User-experience testing of an evidence-to-decision framework for selecting essential medicines.

Essential medicine lists (EMLs) are important medicine prioritization tools used by the World Health Organization (WHO) EML and over 130 countries. The criteria used by WHO's Expert Committee on the Selection and Use of Essential Medicines has parallels to the GRADE Evidence-to-Decision (EtD) frameworks. In this study, we explored the EtD frameworks and a visual abstract as adjunctive tools to strengthen the integrate evidence and improve the transparency of decisions of EML applications. We conducted user-experience testing interviews of key EML stakeholders using Morville's honeycomb model. Interviews explored multifaceted dimensions (e.g., usability) on two EML applications for the 2021 WHO EML-long-acting insulin analogues for diabetes and immune checkpoint inhibitors for lung cancer. Using a pre-determined coding framework and thematic analysis we iteratively improved both the EtD framework and the visual abstract. We coded the transcripts of 17 interviews with 13 respondents in 103 locations of the interview texts across all dimensions of the user-experience honeycomb. Respondents felt the EtD framework and visual abstract presented complementary useful and findable adjuncts to the traditional EML application. They felt this would increase transparency and efficiency in evidence assessed by EML committees. As EtD frameworks are also used in health practice guidelines, including those by the WHO, respondents articulated that the adoption of the EtD by EML applications represents a tangible mechanism to align EMLs and guidelines, decrease duplication of work and improve coordination. Improvements were made to clarify instructions for the EtD and visual abstract, and to refine the design and content included. 'Availability' was added as an additional criterion for EML applications to highlight this criterion in alignment with WHO EML criteria. EtD frameworks and visual abstracts present additional important tools to communicate evidence and support decision-criteria in EML applications, which have global health impact. Access to essential medicines is important for achieving universal health coverage, and the development of essential medicine lists should be as evidence-based and trustworthy as possible.

GRADE Reporting in Systematic Reviews Published in the Urological Literature (2009-2021).

PURPOSE: We evaluate the reporting of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to rating the certainty of evidence in systematic reviews published in the urological literature. MATERIALS AND METHODS: Based on a predefined protocol, we identified all systematic reviews published in 5 major urological journals from 1998 to 2021 that reported the use of GRADE. Two authors performed study selection and data abstraction independently to assess reporting in accordance with established criteria for applying GRADE. RESULTS: We included 68 of 522 (13.0%) systematic reviews that reported the use of GRADE; the first was published in 2009. Approximately half were published between 2009-2018 (n=36) and the other half between 2019-2021 (n=32). Oncology (24; 35.3%) was the most common clinical topic, and the authors were mostly based in Europe (34; 50%). In their abstract, less than half of all systematic reviews (32; 47.1%) provided any certainty of evidence rating. Only 41 (60.3%) included a tabular result summary in the format of a summary of findings table (24; 35.3%) or evidence profile (17; 25.0%). Few (35.3%) addressed the GRADE certainty of evidence rating in the discussion section. Reporting did not improve over time when comparing the 2 time periods. CONCLUSIONS: Whereas GRADE is increasingly being applied for rating the certainty of evidence, systematic reviews published in the urological literature frequently have not followed established criteria for applying or using GRADE. There is a need for better training of authors and editors, as well as for a GRADE reporting checklist for systematic review authors.

American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing.

Hereditary and acquired thrombophilia are risk factors for venous thromboembolism (VTE). Whether testing helps guide management decisions is controversial. These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about thrombophilia testing. ASH formed a multidisciplinary guideline panel covering clinical and methodological expertise and minimizing bias from conflicts of interest. The McMaster University GRADE Centre provided logistical support, performed systematic reviews, and created evidence profiles and evidence-to-decision tables. The Grading of Recommendations Assessment, Development, and Evaluation approach (GRADE) was used. Recommendations were subject to public comment. The panel agreed on 23 recommendations regarding thrombophilia testing and associated management. Nearly all recommendations are based on very low certainty in the evidence due to modeling assumptions. The panel issued a strong recommendation against testing the general population before starting combined oral contraceptives (COCs) and conditional recommendations for thrombophilia testing in the following scenarios: (a) patients with VTE associated with nonsurgical major transient or hormonal risk factors; (b) patients with cerebral or splanchnic venous thrombosis, in settings where anticoagulation would otherwise be discontinued; (c) individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance to avoid COCs/hormone replacement therapy; (d) pregnant women with a family history of high-risk thrombophilia types; and (e) patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE. For all other questions, the panel provided conditional recommendations against testing for thrombophilia.

