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Contains fulltext : 290851.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVES: Our objective was to develop an extension of the widely used GIN-McMaster Guideline Development Checklist and Tool for the integration of quality assurance and improvement (QAI) schemes with guideline development. METHODS: We used a mixed-methods approach incorporating evidence from a systematic review, an expert workshop and a survey of experts to iteratively create an extension of the checklist for QAI through three rounds of feedback. As a part of this process, we also refined criteria of a good guideline-based quality indicator. RESULTS: We developed a 40-item checklist extension addressing steps for the integration of QAI into guideline development across the existing 18 topics and created one new topic specific to QAI. The steps span from 'organization, budget, planning and training', to updating of QAI and guideline implementation. CONCLUSION: The tool supports integration of QAI schemes with guideline development initiatives and it will be used in the forthcoming integrated European Commission Initiative on Colorectal Cancer. Future work should evaluate this extension and QAI items requiring additional support for guideline developers and links to QAI schemes. 01 februari 2023

Objectives: To describe divergence between actionable statements issued by coronavirus disease 2019 (COVID-19) guideline developers cataloged on the “COVID-19 Recommendations and Gateway to Contextualization” platform. Study Design and Setting: We defined divergence as at least two comparable actionable statements with different explicit judgments of strength, direction, or subgroup consideration of the population or intervention. We applied a content analysis to compare guideline development methods for a sample of diverging statements and to evaluate factors associated with divergence. Results: Of the 138 guidelines evaluated, 85 (62%) contained at least one statement that diverged from another guideline. We identified 223 diverging statements in these 85 guidelines. We grouped statements into 66 clusters. Each cluster addressed the same population, intervention, and comparator group or just similar interventions. Clinical practice statements were more likely to diverge in an explicit judgment of strength or direction compared to public health statements. Statements were more likely to diverge in strength than direction. The date of publication, used evidence, interpretation of evidence, and contextualization considerations were associated with divergence. Conclusion: More than half of the assessed guidelines issued at least one diverging statement. This study helps in understanding the types of differences between guidelines issuing comparable statements and factors associated with their divergence. © 2022

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Purpose Prenatal factors such as maternal stress, infection and nutrition affect fetal brain development and may also influence later risk for dementia. The purpose of this systematic review was to provide an overview of all studies which investigated the association between prenatal factors and later risk for dementia. Methods We systematically searched MEDLINE and Embase for original human studies reporting on associations between prenatal factors and dementia from inception to 23 November 2022. Prenatal factors could be any factor assessed during pregnancy, at birth or postnatally, provided they were indicative of a prenatal exposure. Risk of bias was assessed using the Newcastle Ottawa Scale. We followed PRISMA guidelines for reporting. Results A total of 68 studies met eligibility criteria (including millions of individuals), assessing maternal age (N = 30), paternal age (N = 22), birth order (N = 15), season of birth (N = 16), place of birth (N = 13), prenatal influenza pandemic (N = 1) or Chinese famine exposure (N = 1), birth characteristics (N = 3) and prenatal hormone exposure (N = 4). We observed consistent results for birth in a generally less optimal environment (e.g. high infant mortality area) being associated with higher dementia risk. Lower and higher birth weight and prenatal famine exposure were associated with higher dementia risk. The studies on season of birth, digit ratio, prenatal influenza pandemic exposure, parental age and birth order showed inconsistent results and were hampered by relatively high risk of bias. Conclusion Our findings suggest that some prenatal factors, especially those related to a suboptimal prenatal environment, are associated with an increased dementia risk. As these associations may be confounded by factors such as parental socioeconomic status, more research is needed to examine the potential causal role of the prenatal environment in dementia.

Purpose Heterogeneity in work participation (WP) outcomes measurements hampers large scale evidence synthesis in systematic reviews of trials. In this survey we explore authors’ reasons for choosing specific WP outcomes and their measurement methods, including employment status, absence from work, at-work productivity loss, and employability. Methods We contacted authors of 260 trials and 69 systematic reviews and asked closed and open-ended questions about previously used WP outcomes and measurement methods as well as their opinion on the best way to measure WP. Results In total, 91 authors from a wide range of professional backgrounds completed the survey. The majority of authors (86%) chose WP outcomes based on their use in previous similar studies. In most studies (88%), patients had not been involved in the process of selecting the WP outcome. Authors judged feasibility to be an important factor for choosing a measurement instrument (67%). Additionally, valid measurement tools should be available, easy to administer and not too time consuming. Although authors preferred registry data for long term follow-up, the availability and validity of registries was seen as a barrier. Most of the reviewers (72%) struggled to pool data because of variation in follow-up times and cut off points and varying definitions of work outcomes. Almost all (92%) respondents support the use of a Core Outcome Set for Work. Conclusions There is strong support from authors of trials and systematic reviews to develop a core outcome set on work participation outcomes for the evaluation of interventions.

Aims Lipoprotein(a) [Lp(a)] is a causal and independent risk factor for cardiovascular disease (CVD). People with elevated Lp(a) are often prescribed statins as they also often show elevated low-density lipoprotein cholesterol (LDL-C) levels. While statins are well-established in lowering LDL-C, their effect on Lp(a) remains unclear. We evaluated the effect of statins compared to placebo on Lp(a) and the effects of different types and intensities of statin therapy on Lp(a). Methods and results We conducted a systematic review and meta-analysis of randomized trials with a statin and placebo arm. Medline and EMBASE were searched until August 2019. Quality assessment of studies was done using Cochrane risk-of-bias tool (RoB 2). Mean difference of absolute and percentage changes of Lp(a) in the statin vs. the placebo arms were pooled using a random-effects meta-analysis. We compared effects of different types and intensities of statin therapy using subgroup- and network meta-analyses. Certainty of the evidence was determined using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Overall, 39 studies (24 448 participants) were included. Mean differences (95% confidence interval) of absolute and percentage changes in the statin vs. the placebo arms were 1.1 mg/dL (0.5–1.6, P Conclusion Statin therapy does not lead to clinically important differences in Lp(a) compared to placebo in patients at risk for CVD. Our findings suggest that in these patients, statin therapy will not change Lp(a)-associated CVD risk.

Objective To investigate how work participation outcomes in randomized controlled trials are measured internationally and across disciplines. Study design and setting We identified trials that reported on work participation in Medline, Embase, PsycINFO and Cochrane Central published between 2014 and 2019. Screening, selection and data extraction were done by two authors independently. We grouped outcomes into four categories (“employment status”, “absence from work”, “at-work productivity loss” and “employability”) and created sub-categories according to how the outcome was measured. Results From 10,022 database hits we selected 269 trials reporting on 435 work participation outcomes. Authors used inconsistent outcome terminology to describe the measured constructs. Grouped in four main categories we identified 70 outcomes that reported on “employment status”, 196 on “absence from work” and return-to-work, 132 on “at-work productivity loss” and 37 on “employability” outcomes. Variability in measurement methods existed across all categories. Employment status and absenteeism measures consisted mostly of clinimetrically unvalidated tools. “At-work productivity loss” and “employability” were measured by at least 41 different questionnaires. Conclusion Extensive variability exists among trials in the measurement of outcomes, measurement methods and measurement instruments that focus on work participation. This study is a first step towards the development of a Core Outcome Set for work participation.

Contains fulltext : 286726.pdf (Publisher’s version ) (Open Access) Since the early 1990s the number of systematic reviews (SR) of animal studies has steadily increased. There is, however, little guidance on when and how to conduct a meta-analysis of human-health-related animal studies. To gain insight about the methods that are currently used we created an overview of the key characteristics of published meta-analyses of animal studies, with a focus on the choice of effect size measures. An additional goal was to learn about the rationale behind the meta-analysis methods used by the review authors. We show that important details of the meta-analyses are not fully described, only a fraction of all human-health-related meta-analyses provided rationales for their decision to use specific effect size measures. In addition, our data may suggest that authors make post-hoc decisions to switch to another effect size measure during the course of their meta-analysis, and possibly search for significant effects. Based on analyses in this paper we recommend that review teams: 1) publish a review protocol before starting the conduct of a SR, prespecifying all methodological details (providing special attention to the planned meta-analysis including the effect size measure and the rational behind choosing a specific effect size, prespecifying subgroups and restricting the number of subgroup analyses), 2) always use the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) checklist to report your SR of animal studies, and 3) use the random effects model (REM) in human-health-related meta-analysis of animal studies, unless the assumptions for using the fixed effect model (FEM) are all met.

