Template for MECIR (Review)

Template for MECIR (Review) This guidance document contains information regarding the Cochrane Collaboration's mandatory MECIR Conduct and Reporting Standards and editorial suggestions specific to PaPaS, to support the development of your REVIEW. See comments below. Review information Review type: Intervention Authors Anna Hobson 1 1 Cochrane Pain, Palliative and Supportive Care Group, Pain Research Unit, Oxford, UK Citation example: Hobson A. Template for MECIR (Review). Cochrane Database of Systematic Reviews, Issue. Art. No.:. DOI:. Check that authors are listed in the correct order, with the correct affiliations, and have agreed to the order in which they are listed. Authors: do not add/remove any authors or amend contact details in RevMan: adding/deleting authors and amending contact details must be done centrally by the CRG. Contact PaPaS to arrange this if necessary. Contact person Anna Hobson Managing Editor Cochrane Pain, Palliative and Supportive Care Group Pain Research Unit The Churchill Hospital Old Road Oxford OX3 7LE UK E-mail: anna.hobson@ndcn.ox.ac.uk Dates Assessed as Up-to-date:Not provided Date of Search: Not provided Next Stage Expected: Not provided Protocol First Published: Not specified Review First Published: Not specified Last Citation Issue: Not specified Assessed as up to date and Date of search: must both match the date of the most recent search. Must reflect what is written in the review text. Next stage expected: when the next full publication is due: for a new Review, this date should reflect when the next update is due, usually two years after anticipated publication. Reviews can be 'stabilised' if no new evidence is likely. Please discuss with PaPaS re. postponing the update beyond the normal two years if applicable. What's new Date Event Description No need to add anything here unless the review is an Update. See 'Updating your review' document. History Date Event Description Abstract Background This guidance document contains information regarding the Cochrane Collaboration's mandatory MECIR Conduct and Reporting Standards (also visible in the right-hand viewing pane in RevMan 5.3), Cochrane Handbook guidance, common 1 / 18

errors, and editorial suggestions/template wording recommended by PaPaS Information has been added to this document in individual sections under headings/sub-headings, and as yellow notes. Please ensure the following guidance is adhered to during the development of the review; if these minimum required standards are not met, revisions will be requested, which will prolong the editorial process. - Methodological Expectations of Cochrane Intervention Reviews (MECIR) Standards (http://editorial-unit.cochrane.org/mecir) - Cochrane Style Guide (http://community.cochrane.org/training/cochrane-style-resource/cochrane-style-guide) - Cochrane Handbook (http://handbook.cochrane.org/) - The PaPaS website contains more useful links and guidance in our Resource Hub (http://papas.cochrane.org/useful-linksauthors), including our 'Author and Referee Guide' and screenshots to help with some common queries ( http://papas.cochrane.org/screenshots-common-issues) For further training and support - Find your local Cochrane Centre: http://www.cochrane.org/contact/centres. - Visit the Cochrane Training website: http://training.cochrane.org/. Videos are also available on YouTube here. - Use the latest version of RevMan (check for updates here http://tech.cochrane.org/revman/download/updates). For technical hitches/problems, please see the Help section in RevMan, or visit the Cochrane Informatics and Knowledge Management Department (IKMD) website http://tech.cochrane.org/home. A few important points to remember - First draft reviews are expected to be submitted for editorial approval within 9 months of publishing the protocol and receiving the search results. Reviews are expected to be published within a maximum of 2 years. PaPaS reserves the right to withdraw titles that greatly exceed the submission deadlines. - Always check your review in and out using RevMan, as files can get lost and version control can be disrupted. You can create as many versions as necessary. 'Checking in' via RevMan ensures your latest draft is always available to everyone. - Style: use the past tense and active voice. Some sections will be copied automatically from the protocol; these sections will need to be changed from future tense to past tense. - All the authors listed must see and approve this version and take full responsibility for the accuracy of the contents. Ensure all affiliation details are correct (see yellow note above). - Convert this file into 'full review', and activate the relevant headings in RevMan to complete each section. - Proofread the review carefully in accordance with the Cochrane Style Guide Basics. - If additional subheadings have been added, select the appropriate Heading Style using the drop down box on the RevMan toolbar. The next available heading style from the pull-down list in the tool bar should be applied to any additional subheadings; for example, Heading level 1 is used for Background, and users would then apply Heading level 2 for the first author-defined subheading used in this section. - Use either UK or US English consistently throughout the review (e.g. either randomised or randomized ). - Explain all acronyms and abbreviations in full on first use (e.g. World Health Organization (WHO)). - Spell in full all numbers at the beginning of a sentence, and those up to and including nine. For numbers 10 and higher, and all numbers in tables, please use numerals. - Include a space before and after each unit of measurement or mathematical symbol (e.g. 5 ml, P = 0.03). - Back up all key supporting statements with references and avoid the use of plagiarized text. The editorial team will use plagiarism detection software upon receipt of the first draft, in accordance with Cochrane's Plagiarism Policy ( http://community.cochrane.org/editorial-and-publishing-policy-resource/plagiarism). Authors can check whether references are correctly linked using the Find and Mark Links tool in RevMan (Edit > Find and mark links). - Before accepting our standard suggested wording, please check that you agree with the statements and that they accurately reflect what you did, eg 'We searched the metaregister of controlled trials (mrct) on x date'. - Before submission, complete a validation check in RevMan (File menu > Reports > Validation report), and make corrections where possible. - Before submission, complete a spell check in RevMan (Tools menu > Check spelling). - Please use the 'Submit for editorial approval' option when submitting the first draft to the CRG (click 'Next' when checking in). General points for Abstract section: MECIR R3: Prepare a structured abstract to provide a succinct summary of the review. In the interests of brevity it is highly desirable for authors to provide an abstract of less than 700 words, and it should be no more than 1000 words in length. [You can check the word count in the Status Report: File > Reports > Status Report.] MECIR R4: Summarize the rationale and context of the review. 2 / 18

