Search

Background The Cochrane Bias Methods Group recently developed the “Risk of Bias (ROB) in Non-randomized Studies of Interventions” (ROBINS-I) tool to assess ROB for non-randomized studies of interventions (NRSI). It is important to establish consistency in its application and interpretation across review teams. In addition, it is important to understand if specialized training and guidance will improve the reliability of the results of the assessments. Therefore, the objective of this cross-sectional study is to establish the inter-rater reliability (IRR), inter-consensus reliability (ICR), and concurrent validity of ROBINS-I. Furthermore, as this is a relatively new tool, it is important to understand the barriers to using this tool (e.g., time to conduct assessments and reach consensus—evaluator burden). Methods Reviewers from four participating centers will appraise the ROB of a sample of NRSI publications using the ROBINS-I tool in two stages. For IRR and ICR, two pairs of reviewers will assess the ROB for each NRSI publication. In the first stage, reviewers will assess the ROB without any formal guidance. In the second stage, reviewers will be provided customized training and guidance. At each stage, each pair of reviewers will resolve conflicts and arrive at a consensus. To calculate the IRR and ICR, we will use Gwet’s AC1 statistic. For concurrent validity, reviewers will appraise a sample of NRSI publications using both the New-castle Ottawa Scale (NOS) and ROBINS-I. We will analyze the concordance between the two tools for similar domains and for the overall judgments using Kendall’s tau coefficient. To measure the evaluator burden, we will assess the time taken to apply the ROBINS-I (without and with guidance), and the NOS. To assess the impact of customized training and guidance on the evaluator burden, we will use the generalized linear models. We will use Microsoft Excel and SAS 9.4 to manage and analyze study data, respectively. Discussion The quality of evidence from systematic reviews that include NRS depends partly on the study-level ROB assessments. The findings of this study will contribute to an improved understanding of the ROBINS-I tool and how best to use it.

Objective: The objective of the study was to clarify how the Grading of Recommendations Assessment, Development and Evaluation (GRADE) concept of certainty of evidence applies to certainty ratings of test accuracy. Study Design and Setting: After initial brainstorming with GRADE Working Group members, we iteratively refined and clarified the approaches for defining ranges when assessing the certainty of evidence for test accuracy within a systematic review, health technology assessment, or guideline. Results: Ranges can be defined both for single test accuracy and for comparative accuracy of multiple tests. For systematic reviews and health technology assessments, approaches for defining ranges include some that do not require value judgments regarding downstream health outcomes. Key challenges arise in the context of a guideline that requires ranges for sensitivity and specificity that are set considering possible effects on all critical outcomes. We illustrate possible approaches and provide an example from a systematic review of a direct comparison between two test strategies. Conclusions: This GRADE concept paper provides a framework for assessing, presenting, and making decisions based on the certainty of evidence for test accuracy. More empirical research is needed to support future GRADE guidance on how to best operationalize the candidate approaches.

Background: Peroral endoscopic myotomy (POEM) is increasingly used as primary treatment for esophageal achalasia, in place of the options such as Heller myotomy (HM) and pneumatic dilatation (PD) Objective: These evidence-based guidelines from the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) intend to support clinicians, patients and others in decisions about the use of POEM for treatment of achalasia. Results: The panel agreed on 4 recommendations for adults and children with achalasia. Conclusions: Strong recommendation for the use of POEM over PD was issued unless the concern of continued postoperative PPI use remains a key decision-making concern to the patient. Conditional recommendations included the option of using either POEM or HM with fundoplication to treat achalasia, and favored POEM over HM for achalasia subtype III.

Objectives To evaluate the impact of guidance and training on the inter-rater reliability (IRR), inter-consensus reliability (ICR) and evaluator burden of the Risk of Bias (RoB) in Non-randomized Studies (NRS) of Interventions (ROBINS-I) tool, and the RoB instrument for NRS of Exposures (ROB-NRSE). Study design and Setting In a before-and-after study, seven reviewers appraised the RoB using ROBINS-I (n = 44) and ROB-NRSE (n = 44), before and after guidance and training. We used Gwet's AC1 statistic to calculate IRR and ICR. Results After guidance and training, the IRR and ICR of the overall bias domain of ROBINS-I and ROB-NRSE improved significantly; with many individual domains showing either a significant (IRR and ICR of ROB-NRSE; ICR of ROBINS-I), or nonsignificant improvement (IRR of ROBINS-I). Evaluator burden significantly decreased after guidance and training for ROBINS-I, whereas for ROB-NRSE there was a slight nonsignificant increase. Conclusion Overall, there was benefit for guidance and training for both tools. We highly recommend guidance and training to reviewers prior to RoB assessments and that future research investigate aspects of guidance and training that are most effective.

