8.14.1  Rationale for concern about bias

Selective outcome reporting has been defined as the selection of a subset of the original variables recorded, on the basis of the results, for inclusion in publication of trials (Hutton 2000); see also Chapter 10 (Section 10.2.2.5).  The particular concern is that statistically non-significant results might be selectively withheld from publication. Until recently, published evidence of selective outcome reporting was limited. There were initially a few case studies. Then a small study of a complete cohort of applications approved by a single Local Research Ethics Committee found that the primary outcome was stated in only six of the protocols for the 15 publications obtained. Eight protocols made some reference to an intended analysis, but seven of the publications did not follow this analysis plan (Hahn 2002). Within-study selective reporting was evident or suspected in several trials included in a review of a cohort of five meta-analyses in the Cochrane Database of Systematic Reviews (Williamson 2005a).

 

Convincing direct empirical evidence for the existence of within-study selective reporting bias comes from three recent studies. In the first study (Chan 2004a), 102 trials with 122 publications and 3736 outcomes were identified. Overall, (a median of) 38% of efficacy and 50% of safety outcomes per parallel group trial were incompletely reported, i.e. with insufficient information to be included in a meta-analysis. Statistically significant outcomes had a higher odds ratio of being fully reported when compared with non-significant outcomes, both for efficacy (pooled odds ratio 2.4; 95% confidence interval 1.4 to 4.0) and for harms (4.7, 1.8 to 12) data. Further, when comparing publications with protocols, 62% of trials had at least one primary outcome that was changed, introduced or omitted. A second study of 48 trials funded by the Canadian Institutes of Health Research found closely similar results (Chan 2004b). A third study, involving a retrospective review of 519 trial publications and a follow-up survey of authors, compared the presented results with the outcomes mentioned in the methods section of the same article (Chan 2005). On average, over 20% of the outcomes measured in parallel group trials were incompletely reported. Within trials, such outcomes had a higher odds of being statistically non-significant compared with fully reported outcomes (odds ratio 2.0 (1.6 to 2.7) for efficacy outcomes; 1.9 (1.1 to 3.5) for harm outcomes). These three studies suggest an odds ratio of about 2.4 associated with selective outcome reporting which corresponds, for example, to about 50% of non-significant outcomes being published compared to 72% of significant ones.

 

In all three studies, authors were asked whether there were unpublished outcomes, whether those showed significant differences and why those outcomes had not been published. The most common reasons for non-publication of results were ‘lack of clinical importance’ or lack of statistical significance. Therefore, meta-analyses excluding unpublished outcomes are likely to overestimate intervention effects. Further, authors commonly failed to mention the existence of unpublished outcomes even when those outcomes had been mentioned in the protocol or publication.

 

Recent studies have found similar results (Ghersi 2006, von Elm 2006). In a different type of study, the effect in meta-analyses was larger when fewer of the available trials contributed data to that meta-analysis (Furukawa 2007). This finding also suggests that results may have been selectively withheld by trialists on the basis of the magnitude of effect.

 

Bias associated with selective reporting of different measures of the same characteristic seems likely. In trials of treatments for schizophrenia, an intervention effect has been observed to be more likely when unpublished, rather than published, rating scales were used (Marshall 2000). The authors hypothesized that data from unpublished scales may be less likely to be published when they are not statistically significant or that, following analysis, unfavourable items may have been dropped to create an apparent beneficial effect.

 

In many systematic reviews, only a few eligible studies can be included in a meta-analysis for a specific outcome because the necessary information was not reported by the other studies. While that outcome may not have been assessed in some studies, there is almost always a risk of biased reporting for some studies. Review authors need to consider whether an outcome was collected but not reported or simply not collected.

 

Selective reporting of outcomes may arise in several ways, some affecting the study as a whole (point 1 below) and others relating to specific outcomes (points 2-6 below):

  1. Selective omission of outcomes from reports: Only some of the analysed outcomes may be included in the published report. If that choice is made based on the results, in particular the statistical significance, the corresponding meta-analytic estimates are likely to be biased.

  2. Selective choice of data for an outcome: For a specific outcome there may be different time points at which the outcome has been measured, or there may have been different instruments used to measure the outcome at the same time point (e.g. different scales, or different assessors). For example, in a report of a trial in osteoporosis, there were 12 different data sets to choose from for estimating bone mineral content. The standardized mean difference for these 12 possibilities varied between −0.02 and 1.42 (Gøtzsche 2007). If study authors make choices in relation to such results, then the meta-analytic estimate will be biased.

  3. Selective reporting of analyses using the same data: There are often several different ways in which an outcome can be analysed. For example, continuous outcomes such as blood pressure reduction might be analysed as a continuous or dichotomous variable, with the further possibility of selecting from multiple cut-points. Another common analysis choice is between endpoint scores versus changes from baseline (Williamson 2005b). Switching from an intended comparison of final values to a comparison of changes from baseline because of an observed baseline imbalance actually introduces bias rather than removes it (as the study authors may suppose) (Senn 1991, Vickers 2001).

  4. Selective reporting of subsets of the data: Selective reporting may occur if outcome data can be subdivided, for example selecting sub-scales of a full measurement scale or a subset of events. For example, fungal infections may be identified at baseline or within a couple of days after randomization or may be so-called ‘break-through’ fungal infections that are detected some days after randomization, and selection of a subset of these infections may lead to reporting bias (Jørgensen 2006, Jørgensen 2007).

  5. Selective under-reporting of data: Some outcomes may be reported but with inadequate detail for the data to be included in a meta-analysis. Sometimes this is explicitly related to the result, for example reported only as “not significant” or “P>0.05”.

 

Yet other forms of selective reporting are not addressed here; they include selected reporting of subgroup analyses or adjusted analyses, and presentation of the first period results in cross-over trials (Williamson 2005a). Also, descriptions of outcomes as ‘primary’, ‘secondary’ etc may sometimes be altered retrospectively in the light of the findings (Chan 2004a, Chan 2004b). This issue alone should not generally be of concern to review authors (who do not take note of which outcomes are so labelled in each study), provided it does not influence which results are published.