MECIR R18: Ensure that reporting of objectives, important outcomes, results, caveats and conclusions is consistent across the text, the abstract, the plain language summary and the Summary of findings table (if included). Common error identified by CEU screening: Inaccurate reporting of statistical imprecision. In particular, there is a tendency for results with wide confidence intervals to be described as showing "no effect" in the abstract, PLS, discussion and full-text conclusions. Objectives MECIR R5: State the main objective(s), preferably in a single concise sentence, 'To assess the effects of [intervention or comparison] for [health problem] for/in [types of people, disease or problem and setting if specified]'. This should be identical to the objective(s) in the main review text, ideally in a single sentence. Search methods MECIR R6: Provide the date of the last search from which records were evaluated and any studies identified were incorporated into the review, and an indication of the databases and other sources searched. Suggested wording: 'We searched the following databases: CENTRAL (The Cochrane Library), MEDLINE, EMBASE, [Other], two clinical trial registries, and the reference lists of articles. The date of the most recent search was [x month year].' The date here must match Date of search and Date assessed as up to date as stated in 'Dates' section above. All reviews must be published within 12 months of the latest search. Searches can be updated during the editorial process, usually during peer review, if necessary. Selection criteria MECIR R7: Summarize eligibility criteria of the review, including information on study design, population and comparison. Data collection and analysis MECIR R8: Summarize any noteworthy methods for selecting studies, collecting data, evaluating risk of bias and synthesizing findings. Suggested wording: 'We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. We calculated the risk ratio (RR) and number needed to treat to benefit (NNT). We also collected information on adverse effects.' Main results MECIR R9: Report the number of included studies and participants. MECIR R11: Provide a comment on the findings of the bias assessment. MECIR R12: Report findings for all primary outcomes, irrespective of the strength and direction of the result, and of the availability of data. MECIR R13: Ensure that any findings related to adverse effects are reported. If adverse effects data were sought, but availability of data was limited, this should be reported. MECIR R14: Present summaries of statistical analyses in the same way as they are reported in the review and in a standard way, ensuring that readers will understand the direction of benefit and the measurement scale used, and that confidence intervals are included where appropriate. Ensure the results stated here match the analyses exactly [to check: right click anywhere in the text; select 'Insert Analysis results': e.g. Analysis 1.1 (SMD -2.24, 95% CI -2.69 to -1.78)]. Common errors identified by CEU screening: 1) Discrepancies between results presented in the analyses and their reporting across the text of reviews. 2) Inconsistencies in the reporting of results or interpretation of evidence across different sections of reviews. 3) Overly optimistic conclusions that do not take proper account of the quality of the evidence, particularly when the review is empty or the data are sparse. 4) Common under-utilisation of information from Summary of Findings tables in reporting the review findings. 5) Often unclear or inexplicable decisions in relation to GRADE assessments and assessments that seem to be restricted to risk of bias only. Authors' conclusions MECIR R16: State key conclusions drawn. MECIR R18: Consistency of summary versions of the review: Ensure that reporting of objectives, important outcomes, results, caveats and conclusions is consistent across the text, the abstract, the plain language summary and the Summary of findings table (if included). Plain language summary Plain language title PaPaS PLS criteria, proposed by Professor Andrew Moore: 1: Condition: A sentence or two about the condition under study. E.g. 'People with condition X may experience symptoms such as pain, anxiety or distress. Intervention Y may help relieve these symptoms.' 3 / 18

