Unmeasured confounding is a key threat to reliable causal inference based on observational studies. Motivated from two powerful natural experiment devices, the instrumental variables and difference-in-differences, we propose a new method called instrumented difference-in-differences that explicitly leverages exogenous randomness in an exposure trend to estimate the average and conditional average treatment effect in the presence of unmeasured confounding. We develop the identification assumptions using the potential outcomes framework. We propose a Wald estimator and a class of multiply robust and efficient semiparametric estimators, with provable consistency and asymptotic normality. In addition, we extend the instrumented difference-in-differences to a two-sample design to facilitate investigations of delayed treatment effect and provide a measure of weak identification. We demonstrate our results in simulated and real datasets.
In the standard difference-in-differences research design, the parallel trends assumption may be violated when the relationship between the exposure trend and the outcome trend is confounded by unmeasured confounders. Progress can be made if there is an exogenous variable that (i) does not directly influence the change in outcome means (i.e. the outcome trend) except through influencing the change in exposure means (i.e. the exposure trend), and (ii) is not related to the unmeasured exposure - outcome confounders on the trend scale. Such exogenous variable is called an instrument for differenc…
Instrumented difference-in-differences under case-control sampling
EPILOGY, Institut Mondor of Biomedical Research, INSERM U955, University Paris Est Créteil（蒙多尔生物医学研究所，INSERM U955，巴黎东克雷泰伊大学）；Department of Dermatology, Henri Mondor Hospital（亨利·蒙多尔医院皮肤科）
A central question in causal inference with observational studies is the sensitivity of conclusions to unmeasured confounding. The classical Cornfield condition allows us to assess whether an unmeasured binary confounder can explain away the observed relative risk of the exposure on the outcome. It states that for an unmeasured confounder to explain away an observed relative risk, the association between the unmeasured confounder and the exposure, and also that between the unmeasured confounder and the outcome, must both be larger than the observed relative risk. In this paper, we extend the c…
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…
MPI for Intelligent Systems（马克斯·普朗克智能系统研究所）；University of Cambridge（剑桥大学）；Microsoft Research（微软研究院）；University of Oxford（牛津大学）；The Alan Turing Institute（艾伦·图灵研究所）；University College London（伦敦大学学院）
Causal approaches to fairness have seen substantial recent interest, both from the machine learning community and from wider parties interested in ethical prediction algorithms. In no small part, this has been due to the fact that causal models allow one to simultaneously leverage data and expert knowledge to remove discriminatory effects from predictions. However, one of the primary assumptions in causal modeling is that you know the causal graph. This introduces a new opportunity for bias, caused by misspecifying the causal model. One common way for misspecification to occur is via unmeasure…
Observational studies can play a useful role in assessing the comparative effectiveness of competing treatments. In a clinical trial the randomization of participants to treatment and control groups generally results in well-balanced groups with respect to possible confounders, which makes the analysis straightforward. However, when analysing observational data, the potential for unmeasured confounding makes comparing treatment effects much more challenging. Causal inference methods such as Instrumental Variable and Prior Even Rate Ratio approaches make it possible to circumvent the need to ad…
Outcome-dependent sampling designs are common in many different scientific fields including epidemiology, ecology, and economics. As with all observational studies, such designs often suffer from unmeasured confounding, which generally precludes the nonparametric identification of causal effects. Nonparametric bounds can provide a way to narrow the range of possible values for a nonidentifiable causal effect without making additional untestable assumptions. The nonparametric bounds literature has almost exclusively focused on settings with random sampling, and the bounds have often been derive…
The method of difference-in-differences (DID) is widely used to study the causal effect of policy interventions in observational studies. DID employs a before and after comparison of the treated and control units to remove bias due to time-invariant unmeasured confounders under the parallel trends assumption. Estimates from DID, however, will be biased if the outcomes for the treated and control units evolve differently in the absence of treatment, namely if the parallel trends assumption is violated. We propose a general identification strategy that leverages two groups of control units whose…
We consider the problem of estimating the effects of a binary treatment on a continuous outcome of interest from observational data in the absence of confounding by unmeasured factors. We provide a new estimator of the population average treatment effect (ATE) based on the difference of novel double-robust (DR) estimators of the treatment-specific outcome means. We compare our new estimator with previously estimators both theoretically and via simulation. DR-difference estimators may have poor finite sample behavior when the estimated propensity scores in the treated and untreated do not overl…
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…
Governments issue "stay at home" orders to reduce the spread of contagious diseases, but the magnitude of such orders' effectiveness is uncertain. In the United States these orders were not coordinated at the national level during the coronavirus disease 2019 (COVID-19) pandemic, which creates an opportunity to use spatial and temporal variation to measure the policies' effect with greater accuracy. Here, we combine data on the timing of stay-at-home orders with daily confirmed COVID-19 cases and fatalities at the county level in the United States. We estimate the effect of stay-at-home orders…
Interventional effects have been proposed as a solution to the unidentifiability of natural (in)direct effects under mediator-outcome confounders affected by the exposure. Such confounders are an intrinsic characteristic of studies with time-varying exposures and mediators, yet the generalization of the interventional effect framework to the time-varying case has received little attention in the literature. We present an identification result for interventional effects in a general longitudinal data structure that allows flexibility in the specification of treatment-outcome, treatment-mediator…
