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Regionalization of intensive care for premature infants refers to a triage system that directs mothers to hospitals with varying capabilities based on the risks their babies face. Given the limited capacity of highly specialized hospitals, understanding the impact of delivering premature infants at these facilities on infant mortality could facilitate the design of a more efficient perinatal regionalization system. To address this, Baiocchi et al. (2010) proposed strengthening a continuous instrumental variable (IV) in an IV-based matched-pair design by focusing on a smaller cohort that could be paired with a larger separation in the IV dose. Three elements changed with the strengthened IV: the study cohort, compliance rate and latent complier subgroup. Here, we introduce a non-bipartite, template matching algorithm that strengthens the IV while maintaining fidelity to the original study cohort. We then study randomization-based and IV dose-dependent, biased randomization-based inference for partial identification bounds of the sample average treatment effect. We found that delivering preterm babies at a high-level, as opposed to a low-level, hospital reduced infant mortality rate for 163, 532 mothers, whereas the treatment effect was minimal among a subgroup of non-black, low-risk mothers.

In many clinical settings, an active-controlled trial design (e.g., a non-inferiority or superiority design) is often used to compare an experimental medicine to an active control (e.g., an FDA-approved, standard therapy). One prominent example is a recent phase 3 efficacy trial, HIV Prevention Trials Network Study 084 (HPTN 084), comparing long-acting cabotegravir, a new HIV pre-exposure prophylaxis (PrEP) agent, to the FDA-approved daily oral tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) in a population of heterosexual women in 7 African countries. One key complication of interpreting study results in an active-controlled trial like HPTN 084 is that the placebo arm is not present and the efficacy of the active control (and hence the experimental drug) compared to the placebo can only be inferred by leveraging other data sources. In this article, we study statistical inference for the intention-to-treat (ITT) effect of the active control using relevant historical placebo-controlled trials data under the potential outcomes (PO) framework. We highlight the role of adherence and unmeasured confounding, discuss in detail identification assumptions and two modes of inference (point vs. partial identification), propose estimators under identification assumptions permitting point identification, and lay out sensitivity analyses needed to relax identification assumptions. We applied our framework to estimating the intention-to-treat effect of daily oral TDF/FTC versus placebo in HPTN 084 using data from an earlier Phase 3, placebo-controlled trial of daily oral TDF/FTC (Partners PrEP). Supplementary materials for this article are available online, including a standardized description of the materials available for reproducing the work.

Instrumental variables (IVs) are extensively used to estimate treatment effects when the treatment and outcome are confounded by unmeasured confounders; however, weak IVs are often encountered in empirical studies and may cause problems. Many studies have considered building a stronger IV from the original, possibly weak, IV in the design stage of a matched study at the cost of not using some of the samples in the analysis. It is widely accepted that strengthening an IV tends to render nonparametric tests more powerful and will increase the power of sensitivity analyses in large samples. In this article, we re-evaluate this conventional wisdom to bring new insights into this topic. We consider matched observational studies from three perspectives. First, we evaluate the trade-off between IV strength and sample size on nonparametric tests assuming the IV is valid and exhibit conditions under which strengthening an IV increases power and conversely conditions under which it decreases power. Second, we derive a necessary condition for a valid sensitivity analysis model with continuous doses. We show that the Γ sensitivity analysis model, which has been previously used to come to the conclusion that strengthening an IV increases the power of sensitivity analyses in large samples, does not apply to the continuous IV setting and thus this previously reached conclusion may be invalid. Third, we quantify the bias of the Wald estimator with a possibly invalid IV under an oracle and leverage it to develop a valid sensitivity analysis framework; under this framework, we show that strengthening an IV may amplify or mitigate the bias of the estimator, and may or may not increase the power of sensitivity analyses. We also discuss how to better adjust for the observed covariates when building an IV in matched studies.

Multivariate matching has two goals: (i) to construct treated and control groups that have similar distributions of observed covariates, and (ii) to produce matched pairs or sets that are homogeneous in a few key covariates. When there are only a few binary covariates, both goals may be achieved by matching exactly for these few covariates. Commonly, however, there are many covariates, so goals (i) and (ii) come apart, and must be achieved by different means. As is also true in a randomized experiment, similar distributions can be achieved for a high-dimensional covariate, but close pairs can be achieved for only a few covariates. We introduce a new polynomial-time method for achieving both goals that substantially generalizes several existing methods; in particular, it can minimize the earthmover distance between two marginal distributions. The method involves minimum cost flow optimization in a network built around a tripartite graph, unlike the usual network built around a bipartite graph. In the tripartite graph, treated subjects appear twice, on the far left and the far right, with controls sandwiched between them, and efforts to balance covariates are represented on the right, while efforts to find close individual pairs are represented on the left. In this way, the two efforts may be pursued simultaneously without conflict. The method is applied to our on-going study in the Medicare population of the relationship between superior nursing and sepsis mortality. The match2C package in R implements the method.