Objectives This article provides GRADE guidance on how authors of evidence syntheses and health decision makers, including guideline developers, can rate the certainty across a body of evidence for comparative test accuracy questions. Study design and setting This guidance extends the previously published GRADE guidance for assessing certainty of evidence for test accuracy to scenarios in which two or more index tests are compared. Through an iterative brainstorm-discussion-feedback process within the GRADE working group, we developed a guidance accompanied by practical examples. Results Rating the certainty of evidence for comparative test accuracy shares many concepts and ideas with the existing GRADE guidance for test accuracy. The rating in comparisons of test accuracy requires additional considerations, such as the selection of appropriate comparative study designs, additional criteria for judging risk of bias, and the consequences of using comparative measures of test accuracy. Distinct approaches to rating certainty are required for comparative test accuracy studies and between-study (indirect) comparisons. Conclusion This GRADE guidance will support transparent assessment of the certainty for a body of comparative test accuracy evidence.

GRADE ("Grading of Recommendations Assessment, Development and Evaluation") provides a transparent framework to evaluate scientific evidence and to develop healthcare recommendations. The GRADE method has been further developed, its application has been significantly broadened and over 100 organizations have endorsed GRADE. In this article, we give an overview of the most important methodological developments and discuss the basic principles. The transparent approach to make it easier for users of evidence to assess the judgments behind recommendations is not only applicable to the EBM domains but also to other disciplines. The methods developments show that GRADE is still evolving, and is constantly being further developed based on the latest methodological insights and users perspective. GRADE is not an instrument to determine the "true" certainty of the evidence. The value of applying GRADE is that judgments about the quality of evidence and the considerations behind recommendations are structured, transparent and explicit.

Objective Inappropriate prescribing of drugs is associated with unnecessary harms for patients and healthcare costs. Interventions to reduce these prescriptions are widely studied, yet the effectiveness of different types of interventions remains unclear. Therefore, we provide an overview regarding the effectiveness of intervention types that aim to reduce inappropriate drug prescriptions, unrestricted by target drugs, population or setting. Methods For this overview, systematic reviews (SRs) were used as the source for original studies. EMBASE and MEDLINE were searched from inception to August 2018. All SRs aiming to evaluate the effectiveness of interventions to reduce inappropriate prescribing of drugs were eligible for inclusion. The SRs and their original studies were screened for eligibility. Interventions of the original studies were categorized by type of intervention. The percentage of interventions showing a significant reduction of inappropriate prescribing were reported per intervention category. Key findings Thirty-two SRs were included, which provided 319 unique interventions. Overall, 61.4% of these interventions showed a significant reduction in inappropriate prescribing of drugs. Strategies that were most frequently effective in reducing inappropriate prescribing were multifaceted interventions (73.2%), followed by interventions containing additional diagnostic tests (antibiotics) (70.4%), computer interventions (69.2%), audit and feedback (66.7%), patient-mediated interventions (62.5%) and multidisciplinary (team) approach (57.1%). The least frequently effective intervention was an education for healthcare professionals (50.0%). Conclusion The majority of the interventions were effective in reducing inappropriate prescribing of drugs. Multifaceted interventions most frequently showed a significant reduction of inappropriate prescribing. Education for healthcare professionals is the most frequently included intervention in this overview, yet this category is least frequently effective.

Background and Objective This article explores the need for conceptual advances and practical guidance in the application of the GRADE approach within public health contexts. Methods We convened an expert workshop and conducted a scoping review to identify challenges experienced by GRADE users in public health contexts. We developed this concept article through thematic analysis and an iterative process of consultation and discussion conducted with members electronically and at three GRADE Working Group meetings. Results Five priority issues can pose challenges for public health guideline developers and systematic reviewers when applying GRADE: (1) incorporating the perspectives of diverse stakeholders; (2) selecting and prioritizing health and “nonhealth” outcomes; (3) interpreting outcomes and identifying a threshold for decision-making; (4) assessing certainty of evidence from diverse sources, including nonrandomized studies; and (5) addressing implications for decision makers, including concerns about conditional recommendations. We illustrate these challenges with examples from public health guidelines and systematic reviews, identifying gaps where conceptual advances may facilitate the consistent application or further development of the methodology and provide solutions. Conclusion The GRADE Public Health Group will respond to these challenges with solutions that are coherent with existing guidance and can be consistently implemented across public health decision-making contexts. post-print 456 KB

(1) Background: Given the high prevalence of non-alcoholic fatty liver disease (NAFLD) and the limitations of liver biopsies, multiple non-invasive tests (NITs) have been developed to identify non-alcoholic fatty liver disease (NAFLD) patients at-risk of progression. The availability of these new NITs varies from country to country, and little is known about their implementation and adoption in routine clinical practice. This study aims to explore barriers and facilitators that influence the adoption of NAFLD NITs, from healthcare professionals’ perspectives. (2) Methods: A cross-sectional study was performed using an exploratory mixed-methods approach. Twenty-seven clinicians from eight different countries with different specialties filled in our questionnaire. Of those, 16 participated in semi-structured interviews. Qualitative and quantitative data were collected and summarized using the recently published Non-adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework for new medical technologies in healthcare organizations. (3) Results: Several factors were reported as influencing the uptake of NITs for NAFLD in clinical practice. Among those: insufficient awareness of tests; lack of practical guidelines and evidence for the performance of tests in appropriate patient populations and care settings; and absence of sufficient reimbursement systems were reported as the most important barriers. Other factors, most notably ‘local champions’, proper functional payment systems, and sufficient resources in academic hospitals, were indicated as important facilitating factors. (4) Conclusions: Clinicians see the adoption of NITs for NAFLD as a complex process that is modulated by several factors, such as robust evidence, practical guidelines, a proper payment system, and local champions. Future research could explore perspectives from other stakeholders on the adoption of NITs.

Background Diagnostic mammography projections (DxMM) have been traditionally used in the assessment of women recalled after a suspicious screening mammogram. Digital breast tomosynthesis (DBT) reduces the tissue overlap effect, thus improving image assessment. Some studies have suggested DBT might replace DxMM with at least equivalent performance. Objective To evaluate the replacement of DxMM with DBT in women recalled at screening. Methods We searched PubMed, EMBASE, and the Cochrane Library databases to identify diagnostic paired cohort studies or RCTs comparing DBT vs DxMM, published in English that: reported accuracy outcomes, recruited women recalled for assessment at mammography screening, and included a reference standard. Subgroup analysis was performed over lesion characteristics. We provided pooled accuracy estimates and differences between tests using a quadrivariate model. We assessed the certainty of the evidence using the GRADE approach. Results We included ten studies that reported specificity and sensitivity. One study included 7060 women while the remaining included between 52 and 738 women. DBT compared with DxMM showed a pooled difference for the sensitivity of 2% (95% CI 1%–3%) and a pooled difference for the specificity of 6% (95%CI 2%–11%). Restricting the analysis to the six studies that included women with microcalcification lesions gave similar results. In the context of a prevalence of 21% of breast cancer (BC) in recalled women, DBT probably detects 4 (95% CI 2–6) more BC cases and has 47 (95%CI 16–87) fewer false‐positive results per 1000 assessments. The certainty of the evidence was moderate due to risk of bias. Conclusion The evidence in the assessment of screen‐recalled findings with DBT is sparse and of moderate certainty. DBT probably has higher sensitivity and specificity than DxMM. Women, health care providers and policymakers might value as relevant the reduction of false‐positive results and related fewer invasive diagnostic procedures with DBT, without missing BC cases., This systematic review found that in women of average risk of breast cancer with suspicious lesions at mammography screening, DBT probably has higher specificity difference (6%) than diagnostic views of 2D mammography in women recalled for assessment (moderate certainty evidence). The sensitivity is also probably higher with DBT; however, the difference was not so large (2%). The clinical impact of these results in a screening program is a probable reduction of 47 false positive results, including related invasive procedures, and most likely a small increase of 4 additional true BC lesions per 1000 women recalled for assessment. Our results were consistent in women with calcified lesions, but with a larger imprecision in the sensitivity differences. These results were taken into account by the GDG, together with other considerations (ie, feasibility) to issue a conditional recommendation in favor of DBT which is available on the ECIBC website (https://healthcare‐quality.jrc.ec.europa.eu/european‐breast‐cancer‐guidelines/diagnosis/DBT).

