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Background In many applications of instrumental variable (IV) methods, the treatments of interest are intrinsically time-varying and outcomes of interest are failure time outcomes. A common example is Mendelian randomization (MR), which uses genetic variants as proposed IVs. In this article, we present a novel application of g-estimation of structural nested cumulative failure models (SNCFTMs), which can accommodate multiple measures of a time-varying treatment when modelling a failure time outcome in an IV analysis. Methods A SNCFTM models the ratio of two conditional mean counterfactual outcomes at time k under two treatment strategies which differ only at an earlier time m . These models can be extended to accommodate inverse probability of censoring weights, and can be applied to case-control data. We also describe how the g-estimates of the SNCFTM parameters can be used to calculate marginal cumulative risks under nondynamic treatment strategies. We examine the performance of this method using simulated data, and present an application of these models by conducting an MR study of alcohol intake and endometrial cancer using longitudinal observational data from the Nurses’ Health Study. Results Our simulations found that estimates from SNCFTMs which used an IV approach were similar to those obtained from SNCFTMs which adjusted for confounders, and similar to those obtained from the g-formula approach when the outcome was rare. In our data application, the cumulative risk of endometrial cancer from age 45 to age 72 under the “never drink” strategy (4.0%) was similar to that under the “always ½ drink per day” strategy (4.3%). Conclusions SNCFTMs can be used to conduct MR and other IV analyses with time-varying treatments and failure time outcomes.

Dynamic treatment regimes (DTRs) aim to formalize personalized medicine by tailoring treatment decisions to individual patient characteristics. G-estimation for DTR identification targets the parameters of a structural nested mean model, known as the blip function, from which the optimal DTR is derived. Despite its potential, G-estimation has not seen widespread use in the literature, owing in part to its often complex presentation and implementation, but also due to the necessity for correct specification of the blip. Using a quadratic approximation approach inspired by iteratively reweighted least squares, we derive a quasilikelihood function for G-estimation within the DTR framework, and show how it can be used to form an information criterion for blip model selection. We outline the theoretical properties of this model selection criterion and demonstrate its application in a variety of simulation studies as well as in data from the Sequenced Treatment Alternatives to Relieve Depression study.

In mobile health interventions aimed at behavior change and maintenance, treatments are provided in real time to manage current or impending high-risk situations or promote healthy behaviors in near real time. Currently there is great scientific interest in developing data analysis approaches to guide the development of mobile interventions. In particular data from mobile health studies might be used to examine effect moderators-individual characteristics, time-varying context, or past treatment response that moderate the effect of current treatment on a subsequent response. This article introduces a formal definition for moderated effects in terms of potential outcomes, a definition that is particularly suited to mobile interventions, where treatment occasions are numerous, individuals are not always available for treatment, and potential moderators might be influenced by past treatment. Methods for estimating moderated effects are developed and compared. The proposed approach is illustrated using BASICS-Mobile, a smartphone-based intervention designed to curb heavy drinking and smoking among college students. Supplementary materials for this article are available online.

The United States Environmental Protection Agency considers nutrient pollution in stream ecosystems one of the United States' most pressing environmental challenges. But limited independent replicates, lack of experimental randomization, and space- and time-varying confounding handicap causal inference on effects of nutrient pollution. In this article, the causal g-methods are extended to allow for exposures to vary in time and space in order to assess the effects of nutrient pollution on chlorophyll a-a proxy for algal production. Publicly available data from North Carolina's Cape Fear River and a simulation study are used to show how causal effects of upstream nutrient concentrations on downstream chlorophyll a levels may be estimated from typical water quality monitoring data. Estimates obtained from the parametric g-formula, a marginal structural model, and a structural nested model indicate that chlorophyll a concentrations at Lock and Dam 1 were influenced by nitrate concentrations measured 86 to 109 km upstream, an area where four major industrial and municipal point sources discharge wastewater. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

In observational studies, treatment may be adapted to covariates at several times without a fixed protocol, in continuous time. Treatment influences covariates, which influence treatment, which influences covariates and so on. Then even time-dependent Cox-models cannot be used to estimate the net treatment effect. Structural nested models have been applied in this setting. Structural nested models are based on counterfactuals: the outcome a person would have had had treatment been withheld after a certain time. Previous work on continuous-time structural nested models assumes that counterfactuals depend deterministically on observed data, while conjecturing that this assumption can be relaxed. This article proves that one can mimic counterfactuals by constructing random variables, solutions to a differential equation, that have the same distribution as the counterfactuals, even given past observed data. These \"mimicking\" variables can be used to estimate the parameters of structural nested models without assuming the treatment effect to be deterministic.

