Causal inference methods are gaining increasing prominence in pharmaceutical drug development in light of the recently published addendum on estimands and sensitivity analysis in clinical trials to the E9 guideline of the International Council for Harmonisation. The E9 addendum emphasises the need to account for post-randomization or `intercurrent' events that can potentially influence the interpretation of a treatment effect estimate at a trial's conclusion. Instrumental Variables (IV) methods have been used extensively in economics, epidemiology and academic clinical studies for `causal inference', but less so in the pharmaceutical industry setting until now. In this tutorial paper we review the basic tools for causal inference, including graphical diagrams and potential outcomes, as well as several conceptual frameworks that an IV analysis can sit within. We discuss in detail how to map these approaches to the Treatment Policy, Principal Stratum and Hypothetical `estimand strategies' introduced in the E9 addendum, and provide details of their implementation using standard regression models. Specific attention is given to discussing the assumptions each estimation strategy relies on in order to be consistent, the extent to which they can be empirically tested and sensitivity analyses in which specific assumptions can be relaxed. We finish by applying the methods described to simulated data closely matching two recent pharmaceutical trials to further motivate and clarify the ideas
Instrumental variable methods are widely used in medical and social science research to draw causal conclusions when the treatment and outcome are confounded by unmeasured confounding variables. One important feature of such studies is that the instrumental variable is often applied at the cluster level, e.g., hospitals' or physicians' preference for a certain treatment where each hospital or physician naturally defines a cluster. This paper proposes to embed such observational instrumental variable data into a cluster-randomized encouragement experiment using statistical matching. Potential o…
Applying the estimands framework to non-inferiority trials: guidance on choice of hypothetical estimands for non-adherence and comparison of estimation methods
Unmeasured confounding is a threat to causal inference and individualized decision making. Similar to Cui and Tchetgen Tchetgen (2020); Qiu et al. (2020); Han (2020a), we consider the problem of identification of optimal individualized treatment regimes with a valid instrumental variable. Han (2020a) provided an alternative identifying condition of optimal treatment regimes using the conditional Wald estimand of Cui and Tchetgen Tchetgen (2020); Qiu et al. (2020) when treatment assignment is subject to endogeneity and a valid binary instrumental variable is available. In this note, we provide …
Instrumental variable methods are widely used for inferring the causal effect in the presence of unmeasured confounders. Existing instrumental variable methods for nonlinear outcome models require stringent identifiability conditions. This paper considers a flexible semi-parametric potential outcome model that allows for possibly invalid instruments. We propose new identifiability conditions to identify the causal parameters when the majority of the instrumental variables are valid. We devise a novel inference procedure for a new average structural function and the conditional average treatmen…
Background: Interpreting instrumental variable results often requires further assumptions in addition to the core assumptions of relevance, independence, and the exclusion restriction. Methods: We assess whether instrument-exposure additive homogeneity renders the Wald estimand equal to the average derivative effect (ADE) in the case of a binary instrument and a continuous exposure. Results: Instrument-exposure additive homogeneity is insufficient for ADE identification when the instrument is binary, the exposure is continuous and the effect of the exposure on the outcome is non-linear on the …
Average Treatment Effect Estimation with Non-binary Instrumental Variables
University of Toronto（多伦多大学）；Shanghai Jiao Tong University（上海交通大学）；University of Ottawa（渥太华大学）；Princess Margaret Cancer Centre, University Health Network（公主玛格丽特癌症中心，联合健康网络）
Living forwards or understanding backwards? A comparison of Inverse Probability of Treatment Weighting and G-estimation methods for targeting hypothetical full adherence estimands in longitudinal cohort studies
Mediation analysis is a strategy for understanding the mechanisms by which treatments or interventions affect later outcomes. Mediation analysis is frequently applied in randomized trial settings, but typically assumes: a) that randomized assignment is the exposure of interest as opposed to actual take-up of the intervention, and b) no unobserved confounding of the mediator-outcome relationship. In contrast to the rich literature on instrumental variable (IV) methods to estimate a total effect of a non-randomized exposure, there has been almost no research into using IV as an identification st…
Recent work on dynamic interventions has greatly expanded the range of causal questions researchers can study while weakening identifying assumptions and yielding effects that are more practically relevant. However, most work in dynamic interventions to date has focused on settings where we directly alter some unconfounded treatment of interest. In policy analysis, decision makers rarely have this level of control over behaviors or access to experimental data. Instead, they are often faced with treatments they can affect only indirectly and whose effects must be learned from observational data…
This paper evaluates the effects of being an only child in a family on psychological health, leveraging data on the One-Child Policy in China. We use an instrumental variable approach to address the potential unmeasured confounding between the fertility decision and psychological health, where the instrumental variable is an index on the intensity of the implementation of the One-Child Policy. We establish an analytical link between the local instrumental variable approach and principal stratification to accommodate the continuous instrumental variable. Within the principal stratification fram…
