1 ICEBOH Split-mouth studies and systematic reviews Ian Needleman 1 & Helen Worthington 2 1 Unit of Periodontology UCL Eastman Dental Institute International Centre for Evidence-Based Oral Health, London UK 2 School of Dentistry, University of Manchester, UK

2 Split-mouth studies and systematic reviews What is the issue? Why include them? How to include them Examples

3 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

4 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

5 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?

6 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

7 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 

8 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

9 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

10 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

11 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.

12 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

13 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

14 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

15 How to include split-mouth studies in systematic reviews Example of meta-analysis of split mouth and parallel group trials.

16 Needleman, Worthington, Giedrys-Leeper, & Tucker 2006, Cochrane Database of Systematic Reviews

17 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

18 Split-mouth studies and systematic reviews Resources –Cochrane Handbook and RevMan: –Elbourne et al Int J Epidem, 31: –Follman et al J Clin Epidem, 45: Contact: ICEBOH