A framework for the analysis of heterogeneity of treatment effect in patient-centered outcomes research

Abstract

Individuals vary in their response to a treatment. Understanding this heterogeneity of treatment effect is critical for evaluating how well a treatment can be expected to work for an individual or a subgroup of individuals. An overemphasis on hypothesis testing has resulted in a dichotomy of all heterogeneity of treatment effect analyses into confirmatory (hypothesis testing) and exploratory (hypothesis finding) analyses. This limited view of heterogeneity of treatment effect is inadequate for creating evidence that is useful for informing patient-centered decisions. An expanded framework for heterogeneity of treatment effect assessment is proposed. It recognizes four distinct goals of heterogeneity of treatment effect analyses: hypothesis testing, hypothesis finding, reporting subgroup effects for meta-analysis, and individual-level prediction. Accordingly, two new types of heterogeneity of treatment effect analyses are proposed: descriptive and predictive. Descriptive heterogeneity of treatment effect analyses report treatment effects for prespecified subgroups in accordance with prospectively specified analytic strategy. They need not be powered to detect heterogeneity of treatment effect. They emphasize estimation and reporting of subgroup effects rather than hypothesis testing. Sampling properties (e.g., standard error) of descriptive analysis can be characterized, thus facilitating meta-analysis of subgroup effects. Predictive heterogeneity of treatment effect analyses estimate probabilities of beneficial and adverse responses of individuals to treatments and facilitates optimal treatment decisions for different types of individuals. Procedures are also suggested to improve reliability of heterogeneity of treatment effect assessment from observational studies. Heterogeneity of treatment effect analysis should be identified as confirmatory, descriptive, exploratory, or predictive analysis. Evidence should be interpreted in a manner consistent with the analytic goal.