Evidence Evaluation Process and Management of Potential Conflicts of Interest: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.

Abstract

HomeCirculationVol. 142, No. 16_suppl_1Evidence Evaluation Process and Management of Potential Conflicts of Interest: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessReview ArticlePDF/EPUBEvidence Evaluation Process and Management of Potential Conflicts of Interest: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Peter T. Morley, MBBS, Dianne L. Atkins, MD, Judith C. Finn, RN, PhD, Ian Maconochie, PhD, Jerry P. Nolan, MBChB, Yacov Rabi, MD, Eunice M. Singletary, MD, Tzong-Luen Wang, MD, PhD, Michelle Welsford, MD, Theresa M. Olasveengen, MD, PhD, Richard Aickin, MBChB, John E. Billi, MD, Robert Greif, MD, MME, Eddy Lang, MD, Mary E. Mancini, RN, PhD, William H. Montgomery, MD, Robert W. Neumar, MD, PhD, Gavin D. Perkins, MD, Jasmeet Soar, MA, MBBChir, Myra H. Wyckoff, MD and Laurie J. Morrison, MD, MSc Peter T. MorleyPeter T. Morley Search for more papers by this author , Dianne L. AtkinsDianne L. Atkins Search for more papers by this author , Judith C. FinnJudith C. Finn Search for more papers by this author , Ian MaconochieIan Maconochie Search for more papers by this author , Jerry P. NolanJerry P. Nolan Search for more papers by this author , Yacov RabiYacov Rabi Search for more papers by this author , Eunice M. SingletaryEunice M. Singletary Search for more papers by this author , Tzong-Luen WangTzong-Luen Wang Search for more papers by this author , Michelle WelsfordMichelle Welsford Search for more papers by this author , Theresa M. OlasveengenTheresa M. Olasveengen Search for more papers by this author , Richard AickinRichard Aickin Search for more papers by this author , John E. BilliJohn E. Billi Search for more papers by this author , Robert GreifRobert Greif Search for more papers by this author , Eddy LangEddy Lang Search for more papers by this author , Mary E. ManciniMary E. Mancini Search for more papers by this author , William H. MontgomeryWilliam H. Montgomery Search for more papers by this author , Robert W. NeumarRobert W. Neumar Search for more papers by this author , Gavin D. PerkinsGavin D. Perkins Search for more papers by this author , Jasmeet SoarJasmeet Soar Search for more papers by this author , Myra H. WyckoffMyra H. Wyckoff Search for more papers by this author and Laurie J. MorrisonLaurie J. Morrison Search for more papers by this author Originally published21 Oct 2020https://doi.org/10.1161/CIR.0000000000000891Circulation. 2020;142:S28–S40ContentsEvidence Evaluation Process S292015 Evidence Evaluation Process S292016 to 2020 Evolution of the Evidence Evaluation Process S29Types of Evidence Evaluation S30Management of Potential Conflicts of Interest Throughout the Process S35Next Steps S36Disclosures S36References S38“Measurement is the first step that leads to control and eventually to improvement. If you can’t measure something, you can’t understand it. If you can’t understand it, you can’t control it. If you can’t control it, you can’t improve it.”— H. James HarringtonThe 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR) is the result of a long period of collaboration of international experts under the umbrella of the International Liaison Committee on Resuscitation (ILCOR). The ILCOR organization comprises the world’s leading resuscitation councils: the American Heart Association (AHA), the European Resuscitation Council, the Heart and Stroke Foundation of Canada, the Australian and New Zealand Committee on Resuscitation, the Resuscitation Council of Southern Africa, the InterAmerican Heart Foundation, and the Resuscitation Council of Asia. The vision of ILCOR is “saving more lives globally through resuscitation,” and its mission is “to promote, disseminate, and advocate international implementation of evidence-informed resuscitation and first aid, using transparent evaluation and consensus summary of scientific data.” These goals are outlined in more detail in the 2016 to 2020 ILCOR Strategic Plan (as electronic supplement).1There are 6 ILCOR task forces: Basic Life Support; Advanced Life Support; Pediatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Aid.2 Task force members represent diverse countries and bring expertise in all aspects of prearrest, arrest, postarrest care, and first aid. ILCOR appoints task force members by using a request for application and a rigorous selection process, with the goal of balancing scientific and clinical expertise, representation across ILCOR member councils, representation across gender, and diversity across career levels (early, mid, senior). Each task force also has an elected chair and deputy chair, and all positions have a required (time-based) turnover of positions. The Acute Coronary Syndromes Task Force was not continued after 