The BIGG-REC database makes available all WHO/PAHO evidence informed recommendations.

OBJECTIVES: To build and maintain a living database of the Pan American Health Organization/World Health Organization (PAHO/WHO) recommendations developed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). STUDY DESIGN AND SETTING: Guidelines are identified from WHO and PAHO databases. We periodically extract recommendations, according to the health and well-being targets of sustainable development goal 3 (SDG-3). RESULTS: As of March 2022, the International database of GRADE guidelines (https://bigg-rec.bvsalud.org/en) database hosted 2,682 recommendations contained in 285 WHO/PAHO guidelines. Recommendations were classified as follows: communicable diseases (1,581), children's health (1,182), universal health (1,171), sexual and reproductive health (910), noncommunicable diseases (677), maternal health (654), COVID-19 (224), use of psychoactive substances (99), tobacco (14) and road and traffic accidents (16). International database of GRADE guidelines allows searching by SDG-3, condition or disease, type of intervention, institution, year of publication, and age. CONCLUSION: Recommendation maps provide an important resource for health professionals, organizations and member states that use evidence-informed guidance to make better decisions, providing a source for the adoption or adaptation of recommendations to meet their needs. This one-stop shop database of evidence-informed recommendations built with intuitive functionalities undoubtedly represents a long-needed tool for decision-makers, guideline developers, and the public at large.

Joint 2022 European Society of Thoracic Surgeons and The American Association for Thoracic Surgery guidelines for the prevention of cancer-associated venous thromboembolism in thoracic surgery.

BACKGROUND: Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a potentially fatal but preventable postoperative complication. Thoracic oncology patients undergoing surgical resection, often after multimodality induction therapy, represent among the highest risk groups for postoperative VTE. Currently there are no VTE prophylaxis guidelines specific to these thoracic surgery patients. Evidenced-based recommendations will help clinicians manage and mitigate risk of VTE in the postoperative period and inform best practice. OBJECTIVE: These joint evidence-based guidelines from The American Association for Thoracic Surgery and the European Society of Thoracic Surgeons aim to inform clinicians and patients in decisions about prophylaxis to prevent VTE in patients undergoing surgical resection for lung or esophageal cancer. METHODS: The American Association for Thoracic Surgery and the European Society of Thoracic Surgeons formed a multidisciplinary guideline panel that included broad membership to minimize potential bias when formulating recommendations. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to public comment. RESULTS: The panel agreed on 24 recommendations focused on pharmacological and mechanical methods for prophylaxis in patients undergoing lobectomy and segmentectomy, pneumonectomy, and esophagectomy, as well as extended resections for lung cancer. CONCLUSIONS: The certainty of the supporting evidence for the majority of recommendations was judged as low or very low, largely due to a lack of direct evidence for thoracic surgery. The panel made conditional recommendations for use of parenteral anticoagulation for VTE prevention, in combination with mechanical methods, over no prophylaxis for cancer patients undergoing anatomic lung resection or esophagectomy. Other key recommendations include: conditional recommendations for using parenteral anticoagulants over direct oral anticoagulants, with use of direct oral anticoagulants suggested only in the context of clinical trials; conditional recommendation for using extended prophylaxis for 28 to 35 days over in-hospital prophylaxis only for patients at moderate or high risk of thrombosis; and conditional recommendations for VTE screening in patients undergoing pneumonectomy and esophagectomy. Future research priorities include the role of preoperative thromboprophylaxis and the role of risk stratification to guide use of extended prophylaxis.

Meta-analysis: Use of proton pump inhibitors and risk of gastric cancer in patients requiring gastric acid suppression.