2: Intervention: A sentence or two about the intervention(s) under study. E.g. 'Pain in condition X is usually treated with painkillers taken by mouth. This review looked at how good Y was in relieving X.' 3: Found: What was found, mainly in terms of the number of studies and patients, but including outcomes or other appropriate or important topics. E.g. 'In July 2014, we searched for clinical trials looking at intervention Y in patients with condition X. We found 16 small studies of low quality.' 4: Work: What was the effect of the intervention in terms of benefit. For benefit we use the simple odds (X in 10) of getting a benefit that is important to patients, with and without using the intervention. The reason for using simple offs as a numerical is because research on understanding shows that this is most accessible to most people (see Arthritis Res Ther. 2008;10(1):R20 for a systematic review). E.g. 'Some studies showed that Intervention Y may help relieve short-term pain and anxiety in patients with X. Intervention Y worked for 3 in 10 people in these studies.' 5: Harm: What was the effect of the intervention in terms of harm. What harm, and what was the risk usually here we stick with X in 10 because the issue of RCTs is common and irreversible harm, but obviously it can be Y in 1000 or 10000 if the review discusses rare, serious, and irreversible harm. E.g. 'We found that around 2 out of 10 people experienced side effects such as A, B and C.' 6: Next up: What next? New trials? E.g. 'There was not enough good quality evidence available to draw any conclusions. More research is needed.' MECIR R17: Ensure that all findings reported in the abstract and plain language summary, including re-expressions of metaanalysis results, also appear in the main text of the review. MECIR R18: Consistency of summary versions of the review: Ensure that reporting of objectives, important outcomes, results, caveats and conclusions is consistent across the text, the abstract, the plain language summary and the Summary of findings table (if included). Common error identified by CEU screening: Discrepancies between results presented in the analyses and their reporting across the text of reviews. Background [This section will be automatically copied from the protocol] Description of the condition [This section will be automatically copied from the protocol] Description of the intervention [This section will be automatically copied from the protocol] How the intervention might work [This section will be automatically copied from the protocol] Why it is important to do this review [This section will be automatically copied from the protocol] Objectives [This section will be automatically copied from the protocol] Methods Criteria for considering studies for this review Types of studies [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('We will include...') to past tense ('We included...').] MECIR R29: If studies are excluded on the basis of publication status or language of publication, explain and justify this. Types of participants [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('We will include...') to past tense ('We included...').] MECIR R30: State eligibility criteria for participants, including any criteria around location, setting, diagnosis or definition of condition and demographic factors, and how studies including subsets of relevant participants are handled. Suggested wording: We included studies of adult participants (18 years or older). Types of interventions [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('We will include...') to past tense ('We included...').] MECIR R31: State eligibility criteria for interventions and comparators, including any criteria around delivery, dose, duration, intensity, co-interventions and characteristics of complex interventions. 4 / 18

List comparators for the intervention that are consistent with the objectives of the Cochrane Review (e.g. comparison with a placebo addresses a different objective from comparison with an active intervention). Types of outcome measures [This section will be automatically copied from the protocol] MECIR R32: If measurement of particular outcomes is used as an eligibility criterion, state and justify this. MECIR R33: Outcomes of interest: State primary and secondary outcomes of interest to the review, and define acceptable ways of measuring them. Suggested wording (if relevant): 'We included a 'Summary of findings' table as set out in the PaPaS author guide (AUREF 2012) and recommended in the Cochrane Handbook, chapter 4.6.6 (Higgins 2011). The 'Summary of findings' table includes outcomes of [a, b, and c] [include link to SoF table]'. [If it was planned but not possible to include a Summary of findings table, add a brief explanation here.] Primary outcomes [This section will be automatically copied from the protocol] Secondary outcomes [This section will be automatically copied from the protocol] Search methods for identification of studies Electronic searches [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('We will search...') to past tense ('We searched...').] Suggested wording: We searched the following databases without language restrictions. The Cochrane Central Register of Controlled Trials (CENTRAL) (via the Cochrane Library) (Issue x of 12, 201x). MEDLINE (via Ovid) 1946 to x month year. EMBASE (via Ovid) 1974 to x month year. [Other] [add date searched]. We used medical subject headings (MeSH) or equivalent and text word terms. There were no language or date restrictions. The search strategy for CENTRAL, MEDLINE, EMBASE and [Other] are in Appendix 1 [ensure link is added]. Searching other resources [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('We will search...') to past tense ('We searched...').] Suggested wording [ensure internet links are added]: We searched the metaregister of controlled trials (mrct) ( www.controlled-trials.com/mrct), clinicaltrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/) on [x month year] to identify additional completed or ongoing studies. We reviewed the bibliographies of any randomised trials and review articles identified, and contacted the authors and known experts in the field, to identify additional published or unpublished data. [Include a comment about whether or not the authors/experts responded to requests.] Data collection and analysis [No need to add anything here] Selection of studies [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('Two review authors [XX, YY] will assess...') to past tense ('Two review authors [XX, YY] assessed...').] MECIR R40: State how inclusion decisions were made (i.e. from search results to included studies), clarifying how many people were involved (at least two) and whether they worked independently. Describe a strategy for resolving disagreements. Suggested wording, 'Two review authors [XX, YY] independently assessed the search results and agreed on the studies to be included in the review. Disagreements were resolved by consensus or referral to a third review author [ZZ] where necessary.' Data extraction and management [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('Data will be extracted independently...') to past tense ('Two review authors [XX, YY] independently extracted data...).] MECIR R41: State how data were extracted from reports of included studies, clarifying how many people were involved (and whether independently), and how disagreements were handled. Describe data collection process for any reports requiring translation. MECIR R43: List the types of information that were sought from reports of included studies. 5 / 18

