A hierarchical modelling approach to analysing longitudinal data with drop-out and non-compliance, with application to an equivalence trial in paediatric acquired immune deficiency syndrome

Longitudinal clinical trials with long follow-up periods almost invariably suffer from a loss to follow-up and non-compliance with the assigned therapy. An example is protocol 128 of the AIDS Clinical Trials Group, a 5-year equivalency trial comparing reduced dose zidovudine with the standard dose for treatment of paediatric acquired immune deficiency syndrome patients. This study compared responses to treatment by using both clinical and cognitive outcomes. The cognitive outcomes are of particular interest because the effects of human immunodeficiency virus infection of the central nervous system can be more acute in children than in adults. We formulate and apply a Bayesian hierarchical model to estimate both the intent-to-treat effect and the average causal effect of reducing the prescribed dose of zidovudine by 50%. The intent-to-treat effect quantifies the causal effect of assigning the lower dose, whereas the average causal effect represents the causal effect of actually taking the lower dose. We adopt a potential outcomes framework where, for each individual, we assume the existence of a different potential outcomes process at each level of time spent on treatment. The joint distribution of the potential outcomes and the time spent on assigned treatment is formulated using a hierarchical model: the potential outcomes distribution is given at the first level, and dependence between the outcomes and time on treatment is specified at the second level by linking the time on treatment to subject-specific effects that characterize the potential outcomes processes. Several distributional and structural assumptions are used to identify the model from observed data, and these are described in detail. A detailed analysis of AIDS Clinical Trials Group protocol 128 is given; inference about both the intent-to-treat effect and average causal effect indicate a high probability of dose equivalence with respect to cognitive functioning.     

Causal inference with generalized structural mean models

Summary.  We estimate cause–effect relationships in empirical research where exposures are not completely controlled, as in observational studies or with patient non-compliance and self-selected treatment switches in randomized clinical trials. Additive and multiplicative structural mean models have proved useful for this but suffer from the classical limitations of linear and log-linear models when accommodating binary data. We propose the generalized structural mean model to overcome these limitations. This is a semiparametric two-stage model which extends the structural mean model to handle non-linear average exposure effects. The first-stage structural model describes the causal effect of received exposure by contrasting the means of observed and potential exposure-free outcomes in exposed subsets of the population. For identification of the structural parameters, a second stage 'nuisance' model is introduced. This takes the form of a classical association model for expected outcomes given observed exposure. Under the model, we derive estimating equations which yield consistent, asymptotically normal and efficient estimators of the structural effects. We examine their robustness to model misspecification and construct robust estimators in the absence of any exposure effect. The double-logistic structural mean model is developed in more detail to estimate the effect of observed exposure on the success of treatment in a randomized controlled blood pressure reduction trial with self-selected non-compliance.     

Estimating the causal effects in randomized trials for survival data with a cure fraction and non compliance

We consider causal inference in randomized studies for survival data with a cure fraction and all-or-none treatment non compliance. To describe the causal effects, we consider the complier average causal effect (CACE) and the complier effect on survival probability beyond time t (CESP), where CACE and CESP are defined as the difference of cure rate and non cured subjects’ survival probability between treatment and control groups within the complier class. These estimands depend on the distributions of survival times in treatment and control groups. Given covariates and latent compliance type, we model these distributions with transformation promotion time cure model whose parameters are estimated by maximum likelihood. Both the infinite dimensional parameter in the model and the mixture structure of the problem create some computational difficulties which are overcome by an expectation-maximization (EM) algorithm. We show the estimators are consistent and asymptotically normal. Some simulation studies are conducted to assess the finite-sample performance of the proposed approach. We also illustrate our method by analyzing a real data from the Healthy Insurance Plan of Greater New York.     

