Methods and Applications of Statistics in Clinical Trials, Volume 2: Planning, Analysis, and Inferential Methods

Chapter 49

Subgroup Analysis

Richard M. Simon

49.1 Introduction

Subgroup analysis refers to the practice of attempting to determine whether and how treatment effects vary among subgroups of subjects who are studied in intervention studies. This article reviews the variety of statistical methods that have been used and developed for subgroup analyses and the criticisms that have been made of subgroup analyses. The article provides guidance for the conduct of subgroup analyses in a manner that limits the opportunity for misleading claims.

49.2 The Dilemma of Subgroup Analysis

Most clinical trials have as primary objective the evaluation of an intervention (treatment) relative to a control for a representative sample of patients who satisfy prospectively defined eligibility criteria. The evaluation is made with regard to a prospectively defined end point, that is, a measure of patient outcome. This experimental paradigm is frequently used for laboratory and observational studies. The focus on a single treatment effect is consistent with the Neyman–Pearson theory of hypothesis testing that is the general basis for analysis of such studies. Subgroup analysis, which is also called subset analysis, refers to examination of treatment effects in subgroups of study patients. For clinical trials, the subgroups should be defined based on baseline covariates measured before randomization.

Subgroup analysis is frequently observed in even the most prominent journals of medicine and science. Assmann ...