Objective To propose an approach for developing trustworthy recommendations as part of urgent responses (1-2 weeks) in the clinical, public health, and health systems fields. Study design and setting We conducted a review of the literature, outlined a draft approach, refined the concept through iterative discussions, a workshop by the GRADE Rapid Guidelines project group, and obtained feedback from the larger GRADE working group. Results A request for developing recommendations within two weeks is the usual trigger for an urgent response. While the approach builds on the general principles of trustworthy guideline development, we highlight the following steps: (1) assess the level of urgency; (2) assess feasibility; (3) set up the organizational logistics; (4) specify the question(s); (5) collect the information needed; (6) assess the adequacy of identified information; (7) develop the recommendations using one of four potential approaches: adopt existing recommendations; adapt existing recommendations; develop new recommendations using existing adequate systematic review; or develop new recommendations using expert panel input; and (8) consider an updating plan. Conclusion An urgent response for developing recommendations requires building a cohesive, skilled and highly motivated multidisciplinary team with the necessary clinical, scientific, and methodological expertise, adapting to shifting needs, complying with the principles of transparency and properly managing conflicts of interest., Highlights • The proposed approach for developing trustworthy recommendations as part of urgent responses (1-2 weeks) builds on the general principles of trustworthy guideline development; • The approach proposes the following steps: (1) assess the level of urgency; (2) clarify and focus the scope of question(s); (3) prioritize and collect the information needed; (4) assess the adequacy of identified information; and then (5) develop recommendations; • Developing recommendations can consist of a) adopting existing recommendations; (b) adapting existing recommendations; c) developing new recommendations using existing systematic reviews; or d) developing new recommendations using identified information and panel input.

Objective To assess the real-world interrater reliability (IRR), interconsensus reliability (ICR), and evaluator burden of the Risk of Bias (RoB) in Nonrandomized Studies (NRS) of Interventions (ROBINS-I), and the ROB Instrument for NRS of Exposures (ROB-NRSE) tools. Study Design and Setting A six-center cross-sectional study with seven reviewers (2 reviewer pairs) assessing the RoB using ROBINS-I (n = 44 NRS) or ROB-NRSE (n = 44 NRS). We used Gwet’s AC1 statistic to calculate the IRR and ICR. To measure the evaluator burden, we assessed the total time taken to apply the tool and reach a consensus. Results For ROBINS-I, both IRR and ICR for individual domains ranged from poor to substantial agreement. IRR and ICR on overall RoB were poor. The evaluator burden was 48.45 min (95% CI 45.61 to 51.29). For ROB-NRSE, the IRR and ICR for the majority of domains were poor, while the rest ranged from fair to perfect agreement. IRR and ICR on overall RoB were slight and poor, respectively. The evaluator burden was 36.98 min (95% CI 34.80 to 39.16). Conclusions We found both tools to have low reliability, although ROBINS-I was slightly higher. Measures to increase agreement between raters (e.g., detailed training, supportive guidance material) may improve reliability and decrease evaluator burden.

Background A new tool, “risk of bias (ROB) instrument for non-randomized studies of exposures (ROB-NRSE),” was recently developed. It is important to establish consistency in its application and interpretation across review teams. In addition, it is important to understand if specialized training and guidance will improve the reliability in the results of the assessments. Therefore, the objective of this cross-sectional study is to establish the inter-rater reliability (IRR), inter-consensus reliability (ICR), and concurrent validity of the new ROB-NRSE tool. Furthermore, as this is a relatively new tool, it is important to understand the barriers to using this tool (e.g., time to conduct assessments and reach consensus—evaluator burden). Methods Reviewers from four participating centers will apprise the ROB of a sample of NRSE publications using ROB-NRSE tool in two stages. For IRR and ICR, two pairs of reviewers will assess the ROB for each NRSE publication. In the first stage, reviewers will assess the ROB without any formal guidance. In the second stage, reviewers will be provided customized training and guidance. At each stage, each pair of reviewers will resolve conflicts and arrive at a consensus. To calculate the IRR and ICR, we will use Gwet’s AC1 statistic. For concurrent validity, reviewers will appraise a sample of NRSE publications using both the Newcastle-Ottawa Scale (NOS) and ROB-NRSE tool. We will analyze the concordance between the two tools for similar domains and for the overall judgments using Kendall’s tau coefficient. To measure evaluator burden, we will assess the time taken to apply ROB-NRSE tool (without and with guidance), and the NOS. To assess the impact of customized training and guidance on the evaluator burden, we will use the generalized linear models. We will use Microsoft Excel and SAS 9.4, to manage and analyze study data, respectively. Discussion The quality of evidence from systematic reviews that include NRSE depends partly on the study-level ROB assessments. The findings of this study will contribute to an improved understanding of ROB-NRSE and how best to use it.

