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Reply to: Concern for the validity of short-term dietary crossover trials

Nature Medicine volume 31, pages 2915–2916 (2025)Cite this article

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The Original Article was published on 22 August 2025

replying to D. S. Ludwig et al. Nature Medicine https://doi.org/10.1038/s41591-025-03909-y (2025)

Human nutrition research is difficult. Observational epidemiological studies estimate associations between diet and health outcomes in large numbers of people, but the field is challenged by reverse causality, selection bias, weak effects, analytical flexibility and unmeasured or residual confounders that can result in spurious relationships between diet variables and health outcomes1. Outpatient randomized controlled trials of diet advice are often challenged by poor adherence to prescribed diets over the long time periods needed to observe differences in hard endpoints. Controlled feeding trials can study mechanisms and surrogate outcomes may and offer better diet adherence over short periods, but off-study food intake in outpatient studies can still amount to several hundred kcal per day2. By contrast, inpatient feeding studies have excellent diet adherence and high internal validity, but their external validity is compromised by artificial environments and short durations.

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Acknowledgements

I thank S. Senn for educating me about the problems with the two-stage procedure of analyzing crossover trials.

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  1. Unaffiliated, Kensington, MD, USA

    Kevin D. Hall

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  1. Kevin D. Hall
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Correspondence to Kevin D. Hall.

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Competing interests

I have engaged in public debates with D. S. Ludwig about the carbohydrate–insulin model of obesity. I declare no competing interests.

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Hall, K.D. Reply to: Concern for the validity of short-term dietary crossover trials. Nat Med 31, 2915–2916 (2025). https://doi.org/10.1038/s41591-025-03911-4

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