Objectives Health guidelines are a key knowledge translation tool produced and used by numerous stakeholders worldwide. Effective participation in guideline development groups or development groups is crucial for guideline success, yet little guidance exists for members of these groups. In this study, we present the Guideline Participant Tool (GPT) to support effective participation in guideline groups, in particular those using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Study Design and Setting We used a mixed methods and iterative approach to develop a tool to support guideline participation. We used the findings of a published systematic review to develop an initial list of items for considerations for guideline participants. Then, we refined this list through key informant interviews with guideline chairs, sponsors, and participants. Finally, we validated the GPT in three guideline groups with 26 guideline group members. Results The initial list of items based on 37 articles from the existing systematic review included 15 themes and 61 items for a draft tool. Ten key informant interviews helped us refine the list to include the following themes: selection of participants, guideline group process, and tool format. 26 respondents completed the validation survey from three guideline groups. Refinement of the tool ultimately generated a GPT with 33 items for participant consideration before, during, and in follow-up to guideline group meetings. Conclusion The GPT contains helpful guidance for all guideline participants, particularly those without previous guideline experience. Future research should further explore the need for additional tools to support guideline participants and identify and develop strategies for improving guideline members’ participation in guideline groups. This work will be incorporated into INGUIDE.org guideline training and credentialing efforts by the Guidelines International Network and McMaster University.

Rationale, aims and objectives Supporting evidence for diagnostic test recommendations in clinical practice guidelines (CPGs) should not only include diagnostic accuracy, but also downstream consequences of the test result on patient-relevant outcomes. The aim of this study is to assess the extent to which evidence-based CPGs about diagnostic tests cover all relevant test-treatment pathway components. Methods We performed a systematic document analysis and quality assessment of publicly accessible CPGs about three common diagnostic tests: C-reactive protein, colonoscopy and fractional exhaled nitric oxide. Evaluation of the impact of the full test-treatment pathway (diagnostic accuracy, burden of the test, natural course of target condition, treatment effectiveness, and link between test result and administration of treatment) on patient relevant outcomes was considered best practice for developing medical test recommendations. Results We retrieved 15 recommendations in 15 CPGs. The methodological quality of the CPGs varied from poor to excellent. Ten recommendations considered diagnostic accuracy. Four of these were funded on a systematic review and rating of the certainty in the evidence. None of the CPGs evaluated all steps of the test-treatment pathway. Burden of the test was considered in three CPGs, but without systematically reviewing the evidence. Natural course was considered in two CPGs, without a systematic review of the evidence. In three recommendations, treatment effectiveness was considered, supported with a systematic review and rating of the certainty in the evidence in one CPG. The link between test result and treatment administration was not considered in any CPG. Conclusions The included CPGs hardly seem to consider evidence about test consequences on patient-relevant outcomes. This might be explained by reporting issues and challenging methodology. Future research is needed to investigate how to facilitate guideline developers in explicit reliable consideration of all steps of a test-treatment pathway when developing diagnostic test recommendations.

Background: Systematic screening in high-burden settings is recommended as a strategy for early detection of pulmonary tuberculosis disease, reducing mortality, morbidity and transmission, and improving equity in access to care. Questioning for symptoms and chest radiography (CXR) have historically been the most widely available tools to screen for tuberculosis disease. Their accuracy is important for the design of tuberculosis screening programmes and determines, in combination with the accuracy of confirmatory diagnostic tests, the yield of a screening programme and the burden on individuals and the health service. Objectives: To assess the sensitivity and specificity of questioning for the presence of one or more tuberculosis symptoms or symptom combinations, CXR, and combinations of these as screening tools for detecting bacteriologically confirmed pulmonary tuberculosis disease in HIV-negative adults and adults with unknown HIV status who are considered eligible for systematic screening for tuberculosis disease. Second, to investigate sources of heterogeneity, especially in relation to regional, epidemiological, and demographic characteristics of the study populations. Search methods: We searched the MEDLINE, Embase, LILACS, and HTA (Health Technology Assessment) databases using pre-specified search terms and consulted experts for unpublished reports, for the period 1992 to 2018. The search date was 10 December 2018. This search was repeated on 2 July 2021. Selection criteria: Studies were eligible if participants were screened for tuberculosis disease using symptom questions, or abnormalities on CXR, or both, and were offered confirmatory testing with a reference standard. We included studies if diagnostic two-by-two tables could be generated for one or more index tests, even if not all participants were subjected to a microbacteriological reference standard. We excluded studies evaluating self-reporting of symptoms. Data collection and analysis: We categorized symptom and CXR index tests according to commonly used definitions. We assessed the methodological quality of included studies using the QUADAS-2 instrument. We examined the forest plots and receiver operating characteristic plots visually for heterogeneity. We estimated summary sensitivities and specificities (and 95% confidence intervals (CI)) for each index test using bivariate random-effects methods. We analyzed potential sources of heterogeneity in a hierarchical mixed-model. Main results: The electronic database search identified 9473 titles and abstracts. Through expert consultation, we identified 31 reports on national tuberculosis prevalence surveys as eligible (of which eight were already captured in the search of the electronic databases), and we identified 957 potentially relevant articles through reference checking. After removal of duplicates, we assessed 10,415 titles and abstracts, of which we identified 430 (4%) for full text review, whereafter we excluded 364 articles. In total, 66 articles provided data on 59 studies. We assessed the 2 July 2021 search results; seven studies were potentially eligible but would make no material difference to the review findings or grading of the evidence, and were not added in this edition of the review. We judged most studies at high risk of bias in one or more domains, most commonly because of incorporation bias and verification bias. We judged applicability concerns low in more than 80% of studies in all three domains. The three most common symptom index tests, cough for two or more weeks (41 studies), any cough (21 studies), and any tuberculosis symptom (29 studies), showed a summary sensitivity of 42.1% (95% CI 36.6% to 47.7%), 51.3% (95% CI 42.8% to 59.7%), and 70.6% (95% CI 61.7% to 78.2%, all very low-certainty evidence), and a specificity of 94.4% (95% CI 92.6% to 95.8%, high-certainty evidence), 87.6% (95% CI 81.6% to 91.8%, low-certainty evidence), and 65.1% (95% CI 53.3% to 75.4%, low-certainty evidence), respectively. The data on symptom index tests were more heterogenous than those for CXR. The studies on any tuberculosis symptom were the most heterogeneous, but had the lowest number of variables explaining this variation. Symptom index tests also showed regional variation. The summary sensitivity of any CXR abnormality (23 studies) was 94.7% (95% CI 92.2% to 96.4%, very low-certainty evidence) and 84.8% (95% CI 76.7% to 90.4%, low-certainty evidence) for CXR abnormalities suggestive of tuberculosis (19 studies), and specificity was 89.1% (95% CI 85.6% to 91.8%, low-certainty evidence) and 95.6% (95% CI 92.6% to 97.4%, high-certainty evidence), respectively. Sensitivity was more heterogenous than specificity, and could be explained by regional variation. The addition of cough for two or more weeks, whether to any (pulmonary) CXR abnormality or to CXR abnormalities suggestive of tuberculosis, resulted in a summary sensitivity and specificity of 99.2% (95% CI 96.8% to 99.8%) and 84.9% (95% CI 81.2% to 88.1%) (15 studies; certainty of evidence not assessed). Authors' conclusions: The summary estimates of the symptom and CXR index tests may inform the choice of screening and diagnostic algorithms in any given setting or country where screening for tuberculosis is being implemented. The high sensitivity of CXR index tests, with or without symptom questions in parallel, suggests a high yield of persons with tuberculosis disease. However, additional considerations will determine the design of screening and diagnostic algorithms, such as the availability and accessibility of CXR facilities or the resources to fund them, and the need for more or fewer diagnostic tests to confirm the diagnosis (depending on screening test specificity), which also has resource implications. These review findings should be interpreted with caution due to methodological limitations in the included studies and regional variation in sensitivity and specificity. The sensitivity and specificity of an index test in a specific setting cannot be predicted with great precision due to heterogeneity. This should be borne in mind when planning for and implementing tuberculosis screening programmes.

