Expressing Estimators of Expected Quality Adjusted Survival as Functions of Nelson-Aalen Estimators

Quality adjusted survival has been increasingly advocated in clinical trials to be assessed as a synthesis of survival and quality of life. We investigate nonparametric estimation of its expectation for a general multistate process with incomplete follow-up data. Upon establishing a representation of expected quality adjusted survival through marginal distributions of a set of defined events, we propose two estimators for expected quality adjusted survival. Expressed as functions of Nelson-Aalen estimators, the two estimators are strongly consistent and asymptotically normal. We derive their asymptotic variances and propose sample-based variance estimates, along with evaluation of asymptotic relative efficiency. Monte Carlo studies show that these estimation procedures perform well for practical sample sizes. We illustrate the methods using data from a national, multicenter AIDS clinical trial.     

Failure time studies with intermittent observation and losses to follow-up

In health research interest often lies in modeling a failure time process but in many cohort studies failure status is only determined at scheduled assessment times. While the assessment times may be fixed upon study entry, individuals may become lost to follow-up and miss visits subsequent to the time of loss to follow-up. We consider a three-state model to characterize a joint failure and loss to follow-up process, and use it to investigate the impact of dependent loss to follow-up on standard parametric, nonparametric, and semiparametric analysis. The effect of dependent loss to follow-up is mitigated by fitting the joint model. The performance of standard methods is studied using the asymptotic theory of misspecified models, and the finite sample performance is examined for the standard and joint analyses through simulation studies. An application to data from a youth smoking prevention study is presented for illustration.     

A Bayesian model for estimating the malaria transition probabilities considering individuals lost to follow-up

It is known that patients may cease participating in a longitudinal study and become lost to follow-up. The objective of this article is to present a Bayesian model to estimate the malaria transition probabilities considering individuals lost to follow-up. We consider a homogeneous population, and it is assumed that the considered period of time is small enough to avoid two or more transitions from one state of health to another. The proposed model is based on a Gibbs sampling algorithm that uses information of lost to follow-up at the end of the longitudinal study. To simulate the unknown number of individuals with positive and negative states of malaria at the end of the study and lost to follow-up, two latent variables were introduced in the model. We used a real data set and a simulated data to illustrate the application of the methodology. The proposed model showed a good fit to these data sets, and the algorithm did not show problems of convergence or lack of identifiability. We conclude that the proposed model is a good alternative to estimate probabilities of transitions from one state of health to the other in studies with low adherence to follow-up.     

Semiparametric estimation method for accelerated failure time model with dependent censoring

Independent censoring is commonly assumed in survival analysis. However, it may be questionable when censoring is related to event time. We model the event and censoring time marginally through accelerated failure time models, and model their association by a known copula. An iteration algorithm is proposed to estimate the regression parameters. Simulation results show the improvement of the proposed method compared to the naive method under independent censoring. Sensitivity analysis gives the evidences that the proposed method can obtain reasonable estimates even when the forms of copula are misspecified. We illustrate its application by analyzing prostate cancer data.     

Quantification of follow-up time in oncology clinical trials with a time-to-event endpoint: Asking the right questions

For the analysis of a time-to-event endpoint in a single-arm or randomized clinical trial it is generally perceived that interpretation of a given estimate of the survival function, or the comparison between two groups, hinges on some quantification of the amount of follow-up. Typically, a median of some loosely defined quantity is reported. However, whatever median is reported, is typically not answering the question(s) trialists actually have in terms of follow-up quantification. In this paper, inspired by the estimand framework, we formulate a comprehensive list of relevant scientific questions that trialists have when reporting time-to-event data. We illustrate how these questions should be answered, and that reference to an unclearly defined follow-up quantity is not needed at all. In drug development, key decisions are made based on randomized controlled trials, and we therefore also discuss relevant scientific questions not only when looking at a time-to-event endpoint in one group, but also for comparisons. We find that different thinking about some of the relevant scientific questions around follow-up is required depending on whether a proportional hazards assumption can be made or other patterns of survival functions are anticipated, for example, delayed separation, crossing survival functions, or the potential for cure. We conclude the paper with practical recommendations.     

The gamma-linear failure rate distribution: theory and applications

For any continuous baseline G distribution, Zografos and Balakrishnan [On families of beta- and generalized gamma-generated distributions and associated inference. Statist Methodol. 2009;6:344–362] introduced the generalized gamma-generated distribution with an extra positive parameter. A new three-parameter continuous model called the gamma-linear failure rate (LFR) distribution, which extends the LFR model, is proposed and studied. Various structural properties of the new distribution are derived, including some explicit expressions for ordinary and incomplete moments, generating function, probability-weighted moments, mean deviations and Rényi and Shannon entropies. We estimate the model parameters by maximum likelihood and obtain the observed information matrix. The new model is modified to cope with possible long-term survivors in lifetime data. We illustrate the usefulness of the proposed model by means of two applications to real data.     

