Overview of modern approaches for identifying and evaluating heterogeneous treatment effects from clinical data

There has been much interest in the evaluation of heterogeneous treatment effects (HTE) and multiple statistical methods have emerged under the heading of personalized/precision medicine combining ideas from hypothesis testing, causal inference, and machine learning over the past 10-15 years. We discuss new ideas and approaches for evaluating HTE in randomized clinical trials and observational studies using the features introduced earlier by Lipkovich, Dmitrienko, and D’Agostino that distinguish principled methods from simplistic approaches to data-driven subgroup identification and estimating individual treatment effects and use a case study to illustrate these approaches. We identified and provided a high-level overview of several classes of modern statistical approaches for personalized/precision medicine, elucidated the underlying principles and challenges, and compared findings for a case study across different methods. Different approaches to evaluating HTEs may produce (and actually produced) highly disparate results when applied to a specific data set. Evaluating HTE with machine learning methods presents special challenges since most of machine learning algorithms are optimized for prediction rather than for estimating causal effects. An additional challenge is in that the output of machine learning methods is typically a “black box” that needs to be transformed into interpretable personalized solutions in order to gain acceptance and usability.