MECIR R44: Explain any transformations of reported data prior to presentation in the review, along with any assumptions made. Explain any procedures for extracting numeric data from graphs. Suggested wording: 'Two review authors [XX, YY] independently extracted data and recorded them on a standard data extraction form. One review author entered data suitable for pooling into Cochrane software Review Manager version 5.3 ( RevMan 2014)'. Assessment of risk of bias in included studies [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('We will assess...') to past tense ('We assessed...).] MECIR R46: State the tool(s) used to assess risk of bias for included studies, how the tool(s) was implemented, and the criteria used to assign studies, for example, to judgements of low risk, high risk and unclear risk of bias. Suggested wording: Two authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions, resolving any disagreements by discussion (Higgins 2011). We completed a 'Risk of bias' table for each included study. The following were assessed for each study. 1. Random sequence generation (checking for possible selection bias). We assessed the method used to generate the allocation sequence as: low risk of bias (any truly random process: random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). We excluded studies using a nonrandom process, which were therefore at high risk of bias (odd or even date of birth; hospital or clinic record number). 2. Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions before assignment determines whether the intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We assessed the methods as: low risk of bias (telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). We excluded studies that did not conceal allocation, which were therefore at high risk of bias (open list). 3. Blinding of outcome assessment (checking for possible detection bias). We assessed the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We assessed the methods as: low risk of bias (study stated that it was blinded and described the method used to achieve blinding: identical tablets; matched in appearance and smell); unclear risk of bias (study stated that it was blinded but did not provide an adequate description of how blinding was achieved). We excluded studies that were not double-blind and therefore at high risk of bias. 4. Size (checking for possible biases confounded by small size). Small studies have been shown to overestimate treatment effects, probably because the conduct of small studies is more likely to be less rigorous, allowing critical criteria to be compromised (Dechartres 2013; Nüesch 2010). Studies were considered to be at low risk of bias if they had 200 participants or more, at unclear risk if they had 50 to 200 participants, and at high risk if they had fewer than 50 participants. 5. Add any further items here, e.g. selective outcome reporting, as per the domains assessed in the Risk of bias tables. Measures of treatment effect [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('We will consider the risk ratio (RR)...') to past tense ('We used risk ratio (or relative risk, RR)...).] MECIR R47: State the effect measures used by the review authors to describe effect sizes (e.g. risk ratio, mean difference) in any included studies and/or meta-analyses. Unit of analysis issues [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('Outcomes will be assessed at the patient level...') to past tense ('We accepted only randomisation of the individual patient...).] Dealing with missing data [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('Study authors will be contacted...') to past tense ('We contacted...).] Assessment of heterogeneity [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('We will examine...') to past tense ('We examined...).] MECIR R87: Explain how studies measuring an outcome of interest using different scales (such as alternative rating scales that measure symptoms or behaviour) were combined, stating whether positive or negative values reflect benefit or harm. Assessment of reporting biases [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('We will assess...') to past tense ('We assessed...).] We do not recommend using funnel plots. Suggested wording: 'We examined heterogeneity using L'Abbé plots (L'Abbé 1987 ), a visual method for assessing differences in results of individual studies'. Data synthesis 6 / 18

[This section will be automatically copied from the protocol. Ensure this is changed from future tense ('Data will be extracted independently...') to past tense ('Data were extracted independently...).] MECIR R48: Quantitative synthesis: Describe any methods for combining results across studies (e.g. meta-analysis, subgroup analysis, meta-regression, sensitivity analysis), including methods for assessing heterogeneity (e.g. I 2, tausquared, statistical test). Reference the software and command/macro/program used for analyses performed outside of RevMan. MECIR R49: Addressing risk of bias: Describe how studies with high or variable risks of bias are addressed in the synthesis. MECIR R50: If designs other than individually randomized, parallel-group randomized trials are included, describe any methods used to address clustering, matching or other design features of the included studies. MECIR R51: If multi-arm studies are included, explain how they are addressed and incorporated into syntheses. Subgroup analysis and investigation of heterogeneity [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('Data will be extracted independently...') to past tense ('Data were extracted independently...).] MECIR R53: If subgroup analysis (or meta-regression) was performed, state the potential effect modifiers with rationale for each, stating whether each was defined a priori or post hoc. Sensitivity analysis [This section will be automatically copied from the protocol. Ensure this is changed from future tense ('We will perform...') to past tense ('We performed...).] Describe sensitivity analyses used to determine whether conclusions are robust to decisions made during the review process (e.g. choice of meta-analysis method, exclusion of studies from analysis). Results Description of studies Results of the search Recommendation from PaPaS Trials Search Co-ordinator: The results sections should start with a summary of the results of the search (for example, how many references were retrieved by the electronic searches, and how many were considered as potentially eligible after screening). Review authors are strongly encouraged to include a study flow diagram as recommended by the PRISMA statement (Liberati 2009). Such flow diagrams can be created within RevMan 5.3 (see Section 11.2.1 of the Cochrane Handbook of Systematic Reviews of Interventions for further details on the presentation of flow diagrams). Further information can be found in the Cochrane Handbook of Systematic Reviews of Interventions, http://handbook.cochrane.org/. Part 1, Chapter 4 Guide to the contents of a Cochrane protocol and review and Part 2, Chapter 6 Searching for Studies. See Figure 1 for example flowchart [needs completing with search results]. MECIR R55: Flow of studies: Provide information on the flow of studies from the number(s) of references identified in the search to the number of studies included in the review, ideally using a flowchart. Clarify how multiple references for the same study relate to the individual studies. Include link to Figure 1 flowchart. MECIR R59: Provide details of any identified studies that have not been completed. Include links to Characteristics of studies awaiting classification and Characteristics of ongoing studies if applicable. MECIR R84: Must include link to Characteristics of included studies and Characteristics of excluded studies tables. Included studies MECIR R61: Provide a brief narrative summary of any included studies. This should include the number of participants and a summary of the characteristics of the study populations and settings, interventions, comparators and funding sources. Excluded studies MECIR R57: List key excluded studies and provide justification for each exclusion. 7 / 18

