Development of an international glossary for clinical guidelines collaboration.

OBJECTIVES: Clinical practice guidelines (CPGs) are often created through collaboration among organizations. The use of inconsistent terminology may cause poor communication and delays. This study aimed to develop a glossary of terms related to collaboration in guideline development. STUDY DESIGN AND SETTING: A literature review of collaborative guidelines was performed to develop an initial list of terms related to guideline collaboration. The list of terms was presented to the members of the Guideline International Network Guidelines Collaboration Working Group, who provided presumptive definitions for each term and proposed additional terms to be included. The revised list was subsequently reviewed by an international, multidisciplinary panel of expert stakeholders. Recommendations received during this pre-Delphi review were implemented to augment an initial draft glossary. The glossary was then critically evaluated and refined through two rounds of Delphi surveys and a virtual consensus meeting with all panel members as Delphi participants. RESULTS: Forty-nine experts participated in the pre-Delphi survey, and 44 participated in the two-round Delphi process. Consensus was reached for 37 terms and definitions. CONCLUSION: Uptake and utilization of this guideline collaboration glossary by key organizations and stakeholder groups may facilitate collaboration among guideline-producing organizations by improving communication, minimizing conflicts, and increasing guideline development efficiency.

Knowledge user survey and Delphi process to inform development of a new risk of bias tool to assess systematic reviews with network meta-analysis (RoB NMA tool).

BACKGROUND: Network meta-analysis (NMA) is increasingly used in guideline development and other aspects of evidence-based decision-making. We aimed to develop a risk of bias (RoB) tool to assess NMAs (RoB NMA tool). An international steering committee recommended that the RoB NMA tool to be used in combination with the Risk of Bias in Systematic reviews (ROBIS) tool (i.e. because it was designed to assess biases only) or other similar quality appraisal tools (eg, A MeaSurement Tool to Assess systematic Reviews 2 [AMSTAR 2]) to assess quality of systematic reviews. The RoB NMA tool will assess NMA biases and limitations regarding how the analysis was planned, data were analysed and results were presented, including the way in which the evidence was assembled and interpreted. OBJECTIVES: Conduct (a) a Delphi process to determine expert opinion on an item's inclusion and (b) a knowledge user survey to widen its impact. DESIGN: Cross-sectional survey and Delphi process. METHODS: Delphi panellists were asked to rate whether items should be included. All agreed-upon item were included in a second round of the survey (defined as 70% agreement). We surveyed knowledge users' views and preferences about the importance, utility and willingness to use the RoB NMA tool to evaluate evidence in practice and in policymaking. We included 12 closed and 10 open-ended questions, and we followed a knowledge translation plan to disseminate the survey through social media and professional networks. RESULTS: 22 items were entered into a Delphi survey of which 28 respondents completed round 1, and 22 completed round 2. Seven items did not reach consensus in round 2. A total of 298 knowledge users participated in the survey (14% respondent rate). 75% indicated that their organisation produced NMAs, and 78% showed high interest in the tool, especially if they had received adequate training (84%). Most knowledge users and Delphi panellists preferred a tool to assess both bias in individual NMA results and authors' conclusions. Response bias in our sample is a major limitation as knowledge users working in high-income countries were more represented. One of the limitations of the Delphi process is that it depends on the purposive selection of experts and their availability, thus limiting the variability in perspectives and scientific disciplines. CONCLUSIONS: This Delphi process and knowledge user survey informs the development of the RoB NMA tool.

A memorandum of understanding has facilitated guideline development involving collaborating groups.

