Key concepts in clinical epidemiology: detecting and dealing with heterogeneity in meta-analyses.

In a meta-analysis, a question always arises. Is it worthwhile to combine estimates from studies of different populations using various formulations of an intervention, evaluating outcomes measured differently? Sometimes even study designs differ. Differences are expected in a meta-analysis. These may be negligible, and a pooled estimate of effect can guide the clinical decision. However, when the differences are large, this estimate may mislead. Effect estimates from study to study differ because of real differences (between-study variability) and because of chance (within-study variability). To combine estimates when there is heterogeneity (between-study differences are large) may not be sensible. Two complementary methods may be used to detect heterogeneity: visual inspection of the forest plot and calculating numerical measures of heterogeneity (I2 and Q). Visual inspection can show effects that are different from the rest. A large I2 (proportion of overall variability attributed to between-study variation) or a small P-value associated with Q may suggest heterogeneity. Large P-values, however, do not mean the absence of heterogeneity. It is more informative to report the confidence interval of the I2. If there is no heterogeneity, a pooled estimate of the true effect may be generated using only within-study variation (fixed-effect model). If there is substantial heterogeneity, reasons should be sought. Subgroup analysis or meta-regression using study-level characteristics may be done. Although more involved and potentially challenging, individual-level data (Individual Participant Data, IPD) may also be used. In the case of unexplained heterogeneity, both within- and between-study variation should be used to generate a pooled estimate (random-effects model). This estimate does not estimate a single true effect but estimates the average of a range of effects of the intervention on populations represented by the studies. If precise enough (narrow confidence interval), this estimate, together with the prediction interval (a measure of uncertainty in the effect one might see in a particular context), can guide clinical and policy decisions.