Weighted Mean Survival Test Statistics: a Class of Distance Tests for Censored Survival Data

A class of test statistics is introduced which is sensitive against the alternative of stochastic ordering in the two-sample censored data problem. The test statistics for evaluating a cumulative weighted difference in survival distributions are developed while taking into account the imbalances in base-line covariates between two groups. This procedure can be used to test the null hypothesis of no treatment effect, especially when base-line hazards cross and prognostic covariates need to be adjusted. The statistics are semiparametric, not rank based, and can be written as integrated weighted differences in estimated survival functions, where these survival estimates are adjusted for covariate imbalances. The asymptotic distribution theory of the tests is developed, yielding test procedures that are shown to be consistent under a fixed alternative. The choice of weight function is discussed and relies on stability and interpretability considerations. An example taken from a clinical trial for acquired immune deficiency syndrome is presented.     

Nondifferentiable errors in beta-compliance integrated logistic models: numerical results

In dose-response models, there are cases where only a portion of the administered dose may have an effect. This results in a stochastic compliance of the administered dose. In a previous paper (Chen-Mok and Sen, 1999), we developed suitable adjustments for compliance in the logistic model under the assumption of nondifferential measurement error. These compliance-adjusted models were categorized into three types: (i) Low (or near zero) dose levels, (ii) moderate dose levels, and (iii) high dose levels. In this paper, we analyze a set of data on the atomic bomb survivors of Japan to illustrate the use of the proposed methods. In addition, we examine the performance of these methods under different conditions based on a simulation study. Among all three cases, the adjustments proposed for the moderate dose case do not seem to work adequately. Both bias and variance are larger when using the adjusted model in comparison with the unadjusted model. The adjustments for the low dose case seem to work in reducing the bias in the estimation of the parameters under all types of compliance distributions. The MSEs, however, are larger under some of the compliance distribution considered. Finally, the results of this simulation study show that the adjustments for the high dose case are successful in achieving both a reduction in bias as well as a reduction in MSE, hence the overall efficiency of the estimation is improved.     

Likelihood methods in randomized trials with noncompliance and subsequent nonresponse

This article considers likelihood methods for estimating the causal effect of treatment assignment for a two-armed randomized trial assuming all-or-none treatment noncompliance and allowing for subsequent nonresponse. We first derive the observed data likelihood function as a closed form expression of the parameter given the observed data where both response and compliance state are treated as variables with missing values. Then we describe an iterative procedure which maximizes the observed data likelihood function directly to compute a maximum likelihood estimator (MLE) of the causal effect of treatment assignment. Closed form expressions at each iterative step are provided. Finally we compare the MLE with an alternative estimator where the probability distribution of the compliance state is estimated independent of the response and its missingness mechanism. Our work indicates that direct maximum likelihood inference is straightforward for this problem. Extensive simulation studies are provided to examine the finite sample performance of the proposed methods.     

Covariate selection for estimating the causal effect of control plans by using causal diagrams

Summary. Consider a case where cause–effect relationships between variables can be described by a causal path diagram and the corresponding linear structural equation model. The paper proposes a graphical selection criterion for covariates to estimate the causal effect of a control plan. For designing the control plan, it is essential to determine both covariates that are used for control and covariates that are used for identification. The selection of covariates used for control is only constrained by the requirement that the covariates be non-descendants of a treatment variable. However, the selection of covariates used for identification is dependent on the selection of covariates used for control and is not unique. In the paper, the difference between covariates that are used for identification is evaluated on the basis of the asymptotic variance of the estimated causal effect of an effective control plan. Furthermore, the results can be also described in terms of a graph structure.     

Vitamin A and Infant Mortality: Beyond Intention-to-Treat in a Randomized Trial

This paper investigates the effect of one dose of vitamin A on subsequent 4 month mortality in children under 6 months of age in a randomized, double-blind placebo-controlled community trial in Nepal. An earlier published intention-to-treat analysis showed no benefit, but ignored the information on actual receipt of treatment. Structural failure time models (Robins and Tsiatis, '91) use randomization based inference and incorporate compliance information which is possibly selective. The data presented here offer some new challenges for this approach: ward-based randomization induces correlation between survival outcomes; and the actual receipt of vitamin A dose is not always recorded. To tackle the problem of the clustered survival data we consider a robust version of the structural parameter vector estimator. A sensitivity analysis captures boundaries for the estimated structural parameters reflecting a range of potential values of children whose true receipt of treatment is unknown. The analysis suggests that the effect of vitamin A was beneficial in the beginning of the trial but towards the end of the trial there was a reversal of this effect.     

