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 limited. This paper focuses on the use of simulations for evaluations involving MSMs in studies with a time-to-event outcome. In a simulation, it is important to be able to generate the data in such a way that the correct form of any models to be fitted to those data is known. However, this is not straightforward in the longitudinal setting because it is natural for data to be generated in a sequential conditional manner, whereas MSMs involve fitting marginal rather than conditional hazard models. We provide general results that enable the form of the correctly-specified MSM to be derived based on a conditional data generating procedure, and show how the results can be applied when the conditional hazard model is an Aalen additive hazard or Cox model. Using conditional additive hazard models is advantageous because they imply additive MSMs that can be fitted using standard software. We describe and illustrate a simulation algorithm. Our results will help researchers to effectively evaluate causal inference methods via simulation.
Propensity score methods are increasingly being used to reduce estimation bias of treatment effects for observational studies. Previous research has shown that propensity score methods consistently estimate the marginal hazard ratio for time to event data. However, recurrent data frequently arise in the biomedical literature and there is a paucity of research into the use of propensity score methods when data are recurrent in nature. The objective of this paper is to extend the existing propensity score methods to recurrent data setting. We illustrate our methods through a series of Monte Carl…
In many public health problems, an important goal is to identify the effect of some treatment/intervention on the risk of failure for the whole population. A marginal proportional hazards regression model is often used to analyze such an effect. When dependent censoring is explained by many auxiliary covariates, we utilize two working models to condense high-dimensional covariates to achieve dimension reduction. Then the estimator of the treatment effect is obtained by maximizing a pseudo-likelihood function over a sieve space. Such an estimator is shown to be consistent and asymptotically nor…
Estimating marginal treatment effects from observational studies and indirect treatment comparisons: When are standardization-based methods preferable to those based on propensity score weighting?
MEC-Cox: Machine-Learning-Assisted Generalized Entropy Calibration for ATT Marginal Hazard-Ratio Estimation
Department of Statistics, Texas A&M University（统计学系，德克萨斯A&M大学）；Department of Mathematics, Korea Military Academy（数学系，韩国军事学院）；Department of Statistics, Iowa State University（统计学系，爱荷华州立大学）
Investigating the causal relationship between exposure and the time-to-event outcome is an important topic in biomedical research. Previous literature has discussed the potential issues of using the hazard ratio as a marginal causal effect measure due to its noncollapsibility property. In this paper, we advocate using the restricted mean survival time (RMST) difference as the marginal causal effect measure, which is collapsible and has a simple interpretation as the difference of area under survival curves over a certain time horizon. To address both measured and unmeasured confounding, a matc…
Marginal structural models (MSMs) allow for causal analysis of longitudinal data. The MSMs were originally developed as discrete time models. Recently, continuous-time MSMs were presented as a conceptually appealing alternative for survival analysis. In applied analyses, it is often assumed that the theoretical treatment weights are known, but these weights are usually unknown and must be estimated from the data. Here we provide a sufficient condition for a class of continuous-time MSMs to be consistent even when the weights are estimated, and we show how additive hazard models can be used to …
In two harmonized efficacy studies to prevent HIV infection through multiple infusions of the monoclonal antibody VRC01, a key objective is to evaluate whether the serum concentration of VRC01, which changes cyclically over time along with the infusion schedule, is associated with the rate of HIV infection. Simulation studies are needed in the development of such survival models. In this paper, we consider simulating event time data with a continuous time-varying covariate whose values vary with time through multiple drug administration cycles, and whose effect on survival changes differently …
Clustered observations are ubiquitous in controlled and observational studies and arise naturally in multi-centre trials or longitudinal surveys. We present a novel model for the analysis of clustered observations where the marginal distributions are described by a linear transformation model and the correlations by a joint multivariate normal distribution. The joint model provides an analytic formula for the marginal distribution. Owing to the richness of transformation models, the techniques are applicable to any type of response variable, including bounded, skewed, binary, ordinal, or survi…