BACKGROUND: Proton-pump inhibitors (PPIs) are suspected to increase the risk of gastric cancer. AIM: To assess the risk of gastric cancer associated with the use of PPIs. METHODS: We systematically searched Medline/PubMed, Embase and Scopus databases (until June 1, 2022) for randomised and non-randomised studies (NRS) of the association between PPIs and gastric cancer having considered Histamine-2 receptor antagonists (H2RAs) users as controls. We chose this comparison to minimise confounding by indication, and focus on patients requiring gastric acid suppression. Two authors independently extracted study data and assessed each study's risk of bias. Maximally-adjusted relative risk (RR) estimates were extracted. Heterogeneity and small-study effect were examined, and summary estimates were calculated using random- and fixed-effect models. Stratified analyses and meta-regression were employed to explore heterogeneity. We used GRADE to evaluate the certainty of evidence. RESULTS: Of 8375 records, 12 NRS (>6 million patients; 11,554 gastric cancers) and two randomised clinical trials (498 patients; 1 gastric cancer) fulfilled the eligibility criteria. Randomised evidence was very imprecise and provided very-low certainty evidence. Meta-analysis of six NRS providing a comprehensive adjustment for confounding (2.5 million patients; 7372 gastric cancers) did not show any association between PPIs and gastric cancer (RRrandom  = 1.07, 0.97-1.19; RRfixed  = 1.05, 0.98-1.12). The certainty of the evidence was low. No convincing evidence of dose-response, or increased risk with long-term use, was found. Lack of or minimal adjustment for confounding was associated with larger effect sizes. CONCLUSIONS: We found no association between PPIs and gastric cancer in NRS having adequately controlled for confounding. Published studies may suffer residual confounding. SYSTEMATIC REVIEW REGISTRATION: CRD42022335971.

The GIN-McMaster guideline tool extension for the integration of quality improvement and quality assurance in guidelines: a description of the methods for its development.

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.

Joint 2022 European Society of Thoracic Surgeons and The American Association for Thoracic Surgery guidelines for the prevention of cancer-associated venous thromboembolism in thoracic surgery.

BACKGROUND: Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a potentially fatal but preventable postoperative complication. Thoracic oncology patients undergoing surgical resection, often after multimodality induction therapy, represent among the highest risk groups for postoperative VTE. Currently there are no VTE prophylaxis guidelines specific to these thoracic surgery patients. Evidenced-based recommendations will help clinicians manage and mitigate risk of VTE in the postoperative period and inform best practice. OBJECTIVE: These joint evidence-based guidelines from The American Association for Thoracic Surgery and the European Society of Thoracic Surgeons aim to inform clinicians and patients in decisions about prophylaxis to prevent VTE in patients undergoing surgical resection for lung or esophageal cancer. METHODS: The American Association for Thoracic Surgery and the European Society of Thoracic Surgeons formed a multidisciplinary guideline panel that included broad membership to minimize potential bias when formulating recommendations. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to public comment. RESULTS: The panel agreed on 24 recommendations focused on pharmacological and mechanical methods for prophylaxis in patients undergoing lobectomy and segmentectomy, pneumonectomy, and esophagectomy, as well as extended resections for lung cancer. CONCLUSIONS: The certainty of the supporting evidence for the majority of recommendations was judged as low or very low, largely due to a lack of direct evidence for thoracic surgery. The panel made conditional recommendations for use of parenteral anticoagulation for VTE prevention, in combination with mechanical methods, over no prophylaxis for cancer patients undergoing anatomic lung resection or esophagectomy. Other key recommendations include: conditional recommendations for using parenteral anticoagulants over direct oral anticoagulants, with use of direct oral anticoagulants suggested only in the context of clinical trials; conditional recommendation for using extended prophylaxis for 28 to 35 days over in-hospital prophylaxis only for patients at moderate or high risk of thrombosis; and conditional recommendations for VTE screening in patients undergoing pneumonectomy and esophagectomy. Future research priorities include the role of preoperative thromboprophylaxis and the role of risk stratification to guide use of extended prophylaxis. (J Thorac Cardiovasc Surg 2022;▪:1-31).

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update - XIII - Oral immunotherapy for CMA - Systematic review.

