Sources of bias in non-randomized studies

Bias may be present in findings from NRS in many of the same ways as in poorly designed or conducted randomized trials (see Chapter 8, Section 8.4). For example, numbers of exclusions in NRS are frequently unclear, intervention and outcome assessment are often not conducted according to standardized protocols, and outcomes may not be assessed blind. The biases caused by these problems are likely to be similar to those that occur in randomized trials, and review authors should be familiar with Chapter 8 that describes these issues. None of these problems are any less difficult to overcome in a well-planned non-randomized prospective study than in a randomized trial.


In NRS, use of allocation mechanisms other than concealed randomization means that groups are unlikely to be comparable. These potential systematic differences between characteristics of participants in different intervention ‘groups’ are likely to be the issue of key concern in most NRS, and we refer to this as selection bias. When selection bias produces imbalances in prognostic factors associated with the outcome of interest then ‘confounding’ is said to occur. Statistical methods are sometimes used to counter bias introduced from confounding by producing ‘adjusted’ estimates of intervention effects, and part of the assessment of study quality may involve making judgements about the appropriateness of the analysis as well as the design and execution of the study.


The variety of study designs classified as NRS, and their varying susceptibility to different biases, makes it difficult to produce a generic robust tool that can be used to evaluate risk of bias. Within a review that includes NRS of different designs, several tools for assessment of risk of bias may need to be created. Inclusion of a knowledgeable methodologist in the review team is essential to identify the key areas of weakness in the included study designs.


With randomized trials, assessment of the risk of bias focuses on systematic bias, which is usually assumed to be ‘optimistic’ in direction. The tendency for researchers to design, execute, analyse and report their primary studies to give the findings that are expected, consciously or subconsciously, is also likely to apply to NRS where researchers have control over key decisions (e.g. allocation to intervention, or selection of centres). In truly observational NRS, bias arising from ‘confounding by indication’ may not be so consistent; healthcare professionals may have differing opinions about the appropriateness of alternative interventions for their patients, contingent on the patients’ presenting severity of illness or co-morbidities. Differences in case-mix between locations that are being compared may be haphazard. Therefore, when reviewing NRS, the variability of biases and the between-study heterogeneity they induce is at least as important as systematic bias.