The versatility of multi-state models for the analysis of longitudinal data with unobservable features

Multi-state models provide a convenient statistical framework for a wide variety of medical applications characterized by multiple events and longitudinal data. We illustrate this through four examples. The potential value of the incorporation of unobserved or partially observed states is highlighted. In addition, joint modelling of multiple processes is illustrated with application to potentially informative loss to follow-up, mis-measured or missclassified data and causal inference.     

KERNEL DENSITY ESTIMATION WITH MISSING DATA AND AUXILIARY VARIABLES

In most parametric statistical analyses, knowledge of the distribution of the response variable, or of the errors, is important. As this distribution is not typically known with certainty, one might initially construct a histogram or estimate the density of the variable of interest to gain insight regarding the distribution and its characteristics. However, when the response variable is incomplete, a histogram will only provide a representation of the distribution of the observed data. In the AIDS Clinical Trial Study protocol 175, interest lies in the difference in CD4 counts from baseline to final follow-up, but CD4 counts collected at final follow-up were incomplete. A method is therefore proposed for estimating the density of an incomplete response variable when auxiliary data are available. The proposed estimator is based on the Horvitz–Thompson estimator, and the propensity scores are estimated nonparametrically. Simulation studies indicate that the proposed estimator performs well.     

On the Detection of Contemporaneous Relationships Among Multiple Time Series

A study is carried out of a sampling from a half-normal and exponential distributions to develop a test of hypothesis on the mean. Although these distributions are similar, the corresponding uniformly most paerful test statistics are different. The exact distributions of these statistics my be written in terms of the incomplete gamma function. If the experimental data my be fitted by either distributions, it is advisable to carryout the test based on the half-normal distribution as it is generally more powerful than the one based on the exponential one.     

Missing data techniques for multilevel data: implications of model misspecification

When modeling multilevel data, it is important to accurately represent the interdependence of observations within clusters. Ignoring data clustering may result in parameter misestimation. However, it is not well established to what degree parameter estimates are affected by model misspecification when applying missing data techniques (MDTs) to incomplete multilevel data. We compare the performance of three MDTs with incomplete hierarchical data. We consider the impact of imputation model misspecification on the quality of parameter estimates by employing multiple imputation under assumptions of a normal model (MI/NM) with two-level cross-sectional data when values are missing at random on the dependent variable at rates of 10%, 30%, and 50%. Five criteria are used to compare estimates from MI/NM to estimates from MI assuming a linear mixed model (MI/LMM) and maximum likelihood estimation to the same incomplete data sets. With 10% missing data (MD), techniques performed similarly for fixed-effects estimates, but variance components were biased with MI/NM. Effects of model misspecification worsened at higher rates of MD, with the hierarchical structure of the data markedly underrepresented by biased variance component estimates. MI/LMM and maximum likelihood provided generally accurate and unbiased parameter estimates but performance was negatively affected by increased rates of MD.     

Dimension Reduction in the Linear Model for Right-Censored Data: Predicting the Change of HIV-I RNA Levels using Clinical and Protease Gene Mutation Data

With rapid development in the technology of measuring disease characteristics at molecular or genetic level, it is possible to collect a large amount of data on various potential predictors of the clinical outcome of interest in medical research. It is often of interest to effectively use the information on a large number of predictors to make prediction of the interested outcome. Various statistical tools were developed to overcome the difficulties caused by the high-dimensionality of the covariate space in the setting of a linear regression model. This paper focuses on the situation, where the interested outcomes are subjected to right censoring. We implemented the extended partial least squares method along with other commonly used approaches for analyzing the high-dimensional covariates to the ACTG333 data set. Especially, we compared the prediction performance of different approaches with extensive cross-validation studies. The results show that the Buckley–James based partial least squares, stepwise subset model selection and principal components regression have similar promising predictive power and the partial least square method has several advantages in terms of interpretability and numerical computation.     

Robust Correlation Structure for Multivariate Failure Time Data

When incomplete repeated failure times are collected from a large number of independent individuals, interest is focused primarily on the consistent and efficient estimation of the effects of the associated covariates on the failure times. Since repeated failure times are likely to be correlated, it is important to exploit the correlation structure of the failure data in order to obtain such consistent and efficient estimates. However, it may be difficult to specify an appropriate correlation structure for a real life data set. We propose a robust correlation structure that can be used irrespective of the true correlation structure. This structure is used in constructing an estimating equation for the hazard ratio parameter, under the assumption that the number of repeated failure times for an individual is random. The consistency and efficiency of the estimates is examined through a simulation study, where we consider failure times that marginally follow an exponential distribution and a Poisson distribution is assumed for the random number of repeated failure times. We conclude by using the proposed method to analyze a bladder cancer dataset.     

A reanalysis of a longitudinal scleroderma clinical trial using non-ignorable missingness models

When analyzing incomplete longitudinal clinical trial data, it is often inappropriate to assume that the occurrence of missingness is at random, especially in cases where visits are entirely missed. We present a framework that simultaneously models multivariate incomplete longitudinal data and a non-ignorable missingness mechanism using a Bayesian approach. A criterion measure is presented for comparing models. We demonstrate the feasibility of the methodology through reanalysis of two of the longitudinal measures from a clinical trial of penicillamine treatment for scleroderma patients. We compare the results for univariate and bivariate, ignorable and non-ignorable missingness models.     

