Understanding treatment response heterogeneity using crossover randomised controlled trials: A primer for exercise and nutrition scientists

Atkinson, G ORCID: 0000-0002-5459-9042 Understanding treatment response heterogeneity using crossover randomised controlled trials: A primer for exercise and nutrition scientists. International Journal of Sport Nutrition and Exercise Metabolism. ISSN 1526-484X (Accepted)

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Abstract

Crossover randomised controlled trials (RCT) are common in exercise and nutrition sciences. Since researchers randomise participants to different sequences of the treatment and comparator/control conditions, crossover RCTs are powerful for detecting mean treatment effects under certain circumstances. We aim to review the information that can be derived from crossover RCTs about treatment response heterogeneity - a fundamental issue in precision medicine for tailoring treatments to individuals. After covering the fundamental design issues, we describe the variance components that underlie observed data. The crucial person-by-treatment variance component can be quantified from a repeated or “replicate” crossover RCT by exposing participants to multiple cycles of trial conditions. As a type of n-of-1 trial, replicate crossover RCTs have important design and statistical power considerations, which we describe. By synthesising findings from our six published replicate crossover RCTs, we also compare various data analysis approaches. We find general agreement between these approaches, and a link between within-person consistency of response and the detection of person-by-treatment interactions. We postulate that a paired “variance comparison”, e.g., the Pitman-Morgan test, provides some preliminary information regarding response heterogeneity from a typical single-cycle crossover RCT. Nevertheless, underlying assumptions are critical, rendering these comparisons as merely exploratory until an n-of-1 or replicate crossover RCT is undertaken. Multiple-cycle n-of-1 trials and replicate crossover RCTs are underused but are informative for treatment response heterogeneity. However, these trials are still only one component of the process for predicting individual magnitude of response from any personal traits, which is the “holy grail” of personalised treatment.

Item Type:	Article
Additional Information:	Accepted author manuscript version reprinted, by permission, from International Journal of Sport Nutrition and Exercise Metabolism, 2025 (ahead of print). © Human Kinetics, Inc.
Uncontrolled Keywords:	1106 Human Movement and Sports Sciences; 1116 Medical Physiology; Sport Sciences; 3210 Nutrition and dietetics; 4207 Sports science and exercise
Subjects:	R Medicine > RC Internal medicine > RC1200 Sports Medicine
Divisions:	Sport and Exercise Sciences
Publisher:	Human Kinetics
Date of acceptance:	2 July 2025
Date Deposited:	03 Jul 2025 09:56
Last Modified:	03 Jul 2025 10:00
URI:	https://researchonline.ljmu.ac.uk/id/eprint/26713

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