Grading of evidence: suggested wording Template for MECIR (Review) This section is taken from the Cochrane Drugs and Alcohol Group recommended text. The overall quality of the evidence for each outcome was assessed using the GRADE system (GRADEpro 2008) and presented in the 'Summary of findings' tables, to present the main findings of a review in a transparent and simple tabular format. In particular, we included key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the main outcomes. The GRADE system uses the following criteria for assigning grade of evidence: High = further research is very unlikely to change our confidence in the estimate of effect; Moderate = further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low = further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low = any estimate of effect is very uncertain. We decreased grade if: Serious (-1) or very serious (-2) limitation to study quality; Important inconsistency (-1); Some (-1) or major (-2) uncertainty about directness; Imprecise or sparse data (-1); High probability of reporting bias (-1). We increased grade if: Strong evidence of association - significant relative risk of >2 (<0.5) based on consistent evidence from two or more observational studies, with no plausible confounders (+1); Very strong evidence of association - significant relative risk of >5 (<0.2) based on direct evidence with no major threats to validity (+2); Evidence of a dose response gradient (+1); All plausible confounders would have reduced the effect (+1). Risk of bias in included studies Suggested wording for this section: 'We assessed the risk of bias using the 'Risk of bias' tool (Figure 2; Figure 3).' [Must include links to the RoB summary tables.] MECIR R74: Provide a brief narrative summary of the risks of bias among the included studies in the sub-headings below. Allocation (selection bias) [Comment here about this risk of bias in the included studies] Blinding (performance bias and detection bias) [Comment here about this risk of bias in the included studies] Incomplete outcome data (attrition bias) [Comment here about this risk of bias in the included studies] Selective reporting (reporting bias) [Comment here about this risk of bias in the included studies] Other potential sources of bias [Comment here about this risk of bias in the included studies, e.g. size (see Assessment of risk of bias in included studies section above).] Effects of interventions MECIR R17: Ensure that all findings reported in the abstract and plain language summary, including re-expressions of metaanalysis results, also appear in the main text of the review. MECIR R18: Ensure that reporting of objectives, important outcomes, results, caveats and conclusions is consistent across the text, the abstract, the plain language summary and the Summary of findings table (if included). MECIR R77: State how many studies and how many participants contributed data to results for each outcome, along with the proportion of the included studies and recruited participants potentially available for the relevant comparison. MECIR R79: Describe any post hoc decisions that might give rise to accusations of selective outcome reporting in the included studies, for example when there are multiple outcome measures (e.g. different scales), multiple time points or multiple ways of presenting results. MECIR R81: Report synthesis results for all pre-specified outcomes, irrespective of the strength or direction of the result. Indicate whether data were not available for outcomes of interest, including whether harms were identified. MECIR R82: Accompany all effect size estimates with a measure of statistical uncertainty (e.g. a confidence interval with a 8 / 18

