The use of ‘PICO for synthesis’ and methods for synthesis without meta-analysis: protocol for a survey of current practice in systematic reviews of health interventions

INTRODUCTION: Systematic reviews involve synthesis of research to inform decision making by clinicians, consumers, policy makers and researchers. While guidance for synthesis often focuses on meta-analysis, synthesis begins with specifying the ’PICO for each synthesis’ (i.e. the criteria for deciding which populations, interventions, comparators and outcomes are eligible for each analysis). Synthesis may also involve the use of statistical methods other than meta-analysis (e.g. vote counting based on the direction of effect, presenting the range of effects, combining P values) augmented by visual display, tables and text-based summaries. This study examines these two aspects of synthesis. OBJECTIVES: To identify and describe current practice in systematic reviews of health interventions in relation to: (i) approaches to grouping and definition of PICO characteristics for synthesis; and (ii) methods of summary and synthesis when meta-analysis is not used. METHODS: We will randomly sample 100 systematic reviews of the quantitative effects of public health and health systems interventions published in 2018 and indexed in the Health Evidence and Health Systems Evidence databases. Two authors will independently screen citations for eligibility. Two authors will confirm eligibility based on full text, then extract data for 20% of reviews on the specification and use of PICO for synthesis, and the presentation and synthesis methods used (e.g. statistical synthesis methods, tabulation, visual displays, structured summary). The remaining reviews will be confirmed as eligible and data extracted by a single author. We will use descriptive statistics to summarise the specification of methods and their use in practice. We will compare how clearly the PICO for synthesis is specified in reviews that primarily use meta-analysis and those that do not. CONCLUSION: This study will provide an understanding of current practice in two important aspects of the synthesis process, enabling future research to test the feasibility and impact of different approaches

Critical elements of synthesis questions are incompletely reported: survey of systematic reviews of intervention effects

Objectives: To examine the characteristics of population, intervention and outcome groups and the extent to which they were completely reported for each synthesis in a sample of systematic reviews (SRs) of interventions. Study design and setting: We coded groups that were intended (or used) for comparisons in 100 randomly sampled SRs of public health and health systems interventions published in 2018 from the Health Evidence and Health Systems Evidence databases. Results: Authors commonly used population, intervention and outcome groups to structure comparisons, but these groups were often incompletely reported. For example, of 41 SRs that identified and/or used intervention groups for comparisons, 29 (71%) identified the groups in their methods description before reporting of the results (e.g., in the Background or Methods), 12 (29%) defined the groups in enough detail to replicate decisions about which included studies were eligible for each synthesis, 6 (15%) provided a rationale, and 24 (59%) stated that the groups would be used for comparisons. Sixteen (39%) SRs used intervention groups in their synthesis without any mention in the methods. Reporting for population, outcome and methodological groups was similarly incomplete. Conclusion: Complete reporting of the groups used for synthesis would improve transparency and replicability of reviews, and help ensure that the synthesis is not driven by what is reported in the included studies. Although concerted effort is needed to improve reporting, this should lead to more focused and useful reviews for decision-makers

Theories of behaviour change synthesised into a set of theoretical groupings: Introducing a thematic series on the Theoretical Domains Framework

Behaviour change is key to increasing the uptake of evidence into healthcare practice. Designing behaviour-change interventions first requires problem analysis, ideally informed by theory. Yet the large number of partly overlapping theories of behaviour makes it difficult to select the most appropriate theory. The need for an overarching theoretical framework of behaviour change was addressed in research in which 128 explanatory constructs from 33 theories of behaviour were identified and grouped. The resulting Theoretical Domains Framework (TDF) appears to be a helpful basis for investigating implementation problems. Research groups in several countries have conducted TDF-based studies. It seems timely to bring together the experience of these teams in a thematic series to demonstrate further applications and to report key developments. This overview article describes the TDF, provides a brief critique of the framework, and introduces this thematic series. In a brief review to assess the extent of TDF-based research, we identified 133 papers that cite the framework. Of these, 17 used the TDF as the basis for empirical studies to explore health professionals’ behaviour. The identified papers provide evidence of the impact of the TDF on implementation research. Two major strengths of the framework are its theoretical coverage and its capacity to elicit beliefs that could signify key mediators of behaviour change. The TDF provides a useful conceptual basis for assessing implementation problems, designing interventions to enhance healthcare practice, and understanding behaviour-change processes. We discuss limitations and research challenges and introduce papers in this series

An investigation of the impact of using different methods for network meta-analysis: A protocol for an empirical evaluation

