The study of precision medicine involves dynamic treatment regimes (DTRs), which are sequences of treatment decision rules recommended by taking patient-level information as input. The primary goal of the DTR study is to identify an optimal DTR, a sequence of treatment decision rules that leads to the best expected clinical outcome. Statistical methods have been developed in recent years to estimate an optimal DTR, including Q-learning, a regression-based method in the DTR literature. Although there are many studies concerning Q-learning, little attention has been given in the presence of noisy data, such as misclassified outcomes. In this paper, we investigate the effect of outcome misclassification on Q-learning and propose a correction method to accommodate the misclassification effect. Simulation studies are conducted to demonstrate the satisfactory performance of the proposed method. We illustrate the proposed method in two examples from the National Health and Nutrition Examination Survey Data I Epidemiologic Follow-up Study and the smoking cessation program.
Analysing subgroups defined by biomarkers is of increasing importance in clinical research. In some situations the biomarker is subject to misclassification error, meaning the true subgroups are identified with imperfect sensitivity and specificity. For time-to-event data, it is improper to assume the Cox proportional hazards model for the effects with respect to the true subgroups, since the survival distributions with respect to the diagnosed subgroups will not adhere to the proportional hazards assumption. This precludes the possibility of using simple adjustment procedures. Instead, we pre…
Under what circumstances is it a threat to the parallel trends assumption required for Difference in Differences (DiD) studies if treatment decisions are based on past values of the outcome? We explore via simulation studies whether parallel trends holds across a grid of data generating processes generally conducive to parallel trends (random walk, Hidden Markov Model, and constant direct additive confounding), study designs (never treated, not yet treated, or later treated control groups), and outcome responsiveness of treatment (yes or no). We interpret the upshot of our simulation results t…
We propose a new, flexible model for inference of the effect of a binary treatment on a continuous outcome observed over subsequent time periods. The model allows to seperate association due to endogeneity of treatment selection from additional longitudinal association of the outcomes and hence unbiased estimation of dynamic treatment effects. We investigate the performance of the proposed method on simulated data and employ it to reanalyse data on the longitudinal effects of a long maternity leave on mothers' earnings after their return to the labour market.
Treatment effect estimation by comparing observed and predicted outcomes: conditions for valid inference and practical illustration
University Medical Center Utrecht, Utrecht University（乌得勒支大学医学中心，乌得勒支大学）；University Medical Center Groningen（格罗宁根大学医学中心）；MAASTRO Clinic（MAASTRO诊所）；Erasmus MC Cancer Institute（伊拉斯姆斯癌症研究所）
We propose a reinforcement learning method for estimating an optimal dynamic treatment regime for survival outcomes with dependent censoring. The estimator allows the failure time to be conditionally independent of censoring and dependent on the treatment decision times, supports a flexible number of treatment arms and treatment stages, and can maximize either the mean survival time or the survival probability at a certain time point. The estimator is constructed using generalized random survival forests and can have polynomial rates of convergence. Simulations and data analysis results sugges…
It is common that in multiarm randomized trials, the outcome of interest is "truncated by death," meaning that it is only observed or well defined conditioning on an intermediate outcome. In this case, in addition to pairwise contrasts, the joint inference for all treatment arms is also of interest. Under a monotonicity assumption we present methods for both pairwise and joint causal analyses of ordinal treatments and binary outcomes in presence of truncation by death. We illustrate via examples the appropriateness of our assumptions in different scientific contexts.