OBJECTIVE: Collaboration between groups can facilitate the development of high-quality guidelines. While collaboration is often desirable, misunderstandings can occur. One method to minimize misunderstandings is the pre-specification of terms of engagement in a memorandum of understanding (MOU). This study considered when an MOU may be most helpful, and which key elements should be included. STUDY DESIGN AND SETTING: An international panel of representatives from guideline groups was convened. A literature review to identify publications and other documents relevant to the establishment of MOUs between two or more guideline groups, supplemented by available source documents, was used to inform development of a draft MOU resource. This was iteratively refined until consensus was achieved. RESULTS: The level of detail in an MOU may vary based on institutional preferences and the particular collaboration. Elements within an MOU include those pertaining to: (1) scope and purpose; (2) leadership and team; (3) methods and commitment; (4) review and endorsement; and (5) publication and dissemination. CONCLUSION: Since groups may have different expectations regarding how a collaboration will unfold, an MOU may mitigate preventable misunderstandings. The result may be a higher likelihood of producing a guideline without disruption and delay.

Spotlight on COVID-19 rapid guidance: NICE's experience of producing rapid guidelines during the pandemic.

This article highlights recent guidance from the National Institute for Health and Care Excellence (NICE). It provides an overview of the COVID-19 rapid guidance produced since March 2020, along with an account of how the organization adapted during the pandemic, developing resources to guide practice with the limited time and evidence available. The growing COVID-19 evidence base is also considered, with reference to international initiatives supporting production of the best possible information to guide the global pandemic response. WHAT'S NEW?: Since March 2020, the NICE has developed 21 rapid guidelines with NHS England and NHS Improvement (NHSE&I) and a cross-speciality clinical group, supported by specialist societies and royal colleges. The 21 guidelines can be summarized into three groups-managing symptoms and complications, managing conditions that increase risk, and providing services during the pandemic. The rapid guidelines are part of a suite of rapid resources, including innovative technology briefings, shared learning examples and rapid evidence summaries, such as that for Vitamin D in COVID-19 (ES28).

Core outcome sets through the healthcare ecosystem: the case of type 2 diabetes mellitus.

BACKGROUND: It is increasingly accepted that insufficient attention has been given to the patient health outcomes that are important to measure in comparative effectiveness research that will inform decision-making. The relationship between outcomes chosen for comparative effectiveness research, outcomes used in decision-making in routine care, and outcome data recorded in electronic health records (EHR) is also poorly understood. The COMET Initiative (http://www.comet-initiative.org/. Accessed 3 Apr 2020) supports and encourages the development and use of 'core outcome sets' (COS), which represent the minimum set of patient health outcomes that should be measured and reported for a specific condition. There is growing interest in identifying how COS might fit into the different stages of the healthcare research and delivery ecosystem, and whether inclusion in the EHR might facilitate this. METHODS: We sought to determine the degree of overlap between outcomes within COS for research and routine care, EMA, FDA and NICE guidelines, NICE quality statements/indicators, EHR and a point-of-care randomised clinical trial, using type 2 diabetes (T2D) as a case study. RESULTS: There is substantial agreement about important patient outcomes for T2D for research and healthcare, with associated coverage within the UK general practice EHR. CONCLUSIONS: This case study has demonstrated the potential for efficient research and value-based healthcare when the EHR can include COS for both research and care, where the COS comprises outcomes of importance to all relevant stakeholders. However, this concordance may not hold more generally, as the focus on patient-centred outcomes may well be greater in T2D than in other conditions. Work is ongoing to examine other clinical areas, in order to highlight any current inefficiencies when health outcomes in research and healthcare do not agree with core outcomes identified by patients, clinicians and other key stakeholders.

Reaching a shared understanding of shared decision making in health care: NICE's experience of scoping the shared decision making guideline.

NICE's guideline on shared decision making, currently under development, endeavours to support shared decision making as part of routine health care practice. In this article, we summarize our learning to date, gained through the scoping of the guideline, on the key challenges that need to be addressed in the guideline. The production of a scope is the first stage in the development of a NICE guideline, setting the parameters for what will be considered in the guideline. The process for scoping the shared decision making guideline involved discussion with early recruited committee members and engagement with registered stakeholders, through both a workshop and formal consultation. Important, and sometimes divergent, viewpoints about shared decision making were revealed through this process. The key challenges centred on the issues of a need for a common definition of shared decision making, measurability, opportunities, barriers to implementation, and feasibility. Recognizing these challenges aided the refinement of the scope in terms of what the guideline will cover, draft questions and main outcomes for consideration.