Multiple imputation using multivariate gh transformations

Multiple imputation has emerged as a popular approach to handling data sets with missing values. For incomplete continuous variables, imputations are usually produced using multivariate normal models. However, this approach might be problematic for variables with a strong non-normal shape, as it would generate imputations incoherent with actual distributions and thus lead to incorrect inferences. For non-normal data, we consider a multivariate extension of Tukey's gh distribution/transformation [38] to accommodate skewness and/or kurtosis and capture the correlation among the variables. We propose an algorithm to fit the incomplete data with the model and generate imputations. We apply the method to a national data set for hospital performance on several standard quality measures, which are highly skewed to the left and substantially correlated with each other. We use Monte Carlo studies to assess the performance of the proposed approach. We discuss possible generalizations and give some advices to practitioners on how to handle non-normal incomplete data.     

An algorithm for the Buckley–James estimator with interval-censored data

The Buckley–James estimator (BJE) [J. Buckley and I. James, Linear regression with censored data, Biometrika 66 (1979), pp. 429–436] has been extended from right-censored (RC) data to interval-censored (IC) data by Rabinowitz et al. [D. Rabinowitz, A. Tsiatis, and J. Aragon, Regression with interval-censored data, Biometrika 82 (1995), pp. 501–513]. The BJE is defined to be a zero-crossing of a modified score function H(b), a point at which H(·) changes its sign. We discuss several approaches (for finding a BJE with IC data) which are extensions of the existing algorithms for RC data. However, these extensions may not be appropriate for some data, in particular, they are not appropriate for a cancer data set that we are analysing. In this note, we present a feasible iterative algorithm for obtaining a BJE. We apply the method to our data.     

The analysis of transition times in multistate stochastic processes using proportional hazard regression models

Extensions to Cox's proportional hazards regression model (Cox, 1972) for the analysis of survival data are considered for a more general multistate framework. This framework allows several transient disease states between initial entry state and death as well as incorporating possible competing causes of death. Methods for parameter and function estimation within this extension are presented and applied to the analysis of data from the Stanford Heart Transplantation Program (Crowley and Hu,1977).     

Bayesian Inference from Case–cohort Data with Multiple End-points

Abstract.  In a case–cohort design a random sample from the study cohort, referred as a subcohort, and all the cases outside the subcohort are selected for collecting extra covariate data. The union of the selected subcohort and all cases are referred as the case–cohort set. Such a design is generally employed when the collection of information on an extra covariate for the study cohort is expensive. An advantage of the case–cohort design over more traditional case–control and the nested case–control designs is that it provides a set of controls which can be used for multiple end-points, in which case there is information on some covariates and event follow-up for the whole study cohort. Here, we propose a Bayesian approach to analyse such a case–cohort design as a cohort design with incomplete data on the extra covariate. We construct likelihood expressions when multiple end-points are of interest simultaneously and propose a Bayesian data augmentation method to estimate the model parameters. A simulation study is carried out to illustrate the method and the results are compared with the complete cohort analysis.     

Bayesian analysis for partially complete time and type of failure data

In this paper, we consider the Bayesian analysis of competing risks data, when the data are partially complete in both time and type of failures. It is assumed that the latent cause of failures have independent Weibull distributions with the common shape parameter, but different scale parameters. When the shape parameter is known, it is assumed that the scale parameters have Beta–Gamma priors. In this case, the Bayes estimates and the associated credible intervals can be obtained in explicit forms. When the shape parameter is also unknown, it is assumed that it has a very flexible log-concave prior density functions. When the common shape parameter is unknown, the Bayes estimates of the unknown parameters and the associated credible intervals cannot be obtained in explicit forms. We propose to use Markov Chain Monte Carlo sampling technique to compute Bayes estimates and also to compute associated credible intervals. We further consider the case when the covariates are also present. The analysis of two competing risks data sets, one with covariates and the other without covariates, have been performed for illustrative purposes. It is observed that the proposed model is very flexible, and the method is very easy to implement in practice.     

Earthquakes occurrences estimation through a parametric semi-Markov approach

The estimation of earthquakes’ occurrences prediction in seismic areas is a challenging problem in seismology and earthquake engineering. Indeed, the prevention and the quantification of possible damage provoked by destructive earthquakes are directly linked to this kind of prevision. In our paper, we adopt a parametric semi-Markov approach. This model assumes that a sequence of earthquakes is seen as a Markov process and besides it permits to take into consideration the more realistic assumption of events’ dependence in space and time. The elapsed time between two consecutive events is modeled as a general Weibull distribution. We determine then the transition probabilities and the so-called crossing states probabilities. We conclude then with a Monte Carlo simulation and the model is validated through a large database containing real data.