Intraoperative use of transesophageal echocardiography (TEE) has become commonplace in high-risk noncardiac surgeries but the balance of benefits and harms remains unclear. This systematic review investigated the comparative effectiveness and harms of intraoperative TEE in noncardiac surgery. We searched Ovid MEDLINE, PubMed, EMBASE, and the Cochrane Library from 1946 to March 2017. Two reviewers independently screened the literature for eligibility. Studies were assessed for the risk of selection bias, confounding, measurement bias, and reporting bias. Three comparative and 13 noncomparative studies were included. Intraoperative TEE was employed in a total of 1912 of 3837 patients. Studies had important design limitations. Data were not amenable to quantitative synthesis due to clinical and methodological diversity. Reported incidence of TEE complications ranged from 0% to 1.7% in patients undergoing various procedures (5 studies, 540 patients). No serious adverse events were observed for mixed surgeries (2 studies, 197 patients). Changes in surgical or medical management attributable to the use of TEE were noted in 17% to 81% of patients (7 studies, 558 patients). The only randomized trial of intraoperative TEE was grossly underpowered to detect meaningful differences in 30-day postoperative outcomes. There is lack of high-quality evidence of effectiveness and harms of intraoperative TEE in the management of non-cardiac surgeries. Evidence, however, indicates timely evaluation of cardiac function and structure, and hemodynamics. Future studies should be comparative evaluating confounder-adjusted impact on both intraoperative and 30-day postoperative clinical outcomes.

Background Once a proposed topic has been identified for a systematic review and has undergone a question formulation stage, a protocol must be developed that specifies the scope and research questions in detail and outlines the methodology for conducting the systematic review. Rationale Framework modifications are often needed to accommodate increased complexity. We describe and give examples of adaptations and alternatives to traditional analytic frameworks. Discussion This article identifies and describes elements of frameworks and how they can be adapted to inform the protocol and conduct of systematic reviews of complex interventions. Modifications may be needed to adapt the population, intervention, comparators, and outcomes normally used in protocol development to successfully describe complex interventions; in some instances, alternative frameworks may be better suited. Possible approaches to analytic frameworks for complex interventions that illustrate causal and associative linkages are outlined, including time elements, which systematic reviews of complex interventions may need to address. The need for and specifics of the accommodations vary with details of a specific systematic review. This in turn helps determine whether traditional frameworks are sufficient, can be refined, or if alternate frameworks must be adopted.

Objectives\ud This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments (HTA) and guideline developers can assess the results and the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA).\ud Study Design and Setting\ud We present an overview of the GRADE approach and guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Part 1 of the two parts in this 21st guidance article about how to apply GRADE focuses on understanding study design issues in test accuracy, provide an overiew of the domains and describe risk of bias and indirectness specifically.\ud Results\ud Supplemented by practical examples, we describe how raters of the evidence using GRADE can evaluate study designs focusing on tests and how they apply the GRADE domains risk of bias and indirectness to a body of evidence of TA studies.\ud Conclusions\ud Rating the certainty of a body of evidence using GRADE in Cochrane and other reviews and World Health Organization and other guidelines dealing with in TA studies helped refining our approach. The resulting guidance will help applying GRADE successfully for questions and recommendations focusing on tests.