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）
Covariate balance is crucial in obtaining unbiased estimates of treatment effects in observational studies. Methods based on inverse probability weights have been widely used to estimate treatment effects with observational data. Machine learning techniques have been proposed to estimate propensity scores. These techniques however target accuracy instead of covariate balance. Methods that target covariate balance have been successfully proposed and largely applied to estimate treatment effects on continuous outcomes. However, in many medical and epidemiological applications, the interest lies …
Effect modification and non-collapsibility leads to conflicting treatment decisions: a review of marginal and conditional estimands and recommendations for decision-making
University of Bristol（布里斯托大学）；Novo Nordisk Pharma（诺和诺德制药）；The Hospital for Sick Children（多伦多儿童医院）；Dalla Lana School of Public Health, University of Toronto（多伦多大学达拉拉纳公共卫生学院）；University College London（伦敦大学学院）；University of York（约克大学）
Reframing Population-Adjusted Indirect Comparisons as a Transportability Problem: An Estimand-Based Perspective and Implications for Health Technology Assessment
Transporting summary measures of relative effects from randomised trials to the treated patient population: an application to breast cancer endocrine therapy
University of Oxford（牛津大学）；University of North Carolina at Chapel Hill（北卡罗来纳大学教堂山分校）
The Cox regression, a semi-parametric method of survival analysis, is extremely popular in biomedical applications. The proportional hazards assumption is a key requirement in the Cox model. To accommodate non-proportional hazards, we propose to parameterise the shape parameter of the baseline hazard function using the additional, separate Cox-regression term which depends on the vector of the covariates. We call this model the double-Cox model. The R programs for fitting the double-Cox model are available on Github. We formally introduce the double-Cox model with shared frailty and investigat…
The Cox regression model and its associated hazard ratio (HR) are frequently used for summarizing the effect of treatments on time to event outcomes. However, the HR's interpretation strongly depends on the assumed underlying survival model. The challenge of interpreting the HR has been the focus of a number of recent works. Besides, several alternative measures have been proposed in order to deal with these concerns. The marginal Cox regression models include an identifiable hazard ratio without individual but populational causal interpretation. In this work, we study the properties of one pa…
In this paper I describe some substantial extensions to the survsim command for simulating survival data. survsim can now simulate survival data from a parametric distribution, a custom/user-defined distribution, from a fitted merlin model, from a specified cause-specific hazards competing risks model, or from a specified general multi-state model (with multiple timescales). Left truncation (delayed entry) is now also available for all settings. I illustrate the command with some examples, demonstrating the huge flexibility that can be used to better evaluate statistical methods.
The difference in restricted mean survival times between two groups is a clinically relevant summary measure. With observational data, there may be imbalances in confounding variables between the two groups. One approach to account for such imbalances is to estimate a covariate-adjusted restricted mean difference by modeling the covariate-adjusted survival distribution and then marginalizing over the covariate distribution. We demonstrate that the mean-squared error of the restricted mean difference is bounded by the mean-squared error of the covariate-adjusted survival distribution estimators…
Bayesian nonparametric inferential procedures based on Markov chain Monte Carlo marginal methods typically yield point estimates in the form of posterior expectations. Though very useful and easy to implement in a variety of statistical problems, these methods may suffer from some limitations if used to estimate non-linear functionals of the posterior distribution. The main goal of the present paper is to develop a novel methodology that extends a well-established marginal procedure designed for hazard mixture models, in order to draw approximate inference on survival functions that is not lim…
Survival models are used to analyze time-to-event data in a variety of disciplines. Proportional hazard models provide interpretable parameter estimates, but proportional hazards assumptions are not always appropriate. Non-parametric models are more flexible but often lack a clear inferential framework. We propose a Bayesian tree partition model which is both flexible and inferential. Inference is obtained through the posterior tree structure and flexibility is preserved by modeling the the hazard function in each partition using a latent exponentiated Gaussian process. An efficient reversible…