2015, but relevant questions continue to be addressed within existing task forces.ILCOR maintains its commitment to a rigorous and continuous review of scientific literature focused on resuscitation, cardiac arrest, relevant conditions requiring first aid, related education, implementation strategies, and systems of care.ILCOR is also committed to publishing regular and ongoing CoSTRs. The science evaluation performed by ILCOR underpins the development of international resuscitation council guidelines (including the AHA and the European Resuscitation Council).Evidence Evaluation ProcessThe most important product of the ILCOR evidence evaluation process is the summary of the evidence identified (consensus on science) and the accompanying treatment recommendations. ILCOR is committed to transparency in presenting consensus descriptions and summaries of the evidence, and the creation of treatment recommendations whenever consensus can be achieved. The processes to evaluate the information available has evolved substantially over the past 2 decades, as has ILCOR’s approach to reviewing the science related to its mission.2015 Evidence Evaluation ProcessIn 2015, ILCOR published its detailed 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.3,4 It was a very detailed process in which 250 evidence reviewers from 39 countries completed 165 systematic reviews (SysRevs) on resuscitation-related questions. These reviews were completed according to a detailed process, including the use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE).5,6 These reviews were published in summary format as the 2015 CoSTR.3,4 The supporting documentation for these SysRevs was published in electronic format with the key components of the review (including PICO [population, intervention, comparator, outcome] question, search strategies, bias assessment tools, GRADE evidence profile tables, and CoSTRs) housed in a repository. This process was also underpinned by a rigorous conflict of interest (COI) process, and each SysRev was peer reviewed.5,6The detailed methodology for the SysRevs completed for the 2015 CoSTR is outlined in the evidence evaluation chapter.5,6 Very few of these SysRevs went on to publication.2016 to 2020 Evolution of the Evidence Evaluation ProcessBeginning in 2016, ILCOR reviewed and restructured the evidence evaluation process to better meet its commitment to facilitate a rigorous, continuous evidence review. ILCOR committed to change the CoSTR evidence review and publication from every 5 years to an annual update. The organization then began creating the infrastructure to support these reviews and facilitate ILCOR’s vision and mission.1Continuous Evidence Evaluation Working GroupILCOR created a governance process to support ongoing evidence evaluation. The Continuous Evidence Evaluation Working Group (CEE WG) was created, and it commissioned high-quality SysRevs to be performed by knowledge synthesis units (KSUs) and expert systematic reviewers (ESRs). More details of the role and components of these KSUs and ESRs are described in the subsequent sections. The publication of peer-reviewed SysRevs in addition to the peer-reviewed ILCOR CoSTRs maximizes dissemination of the evidence. The first of these commissioned SysRevs was published in 2017,7 and, on the basis of this review, the basic life support and pediatric life support CoSTR Updates were published in 2017.8,9 Additional SysRevs provided the foundation for CoSTR Updates in 201810,11 and 2019.12,13 In all, 4 KSU pilots and 24 expert SysRev pilots were commissioned. The CoSTRs and evidence-to-decision frameworks and links to the International Prospective Register of Systematic Reviews (PROSPERO) registration and published SysRev manuscripts are posted on ILCOR.org.14The CEE WG provided additional expertise and resources to support the task forces. Domain leads are researchers and clinicians with specialized knowledge in topics such as defibrillation or cardiopulmonary resuscitation adjuncts. They were appointed to assist the task forces in identifying and analyzing relevant evidence. CEE WG members, domain leads, task force chairs and other experts subscribed to publication alerts to keep them aware of studies published relevant to their review topics and areas of expertise.ILCOR also facilitated the creation of a more permanent document and template repository on its website.14 This repository houses the instructional and process documents that support the continuous evidence evaluation process,15 an explanatory video about the continuous evidence evaluation process,16 the draft CoSTRs,17 and final versions of the CoSTRs. This site has a public interface where draft material is posted for public review and comments during the creation of the SysRevs and CoSTRs.The ILCOR SysRev process continues to be based on the