This paper provides a critical review of the Bayesian perspective of causal inference based on the potential outcomes framework. We review the causal estimands, identification assumptions, the general structure of Bayesian inference of causal effects, and sensitivity analysis. We highlight issues that are unique to Bayesian causal inference, including the role of the propensity score, definition of identifiability, the choice of priors in both low and high dimensional regimes. We point out the central role of covariate overlap and more generally the design stage in Bayesian causal inference. W…
Background: Instrumental variables (IVs) can be used to provide evidence as to whether a treatment X has a causal effect on an outcome Y. Even if the instrument Z satisfies the three core IV assumptions of relevance, independence and the exclusion restriction, further assumptions are required to identify the average causal effect (ACE) of X on Y. Sufficient assumptions for this include: homogeneity in the causal effect of X on Y; homogeneity in the association of Z with X; and no effect modification (NEM). Methods: We describe the NO Simultaneous Heterogeneity (NOSH) assumption, which requires…
Manipulating a Continuous Instrumental Variable in an Observational Study of Premature Babies: Algorithm, Partial Identification Bounds, and Inference under Randomization and Biased Randomization Assumptions
Estimating dynamic treatment regimes (DTRs) from retrospective observational data is challenging as some degree of unmeasured confounding is often expected. In this work, we develop a framework of estimating properly defined "optimal" DTRs with a time-varying instrumental variable (IV) when unmeasured covariates confound the treatment and outcome, rendering the potential outcome distributions only partially identified. We derive a novel Bellman equation under partial identification, use it to define a generic class of estimands (termed IV-optimal DTRs), and study the associated estimation prob…
What should researchers do when their baseline model is refuted? We provide four constructive answers. First, researchers can measure the extent of falsification. To do this, we consider continuous relaxations of the baseline assumptions of concern. We then define the falsification frontier: The smallest relaxations of the baseline model which are not refuted. This frontier provides a quantitative measure of the extent of falsification. Second, researchers can present the identified set for the parameter of interest under the assumption that the true model lies somewhere on this frontier. We c…
Principal Stratification with Bayesian Additive Regression Trees for Count-Valued Intermediate Variables: Estimating the Effect of Fertility on Women's Employment
This paper studies the identifying power of an instrumental variable in the nonparametric heterogeneous treatment effect framework when a binary treatment is mismeasured and endogenous. Using a binary instrumental variable, I characterize the sharp identified set for the local average treatment effect under the exclusion restriction of an instrument and the deterministic monotonicity of the true treatment in the instrument. Even allowing for general measurement error (e.g., the measurement error is endogenous), it is still possible to obtain finite bounds on the local average treatment effect.…
Randomization inference for stepped-wedge designs with noncompliance with application to a palliative care pragmatic trial
University of Chicago（芝加哥大学）；Data Science Institute, University of Chicago（芝加哥大学数据科学研究所）；University of Pennsylvania（宾夕法尼亚大学）；Department of Medicine, University of Pennsylvania（宾夕法尼亚大学医学系）；Department of Mathematics and Statistics, Mississippi State University（密西西比州立大学数学与统计系）；Department of Statistics and Data Science, University of Pennsylvania（宾夕法尼亚大学统计与数据科学系）；Yale School of Public Health（耶鲁公共卫生学院）
Non-adherence to assigned treatment is a common issue in cluster randomised trials (CRTs). In these settings, the efficacy estimand may be also of interest. Many methodological contributions in recent years have advocated using instrumental variables to identify and estimate the local average treatment effect (LATE). However, the clustered nature of randomisation in CRTs adds to the complexity of such analyses. In this paper, we show that under certain assumptions, the LATE can be estimated via two-stage least squares (TSLS) using cluster-level summaries of outcomes and treatment received. Imp…
Non-adherence to assigned treatment is common in randomised controlled trials (RCTs). Recently, there has been an increased interest in estimating causal effects of treatment received, for example the so-called local average treatment effect (LATE). Instrumental variables (IV) methods can be used for identification, with estimation proceeding either via fully parametric mixture models or two-stage least squares (TSLS). TSLS is popular but can be problematic for binary outcomes where the estimand of interest is a causal odds ratio. Mixture models are rarely used in practice, perhaps because of …
Instrumental variables (IV) regression is widely used to estimate causal treatment effects in settings where receipt of treatment is not fully random, but there exists an instrument that generates exogenous variation in treatment exposure. While IV can recover consistent treatment effect estimates, they are often noisy. Building upon earlier work in biostatistics (Joffe and Brensinger, 2003) and relating to an evolving literature in econometrics (including Abadie et al., 2019; Huntington-Klein, 2020; Borusyak and Hull, 2020), we study how to improve the efficiency of IV estimates by exploiting…
ProximalFM: Amortized Proximal Causal Inference under Hidden Confounding
University of Oxford（牛津大学）；Harvard University（哈佛大学）；University of Illinois Urbana-Champaign（伊利诺伊大学厄巴纳-香槟分校）；Perelman School of Medicine, University of Pennsylvania（宾夕法尼亚大学佩雷尔曼医学院）；Vector Institute（向量研究所）；University College London（伦敦大学学院）
