The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
Meta-analyses involving cross-over trials: methodological issues
Abstract
BACKGROUND: Meta-analysis of randomized controlled trials (RCTs) is usually based on trials where patients are randomized individually into two different, parallel, treatment groups. This paper concentrates on RCTs of a different design-two-period, two-treatment cross-over trials. METHODS: The characteristics of these trials are outlined, with detailed examples of methods for analysis for both continuous and binary data. These case studies are then extended into the context of a meta-analysis. The Cochrane Library was surveyed to assess current practice for synthesis. RESULTS: Methods are described for continuous and binary data for use both when the necessary paired data are given and also when they need to be calculated or imputed, and some suggestions are provided to help people wishing to synthesize data from cross-over trials into meta-analyses. The survey suggested that about 8% of the trials in the Cochrane library were cross-over trials and 18% of the reviews referred to such trials, although there was no consistent approach to their inclusion into the reviews. CONCLUSIONS: Methods do exist for including valuable information from two-period, two-treatment cross-over trials into quantitative reviews. However, poor reporting of cross-over trials will often impede attempts to perform a meta-analysis using the available methods.
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“In such cases, a conservative correlation value of 0.5 is commonly used (80).”
From Carbohydrate ingestion during prolonged exercise and net skeletal muscle glycogen utilization: A meta-analysis. (2026) · cites this paper as [80]
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“Since all included studies utilised a cross-over design, dependency was accounted for when computing sampling variance using previously described methods [49].”
From The effect of caffeine on subsequent sleep: A systematic review and meta-analysis (2023) · cites this paper as [49]
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“cross-over trials are not appropriate if the condition of interest is unstable (Elbourne 2002).”
From Compulsory community and involuntary outpatient treatment for people with severe mental disorders. (2017) · cites this paper as Elbourne 2002
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“For the implementation of cross-over trials in the meta-analysis, we used the method according to Becker/Balagtas [34]. This method ensures that no participants were counted double in the meta-analysis.”
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“In order to include cross-over trials in our trials using the method by Becker/Balagtas, OR was used to provide a stable effects measure [34].”
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“Non-daily vs. daily statin dosing resulted in an OR of 0.58 (95% CI 0.23–1.43). [34,51,52].”
From Safety outcomes of statin vs non-statin lipid-lowering interventions in patients with prior statin-associated muscle symptoms: A systematic review and meta-analysis (2025) · cites this paper as [34]
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3 retracted
Guided tissue regeneration for periodontal infra-bony defects
Needleman, I. G., Worthington, H. V., Giedrys‐Leeper, E., & Tucker, R. (2006) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001724.pub2 · Cited by 372
Self-citationRetractedOpioids for the palliation of breathlessness in advanced disease and terminal illness.
Jennings, A. L., Davies, A. N., Higgins, J. P. T., Anzures‐Cabrera, J., & Broadley, K. E. (2001) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002066 · Cited by 190
Self-citationRetractedDehydroepiandrosterone (DHEA) supplementation for cognitive function.
Huppert, F., & Van Niekerk, J. (2001) · The Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000304 · Cited by 88
RetractedWasserman, S. S., Hedges, L. V., & Olkin, I. (1988) · Journal of Educational Statistics · doi:10.2307/1164953 · Cited by 10,377
Moher, D., Schulz, K. F., & Altman, D. G. (2001) · The Lancet · doi:10.1016/s0140-6736(00)04337-3 · Cited by 5,373
Self-citationSystematic Reviews in Health Care : Meta-Analysis in Context
Egger, M., Smith, G. D., & Altman, D. G. (2000) · Cited by 2,312
Self-citationDeeks, J. J., Altman, D. G., & Bradburn, M. J. (2001) · Systematic Reviews in Health Care · doi:10.1002/9780470693926.ch15 · Cited by 2,163
Self-citationSmithson, M. J. (2000) · SAGE Publications Ltd eBooks · doi:10.4135/9781446218525 · Cited by 1,871
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Flagged first, then by citations
Research works printed but not linked: 5
- Daya S. Differences between crossover and parallel study designs—debate? Fertil Steril1999;71:771–72.