Objectives This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments (HTA) and guideline developers can rate the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA) on the domains imprecision, inconsistency, publication bias and other domains. It also provides guidance for how to present synthesized information in evidence profiles and summary of findings tables. Study Design and Setting We present guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Results Supplemented by practical examples, we describe how raters of the evidence can apply the GRADE domains inconsistency, imprecision, and publication bias to a body of evidence of TA studies. Conclusions Using GRADE in Cochrane and other reviews as well as World Health Organization and other guidelines helped refining the GRADE approach for rating the certainty of a body of evidence from TA studies. While several of the GRADE domains (e.g., imprecision and magnitude of the association) require further methodological research to help operationalize them, judgments need to be made on the basis of what is known so far.

Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology is used to assess and report certainty of evidence and strength of recommendations. This GRADE concept article is not GRADE guidance but introduces certainty of net benefit, defined as the certainty that the balance between desirable and undesirable health effects is favourable. Determining certainty of net benefit requires considering certainty of effect estimates, the expected importance of outcomes and variability in importance, and the interaction of these concepts. Certainty of net harm is the certainty that the net effect is unfavourable. Guideline panels using or testing this approach might limit strong recommendations to actions with a high certainty of net benefit or against actions with a moderate or high certainty of net harm. Recommendations may differ in direction or strength from that suggested by the certainty of net benefit or harm when influenced by cost, equity, acceptability or feasibility.

© 2018 The Authors Context: Based on the clinical care pathway of delirium in palliative care (PC), a published analytic framework (AF) formulated research questions in key domains and recommended a scoping review to identify evidence gaps. Objectives: To produce a literature map for key domains of the published AF: screening, prognosis and diagnosis, management, and the health-related outcomes. Methods: A standard scoping review framework was used by an interdisciplinary study team of nurse- and physician-delirium researchers, an information specialist, and review methodologists to conduct the review. Knowledge user engagement provided context in refining 19 AF questions. A peer-reviewed search strategy identified citations in Medline, PsycINFO, Embase, and CINAHL databases between 1980 and 2018. Two reviewers independently screened records for inclusion using explicit study eligibility criteria for the population, design, delirium diagnosis, and investigational intent. Results: Of 104 studies reporting empirical data and meeting eligibility criteria, most were conducted in patients with cancer (73.1%) and in inpatient PC units (52%). The most frequent study design was a one or more group, nonrandomized trial or cohort (67.3%). Evidence gaps were identified: delirium risk prediction; comparative effectiveness and harms of prevention, variability in delirium management across PC settings, advanced directive and substitute decision-maker input, and transition of care location; and estimating delirium reversibility. Future rigorous primary studies are required to address these gaps and preliminary concerns regarding the quality of extant literature. Conclusion: Substantial evidence gaps exist, providing opportunities for future research regarding the assessment, prognosis, and management of delirium in PC settings.

BackgroundThe prognostic value of perioperative diastolic dysfunction (PDD) in patients undergoing noncardiac surgery remains uncertain, and the current guidelines do not recognize PDD as a perioperative risk factor. This systematic review aimed to investigate whether existing evidence supports PDD as an independent predictor of adverse events after noncardiac surgery.MethodsOvid MEDLINE, PubMed, EMBASE, the Cochrane Library, and Google search engine were searched for English-language citations in April 2015 investigating PDD as a risk factor for perioperative adverse events in adult patients undergoing noncardiac surgery. Two reviewers independently assessed the study risk of bias. Extracted data were verified. Random-effects model was used for meta-analysis, and reviewers’ certainty was graded.ResultsSeventeen studies met eligibility criteria; however, 13 contributed to evidence synthesis. The entire body of evidence addressing the research question was based on a total of 3,876 patients. PDD was significantly associated with pulmonary edema/congestive heart failure (odds ratio [OR], 3.90; 95% CI, 2.23 to 6.83; 3 studies; 996 patients), myocardial infarction (OR, 1.74; 95% CI, 1.14 to 2.67; 3 studies; 717 patients), and the composite outcome of major adverse cardiovascular events (OR, 2.03; 95% CI, 1.24 to 3.32; 4 studies; 1,814 patients). Evidence addressing other outcomes had low statistical power, but higher long-term cardiovascular mortality was observed in patients undergoing open vascular repair (OR, 3.00; 95% CI, 1.50 to 6.00). Reviewers’ overall certainty of the evidence was moderate.ConclusionEvidence of moderate certainty indicates that PDD is an independent risk factor for adverse cardiovascular outcomes after noncardiac surgery.

