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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A conservative correlation value of 0.5 is commonly used for within-subject designs when prepost correlation is unavailable.
“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]
The section ‘A meta-analysis of cross-over trials with continuous data’ describes assuming a correlation when paired results are unavailable, but its example uses 0.68, not 0.5. The same section says baseline-to-post-treatment correlations are often greater than 0.5; it does not say that 0.5 is a commonly used conservative assumption. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDependency was accounted for when computing sampling variance using previously described methods.
“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]
Cross-over trials are not appropriate if the condition of interest is unstable.
“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
For cross-over trials, the Becker/Balagtas method was used, ensuring no participants were counted double in the meta-analysis.
“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.”
In order to include cross-over trials using the method by Becker/Balagtas, OR was used to provide a stable effects measure.
“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].”
Non-daily vs. daily statin dosing resulted in an odds ratio of 0.58 (95% CI 0.23-1.43) for incidence of muscle symptoms.
“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]
The section on cross-over trials with binary data reports odds ratios for severe hypoglycaemia with insulin lispro versus regular insulin, not muscle symptoms with non-daily versus daily statin dosing. Searches for statin dosing, muscle symptoms, and the stated OR and confidence interval found no passage addressing the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measured
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Bisphosphonate therapy for osteogenesis imperfecta
Dwan, K. M., Phillipi, C. A., Steiner, R. D., & Basel, D. (2016) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd005088.pub4 · Cited by 427 · see citing works
E-learning for health professionals
Vaona, A., Banzi, R., Kwag, K. H., Rigon, G., Cereda, D., Pecoraro, V. L., Tramacere, I., & Moja, L. (2018) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011736.pub2 · Cited by 406 · see citing works
Pit and fissure sealants for preventing dental decay in permanent teeth
Ahovuo-Saloranta, A., Forss, H., Walsh, T., Nordblad, A., Mäkelä, M., & Worthington, H. V. (2017) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001830.pub5 · Cited by 391 · see citing works
Self-citationPowered versus manual toothbrushing for oral health
Yaacob, M., Worthington, H. V., Deacon, S. A., Deery, C., Walmsley, A. D., Robinson, P. G., & Glenny, A.-M. (2014) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002281.pub3 · Cited by 374 · see citing works
Self-citationPregabalin for neuropathic pain in adults
Derry, S., Bell, R. F., Straube, S., Wiffen, P. J., Aldington, D. J., & Moore, A. (2019) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd007076.pub3 · Cited by 386 · see citing works
“Evidence” in chronic pain–establishing best practice in the reporting of systematic reviews
Moore, A. R., Eccleston, C., Derry, S., Wiffen, P., Bell, R. F., Straube, S., & McQuay, H. (2010) · Pain · doi:10.1016/j.pain.2010.05.011 · Cited by 370 · see citing works
Abumweis, S., Barake, R., & Jones, P. (2008) · Food & Nutrition Research · doi:10.3402/fnr.v52i0.1811 · Cited by 369 · see citing works
Enamel matrix derivative (Emdogain®) for periodontal tissue regeneration in intrabony defects
Esposito, M. A., Grusovin, M. G., Papanikolaou, N., Coulthard, P., & Worthington, H. V. (2009) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003875.pub3 · Cited by 367 · see citing works
Self-citationSimon, S. T., Higginson, I. J., Booth, S., Harding, R., Weingärtner, V., & Bausewein, C. (2016) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd007354.pub3 · Cited by 367 · see citing works
Olanzapine versus other atypical antipsychotics for schizophrenia
Komossa, K., Rummel‐Kluge, C., Hunger, H., Schmid, F., Schwarz, S., Duggan, L., Kissling, W., & Leucht, S. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006654.pub2 · Cited by 366 · see citing works
Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators
Tfelt‐Hansen, P. C., Pascual, J., Ramadan, N. M., Dahlöf, C. G. H., D’Amico, D., Diener, H.-C., Hansen, J. M., Lantéri‐Minet, M., Loder, E., McCrory, D. C., et al. (2012) · Cephalalgia · doi:10.1177/0333102411417901 · Cited by 365 · see citing works
Cairo, F., Nieri, M., & Pagliaro, U. (2014) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.12182 · Cited by 365 · see citing works
Meta‐analysis of the relationship between breaks in sedentary behavior and cardiometabolic health
Chastin, S. F. M., Egerton, T., Leask, C., & Stamatakis, E. (2015) · Obesity · doi:10.1002/oby.21180 · Cited by 363 · see citing works
Operative caries management in adults and children
Ricketts, D., Lamont, T., Innes, N., Kidd, E., & Clarkson, J. (2013) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003808.pub3 · Cited by 363 · see citing works
RetractedBratton, D. J., Gaisl, T., Wons, A. M., & Kohler, M. (2015) · JAMA · doi:10.1001/jama.2015.16303 · Cited by 362 · see citing works
Esposito, M. A., Grusovin, M. G., Coulthard, P., & Worthington, H. V. (2006) · PubMed · Cited by 358 · see citing works
Self-citationEffects and safety of periconceptional folate supplementation for preventing birth defects
De-Regil, L. M., Fernández-Gaxiola, A. C., Dowswell, T., & Peña-Rosas, J. P. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd007950.pub2 · Cited by 358 · see citing works
The effects of green exercise on physical and mental wellbeing: a systematic review
Lahart, I., Darcy, P., Gidlow, C., & Calogiuri, G. (2019) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph16081352 · Cited by 353 · see citing works