BACKGROUND: Network meta-analysis, a method to synthesise evidence from multiple treatments, has increased in popularity in the past decade. Two broad approaches are available to synthesise data across networks, namely, arm- and contrast-synthesis models, with a range of models that can be fitted within each. There has been recent debate about the validity of the arm-synthesis models, but to date, there has been limited empirical evaluation comparing results using the methods applied to a large number of networks. We aim to address this gap through the re-analysis of a large cohort of published networks of interventions using a range of network meta-analysis methods. METHODS: We will include a subset of networks from a database of network meta-analyses of randomised trials that have been identified and curated from the published literature. The subset of networks will include those where the primary outcome is binary, the number of events and participants are reported for each direct comparison, and there is no evidence of inconsistency in the network. We will re-analyse the networks using three contrast-synthesis methods and two arm-synthesis methods. We will compare the estimated treatment effects, their standard errors, treatment hierarchy based on the surface under the cumulative ranking (SUCRA) curve, the SUCRA value, and the between-trial heterogeneity variance across the network meta-analysis methods. We will investigate whether differences in the results are affected by network characteristics and baseline risk. DISCUSSION: The results of this study will inform whether, in practice, the choice of network meta-analysis method matters, and if it does, in what situations differences in the results between methods might arise. The results from this research might also inform future simulation studies

Impact of respiratory muscle training on respiratory muscle strength, respiratory function and quality of life in individuals with tetraplegia: A randomised clinical trial

Background Respiratory complications remain a leading cause of morbidity and mortality in people with acute and chronic tetraplegia. Respiratory muscle weakness following spinal cord injury-induced tetraplegia impairs lung function and the ability to cough. In particular, inspiratory muscle strength has been identified as the best predictor of the likelihood of developing pneumonia in individuals with tetraplegia. We hypothesised that 6 weeks of progressive respiratory muscle training (RMT) increases respiratory muscle strength with improvements in lung function, quality of life and respiratory health. Methods Sixty-two adults with tetraplegia participated in a double-blind randomised controlled trial. Active or sham RMT was performed twice daily for 6 weeks. Inspiratory muscle strength, measured as maximal inspiratory pressure (PImax) was the primary outcome. Secondary outcomes included lung function, quality of life and respiratory health. Between-group comparisons were obtained with linear models adjusting for baseline values of the outcomes. Results After 6 weeks, there was a greater improvement in PImax in the active group than in the sham group (mean difference 11.5 cmH 2 O (95% CI 5.6 to 17.4), p<0.001) and respiratory symptoms were reduced (St George Respiratory Questionnaire mean difference 10.3 points (0.01-20.65), p=0.046). Significant improvements were observed in quality of life (EuroQol-Five Dimensional Visual Analogue Scale 14.9 points (1.9-27.9), p=0.023) and perceived breathlessness (Borg score 0.64 (0.11-1.17), p=0.021). There were no significant improvements in other measures of respiratory function (p=0.126-0.979). Conclusions Progressive RMT increases inspiratory muscle strength in people with tetraplegia, by a magnitude which is likely to be clinically significant. Measurement of baseline PImax and provision of RMT to at-risk individuals may reduce respiratory complications after tetraplegia. Trial registration number Australian New Zealand Clinical Trials Registry (ACTRN 12612000929808)

Investigation of Risk Of Bias due to Unreported and SelecTively included results in meta-analyses of nutrition research: The ROBUST study protocol

Background: Dietary guidelines should be informed by systematic reviews (SRs) of the available scientific evidence. However, if the SRs that underpin dietary guidelines are flawed in their design, conduct or reporting, the recommendations contained therein may be misleading or harmful. To date there has been little empirical investigation of bias due to selective inclusion of results, and bias due to missing results, in SRs of food/diet-outcome relationships. Objectives: To explore in SRs with meta-analyses of the association between food/diet and health-related outcomes: (i) whether systematic reviewers selectively included study effect estimates in meta-analyses when multiple effect estimates were available; (ii) what impact selective inclusion of study effect estimates may have on meta-analytic effects, and; (iii) the risk of bias due to missing results (publication bias and selective non-reporting bias) in meta-analyses. Methods: We will systematically search for SRs with meta-analysis of the association between food/diet and health-related outcomes in a generally healthy population, published between January 2018 and June 2019. We will randomly sort titles and abstracts and screen them until we identify 50 eligible SRs. The first reported meta-analysis of a binary or continuous outcome in each SR (the 'index meta-analysis') will be evaluated. We will extract from study reports all study effect estimates that were eligible for inclusion in the index meta-analyses (e.g. from multiple instruments and time points) and will quantify and test for evidence of selective inclusion of results. We will also assess the risk of bias due to missing results in the index meta-analyses using a new tool (ROB-ME). Ethics and dissemination: Ethics approval is not required because information will only be extracted from published studies. Dissemination of the results will be through peer-reviewed publications and presentations at conferences. We will make all data collected from this study publicly available via the Open Science Framework

