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16.9.5  Validity of methods of meta-analysis for rare events

Simulation studies have revealed that many meta-analytical methods can give misleading results for rare events, which is unsurprising given their reliance on asymptotic statistical theory.  Their performance has been judged suboptimal either through results being biased, confidence intervals being inappropriately wide, or statistical power being too low to detect substantial differences.


Below we consider the choice of statistical method for meta-analysis of odds ratios. Appropriate choices appear to depend on the control group risk, the likely size of the treatment effect and consideration of balance in the numbers of treated and control participants in the constituent studies. No research has evaluated risk ratio measures directly, but their performance is likely to be very similar to corresponding odds ratio measurement  When events are rare, estimates of odds and risks are near identical, and results of both can be interpreted as ratios of probabilities.


Bradburn et al. found that many of the most commonly used meta-analytical methods were biased when events were rare (Bradburn 2007).  The bias was greatest in inverse variance and DerSimonian and Laird odds ratio and risk difference methods, and the Mantel-Haenszel odds ratio method using a 0.5 zero-cell correction.  As already noted, risk difference meta-analytical methods tended to show conservative confidence interval coverage and low statistical power when risks of events were low. 


At event rates below 1% the Peto one-step odds ratio method was found to be the least biased and most powerful method, and provided the best confidence interval coverage, provided there was no substantial imbalance between treatment and control group sizes within studies, and treatment effects were not exceptionally large. This finding was consistently observed across three different meta-analytical scenarios, and was also observed by Sweeting et al. (Sweeting 2004). 


This finding was noted despite the method producing only an approximation to the odds ratio. For very large effects (e.g. risk ratio = 0.2) when the approximation is known to be poor, treatment effects were underestimated, but the Peto method still had the best performance of all the methods considered for event risks of 1 in 1000, and the bias was never more than 6% of the control group risk. 


In other circumstances (i.e. event risks above 1%, very large effects at event risks around 1%, and meta-analyses where many studies were substantially imbalanced) the best performing methods were the Mantel-Haenszel OR without zero-cell corrections, logistic regression and an exact method. None of these methods is available in RevMan.


Methods that should be avoided with rare events are the inverse-variance methods (including the DerSimonian and Laird random-effects method). These directly incorporate the study’s variance in the estimation of its contribution to the meta-analysis, but these are usually based on a large-sample variance approximation, which was not intended for use with rare events. The DerSimonian and Laird method is the only random-effects method commonly available in meta-analytic software.  We would suggest that incorporation of heterogeneity into an estimate of a treatment effect should be a secondary consideration when attempting to produce estimates of effects from sparse data – the primary concern is to discern whether there is any signal of an effect in the data.