Estimation of Stratified Mark‐Specific Proportional Hazards Models with Missing Marks

Abstract. An objective of randomized placebo‐controlled preventive HIV vaccine efficacy trials is to assess the relationship between the vaccine effect to prevent infection and the genetic distance of the exposing HIV to the HIV strain represented in the vaccine construct. Motivated by this objective, recently a mark‐specific proportional hazards (PH) model with a continuum of competing risks has been studied, where the genetic distance of the transmitting strain is the continuous ‘mark’ defined and observable only in failures. A high percentage of genetic marks of interest may be missing for a variety of reasons, predominantly because rapid evolution of HIV sequences after transmission before a blood sample is drawn from which HIV sequences are measured. This research investigates the stratified mark‐specific PH model with missing marks where the baseline functions may vary with strata. We develop two consistent estimation approaches, the first based on the inverse probability weighted complete‐case (IPW) technique, and the second based on augmenting the IPW estimator by incorporating auxiliary information predictive of the mark. We investigate the asymptotic properties and finite‐sample performance of the two estimators, and show that the augmented IPW estimator, which satisfies a double robustness property, is more efficient.     

Parametric Inference in Stationary Time Series Models with Dependent Errors

This article is concerned with inference for the parameter vector in stationary time series models based on the frequency domain maximum likelihood estimator. The traditional method consistently estimates the asymptotic covariance matrix of the parameter estimator and usually assumes the independence of the innovation process. For dependent innovations, the asymptotic covariance matrix of the estimator depends on the fourth‐order cumulants of the unobserved innovation process, a consistent estimation of which is a difficult task. In this article, we propose a novel self‐normalization‐based approach to constructing a confidence region for the parameter vector in such models. The proposed procedure involves no smoothing parameter, and is widely applicable to a large class of long/short memory time series models with weakly dependent innovations. In simulation studies, we demonstrate favourable finite sample performance of our method in comparison with the traditional method and a residual block bootstrap approach.     

A generalized Fleming and Harrington's class of tests for interval‐censored data

The class $G^{\rho,\lambda }$ of weighted log‐rank tests proposed by Fleming & Harrington [Fleming & Harrington (1991) Counting Processes and Survival Analysis, Wiley, New York] has been widely used in survival analysis and is nowadays, unquestionably, the established method to compare, nonparametrically, k different survival functions based on right‐censored survival data. This paper extends the $G^{\rho,\lambda }$ class to interval‐censored data. First we introduce a new general class of rank based tests, then we show the analogy to the above proposal of Fleming & Harrington. The asymptotic behaviour of the proposed tests is derived using an observed Fisher information approach and a permutation approach. Aiming to make this family of tests interpretable and useful for practitioners, we explain how to interpret different choices of weights and we apply it to data from a cohort of intravenous drug users at risk for HIV infection. The Canadian Journal of Statistics 40: 501–516; 2012 © 2012 Statistical Society of Canada     

Information-based thinning of point processes and its application to shock models

Thinning of point processes is a useful operation that is implemented in various stochastic models. When the initial point process is the nonhomogeneous Poisson process (NHPP), the thinned processes are also nonhomogeneous Poisson processes independent of each other. The crucial assumption in deriving this result is that the corresponding classification of events is independent of all other events, including the history of the process. However, in practice, this classification is often dependent on the history. In our paper, we define and describe the thinned processes for the history-dependent case using different levels of available information. We also discuss the applications of the obtained general results to the corresponding shocks models.     

Sample size calculation for recurrent events data in one‐arm studies

In some exceptional circumstances, as in very rare diseases, nonrandomized one‐arm trials are the sole source of evidence to demonstrate efficacy and safety of a new treatment. The design of such studies needs a sound methodological approach in order to provide reliable information, and the determination of the appropriate sample size still represents a critical step of this planning process. As, to our knowledge, no method exists for sample size calculation in one‐arm trials with a recurrent event endpoint, we propose here a closed sample size formula. It is derived assuming a mixed Poisson process, and it is based on the asymptotic distribution of the one‐sample robust nonparametric test recently developed for the analysis of recurrent events data. The validity of this formula in managing a situation with heterogeneity of event rates, both in time and between patients, and time‐varying treatment effect was demonstrated with exhaustive simulation studies. Moreover, although the method requires the specification of a process for events generation, it seems to be robust under erroneous definition of this process, provided that the number of events at the end of the study is similar to the one assumed in the planning phase. The motivating clinical context is represented by a nonrandomized one‐arm study on gene therapy in a very rare immunodeficiency in children (ADA‐SCID), where a major endpoint is the recurrence of severe infections. Copyright © 2012 John Wiley & Sons, Ltd.     