Survival analysis using inverse probability of treatment weighted methods based on the generalized propensity score

In survival analysis, treatment effects are commonly evaluated based on survival curves and hazard ratios as causal treatment effects. In observational studies, these estimates may be biased due to confounding factors. The inverse probability of treatment weighted (IPTW) method based on the propensity score is one of the approaches utilized to adjust for confounding factors between binary treatment groups. As a generalization of this methodology, we developed an exact formula for an IPTW log‐rank test based on the generalized propensity score for survival data. This makes it possible to compare the group differences of IPTW Kaplan–Meier estimators of survival curves using an IPTW log‐rank test for multi‐valued treatments. As causal treatment effects, the hazard ratio can be estimated using the IPTW approach. If the treatments correspond to ordered levels of a treatment, the proposed method can be easily extended to the analysis of treatment effect patterns with contrast statistics. In this paper, the proposed method is illustrated with data from the Kyushu Lipid Intervention Study (KLIS), which investigated the primary preventive effects of pravastatin on coronary heart disease (CHD). The results of the proposed method suggested that pravastatin treatment reduces the risk of CHD and that compliance to pravastatin treatment is important for the prevention of CHD. Copyright © 2009 John Wiley & Sons, Ltd.     

Optimizing a control plan using a structural equation model with an application to statistical process analysis

In the case where non-experimental data are available from an industrial process and a directed graph for how various factors affect a response variable is known based on a substantive understanding of the process, we consider a problem in which a control plan involving multiple treatment variables is conducted in order to bring a response variable close to a target value with variation reduction. Using statistical causal analysis with linear (recursive and non-recursive) structural equation models, we configure an optimal control plan involving multiple treatment variables through causal parameters. Based on the formulation, we clarify the causal mechanism for how the variance of a response variable changes when the control plan is conducted. The results enable us to evaluate the effect of a control plan on the variance of a response variable from non-experimental data and provide a new application of linear structural equation models to engineering science.     

Estimating Causal Effects in Trials Involving Multi-Treatment Arms Subject to Non-compliance: A Bayesian framework

Data analysis for randomized trials including multi-treatment arms is often complicated by subjects who do not comply with their treatment assignment. We discuss here methods of estimating treatment efficacy for randomized trials involving multi-treatment arms subject to non-compliance. One treatment effect of interest in the presence of non-compliance is the complier average causal effect (CACE) (Angrist et al. 1996), which is defined as the treatment effect for subjects who would comply regardless of the assigned treatment. Following the idea of principal stratification (Frangakis & Rubin 2002), we define principal compliance (Little et al. 2009) in trials with three treatment arms, extend CACE and define causal estimands of interest in this setting. In addition, we discuss structural assumptions needed for estimation of causal effects and the identifiability problem inherent in this setting from both a Bayesian and a classical statistical perspective. We propose a likelihood-based framework that models potential outcomes in this setting and a Bayes procedure for statistical inference. We compare our method with a method of moments approach proposed by Cheng & Small (2006) using a hypothetical data set, and further illustrate our approach with an application to a behavioral intervention study (Janevic et al. 2003).     

A Likelihood‐Based Analysis for Relaxing the Exclusion Restriction in Randomized Experiments with Noncompliance

The exclusion restriction is usually assumed for identifying causal effects in true or only natural randomized experiments with noncompliance. It requires that the assignment to treatment does not have a direct causal effect on the outcome. Despite its importance, the restriction can often be unrealistic, especially in situations of natural experiments. It is shown that, without the exclusion restriction, the parametric model is identified if the outcome distributions of various compliance statuses are in the same parametric class and that class is a linearly independent set over the field of real numbers. However, the relaxation of the exclusion restriction yields a parametric model that is characterized by the presence of mixtures of distributions. This scenario complicates the likelihood‐based estimation procedures because it implies more than one maximum likelihood point. A two‐step estimation procedure based on detecting the root that is closest to the method of moments estimate of the parameter vector is then proposed and analyzed in detail, under normally distributed outcomes. An economic example with real data concerning returns to schooling concludes the paper.     

