Consider estimating the G-formula for the counterfactual mean outcome under a given treatment regime in a longitudinal study. Bang and Robins provided an estimator for this quantity that relies on a sequential regression formulation of this parameter. This approach is doubly robust in that it is consistent if either the outcome regressions or the treatment mechanisms are consistently estimated. We define a stronger notion of double robustness, termed sequential double robustness, for estimators of the longitudinal G-formula. The definition emerges naturally from a more general definition of sequential double robustness for the outcome regression estimators. An outcome regression estimator is sequentially doubly robust (SDR) if, at each subsequent time point, either the outcome regression or the treatment mechanism is consistently estimated. This form of robustness is exactly what one would anticipate is attainable by studying the remainder term of a first-order expansion of the G-formula parameter. We show that a particular implementation of an existing procedure is SDR. We also introduce a novel SDR estimator, whose development involves a novel translation of ideas used in targeted minimum loss-based estimation to the infinite-dimensional setting.
On a penalised likelihood approach for joint modelling of longitudinal covariates and partly interval-censored data -- an application to the Anti-PD1 brain collaboration trial
We develop flexible multi-parameter regression survival models for interval censored survival data arising in longitudinal prospective studies and longitudinal randomised controlled clinical trials. A multi-parameter Weibull regression survival model, which is wholly parametric, and has non-proportional hazards, is the main focus of the paper. We describe the basic model, develop the interval-censored likelihood and extend the model to include gamma frailty and a dispersion model. We evaluate the models by means of a simulation study and a detailed re-analysis of data from the Signal Tandmobie…
In medical and biological research, longitudinal data and survival data types are commonly seen. Traditional statistical models mostly consider to deal with either of the data types, such as linear mixed models for longitudinal data, and the Cox models for survival data, while they do not adjust the association between these two different data types. It is desirable to have a joint modeling approach which accomadates both data types and the dependency between them. In this paper, we extend traditional single-index models to a new joint modeling approach, by replacing the single-index component…
Joint models are used in ageing studies to investigate the association between longitudinal markers and a time-to-event, and have been extended to multiple markers and/or competing risks. The competing risk of death must be considered in the elderly because death and dementia have common risk factors. Moreover, in cohort studies, time-to-dementia is interval-censored because dementia is only assessed intermittently. So subjects can become demented and die between two follow-up visits without being diagnosed. To study pre-dementia cognitive decline, we propose a joint latent class model combini…
The primary goal of public health efforts to control HIV epidemics is to diagnose and treat people with HIV infection as soon as possible after seroconversion. The timing of initiation of antiretroviral therapy (ART) treatment after HIV diagnosis is, therefore, a critical population-level indicator that can be used to measure the effectiveness of public health programs and policies at local and national levels. However, population-based data on ART initiation are unavailable because ART initiation and prescription are typically measured indirectly by public health departments (e.g., with viral…
Stabilized dynamic treatment regimes are sequential decision rules for individual patients that not only adaptive throughout the disease progression but also remain consistent over time in format. The estimation of stabilized dynamic treatment regimes becomes more complicated when the clinical outcome of interest is a survival time subject to censoring. To address this challenge, we propose two novel methods, censored shared-Q-learning and censored shared-O-learning. Both methods incorporate clinical preferences into a qualitative rule, where the parameters indexing the decision rules are shar…
In a longitudinal study, measures of key variables might be incomplete or partially recorded due to drop-out, loss to follow-up, or early termination of the study occurring before the advent of the event of interest. In this paper, we focus primarily on the implementation of a regression model with a randomly censored predictor. We examine, particularly, the use of inverse probability weighting methods in a generalized linear model (GLM), when the predictor of interest is right-censored, to adjust for censoring. To improve the performance of the complete-case analysis and prevent selection bia…
In medical studies, the collected covariates usually contain underlying outliers. For clustered /longitudinal data with censored observations, the traditional Gehan-type estimator is robust to outliers existing in response but sensitive to outliers in the covariate domain, and it also ignores the within-cluster correlations. To take account of within-cluster correlations, varying cluster sizes, and outliers in covariates, we propose weighted Gehan-type estimating functions for parameter estimation in the accelerated failure time model for clustered data. We provide the asymptotic properties of…
A flexible quantile mixed-effects model for censored outcomes
