply to most real studies, especially multi-center clinical trials. The new results presented fill a substantial gap in the literature regarding the model-driven differences between the two dueling paradigms.     

Modelling small and medium enterprise loan defaults as rare events: the generalized extreme value regression model

A pivotal characteristic of credit defaults that is ignored by most credit scoring models is the rarity of the event. The most widely used model to estimate the probability of default is the logistic regression model. Since the dependent variable represents a rare event, the logistic regression model shows relevant drawbacks, for example, underestimation of the default probability, which could be very risky for banks. In order to overcome these drawbacks, we propose the generalized extreme value regression model. In particular, in a generalized linear model (GLM) with the binary-dependent variable we suggest the quantile function of the GEV distribution as link function, so our attention is focused on the tail of the response curve for values close to one. The estimation procedure used is the maximum-likelihood method. This model accommodates skewness and it presents a generalisation of GLMs with complementary log–log link function. We analyse its performance by simulation studies. Finally, we apply the proposed model to empirical data on Italian small and medium enterprises.     

Penalized likelihood ratio test for a biomarker threshold effect in clinical trials based on generalized linear models

In a clinical trial, the responses to the new treatment may vary among patient subsets with different characteristics in a biomarker. It is often necessary to examine whether there is a cutpoint for the biomarker that divides the patients into two subsets of those with more favourable and less favourable responses. More generally, we approach this problem as a test of homogeneity in the effects of a set of covariates in generalized linear regression models. The unknown cutpoint results in a model with nonidentifiability and a nonsmooth likelihood function to which the ordinary likelihood methods do not apply. We first use a smooth continuous function to approximate the indicator function defining the patient subsets. We then propose a penalized likelihood ratio test to overcome the model irregularities. Under the null hypothesis, we prove that the asymptotic distribution of the proposed test statistic is a mixture of chi-squared distributions. Our method is based on established asymptotic theory, is simple to use, and works in a general framework that includes logistic, Poisson, and linear regression models. In extensive simulation studies, we find that the proposed test works well in terms of size and power. We further demonstrate the use of the proposed method by applying it to clinical trial data from the Digitalis Investigation Group (DIG) on heart failure.     

Likelihood Prediction for Generalized Linear Mixed Models under Covariate Uncertainty

This article presents the techniques of likelihood prediction for the generalized linear mixed models. Methods of likelihood prediction are explained through a series of examples; from a classical one to more complicated ones. The examples show, in simple cases, that the likelihood prediction (LP) coincides with already known best frequentist practice such as the best linear unbiased predictor. This article outlines a way to deal with the covariate uncertainty while producing predictive inference. Using a Poisson errors-in-variable generalized linear model, it has been shown in certain cases that LP produces better results than already known methods.     

A new algorithm to estimate monotone nonparametric link functions and a comparison with parametric approach

The generalized linear model (GLM) is a class of regression models where the means of the response variables and the linear predictors are joined through a link function. Standard GLM assumes the link function is fixed, and one can form more flexible GLM by either estimating the flexible link function from a parametric family of link functions or estimating it nonparametically. In this paper, we propose a new algorithm that uses P-spline for nonparametrically estimating the link function which is guaranteed to be monotone. It is equivalent to fit the generalized single index model with monotonicity constraint. We also conduct extensive simulation studies to compare our nonparametric approach for estimating link function with various parametric approaches, including traditional logit, probit and robit link functions, and two recently developed link functions, the generalized extreme value link and the symmetric power logit link. The simulation study shows that the link function estimated nonparametrically by our proposed algorithm performs well under a wide range of different true link functions and outperforms parametric approaches when they are misspecified. A real data example is used to illustrate the results.     

Classical testing in functional linear models

We extend four tests common in classical regression – Wald, score, likelihood ratio and F tests – to functional linear regression, for testing the null hypothesis, that there is no association between a scalar response and a functional covariate. Using functional principal component analysis, we re-express the functional linear model as a standard linear model, where the effect of the functional covariate can be approximated by a finite linear combination of the functional principal component scores. In this setting, we consider application of the four traditional tests. The proposed testing procedures are investigated theoretically for densely observed functional covariates when the number of principal components diverges. Using the theoretical distribution of the tests under the alternative hypothesis, we develop a procedure for sample size calculation in the context of functional linear regression. The four tests are further compared numerically for both densely and sparsely observed noisy functional data in simulation experiments and using two real data applications.     

A GLM approach to step-stress accelerated life testing with interval censoring

In this paper, we present a statistical inference procedure for the step-stress accelerated life testing (SSALT) model with Weibull failure time distribution and interval censoring via the formulation of generalized linear model (GLM). The likelihood function of an interval censored SSALT is in general too complicated to obtain analytical results. However, by transforming the failure time to an exponential distribution and using a binomial random variable for failure counts occurred in inspection intervals, a GLM formulation with a complementary log-log link function can be constructed. The estimations of the regression coefficients used for the Weibull scale parameter are obtained through the iterative weighted least square (IWLS) method, and the shape parameter is updated by a direct maximum likelihood (ML) estimation. The confidence intervals for these parameters are estimated through bootstrapping. The application of the proposed GLM approach is demonstrated by an industrial example.