We consider a randomized controlled trial between two groups. The objective is to identify a population with characteristics such that the test therapy is more effective than the control therapy. Such a population is called a subgroup. This identification can be made by estimating the treatment effect and identifying interactions between treatments and covariates. To date, many methods have been proposed to identify subgroups for a single outcome. There are also multiple outcomes, but they are difficult to interpret and cannot be applied to outcomes other than continuous values. In this paper,…
Most of the literature on direct and indirect effects assumes that there are no post-treatment common causes of the mediator and the outcome. In contrast to natural direct and indirect effects, organic direct and indirect effects, which were introduced in Lok (2016, 2020), can be extended to provide an identification result for settings with post-treatment common causes of the mediator and the outcome. This article provides a definition and an identification result for organic direct and indirect effects in the presence of post-treatment common causes of mediator and outcome. These new organic…
A pressing challenge in medical research is to identify optimal treatments for individual patients. This is particularly challenging in mental health settings where mean responses are often similar across multiple treatments. For example, the mean longitudinal trajectories for patients treated with an active drug and placebo may be very similar but different treatments may exhibit distinctly different individual trajectory shapes. Most precision medicine approaches using longitudinal data often ignore information from the longitudinal data structure. This paper investigates a powerful precisio…
In classical study designs, the aim is often to learn about the effects of a treatment or intervention on a single outcome; in many modern studies, however, data on multiple outcomes are collected and it is of interest to explore effects on multiple outcomes simultaneously. Such designs can be particularly useful in patient-centered research, where different outcomes might be more or less important to different patients. In this paper we propose scaled effect measures (via potential outcome notation) that translate effects on multiple outcomes to a common scale, using mean-variance and median-…
Identifying compromise solutions across multiple treatment benefit-harm profiles in multivariate network meta-analysis
Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center-University of Freiburg（弗赖堡大学医学院医学生物计量与统计研究所）；Oslo Center for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo（奥斯陆大学生物统计系奥斯陆生物统计与流行病学中心）
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…
Assessing the causal effects of interventions on ordinal outcomes is an important objective of many educational and behavioral studies. Under the potential outcomes framework, we can define causal effects as comparisons between the potential outcomes under treatment and control. However, unfortunately, the average causal effect, often the parameter of interest, is difficult to interpret for ordinal outcomes. To address this challenge, we propose to use two causal parameters, which are defined as the probabilities that the treatment is beneficial and strictly beneficial for the experimental uni…
In randomized experiments, the actual treatments received by some experimental units may differ from their treatment assignments. This non-compliance issue often occurs in clinical trials, social experiments, and the applications of randomized experiments in many other fields. Under certain assumptions, the average treatment effect for the compliers is identifiable and equal to the ratio of the intention-to-treat effects of the potential outcomes to that of the potential treatment received. To improve the estimation efficiency, we propose three model-assisted estimators for the complier averag…
Comparative effectiveness research often involves evaluating the differences in the risks of an event of interest between two or more treatments using observational data. Often, the post-treatment outcome of interest is whether the event happens within a pre-specified time window, which leads to a binary outcome. One source of bias for estimating the causal treatment effect is the presence of confounders, which are usually controlled using propensity score-based methods. An additional source of bias is right-censoring, which occurs when the information on the outcome of interest is not complet…
We propose a novel personalized concept for the optimal treatment selection for a situation where the response is a multivariate vector, that could contain right-censored variables such as survival time. The proposed method can be applied with any number of treatments and outcome variables, under a broad set of models. Following a working semiparametric Single Index Model that relates covariates and responses, we first define a patient-specific composite score, constructed from individual covariates. We then estimate conditional means of each response, given the patient score, correspond to ea…
In precision medicine, Dynamic Treatment Regimes (DTRs) are treatment protocols that adapt over time in response to a patient's observed characteristics. A DTR is a set of decision functions that takes an individual patient's information as arguments and outputs an action to be taken. Building on observed data, the aim is to identify the DTR that optimizes expected patient outcomes. Multiple methods have been proposed for optimal DTR estimation with continuous outcomes. However, optimal DTR estimation with binary outcomes is more complicated and has received comparatively little attention. Sol…
To achieve the goal of providing the best possible care to each patient, physicians need to customize treatments for patients with the same diagnosis, especially when treating diseases that can progress further and require additional treatments, such as cancer. Making decisions at multiple stages as a disease progresses can be formalized as a dynamic treatment regime (DTR). Most of the existing optimization approaches for estimating dynamic treatment regimes including the popular method of Q-learning were developed in a frequentist context. Recently, a general Bayesian machine learning framewo…