methodological principles published by the National Academy of Health and Medicine (formerly the Institute of Medicine) in 2011,18 the Cochrane Library,19–21 GRADE,22 and the reporting guidelines based on the recommendations from Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA23).24 The details of this evidence evaluation process established by the CEE WG for the KSUs and ESRs can be found in the workflow document25 and are outlined in a descriptive video.16Scientific Advisory CommitteeThe CEE WG was created as the interim methodological governance process in 2016, and it continued to function until the ILCOR Scientific Advisory Committee (SAC) was convened. The SAC first met in August 2019, with elected members and some ex-officio representation. Committee appointments required methodological expertise, a track record of involvement with review of resuscitation science, and appropriate content knowledge. Members met regularly (every 1–2 weeks) by webinar and continued the governance of the CEE process. The new and updated process documents and reporting templates were posted on the ILCOR website.15 Specific SAC members were assigned to work with specific ILCOR task forces, to provide a conduit for methodological expertise and advice, and to facilitate completion of and the methodological rigor of the task force–based evidence reviews.Prioritization of Questions AskedThe ILCOR task forces prioritized topics for review in several ways. Topics related to the large existing list of ILCOR PICO questions from 2010 and 2015 were initially prioritized by the relevant ILCOR task forces. The task forces continually reevaluated their priorities using several tools, including areas identified as gaps by the 2015 reviews,26,27 ongoing literature searches performed by the domain leads, information gleaned from recently completed studies, “hot” topics, and areas of controversy or confusion raised by task force members or ILCOR member councils. All prioritized questions were revised and written into a PICOST (population, intervention, comparator, outcome, study design, time frame) format to facilitate the planned review. Diagnostic and prognostic questions required a modification of the standard PICOST format. All PICOSTs for ILCOR reviews were required to be reviewed and approved by members of the CEE WG/SAC.Public CommentILCOR is committed to obtaining input from the broadest community possible to help it establish the most relevant topics, the best way to describe its processes for maximum transparency, and the most useful treatment recommendations. Beginning in 2016, ILCOR has communicated with lay and professional organizations to direct the public to the ILCOR website and sends email communications to those previously engaged to notify them of any additional postings for comment. The individual draft 2020 CoSTRs were accessed and viewed more than 200 000 times.Each submitted CoSTR is accompanied by a completed GRADE evidence-to-decision framework,28,29 which is used by the task force to guide its members through a list of key questions. The ILCOR task forces are given guidance on how to provide background information outlining their discussions in sections of the reviews titled “Justification and Evidence-to-Decision Framework Highlights” and “Task Force Insights.” The task forces are also requested to provide a list of key gaps in knowledge that had been identified. The product of these deliberations is published as a draft CoSTR online,17 in the yearly CoSTR summary documents,8–13 and in the more complete summary documents (such as this publication series).30 The integrity of these products and a transparent description of the processes that underly them is crucial because these products are used by the international guideline-writing bodies to write the resuscitation guidelines.Types of Evidence EvaluationThe 2020 CoSTR includes many SysRevs (performed by the relevant task forces, with or without additional appointed experts), but for the first time it also includes other evidence evaluation processes: task force–based scoping reviews (ScopRevs) and international collaborator-based evidence updates (EvUps). Table 1 lists some of the key components of each of these reviews.Table 1. Overview of the Evidence Evaluation Processes for the 2020 CoSTRKSU SysRevESR SysRevTask Force SysRevTask Force ScopRevEvUpQuestion based on task force priorities✓✓✓✓±Guidance for reviewPRISMAPRISMAPRISMAPRISMA-ScRILCOR and member councilsSearch strategy created by information specialist*✓✓✓✓±Lead for reviewKSUESRILCOR Task ForceILCOR Task ForceILCOR member council collaboratorsContent experts from task force✓✓✓✓±Review of published data✓✓✓✓✓Combination of data (eg meta-analysis)✓✓✓--Bias assessment✓✓✓--GRADE evidence profile tables✓✓✓--GRADE EtD✓✓✓--Task force review and insights incorporated✓✓✓✓-Consensus on science✓✓✓--Revision/creation of treatment recommendation†✓✓✓--Opportunity for public comment✓✓✓✓-Peer-reviewed publication†✓✓±±-Included in 2020 CoSTR manuscriptSummary, including PICOST, CoSTRSummary, including PICOST, CoSTRSummary, including PICOST, CoSTRSummary, including PICOSTSummary, including PICOSTIncluded in 2020 CoSTR appendixes in the Data SupplementEtD:EtD:EtD:Supplement Appendix BSupplement Appendix CSupplement Appendix ASupplement Appendix ASupplement Appendix A* Peer-reviewed search strategies were created by information specialists for all ESR and KSU SysRevs.