specified level of confidence such as 90%, 95% or 99%). Template for MECIR (Review) MECIR R86: Ensure that all statistical results presented in the main review text are consistent between the text and the Data and analysis tables. [To check: right click anywhere in the text; select 'Insert Analysis results': e.g. Analysis 1.1 (SMD -2.24, 95% CI -2.69 to -1.78)]. MECIR R87: Explain how studies measuring an outcome of interest using different scales (such as alternative rating scales that measure symptoms or behaviour) were combined, stating whether positive or negative values reflect benefit or harm. MECIR R88: Ensure that key findings are interpretable, or are re-expressed in an interpretable way. For instance, they might be re-expressed in absolute terms (e.g. assumed and corresponding risks, NNTs, group means), and outcomes combined with a standardized scale (e.g. SMD) might be re-expressed in units that are more naturally understood. If clinically important effect sizes are well understood, these should be provided to aid interpretation. MECIR R89: Comment on the potential impact of studies that apparently measured outcomes but did not contribute data that allowed the study to be included in syntheses. MECIR R98: Provide justification or rationale for any measures of the quality of the body of evidence for each key outcome. If a Summary of findings table is used, use footnotes to explain any downgrading or upgrading according to the GRADE system. Common errors identified by CEU screening: 1) Discrepancies between results presented in the analyses and their reporting across the text of reviews. 2) Inconsistencies in the reporting of results or interpretation of evidence across different sections of reviews. 3) Overly optimistic conclusions that do not take proper account of the quality of the evidence, particularly when the review is empty or the data are sparse. 4) Common under-utilisation of information from Summary of Findings tables in reporting the review findings. 5) Often unclear or inexplicable decisions in relation to GRADE assessments and assessments that seem to be restricted to risk of bias only. Discussion [No need to add anything here] General points for Discussion section MECIR R100: Discuss limitations of the review at study and outcome level (e.g. regarding risk of bias), and at review-level (e.g. incomplete identification of studies, reporting bias). Common errors identified by CEU screening: 1) Discrepancies between results presented in the analyses and their reporting across the text of reviews. 2) Inconsistencies in the reporting of results or interpretation of evidence across different sections of reviews. 3) Overly optimistic conclusions that do not take proper account of the quality of the evidence, particularly when the review is empty or the data are sparse. 4) Common under-utilisation of information from Summary of Findings tables in reporting the review findings. 5) Often unclear or inexplicable decisions in relation to GRADE assessments and assessments that seem to be restricted to risk of bias only. Summary of main results Cochrane Handbook guidance: Summarize the main findings (without repeating the Effects of interventions section) and outstanding uncertainties, balancing important benefits against important harms. Refer explicitly to any Summary of findings tables and add the link. Common errors identified by CEU screening: 1) Common under-utilisation of information from Summary of Findings tables in reporting the review findings. 2) Often unclear or inexplicable decisions in relation to GRADE assessments and assessments that seem to be restricted to risk of bias only. Overall completeness and applicability of evidence Cochrane Handbook guidance: Describe the relevance of the evidence to the review question. This should lead to an overall judgement of the external validity of the review. Are the studies identified sufficient to address all of the objectives of the review? Have all relevant types of data, methods and outcomes been investigated? Comments on how the results of the review fit into the context of current practice might be included here, although authors should bear in mind that current practice might vary internationally. Quality of the evidence Cochrane Handbook guidance: Does the body of evidence identified allow a robust conclusion regarding the objective(s) of the review? Summarize the amount of evidence that has been included (numbers of studies), state key methodological limitations of the studies, and reiterate the consistency or inconsistency of their results. This should lead to an overall judgement of the internal validity of the results of the review. Potential biases in the review process Cochrane Handbook guidance: State the strengths and limitations of the review with regard to preventing bias. These may be factors within, or outside, the control of the review authors. The discussion might include the likelihood that all relevant studies were identified, whether all relevant data could be obtained, or whether the methods used (for example, searching, study selection, data extraction, analysis) could have introduced bias. Agreements and disagreements with other studies or reviews 9 / 18

Cochrane Handbook guidance: Comments on how the included studies fit into the context of other evidence might be included here, stating clearly whether the other evidence was systematically reviewed. Authors' conclusions Implications for practice Cochrane Handbook guidance: The implications for systematic reviews and other evaluations of health care should be as practical and unambiguous as possible. They should not go beyond the evidence that was reviewed and be justifiable by the data presented in the review. No evidence of effect should not be confused with evidence of no effect. Suggested sub-headings (Heading level 3) for this section: For people with X For clinicians For policy makers For Funders MECIR R18: Consistency of summary versions of the review: Ensure that reporting of objectives, important outcomes, results, caveats and conclusions is consistent across the text, the abstract, the plain language summary and the Summary of findings table (if included). MECIR R101: Provide a general interpretation of the evidence so that it can inform healthcare or policy decisions. Avoid making recommendations for practice. Common error identified by CEU screening: Often the Implications for practice go beyond data. Clinical advice should not be given. Implications for research Cochrane Handbook guidance: This section of Cochrane Methodology reviews may used by people making decisions about future research, and authors should try to write something that will be useful for this purpose. As with the Implications for practice, the content should be based on the available evidence and should avoid the use of information that was not included or discussed within the review. In preparing this section, authors should consider the different aspects of research, perhaps using types of study, data, methods and outcome as a framework. Implications for how research might be done and reported should be distinguished from what future research should be done. For example, the need for randomized trials rather than other types of study, for better descriptions of studies in the particular topic of the review, or for the routine collection of specific outcomes, should be distinguished from the need for comparisons of specific types of method, or for research in specific settings. It is important that this section is as clear and explicit as possible. General statements that contain little or no specific information, such as Future research should be better conducted or More research is needed are of little use to people making decisions, and should be avoided. Suggested sub-headings (Heading level 3) for this section: General Design Measurement (endpoints) Other MECIR R18: Consistency of summary versions of the review: Ensure that reporting of objectives, important outcomes, results, caveats and conclusions is consistent across the text, the abstract, the plain language summary and the Summary of findings table (if included). MECIR R102: If recommending further research, structure the implications for research to address the nature of evidence required, including population, intervention comparison, outcome, and type of study. Common error identified by CEU screening: Often the Implications for research are too vague. Desirable are specific (e.g., suggested trial and possible design) and not general (e.g., more research needed) points. Acknowledgements MECIR R103: Acknowledge the contribution of people not listed as authors of the review, including any assistance from the Cochrane Review Group, non-author contributions to searching, data collection, study appraisal or statistical analysis, and the role of any funders. MECIR R108: List sources of funding for the review and the role of the funder, if any. Acknowledge authors who contributed to the protocol but not the review, if relevant. Cochrane Review Group funding acknowledgement: The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane PaPaS Group. Disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, National Health Service (NHS) or the Department of Health. PaPaS is now required to put our funding statement into all reviews. 10 / 18

