Variance estimation for the average treatment effects on the treated and on the controls

Common causal estimands include the average treatment effect (ATE), the average treatment effect of the treated (ATT), and the average treatment effect on the controls (ATC). Using augmented inverse probability weighting methods, parametric models are judiciously leveraged to yield doubly robust estimators, i.e., estimators that are consistent when at least one the parametric models is correctly specified. Three sources of uncertainty are associated when we evaluate these estimators and their variances, i.e., when we estimate the treatment and outcome regression models as well as the desired treatment effect. In this paper, we propose methods to calculate the variance of the normalized, doubly robust ATT and ATC estimators and investigate their finite sample properties. We consider both the asymptotic sandwich variance estimation, the standard bootstrap as well as two wild bootstrap methods. For the asymptotic approximations, we incorporate the aforementioned uncertainties via estimating equations. Moreover, unlike the standard bootstrap procedures, the proposed wild bootstrap methods use perturbations of the influence functions of the estimators through independently distributed random variables. We conduct an extensive simulation study where we vary the heterogeneity of the treatment effect as well as the proportion of participants assigned to the active treatment group. We illustrate the methods using an observational study of critical ill patients on the use of right heart catherization

Shock Index Predicts Patient‐Related Clinical Outcomes in Stroke

The Get With The Guidelines–Stroke (GWTG-Stroke) program is currently supported in part by a charitable contribution from Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership and the American Heart Association Pharmaceutical Roundtable. GWTG-Stroke has been funded in the past through support from Boehringer-Ingelheim and Merck. These funding agencies did not participate in the design or analysis, article preparation, or approval of this study.Peer reviewedPublisher PD

Shock Index Predicts Patient‐Related Clinical Outcomes in Stroke

The Get With The Guidelines–Stroke (GWTG-Stroke) program is currently supported in part by a charitable contribution from Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership and the American Heart Association Pharmaceutical Roundtable. GWTG-Stroke has been funded in the past through support from Boehringer-Ingelheim and Merck. These funding agencies did not participate in the design or analysis, article preparation, or approval of this study.Peer reviewedPublisher PD

Inhibition of the NFAT pathway alleviates amyloid β neurotoxicity in a mouse model of Alzheimer's disease

Amyloid β (Aβ) peptides, the main pathological species associated with Alzheimer’s disease (AD), disturb intracellular calcium homeostasis, which in turn activates the calcium-dependent phosphatase calcineurin (CaN). CaN activation induced by Aβ leads to pathological morphological changes in neurons, and overexpression of constitutively active calcineurin is sufficient to generate a similar phenotype, even without Aβ. Here, we tested the hypothesis that calcineurin mediates neurodegenerative effects via activation of the nuclear transcription factor of activated T-cells (NFAT). We found that both spine loss and dendritic branching simplification induced by Aβ exposure were mimicked by constitutively active NFAT, and abolished when NFAT activation was blocked using the genetically encoded inhibitor VIVIT. When VIVIT was specifically addressed to the nucleus, identical beneficial effects were observed, thus enforcing the role of NFAT transcriptional activity in Aβ-related neurotoxicity. In vivo, when VIVIT or its nuclear counterpart were overexpressed in a transgenic model of Alzheimer’s disease via a gene therapy approach, the spine loss and neuritic abnormalities observed in the vicinity of amyloid plaques were blocked. Overall, these results suggest that NFAT/calcineurin transcriptional cascades contribute to Aβ synaptotoxicity, and may provide a new specific set of pathways for neuroprotective strategies

Temporal Trends in Care and Outcomes of Patients Receiving Fibrinolytic Therapy Compared to Primary Percutaneous Coronary Intervention: Insights From the Get With The Guidelines Coronary Artery Disease (GWTG‐CAD) Registry

Background: Timely reperfusion after ST‐elevation myocardial infarction (STEMI) improves survival. Guidelines recommend primary percutaneous coronary intervention (PPCI) within 90 minutes of arrival at a PCI‐capable hospital. The alternative is fibrinolysis within 30 minutes for those in those for whom timely transfer to a PCI‐capable hospital is not feasible. Methods and Results: We identified STEMI patients receiving reperfusion therapy at 229 hospitals participating in the Get With the Guidelines—Coronary Artery Disease (GWTG‐CAD) database (January 1, 2003 through December 31, 2008). Temporal trends in the use of fibrinolysis and PPCI, its timeliness, and in‐hospital mortality outcomes were assessed. We also assessed predictors of fibrinolysis versus PPCI and compliance with performance measures. Defect‐free care was defined as 100% compliance with all performance measures. We identified 29 190 STEMI patients, of whom 2441 (8.4%) received fibrinolysis; 38.2% of these patients achieved door‐to‐needle times ≤30 minutes. Median door‐to‐needle times increased from 36 to 60 minutes (P=0.005) over the study period. Among PPCI patients, median door‐to‐balloon times decreased from 94 to 64 minutes (P<0.0001) over the same period. In‐hospital mortality was higher with fibrinolysis than with PPCI (4.6% vs 3.3%, P=0.001) and did not change significantly over time. Patients receiving fibrinolysis were less likely to receive defect‐free care compared with their PPCI counterparts. Conclusions: Use of fibrinolysis for STEMI has decreased over time with concomitant worsening of door‐to‐needle times. Over the same time period, use of PPCI increased with improvement in door‐to‐balloon times. In‐hospital mortality was higher with fibrinolysis than with PPCI. As reperfusion for STEMI continues to shift from fibrinolysis to PPCI, it will be critical to ensure that door‐to‐needle times and outcomes do not worsen

Overlap, matching, or entropy weights: what are we weighting for?

There has been a recent surge in statistical methods for handling the lack of adequate positivity when using inverse probability weights (IPW). However, these nascent developments have raised a number of questions. Thus, we demonstrate the ability of equipoise estimators (overlap, matching, and entropy weights) to handle the lack of positivity. Compared to IPW, the equipoise estimators have been shown to be flexible and easy to interpret. However, promoting their wide use requires that researchers know clearly why, when to apply them and what to expect. In this paper, we provide the rationale to use these estimators to achieve robust results. We specifically look into the impact imbalances in treatment allocation can have on the positivity and, ultimately, on the estimates of the treatment effect. We zero into the typical pitfalls of the IPW estimator and its relationship with the estimators of the average treatment effect on the treated (ATT) and on the controls (ATC). Furthermore, we also compare IPW trimming to the equipoise estimators. We focus particularly on two key points: What fundamentally distinguishes their estimands? When should we expect similar results? Our findings are illustrated through Monte-Carlo simulation studies and a data example on healthcare expenditure.</p