Music therapy for people with schizophrenia and schizophrenia-like disorders
Geretsegger, M., Mössler, K. A., Bieleninik, Ł., Chen, X., Heldal, T. O., & Gold, C. (2017) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004025.pub4 · Cited by 357 · see citing works
Bellenger, C. R., FULLER, J. T., Thomson, R. L., Davison, K., Robertson, E. Y., & Buckley, J. D. (2016) · Sports Medicine · doi:10.1007/s40279-016-0484-2 · Cited by 362 · see citing works
Wang, F., Zheng, J., Yang, B., Jiang, J., Fu, Y., & Li, D. (2015) · Journal of the American Heart Association · doi:10.1161/jaha.115.002408 · Cited by 340 · see citing works
Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)
Storebø, O. J., Ramstad, E., Krogh, H. B., Nilausen, T. D., Skoog, M., Holmskov, M., Rosendal, S., Groth, C., Magnusson, F. L., Moreira-Maia, C. R., et al. (2015) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd009885.pub2 · Cited by 347 · see citing works
Herbison, P., Hay-Smith, J. E., Ellis, G., & Moore, K. (2003) · BMJ · doi:10.1136/bmj.326.7394.841 · Cited by 335 · see citing works
Jones, A., Lemma, L. C. G. D., Robinson, E., Christiansen, P., Nevitt, S. J., Smith, C. T., & Field, M. (2015) · Appetite · doi:10.1016/j.appet.2015.11.013 · Cited by 332 · see citing works
Sealants for preventing dental decay in the permanent teeth
Ahovuo-Saloranta, A., FORSS, H., Walsh, T., Hiiri, A., Nordblad, A., Mākelä, M., & Worthington, H. V. (2013) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001830.pub4 · Cited by 335 · see citing works
Self-citationClozapine versus typical neuroleptic medication for schizophrenia
Essali, A., Hasan, N. A., Li, C., & Rathbone, J. (2009) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000059.pub2 · Cited by 326 · see citing works
Interventions for replacing missing teeth: augmentation procedures of the maxillary sinus
Esposito, M. A., Felice, P., & Worthington, H. V. (2014) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd008397.pub2 · Cited by 327 · see citing works
Self-citationDesign, analysis, and presentation of crossover trials
Mills, E. J., Chan, A., Wu, P., Vail, A., Guyatt, G. H., & Altman, D. G. (2009) · Trials · doi:10.1186/1745-6215-10-27 · Cited by 323 · see citing works
Self-citationCompulsory community and involuntary outpatient treatment for people with severe mental disorders
Kisely, S. R., & Campbell, L. A. (2014) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004408.pub4 · Cited by 320 · see citing works
Crisis intervention for people with severe mental illnesses
Murphy, S., Irving, C. B., Adams, C. E., & Waqar, M. U. (2015) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001087.pub5 · Cited by 321 · see citing works
External cephalic version for breech presentation before term
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Dimidi, E., Christodoulides, S., Fragkos, K. C., Scott, S. M., & Whelan, K. (2014) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.089151 · Cited by 316 · see citing works
The effect of caffeine on subsequent sleep: A systematic review and meta-analysis
Gardiner, C., Weakley, J., Burke, L. M., Roach, G. D., Sargent, C., Maniar, N., Townshend, A., & Halson, S. L. (2023) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2023.101764 · Cited by 315 · see citing works
“Since all included studies utilised a cross-over design, dependency was accounted for when computing sampling variance using previously described methods [49].”
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Citalopram versus other anti-depressive agents for depression
Cipriani, A., Purgato, M., Furukawa, T. A., Trespidi, C., Imperadore, G., Signoretti, A., Churchill, R. C., Watanabe, N., & Barbui, C. (2012) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006534.pub2 · Cited by 311 · see citing works
Psychosocial interventions for self-harm in adults
Hawton, K. E., Witt, K., Salisbury, T. T., Arensman, E., Gunnell, D., Hazell, P., Townsend, E., & van Heeringen, K. (2016) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd012189 · Cited by 314 · see citing works
Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis
Brown, J., Crawford, T. J., Allen, C., Hopewell, S., & Prentice, A. (2017) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004753.pub4 · Cited by 308 · see citing works
Hooren, B. V., FULLER, J. T., Buckley, J. D., Miller, J. R., Sewell, K. B., Rao, G., Barton, C. J., Bishop, C., & Willy, R. W. (2019) · Sports Medicine · doi:10.1007/s40279-019-01237-z · Cited by 306 · see citing works
Pharmacological interventions for borderline personality disorder
Stoffers, J., Völlm, B. A., Rücker, G., Timmer, A., Huband, N., & Lieb, K. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd005653.pub2 · Cited by 302 · see citing works
Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia
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Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults
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Nebulised hypertonic saline for cystic fibrosis
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Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease
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Effect of Fructose on Body Weight in Controlled Feeding Trials
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Music therapy for autistic spectrum disorder
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Gabapentin for chronic neuropathic pain and fibromyalgia in adults
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Newer generation antidepressants for depressive disorders in children and adolescents
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Self-citationChristensen, R., Lorenzen, J. K., Svith, C. R., Bartels, E. M., Melanson, E. L., Saris, W. H., Tremblay, A., & Astrup, A. (2009) · Obesity Reviews · doi:10.1111/j.1467-789x.2009.00599.x · Cited by 290 · see citing works
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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