A unified Bayesian framework for interval hypothesis testing in clinical trials

The American Statistical Association (ASA) statement on statistical significance and P-values \cite{wasserstein2016asa} cautioned statisticians against making scientific decisions solely on the basis of traditional P-values. The statement delineated key issues with P-values, including a lack of transparency, an inability to quantify evidence in support of the null hypothesis, and an inability to measure the size of an effect or the importance of a result. In this article, we demonstrate that the interval null hypothesis framework (instead of the point null hypothesis framework), when used in tandem with Bayes factor-based tests, is instrumental in circumnavigating the key issues of P-values. Further, we note that specifying prior densities for Bayes factors is challenging and has been a reason for criticism of Bayesian hypothesis testing in existing literature. We address this by adapting Bayes factors directly based on common test statistics. We demonstrate, through numerical experiments and real data examples, that the proposed Bayesian interval hypothesis testing procedures can be calibrated to ensure frequentist error control while retaining their inherent interpretability. Finally, we illustrate the improved flexibility and applicability of the proposed methods by providing coherent frameworks for competitive landscape analysis and end-to-end Bayesian hypothesis tests in the context of reporting clinical trial outcomes.

When Doubly Robust Methods Meet Machine Learning for Estimating Treatment Effects from Real-World Data: A Comparative Study

Observational cohort studies are increasingly being used for comparative effectiveness research and to assess the safety of therapeutics. Recently, various doubly robust methods have been proposed for average treatment effect estimation by combining the treatment model and the outcome model via different vehicles, such as matching, weighting, and regression. The key advantage of the doubly robust estimators is that they require either the treatment model or the outcome model to be correctly specified to obtain a consistent estimator of the average treatment effect, and therefore lead to a more accurate and often more precise inference. However, little work has been done to understand how doubly robust estimators differ due to their unique strategies of using the treatment and outcome models and how machine learning techniques can be combined with these estimators to boost their performance. Also, little has been understood about the challenges of covariates selection, overlapping of the covariate distribution, and treatment effect heterogeneity on the performance of these doubly robust estimators. Here we examine multiple popular doubly robust methods in the categories of matching, weighting, or regression, and compare their performance using different treatment and outcome modeling via extensive simulations and a real-world application. We found that incorporating machine learning with doubly robust estimators such as the targeted maximum likelihood estimator outperforms. Practical guidance on how to apply doubly robust estimators is provided.