Volume 14, Issue 1 -

In health and social sciences, research questions often involve systematic assessment of the modification of treatment causal effect by patient characteristics. In longitudinal settings, time-varying or post-intervention effect modifiers are also of interest. In this work, we investigate the robust and efficient estimation of the Counterfactual-History-Adjusted Marginal Structural Model (van der Laan MJ, Petersen M. Statistical learning of origin-specific statically optimal individualized treatment rules. Int J Biostat. 2007;3), which models the conditional intervention-specific mean outcome given a counterfactual modifier history in an ideal experiment. We establish the semiparametric efficiency theory for these models, and present a substitution-based, semiparametric efficient and doubly robust estimator using the targeted maximum likelihood estimation methodology (TMLE, e.g. van der Laan MJ, Rubin DB. Targeted maximum likelihood learning. Int J Biostat. 2006;2, van der Laan MJ, Rose S. Targeted learning: causal inference for observational and experimental data, 1st ed. Springer Series in Statistics. Springer, 2011). To facilitate implementation in applications where the effect modifier is high dimensional, our third contribution is a projected influence function (and the corresponding projected TMLE estimator), which retains most of the robustness of its efficient peer and can be easily implemented in applications where the use of the efficient influence function becomes taxing. We compare the projected TMLE estimator with an Inverse Probability of Treatment Weighted estimator (e.g. Robins JM. Marginal structural models. In: Proceedings of the American Statistical Association. Section on Bayesian Statistical Science, 1-10. 1997a, Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology. 2000;11:561–570), and a non-targeted G-computation estimator (Robins JM. A new approach to causal inference in mortality studies with sustained exposure periods - application to control of the healthy worker survivor effect. Math Modell. 1986;7:1393–1512.). The comparative performance of these estimators is assessed in a simulation study. The use of the projected TMLE estimator is illustrated in a secondary data analysis for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial where effect modifiers are subject to missing at random.

The coefficient of variation (CV) is a widely used scaleless measure of variability in many disciplines. However the inference for the CV is limited to parametric methods or standard bootstrap. In this paper we propose two nonparametric methods aiming to construct confidence intervals for the coefficient of variation. The first one is to apply the empirical likelihood after transforming the original data. The second one is a modified jackknife empirical likelihood method. We also propose bootstrap procedures for calibrating the test statistics. Results from our simulation studies suggest that the proposed methods, particularly the empirical likelihood method with bootstrap calibration, are comparable to existing methods for normal data and yield better coverage probabilities for nonnormal data. We illustrate our methods by applying them to two real-life datasets.

In this paper, we study the zero-inflated Conway-Maxwell Poisson (ZICMP) distribution and develop a regression model. Score and likelihood ratio tests are also implemented for testing the inflation/deflation parameter. Simulation studies are carried out to examine the performance of these tests. A data example is presented to illustrate the concepts. In this example, the proposed model is compared to the well-known zero-inflated Poisson (ZIP) and the zero- inflated generalized Poisson (ZIGP) regression models. It is shown that the fit by ZICMP is comparable or better than these models.

The concordance correlation coefficient (CCC) is a widely used scaled index in the study of agreement. In this article, we propose estimating the CCC by a unified Bayesian framework that can (1) accommodate symmetric or asymmetric and light- or heavy-tailed data; (2) select model from several candidates; and (3) address other issues frequently encountered in practice such as confounding covariates and missing data. The performance of the proposal was studied and demonstrated using simulated as well as real-life biomarker data from a clinical study of an insomnia drug. The implementation of the proposal is accessible through a package in the Comprehensive R Archive Network.

Under the three-treatment three-period crossover design with simple carry-over effects, we derive the least-squares estimators for period effects, treatment effects and carry-over effects, as well as their covariance matrix in closed and explicit expressions. Using Monte Carlo simulation, we compare the test procedure adjusting carry-over with that ignoring carry-over with respect to Type I error and power. We further compare interval estimators adjusting carry-over with those ignoring carry-over with respect to the coverage probability and the average length. When the variation of responses within patients is small, the test procedure and interval estimators ignoring carry-over can lose accuracy in the presence of carry-over effects. When the variation of responses within patients is large, this loss of accuracy may become small or even minimal. We note that the loss of efficiency due to the adjustment of carry-over under the simple carry-over three-period crossover design is moderate, and is much less than that found for a two-period crossover design. We use the double-blind three-period crossover trial comparing formoterol solution aerosol and salbutamol suspension aerosol with a placebo for patients suffering from exercise-induced asthma on the forced expiratory volume in one second (FEV 1 ) to illustrate the use of test procedures and interval estimators discussed here.

Methodological development and clinical application of joint models of longitudinal and time-to-event outcomes have grown substantially over the past two decades. However, much of this research has concentrated on a single longitudinal outcome and a single event time outcome. In clinical and public health research, patients who are followed up over time may often experience multiple, recurrent, or a succession of clinical events. Models that utilise such multivariate event time outcomes are quite valuable in clinical decision-making. We comprehensively review the literature for implementation of joint models involving more than a single event time per subject. We consider the distributional and modelling assumptions, including the association structure, estimation approaches, software implementations, and clinical applications. Research into this area is proving highly promising, but to-date remains in its infancy.