Background: Allergy to cow's milk is the most common food allergy in infants and it is usually outgrown by 5 years of age. In some individuals it persists beyond early childhood. Oral immunotherapy (OIT, oral desensitization, specific oral tolerance induction) has been proposed as a promising therapeutic strategy for persistent IgE-mediated cow's milk allergy. We previously published the systematic review of OIT for cow's milk allergy (CMA) in 2010 as part of the World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. Objective: To systematically synthesize the currently available evidence about OIT for IgE-mediated CMA and to inform the updated 2022 WAO guidelines. Methods: We searched the electronic databases including PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations. We included all studies irrespective of the language of the original publication. The last search was conducted in February 2021. We registered the protocol on Open Science Framework (10.17605/OSF.IO/AH2DT). Results: We identified 2147 unique records published between 2010 and 2021, including 13 randomized trials and 109 observational studies addressing cow's milk OIT. We found low-certainty evidence that OIT with unheated cow's milk, compared to elimination diet alone, increased the likelihood of being able to consume ≥150 ml of cow's milk in controlled settings (risk ratio (RR): 12.3, 95% CI: 5.9 to 26.0; risk difference (RD): 25 more per 100, 95% CI 11 to 56) as well as accidently ingest a small amount (≥5 ml) of cow's milk (RR: 8.7, 95% CI: 4.7 to 16.1; RD: 25 more per 100, 95% CI 12 to 50). However, 2-8 weeks after discontinuation of a successful OIT, tolerance of cow's milk persisted in only 36% (range: 20%-91%) of patients. OIT increased the frequency of anaphylaxis (rate ratio: 60.0, 95% CI 15 to 244; rate difference 5 more anaphylactic reactions per 1 person per year, 95% CI: 4 to 6; moderate evidence) and the frequency of epinephrine use (rate ratio: 35.2, 95% CI: 9 to 136.5; rate difference 268 more events per 100 person-years, 95% CI: 203 to 333; high certainty). OIT also increased the risk of gastrointestinal symptoms (RR 6.9, 95% CI 1.6-30.9; RD 28 more per 100, CI 3 to 100) and respiratory symptoms (RR 49.0, 95% CI 3.12-770.6; RD 77 more per 100, CI 62 to 92), compared with avoidance diet alone. Single-arm observational studies showed that on average 6.9% of OIT patients (95% CI: 3.8%-10%) developed eosinophilic esophagitis (very low certainty evidence). We found 1 trial and 2 small case series of OIT with baked milk. Conclusions: Moderate certainty evidence shows that OIT with unheated cow's milk in patients with IgE-mediated CMA is associated with an increased probability of being able to drink milk and, at the same time, an increased risk of serious adverse effects.

Analytical frameworks in colorectal cancer guidelines: development of methods for systematic reviews, their application and practical guidance for their use.

OBJECTIVES: Analytical frameworks are graphical representation of the key questions answered by a systematic review and can support the development of guideline recommendations. Our objectives were to a) conduct a systematic review to identify, describe and compare all analytical frameworks published as part of a systematic and guideline development process related to colorectal cancer (CRC), and b) to use this case study to develop guidance on how to conduct systematic reviews of analytical frameworks. METHODS: We developed a search strategy to identify eligible studies in Medline and Embase from 1996 until December 2020. We also manually searched guideline databases and websites to identify all guidelines and systematic reviews in CRC that used an analytical framework. We assessed the quality of the guidelines using the Appraisal of Guidelines for Research and Evaluation II tool. The systematic review was registered in International Prospective Register of Systematic Reviews, registration CRD42020172117. RESULTS: We screened 34,505 records and identified 1,166 guidelines and 3,127 systematic reviews on CRC of which five met our inclusion criteria. These five publications included four analytical frameworks in colorectal cancer (one update). We also describe our methodological approach to systematic reviews for analytical frameworks and underlying concepts for developing analytical framework using a bottom-up or top-down approach. CONCLUSION: Few guidelines and systematic reviews are utilizing analytical frameworks in the development of recommendations. Development of analytical frameworks should begin with a systematic search for existing analytical frameworks and follow a structured conceptual approach for their development to support guideline recommendations. Our methods may be helpful in achieving these objectives.

Benefits and harms of direct oral anticoagulation and low molecular weight heparin for thromboprophylaxis in patients undergoing non-cardiac surgery: systematic review and network meta-analysis of randomised trials.

