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Randomization, design and analysis for interdependency in aging research: no person or mouse is an island

Nature Aging volume 2, pages 1101–1111 (2022)Cite this article

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An Author Correction to this article was published on 24 January 2023

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Abstract

Investigators traditionally use randomized designs and corresponding analysis procedures to make causal inferences about the effects of interventions, assuming independence between an individual’s outcome and treatment assignment and the outcomes of other individuals in the study. Often, such independence may not hold. We provide examples of interdependency in model organism studies and human trials and group effects in aging research and then discuss methodologic issues and solutions. We group methodologic issues as they pertain to (1) single-stage individually randomized trials; (2) cluster-randomized controlled trials; (3) pseudo-cluster-randomized trials; (4) individually randomized group treatment; and (5) two-stage randomized designs. Although we present possible strategies for design and analysis to improve the rigor, accuracy and reproducibility of the science, we also acknowledge real-world constraints. Consequences of nonadherence, differential attrition or missing data, unintended exposure to multiple treatments and other practical realities can be reduced with careful planning, proper study designs and best practices.

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Acknowledgements

We thank N. Baidwan for contributions to an early version of the paper. This work was supported in part by the National Institute on Aging (grants P30 AG050886; U24 AG056053, K01 AG072615), the Gordon and Betty Moore Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases (grant P30 DK056336).

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Authors and Affiliations

  1. Department of Environmental and Occupational Health, Indiana University-Bloomington, Bloomington, IN, USA

    Daniella E. Chusyd

  2. Department of Biology, University of Alabama at Birmingham, Birmingham, AL, USA

    Steven N. Austad

  3. Nathan Shock Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Steven N. Austad & Daniel L. Smith Jr.

  4. Department of Epidemiology and Biostatistics, Indiana University-Bloomington, Bloomington, IN, USA

    Stephanie L. Dickinson, Keisuke Ejima, Lilian Golzarri-Arroyo, Yasaman Jamshidi-Naeini, Doug Landsittel, Arthur H. Owora, Javier Rojo, Pengcheng Xun, Roger Zoh & David B. Allison

  5. Departments of Statistics, Kansas State University, Manhattan, KS, USA

    Gary L. Gadbury

  6. Department of Health & Wellness Design, Indiana University-Bloomington, Bloomington, IN, USA

    Richard J. Holden

  7. Department of Family and Community Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Tapan Mehta

  8. Department of Quantitative Health Science, Case Western Reserve University, Cleveland, OH, USA

    J. Michael Oakes

  9. School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA

    Greg Pavela

  10. Department of Wildlife, Fisheries and Aquaculture, Mississippi State University, Starkville, MS, USA

    Michael W. Sandel

  11. Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA

    Daniel L. Smith Jr.

  12. Department of Applied Health Science, Indiana University-Bloomington, Bloomington, IN, USA

    Colby J. Vorland

  13. Department of Global Value, Access and Outcomes, Atara Biotherapeutics, Thousand Oaks, CA, USA

    Pengcheng Xun

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  1. Daniella E. Chusyd
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  2. Steven N. Austad
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  20. David B. Allison
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Contributions

D.B.A. conceived the original idea. D.E.C. managed and coordinated contributions from all co-authors. All co-authors contributed to the writing and editing of the manuscript.

Corresponding author

Correspondence to David B. Allison.

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Competing interests

P.X. is currently an employee and shareholder of Atara Biotherapeutics at submission. D.B.A. holds equity in one company (Big Sky) and he and his institutions (Indiana University and the Indiana University Foundation) have received grants, contracts, in-kind donations and consulting fees from numerous governmental agencies, non-profit organizations and for-profit organizations including litigators and dietary supplement, food, pharmaceutical, medical device and publishing companies; however, not funded nor are directly relevant to the topic herein. All other authors declare no competing interests.

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Chusyd, D.E., Austad, S.N., Dickinson, S.L. et al. Randomization, design and analysis for interdependency in aging research: no person or mouse is an island. Nat Aging 2, 1101–1111 (2022). https://doi.org/10.1038/s43587-022-00333-6

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