In this paper I revisit the interpretation of the linear instrumental variables (IV) estimand as a weighted average of conditional local average treatment effects (LATEs). I focus on a situation in which additional covariates are required for identification while the reduced-form and first-stage regressions may be misspecified due to an implicit homogeneity restriction on the effects of the instrument. I show that the weights on some conditional LATEs are negative and the IV estimand is no longer interpretable as a causal effect under a weaker version of monotonicity, i.e. when there are compliers but no defiers at some covariate values and defiers but no compliers elsewhere. The problem of negative weights disappears in the interacted specification of Angrist and Imbens (1995), which avoids misspecification and seems to be underused in applied work. I illustrate my findings in an application to the causal effects of pretrial detention on case outcomes. In this setting, I reject the stronger version of monotonicity, demonstrate that the interacted instruments are sufficiently strong for consistent estimation using the jackknife methodology, and present several estimates that are economically and statistically different, depending on whether the interacted instruments are used.
Applied work often studies the effect of a binary variable ("treatment") using linear models with additive effects. I study the interpretation of the OLS estimands in such models when treatment effects are heterogeneous. I show that the treatment coefficient is a convex combination of two parameters, which under certain conditions can be interpreted as the average treatment effects on the treated and untreated. The weights on these parameters are inversely related to the proportion of observations in each group. Reliance on these implicit weights can have serious consequences for applied work,…
In failure-time settings, a competing risk event is any event that makes it impossible for the event of interest to occur. For example, cardiovascular disease death is a competing event for prostate cancer death because an individual cannot die of prostate cancer once he has died of cardiovascular disease. Various statistical estimands have been defined as possible targets of inference in the classical competing risks literature. Many reviews have described these statistical estimands and their estimating procedures with recommendations about their use. However, this previous work has not used…
The population-attributable fraction (PAF) is a popular epidemiological measure for the burden of a harmful exposure within a population. It is often interpreted causally as proportion of preventable cases after an elimination of exposure. Originally, the PAF has been defined for cohort studies of fixed length with a baseline exposure or cross-sectional studies. An extension of the definition to complex time-to-event data is not straightforward. We revise the proposed approaches in literature and provide a clear concept of the PAF for these data situations. The conceptualization is achieved by…
The ICH E9 addendum introduces the term intercurrent event to refer to events that happen after randomisation and that can either preclude observation of the outcome of interest or affect its interpretation. It proposes five strategies for handling intercurrent events to form an estimand but does not suggest statistical methods for estimation. In this paper we focus on the hypothetical strategy, where the treatment effect is defined under the hypothetical scenario in which the intercurrent event is prevented. For its estimation, we consider causal inference and missing data methods. We establi…
In Regression Discontinuity (RD) design, self-selection leads to different distributions of covariates on two sides of the policy intervention, which essentially violates the continuity of potential outcome assumption. The standard RD estimand becomes difficult to interpret due to the existence of some indirect effect, i.e. the effect due to self selection. We show that the direct causal effect of interest can still be recovered under a class of estimands. Specifically, we consider a class of weighted average treatment effects tailored for potentially different target populations. We show that…
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 …
Case-control designs are an important tool in contrasting the effects of well-defined treatments. In this paper, we reconsider classical concepts, assumptions and principles and explore when the results of case-control studies can be endowed a causal interpretation. Our focus is on identification of target causal quantities, or estimands. We cover various estimands relating to intention-to-treat or per-protocol effects for popular sampling schemes (case-base, survivor, and risk-set sampling), each with and without matching. Our approach may inform future research on different estimands, other …
