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We present a practical guide for the analysis of regression discontinuity (RD) designs in biomedical contexts. We begin by introducing key concepts, assumptions, and estimands within both the continuity-based framework and the local randomization framework. We then discuss modern estimation and inference methods within both frameworks, including approaches for bandwidth or local neighborhood selection, optimal treatment effect point estimation, and robust bias-corrected inference methods for uncertainty quantification. We also overview empirical falsification tests that can be used to support key assumptions. Our discussion focuses on two particular features that are relevant in biomedical research: (i) fuzzy RD designs, which often arise when therapeutic treatments are based on clinical guidelines but patients with scores near the cutoff are treated contrary to the assignment rule; and (ii) RD designs with discrete scores, which are ubiquitous in biomedical applications. We illustrate our discussion with three empirical applications: the effect of CD4 guidelines for anti-retroviral therapy on retention of HIV patients in South Africa, the effect of genetic guidelines for chemotherapy on breast cancer recurrence in the United States, and the effects of age-based patient cost-sharing on healthcare utilization in Taiwan. We provide replication materials employing publicly available statistical software in Python, R and Stata, offering researchers all necessary tools to conduct an RD analysis.

Quantifying treatment effect heterogeneity is a crucial task in many areas of causal inference, e.g. optimal treatment allocation and estimation of subgroup effects. We study the problem of estimating the level sets of the conditional average treatment effect (CATE), identified under the no-unmeasured-confounders assumption. Given a user-specified threshold, the goal is to estimate the set of all units for whom the treatment effect exceeds that threshold. For example, if the cutoff is zero, the estimand is the set of all units who would benefit from receiving treatment. Assigning treatment just to this set represents the optimal treatment rule that maximises the mean population outcome. Similarly, cutoffs greater than zero represent optimal rules under resource constraints. The level set estimator that we study follows the plug-in principle and consists of simply thresholding a good estimator of the CATE. While many CATE estimators have been recently proposed and analysed, how their properties relate to those of the corresponding level set estimators remains unclear. Our first goal is thus to fill this gap by deriving the asymptotic properties of level set estimators depending on which estimator of the CATE is used. Next, we identify a minimax optimal estimator in a model where the CATE, the propensity score and the outcome model are Holder-smooth of varying orders. We consider data generating processes that satisfy a margin condition governing the probability of observing units for whom the CATE is close to the threshold. We investigate the performance of the estimators in simulations and illustrate our methods on a dataset used to study the effects on mortality of laparoscopic vs open surgery in the treatment of various conditions of the colon., Comment: 38 pages, 4 figures

Comparative effectiveness research frequently employs the instrumental variable design since randomized trials can be infeasible for many reasons. In this study, we investigate and compare treatments for emergency cholecystitis -- inflammation of the gallbladder. A standard treatment for cholecystitis is surgical removal of the gallbladder, while alternative non-surgical treatments include managed care and pharmaceutical options. As randomized trials are judged to violate the principle of equipoise, we consider an instrument for operative care: the surgeon's tendency to operate. Standard instrumental variable estimation methods, however, often rely on parametric models that are prone to bias from model misspecification. We outline instrumental variable estimation methods based on the doubly robust machine learning framework. These methods enable us to employ various machine learning techniques for nuisance parameter estimation and deliver consistent estimates and fast rates of convergence for valid inference. We use these methods to estimate the primary target causal estimand in an IV design. Additionally, we expand these methods to develop estimators for heterogeneous causal effects, profiling principal strata, and a sensitivity analyses for a key instrumental variable assumption. We conduct a simulation study to demonstrate scenarios where more flexible estimation methods outperform standard methods. Our findings indicate that operative care is generally more effective for cholecystitis patients, although the benefits of surgery can be less pronounced for key patient subgroups.

Supplemental material, sj-docx-1-mdm-10.1177_0272989X221100799 for Local Instrumental Variable Methods to Address Confounding and Heterogeneity when Using Electronic Health Records: An Application to Emergency Surgery by Silvia Moler-Zapata, Richard Grieve, David Lugo-Palacios, A. Hutchings, R. Silverwood, Luke Keele, Tommaso Kircheis, David Cromwell, Neil Smart, Robert Hinchliffe and Stephen O’Neill in Medical Decision Making

Supplemental material, sj-docx-1-mdm-10.1177_0272989X221100799 for Local Instrumental Variable Methods to Address Confounding and Heterogeneity when Using Electronic Health Records: An Application to Emergency Surgery by Silvia Moler-Zapata, Richard Grieve, David Lugo-Palacios, A. Hutchings, R. Silverwood, Luke Keele, Tommaso Kircheis, David Cromwell, Neil Smart, Robert Hinchliffe and Stephen O’Neill in Medical Decision Making

The Regression Discontinuity (RD) design is a widely used non-experimental method for causal inference and program evaluation. While its canonical formulation only requires a score and an outcome variable, it is common in empirical work to encounter RD analyses where additional variables are used for adjustment. This practice has led to misconceptions about the role of covariate adjustment in RD analysis, from both methodological and empirical perspectives. In this chapter, we review the different roles of covariate adjustment in RD designs, and offer methodological guidance for its correct use.