Threshold Analysis as an Alternative to GRADE for Assessing Confidence in Guideline Recommendations Based on Network Meta-analyses.

Guideline development requires the synthesis of evidence on several treatments of interest, typically by using network meta-analysis (NMA). Because treatment effects may be estimated imprecisely or be based on evidence lacking internal or external validity, guideline developers must assess the robustness of recommendations made on the basis of the NMA to potential limitations in the evidence. Such limitations arise because the observed estimates differ from the true effects of interest, for example, because of study biases, sampling variation, or issues of relevance. The widely used GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework aims to assess the quality of evidence supporting a recommendation by using a structured series of qualitative judgments. This article argues that GRADE approaches proposed for NMA are insufficient for the purposes of guideline development, because the influence of the evidence on the final recommendation is not taken into account. It outlines threshold analysis as an alternative approach, demonstrating the method with 2 examples of clinical guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom. Threshold analysis quantifies precisely how much the evidence could change (for any reason, such as potential biases, or simply sampling variation) before the recommendation changes, and what the revised recommendation would be. If it is judged that the evidence could not plausibly change by more than this amount, then the recommendation is considered robust; otherwise, it is sensitive to plausible changes in the evidence. In this manner, threshold analysis directly informs decision makers and guideline developers of the robustness of treatment recommendations.

A threshold analysis assessed the credibility of conclusions from network meta-analysis.

OBJECTIVE: To assess the reliability of treatment recommendations based on network meta-analysis (NMA). STUDY DESIGN AND SETTING: We consider evidence in an NMA to be potentially biased. Taking each pairwise contrast in turn, we use a structured series of threshold analyses to ask: (1) "How large would the bias in this evidence base have to be before it changed our decision?" and (2) "If the decision changed, what is the new recommendation?" We illustrate the method via two NMAs in which a Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment for NMAs has been implemented: weight loss and osteoporosis. RESULTS: Four of the weight-loss NMA estimates were assessed as "low" and six as "moderate" quality by GRADE; for osteoporosis, six were "low," nine were "moderate," and 1 was "high." The threshold analysis suggests plausible bias in 3 of 10 estimates in the weight-loss network could have changed the treatment recommendation. For osteoporosis, plausible bias in 6 of 16 estimates could change the recommendation. There was no relation between plausible bias changing a treatment recommendation and the original GRADE assessments. CONCLUSIONS: Reliability judgments on individual NMA contrasts do not help decision makers understand whether a treatment recommendation is reliable. Threshold analysis reveals whether the final recommendation is robust against plausible degrees of bias in the data.

NICE guidance on long-term sickness and incapacity.

Long-term sickness absence and incapacity benefits (disability pension) rates have increased across industrialised countries. Effective measures are needed to support return to work. The recommendations of this guidance were informed by the most appropriate available evidence of effectiveness and cost-effectiveness. Public health evidence was provided by research using a variety of study designs that attempted to determine the outcome of a particular intervention by evaluating status before and after the intervention had been effected, and was not limited to randomised control trials. Where the evidence base was depleted or underdeveloped, expert witnesses were called to give their opinion on the best available evidence and emerging interventions. The process enabled challenge and contestability from stakeholder groups at different points as the guidance was developed. Forty-five heterogeneous studies were included in the review of interventions to reduce long-term sickness absence and transitions from short-term to long-term absence (mainly covering the former and also mainly examining musculoskeletal conditions). The analysis of evidence was restricted to descriptive synthesis. Three general themes emerged from an analysis of the studies that were more likely to report positive results: early interventions; multidisciplinary approaches; and interventions with a workplace component. Two further reviews were undertaken, one on interventions to reduce the re-occurrence of sickness absence, which identified seven studies on lower back pain, and concluded that early intervention and direct workplace input are important factors. The final evidence review focused on six studies of interventions for those in receipt of incapacity benefit. The evidence was that work-focused interviews coupled with access to tailored support are effective and cost-effective interventions. Practitioners should consider the impact of interventions and management options on work ability for patients of working age. Work ability should be considered a key outcome for future intervention studies.