Intercurrent events (ICEs) and missing values are inevitable in clinical trials of any size and duration, making it difficult to assess the treatment effect for all patients in randomized clinical trials. Defining the appropriate estimand that is relevant to the clinical research question is the first step in analyzing data. The tripartite estimands, which evaluate the treatment differences in the proportion of patients with ICEs due to adverse events, the proportion of patients with ICEs due to lack of efficacy, and the primary efficacy outcome for those who can adhere to study treatment unde…
We discuss some causal estimands used to study racial discrimination in policing. A central challenge is that not all police-civilian encounters are recorded in administrative datasets and available to researchers. One possible solution is to consider the average causal effect of race conditional on the civilian already being detained by the police. We find that such an estimand can be quite different from the more familiar ones in causal inference and needs to be interpreted with caution. We propose using an estimand new for this context -- the causal risk ratio, which has more transparent in…
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…
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 infe…
Single-arm trials (SATs) may be used to support regulatory submissions in settings where there is a high unmet medical need and highly promising early efficacy data undermine the equipoise needed for randomization. In this context, patient-level real-world data (RWD) may be used to create an external control arm (ECA) to contextualize the SAT results. However, naive comparisons of the SAT with its ECA will yield biased estimates of causal effects if groups are imbalanced with regards to (un)measured prognostic factors. Several methods are available to adjust for measured confounding, but the i…
Causal mediation in cluster-randomized trials with multiple mediators: spillover-aware decomposition, identification, and semiparametric efficient inference
Reframing Population-Adjusted Indirect Comparisons as a Transportability Problem: An Estimand-Based Perspective and Implications for Health Technology Assessment
From Estimands to Robust Inference of Treatment Effects in Master Protocol Trials
University of Washington（华盛顿大学）；The University of Texas MD Anderson Cancer Center（德克萨斯大学安德森癌症中心）；University of Wisconsin-Madison（威斯康星大学麦迪逊分校）；Eli Lilly and Company（礼来公司）；Food and Drug Administration（食品药品监督管理局）；Seattle Children’s Research Institute（西雅图儿童研究所）
Causal identification of treatment effects for infectious disease outcomes in interconnected populations is challenging because infection outcomes may be transmissible to others, and treatment given to one individual may affect others' outcomes. Contagion, or transmissibility of outcomes, complicates standard conceptions of treatment interference in which an intervention delivered to one individual can affect outcomes of others. Several statistical frameworks have been proposed to measure causal treatment effects in this setting, including structural transmission models, mediation-based partne…
Causal mediation analysis is complicated with multiple effect definitions that require different sets of assumptions for identification. This paper provides a systematic explanation of such assumptions. We define five potential outcome types whose means are involved in various effect definitions. We tackle their mean/distribution's identification, starting with the one that requires the weakest assumptions and gradually building up to the one that requires the strongest assumptions. This presentation shows clearly why an assumption is required for one estimand and not another, and provides a s…
Evaluating treatment effects on longitudinal outcomes with attrition due to death: Methods for a two-dimentional estimand with a case study in Quality of Life
Ghent University（根特大学）；Leiden University Medical Center（莱顿大学医学中心）；Pfizer Inc（辉瑞公司）；Oslo University Hospital（奥斯陆大学医院）；European Organisation for Research and Treatment of Cancer (EORTC) Headquarters（欧洲癌症研究与治疗组织（EORTC）总部）；University of Freiburg（弗赖堡大学）
Estimation of treatment effect for principal strata has been studied for more than two decades. Existing research exclusively focuses on the estimation, but there is little research on forming and testing hypotheses for principal stratification-based estimands. In this brief report, we discuss a phenomenon in which the true treatment effect for a principal stratum may not equal zero even if the two treatments have the same effect at patient level which implies an equal average treatment effect for the principal stratum. We explain this phenomenon from the perspective of selection bias. This is…
A Framework for Parametric Time-Varying Treatment Effects in Multiple Intervention Stepped Wedge Design Clinical Trials in the Presence of Non-Uniform Cluster-Period Correlation Structures
The Johns Hopkins University Applied Physics Laboratory（约翰斯·霍普金斯大学应用物理实验室）；UTHealth Houston School of Public Health, The University of Texas Health Science Center at Houston（休斯顿德克萨斯大学健康科学中心休斯顿公共卫生学院）