Handling of missing data in long‐term clinical trials: a case study

Missing data in clinical trials is a well‐known problem, and the classical statistical methods used can be overly simple. This case study shows how well‐established missing data theory can be applied to efficacy data collected in a long‐term open‐label trial with a discontinuation rate of almost 50%. Satisfaction with treatment in chronically constipated patients was the efficacy measure assessed at baseline and every 3 months postbaseline. The improvement in treatment satisfaction from baseline was originally analyzed with a paired t‐test ignoring missing data and discarding the correlation structure of the longitudinal data. As the original analysis started from missing completely at random assumptions regarding the missing data process, the satisfaction data were re‐examined, and several missing at random (MAR) and missing not at random (MNAR) techniques resulted in adjusted estimate for the improvement in satisfaction over 12 months. Throughout the different sensitivity analyses, the effect sizes remained significant and clinically relevant. Thus, even for an open‐label trial design, sensitivity analysis, with different assumptions for the nature of dropouts (MAR or MNAR) and with different classes of models (selection, pattern‐mixture, or multiple imputation models), has been found useful and provides evidence towards the robustness of the original analyses; additional sensitivity analyses could be undertaken to further qualify robustness. Copyright © 2012 John Wiley & Sons, Ltd.     

A generalisation of T‐optimality for discriminating between competing models with an application to pharmacokinetic studies

The T‐optimality criterion is used in optimal design to derive designs for model selection. To set up the method, it is required that one of the models is considered to be true. We term this local T‐optimality. In this work, we propose a generalisation of T‐optimality (termed robust T‐optimality) that relaxes the requirement that one of the candidate models is set as true. We then show an application to a nonlinear mixed effects model with two candidate non‐nested models and combine robust T‐optimality with robust D‐optimality. Optimal design under local T‐optimality was found to provide adequate power when the a priori assumed true model was the true model but poor power if the a priori assumed true model was not the true model. The robust T‐optimality method provided adequate power irrespective of which model was true. The robust T‐optimality method appears to have useful properties for nonlinear models, where both the parameter values and model structure are required to be known a priori, and the most likely model that would be applied to any new experiment is not known with certainty. Copyright © 2012 John Wiley & Sons, Ltd.     

Austérité budgétaire et flexibilisation du marché du travail: une association risquée

Les auteurs évaluent les effets de l'association entre politiques d'austérité budgétaire et de réduction du coût du travail, et apportent ainsi quelque éclairage sur les débats en cours. Ils s'attaquent au problème de l'agrégation dans une perspective mondiale au moyen d'un macromodèle mettant en évidence la dynamique de la répartition. La flexibilisation réduit la part salariale et entraîne des rétroactions qui s'enchaînent dans une spirale descendante avec une contraction de l'activité, même dans les économies tirées par les exportations. Les gains initiaux de compétitivité se révèlent éphémères. Sur le long terme, les salaires sont les premiers moteurs de l'économie mondiale, qui réagit positivement aux stimuli keynésiens coordonnés.     

Cross‐Cultural Comparison of the Effects of Optimism,Intrinsic Motivation,and Family Relations on Vocational Identity

This study explored the effects of optimism, intrinsic motivation, and family relations on vocational identity in college students in the United States and South Korea. The results yielded support for the hypothesized multivariate model. Across both cultures, optimism was an important contributing factor to vocational identity, and intrinsic motivation partially mediated the link from optimism to vocational identity. In addition, family relations moderated the mediation effect of intrinsic motivation with American students but not Korean students. With Korean students, family relations moderated the direct link from optimism to vocational identity. These results have significant implications for counseling to promote vocational identity development for diverse college students.