The average treatment effect (ATE) is popularly used to assess the treatment effect. However, the ATE implicitly assumes a homogenous treatment effect even amongst individuals with different characteristics. In this paper, we mainly focus on assessing the treatment effect heterogeneity, which has important implications in designing the optimal individual treatment regimens and in policy making. The treatment benefit rate (TBR) and treatment harm rate (THR) have been defined to characterize the magnitude of heterogeneity for binary outcomes. When the outcomes are continuous, we extend the defin…
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…
Individualized treatment rule (ITR) recommends treatment on the basis of individual patient characteristics and the previous history of applied treatments and their outcomes. Despite the fact there are many ways to estimate ITR with binary treatment, algorithms for continuous treatment have only just started to emerge. We propose a novel approach to continuous ITR estimation based on explicit modelling of uncertainty in the subject's outcome as well as direct estimation of the mean outcome using gaussian process regression. Our method incorporates two intuitively appealing properties - it is m…
Semi-parametric methods are often used for the estimation of intervention effects on correlated outcomes in cluster-randomized trials (CRTs). When outcomes are missing at random (MAR), Inverse Probability Weighted (IPW) methods incorporating baseline covariates can be used to deal with informative missingness. Also, augmented generalized estimating equations (AUG) correct for imbalance in baseline covariates but need to be extended for MAR outcomes. However, in the presence of interactions between treatment and baseline covariates, neither method alone produces consistent estimates for the mar…
We are interested in the estimation of average treatment effects based on right-censored data of an observational study. We focus on causal inference of differences between t-year absolute event risks in a situation with competing risks. We derive doubly robust estimation equations and implement estimators for the nuisance parameters based on working regression models for the outcome, the censoring and the treatment distribution conditional on auxiliary baseline covariates. We use the functional delta method to show that our estimators are regular asymptotically linear estimators and estimate …
Personalized medicine has received increasing attention among statisticians, computer scientists, and clinical practitioners. A major component of personalized medicine is the estimation of individualized treatment rules (ITRs). Recently, Zhao et al. (2012) proposed outcome weighted learning (OWL) to construct ITRs that directly optimize the clinical outcome. Although OWL opens the door to introducing machine learning techniques to optimal treatment regimes, it still has some problems in performance. In this article, we propose a general framework, called Residual Weighted Learning (RWL), to i…
In this paper we present a data-adaptive estimation procedure for estimation of average treatment effects in a time-to-event setting based on generalized random forests. In these kinds of settings, the definition of causal effect parameters are complicated by competing risks; here we distinguish between treatment effects on the crude and the net probabilities, respectively. To handle right-censoring, and to switch between crude and net probabilities, we propose a two-step procedure for estimation, applying inverse probability weighting to construct time-point specific weighted outcomes as inpu…
Estimation of Time-Varying Treatment Effects in a Joint Model for Longitudinal and Recurrent Event Outcomes in Mobile Health Data
University of Michigan（密歇根大学）；Institute for Social Research, University of Michigan（密歇根大学社会研究所）；Department of Population Health Sciences and Huntsman Cancer Insti（人口健康科学与亨斯曼癌症研究所）
In the absence of a randomized experiment, a key assumption for drawing causal inference about treatment effects is the ignorable treatment assignment. Violations of the ignorability assumption may lead to biased treatment effect estimates. Sensitivity analysis helps gauge how causal conclusions will be altered in response to the potential magnitude of departure from the ignorability assumption. However, sensitivity analysis approaches for unmeasured confounding in the context of multiple treatments and binary outcomes are scarce. We propose a flexible Monte Carlo sensitivity analysis approach…
Causal treatment effect decompositions with time-to-event outcomes under competing events
University of Turku（图尔库大学）；Finnish Institute for Health and Welfare（芬兰健康福利研究所）；University of Eastern Finland（东芬兰大学）；Karolinska Institutet（卡罗林斯卡学院）；Imperial College London（伦敦帝国理工学院）；Karolinska University Hospital（卡罗林斯卡大学医院）
Adaptive seamless designs combine confirmatory testing, a domain of phase III trials, with features such as treatment or subgroup selection, typically associated with phase II trials. They promise to increase the efficiency of development programmes of new drugs, e.g. in terms of sample size and / or development time. It is well acknowledged that adaptive designs are more involved from a logistical perspective and require more upfront planning, often in form of extensive simulation studies, than conventional approaches. Here we present a framework for adaptive treatment and subgroup selection …
Cause-effect relationships are typically evaluated by comparing outcome responses to binary treatment values, representing two arms of a hypothetical randomized controlled trial. However, in certain applications, treatments of interest are continuous and multidimensional. For example, understanding the causal relationship between severity of radiation therapy, summarized by a multidimensional vector of radiation exposure values and post-treatment side effects is a problem of clinical interest in radiation oncology. An appropriate strategy for making interpretable causal conclusions is to reduc…
Successive classification learning for estimating quantile optimal treatment regimes
Center for Applied Statistics, Renmin University of China（中国人民大学应用统计中心）；School of Statistics, Renmin University of China（中国人民大学统计学院）；Department of Statistical Sciences, University of Toronto（多伦多大学统计科学系）