Marginal Structural Models (MSMs), with the associated method of inverse probability weighting (IPW), have become increasingly popular in epidemiology to model and estimate the joint effects of a sequence of exposures. This popularity is largely related to the relative simplicity of the method, as compared to other techniques to adjust for time-varying confounding, such as g-estimation and g-computation. However, the price to pay for this simplicity can be substantial. The IPW estimators that are routinely used in applications make inefficient use of the information in the data, and are susceptible to large finite-sample bias when some confounders are strongly predictive of exposure. Moreover, the handling of continuous exposures easily becomes impractical, and the study of effect modification by time-varying covariates even impossible. In view of this, we revisit Structural Nested Mean Models (SNMMs) with the associated method of g-estimation as a useful remedy, and show how this can be implemented through standard software.

In comparative effectiveness research, it is often of interest to calibrate treatment effect estimates from a clinical trial to a target population that differs from the study population. One important application is an indirect comparison of a new treatment with a placebo control on the basis of two separate randomized clinical trials: a non-inferiority trial comparing the new treatment with an active control and a historical trial comparing the active control with placebo. The available methods for treatment effect calibration include an outcome regression (OR) method based on a regression model for the outcome and a weighting method based on a propensity score (PS) model. This article proposes new methods for treatment effect calibration: one based on a conditional effect (CE) model and two doubly robust (DR) methods. The first DR method involves a PS model and an OR model, is asymptotically valid if either model is correct, and attains the semiparametric information bound if both models are correct. The second DR method involves a PS model, a CE model, and possibly an OR model, is asymptotically valid under the union of the PS and CE models, and attains the semiparametric information bound if all three models are correct. The various methods are compared in a simulation study and applied to recent clinical trials for treating human immunodeficiency virus infection.

Dysphagia is a primary cause of death among patients diagnosed with amyotrophic lateral sclerosis (ALS), and percutaneous endoscopic gastrostomy (PEG) is a procedure to insert a tube into the stomach to assist or replace oral feeding. It is believed that PEG is beneficial and, generally, earlier insertion is preferable to later. However, gathering clinical evidence to support these beliefs on the use and timing of PEG is challenging because controlled clinical trials are not feasible and clinical endpoints are confounded with PEG in observational data. Moreover, the confounders are time-varying and time to PEG insertion may be only partially observed. We show how one can view this problem as an adaptive treatment length policy and propose a new estimator via g-computation. We show that our estimator is consistent and asymptotically normal for the causal estimand and explore its finite sample properties in simulation studies. Finally, using more than 10 years of data from Emory ALS clinic registry, we found no evidence to suggest that earlier PEG reduced 4-year mortality; thus, our results do not support the hypothesis and belief that initiating palliative care earlier extends life, on average. At the same, we cannot be certain that all important confounding variables are collected and observed to ensure our modeling assumptions are correct, so more work is needed to address these important end-of-life questions for ALS patients.

Behavioral science researchers have shown strong interest in disaggregating within-person relations from between-person differences (stable traits) using longitudinal data. In this paper, we propose a method of within-person variability score-based causal inference for estimating joint effects of time-varying continuous treatments by controlling for stable traits of persons. After explaining the assumed data-generating process and providing formal definitions of stable trait factors, within-person variability scores, and joint effects of time-varying treatments at the within-person level, we introduce the proposed method, which consists of a two-step analysis. Within-person variability scores for each person, which are disaggregated from stable traits of that person, are first calculated using weights based on a best linear correlation preserving predictor through structural equation modeling (SEM). Causal parameters are then estimated via a potential outcome approach, either marginal structural models (MSMs) or structural nested mean models (SNMMs), using calculated within-person variability scores. Unlike the approach that relies entirely on SEM, the present method does not assume linearity for observed time-varying confounders at the within-person level. We emphasize the use of SNMMs with G-estimation because of its property of being doubly robust to model misspecifications in how observed time-varying confounders are functionally related to treatments/predictors and outcomes at the within-person level. Through simulation, we show that the proposed method can recover causal parameters well and that causal estimates might be severely biased if one does not properly account for stable traits. An empirical application using data regarding sleep habits and mental health status from the Tokyo Teen Cohort study is also provided.

The objective of many scientific studies is to evaluate the effect of a treatment on an outcome of interest ceteris paribus. Instrumental variables (IVs) serve as an experimental handle, independent of potential outcomes and potential treatment status and affecting potential outcomes only through potential treatment status. We propose marginal and nested structural models using IVs, in the spirit of marginal and nested structural models under no unmeasured confounding. A marginal structural IV model parameterizes the expectations of two potential outcomes under an active treatment and the null treatment respectively, for those in a covariate-specific subpopulation who would take the active treatment if the instrument were externally set to each specific level. A nested structural IV model parameterizes the difference between the two expectations after transformed by a link function and hence the average treatment effect on the treated at each instrument level. We develop IV outcome regression, IV propensity score weighting, and doubly robust methods for estimation, in parallel to those for structural models under no unmeasured confounding. The regression method requires correctly specified models for the treatment propensity score and the outcome regression function. The weighting method requires a correctly specified model for the instrument propensity score. The doubly robust estimators depend on the two sets of models and remain consistent if either set of models are correctly specified. We apply our methods to study returns to education using data from the National Longitudinal Survey of Young Men.