Radical radiotherapy (RT) is a potentially curative treatment in non-small cell lung cancer (NSCLC) and is delivered in conventional 2-Gy fractions, hypofractionated and ablative stereotactic courses. No reliable, predictive biomarkers for the clinical events of local control, appearance of distant metastases and development of toxicity have been introduced in routine clinical practice. Such a test would enable the Radiotherapist to tailor the clinical management of individual patients, considering their pre-treatment characteristics, in order reduce the risk of recurrence or toxicity e.g., dose modification, accelerated fractionation, hypofractionation, or concurrent systemic therapy. The aim of this review was to map the published literature relating to investigations of the potential predictive value of patient or treatment characteristics in radical RT for NSCLC. These investigations should remain a research focus for disease control given the upward trends in lung cancer incidence, and for the avoidance of toxicity, given the survivorship afforded to the cohort of patients that do well with radical RT, or with the increasing range of systemic agents following metastatic relapse. The conclusion of the presented analysis is that there are no published, effective and validated predictive tools for estimation of risk of local/distant recurrence or toxicity after radical RT for NSCLC. The authors have identified an important space for future research in the field of lung cancer radiotherapy.

Objective: To clarify the grading of recommendations assessment, development and evaluation (GRADE) definition of certainty of evidence and suggest possible approaches to rating certainty of the evidence for systematic reviews, health technology assessments, and guidelines. Study Design and Setting: This work was carried out by a project group within the GRADE Working Group, through brainstorming and iterative refinement of ideas, using input from workshops, presentations, and discussions at GRADE Working Group meetings to produce this document, which constitutes official GRADE guidance. Results: Certainty of evidence is best considered as the certainty that a true effect lies on one side of a specified threshold or within a chosen range. We define possible approaches for choosing threshold or range. For guidelines, what we call a fully contextualized approach requires simultaneously considering all critical outcomes and their relative value. Less-contextualized approaches, more appropriate for systematic reviews and health technology assessments, include using specified ranges of magnitude of effect, for example, ranges of what we might consider no effect, trivial, small, moderate, or large effects. Conclusion: It is desirable for systematic review authors, guideline panelists, and health technology assessors to specify the threshold or ranges they are using when rating the certainty in evidence. (C) 2017 The Authors. Published by Elsevier Inc.

Introduction Rapid reviews (RR), using abbreviated systematic review (SR) methods, are becoming more popular among decision-makers. This World Health Organization commissioned study sought to summarize RR methods, identify differences, and highlight potential biases between RR and SR. Methods Review of RR methods (Key Question 1 [KQ1]), meta-epidemiologic studies comparing reliability/ validity of RR and SR methods (KQ2), and their potential associated biases (KQ3). We searched Medline, EMBASE, Cochrane Library, grey literature, and checked reference lists, used personal contacts, and crowdsourcing (e.g. email listservs). Selection and data extraction was conducted by one reviewer (KQ1) or two reviewers independently (KQ2-3). Results Across all KQs, we identified 42,743 citations through the literature searches. KQ1: RR methods from 29 organizations were reviewed. There was no consensus on which aspects of the SR process to abbreviate. KQ2: Studies comparing the conclusions of RR and SR (n = 9) found them to be generally similar. Where major differences were identified, it was attributed to the inclusion of evidence from different sources (e.g. searching different databases or including different study designs). KQ3: Potential biases introduced into the review process were well-identified although not necessarily supported by empirical evidence, and focused mainly on selective outcome reporting and publication biases. Conclusion RR approaches are context and organization specific. Existing comparative evidence has found similar conclusions derived from RR and SR, but there is a lack of evidence comparing the potential of bias in both evidence synthesis approaches. Further research and decision aids are needed to help decision makers and reviewers balance the benefits of providing timely evidence with the potential for biased findings.

Non-randomized studies of the effects of interventions are critical to many areas of health care evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomized Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomization to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomized studies.

Objectives: The aim of this paper is to describe a conceptual framework for how to consider health equity in the Grading Recommendations Assessment and Development Evidence (GRADE) guideline development process. Study Design and Setting: Consensus-based guidance developed by the GRADE working group members and other methodologists. Results: We developed consensus-based guidance to help address health equity when rating the certainty of synthesized evidence (i.e., quality of evidence). When health inequity is determined to be a concern by stakeholders, we propose five methods for explicitly assessing health equity: (1) include health equity as an 'outcome; (2) consider patient-important outcomes relevant to health equity; (3) assess differences in the relative effect size of the treatment; (4) assess differences in baseline risk and the differing impacts on absolute effects; and (5) assess indirectness of evidence to disadvantaged populations and/or settings. Conclusion: The most important priority for research on health inequity and guidelines is to identify and document examples where health equity has been considered explicitly in guidelines. Although there is a weak scientific evidence base for assessing health equity, this should not discourage the explicit consideration of how guidelines and recommendations affect the most vulnerable members of society. (C) 2017 The Authors. Published by Elsevier Inc.