- Morris JA, Gardner MJ. Epidemiological studies. In: Altman DG, Machin D, Bryant TN, Gardner MJ (eds). Statistics with Confidence. 2nd Edn. London: BMJ Books, 2000, pp.57–72.
- Jennings AL, Davies A, Higgins JPT, Broadley K. Opioids for the palliation of breathlessness in terminal illness (Cochrane review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, 2001.
- Cochrane Collaboration. The Cochrane Library. Issue 1. Oxford: Update Software, 2001.
- Smyth A, Walters S. Prophylactic antibiotics for cystic fibrosis (Cochrane Review). In: The Cochrane Library, Issue 1, 2001. Oxford: Update Software. Updated quarterly.
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Treatment for inclusion body myositis
Rose, M. R., Jones, K. L., Leong, K. M. W., Walter, M. C., Miller, J. A. L., Dalakas, M. C., Brassington, R., & Griggs, R. C. (2015) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001555.pub5 · Cited by 30
Morita therapy for anxiety disorders in adults
Wu, H., Yu, D., He, Y., Wang, J., Xiao, Z., & Li, C. (2015) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd008619.pub2 · Cited by 23
Wolever, T. M., Zurbau, A., Koecher, K., & Au-Yeung, F. (2024) · The Journal of Nutrition · doi:10.1016/j.tjnut.2024.07.011 · Cited by 18
A systematic review and meta-analysis of the acute effect of caffeine on attention
Kløve, K., & Petersen, A. (2025) · Psychopharmacology · doi:10.1007/s00213-025-06775-1 · Cited by 10
Rothschild, J. A., Dudley-Rode, H., Carpenter, H., Smith, A. S. M., Plews, D. J., & Maunder, E. (2026) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00861.2025 · Cited by 10
Horticultural therapy for schizophrenia
Roberts, S., & Bradley, A. J. (2011) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd009413 · Cited by 4
Aebi, P. S., Villoz, F., Bührer, J., Lyko, C., Abolhassani, N., Del Giovane, C., Gencer, B., Rodondi, N., & Blum, M. R. (2025) · PLOS One · doi:10.1371/journal.pone.0338575
“For the implementation of cross-over trials in the meta-analysis, we used the method according to Becker/Balagtas [34].”
Metadata
- Authors
- Elbourne, D. R., Altman, D. G., Higgins, J. P., Curtin, F., Worthington, H. V., & Vail, A.
- Affiliations
- London School of Hygiene & Tropical Medicine (GB)
- Merck KGaA, Darmstadt (Germany) (DE)
- University Dental Hospital of Manchester (GB)
- Salford Royal Hospital (GB)
- Corresponding author
- Elbourne, Diana R
- Venue
- International Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-02
- Volume
- 31
- Issue
- 1
- Pages
- 140-149
- ISSN
- 0300-5771 (ISSN-L)
- 1464-3685
- OpenAlex
- W2130235475
- Cited by
- 2,305
- References
- 37
- Citations by year
- 2026: 58 · 2025: 58 · 2024: 72 · 2023: 87 · 2022: 116 · 2021: 129 · 2020: 107 · 2019: 111 · 2018: 128 · 2017: 131 · 2016: 145 · 2015: 147 · 2014: 174 · 2013: 135 · 2012: 144
- FWCI
- 47.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Medical Research Council
- Topics
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
- Keywords
- crossover trial, meta-analysis, randomized controlled trials, continuous data, binary data, missing data imputation, trial reporting quality, Cochrane Library
- MeSH terms
- Humans, Review Literature as Topic, Meta-Analysis as Topic, Randomized Controlled Trials as Topic, Cross-Over Studies
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