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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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
The cited source says what the claim attributes to it.
In the citing paper
“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.”
The cited source says what the claim attributes to it.
In the citing paper
“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].”
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
Modern Epidemiology 3rd edition
Rothman, K. J., Lash, T. L., & Greenland, S. (1986) · Cited by 1,736
Systematic Reviews in Health Care: Meta‐Analysis in Context
(2001) · doi:10.1002/9780470693926 · Cited by 1,693
Moher, D., Schulz, K. F., Altman, D. G., & for the CONSORT Group* (2001) · Annals of Internal Medicine · doi:10.7326/0003-4819-134-8-200104170-00011 · Cited by 1,426
Self-citationThe two‐period cross‐over clinical trial.
Hills, M., & Armitage, P. (1979) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1979.tb05903.x · Cited by 1,399
Variance imputation for overviews of clinical trials with continuous response
Follmann, D. A., Elliott, P., Suh, I., & Cutler, J. A. (1992) · Journal of Clinical Epidemiology · doi:10.1016/0895-4356(92)90054-q · Cited by 1,391
Review papers : The statistical basis of meta-analysis
Fleiss, J. (1993) · Statistical Methods in Medical Research · doi:10.1177/096228029300200202 · Cited by 1,286
15 Design and Analysis of Cross-Over Trials
Kenward, M. G., & Jones, B. C. (2007) · Handbook of statistics · doi:10.1016/s0169-7161(07)27015-4 · Cited by 873
The Two-Period Change-Over Design and Its Use in Clinical Trials
Grizzle, J. E. (1965) · Biometrics · doi:10.2307/2528104 · Cited by 784
Cross-Over Trials in Clinical Research
Senn, S. J. (1994) · Technometrics · doi:10.1080/00401706.1994.10485798 · Cited by 777
Design and Analysis of Cross-Over Trials
Jones, B. C., & Kenward, M. G. (1989) · Chapman & Hall/CRC eBooks · doi:10.4324/9780203009277 · Cited by 694
Content and quality of 2000 controlled trials in schizophrenia over 50 years
Thornley, B., & Adams, C. E. (1998) · BMJ · doi:10.1136/bmj.317.7167.1181 · Cited by 362
Anderson, J. H., Brunelle, R. L., Koivisto, V. A., Pfützner, A., TRAUTMANN, M. E., Vignati, L., & DiMarchi, R. D. (1997) · Diabetes · doi:10.2337/diab.46.2.265 · Cited by 331
People and eyes: statistical approaches in ophthalmology
Murdoch, I., Morris, S. S., & Cousens, S. (1998) · British Journal of Ophthalmology · doi:10.1136/bjo.82.8.971 · Cited by 322
The performance of the two‐stage analysis of two‐treatment, two‐period crossover trials
Freeman, P. R. (1989) · Statistics in Medicine · doi:10.1002/sim.4780081202 · Cited by 274
Brunelle, R. L., Llewelyn, J., Anderson, J. H., Gale, E. A. M., & Koivisto, V. A. (1998) · Diabetes Care · doi:10.2337/diacare.21.10.1726 · Cited by 216
Meta‐analysis combining parallel and cross‐over clinical trials. I: Continuous outcomes
Curtin, F., Altman, D. G., & Elbourne, D. R. (2002) · Statistics in Medicine · doi:10.1002/sim.1205 · Cited by 208
Self-citationValidation of a meta-analysis: The effects of fish oil in rheumatoid arthritis
Fortin, P. R., Lew, R., Liang, M. H., Wright, E. A., Beckett, L. A., Chalmers, T. C., & Sperling, R. I. (1995) · Journal of Clinical Epidemiology · doi:10.1016/0895-4356(95)00028-3 · Cited by 205
Statistical methods for the meta-analysis of cluster randomization trials
Donner, A. P., Piaggio, G. G., & Villar, J. (2001) · Statistical Methods in Medical Research · doi:10.1177/096228020101000502 · Cited by 159
Meta‐analysis combining parallel and cross‐over clinical trials. II: Binary outcomes
Curtin, F., Elbourne, D. R., & Altman, D. G. (2002) · Statistics in Medicine · doi:10.1002/sim.1206 · Cited by 127
Self-citationMeta‐analysis combining parallel and cross‐over clinical trials. III: The issue of carry‐over
Curtin, F., Elbourne, D. R., & Altman, D. G. (2002) · Statistics in Medicine · doi:10.1002/sim.1207 · Cited by 120
Self-citationDihydrocodeine for breathlessness in "pink puffers".
Johnson, M. A., Woodcock, A. A., & Geddes, D. M. (1983) · BMJ · doi:10.1136/bmj.286.6366.675 · Cited by 114
A review of randomised controlled trials published in Archives of Disease in Childhood from 1982-96
Campbell, H. J., Surry, S. A. M., & Royle, E. M. (1998) · Archives of Disease in Childhood · doi:10.1136/adc.79.2.192 · Cited by 82
Marginal Modeling of Binary Cross-Over Data
Becker, M. P., & Balagtas, C. C. (1993) · Biometrics · doi:10.2307/2532242 · Cited by 75
Therapeutic bioequivalency study of brand name versus generic carbamazepine
Oles, K. S., PENRY, J. K., Smith, L. D., Anderson, R. L., Dean, J. C., & Riela, A. R. (1992) · Neurology · doi:10.1212/wnl.42.6.1147 · Cited by 56
PATIENTS' PREFERENCE IN INDOMETHACIN TRIALS: AN OVERVIEW
Gotzsche, P. C. (1989) · The Lancet · doi:10.1016/s0140-6736(89)91439-6 · Cited by 36
Crossover or parallel design in infertility trials? The discussion continues
Cohlen, B., Velde, E. R. T., Looman, C. W. N., Eijckemans, R., & Habbema, J. D. F. (1998) · Fertility and Sterility · doi:10.1016/s0015-0282(98)00114-9 · Cited by 23
Outcome measures in split mouth caries trials and their statistical evaluation
Riordan, P. J., & FitzGerald, P. E. B. (1994) · Community Dentistry And Oral Epidemiology · doi:10.1111/j.1600-0528.1994.tb01839.x · Cited by 21
Daya, S. (1999) · Fertility and Sterility · doi:10.1016/s0015-0282(98)00495-6 · Cited by 10
Serum phenytoin levels with different brands.
Kishore, K., Bl, J., Sharma, J. N., & Gk, A. (1986) · PubMed · Cited by 9
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.
Cited by
Sorted by citations
Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gøtzsche, P. C., Ioannidis, J. P. A., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009) · PLoS Medicine · doi:10.1371/journal.pmed.1000100 · Cited by 28,164
“Standard deviations may have to be reconstructed from other statistics such as p-values and t statistics [115,116], or occasionally they may be imputed from the standard deviations observed in other studies [117].”
ResultSelf-citationCochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series
(2008) · doi:10.1002/9780470712184 · Cited by 25,048
Self-citationLiberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P. A., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009) · BMJ · doi:10.1136/bmj.b2700 · Cited by 17,648
Self-citationLiberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gøtzsche, P. C., Ioannidis, J. P. A., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2009.06.006 · Cited by 10,578
Self-citationLiberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gøtzsche, P. C., Ioannidis, J. P. A., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-151-4-200908180-00136 · Cited by 10,349
Self-citation
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
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