Subclassification and matching are often used to adjust for observed covariates in observational studies; however, they are largely restricted to relatively simple study designs with a binary treatment. One important exception is Lu et al.(2001), who considered optimal pair matching with a continuous treatment dose. In this article, we propose two criteria for optimal subclassification/full matching based on subclass homogeneity with a continuous treatment dose, and propose an efficient polynomial-time algorithm that is guaranteed to find an optimal subclassification with respect to one criterion and serves as a 2-approximation algorithm for the other criterion. We discuss how to incorporate treatment dose and use appropriate penalties to control the number of subclasses in the design. Via extensive simulations, we systematically examine the performance of our proposed method, and demonstrate that combining our proposed subclassification scheme with regression adjustment helps reduce model dependence for parametric causal inference with a continuous treatment dose. We illustrate the new design and how to conduct randomization-based statistical inference under the new design using Medicare and Medicaid claims data to study the effect of transesophageal echocardiography (TEE) during CABG surgery on patients' 30-day mortality rate.

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 problem. We then extend the IV-optimality framework to tackle the policy improvement problem, delivering IV-improved DTRs that are guaranteed to perform no worse and potentially better than a pre-specified baseline DTR. Importantly, our IV-improvement framework opens up the possibility of strictly improving upon DTRs that are optimal under the no unmeasured confounding assumption (NUCA). We demonstrate via extensive simulations the superior performance of IV-optimal and IV-improved DTRs over the DTRs that are optimal only under the NUCA. In a real data example, we embed retrospective observational registry data into a natural, two-stage experiment with noncompliance using a time-varying IV and estimate useful IV-optimal DTRs that assign mothers to high-level or low-level neonatal intensive care units based on their prognostic variables.

Social distancing is widely acknowledged as an effective public health policy combating the novel coronavirus. But extreme forms of social distancing like isolation and quarantine have costs and it is not clear how much social distancing is needed to achieve public health effects. In this article, we develop a design-based framework to test the causal null hypothesis and make inference about the dose-response relationship between reduction in social mobility and COVID-19 related public health outcomes. We first discuss how to embed observational data with a time-independent, continuous treatment dose into an approximate randomized experiment, and develop a randomization-based procedure that tests if a structured dose-response relationship fits the data. We then generalize the design and testing procedure to accommodate a time-dependent treatment dose in a longitudinal setting. Finally, we apply the proposed design and testing procedures to investigate the effect of social distancing during the phased reopening in the United States on public health outcomes using data compiled from sources including Unacast, the United States Census Bureau, and the County Health Rankings and Roadmaps Program. We rejected a primary analysis null hypothesis that stated the social distancing from April 27, 2020, to June 28, 2020, had no effect on the COVID-19-related death toll from June 29, 2020, to August 2, 2020 (p-value < 0.001), and found that it took more reduction in mobility to prevent exponential growth in case numbers for non-rural counties compared to rural counties.

One central goal of design of observational studies is to embed non-experimental data into an approximate randomized controlled trial using statistical matching. Researchers then make the randomization assumption in their downstream, outcome analysis. For matched pair design, the randomization assumption states that the treatment assignment across all matched pairs are independent, and that the probability of the first subject in each pair receiving treatment and the other control is the same as the first receiving control and the other treatment. In this article, we develop a novel framework for testing the randomization assumption based on solving a clustering problem with side-information using modern statistical learning tools. Our testing framework is nonparametric, finite-sample exact, and distinct from previous proposals in that it can be used to test a relaxed version of the randomization assumption called the biased randomization assumption. One important by-product of our testing framework is a quantity called residual sensitivity value (RSV), which quantifies the level of minimal residual confounding due to observed covariates not being well matched. We advocate taking into account RSV in the downstream primary analysis. The proposed methodology is illustrated by re-examining a famous observational study concerning the effect of right heart catheterization (RHC) in the initial care of critically ill patients.

Nearly 150,000 patients undergo open cardiac valve or aortic surgery each year in the US. Intraoperative transesophageal echocardiography (TEE) is used frequently during cardiac surgery, but there is a lack of evidence associating TEE use to improved clinical outcomes. This matched, retrospective cohort study used national registry data from the Society of Thoracic Surgeon (STS), Adult Cardiac Surgery Database (ACSD) between 2011–2019 to compare clinical outcomes among patients undergoing cardiac valve or aortic surgery with vs without intraoperative TEE. Statistical analyses consisted of multiple matched comparisons (including within-hospital and within-surgeon matches), a negative control outcome analysis, and sensitivity analyses.

The systolic, diastolic, and mean CBFVs and Windkessel notch explain more than 98% of total TCD data variation. Statistical learning algorithm identified 7 phenotypic clusters for the MCA TCD data.Phenotypic clusters are not associated with demographics, clinical features or laboratory measurements. TCD measurements are associated with survival hazards rates after adjusting for age and gender.