Contributions of authors MECIR R104: Describe the contributions of each author. Template for MECIR (Review) Use text, e.g. 'AB screened the search results and contributed to writing the review; BC developed the search strategy,' or a table: Draft the protocol Develop and run the search strategy Obtain copies of studies AB, CD CD PaPaS TSC provided support. AB Select which studies to include (2 people) CD Extract data from studies (2 people) Enter data into RevMan Carry out the analysis Interpret the analysis Draft the final review Update the review AB CD AB CD AB CD Declarations of interest MECIR R105: Report any present or past affiliations or other involvement in any organization or entity with an interest in the review s findings that might lead to a real or perceived conflict of interest. Must be listed separately for each author, noting present or past affiliations or other involvement in any organization or entity with an interest in the review s findings that might lead to a real or perceived conflict of interest, including whether authors are investigators on studies likely to be included in the review. If no potential conflicts are identified for a particular author, please state e.g. 'AB has no known conflicts of interest to declare that are relevant to the development of this review. CD has no known conflicts to declare'. The DoI statements listed here must be identical to the declarations in each electronic 'Conflicts of Interest' form, which will be circulated by the editorial team upon receipt of the first draft. The Cochrane Collaboration has recently updated its Commercial Sponsorship Policy (2014). Please ensure this section is fully compliant. See the policy in full online or contact PaPaS for further information. Differences between protocol and review MECIR R106: Explain and justify any changes from the protocol (including any post hoc decisions about eligibility criteria or the addition of subgroup analyses). Published notes Characteristics of studies Characteristics of included studies TEST 001 11 / 18

Methods Complete this section: Methods: study design (stating whether or not the study was randomized), including, where relevant, a clear indication of how the study differs from a standard parallel group design (e.g. a cross-over or cluster-randomized design); duration of the study (if not included under Intervention). Note: the Methods entry should not include measures of risk of bias; these should appear in a Risk of bias table (see Chapter 8, Section 8.5). Participants Complete this section: Participants: setting; relevant details of health status of participants; age; sex; country. Sufficient information should be provided to allow users of the review to determine the applicability of the study to their population, and to allow exploration of differences in participants across studies. Interventions Complete this section: Intervention: a clear list of the intervention groups included in the study. If feasible, sufficient information should be provided for each intervention to be replicated in practice; for drug interventions, include details of drug name, dose, frequency, mode of administration (if not obvious), duration (if not included under Methods); for non-drug interventions, include relevant considerations and components related to the intervention. Outcomes Complete this section: Outcomes: a clear list of either (i) outcomes and time -points from the study that are considered in the review; or (ii) outcomes and time-points measured (or reported) in the study. Study results should not be included here (or elsewhere in this table). Notes : Notes: further comments from the review authors on aspects of the study that are not covered by the categories above. Note that assessments of risk of bias should be made in a Risk of bias table. It is possible to add up to three extra fields in the Characteristics of included studies table. Where appropriate, review authors are recommended to use an extra field to provide information about the funding of each study. Risk of bias table 12 / 18

Bias Random sequence generation (selection bias) Authors' judgement Low risk Support for judgement Complete this section: for example: Low risk. Quote: patients were randomly allocated. Comment: Probably done, since earlier reports from the same investigators clearly describe use of random sequences (Cartwright 1980). Allocation concealment (selection bias) High risk Complete this section: for example: High risk. Quote:...using a table of random numbers. Comment: Probably not done. Blinding of participants and personnel (performance bias) Low risk Complete this section: for example: Low risk. Quote: double blind, double dummy ; High and low dose tablets or capsules were indistinguishable in all aspects of their outward appearance. For each drug an identically matched placebo was available (the success of blinding was evaluated by examining the drugs before distribution). Blinding of outcome assessment (detection bias) Low risk Complete this section: for example: Low risk. Quote: double blind. Comment: Probably done. Incomplete outcome data (attrition bias) High risk Complete this section: for example: High risk: 4 weeks: 17/110 missing from intervention group (9 due to 'lack of efficacy'); 7/113 missing from control group (2 due to 'lack of efficacy'). Selective reporting (reporting bias) High risk Complete this section: for example: High risk: Three rating scales for cognition listed in Methods, but only one (with statistically significant results) is reported. Other bias Unclear risk Complete this section: for example: Unclear risk: 99 participants per treatment arm. TEST 002 Methods Participants Interventions Outcomes Notes Risk of bias table 13 / 18