Double robust estimation in longitudinal marginal structural models

In this article we consider estimation of causal parameters in a marginal structural model for the discrete intensity of the treatment specific counting process (e.g. hazard of a treatment specific survival time) based on longitudinal observational data on treatment, covariates and survival. We define three estimators: the inverse probability of treatment weighted (IPTW) estimator, the maximum likelihood estimator (MLE), and a double robust (DR) estimator. The DR estimator is obtained by following a general methodology for constructing double robust estimating functions in censored data models as described in van der Laan and Robins (Unified Methods for Censored Longitudinal Data and Causality, 2002). The double-robust estimator is consistent and asymptotically linear when either the treatment mechanism or the partial likelihood of the observed data is consistently estimated. We illustrate the superiority of the DR estimator relative to the IPTW and ML estimators in a simulation study. The proposed methodology is also applied to estimate the causal effect of exercise on physical functioning in a longitudinal study of seniors in Sonoma County.     

The challenges of evaluating dose response in flexible‐dose trials using marginal structural models

Assessing dose response from flexible‐dose clinical trials is problematic. The true dose effect may be obscured and even reversed in observed data because dose is related to both previous and subsequent outcomes. To remove selection bias, we propose marginal structural models, inverse probability of treatment‐weighting (IPTW) methodology. Potential clinical outcomes are compared across dose groups using a marginal structural model (MSM) based on a weighted pooled repeated measures analysis (generalized estimating equations with robust estimates of standard errors), with dose effect represented by current dose and recent dose history, and weights estimated from the data (via logistic regression) and determined as products of (i) inverse probability of receiving dose assignments that were actually received and (ii) inverse probability of remaining on treatment by this time. In simulations, this method led to almost unbiased estimates of true dose effect under various scenarios. Results were compared with those obtained by unweighted analyses and by weighted analyses under various model specifications. The simulation showed that the IPTW MSM methodology is highly sensitive to model misspecification even when weights are known. Practitioners applying MSM should be cautious about the challenges of implementing MSM with real clinical data. Clinical trial data are used to illustrate the methodology. Copyright © 2012 John Wiley & Sons, Ltd.     

A comparison of population average and random-effect models for the analysis of longitudinal count data with base-line information

The generalized estimating equation (GEE) approach to the analysis of longitudinal data has many attractive robustness properties and can provide a 'population average' characterization of interest, for example, to clinicians who have to treat patients on the basis of their observed characteristics. However, these methods have limitations which restrict their usefulness in both the social and the medical sciences. This conclusion is based on the premise that the main motivations for longitudinal analysis are insight into microlevel dynamics and improved control for omitted or unmeasured variables. We claim that to address these issues a properly formulated random-effects model is required. In addition to a theoretical assessment of some of the issues, we illustrate this by reanalysing data on polyp counts. In this example, the covariates include a base-line outcome, and the effectiveness of the treatment seems to vary by base-line. We compare the random-effects approach with the GEE approach and conclude that the GEE approach is inappropriate for assessing the treatment effects for these data.     

Causal inference for recurrent events data with all-or-none compliance

ABSTRACT

In this article, causal inference in randomized studies with recurrent events data and all-or-none compliance is considered. We use the counting process to analyze the recurrent events data and propose a causal proportional intensity model. The maximum likelihood approach is adopted to estimate the parameters of the proposed causal model. To overcome the computational difficulties created by the mixture structure of the problem, we develop an expectation-maximization (EM) algorithm. The resulting estimators are shown to be consistent and asymptotically normal. We further estimate the complier average causal effect (CACE), which is defined as the difference of the average numbers of recurrence between treatment and control groups within the complier class. The corresponding inferential procedures are established. Some simulation studies are conducted to assess the finite sample performance of the proposed approach.     