Assessment of the methods used to develop vitamin d and calcium recommendations—a systematic review of bone health guidelines

Background: There are numerous guidelines developed for bone health. Yet, it is unclear whether the differences in guideline development methods explain the variability in the recommendations for vitamin D and calcium intake. The objective of this systematic review was to collate and compare recommendations for vitamin D and calcium across bone health guidelines, assess the methods used to form the recommendations, and explore which methodological factors were associated with these guideline recommendations. Methods: We searched MEDLINE, EMBASE, CINAHL, and other databases indexing guidelines to identify records in English between 2009 and 2019. Guidelines or policy statements on bone health or osteoporosis prevention for generally healthy adults aged ≥40 years were eligible for inclusion. Two reviewers independently extracted recommendations on daily vitamin D and calcium intake, supplement use, serum 25 hydroxyvitamin D [25(OH)D] level, and sunlight exposure. They assessed guideline development methods against 25 recommended criteria in the World Health Organization (WHO) handbook for guideline development. Additionally, they identified types of evidence underpinning the recommendations. Results: we included 47 eligible guidelines from 733 records: 74% of the guidelines provided vitamin D (200~600–4000 IU/day) and 70% provided calcium (600–1200 mg/day) recommendations, 96% and 88% recommended vitamin D and calcium supplements, respectively, and 70% recommended a specific 25(OH)D concentration. On average, each guideline met 10 (95% CI: 9–12) of the total of 25 methodological criteria for guideline development recommended by the WHO Handbook. There was uncertainty in the association between the methodological criteria and the proportion of guidelines that provided recommendations on daily vitamin D or calcium. Various types of evidence, including previous bone guidelines, nutrient reference reports, systematic reviews, observational studies, and perspectives/editorials were used to underpin the recommendations. Conclusions: There is considerable variability in vitamin D and calcium recommendations and in guideline development methods in bone health guidelines. Effort is required to strengthen the methodological rigor of guideline development and utilize the best available evidence to underpin nutrition recommendations in evidence-based guidelines on bone health

Selective inhibition of T suppressor-cell function by a monosaccharide

Interactions between regulatory T lymphocytes and other cells are assumed to occur at the level of the cell surface. T cells which suppress the generation of specifically effector cells have been described as having antigenic, idiotypic, allotypic and I-region specificity1−4. Other T suppressor cells generated by in vitro cultivation with or without mitogenic stimulation5,6 have suppressive activity for T and B cells but no specificity can be assigned to them. These T suppressor cells (Ts) inhibit various lymphoid functions—this either reflects their polyclonal origin or indicates that the structures recognized by the Ts receptors must be common for many cell types. Carbohydrates on cell membrane-inserted glycoproteins or glycolipids might function as specific ligands for recognition by cellular receptors or soluble factors. Almost all cell-surface proteins of mammalian cells are glycosylated. There is evidence for lectin-like carbohydrate binding proteins not only in plants7 but also in toxins8, viruses9, prokaryotic cells10 and even mammalian cells, including T cells11. A functional role for these lectin-like proteins has been described for slime moulds and suggested for the selective association of embryonic cells12,13. We report here that addition of a monosaccharide can counteract the effect of T suppressor cells during the generation of alloreactive cytotoxic T cells (CTLs) in vitro

Using Rasch analysis to form plausible health states amenable to valuation: the development of CORE-6D from CORE-OM in order to elicit preferences for common mental health problems

Purpose: To describe a new approach for deriving a preference-based index from a condition specific measure that uses Rasch analysis to develop health states. Methods: CORE-OM is a 34-item instrument monitoring clinical outcomes of people with common mental health problems. CORE-OM is characterised by high correlation across its domains. Rasch analysis was used to reduce the number of items and response levels in order to produce a set of unidimensionally-behaving items, and to generate a credible set of health states corresponding to different levels of symptom severity using the Rasch item threshold map. Results: The proposed methodology resulted in the development of CORE-6D, a 2-dimensional health state description system consisting of a unidimensionally-behaving 5-item emotional component and a physical symptom item. Inspection of the Rasch item threshold map of the emotional component helped identify a set of 11 plausible health states, which, combined with the physical symptom item levels, will be used for the valuation of the instrument, resulting in the development of a preference-based index. Conclusions: This is a useful new approach to develop preference-based measures where the domains of a measure are characterised by high correlation. The CORE-6D preference-based index will enable calculation of Quality Adjusted Life Years in people with common mental health problems