To limit the spread of the novel coronavirus, governments across the world implemented extraordinary physical distancing policies, such as stay-at-home orders, and numerous studies aim to estimate their effects. Many statistical and econometric methods, such as difference-in-differences, leverage repeated measurements and variation in timing to estimate policy effects, including in the COVID-19 context. While these methods are less common in epidemiology, epidemiologic researchers are well accustomed to handling similar complexities in studies of individual-level interventions. "Target trial emulation" emphasizes the need to carefully design a non-experimental study in terms of inclusion and exclusion criteria, covariates, exposure definition, and outcome measurement -- and the timing of those variables. We argue that policy evaluations using group-level longitudinal ("panel") data need to take a similar careful approach to study design, which we refer to as "policy trial emulation." This is especially important when intervention timing varies across jurisdictions; the main idea is to construct target trials separately for each "treatment cohort" (states that implement the policy at the same time) and then aggregate. We present a stylized analysis of the impact of state-level stay-at-home orders on total coronavirus cases. We argue that estimates from panel methods -- with the right data and careful modeling and diagnostics -- can help add to our understanding of many policies, though doing so is often challenging.
A randomized trial and an analysis of observational data designed to emulate the trial sample observations separately, but have the same eligibility criteria, collect information on some shared baseline covariates, and compare the effects of the same treatments on the same outcomes. Treatment effect estimates from the trial and its emulation can be compared to benchmark observational analysis methods. In a simplified setting with complete adherence to the assigned treatment strategy and no loss-to-follow-up, we show that benchmarking relies on an exchangeability condition between the populatio…
Causal inference from observational data can be viewed as a missing data problem arising from a hypothetical population-scale randomized trial matched to the observational study. This links a target trial protocol with a corresponding generative predictive model for inference, providing a complete framework for transparent communication of causal assumptions and statistical uncertainty on treatment effects, without the need for counterfactuals. The intuitive foundation for the work is that a whole population randomized trial would provide answers to any observable causal question with certaint…
Inference procedures in sequential trial emulation with survival outcomes: comparing confidence intervals based on the sandwich variance estimator, bootstrap and jackknife
Assessing Vaccine Effectiveness in Observational Studies via Nested Trial Emulation
Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill（北卡罗来纳大学教堂山分校吉林斯全球公共卫生学院生物统计系）；Nuffield Department of Population Health, University of Oxford（牛津大学努菲尔德人口健康系）
Sorbonne Université（索邦大学）；Inserm（法国国家健康与医学研究院）；Sorbonne Public Health Institute（索邦公共卫生研究所）；Equipe PEPITES（PEPITES团队）；Assistance Publique - Hôpitaux de Paris（巴黎公立协助医院）；Hôpital Pitié Salpêtrière（皮蒂埃-萨尔佩特里耶尔医院）；Département de Santé Publique（公共卫生系）；Centre de Pharmacoépidémiologie (Cephepi)（药物流行病学中心）；APHP（巴黎公立协助医院）；Hôpital Saint-Antoine（圣安东医院）；Inria（法国国家计算机科学与控制研究院）；CNRS（法国国家科学研究中心）；Paris Brain Institute（巴黎脑研究所）
Bridging disconnected networks of first and second lines of biologic therapies in rheumatoid arthritis with registry data: Bayesian evidence synthesis with target trial emulation
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…
Trial-based economic evaluations are typically performed on cross-sectional variables, derived from the responses for only the completers in the study, using methods that ignore the complexities of utility and cost data (e.g. skewness and spikes). We present an alternative and more efficient Bayesian parametric approach to handle missing longitudinal outcomes in economic evaluations, while accounting for the complexities of the data. We specify a flexible parametric model for the observed data and partially identify the distribution of the missing data with partial identifying restrictions and…
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…
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…
An efficient monotone data augmentation (MDA) algorithm is proposed for missing data imputation for incomplete multivariate nonnormal data that may contain variables of different types, and are modeled by a sequence of regression models including the linear, binary logistic, multinomial logistic, proportional odds, Poisson, negative binomial, skew-normal, skew-t regressions or a mixture of these models. The MDA algorithm is applied to the sensitivity analyses of longitudinal trials with nonignorable dropout using the controlled pattern imputations that assume the treatment effect reduces or di…
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）
Missing data is inevitable in longitudinal clinical trials. Conventionally, the missing at random assumption is assumed to handle missingness, which however is unverifiable empirically. Thus, sensitivity analysis is critically important to assess the robustness of the study conclusions against untestable assumptions. Toward this end, regulatory agencies often request using imputation models such as return-to-baseline, control-based, and washout imputation. Multiple imputation is popular in sensitivity analysis; however, it may be inefficient and result in an unsatisfying interval estimation by…
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…
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
In many clinical trials treatments need to be repeatedly applied as diseases relapse frequently after remission over a long period of time (e.g., 35 weeks). Most research in statistics focuses on the overall trial design, such as sample size and power calculation, or on the data analysis after trials are completed. Little is done to improve the efficiency of trial monitoring, such as early termination of trials due to futility. The challenge faced in such trial monitoring is mostly caused by the need to properly model repeated outcomes from patients. We propose a Bayesian trial monitoring sche…
A sensitivity analysis approach to principal stratification with a continuous longitudinal intermediate outcome: Applications to a cohort stepped wedge trial
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…
Bayesian joint modelling of longitudinal biomarkers to enable extrapolation of overall survival: an application using larotrectinib trial clinical data
When Method Choice Changes Statistical Inference: A Comparison of a Baseline Two-Stage Approach and Bayesian Joint Modeling for Longitudinal and Survival Data in an HIV Clinical Trial
Two-part joint models for a longitudinal semicontinuous biomarker and a terminal event have been recently introduced based on frequentist estimation. The biomarker distribution is decomposed into a probability of positive value and the expected value among positive values. Shared random effects can represent the association structure between the biomarker and the terminal event. The computational burden increases compared to standard joint models with a single regression model for the biomarker. In this context, the frequentist estimation implemented in the R package frailtypack can be challen…
The mixed effects model for repeated measures (MMRM) has been widely used for the analysis of longitudinal clinical data collected at a number of fixed time points. We propose a robust extension of the MMRM for skewed and heavy-tailed data on basis of the multivariate skew-t distribution, and it includes the multivariate normal, t, and skew-normal distributions as special cases. An efficient Markov chain Monte Carlo algorithm is developed using the monotone data augmentation and parameter expansion techniques. We employ the algorithm to perform controlled pattern imputations for sensitivity an…