Syneos Health；Department of Mathematical Statistics and Actuarial Science, University of the Free State（自由州大学数学统计与精算科学系）；I-BioStat, KU Leuven（KU鲁汶大学生物统计研究所）；Department of Statistics and Actuarial Science, University of Stellenbosch（斯泰伦博斯大学统计与精算科学系）
A dynamic treatment regimen (DTR) is a pre-specified sequence of decision rules which maps baseline or time-varying measurements on an individual to a recommended intervention or set of interventions. Sequential multiple assignment randomized trials (SMARTs) represent an important data collection tool for informing the construction of effective DTRs. A common primary aim in a SMART is the marginal mean comparison between two or more of the DTRs embedded in the trial. This manuscript develops a mixed effects modeling and estimation approach for these primary aim comparisons based on a continuou…
Often in Phase 3 clinical trials measuring a long-term time-to-event endpoint, such as overall survival or progression-free survival, investigators also collect repeated measures on biomarkers which may be predictive of the primary endpoint. Although these data may not be leveraged directly to support early stopping decisions, can we make greater use of these data to increase efficiency and improve interim decision making? We present a joint model for longitudinal and time-to-event data and a method which establishes the distribution of successive estimates of parameters in the joint model acr…
Longitudinal observational patient data can be used to investigate the causal effects of time-varying treatments on time-to-event outcomes. Several methods have been developed for controlling for the time-dependent confounding that typically occurs. The most commonly used is inverse probability weighted estimation of marginal structural models (MSM-IPTW). An alternative, the sequential trials approach, is increasingly popular, in particular in combination with the target trial emulation framework. This approach involves creating a sequence of `trials' from new time origins, restricting to indi…
Biased sampling designs can be highly efficient when studying rare (binary) or low variability (continuous) endpoints. We consider longitudinal data settings in which the probability of being sampled depends on a repeatedly measured response through an outcome-related, auxiliary variable. Such auxiliary variable- or outcome-dependent sampling improves observed response and possibly exposure variability over random sampling, {even though} the auxiliary variable is not of scientific interest. {For analysis,} we propose a generalized linear model based approach using a sequence of two offsetted r…
Clinicians and researchers alike are increasingly interested in how best to personalize interventions. A dynamic treatment regimen (DTR) is a sequence of pre-specified decision rules which can be used to guide the delivery of a sequence of treatments or interventions that are tailored to the changing needs of the individual. The sequential multiple-assignment randomized trial (SMART) is a research tool which allows for the construction of effective DTRs. We derive easy-to-use formulae for computing the total sample size for three common two-stage SMART designs in which the primary aim is to co…
The primary analysis in two-arm clinical trials usually involves inference on a scalar treatment effect parameter; e.g., depending on the outcome, the difference of treatment-specific means, risk difference, risk ratio, or odds ratio. Most clinical trials are monitored for the possibility of early stopping. Because ordinarily the outcome on any given subject can be ascertained only after some time lag, at the time of an interim analysis, among the subjects already enrolled, the outcome is known for only a subset and is effectively censored for those who have not been enrolled sufficiently long…
The R package lcmm provides a series of functions to estimate statistical models based on linear mixed model theory. It includes the estimation of mixed models and latent class mixed models for Gaussian longitudinal outcomes (hlme), curvilinear and ordinal univariate longitudinal outcomes (lcmm) and curvilinear multivariate outcomes (multlcmm), as well as joint latent class mixed models (Jointlcmm) for a (Gaussian or curvilinear) longitudinal outcome and a time-to-event that can be possibly left-truncated right-censored and defined in a competing setting. Maximum likelihood esimators are obtai…
We focus on causal inference for longitudinal treatments, where units are assigned to treatments at multiple time points, aiming to assess the effect of different treatment sequences on an outcome observed at a final point. A common assumption in similar studies is Sequential Ignorability (SI): treatment assignment at each time point is assumed independent of future potential outcomes given past observed outcomes and covariates. SI is questionable when treatment participation depends on individual choices, and treatment assignment may depend on unobservable quantities associated with future ou…
Enriching existing predictive models with new biomolecular markers is an important task in the new multi-omic era. Clinical studies increasingly include new sets of omic measurements which may prove their added value in terms of predictive performance. We introduce a two-step approach for the assessment of the added predictive ability of omic predictors, based on sequential double cross-validation and regularized regression models. We propose several performance indices to summarize the two-stage prediction procedure and a permutation test to formally assess the added predictive value of a sec…
Missing data is unavoidable in longitudinal clinical trials, and outcomes are not always normally distributed. In the presence of outliers or heavy-tailed distributions, the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect (ATE) based on the multivariate normal assumption may produce bias and power loss. Control-based imputation (CBI) is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those wi…