Understanding how effective high-level NICUs (neonatal intensive care units that have the capacity for sustained mechanical assisted ventilation and high volume) are compared to low-level NICUs is important and valuable for both individual mothers and for public policy decisions. The goal of this paper is to estimate the effect on mortality of premature babies being delivered in a high-level NICU vs. a low-level NICU through an observational study where there are unmeasured confounders as well as nonignorable missing covariates. We consider the use of excess travel time as an instrumental vari…
We develop a new approach for identifying and estimating average causal effects in panel data under a linear factor model with unmeasured confounders. Compared to other methods tackling factor models such as synthetic controls and matrix completion, our method does not require the number of time periods to grow infinitely. Instead, we draw inspiration from the two-way fixed effect model as a special case of the linear factor model, where a simple difference-in-differences transformation identifies the effect. We show that analogous, albeit more complex, transformations exist in the more genera…
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…
Centre for Big Data Research in Health (CBDRH)（健康大数据研究中心）
Causal inference for observational longitudinal studies often requires the accurate estimation of treatment effects on time-to-event outcomes in the presence of time-dependent patient history and time-dependent covariates. To tackle this longitudinal treatment effect estimation problem, we have developed a time-variant causal survival (TCS) model that uses the potential outcomes framework with an ensemble of recurrent subnetworks to estimate the difference in survival probabilities and its confidence interval over time as a function of time-dependent covariates and treatments. Using simulated …
When assessing causal effects, determining the target population to which the results are intended to generalize is a critical decision. Randomized and observational studies each have strengths and limitations for estimating causal effects in a target population. Estimates from randomized data may have internal validity but are often not representative of the target population. Observational data may better reflect the target population, and hence be more likely to have external validity, but are subject to potential bias due to unmeasured confounding. While much of the causal inference litera…
Risk Set Matched Difference-in-Differences for the Analysis of Effect Modification in an Observational Study on the Impact of Gun Violence on Health Outcomes
提出结合profile matching和risk set matching的difference-in-differences框架研究异质性处理效应，发现非致命枪伤对幸存者及其家人健康有显著持续影响，且因受伤严重程度和意图而异。
Epidemiologists and applied statisticians often believe that relative effect measures conditional on covariates, such as risk ratios and mean ratios, are ``transportable'' across populations. Here, we examine the identification of causal effects in a target population using an assumption that conditional relative effect measures (e.g., conditional risk ratios or mean ratios) are transportable from a trial to the target population. We show that transportability for relative effect measures is largely incompatible with transportability for difference effect measures, unless the treatment has no …
Zhejiang University（浙江大学）；Emory University（埃默里大学）；Tsinghua University（清华大学）；Shanghai AI Laboratory（上海人工智能实验室）；Shanghai Institute for Advanced Study of Zhejiang University（浙江大学上海高等研究院）
The advent of the big data era brought new opportunities and challenges to draw treatment effect in data fusion, that is, a mixed dataset collected from multiple sources (each source with an independent treatment assignment mechanism). Due to possibly omitted source labels and unmeasured confounders, traditional methods cannot estimate individual treatment assignment probability and infer treatment effect effectively. Therefore, we propose to reconstruct the source label and model it as a Group Instrumental Variable (GIV) to implement IV-based Regression for treatment effect estimation. In thi…
Just what the doctor ordered: An evaluation of provider preference-based Instrumental Variable methods in observational studies, with application for comparative effectiveness of type 2 diabetes therapy
Since the early 2000s, evidence has accumulated for a significant differential effect of first-line antiretroviral therapy (ART) regimens on human immunodeficiency virus (HIV) viral load suppression. This finding was replicated in our data from the Harvard President's Emergency Plan for AIDS Relief (PEPFAR) program in Nigeria. Investigators were interested in finding the source of these differences, i.e., understanding the mechanisms through which one regimen outperforms another, particularly via adherence. This question can be naturally formulated via mediation analysis with adherence playing…
Observing the unobserved confounding through its effects: toward randomized trial-like estimates from real-world survival data
Operations Research Center, Massachusetts Institute of Technology（麻省理工学院运营研究中心）；Sloan School of Management, Massachusetts Institute of Technology（麻省理工学院斯隆管理学院）；Department of Surgery, Memorial Sloan Kettering Cancer Center（纪念斯隆凯特琳癌症中心外科部）；Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin（柏林夏里特医学院，柏林自由大学和洪堡大学联合成员）
We discovered secular trend bias in a drug effectiveness study for a recently approved drug. We compared treatment outcomes between patients who received the newly approved drug and patients exposed to the standard treatment. All patients diagnosed after the new drug's approval date were considered. We built a machine learning causal inference model to determine patient subpopulations likely to respond better to the newly approved drug. After identifying the presence of secular trend bias in our data, we attempted to adjust for the bias in two different ways. First, we matched patients on the …
A Spectral Confounder Adjustment for Spatial Regression with Multiple Exposures and Outcomes
North Carolina State University（北卡罗来纳州立大学）；Colorado State University（科罗拉多州立大学）；US EPA, Center for Public Health and Environmental Assessment（美国环境保护署，公共健康与环境评估中心）
In randomized trials, once the total effect of the intervention has been estimated, it is often of interest to explore mechanistic effects through mediators along the causal pathway between the randomized treatment and the outcome. In the setting with two sequential mediators, there are a variety of decompositions of the total risk difference into mediation effects. We derive sharp and valid bounds for a number of mediation effects in the setting of two sequential mediators both with unmeasured confounding with the outcome. We provide five such bounds in the main text corresponding to two diff…
In the comparative interrupted time series design (also called the method of difference-in-differences), the change in outcome in a group exposed to treatment in the periods before and after the exposure is compared to the change in outcome in a control group not exposed to treatment in either period. The standard difference-in-difference estimator for a comparative interrupted time series design will be biased for estimating the causal effect of the treatment if there is an interaction between history in the after period and the groups; for example, there is a historical event besides the sta…