Instrumental variable (IV) analyses are becoming common in health services research and epidemiology. IV analyses can be used both to analyze randomized trials with noncompliance and as a form of natural experiment. In these analyses, investigators often adopt a monotonicity assumption, which implies that the relevant effect only applies to a subset of the study population known as compliers. Since the estimated effect is not the average treatment effect of the study population, it is important to compare the characteristics of compliers and non-compliers. Profiling compliers and non-compliers is necessary to understand what subpopulation the researcher is making inferences about, and an important first step in evaluating the external validity (or lack thereof) of the IV estimate for compliers. Here, we discuss the assumptions necessary for profiling, which are weaker than the assumptions necessary for identifying the local average treatment effect if the instrument is randomly assigned. We then outline a simple and general method to characterize compliers and noncompliers using baseline covariates. Next, we extend current methods by deriving standard errors for these estimates. We demonstrate these methods using an IV known as tendency to operate (TTO) from health services research.

Surface mining has become a major method of coal mining in Central Appalachia alongside the traditional underground mining. Concerns have been raised about the health effects of this surface mining, particularly mountaintop removal mining where coal is mined upon steep mountaintops by removing the mountaintop through clearcutting forests and explosives. We have designed a matched observational study to assess the effects of surface mining in Central Appalachia on adverse birth outcomes. This protocol describes for the study the background and motivation, the sample selection and the analysis plan.

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 outcomes relative to the treated units exhibit a negative correlation, and achieves partial identification of the average treatment effect for the treated. The identified set is of a union bounds form that involves the minimum and maximum operators, which makes the canonical bootstrap generally inconsistent and naive methods overly conservative. By utilizing the directional inconsistency of the bootstrap distribution, we develop a novel bootstrap method to construct uniformly valid confidence intervals for the identified set and parameter of interest when the identified set is of a union bounds form, and we establish the method's theoretical properties. We develop a simple falsification test and sensitivity analysis. We apply the proposed strategy for bracketing to study whether minimum wage laws affect employment levels.

Applied analysts often use the differences-in-differences (DID) method to estimate the causal effect of policy interventions with observational data. The method is widely used, as the required before and after comparison of a treated and control group is commonly encountered in practice. DID removes bias from unobserved time-invariant confounders. While DID removes bias from time-invariant confounders, bias from time-varying confounders may be present. Hence, like any observational comparison, DID studies remain susceptible to bias from hidden confounders. Here, we develop a method of sensitivity analysis that allows investigators to quantify the amount of bias necessary to change a study's conclusions. Our method operates within a matched design that removes bias from observed baseline covariates. We develop methods for both binary and continuous outcomes. We then apply our methods to two different empirical examples from the social sciences. In the first application, we study the effect of changes to disability payments in Germany. In the second, we re-examine whether election day registration increased turnout in Wisconsin.

Cluster randomized trials (CRTs) are popular in public health and in the social sciences to evaluate a new treatment or policy where the new policy is randomly allocated to clusters of units rather than individual units. CRTs often feature both noncompliance, when individuals within a cluster are not exposed to the intervention, and individuals within a cluster may influence each other through treatment spillovers where those who comply with the new policy may affect the outcomes of those who do not. Here, we study the identification of causal effects in CRTs when both noncompliance and treatment spillovers are present. We prove that the standard analysis of CRT data with noncompliance using instrumental variables does not identify the usual complier average causal effect when treatment spillovers are present. We extend this result and show that no analysis of CRT data can unbiasedly estimate local network causal effects. Finally, we develop bounds for these causal effects under the assumption that the treatment is not harmful compared to the control. We demonstrate these results with an empirical study of a deworming intervention in Kenya.

In observational studies of treatment effects, matched samples are created so treated and control groups are similar in terms of observable covariates. Traditionally such matched samples consist of matched pairs. If a pair match fails to make treated and control units sufficiently comparable, alternative forms of matching may be necessary. One general strategy to improve balance is to match a variable number of control units to each treated unit. A more tailored strategy is to adopt a fine balance constraint. Under a fine balance constraint, a nominal covariate is exactly balanced, but it does not require individually matched treated and control subjects for this variable. In the example, we seek to construct a matched sample for an ongoing evaluation of Peer Health Exchange, an intervention in schools designed to decrease risky health behaviors among youth. We find that an optimal pair match that minimizes distances between pairs creates a matched sample where balance is poor. Here we propose a method to allow for fine balance constraints when each treated unit is matched to a variable number of control units, which is not currently possible using existing matching algorithms. Our approach uses the entire number to first determine the optimal number of controls for each treated unit. For each strata of matched treated units, we can then apply a fine balance constraint. We then demonstrate that a matched sample for the evaluation of the Peer Health Exchange based on a variable number of controls and fine balance constraint is superior to simply using a variable-ratio match., Comment: 30 pages, 2 figures