Most causal inference methods consider counterfactual variables under interventions that set the treatment deterministically. With continuous or multi-valued treatments or exposures, such counterfactuals may be of little practical interest because no feasible intervention can be implemented that would bring them about. Furthermore, violations to the positivity assumption, necessary for identification, are exacerbated with continuous and multi-valued treatments and deterministic interventions. In this paper we propose longitudinal modified treatment policies (LMTPs) as a non-parametric alternat…
Dynamic prediction of causal effects under different treatment regimes conditional on an individual's characteristics and longitudinal history is an essential problem in precision medicine. This is challenging in practice because outcomes and treatment assignment mechanisms are unknown in observational studies, an individual's treatment efficacy is a counterfactual, and the existence of selection bias is often unavoidable. We propose a Bayesian framework for identifying subgroup counterfactual benefits of dynamic treatment regimes by adapting Bayesian g-computation algorithm (J. Robins, 1986; …
Observational longitudinal data on treatments and covariates are increasingly used to investigate treatment effects, but are often subject to time-dependent confounding. Marginal structural models (MSMs), estimated using inverse probability of treatment weighting or the g-formula, are popular for handling this problem. With increasing development of advanced causal inference methods, it is important to be able to assess their performance in different scenarios to guide their application. Simulation studies are a key tool for this, but their use to evaluate causal inference methods has been lim…
The sequential treatment decisions made by physicians to treat chronic diseases are formalized in the statistical literature as dynamic treatment regimes. To date, methods for dynamic treatment regimes have been developed under the assumption that observation times, i.e., treatment and outcome monitoring times, are determined by study investigators. That assumption is often not satisfied in electronic health records data in which the outcome, the observation times, and the treatment mechanism are associated with patients' characteristics. The treatment and observation processes can lead to spu…
The R package merlin performs flexible joint modelling of hierarchical multi-outcome data. Increasingly, multiple longitudinal biomarker measurements, possibly censored time-to-event outcomes and baseline characteristics are available. However, there is limited software that allows all of this information to be incorporated into one model. In this paper, we present merlin which allows for the estimation of models with unlimited numbers of continuous, binary, count and time-to-event outcomes, with unlimited levels of nested random effects. A wide variety of link functions, including the expecte…
Construction of just-in-time adaptive interventions, such as prompts delivered by mobile apps to promote and maintain behavioral change, requires knowledge about time-varying moderated effects to inform when and how we deliver intervention options. Micro-randomized trials (MRT) have emerged as a sequentially randomized design to gather requisite data for effect estimation. The existing literature (Qian et al., 2020; Boruvka et al., 2018; Dempsey et al., 2020) has defined a general class of causal estimands, referred to as "causal excursion effects", to assess the time-varying moderated effect.…
In animal behavior studies, a common goal is to investigate the causal pathways between an exposure and outcome, and a mediator that lies in between. Causal mediation analysis provides a principled approach for such studies. Although many applications involve longitudinal data, the existing causal mediation models are not directly applicable to settings where the mediators are measured on irregular time grids. In this paper, we propose a causal mediation model that accommodates longitudinal mediators on arbitrary time grids and survival outcomes simultaneously. We take a functional data analys…
Causal mediation analysis for zero-inflated longitudinal data in the presence of treatment non-compliance and multiple mediators
University of Chicago（芝加哥大学）；Smeal College of Business, The Pennsylvania State University（宾夕法尼亚州立大学斯米尔商学院）；University of Florida（佛罗里达大学）；University of Wisconsin–Madison（威斯康星大学麦迪逊分校）
Dynamic treatment regimens (DTRs), also known as treatment algorithms or adaptive interventions, play an increasingly important role in many health domains. DTRs are motivated to address the unique and changing needs of individuals by delivering the type of treatment needed, when needed, while minimizing unnecessary treatment. Practically, a DTR is a sequence of decision rules that specify, for each of several points in time, how available information about the individual's status and progress should be used in practice to decide which treatment (e.g., type or intensity) to deliver. The sequen…
Best for which estimand? A known-truth benchmark of longitudinal-matching and target-trial-emulation methods for time-varying treatments
School of Population and Public Health, University of British Columbia（不列颠哥伦比亚大学公共卫生与人口健康学院）；Centre for Advancing Health Outcomes, St. Paul’s Hospital（圣保罗医院健康结果促进中心）
A Bayesian joint model of multiple nonlinear longitudinal and competing risks outcomes for dynamic prediction in multiple myeloma: joint estimation and corrected two-stage approaches