Background: Work participation is important for health and can be considered as engagement in a major area of life which is of significance for most people, but it can also be thought of as fulfilling or discharging a role. Currently, academic research lacks a comprehensive classification of work participation outcomes. The International Classification of Functioning is the foremost model in defining work functioning and its counterpart work disability, but it does not provide a critical (core) set of outcomes. It is important to standardize the definitions and the nomenclature used in the research of work participation, so that the outcomes of studies are comparable, and practitioners and guideline developers can better decide what works best. As work participation is a broad umbrella term including outcome categories which need unambiguous differentiation, a framework needs to be developed first.Aim: To propose a framework which can be used to develop a generic core outcome set for work participation.Methods: First, we performed a systematic literature search on the concept of (work) participation, perspectives on how to measure it, and existing classifications for outcome measurements. Next, we derived criteria for the framework and proposed a framework based on the criteria. Last, we applied the framework to six case studies as a proof of concept. Results: Our literature search provided 2106 hits and we used 59 studies for full-text analysis. Based on the literature and the developed criteria we propose four overarching outcome categories: (1) initiating employment, (2) having employment, (3) increasing or maintaining productivity at work and (4) return to employment. These categories appeared feasible in our proof-of-concept assessment with six different case studies. Conclusion: We propose to use the framework for work participation outcomes to develop a core outcome set for intervention studies to improve work participation.

Background During healthcare guideline development, panel members often have implicit, different definitions of health outcomes that can lead to misunderstandings about how important these outcomes are and how to balance benefits and harms. McMaster GRADE Centre researchers developed ‘health outcome descriptors’ for standardizing descriptions of health outcomes and overcoming these problems to support the European Commission Initiative on Breast Cancer (ECIBC) Guideline Development Group (GDG). We aimed to determine which aspects of the development, content, and use of health outcome descriptors were valuable to guideline developers. Methods We developed 24 health outcome descriptors related to breast cancer screening and diagnosis for the European Commission Breast Guideline Development Group (GDG). Eighteen GDG members provided feedback in written format or in interviews. We then evaluated the process and conducted two health utility rating surveys. Results Feedback from GDG members revealed that health outcome descriptors are probably useful for developing recommendations and improving transparency of guideline methods. Time commitment, methodology training, and need for multidisciplinary expertise throughout development were considered important determinants of the process. Comparison of the two health utility surveys showed a decrease in standard deviation in the second survey across 21 (88%) of the outcomes. Conclusions Health outcome descriptors are feasible and should be developed prior to the outcome prioritization step in the guideline development process. Guideline developers should involve a subgroup of multidisciplinary experts in all stages of development and ensure all guideline panel members are trained in guideline methodology that includes understanding the importance of defining and understanding the outcomes of interest.

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 In 2017, the European Commission’s Joint Research Centre (JRC) started developing a methodological framework for a guideline-based quality assurance (QA) scheme to improve cancer quality of care. During the first phase of the work, inconsistency emerged about the use of terminology for the definition, the conceptual underpinnings and the way QA relates to health questions that are answered in guidelines. The objective of this final of three articles is to propose a conceptual framework for an integrated approach to guideline and QA development and clarify terms and definitions for key elements. This work will inform the upcoming European Commission Initiative on Colorectal Cancer (ECICC). Methods A multidisciplinary group of 23 experts from key organizations in the fields of guideline development, performance measurement and quality assurance participated in a mixed method approach including face-to-face dialogue and several rounds of virtual meetings. Informed by results of a systematic literature review that indicated absence of an existing framework and practical examples, we first identified the relations of key elements in guideline-based QA and then developed appropriate concepts and terminology to provide guidance. Results Our framework connects the three key concepts of quality indicators, performance measures and performance indicators integrated with guideline development. Quality indicators are constructs used as a guide to monitor, evaluate, and improve the quality of the structure, process and outcomes of healthcare services; performance measures are tools that quantify or describe measurable elements of practice performance; and performance indicators are quantifiable and measurable units or scores of practice, which should be guided by guideline recommendations. Conclusions The inconsistency in the way key terms of QA are used and defined has confused the field. Our conceptual framework defines the role, meaning and interactions of the key elements for improving quality in healthcare. It directly builds on the questions asked in guidelines and answered through recommendations. These findings will be applied in the forthcoming ECICC and for the future updates of ECIBC. These are large-scale integrated projects aimed at improving healthcare quality across Europe through the development of guideline-based QA schemes; this will help in implementing and improving our approach.

Objective To propose a taxonomy and framework that identifies and presents actionable statements in guidelines. Study design and setting We took an iterative approach reviewing case studies of guidelines produced by the World Health Organization and the American Society of Hematology to develop an initial conceptual framework. We then tested it using randomly selected recommendations from published guidelines addressing COVID-19 from different organizations, evaluated its results, and refined it before retesting. The urgency and availability of evidence for development of these recommendations varied. We consulted with experts in research methodology and guideline developers to improve the final framework. Results The resulting taxonomy and framework distinguishes five types of actional statements: formal recommendations; research recommendations; good practice statements; implementation considerations, tools and tips; and informal recommendations. These statements should respond to a priori established criteria and require a clear structure and recognizable presentation in a guideline. Most importantly, this framework identifies informal recommendations that differ from formal recommendations by how they consider evidence and in their development process. Conclusion The identification, standardization and explicit labelling of actionable statements according to the framework may support guideline developers to create actionable statements with clear intent, avoid informal recommendations and improve their understanding and implementation by users.

ObjectivesThis is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To assess the accuracy of routine blood-based laboratory tests to predict mortality and deterioration to severe or critical (from mild or moderate) COVID-19 in people with SARS-CoV-2 infection.Secondary objectivesWhere data are available, we will investigate whether prognostic accuracy varies according to a specific measurement or test, reference standard, timing of outcome verification, sample type, study design, and setting, including prevalence of the target condition (either by stratified analysis or meta-regression).