A Linear Relationship between Correlation and Cohen's Kappa for Binary Data and Simulating Multivariate Nominal and Ordinal Data with Specified Kappa Matrix
This proposal is motivated by an analysis of the English Longitudinal Study of Ageing (ELSA), which aims to investigate the role of loneliness in explaining the negative impact of hearing loss on dementia. The methodological challenges that complicate this mediation analysis include the use of a time-to-event endpoint subject to competing risks, as well as the presence of feedback relationships between the mediator and confounders that are both repeatedly measured over time. To account for these challenges, we introduce natural effect proportional (cause-specific) hazard models. These extend m…
Clustered competing risks data are commonly encountered in multicenter studies. The analysis of such data is often complicated due to informative cluster size, a situation where the outcomes under study are associated with the size of the cluster. In addition, cause of failure is frequently incompletely observed in real-world settings. To the best of our knowledge, there is no methodology for population-averaged analysis with clustered competing risks data with informative cluster size and missing causes of failure. To address this problem, we consider the semiparametric marginal proportional …
Analysis of 2 by 2 tables and two-sample survival data has been widely used. Exact calculation is computational intractable for conditional likelihood inference in odds ratio models with large marginals in 2 by 2 tables, or partial likelihood inference in Cox's proportional hazards models with considerable tied event times. Approximate methods are often employed, but their statistical properties have not been formally studied while taking into account the approximation involved. We develop new methods and theory by constructing suitable estimating functions while leveraging knowledge from cond…
Population-adjusted indirect comparisons estimate treatment effects when access to individual patient data is limited and there are cross-trial differences in effect modifiers. Popular methods include matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC). There is limited formal evaluation of these methods and whether they can be used to accurately compare treatments. Thus, we undertake a comprehensive simulation study to compare standard unadjusted indirect comparisons, MAIC and STC across 162 scenarios. This simulation study assumes that the trials are investi…
This project was motivated by a dialysis study in northern Taiwan. Dialysis patients, after shunt implantation, may experience two types ("acute" or "non-acute") of shunt thrombosis, both of which may recur. We formulate the problem under the framework of recurrent events data in the presence of competing risks. In particular we focus on marginal inference for the gap time variable of specific type. The functions of interest are the cumulative incidence function and cause-specific hazard function. The major challenge of nonparametric inference is the problem of induced dependent censoring. We …
Diffusions are a fundamental class of models in many fields, including finance, engineering, and biology. Simulating diffusions is challenging as their sample paths are infinite-dimensional and their transition functions are typically intractable. In statistical settings such as parameter inference for discretely observed diffusions, we require simulation techniques for diffusions conditioned on hitting a given endpoint, which introduces further complication. In this paper we introduce a Markov chain Monte Carlo algorithm for simulating bridges of ergodic diffusions which (i) is exact in the s…
As a motivating problem, we aim to study some special aspects of the marginal distributions of the order statistics for exchangeable and (more generally) for minimally stable non-negative random variables $T_{1},...,T_{r}$. In any case, we assume that $T_{1},...,T_{r}$ are identically distributed, with a common survival function $\overline{G}$ and their survival copula is denoted by $K$. The diagonal's and subdiagonals' sections of $K$, along with $\overline{G}$, are possible tools to describe the information needed to recover the laws of order statistics. When attention is restricted to the a…
We propose a new class of multivariate survival models based on archimedean copulas with margins modeled by the Yang and Prentice (YP) model. The Ali-Mikhail-Haq (AMH), Clayton, Frank, Gumbel-Hougaard (GH), and Joe copulas are employed to accommodate the dependency among marginal distributions. Baseline distributions are modeled semiparametrically by the piecewise exponential (PE) distribution and the Bernstein polynomials. The new class of models possesses some attractive features: i) the ability to take into account survival data with crossing survival curves; ii) the inclusion of the well-k…
