Structural Nested Models and G-estimation: The Partially Realized Promise

Structural nested models (SNMs) and the associated method of G-estimation were first proposed by James Robins over two decades ago as approaches to modeling and estimating the joint effects of a sequence of treatments or exposures. The models and estimation methods have since been extended to dealing with a broader series of problems, and have considerable advantages over the other methods developed for estimating such joint effects. Despite these advantages, the application of these methods in applied research has been relatively infrequent; we view this as unfortunate. To remedy this, we provide an overview of the models and estimation methods as developed, primarily by Robins, over the years. We provide insight into their advantages over other methods, and consider some possible reasons for failure of the methods to be more broadly adopted, as well as possible remedies. Finally, we consider several extensions of the standard models and estimation methods.Comment: Published in at http://dx.doi.org/10.1214/14-STS493 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Causal inference for continuous-time processes when covariates are observed only at discrete times

Most of the work on the structural nested model and g-estimation for causal inference in longitudinal data assumes a discrete-time underlying data generating process. However, in some observational studies, it is more reasonable to assume that the data are generated from a continuous-time process and are only observable at discrete time points. When these circumstances arise, the sequential randomization assumption in the observed discrete-time data, which is essential in justifying discrete-time g-estimation, may not be reasonable. Under a deterministic model, we discuss other useful assumptions that guarantee the consistency of discrete-time g-estimation. In more general cases, when those assumptions are violated, we propose a controlling-the-future method that performs at least as well as g-estimation in most scenarios and which provides consistent estimation in some cases where g-estimation is severely inconsistent. We apply the methods discussed in this paper to simulated data, as well as to a data set collected following a massive flood in Bangladesh, estimating the effect of diarrhea on children's height. Results from different methods are compared in both simulation and the real application.Comment: Published in at http://dx.doi.org/10.1214/10-AOS830 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Defining and Estimating Intervention Effects for Groups that will Develop an Auxiliary Outcome

It has recently become popular to define treatment effects for subsets of the target population characterized by variables not observable at the time a treatment decision is made. Characterizing and estimating such treatment effects is tricky; the most popular but naive approach inappropriately adjusts for variables affected by treatment and so is biased. We consider several appropriate ways to formalize the effects: principal stratification, stratification on a single potential auxiliary variable, stratification on an observed auxiliary variable and stratification on expected levels of auxiliary variables. We then outline identifying assumptions for each type of estimand. We evaluate the utility of these estimands and estimation procedures for decision making and understanding causal processes, contrasting them with the concepts of direct and indirect effects. We motivate our development with examples from nephrology and cancer screening, and use simulated data and real data on cancer screening to illustrate the estimation methods.Comment: Published at http://dx.doi.org/10.1214/088342306000000655 in the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Methodological Issues in the Study of the Effects of Hemoglobin Variability

We consider estimating the effect of hemoglobin variability on mortality in hemodialysis patients. Causal effects can be defined as comparisons of outcomes under different hypothetical interventions. Defining measures of the effect of hemoglobin variability and clinical outcomes is complicated by the fact that hypothetical interventions on variability used to define its effect inevitably involve manipulation of related variables. We propose a model-based definition of the effect of the hemoglobin variability as a parameter for variability in a causal model for the effect of an overall intervention on hemoglobin levels over time. We consider this problem using history-adjusted marginal structural models, and apply this approach to data from a large observational database. We consider issues arising when the variable of interest is endogenous, and consider in principle alternate estimands

Optimal Restricted Estimation for More Efficient Longitudinal Causal Inference

Efficient semiparametric estimation of longitudinal causal effects is often analytically or computationally intractable. We propose a novel restricted estimation approach for increasing efficiency, which can be used with other techniques, is straightforward to implement, and requires no additional modeling assumptions

Casual Mediation Analyses with Structural Mean Models

We represent a linear structural mean model (SMM)approach for analyzing mediation of a randomized baseline intervention\u27s effect on a univariate follow-up outcome. Unlike standard mediation analyses, our approach does not assume that the mediating factor is randomly assigned to individuals (i.e., sequential ignorability). Hence, a comparison of the results of the proposed and standard approaches in with respect to mediation offers a sensitivity analyses of the sequential ignorability assumption. The G-estimation procedure for the proposed SMM represents an extension of the work on direct effects of randomized treatment effects for survival outcomes by Robins and Greenland (1994) (Section 5.0 and Appendix B) and on treatment non-adherence for continuous outcomes by TenHave et al. (2004). Simulations show good estimation and confidence interval performance under unmeasured confounding relative mediation approach. Sensitivity analyses of the sequential ignorability assumption comparing the results of the two approaches are presented in the context of two suicide/depression treatment studies

Random Effects Logistic Models for Analyzing Efficacy of a Longitudinal Randomized Treatment With Non-Adherence

We present a random effects logistic approach for estimating the efficacy of treatment for compliers in a randomized trial with treatment non-adherence and longitudinal binary outcomes. We use our approach to analyse a primary care depression intervention trial. The use of a random effects model to estimate efficacy supplements intent-to-treat longitudinal analyses based on random effects logistic models that are commonly used in primary care depression research. Our estimation approach is an extension of Nagelkerke et al.\u27s instrumental variables approximation for cross-sectional binary outcomes. Our approach is easily implementable with standard random effects logistic regression software. We show through a simulation study that our approach provides reasonably accurate inferences for the setting of the depression trial under model assumptions. We also evaluate the sensitivity of our approach to model assumptions for the depression trial