The overall objective of project OC/EFSA/AMU/2018/01 was to support EFSA to develop in-house capacity to collect, appraise and synthesize evidence coming from literature sources in the context of food and feed scientific assessment. This objective had to be reached by offering 3 different types of training courses to EFSA staff (including Trainees) and Experts (of Panels, Working Groups and Member States). This report summarizes these trainings and their evaluation. Between 15 October 2018 and 24 November 2020, 9 trainings were delivered by a team of trainers from SYRCLE (SYstematic Review Centre for Laboratory animal Experimentation, www.syrcle.nl) and partners. A total number of 160 people participated in these trainings (an average of 18 per training), some of whom participated in more than one training (day). The individual trainings were evaluated using an online evaluation form, which consisted of general questions (e.g. about the training room or course material) and specific questions about the various parts of the training courses. The participants had the option of adding qualitative comments. Moreover, a so-called second level evaluation was used to assess the extent to which the trainings improved the capacity of participants to use the techniques explained in the courses in the context of EFSA assessments. With an average score of 8.23 (out of 10), the trainings were evaluated very positively. Major revisions of the content were only necessary for two of the courses and only after the first editions. Overall, the participants assessed their knowledge and practical skills to be higher after the training compared to before. Moreover, two of the online editions of the courses received an EFSA Golden Globe for the most successful EFSA scientific courses delivered in 2020. Based on the experiences with this series of trainings, recommendations are made for future EFSA trainings in evidence synthesis.

Background Supporting evidence for medical test recommendations in clinical practice guidelines (CPGs) should not only include diagnostic accuracy, but also the downstream consequences of the test result on patient relevant outcomes. The aim of this study is to assess the methodology of developing of evidence-based CPGs about medical tests, and to explore determinants of best CPGs. Methods We performed a systematic document analysis and quality assessment of publicly accessible CPGs about three common diagnostic topics: C-reactive protein (CRP), colonoscopy and fractional exhaled nitric oxide (FeNO). Evaluation of the complete test-treatment pathway (diagnostic accuracy as well as downstream consequences on patient relevant outcomes (i.e. burden of the test, natural course, treatment effectiveness, and link between test result and administration of treatment)) was considered best practice for developing medical test recommendations. Results We retrieved 15 recommendations in 15 CPGs. The methodological quality of the CPGs varied from poor to excellent. Seven CPGs reported the use of the GRADE approach. In three CPGs, however, we could not find elements of that approach in the guideline documents. Ten recommendations considered diagnostic accuracy. Four of these were supported with a systematic review of the literature and rating of the certainty in the evidence. None of the CPGs evaluated all steps of the test-treatment pathway. Burden of the test was considered in three CPGs, but not with a systematic review of the evidence. Natural course was considered in two CPGs, and also not with a systematic review of the evidence. In three recommendations, treatment effectiveness was considered, which was supported with a systematic review and rating of the certainty in the evidence in one CPG. The link between test result and administration of treatment was not considered in any CPG. Conclusions CPGs with recommendations about medical tests do not seem to consider evidence about test consequences on patient relevant outcomes. This might be explained by reporting issues and challenging methodology. Future research is needed to investigate how to facilitate guideline developers in explicitly and reliably considering all steps of a test-treatment pathway when developing medical test recommendations.

Sciatica impacts on the ability to work and may lead to a reduced return to work. This study reviewed and summarised prognostic factors of work participation in patients who received conservative or surgical treatment for clinically diagnosed sciatica. We searched MEDLINE, CINAHL, EMBASE and PsycINFO until January 2018. Cohort studies, using a measure of work participation as outcome, were included. Two independent reviewers performed study inclusion and used the Quality In Prognosis Studies tool for risk of bias assessment and GRADE to rate the quality of the evidence. Based on seven studies describing six cohorts (n=1408 patients) that assessed 21 potential prognostic factors, favourable factors for return to work (follow-up ranging from 3 months to 10 years) included younger age, better general health, less low back pain or sciatica bothersomeness, better physical function, negative straight leg raise-test, physician expecting surgery to be beneficial, better pain coping, less depression and mental stress, less fear of movement and low physical work load. Study results could not be pooled. Using GRADE, the quality of the evidence ranged from moderate to very low, with downgrading mainly for a high risk of bias and imprecision. Several prognostic factors like pain, disability and psychological factors were identified and reviewed, and these could be targeted using additional interventions to optimise return to work. PROSPERO registration number: CRD42016042497.

Objectives:Gastroesophageal reflux disease (GERD) is defined as gastroesophageal reflux causing troublesome symptoms or complications. In this study we reviewed the literature regarding the prevalence of GERD symptoms in infants and children.Methods:Databases of PubMed, EMBASE, and Cochrane were systematically searched from inception to June 26, 2018. English-written studies based on birth cohort, school-based, or general population samples of ≥50 children aged 0 to 21 years were included. Convenience samples were excluded.Results:In total, 3581 unique studies were found, of which 25 studies (11 in infants and 14 in children) were included with data on the prevalence of GERD symptoms comprising a total population of 487,969 children. In infants (0-18 months), GERD symptoms are present in more than a quarter of infants on a daily basis and show a steady decline in frequency with almost complete disappearance of symptoms at the age of 12 months. In children older than 18 months, GERD symptoms show large variation in prevalence between studies (range 0%-38% of study population) and overall, are present in >10% and in 25% on respectively a weekly and monthly basis. Of the risk factors assessed, higher body mass index and the use of alcohol and tobacco were associated with higher GERD symptom prevalence.Conclusions:This systematic review demonstrates that the reported prevalence of GERD symptoms varies considerably, depending on method of data collection and criteria used to define symptoms. Nevertheless, the high reported prevalence rates support better investment of resources and educational campaigns focused on prevention.

Objective: To identify challenges in the application of GRADE for diagnosis when assessing the certainty of evidence in the test-treatment strategy (diagnostic accuracy, test burden, management effectiveness, natural course, linked evidence) in an illustrative example and to propose solutions to these challenges.Study design and setting: A case study in applying GRADE for diagnosis that looked at the added value of IgE for diagnosing allergic rhinitis.Results: Evaluation of the full test-treatment strategy showed a lack of (high-quality) evidence for all elements. In our example, we found a lack of evidence for test burden, natural course, and link between the test result and clinical management. Overall, systematically reviewing the evidence for all elements of a test-treatment strategy is more time-consuming than only considering test accuracy results and management effectiveness. For increasing efficiency, the guideline panel could determine critical elements of the test-treatment strategy that need a systematic review of the evidence. For less critical elements, a guideline panel can rely on gray literature and professional expertise.Conclusion: A lack of high-quality evidence and time investment if the full test-treatment strategy is assessed, creating challenges in applying GRADE for diagnosis. Discussion within guideline panels about critical elements that need to be reviewed might help. (C) 2020 Elsevier Inc. All rights reserved.

Systematic reviews (SRs) are common practice in clinical and public health research, but less common in non-human animal research. Systematic reviews of animal studies can be valuable to inform clinical research, to evaluate the need for further animal experiments on a given topic, and to assess the hazard of an environmental exposure in the evaluation of toxicological studies. In the last 10 years, there has been an increase in the number of SRs of animal research, as well as several publications with detailed guidance on how to perform high-quality systematic reviews of experimental animal studies. In order to evaluate current analytical approaches used in SRs of animal studies, easily identify all systematic reviews on a specific topic, and subsequently the original animal studies and their results and promote awareness and understanding of these emerging approaches, we compiled a database of SRs of animal studies. The database was developed using a rigorous, systematic approach and covers a broad range of research fields: preclinical research, toxicology, environmental health, and veterinary medicine. The database currently includes 3113 SRs of animal studies (search date June 2019). In addition to bibliographical information, data on whether or not a risk of bias assessment and meta-analysis were conducted were extracted. For future users, the search features of the database provide users with a platform to identify and select SRs with a particular characteristic for export to Microsoft Word or Microsoft Excel. From there, users may perform additional data extraction to meet their research needs. The database is freely available at www.Mendeley.com (link). The database provides methodologists a comprehensive source that can be used to explore and advance the current methodology applied to SRs of animal studies, and can help researchers to easily identify all systematic reviews on a specific topic, and subsequently the original animal studies and their results and avoid duplication and unnecessary animal research.

