Juan José Yepes-Nuñez

World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics

BackgroundPrevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10% and reaches 20–30% in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention.ObjectiveThe World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of probiotics in the prevention of allergy.MethodsWe identified the most relevant clinical questions and performed a systematic review of randomized controlled trials of probiotics for the prevention of allergy. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. We searched for and reviewed the evidence about health effects, patient values and preferences, and resource use (up to November 2014). We followed the GRADE evidence-to-decision framework to develop recommendations.ResultsCurrently available evidence does not indicate that probiotic supplementation reduces the risk of developing allergy in children. However, considering all critical outcomes in this context, the WAO guideline panel determined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema. The WAO guideline panel suggests: a) using probiotics in pregnant women at high risk for having an allergic child; b) using probiotics in women who breastfeed infants at high risk of developing allergy; and c) using probiotics in infants at high risk of developing allergy. All recommendations are conditional and supported by very low quality evidence.ConclusionsWAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding, and whether to give them to infants.

Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND Allergic diseases are considered a health burden because of their high and constantly increasing prevalence, high direct and indirect costs, and undesirable effects on quality of life. Probiotics have been suggested as an intervention to prevent allergic diseases. OBJECTIVE We sought to synthesize the evidence supporting use of probiotics for the prevention of allergies and inform World Allergy Organization guidelines on probiotic use. METHODS We performed a systematic review of randomized trials assessing the effects of any probiotic administered to pregnant women, breast-feeding mothers, and/or infants. RESULTS Of 2403 articles published until December 2014 identified in Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, 29 studies fulfilled a priori specified inclusion criteria for the analyses. Probiotics reduced the risk of eczema when used by women during the last trimester of pregnancy (relative risk [RR], 0.71; 95% CI, 0.60-0.84), when used by breast-feeding mothers (RR, 0.57; 95% CI, 0.47-0.69), or when given to infants (RR, 0.80; 95% CI, 0.68-0.94). Evidence did not support an effect on other allergies, nutrition status, or incidence of adverse effects. The certainty in the evidence according to the Grading of Recommendation Assessment Development and Evaluation approach is low or very low because of the risk of bias, inconsistency and imprecision of results, and indirectness of available research. CONCLUSION Probiotics used by pregnant women or breast-feeding mothers and/or given to infants reduced the risk of eczema in infants; however, the certainty in the evidence is low. No effect was observed for the prevention of other allergic conditions.

Vitamin D supplementation in primary allergy prevention: Systematic review of randomized and non-randomized studies

To date, a systematic review of the evidence regarding the association between vitamin D and allergic diseases development has not yet been undertaken.

Using patient values and preferences to inform the importance of health outcomes in practice guideline development following the GRADE approach

BackgroundThere are diverse opinions and confusion about defining and including patient values and preferences (i.e. the importance people place on the health outcomes) in the guideline development processes. This article aims to provide an overview of a process for systematically incorporating values and preferences in guideline development.MethodsIn 2013 and 2014, we followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to adopt, adapt and develop 226 recommendations in 22 guidelines for the Ministry of Health of the Kingdom of Saudi Arabia. To collect context-specific values and preferences for each recommendation, we performed systematic reviews, asked clinical experts to provide feedback according to their clinical experience, and consulted patient representatives.ResultsWe found several types of studies addressing the importance of outcomes, including those reporting utilities, non-utility measures of health states based on structured questionnaires or scales, and qualitative studies. Guideline panels used the relative importance of outcomes based on values and preferences to weigh the balance of desirable and undesirable consequences of alternative intervention options. However, we found few studies addressing local values and preferences.ConclusionsCurrently there are different but no firmly established processes for integrating patient values and preferences in healthcare decision-making of practice guideline development. With GRADE Evidence-to-Decision (EtD) frameworks, we provide an empirical strategy to find and incorporate values and preferences in guidelines by performing systematic reviews and eliciting information from guideline panel members and patient representatives. However, more research and practical guidance are needed on how to search for relevant studies and grey literature, assess the certainty of this evidence, and best summarize and present the findings.