Linkage and mutational analysis of CLCN2 in childhood absence epilepsy.

In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score=2.3, p<0.009; HLOD=1.5, alpha=0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent-child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT chi(1)2 = 5.17, p<0.03. Case-control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele: chi(1)2 = 7.27, p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11 and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy.

Linkage and association analysis of CACNG3 in childhood absence epilepsy.

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12-p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD = 3.54, alpha = 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 (P < 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P < or = 0.01) was found for SNPs within a approximately 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.

Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14.

A previous study of 34 nuclear pedigrees segregating juvenile myoclonic epilepsy (JME) gave significant evidence of linkage with heterogeneity to marker loci on chromosome 15q13-14 close to the candidate gene CHRNA7 (Hum. Mol. Genet. 6 (1997) 1329). The aim of this work was to further evaluate the putative aetiological role of CHRNA7 in JME within the 34 families originally described, and to assess the contribution of this locus to a broader phenotype of idiopathic generalised epilepsy (IGE). Multipoint linkage analysis and intrafamilial association studies were performed with microsatellite markers that encompass both CHRNA7 and its partial duplication (CHRFAM7A). A maximum HLOD of 3.45 [alpha=0.58; (Zall=2.88, P=0.0008)] was observed 8 cM distal to D15S1360, a CHRNA7 intragenic marker. Significant exclusion lod scores were obtained across the region in 12 mixed phenotype JME/IGE families. Mutation screening of the CHRNA7 gene (and consequently exons 5-10 of CHRFAM7A) and its putative promoter sequence identified a total of 13 sequence variants across 23 of 34 JME-affected families. Two variants (c.1354G>A and c.1466C>T) are predicted to result in amino acid changes and one (IVS9+5G>A) is predicted to result in aberrant transcript splicing. However, none of the variants alone appeared either necessary or sufficient to cause JME in the families in which they occurred. In conclusion, linkage analyses continue to support the existence of a locus on chromosome 15q13-14 that confers susceptibility to JME but not to a broader IGE phenotype. Causal sequence variants in the positional candidate CHRNA7 have not been identified but the presence of multiple segmental duplications in this region raises the possibility of undetected disease-causing genomic rearrangements.

Linkage analysis between childhood absence epilepsy and genes encoding GABAA and GABAB receptors, voltage-dependent calcium channels, and the ECA1 region on chromosome 8q.

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy (IGE) characterised by onset of typical absence seizures in otherwise normal children of school age. A genetic component to aetiology is well established but the mechanism of inheritance and the genes involved are unknown. Available evidence suggests that mutations in genes encoding GABA receptors or brain expressed voltage-dependent calcium channels (VDCCs) may underlie CAE. The aim of this work was to test this hypothesis by linkage analysis using microsatellite loci spanning theses genes in 33 nuclear families each with two or more individuals with CAE. Seventeen VDCC subunit genes, ten GABA(A)R subunit genes, two GABA(B) receptor genes and the ECA1 locus on 8q24 were investigated using 35 microsatellite loci. Assuming locus homogeneity, all loci gave statistically significant negative LOD scores, excluding these genes as major loci in the majority of these families. Positive HLOD scores assuming locus heterogeneity were observed for CACNG3 on chromosome 16p12-p13.1 and the GABRA5, GABRB3, GABRG3 cluster on chromosome 15q11-q13. Association studies are required to determine whether these loci are the site of susceptibility alleles in a subset of patients with CAE.