Background Although quality indicators are frequently derived from guidelines, there is a substantial gap in collaboration between the corresponding parties. To optimise workflow, guideline recommendations and quality assurance should be aligned methodologically and practically. Learning from the European Commission Initiative on Breast Cancer (ECIBC), our objective was to bring the key knowledge and most important considerations from both worlds together to inform European Commission future initiatives. Methods We undertook several steps to address the problem. First, we conducted a feasibility study that included a survey, interviews and a review of manuals for an integrated guideline and quality assurance (QA) scheme that would support the European Commission. The feasibility study drew from an assessment of the ECIBC experience that followed commonly applied strategies leading to separation of the guideline and QA development processes. Secondly, we used results of a systematic review to inform our understanding of methodologies for integrating guideline and QA development. We then, in a third step, used the findings to prepare an evidence brief and identify key aspects of a methodological framework for integrating guidelines QA through meetings with key informants. Results Seven key themes emerged to be taken into account for integrating guidelines and QA schemes: (1) evidence-based integrated guideline and QA frameworks are possible, (2) transparency is key in clearly documenting the source and rationale for quality indicators, (3) intellectual and financial interests should be declared and managed appropriately, (4) selection processes and criteria for quality indicators need further refinement, (5) clear guidance on retirement of quality indicators should be included, (6) risks of an integrated guideline and QA Group can be mitigated, and (7) an extension of the GIN-McMaster Guideline Development Checklist should incorporate QA considerations. Discussion We concluded that the work of guideline and QA developers can be integrated under a common methodological framework and we provided key findings and recommendations. These two worlds, that are fundamental to improving health, can both benefit from integration.

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.

Background Guidelines and quality indicators (for example as part of a quality assurance scheme) aim to improve health care delivery and health outcomes. Ideally, the development of quality indicators should be grounded in evidence-based, trustworthy guideline recommendations. However, anecdotally, guidelines and quality assurance schemes are developed independently, by different groups of experts who employ different methodologies. We conducted an extension and update of a previous systematic review to identify, describe and evaluate approaches to the integrated development of guidelines and related quality indicators. Methods On May 24th, 2019 we searched in Medline, Embase and CINAHL and included studies if they reported a methodological approach to guideline-based quality indicator development and were published in English, French, or German. Results: Out of 16,034 identified records, we included 17 articles that described a method to integrate guideline recommendations development and quality indicator development. Added to the 13 method articles from original systematic review we included a total 30 method articles. We did not find any evaluation studies. In most approaches, guidelines were a source of evidence to inform the quality indicator development. The criteria to select recommendations (e.g. level of evidence or strength of the recommendation) and to generate, select and assess quality indicators varied widely. We found methodological approaches that linked guidelines and quality indicator development explicitly, however none of the articles reported a conceptual framework that fully integrated quality indicator development into the guideline process or where quality indicator development was part of the question formulation for developing the guideline recommendations. Conclusions In our systematic review we found approaches which explicitly linked guidelines with quality indicator development, nevertheless none of the articles reported a comprehensive and well-defined conceptual framework which integrated quality indicator development fully into the guideline development process.

Background Specific diagnostic tests to detect severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and resulting COVID‐19 disease are not always available and take time to obtain results. Routine laboratory markers such as white blood cell count, measures of anticoagulation, C‐reactive protein (CRP) and procalcitonin, are used to assess the clinical status of a patient. These laboratory tests may be useful for the triage of people with potential COVID‐19 to prioritize them for different levels of treatment, especially in situations where time and resources are limited. Objectives To assess the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID‐19. Search methods On 4 May 2020 we undertook electronic searches in the Cochrane COVID‐19 Study Register and the COVID‐19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID‐19 publications. We did not apply any language restrictions. Selection criteria We included both case‐control designs and consecutive series of patients that assessed the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID‐19. The reference standard could be reverse transcriptase polymerase chain reaction (RT‐PCR) alone; RT‐PCR plus clinical expertise or and imaging; repeated RT‐PCR several days apart or from different samples; WHO and other case definitions; and any other reference standard used by the study authors. Data collection and analysis Two review authors independently extracted data from each included study. They also assessed the methodological quality of the studies, using QUADAS‐2. We used the 'NLMIXED' procedure in SAS 9.4 for the hierarchical summary receiver operating characteristic (HSROC) meta‐analyses of tests for which we included four or more studies. To facilitate interpretation of results, for each meta‐analysis we estimated summary sensitivity at the points on the SROC curve that corresponded to the median and interquartile range boundaries of specificities in the included studies. Main results We included 21 studies in this review, including 14,126 COVID‐19 patients and 56,585 non‐COVID‐19 patients in total. Studies evaluated a total of 67 different laboratory tests. Although we were interested in the diagnotic accuracy of routine tests for COVID‐19, the included studies used detection of SARS‐CoV‐2 infection through RT‐PCR as reference standard. There was considerable heterogeneity between tests, threshold values and the settings in which they were applied. For some tests a positive result was defined as a decrease compared to normal vaues, for other tests a positive result was defined as an increase, and for some tests both increase and decrease may have indicated test positivity. None of the studies had either low risk of bias on all domains or low concerns for applicability for all domains. Only three of the tests evaluated had a summary sensitivity and specificity over 50%. These were: increase in interleukin‐6, increase in C‐reactive protein and lymphocyte count decrease. Blood count Eleven studies evaluated a decrease in white blood cell count, with a median specificity of 93% and a summary sensitivity of 25% (95% CI 8.0% to 27%; very low‐certainty evidence). The 15 studies that evaluated an increase in white blood cell count had a lower median specificity and a lower corresponding sensitivity. Four studies evaluated a decrease in neutrophil count. Their median specificity was 93%, corresponding to a summary sensitivity of 10% (95% CI 1.0% to 56%; low‐certainty evidence). The 11 studies that evaluated an increase in neutrophil count had a lower median specificity and a lower corresponding sensitivity. The summary sensitivity of an increase in neutrophil percentage (4 studies) was 59% (95% CI 1.0% to 100%) at median specificity (38%; very low‐certainty evidence). The summary sensitivity of an increase in monocyte count (4 studies) was 13% (95% CI 6.0% to 26%) at median specificity (73%; very low‐certainty evidence). The summary sensitivity of a decrease in lymphocyte count (13 studies) was 64% (95% CI 28% to 89%) at median specificity (53%; low‐certainty evidence). Four studies that evaluated a decrease in lymphocyte percentage showed a lower median specificity and lower corresponding sensitivity. The summary sensitivity of a decrease in platelets (4 studies) was 19% (95% CI 10% to 32%) at median specificity (88%; low‐certainty evidence). Liver function tests The summary sensitivity of an increase in alanine aminotransferase (9 studies) was 12% (95% CI 3% to 34%) at median specificity (92%; low‐certainty evidence). The summary sensitivity of an increase in aspartate aminotransferase (7 studies) was 29% (95% CI 17% to 45%) at median specificity (81%) (low‐certainty evidence). The summary sensitivity of a decrease in albumin (4 studies) was 21% (95% CI 3% to 67%) at median specificity (66%; low‐certainty evidence). The summary sensitivity of an increase in total bilirubin (4 studies) was 12% (95% CI 3.0% to 34%) at median specificity (92%; very low‐certainty evidence). Markers of inflammation The summary sensitivity of an increase in CRP (14 studies) was 66% (95% CI 55% to 75%) at median specificity (44%; very low‐certainty evidence). The summary sensitivity of an increase in procalcitonin (6 studies) was 3% (95% CI 1% to 19%) at median specificity (86%; very low‐certainty evidence). The summary sensitivity of an increase in IL‐6 (four studies) was 73% (95% CI 36% to 93%) at median specificity (58%) (very low‐certainty evidence). Other biomarkers The summary sensitivity of an increase in creatine kinase (5 studies) was 11% (95% CI 6% to 19%) at median specificity (94%) (low‐certainty evidence). The summary sensitivity of an increase in serum creatinine (four studies) was 7% (95% CI 1% to 37%) at median specificity (91%; low‐certainty evidence). The summary sensitivity of an increase in lactate dehydrogenase (4 studies) was 25% (95% CI 15% to 38%) at median specificity (72%; very low‐certainty evidence). Authors' conclusions Although these tests give an indication about the general health status of patients and some tests may be specific indicators for inflammatory processes, none of the tests we investigated are useful for accurately ruling in or ruling out COVID‐19 on their own. Studies were done in specific hospitalized populations, and future studies should consider non‐hospital settings to evaluate how these tests would perform in people with milder symptoms., Plain language summary How accurate are routine laboratory tests for diagnosis of COVID‐19? What are routine laboratory tests? Routine laboratory tests are blood tests that assess the health status of a patient. Tests include counts of different types of white blood cells (these help the body fight infection), and detection of markers (proteins) that indicate organ damage, and general inflammation. These tests are widely available and in some places they may be the only tests available for diagnosis of COVID‐19. What did we want to find out? People with suspected COVID‐19 need to know quickly whether they are infected so that they can self‐isolate, receive treatment, and inform close contacts. Currently, the standard test for COVID‐19 is usually the RT‐PCR test. In the RT‐PCR, samples from the nose and throat are sent away for testing, usually to a large, central laboratory with specialist equipment. Other tests include imaging tests, like X‐rays, which also require specialist equipment. We wanted to know whether routine laboratory tests were sufficiently accurate to diagnose COVID‐19 in people with suspected COVID‐19. We also wanted to know whether they were accurate enough to prioritize patients for different levels of treatment. What did we do? We searched for studies that assessed the accuracy of routine laboratory tests to diagnose COVID‐19 compared with RT‐PCR or other tests. Studies could be of any design and be set anywhere in the world. Studies could include participants of any age or sex, with suspected COVID‐19, or use samples from people known to have – or not to have ‐ COVID‐19. What we found We found 21 studies that looked at 67 different routine laboratory tests for COVID‐19. Most of the studies looked at how accurately these tests diagnosed infection with the virus causing COVID‐19. Four studies included both children and adults, 16 included only adults and one study only children. Seventeen studies were done in China, and one each in Iran, Italy, Taiwan and the USA. All studies took place in hospitals, except one that used samples from a database. Most studies used RT‐PCR to confirm COVID‐19 diagnosis. Accuracy of tests is most often reported using ‘sensitivity’ and ‘specificity’. Sensitivity is the proportion of people with COVID‐19 correctly detected by the test; specificity is the proportion of people without COVID‐19 who are correctly identified by the test. The nearer sensitivity and specificity are to 100%, the better the test. A test to prioritize people for treatment would require a high sensitivity of more than 80%. Where four or more studies evaluated a particular test, we pooled their results and analyzed them together. Our analyses showed that only three of the tests had both sensitivity and specificity over 50%. Two of these were markers for general inflammation (increases in interleukin‐6 and C‐reactive protein). The third was for lymphocyte count decrease. Lymphocytes are a type of white blood cell where a low count might indicate infection. How reliable are the results? Our confidence in the evidence from this review is low because the studies were different from each other, which made them difficult to compare. For example, some included very sick people, while some included people with hardly any COVID‐19 symptoms. Also, the diagnosis of COVID‐19 was confirmed in different ways: RT‐PCR was sometimes used in combination with other tests. Who do the results of this review apply to? Routine laboratory tests can be issued by most healthcare facilities. However, our results are probably not representative of most clinical situations in which these tests are being used. Most studies included very sick people with high rates of COVID‐19 virus infection of between 27% and 76%. In most primary healthcare facilities, this percentage will be lower. What does this mean? Routine laboratory tests cannot distinguish between COVID‐19 and other diseases as the cause of infection, inflammation or tissue damage. None of the tests performed well enough to be a standalone diagnostic test for COVID‐19 nor to prioritize patients for treatment. They will mainly be used to provide an overall picture about the health status of the patient. The final COVID‐19 diagnosis has to be made based on other tests. How up‐to‐date is this review? We searched all COVID‐19 studies up to 4 May 2020.