† Independent peer review was required for all KSU and ESR SysRevs before posting of CoSTRs and journal submission of SysRevs.✓ indicates required; ±, not required but preferred; -, not consistent with methodology; CoSTR, Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations; ESR, expert systematic reviewer; EtD, evidence-to-decision framework; EvUp, evidence update; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; ILCOR, International Liaison Committee on Resuscitation; KSU, knowledge synthesis unit; PICOST, population, intervention, comparator, outcome, study design, time frame; PRISMA, Preferred Reporting Items for a Systematic Review and Meta-Analysis23; PRISMA-ScR, Preferred Reporting Items for a Systematic Review and Meta-Analysis–extension for Scoping Reviews32; ScopRev, scoping review; and SysRev, systematic review.Systematic ReviewsIdeally, every ILCOR topic reviewed would have the benefit of a meticulously performed SysRev as the basis for critical appraisal. The Academy of Medicine defines a SysRev as a “scientific investigation that focuses on a specific question and uses explicit, prespecified scientific methods to identify, select, assess, and summarize the findings of similar but separate studies. It may include a quantitative synthesis (meta-analysis), depending on the availability of data.”18 Although the ILCOR membership values SysRevs, many resuscitation topics and questions are still not addressed by adequately powered, randomized clinical trials or high-quality observational studies to evaluate outcomes that the task forces agree are critical.31,32The list of processes common to all ILCOR SysRevs is outlined in Table 2. Some of these steps are outlined in more detail in the sections that follow. The information from these SysRevs has been incorporated into the respective task force chapters. The CoSTR and evidence-to-decision frameworks for these reviews were posted in draft form on the ILCOR website,17 and the approved CoSTRs are included in the respective task force publication, with an evidence-to-decision table for each new CoSTR in Supplement Appendix A in the Data Supplement.Pathways to Completion of SysRevsIn the evidence evaluation process that resulted in the 2015 CoSTR, all SysRevs were performed by the task forces. Since 2016, the process has involved several options for completing SysRevs; these options are outlined below.Knowledge Synthesis Units.ILCOR began a pilot program that commissioned internationally renowned groups of systematic-review methodologists who had completed a request for proposals to perform SysRevs. These groups had experience publishing high-quality SysRevs, and some adopted the name knowledge synthesis unit. The KSUs were commissioned to research evidence addressing particularly complex questions and multiple PICOSTs that usually involved more than 1 task force and to capture and analyze data to address multiple subgroup issues. The KSU staff worked in conjunction with content experts (as well as members of the CEE WG/SAC) who ensured that all relevant task forces were involved when questions were common to 2 or more of the task forces.The KSUs performed a commissioned review, based on contracts created with strict timelines for delivery. The KSU process included clear instructions about engagement of task force(s) and expectations for the final product, which included a peer-reviewed publication. Details are included in an online instructional document35 (see Table 1 summary for more details).Expert Systematic Reviewer.ILCOR invited expressions of interest for the ESR roles. These individuals or small collaborative groups were required to have methodological expertise and a track record of publications within the relevant domains. The appointed ESRs were then commissioned to perform SysRevs (see Table 1 for more details). The PICOSTs assigned to ESRs were less complex, with limited subgroup analyses, and usually involved a single task force. The first SysRev conducted by an ESR was published in 2018.36Task Force SysRev.The detailed KSU and ESR process for completion of SysRevs was commissioned by ILCOR with a contractual requirement to publish a SysRev in a peer-reviewed journal. The task forces, however, identified many