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Split-mouth studies and Split-mouth studies and systematic reviewssystematic reviews
Ian Needleman1 & Helen Worthington2
1Unit of PeriodontologyUCL Eastman Dental Institute
International Centre for Evidence-Based Oral Health, London UK
2School of Dentistry, University of Manchester, UK
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Split-mouth studies and systematic reviews
• What is the issue?• Why include them?• How to include them• Examples
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Split-mouth studies and systematic reviews – the analysis issue
• As we know, the analysis of split-mouth and parallel group studies is not the same.
• As a result, if a meta-analysis includes both types of trials without considering the differences, the result might be unreliable
• The confidence interval will be incorrect, possibly leading to;– An inappropriate conclusion on clinical
importance (and statistical significance)– Distortion of impact of clinical heterogeneity
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Why include split-mouth studies in systematic reviews?
• Because of the totality of the evidence• Possible advantages of split-mouth trials
over parallel group;– Each participant acts as own control– Therefore, fewer participants are required to
obtain same study power as parallel group– Every participant receives each intervention,
therefore good for determining preferences
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How to include split-mouth studies in systematic reviews
Designing the systematic review: • Is split-mouth an appropriate design
to answer this question? • Are carry-over effects a risk?
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How to include split-mouth studies in systematic reviews
Conducting the systematic review: • Fundamental question: Is meta-
analysis justified in principle?• Are the trials similar enough in chief
characteristics:– Types of populations– Types of interventions– Types of outcomes
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How to include split-mouth studies in systematic reviews
Possible ways:1. Narrative (qualitative) summary in
evidence tables only. • Advantage: split-mouth studies contribute to
totality of evidence and analytic issues (may be) avoided
• Disadvantage: Do not contribute to summary estimate or to investigation of heterogeneity
2. Analyse as if parallel group• Not recommended due to potentially unreliable
meta-analysis summary estimate
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How to include split-mouth studies in systematic reviews
Possible ways:3. Meta-analyse those split-mouth trials with
adequate data separately from parallel group trials and ignore those without such data
• Advantage: More information• Disadvantage: Selection bias
4. Incorporate data from first intervention side if reported separately
• Advantage: More information• Disadvantage: May be biased sample where
trialists identified carry-over effects
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How to include split-mouth studies in systematic reviews
Possible ways:5. Approximate a paired analysis by
inputing a measure describing the similarity of outcomes within each participant.
• Advantages: Makes use of all trials• Disadvantages:
• May make assumptions about data (that can be tested)
• May need statistical support
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Approximating a paired analysis - you will need one of the following
1. Individual patient data in publication or from contact with trialist
2. Mean and SD/SE of patient specific differences between intervention A and B measurement
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Approximating a paired analysis - you will need one of the following
3. Mean difference (or difference between means) and one of:
• t-statistic (paired t-test)• P-value from paired t-test• Confidence interval from paired analysis
4. Graph of measurement of intervention A and B from which matched individual data values can be extracted.
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Approximating a paired analysis
• Step one. Calculate the correlation coefficient (r) for each study.
– The correlation coefficient describes how similar the measurement of intervention A and B were within a participant
– Assumes that mean and SD for each intervention treatment side/period would be the same
– If r is inconsistent between studies, then caution on proceeding further.
– If r cannot be calculated for a trial, use representative value from other trials as the trials should be very similar for a particular intervention in a systematic review
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Approximating a paired analysis
• Step two. Calculate SE of the mean difference between the interventions
• Step three. Enter the data into meta-analysis software. Generic inverse variance method of Cochrane Software - RevMan - particularly flexible (free download).
• Step four. Conduct sensitivity analyses employing different values for r to investigate robustness of estimates especially for studies were r could not be calculated
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How to include split-mouth studies in systematic reviews
Further issues: • Generally advisable to meta-analyse
split-mouth and parallel group trials separately as sub-groups to investigate systematic differences
• Authors of systematic reviews: please state explicitly how data from split-mouth studies has been managed
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How to include split-mouth studies in systematic reviews
Example of meta-analysis of split mouth and parallel group trials.
16Needleman, Worthington, Giedrys-Leeper, & Tucker 2006, Cochrane Database of Systematic Reviews
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Split-mouth studies and systematic reviews
• Conclusions– Split-mouth studies should be included
in systematic reviews when appropriate– It is possible to combine split-mouth and
parallel group studies in meta-analysis– Our observation within the Cochrane
Oral Health Group is that differences in effect sizes exist between split-mouth and parallel group studies of the same intervention
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Split-mouth studies and systematic reviews
• Resources– Cochrane Handbook and RevMan:
www.cochrane.org– Elbourne et al. 2002. Int J Epidem, 31:
140-149– Follman et al. 1992. J Clin Epidem, 45:
769-773• Contact: [email protected]
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