Objective Comparative diagnostic test accuracy systematic reviews (DTA reviews) assess the accuracy of two or more tests and compare their diagnostic performance. We investigated how comparative DTA reviews assessed the risk of bias (RoB) in primary studies that compared multiple index tests. Study Design and Setting Overview of comparative DTA reviews indexed in MEDLINE from January 1st to December 31st 2017. Two assessors independently identified DTA reviews including at least two index tests and containing at least one statement in which the accuracy of the index tests was compared. Two assessors independently extracted data on methods used to assess RoB in studies that directly compared the accuracy of multiple index tests. Results We included 238 comparative DTA reviews. Only two reviews (0.8%, 95% confidence interval 0.1 to 3.0%) conducted RoB assessment of test comparisons undertaken in primary studies; neither used a RoB tool specifically designed to assess bias in test comparisons. Conclusion Assessment of RoB in test comparisons undertaken in primary studies was uncommon in comparative DTA reviews, possibly due to lack of existing guidance on and awareness of potential sources of bias. Based on our findings, guidance on how to assess and incorporate RoB in comparative DTA reviews is needed.

Background Invasive pneumococcal disease (IPD) is associated with high morbidity and mortality, with immunocompromised patients (ICPs) at particular risk. Therefore, guidelines recommend pneumococcal vaccination for these patients. However, guidelines are scarcely underpinned with references to incidence studies of IPD in this population. This, potentially results in unawareness of the importance of vaccination and low vaccination rates. The objective of this systematic review and meta-analysis was to assess the incidence of IPD in ICPs. Methods We systematically searched PubMed and Embase to identify studies in English published before December 6th, 2017 that included terms related to ‘incidence’, ‘rate’, ‘pneumococcal’, ‘pneumoniae’, ‘meningitis’, ‘septicemia’, or ‘bacteremia’. We focused on patients with HIV, transplantation and chronic inflammatory diseases. Results We included 45 studies in the systematic review reporting an incidence or rate of IPD, defined as isolation of Streptococcus pneumoniae from a normally sterile site. Random effects meta-analysis of 38 studies showed a pooled IPD incidence of 331/100,000 person years in patients with HIV in the late-antiretroviral treatment era in non-African countries, and 318/100,000 in African countries; 696 and 812/100,000 in patients who underwent an autologous or allogeneic stem cell transplantation, respectively; 465/100,000 in patients with a solid organ transplantation; and 65/100,000 in patients with chronic inflammatory diseases. In healthy control cohorts, the pooled incidence was 10/100,000. Discussion ICPs are at increased risk of contracting IPD, especially those with HIV, and those who underwent transplantation. Based on our findings, we recommend pneumococcal vaccination in immunocompromised patients. Prospero registration ID: CRD42016048438.

Children with alleged child sexual abuse (CSA) need to be assessed systematically. The use of validated instruments during the assessment, like the Child Sexual Behavior Inventory (CSBI), could add diagnostic value. We aim to assess the diagnostic utility of the CSBI to differentiate between sexually abused and non-abused children. We conducted a systematic review. We searched the electronic databases MEDLINE and PsychInfo for studies comparing CSBI scores in sexually abused children and non-abused children (2–12 years old). Two independent reviewers extracted data and assessed the methodological quality. We included 7 (out of 1048) articles. The CSBI total scores were significantly higher in CSA-victims compared with non-abused children (in case–control settings). However, in children with suspected CSA, the results were ambiguous. One study reported significant differences. Another study reported weak diagnostic ability for the CSBI-3 in children with suspected CSA (a sensitivity and specificity of 0.50, with a positive predictive value of 0.28, and a negative predictive value of 0.72). Research on the diagnostic utility of the CSBI for suspected CSA is limited and shows disappointing results. Until more research is done, the CSBI should not be used on its own to differentiate between sexually abused and non-abused children.

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.