topics that did not address complex questions or require extensive subgroup analyses. As in the ILCOR evidence evaluation processes through 2015, the ILCOR task forces were empowered to complete such reviews. If a topic was considered appropriate for a task force SysRev, the task force created a SysRev team and followed a formal process37 (see Table 2). The CoSTRs for these SysRevs are incorporated into the task force chapters. The supporting evidence-to-decision framework for each of the task force SysRevs is published in Supplement Appendix A. The first task force–based SysRev was published in 2020.38Table 2. Summary Outline of the Process Steps for the 2020 CoSTR SysRevsTask forces select, prioritize, and refine questions (using PICOST format)Task forces allocate level of importance to individual outcomesTask forces allocate PICOST question to SysRev team*SysRev registered with PROSPEROSysRev team works with information specialists to develop and fine-tune database-specific search strategiesRevised search strategies used to search databasesArticles identified by the search are screened by allocated members of the SysRev team using inclusion and exclusion criteriaSysRev team agrees on final list of studies to includeSysRev team agrees on assessment of bias for individual studiesGRADE Evidence Profile table createdDraft CoSTRs created by SysRev teamEvidence-to-decision framework completed by task forcePublic invited to comment on draft CoSTRsDetailed iterative review of CoSTRs to create final versionPeer review of final CoSTR documentCoSTR indicates Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; PICOST, population, intervention, comparison, outcome, study design, time frame; PROSPERO, International Prospective Register of Systematic Reviews; and SysRev, systematic review.* Systematic review team could be knowledge synthesis unit, expert systematic reviewer, or task-force-led team involving content experts from the International Liaison Committee on Resuscitation task force(s), and delegated member of the Continuous Evidence Evaluation Working Group and Scientific Advisory Committee.Adolopment.For some prioritized questions, the task force identified an existing, relevant, recently published SysRev (with or without a meta-analysis). The SAC recognized that duplication of effort to complete a new SysRev would be a waste of resources. For these situations, the CEE WG/SAC recommended use of the GRADE-Adolopment methodology39 to assess whether the identified review could be adopted and adapted as needed. This methodology includes a rigorous process with strict steps to allow the incorporation of the information into an ILCOR SysRev. The result of this process could be the construction of a CoSTR. This process was first used by the Advanced Life Support Task Force to review prophylactic antibiotic use after cardiac arrest.40,40a,41Components of a SysRevFormulating the Question.Existing and new questions for any SysRevs were formulated to comply with the population, intervention, comparison, outcome, study design42 and time frame. The CEE WG/SAC developed a generic template to facilitate the development of a sensitive and specific search strategy.43Search Strategy.The search strategies were created by information specialists on the basis of the PICOST question. Most of the searches were conducted by an information specialist contracted by ILCOR, while some were conducted by information specialists working with topic experts. Many of the search strategies themselves were independently peer reviewed. The CEE WG/SAC requested that the searches be performed, at a minimum, using MEDLINE, Embase, and the Cochrane Library. The CEE WG/SAC also requested a search of relevant databases of submitted protocols, to identify any incomplete or unpublished trials, and for the search to be registered with PROSPERO.Questions Related to Prognosis and Diagnostic Test Accuracy.Most topics reviewed by the task forces related to interventions, but some by necessity were focused on prognosis or diagnostic test accuracy. GRADE has formulated processes to support these,44,45 and the CEE WG/SAC provided guidance on outcome selection, tools for bias assessment, evidence profile tables, and variation in the evidence-to-decision framework. For some of the prognostic questions, the outcome measures used for diagnostic methodology (eg, specificity) were considered to have especially significant clinical relevance.46Combination of Data (Meta-Analysis).One reason to complete a SysRev is to facilitate the performance of meta-analyses. It is not always appropriate to combine data from identified studies, and reviewers were encouraged to consider the methodological rigor of the identified studies, and how similar they were with regard to components of the PICOST. If there were limitations to performing the