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13.1.3  Key issues about the inclusion of non-randomized studies in a Cochrane review

Randomized trials are the preferred design for studying the effects of healthcare interventions because, in most circumstances, the randomized trial is the study design that is least likely to be biased. Any Cochrane review must consider the risk of bias in individual primary studies, including both the likely direction and magnitude of bias (see Chapter 8). A review that includes NRS also requires review authors to do this. The principle of considering risk of bias is exactly the same. However, potential biases are likely to be greater for NRS compared with randomized trials. Review authors need to consider (a) the weaknesses of the designs that have been used (such as noting their potential to ascertain causality), (b) the execution of the studies through a careful assessment of their risk of bias, especially (c) the potential for selection bias and confounding to which all NRS are suspect and (d) the potential for reporting biases, including selective reporting of outcomes.


Susceptibility to selection bias (understood in this Handbook to mean differences in the baseline characteristics of individuals in different intervention groups, rather than whether the selected sample is representative of the population) is widely regarded as the principal difference between randomized trials and NRS. Randomization with adequate allocation sequence concealment reduces the possibility of systematic selection bias in randomized trials so that differences in characteristics between groups can be attributed to chance. In NRS, allocation to groups depends on other factors, often unknown. Confounding occurs when selection bias gives rise to imbalances between intervention and control groups (or case and control groups in case-control studies) on prognostic factors, i.e. the distributions of the factors differ between groups and the factors are associated with outcome. Confounding can have two effects in a meta-analysis: (a) shifting the estimate of the intervention effect (systematic bias) and (b) increasing the variability of the observed effects, introducing excessive heterogeneity among studies (Deeks 2003). It is important to consider both of these possible effects (see Section 13.6.1). Section 13.5 provides a more detailed discussion of susceptibility to bias in NRS.