ObjectiveMany treatment decisions are preference-sensitive and call for shared decision-making, notably when benefits are limited or uncertain, and harms impact quality of life. We explored if clinical practice guidelines (CPGs) acknowledge preference-sensitive decisions in how they motivate and phrase their recommendations.DesignWe performed a qualitative analysis of the content of CPGs and verified the results in semistructured interviews with CPG panel members.SettingDutch oncology CPGs issued in 2010 or later, concerning primary treatment with curative intent.Participants14 CPG panel members.Main outcomesFor treatment recommendations from six CPG modules, two researchers extracted the following: strength of recommendation in terms of the Grading of Recommendations Assessment, Development and Evaluation and its consistency with the CPG text; completeness of presentation of benefits and harms; incorporation of patient preferences; statements on the panel’s benefits–harm trade-off underlying recommendation; and advice on patient involvement in decision-making.ResultsWe identified 32 recommendations, 18 were acknowledged preference-sensitive decisions. Three of 14 strong recommendations should have been weak based on the module text. The reporting of benefits and harms, and their probabilities, was sufficiently complete and clear to inform the strength of the recommendation in one of the six modules only. Numerical probabilities were seldom presented. None of the modules presented information on patient preferences. CPG panel’s preferences were not made explicit, but appeared to have impacted 15 of 32 recommendations. Advice to involve patients and their preferences in decision-making was given for 20 recommendations (14 weak). Interviewees confirmed these findings. Explanations for lack of information were, for example, that clinicians know the information and that CPGs must be short. Explanations for trade-offs made were cultural-historical preferences, compliance with daily care, presumed role of CPGs and lack of time.ConclusionsThe motivation and phrasing of CPG recommendations do not stimulate choice awareness and a neutral presentation of options, thus hindering shared decision-making.

Objectives The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group has developed GRADE evidence profiles (EP) and summary of findings (SoF) tables to present evidence summaries in systematic reviews, clinical guidelines, and health technology assessments. Explanatory notes are used to explain choices and judgments in these summaries, for example, on rating of the quality of evidence. Study Design and Setting A systematic survey of the explanations in SoF tables in 132 randomly selected Cochrane Intervention reviews and in EPs of 10 guidelines. We analyzed the content of 1,291 explanations using a predefined list of criteria. Results Most explanations were used to describe or communicate results and to explain downgrading of the quality of evidence, in particular for risk of bias and imprecision. Addressing the source of baseline risk (observational data or control group risk) was often missing. For judgments about downgrading the quality of evidence, the percentage of informative explanations ranged between 41% (imprecision) and 79% (indirectness). Conclusion We found that by and large explanations were informative but detected several areas for improvement (e.g., source of baseline risk and judgments on imprecision). Guidance about explanatory footnotes and comments will be provided in the last article in this series.

Objectives: To develop a guideline on Responsible Epidemiologic Research Practice that will increase value and transparency, increase the accountability of the epidemiologists, and reduce research waste. Setting: A working group of the Netherland Epidemiological Society was given the task of developing a guideline that would meet these objectives. Several publications about the need to prevent Detrimental Research Practices triggered this work. Among these were a series in the Lancet on research waste and a subsequent series on transparency in the Journal of Clinical Epidemiology. The reputation and trust in epidemiologic research is still high, and the Netherlands Epidemiological Society wishes to keep it that way. The guideline deals with how epidemiologic research should be conducted, archived, and disclosed. It does not deal with the more technical aspects, such as required sample size, choice of study design, and so forth. The guideline describes each step in the process of conducting an epidemiologic study, from the first idea to the ultimate publication and beyond. Methods: The working group reviewed the literature on responsible research conduct, including the various existing codes of conduct. It applied the general principles from these codes to the elements of an epidemiologic study and formulated specific recommendations for each of these. Next step was to draft the guideline. Preceding the 2016 annual national epidemiology conference in Wageningen, a preconference was organized to discuss the draft guideline and to assess support. Support was clearly present, and the provided recommendations were incorporated into the draft guideline. In March 2017, a draft version of the guideline was sent to all 1,100 members of the society with the request to review and provide comments. All received responses were positive, and some minor additions were made. The Responsible Epidemiologic Research Practice guideline has now been approved by the board of the Netherlands Epidemiological Society. Conclusion: With the Responsible Epidemiologic Research Practice guideline, we hope to contribute to better research practices in epidemiology but perhaps also in adjacent disciplines. (C) 2018 The Authors. Published by Elsevier Inc.

Introduction Sciatica is usually self-limiting with pain and disability decreasing over time, but not all patients fully recover. Prognostic evidence could assist clinicians to better define high risk groups and inform both clinicians and patients with regard to counselling and treatment choices to promote return to work. The objective of this study was to review and summarise prognostic factors of work participation in patients with sciatica. Methods We searched MEDLINE, CINAHL, EMBASE and PsycINFO till May 2016. Cohort studies, using a measure of work participation as outcome, were included. We used the QUIPS tool for risk of bias assessment and GRADE to rate the quality of the evidence. Results Based on five studies describing four cohorts (n=983 patients) that assessed 19 potential prognostic factors, favourable factors for return to work at long term-term follow up (up to 10 years) included: younger age, better general health, less low back pain or sciatica bothersomeness, better physical function, positive SLR-test, a physician expecting surgery to be beneficial, better pain coping, less depression and mental stress, low physical work load. Study results could not be pooled. Using GRADE, the quality of the evidence ranged from moderate to very low. Discussion Five studies describing four cohorts identified a wide range of factors: general health, pain and disability, psychological factors and work related factors. Although the number of studies was low and the quality of evidence ranged from moderate to very low, prognostic (modifiable) factors may be used to assist clinicians and occupational healthcare professionals in guiding high risk patients and consider referral for additional care or vocational rehabilitation, or in managing patients’ expectations regarding return to work.

Objective: T o de v elop a North American Society for Pediatric Ga str oen te rol og y , He pat olo gy , and Nut ri tio n (N ASP GH AN) and Eu rop ea n Soc ie ty fo r Pe di atr ic Gas tr oen te ro log y , Hep at ol og y , and Nut rit io n (ES PGH AN ) int er nat io nal con se ns us on th e di agn os is an d ma nag em ent of gas tr oes op hag eal refl ux and gas tr oes op hag eal re flu x di sea se in th e ped ia tr ic po pu la tio n. Methods: An international panel of 9 pediatric gastroenterologists and 2 epidemiologists were selected by both societies, which de v eloped these guidelines based on the Delphi principle. Statements were based on systematic literature searches using the best-av ailable e vidence from PubMed, Cumulati ve Index to Nursing and Allied Health Literature, and bibliographies. The committee con v ened in face-to-face meetings 3 times. Consensus was achie v ed for all recommendations through nominal group technique, a structured, quantitati v e method. Articles were e v aluated using the Oxford Centre for Evidence-based Medicine Le vels of Evidence. Using the Oxford Grades of Recommendation, the quality of e vidence of each of the recommendations made by the committee was determined and is summarized in appendices. Results: More than 600 articles were re vie wed for this work. The document provides e vidence-based guidelines for the diagnosis and management of gastroesophageal reflux and gastroesophageal reflux disease in the pediatric population. Conclusions: Th is do cum ent is int end ed to be us ed in dai ly pra cti ce fo r th e de v el op me nt of fut ure cli ni cal pra ct ic e gu ide lin es and as a bas is for cli ni cal tr ia ls . JP GN 49 :49 8 – 54 7, 20 09 . Ke y Wo rd s: Cli nic al pra ct ic e gu id el ine s — Di agn os tic te sts — Ga str oes op hag ea l refl ux (GE R) — Ga str oes op hag ea l refl ux di sea se (GE RD ) — The rap eut ic mod al iti es. # 20 09 by Eu rop ea n Soc ie ty fo r Pe di atr ic Gas tr oen te ro log y , Hep at ol og y , and Nut rit io n and No rt h Am er ica n So ci ety for Pe dia tri c Ga str oen te rol og y , Hep at ol og y , an d Nu tr iti on