Background Clinical decisions are made based on Cochrane reviews, but the implementation of results of evidence syntheses such as Cochrane reviews is problematic if the evidence is not prepared consistently. All systematic reviews should assess the risk of bias (RoB) in included studies, and in Cochrane reviews, this is done by using Cochrane RoB tool. However, the tool is not necessarily applied according to the instructions. In this study, we aimed to determine the types of bias and their corresponding judgements noted in the ‘other bias’ domain of Cochrane RoB tool. Methods We analyzed Cochrane reviews that included randomized controlled trials (RCTs) and extracted data regarding ‘other bias’ from the RoB table and accompanying support for the judgment. We categorized different types of other bias. Results We analyzed 768 Cochrane reviews that included 11,369 RCTs. There were 602 (78%) Cochrane reviews that had ‘other bias’ domain in the RoB tool, and they included a total of 7811 RCTs. In the RoB table of 337 Cochrane reviews for at least one of the included trials it was indicated that no other bias was found and supporting explanations were inconsistently judged as low, unclear or high RoB. In the 524 Cochrane reviews that described various sources of other bias, there were 5762 individual types of explanations which we categorized into 31 groups. The judgments of the same supporting explanations were highly inconsistent. We found numerous other inconsistencies in reporting of sources of other bias in Cochrane reviews. Conclusion Cochrane authors mention a wide range of sources of other bias in the RoB tool and they inconsistently judge the same supporting explanations. Inconsistency in appraising risk of other bias hinders reliability and comparability of Cochrane systematic reviews. Discrepant and erroneous judgments of bias in evidence synthesis may hinder implementation of evidence in routine clinical practice and reduce confidence in otherwise trustworthy sources of information. These results can help authors of Cochrane and non-Cochrane reviews to gain insight into various sources of other bias that can be found in trials, and also to help them avoid mistakes that were recognized in published Cochrane reviews. Electronic supplementary material The online version of this article (10.1186/s12874-019-0718-8) contains supplementary material, which is available to authorized users.

22Background: Clinical decisions are made based on Cochrane systematic reviews (CSRs), but 23 implementation of results of evidence syntheses such as CSRs is problematic if the evidence 24 is not prepared consistently. All systematic reviews should assess risk of bias (RoB) in 25 included studies, and in CSRs this is done by using Cochrane RoB tool. However, the tool is 26 not necessarily applied according to the instructions. In this study we aimed to analyze types 27 and judgments of 'other bias' in the RoB tool in CSRs of interventions. 28 Methods:We analyzed CSRs that included randomized controlled trials (RCTs) and 29 extracted data regarding 'other bias' from the RoB table and accompanying support for the 30 judgment. We categorized different types of other bias. 31 Results:We analyzed 768 CSRs that included 11369 RCTs. There were 602 (78%) CSRs that 32 had 'other bias' domain in the RoB tool, and they included a total of 7811 RCTs. In the RoB 33 table of 337 CSRs for at least one of the included trials it was indicated that no other bias was 34 found and supporting explanations were inconsistently judged as low, unclear or high RoB. In 35 the 524 CSRs that described various sources of other bias there were 5762 individual types of 36 explanations which we categorized into 31 groups. The judgments of the same supporting 37 explanations were highly inconsistent. Furthermore, we found numerous other inconsistencies 38 in reporting of sources of other bias in CSRs. 39 Conclusion: Cochrane authors mention a wide range of sources of other bias in the RoB tool 40 and they inconsistently judge the same supporting explanations. Inconsistency in appraising 41 risk of other bias hinders reliability and comparability of Cochrane systematic reviews. 42 Furthermore, discrepant and erroneous judgments of bias in evidence synthesis will inevitably 43 hinder implementation of evidence in routine clinical practice and reduce confidence of 44 practitioners in otherwise trustworthy sources of information. 45 3 46 Keywords: systematic review; Cochrane; risk of bias; other bias, inconsistency 47 Running title: Other bias in Cochrane reviews 48 49

Obinutuzumab (G) has become part of front-line treatment of follicular lymphoma (FL) based on results of a large randomized study. Data on patients treated outside of clinical trials are lacking. We have retrospectively investigated efficacy and safety of G-based immunochemotherapy regimens in 114 patients treated in a real-life setting during a period of 2 years, largely coinciding with the COVID-19 pandemic. The response rate was 93.8%; 18-months overall (OS) and progression-free survival (PFS) were 88% and 84%, respectively. Patients treated with G-cyclophosphamide, vincristine and glucocorticoid + doxorubicine (CHOP) had statistically significantly superior OS and PFS compared to patients treated with G-bendamustine (G-B) (P = 0.002 and P = 0.006, respectively) due to an increase in lethal infections, most notably COVID-19, in the latter group. A total of 12 patients died during follow-up; 9 of 61 treated with G-B, 1 of 49 treated with G-CHOP and 2 of 4 treated with G-cyclophosphamide, vincristine and glucocorticoid (CVP). SARS-CoV-2 infection was diagnosed in 20 (17.5%) patients. All of the 7 treated with G-CHOP recovered, while 4 of 12 treated with G-B died. Immunoglobulin levels and severity of neutropenia were similar between the groups. In multivariate analysis, G-B in comparison to G-CHOP was an independent prognostic factor (P = 0.044, hazard ratio = 9.81) after adjustment for age, sex and Follicular Lymphoma International Prognostic Index (FLIPI). Based on our experience G has excellent antilymphoma activity in patients receiving front-line treatment for FL in real-life setting, but during the COVID-19 pandemic, it should be preferentially combined with CHOP, at least in patients younger than 65.

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