OBJECTIVE: To systematically compare the effect of direct oral anticoagulants and low molecular weight heparin for thromboprophylaxis on the benefits and harms to patients undergoing non-cardiac surgery. DESIGN: Systematic review and network meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL), up to August 2021. REVIEW METHODS: Randomised controlled trials in adults undergoing non-cardiac surgery were selected, comparing low molecular weight heparin (prophylactic (low) or higher dose) with direct oral anticoagulants or with no active treatment. Main outcomes were symptomatic venous thromboembolism, symptomatic pulmonary embolism, and major bleeding. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for network meta-analyses. Abstracts and full texts were screened independently in duplicate. Data were abstracted on study participants, interventions, and outcomes, and risk of bias was assessed independently in duplicate. Frequentist network meta-analysis with multivariate random effects models provided odds ratios with 95% confidence intervals, and GRADE (grading of recommendations, assessment, development, and evaluation) assessments indicated the certainty of the evidence. RESULTS: 68 randomised controlled trials were included (51 orthopaedic, 10 general, four gynaecological, two thoracic, and one urological surgery), involving 45 445 patients. Low dose (odds ratio 0.33, 95% confidence interval 0.16 to 0.67) and high dose (0.19, 0.07 to 0.54) low molecular weight heparin, and direct oral anticoagulants (0.17, 0.07 to 0.41) reduced symptomatic venous thromboembolism compared with no active treatment, with absolute risk differences of 1-100 per 1000 patients, depending on baseline risks (certainty of evidence, moderate to high). None of the active agents reduced symptomatic pulmonary embolism (certainty of evidence, low to moderate). Direct oral anticoagulants and low molecular weight heparin were associated with a 2-3-fold increase in the odds of major bleeding compared with no active treatment (certainty of evidence, moderate to high), with absolute risk differences as high as 50 per 1000 in patients at high risk. Compared with low dose low molecular weight heparin, high dose low molecular weight heparin did not reduce symptomatic venous thromboembolism (0.57, 0.26 to 1.27) but increased major bleeding (1.87, 1.06 to 3.31); direct oral anticoagulants reduced symptomatic venous thromboembolism (0.53, 0.32 to 0.89) and did not increase major bleeding (1.23, 0.89 to 1.69). CONCLUSIONS: Direct oral anticoagulants and low molecular weight heparin reduced venous thromboembolism compared with no active treatment but probably increased major bleeding to a similar extent. Direct oral anticoagulants probably prevent symptomatic venous thromboembolism to a greater extent than prophylactic low molecular weight heparin. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018106181.

Global status of essential medicine selection: a systematic comparison of national essential medicine lists with recommendations by WHO.

OBJECTIVES: Examining the availability of essential medicines is a necessary step to monitor country-level progress towards universal health coverage. We compared the 2017 essential medicine lists (EML) of 137 countries to the WHO Model List to assess differences by drug class and country setting. METHODS: We extracted all medicines prioritised at country level from most recently available national EMLs and compared each national EML with the 2017 WHO Model List of Essential Medicines (MLEM) as the reference standard. We assess EMLs by WHO region and for different types of medicine subgroups (eg, cancer, anti-infectives, cardiac, psychiatric and anaesthesia medicines) using within second-level anatomical therapeutic class (ATC) drug classes of the ATC Index. RESULTS: We included 406 medicines from WHO's 2017 MLEM to compare to 137 concurrent national EMLs. We found a median of 315 (range from 44 to 983) medicines listed on national EMLs. The global median F1 score was 0.59 (IQR 0.47-0.70, maximum possible score indicating alignment with MLEM is 1). The F1 score was the highest (ie, most similar to MLEM) in the South-East Asia region and the lowest in the European region (ie, most dissimilar to MLEM). The F1 score was highest for stomatological preparations (median: 1.00), gynaecological-anti-infectives and antiseptics (median: 1.00), and medicated dressings (median: 1.00), and lowest for 9 anatomical or pharmacological groups (median: 0.00, eg, treatments for bone diseases, digestive enzymes). CONCLUSIONS: Most countries are expected to improve their national health coverage by 2030 offering access to essential medicines, but our results revealed substantial gaps in selection of medicines at the national level compared with those recommended by WHO. It is crucial that governments consider investing in those effective medicines that are now neglected and continue monitoring progress towards essential medicine access as part of universal health coverage.

Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia.