Bias Authors' judgement Support for judgement Random sequence generation Unclear risk (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Unclear risk Unclear risk Unclear risk Unclear risk Selective reporting (reporting bias) Unclear risk Other bias Unclear risk Footnotes Characteristics of excluded studies TEST 003 Reason for exclusion, e.g. not an RCT Footnotes Characteristics of studies awaiting classification TEST 004 Methods Participants Interventions Outcomes Notes Footnotes Characteristics of ongoing studies TEST 05 14 / 18

Study name Methods Participants Interventions Outcomes Starting date Contact information Notes Footnotes R62 Include the sample size for each included study in the table of Characteristics of included studies. R63 Provide the basic study design or design features (e.g. parallel group randomized trial, cluster-randomized trial, controlled before and after study). R64 Provide sufficient information about the study populations to enable a user of the review to assess the applicability of the review s findings to their own setting. R65 Provide sufficient information to enable users of the review to assess the applicability of the intervention to their own setting, and if possible in a way that allows the intervention to be replicated. R66 Provide clear and consistent information about outcomes measured (or reported), how they were measured and the times at which they were measured. R68 Include details of funding sources for the study, where available. R69 Include details of any declarations of interest among the primary researchers. R71 List all reports of each included study under the relevant Study ID. Summary of findings tables Common errors identified by CEU screening: 1) Common under-utilisation of information from Summary of Findings tables in reporting the review findings. 2) Often unclear or inexplicable decisions in relation to GRADE assessments and assessments that seem to be restricted to risk of bias only. Additional tables R84 Link to each Table and Figure. References to studies Included studies TEST 001 TEST 002 Excluded studies TEST 003 Studies awaiting classification TEST 004 Ongoing studies TEST 05 15 / 18

R71 List all reports of each included study under the relevant Study ID. R72 Present a Risk of bias table for each included study, with judgements about risks of bias, and explicit supports for these judgements. Reference citation IDs are in the correct format (first author or group abbreviation and year of publication, e.g. Smith 1983 or UKPDS 1990) Included each journal title in full, with no abbreviations. Checked how each reference is displayed to remove unnecessary punctuation. Where applicable, listed the first six authors before using et al. Written the page numbers correctly (e.g. 354-7). Included the date accessed in any references to web pages. Other references Additional references AUREF 2012 Cochrane PaPaS. Authoring or assessing a Cochrane Protocol, Review, or Review Updatefor the PaPaS Review Group (AUREF). PaPaS website [add date accessed] 2012;1. Dechartres 2013 Dechartres A, Trinquart L, Boutron I, Ravaud P. Influence of trial sample size on treatment effect estimates: metaepidemiological study. BMJ 2013;346(f2304). [10.1136/bmj.f2304] GRADEpro 2008 GRADEpro [Computer program]. Jan Brozek, Andrew Oxman, Holger Schünemann. Version 3.2. for Windows, 2008. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. 5.1.0 (Available from www.cochrane-handbook.org) edition. The Cochrane Collaboration, 2009 (Updated March 2011). L'Abbé 1987 L'Abbé KA, Detsky AS, O'Rourke K. Meta-analysis in clinical research. Annals of Internal Medicine 1987;107:224-33. Liberati 2009 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidiset JPA et al. The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration. Annals of Internal Medicine 2009;151(4):W-65-W-94. [10.7326/0003-4819-151-4-200908180-00136] Nüesch 2010 Nüesch E, Trelle S, Reichenbach S, Rutjes AW, Tschannen B, Altman DG, et al. Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study. BMJ 2010;341(c3515). [10.1136/bmj.c3515] RevMan 2014 Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. Commonly used references have been added here. Ensure the Cochrane Style Guide is followed for references, e.g.: 1. No full stops 2. Page numbers 123-4 not 123-124 3. List first six authors, then use 'et al' 4. Include 'Date accessed' for web links 5. Include DOI where possible Other published versions of this review Classification pending references Data and analyses 1 TEST 199 Outcome or Subgroup Studies Participants Statistical Method Effect Estimate 1.1 test 199 2 279 Std. Mean Difference(IV, Fixed, 95% CI) -2.24[-2.69, -1.78] 16 / 18

Ensure the axes labels and totals accurately reflect the data. Ensure the axes labels are consistent (e.g. 'Control' always on the left) Add links to each analysis in the Results section. Figures Figure 1 Caption Flow diagram. Figure 2 Caption Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. Figure 3 17 / 18