Correcting for non-compliance in randomized trials using structural nested mean models

In a randomized trial designed to study the effect of a treatment of interest on the evolution of the mean of a time-dependent outcome variable, subjects are assigned to a treatment regime, or, equivalently, a treatment protocol. Unfortunately, subjects often fail to comply with their assigned regime. From a public health point of view, the causal parameter of interest will often be a function of the treatment differences that would have been observed hadcontrary to fact, all subjects remained on protocol. This paper considers the identification and estimation of these treatment differences based on a new class of structural models, the multivariate structural nested mean models, when reliable estimates of each subject's actual treatment are available. Estimates of “actual treatment” might, for example, be obtained by measuring the amount of “active drug” in the subject's blood or urine at each follow-up visit or by pill counting techniques. In addition, we discuss a natural extension of our methods to observational studies.     

Causal Proportional Hazards Models and Time-constant Exposure in Randomized Clinical Trials

The last decade saw enormous progress in the development of causal inference tools to account for noncompliance in randomized clinical trials. With survival outcomes, structural accelerated failure time (SAFT) models enable causal estimation of effects of observed treatments without making direct assumptions on the compliance selection mechanism. The traditional proportional hazards model has however rarely been used for causal inference. The estimator proposed by Loeys and Goetghebeur (2003, Biometrics vol. 59 pp. 100–105) is limited to the setting of all or nothing exposure. In this paper, we propose an estimation procedure for more general causal proportional hazards models linking the distribution of potential treatment-free survival times to the distribution of observed survival times via observed (time-constant) exposures. Specifically, we first build models for observed exposure-specific survival times. Next, using the proposed causal proportional hazards model, the exposure-specific survival distributions are backtransformed to their treatment-free counterparts, to obtain – after proper mixing – the unconditional treatment-free survival distribution. Estimation of the parameter(s) in the causal model is then based on minimizing a test statistic for equality in backtransformed survival distributions between randomized arms.     

Assessing the treatment effect in a randomized controlled trial with extensive non‐adherence: the EVOLVE trial

Intention‐to‐treat (ITT) analysis is widely used to establish efficacy in randomized clinical trials. However, in a long‐term outcomes study where non‐adherence to study drug is substantial, the on‐treatment effect of the study drug may be underestimated using the ITT analysis. The analyses presented herein are from the EVOLVE trial, a double‐blind, placebo‐controlled, event‐driven cardiovascular outcomes study conducted to assess whether a treatment regimen including cinacalcet compared with placebo in addition to other conventional therapies reduces the risk of mortality and major cardiovascular events in patients receiving hemodialysis with secondary hyperparathyroidism. Pre‐specified sensitivity analyses were performed to assess the impact of non‐adherence on the estimated effect of cinacalcet. These analyses included lag‐censoring, inverse probability of censoring weights (IPCW), rank preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE). The relative hazard (cinacalcet versus placebo) of mortality and major cardiovascular events was 0.93 (95% confidence interval 0.85, 1.02) using the ITT analysis; 0.85 (0.76, 0.95) using lag‐censoring analysis; 0.81 (0.70, 0.92) using IPCW; 0.85 (0.66, 1.04) using RPSFTM and 0.85 (0.75, 0.96) using IPE. These analyses, while not providing definitive evidence, suggest that the intervention may have an effect while subjects are receiving treatment. The ITT method remains the established method to evaluate efficacy of a new treatment; however, additional analyses should be considered to assess the on‐treatment effect when substantial non‐adherence to study drug is expected or observed. Copyright © 2015 John Wiley & Sons, Ltd.     

Did the Military Interventions in the Mexican Drug War Increase Violence?

We analyze publicly available data to estimate the causal effects of military interventions on the homicide rates in certain problematic regions in Mexico. We use the Rubin causal model to compare the post-intervention homicide rate in each intervened region to the hypothetical homicide rate for that same year had the military intervention not taken place. Because the effect of a military intervention is not confined to the municipality subject to the intervention, a nonstandard definition of units is necessary to estimate the causal effect of the intervention under the standard no-interference assumption of stable-unit treatment value assumption (SUTVA). Donor pools are created for each missing potential outcome under no intervention, thereby allowing for the estimation of unit-level causal effects. A multiple imputation approach accounts for uncertainty about the missing potential outcomes.