A systematic survey of the methods literature on the reporting quality and optimal methods of handling participants with missing outcome data for continuous outcomes in randomized controlled trials

OBJECTIVE To conduct (1) a systematic survey of the reporting quality of simulation studies dealing with how to handle missing participant data (MPD) in randomized control trials and (2) summarize the findings of these studies. STUDY DESIGN AND SETTING We included simulation studies comparing statistical methods dealing with continuous MPD in randomized controlled trials addressing bias, precision, coverage, accuracy, power, type-I error, and overall ranking. For the reporting of simulation studies, we adapted previously developed criteria for reporting quality and applied them to eligible studies. RESULTS Of 16,446 identified citations, the 60 eligible generally had important limitations in reporting, particularly in reporting simulation procedures. Of the 60 studies, 47 addressed ignorable and 32 addressed nonignorable data. For ignorable missing data, mixed model was most frequently the best on overall ranking (9 times best, 34.6% of times tested) and bias (10, 55.6%). Multiple imputation was also performed well. For nonignorable data, mixed model was most frequently the best on overall ranking (7, 46.7%) and bias (8, 57.1%). Mixed model performance varied on other criteria. Last observation carried forward (LOCF) was very seldom the best performing, and for nonignorable MPD frequently the worst. CONCLUSION Simulation studies addressing methods to deal with MPD suffered from serious limitations. The mixed model approach was superior to other methods in terms of overall performance and bias. LOCF performed worst.Please cite this article as: Zhang Y, Alyass A, Vanniyasingam T, Sadeghirad B, Flórez ID, Pichika SC, Kennedy SA, Abdulkarimova U, Zhang Y, Iljon T, Morgano GP, Colunga Lozano LE, Aloweni FAB, Lopes LC, Yepes-Nuñez JJ, Fei Y, Wang L, Kahale LA, Meyre D, Akl EA, Thabane L, Guyatt G, Reporting quality and optimal methods of handling participants with missing outcome data for continuous outcomes in randomized controlled trials: a systematic survey of the methods literature, Journal of Clinical Epidemiology (2017), doi: 10.1016/j.jclinepi.2017.05.016.

Prebiotics for the prevention of allergies: A systematic review and meta-analysis of randomized controlled trials

Prevalence of allergic diseases in infants is approximately 10% reaching 20 to 30% in those with an allergic first‐degree relative. Prebiotics are selectively fermented food ingredients that allow specific changes in composition/activity of the gastrointestinal microflora. They modulate immune responses, and their supplementation has been proposed as an intervention to prevent allergies.

Reply: To PMID 26044853.