Long-term treatment with 6-thioguanine (6-TG) for pediatric acute lymphoblastic leukemia (ALL) is associated with high rates of hepatic sinusoidal obstruction syndrome (SOS). Nevertheless, current treatment continues to use short-term applications of 6-TG with only sparse information on toxicity. 6-TG is metabolized by thiopurine methyltransferase (TPMT) which underlies clinically relevant genetic polymorphism. We analyzed the association between hepatic SOS reported as a serious adverse event (SAE) and short-term 6-TG application in 3983 pediatric ALL patients treated on trial AIEOP-BFM ALL 2000 (derivation cohort) and defined the role of TPMT genotype in this relationship. We identified 17 patients (0.43%) with hepatic SOS, 13 of which with short-term exposure to 6-TG (P < 0.0001). Eight of the 13 patients were heterozygous for low-activity TPMT variants, resulting in a 22.4-fold (95% confidence interval 7.1-70.7; P ≤ 0.0001) increased risk of hepatic SOS for heterozygotes in comparison to TPMT wild-type patients. Results were supported by independent replication analysis. All patients with hepatic SOS after short-term 6-TG recovered and did not demonstrate residual symptoms. Thus, hepatic SOS is associated with short-term exposure to 6-TG during treatment of pediatric ALL and SOS risk is increased for patients with low-activity TPMT genotypes.

Guideline-based quality assurance: a conceptual framework for the definition of key elements.

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.

Bringing two worlds closer together: a critical analysis of an integrated approach to guideline development and quality assurance schemes.

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.

Recommendations from the European Commission Initiative on Breast Cancer for multigene testing to guide the use of adjuvant chemotherapy in patients with early breast cancer, hormone receptor positive, HER-2 negative.

BACKGROUND: Predicting the risk of recurrence and response to chemotherapy in women with early breast cancer is crucial to optimise adjuvant treatment. Despite the common practice of using multigene tests to predict recurrence, existing recommendations are inconsistent. Our aim was to formulate healthcare recommendations for the question "Should multigene tests be used in women who have early invasive breast cancer, hormone receptor-positive, HER2-negative, to guide the use of adjuvant chemotherapy?" METHODS: The European Commission Initiative on Breast Cancer (ECIBC) Guidelines Development Group (GDG), a multidisciplinary guideline panel including experts and three patients, developed recommendations informed by systematic reviews of the evidence. Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision frameworks were used. Four multigene tests were evaluated: the 21-gene recurrence score (21-RS), the 70-gene signature (70-GS), the PAM50 risk of recurrence score (PAM50-RORS), and the 12-gene molecular score (12-MS). RESULTS: Five studies (2 marker-based design RCTs, two treatment interaction design RCTs and 1 pooled individual data analysis from observational studies) were included; no eligible studies on PAM50-RORS or 12-MS were identified and the GDG did not formulate recommendations for these tests. CONCLUSIONS: The ECIBC GDG suggests the use of the 21-RS for lymph node-negative women (conditional recommendation, very low certainty of evidence), recognising that benefits are probably larger in women at high risk of recurrence based on clinical characteristics. The ECIBC GDG suggests the use of the 70-GS for women at high clinical risk (conditional recommendation, low certainty of evidence), and recommends not using 70-GS in women at low clinical risk (strong recommendation, low certainty of evidence).

Minimal important difference estimates for patient-reported outcomes: A systematic survey.

OBJECTIVES: The objective of the study was to develop an inventory summarizing all anchor-based minimal important difference (MID) estimates for patient-reported outcome measures (PROMs) available in the medical literature. STUDY DESIGN AND SETTING: We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and the Patient-Reported Outcome and Quality of Life Instruments Database internal library (January 1989-October 2018). We included primary studies empirically calculating an anchor-based MID estimate for any PROM in adults and adolescents. Pairs of reviewers independently screened and selected studies, extracted data, and evaluated the credibility of the MIDs. RESULTS: We identified 585 eligible studies, the majority conducted in Europe (n = 211) and North America (n = 179), reporting 5,324 MID estimates for 526 distinct PROMs. Investigators conducted their studies in the context of patients receiving surgical (n = 105, 18%), pharmacological (n = 85, 15%), rehabilitation (n = 65, 11%), or a combination of interventions (n = 194, 33%). Of all MID estimates, 59% (n = 3,131) used a global rating of change anchor. Major credibility limitations included weak correlation (n = 1,246, 23%) or no information regarding the correlation (n = 3,498, 66%) between the PROM and anchor and imprecision in the MID estimate (n = 2,513, 47%). CONCLUSION: A large number of MIDs for assisting in the interpretation of PROMs exist. The MID inventory will facilitate the use of MID estimates to inform the interpretation of the magnitude of treatment effects in clinical research and guideline development.

Improving the trustworthiness of findings from nutrition evidence syntheses: assessing risk of bias and rating the certainty of evidence.