Objectives This article introduces the rationale and methods for explicitly considering health equity in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology for development of clinical, public health, and health system guidelines. Study Design and Setting We searched for guideline methodology articles, conceptual articles about health equity, and examples of guidelines that considered health equity explicitly. We held three meetings with GRADE Working Group members and invited comments from the GRADE Working Group listserve. Results We developed three articles on incorporating equity considerations into the overall approach to guideline development, rating certainty, and assembling the evidence base and evidence to decision and/or recommendation. Conclusion Clinical and public health guidelines have a role to play in promoting health equity by explicitly considering equity in the process of guideline development.

Introduction Preterm birth (PTB) at

Background: Cardiovascular disease and type 2 diabetes are examples of chronic diseases that impose significant morbidity and mortality in the general population worldwide. Most chronic diseases are associated with underlying preventable risk factors, such as elevated blood pressure, high blood glucose or glucose intolerance, high lipid levels, physical inactivity, excessive sedentary behaviours, and overweight/obesity. The occurrence of intermediate outcomes during childhood increases the risk of disease in adulthood. Sugar-sweetened beverages are known to be significant sources of additional caloric intake, and given recent attention to their contribution in the development of chronic diseases, a systematic review is warranted. We will assess whether the consumption of sugar-sweetened beverages in children is associated with adverse health outcomes and what the potential moderating factors are. Methods/Design: Of interest are studies addressing sugar-sweetened beverage consumption, taking a broad perspective. Both direct consumption studies as well as those evaluating interventions that influence consumption (e.g. school policy, educational) will be relevant. Non-specific or multi-faceted behavioural, educational, or policy interventions may also be included subject to the level of evidence that exists for the other interventions/exposures. Comparisons of interest and endpoints of interest are pre-specified. We will include randomized controlled trials, controlled clinical trials, interrupted time series studies, controlled before-after studies, prospective and retrospective comparative cohort studies, case–control studies, and nested case–control designs. The MEDLINE®, Embase, The Cochrane Library, CINAHL, ERIC, and PsycINFO® databases and grey literature sources will be searched. The processes for selecting studies, abstracting data, and resolving conflicts are described. We will assess risk of bias using design-specific tools. To determine sets of confounding variables that should be adjusted for, we have developed causal directed acyclic graphs and will use those to inform our risk of bias assessments. Meta-analysis will be conducted where appropriate; parameters for exploring statistical heterogeneity and effect modifiers are pre-specified. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used to determine the quality of evidence for outcomes.

peer-reviewed Context. Delirium often presents difficult management challenges in the context of goals of care in palliative care settings. Objectives. The aim was to formulate an analytical framework for further research on delirium in palliative care settings, prioritize the associated research questions, discuss the inherent methodological challenges associated with relevant studies, and outline the next steps in a program of delirium research.Methods. We combined multidisciplinary input from delirium researchers and knowledge users at an international delirium study planning meeting, relevant literature searches, focused input of epidemiologic expertise, and a meeting participant and coauthor survey to formulate a conceptual research framework and prioritize research questions.Results. Our proposed framework incorporates three main groups of research questions: the first was predominantly epidemiologic, such as delirium occurrence rates, risk factor evaluation, screening, and diagnosis; the second covers pragmatic management questions; and the third relates to the development of predictive models for delirium outcomes. Based on aggregated survey responses to each research question or domain, the combined modal ratings of "very'' or "extremely'' important confirmed their priority.Conclusion. Using an analytical framework to represent the full clinical care pathway of delirium in palliative care settings, we identified multiple knowledge gaps in relation to the occurrence rates, assessment, management, and outcome prediction of delirium in this population. The knowledge synthesis generated from adequately powered, multicenter studies to answer the framework's research questions will inform decision making and policy development regarding delirium detection and management and thus help to achieve better outcomes for patients in palliative care settings. (C) 2014 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. PUBLISHED peer-reviewed