meta-analysis (including heterogeneity), task forces were asked to describe these and to consider sensitivity analyses by including or excluding specific types of studies.19 The task forces were asked to state explicitly situations where the heterogeneity of studies precluded meta-analysis (eg, the nature of the results, the extent to which the results addressed the PICOST question, the methodology).GRADE ProcessGRADE was adopted by ILCOR for the 2015 evidence evaluation process.5,6 The GRADE process and ILCOR evidence evaluation have both continued to evolve, and a number of changes were made to the ILCOR evidence evaluation process to ensure consistency with the GRADE process. The GRADE risk-of-bias tools for randomized controlled trials and nonrandomized studies have changed, and the online guideline development tool has been updated. The GRADE developers continue to refine their processes, including improving ways to explain the published evidence.47 These updates were introduced through use of the online GRADE handbook22 and via specific publications.Key components of the GRADE process that were incorporated into the SysRevs completed for the 2020 ILCOR CoSTRs are listed below.Bias Assessment for Randomized Controlled Trials.The recommended risk of bias tool for randomized controlled trials is now the revised Cochrane Risk of Bias tool.48 This tool assesses the risk of bias using signaling questions to explore 5 domains for individually randomized trials, including bias arising from the randomization process, due to deviations from intended interventions, due to missing outcome data, in measurement of the outcome, and in selection of the reported result.Bias Assessment for Nonrandomized Trials.When using GRADE to evaluate certainty of evidence, the original certainty of evidence started at high for randomized controlled trials for interventions and started at low for observational (nonrandomized studies).49 As the types of evidence reviewed using the GRADE methodology expanded, some concern was expressed that the GRADE approach was unnecessarily harsh in its assessment of the certainty of the evidence.50 The GRADE group revisited this automatic allocation of evidence. The new recommended tool to assess risk of bias for nonrandomized studies was Risk of Bias In Non-randomised Studies - of Interventions (ROBINS-I).51 This tool enables all nonrandomized studies to start at low risk of bias, but it is expected that they will be adjusted to moderate, serious, or critical risk on the basis of methodological concerns.50Evidence Profile Tables.The GRADE evidence profile tables have been created to present a summary of the evidence that addresses the particular outcome. The ILCOR task forces continue to use the guidance from instructional documents on the ILCOR website, and the online GRADE guideline development tool52 to complete these tables. These tables include the following information: the specific outcome; the number of studies and their study design(s); judgments about risk of bias, inconsistency, indirectness, imprecision, and other considerations (including publication bias and factors that increase the certainty of evidence); relative and absolute effects for that outcome; a rating of the overall certainty of evidence for each outcome (which may vary by outcome); classification of the importance of each outcome; and explanatory footnotes, if needed. The use of these tables facilitates the translation of a body of science into a summary of science. The ILCOR task forces use the content of the evidence profile tables as a way to create the consensus on science statements. Wording may be: “For the critical outcome of survival to hospital discharge, we identified low-certainty evidence (downgraded for risk of bias and indirectness) from 3 randomized studies that enrolled 873 patients.” The evidence profile tables are not included in the task force chapter or appendices but are included in the SysRevs published in the peer-reviewed literature.Certainty (Quality) of Evidence.The GRADE process requires an allocation of the overall quality of the evidence identified to support each important or critical outcome. ILCOR adopted the phrase “certainty of evidence” as recently recommended by the GRADE working group.53 The ratings of the certainty of evidence reflect the extent of our confidence that the estimates of the effect are correct. This certainty of evidence, which is based on our confidence in the estimate of the relative importance of the outcomes (and their variability) is adequate to support a particular recommendation.54 The allocated certainty can be high, moderate, low, or very low (see Table 3).22Table 3. Certainty (Quality) of Evidence for a Specific Outcome (or Across Outcomes)22GradeDefinitionHighWe are very confident that the true effect lies close to tha