Suboptimal diet is recognized as a leading modifiable risk factor for non-communicable diseases. Non-randomized studies (NRSs) with patient relevant outcomes provide many insights into diet-disease relationships. Dietary guidelines are based predominantly on findings from systematic reviews of NRSs-mostly prospective observational studies, despite that these have been repeatedly criticized for yielding potentially less trustworthy results than randomized controlled trials (RCTs). It is assumed that these are a result of bias due to prevalent-user designs, inappropriate comparators, residual confounding, and measurement error. In this article, we aim to highlight the importance of applying risk of bias (RoB) assessments in nutritional studies to improve the credibility of evidence of systematic reviews. First, we discuss the importance and challenges of dietary RCTs and NRSs, and provide reasons for potentially less trustworthy results of dietary studies. We describe currently used tools for RoB assessment (Cochrane RoB, and ROBINS-I), describe the importance of rigorous RoB assessment in dietary studies and provide examples that further the understanding of the key issues to overcome in nutrition research. We then illustrate, by comparing the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach with current approaches used by United States Department of Agriculture Dietary Guidelines for Americans, and the World Cancer Research Fund, how to establish trust in dietary recommendations. Our overview shows that the GRADE approach provides more transparency about the single domains for grading the certainty of the evidence and the strength of recommendations. Despite not increasing the certainty of evidence itself, we expect that the rigorous application of the Cochrane RoB and the ROBINS-I tools within systematic reviews of both RCTs and NRSs and their integration within the GRADE approach will strengthen the credibility of dietary recommendations.

Evaluating prophylactic heparin in ambulatory patients with solid tumours: a systematic review and individual participant data meta-analysis.

BACKGROUND: Study-level meta-analyses provide high-certainty evidence that heparin reduces the risk of symptomatic venous thromboembolism for patients with cancer; however, whether the benefits and harms associated with heparin differ by cancer type is unclear. This individual participant data meta-analysis of randomised controlled trials examines the effect of heparin on survival, venous thromboembolism, and bleeding in patients with cancer in general and by type. METHODS: In this systematic review and meta-analysis we searched MEDLINE, Embase, and The Cochrane Library for randomised controlled trials comparing parenteral anticoagulants with placebo or standard care in ambulatory patients with solid tumours and no indication for anticoagulation published from the inception of each database to January 14, 2017, and updated it on May 14, 2020, without language restrictions. We calculated the effect of parenteral anticoagulant administration on all-cause mortality, venous thromboembolism occurrence, and bleeding related outcomes through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect, adjusting for age, cancer type, and metastatic status. Interaction terms were tested to investigate effects in predefined subgroups. This study is registered with PROSPERO, CRD42013003526. FINDINGS: We obtained individual participant data from 14 of 20 eligible randomised controlled trials (8278 [79%] of 10 431 participants; 4139 included in the low-molecular-weight heparin group and 4139 in the control group). Meta-analysis showed an adjusted relative risk (RR) of mortality at 1 year of 0·99 (95% CI 0·93-1·06) and a hazard ratio of 1·01 (95% CI 0·96-1·07). The number of patients with venous thromboembolic events was 158 (4·0%) of 3958 with available data in the low-molecular-weight heparin group compared with 279 (7·1%) of 3957 in the control group. Major bleeding events occurred in 71 (1·7%) of 4139 patients in the control population and 88 (2·1%) in the low-molecular-weight heparin group, and minor bleeding events in 478 (12·1%) of 3945 patients with available data in the control group and 652 (16·6%) of 3937 patients in the low-molecular-weight heparin group. The adjusted RR was 0·58 (95% CI 0·47-0·71) for venous thromboembolism, 1·27 (0·92-1·74) for major bleeding, and 1·34 (1·19-1·51) for minor bleeding. Prespecified subgroup analysis of venous thromboembolism occurrence by cancer type identified the most certain benefit from heparin treatment in patients with lung cancer (RR 0·59 [95% CI 0·42-0·81]), which dominated the overall reduction in venous thromboembolism. Certainty of the evidence for the outcomes ranged from moderate to high. INTERPRETATION: Low-molecular-weight heparin reduces risk of venous thromboembolism without increasing risk of major bleeding compared with placebo or standard care in patients with solid tumours, but it does not improve survival. FUNDING: Canadian Institutes of Health Research.