To the Editor: We thank Szajewska et al for raising important issues in the discussion about the use of probiotics with the intent of prevention of development of allergies in children. Please allow us to begin by clarifying that in our systematic review we attempted only to summarize the currently available evidence about the health effects of probiotics in this setting and we deliberately refrained from making any recommendations for clinical practice. Specific recommendations were provided by the World Allergy Organization (WAO) guideline panel in a separate document. We believe that authors of systematic reviews should not make clinical recommendations. They typically review only the studies of health effects of interventions and do not seek information about other factors required to make a decision whether or not to use an intervention, for example, patients’ values and preferences, acceptability, resource requirements, and feasibility of implementation. This point of view is shared by Cochrane as expressed in the Cochrane Handbook for Systematic Reviews of Interventions (chapter 12: Interpreting results and drawing conclusions, 12.7.2 Implications for practice). Thus, allow us to discuss only the evidence synthesis and abstain from discussion of clinical recommendations and implications for practice. Szajewska et al pointed out that our review did not answer a few specific questions: which probiotics should be used, in what dose, and when should the probiotic supplementation be stopped. Our review was designed to summarize the evidence required to answer the questions determined by the WAO guideline panel. Both the WAO guidelines and our systematic review did not intend to be comprehensive and answer all questions in this area. As much as we agree with Szajewska et al that the answer to the above questions would be beneficial, it was either beyond the scope of our project or impossible to answer on the basis of currently available data, which we discuss in the next paragraph. Any clinical practice guidelines should be reviewed and updated once new evidence becomes available. We are confident that the WAO guideline panel will address these and similar questions in the update of the guidelines if they determine that clinicians seek advice in this area and the information to answer them is available. Szajewska et al suggest that we should have refrained from pooling data on different probiotics to avoid misleading consumers, parents, and health care professionals. Our choice to combine the results of all studies followed a standard approach in systematic reviews designed to summarize information for decision making by attempting a meta-analysis of all studies and investigating heterogeneity. We saw inconsistency not only in results among studies of different probiotics but also among studies that used the same strain (Fig 1). In our view, the magnitude of heterogeneity did not provide a compelling reason not to combine the results. We recognize that decisions concerning which results should or should not be combined are inevitably subjective and consensus may be difficult to reach in many cases. We agree with Szajewska et al that the conclusion that all probiotics are equal would be premature. However, on the basis of available data from randomized trials in humans, we also believe that it is too early for an opposite conclusion, that is, that probiotics differ in their effect on the development of eczema. The available evidence from randomized trials does not allow excluding the possibility that the effect of probiotics is a class effect or that, indeed, there are differences among the strains. We also emphasized in our review that because of the very inconsistency in study results and other limitations one might have only very low confidence that observed effects reflect the actual effect of each and all probiotics. Furthermore, we identified a study that directly compared the effects of 2 strains of probiotics: Lactobacillus rhamnosus HN001 with Bifidobacterium animalis subsp lactis HN019. This study found a reduced risk of developing eczema in those children who received HN001 (hazard ratio, 0.57; 95% CI, 0.39-0.83). The estimate of the effect of HN019 was not statistically significant; however, point estimate and the CI did not exclude an appreciable benefit (hazard ratio, 0.79; 95% CI, 0.56-1.11). Thus, on the basis of currently available data from experimental studies in humans, we believe that one cannot confidently determinewhether the effects of various strains are similar or whether there are some strains whose effects are different (larger or smaller) from those of other strains. We share the view of Szajewska et al that data on the effects of individual probiotic strains are needed. Until they become available, clinicians, parents, and others will need to make decisions under uncertainty about the magnitude of benefits from different strains of probiotics. Carlos A. Cuello-Garcia, MD Jan L. Bro _ zek, MD, PhD Alessandro Fiocchi, MD Ruby Pawankar, MD, PhD Juan Jos e Yepes-Nu~ nez, MD, MSc Luigi Terracciano, MD Shreyas Gandhi, BHSc Arnav Agarwal, BHSc Yuan Zhang, MSc Holger J. Sch€ unemann, MD, MSc, PhD From the Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada; the Tecnologico de Monterrey School of Medicine, Monterrey, Mexico; the Department of Medicine, McMaster University, Hamilton, Ontario, Canada; the Pediatric Hospital Bambino Ges u, Vatican City; the Department of Pediatrics, Nippon Medical School, Tokyo, Japan; the School of Medicine, University of Antioquia, Medell ın, Colombia; the Department of Child and Maternal Medicine, University of Milan Medical School at the Melloni Hospital, Milan, Italy; and the Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada E-mail: brozekj@mcmaster.ca. The World Allergy Organization supported this study. Disclosure of potential conflict of interest: C. A. Cuello-Garcia has received consultancy fees and travel support, paid through McMaster University, from the World Allergy Organization (WAO). J. L. Bro _ zek has received research support paid to McMaster University and travel support from the WAO. A. Fiocchi has received travel support from the WAO; has received consultancy fees from GlaxoSmithKline; and has received travel support and lecture fees from Danone. R. Pawankar is employed by Nippon Medical School in Tokyo; has received research support from the Ministry of Education of Japan; and receives royalties from Springer. J. J. Yepes-Nu~nez has received consultancy fees and fees for the creation of WAO clinical practice guidelines paid to McMaster University from the WAO and has received travel support from the WAO. L. Terracciano has received travel support from the WAO and has received consultancy fees from Heinz-Plada. S. Gandhi and Y. Zhang have received consultancy fees paid to McMaster University from the WAO and travel support from the WAO. H. J. Sch€unemann has received consultancy fees, travel support, and payment for systematic reviews from the WAO. A. Agarwal declares no relevant conflicts of interest.

GRADE guidelines: 20. Assessing the certainty of evidence in the importance of outcomes or values and preferences—inconsistency, imprecision, and other domains

OBJECTIVE To provide Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidance for assessing inconsistency, imprecision, and other domains for the certainty of evidence about the relative importance of outcomes. STUDY DESIGN AND SETTING We applied the GRADE domains to rate the certainty of evidence in the importance of outcomes to several systematic reviews, iteratively reviewed draft guidance, and consulted GRADE members and other stakeholders for feedback. RESULTS We describe the rationale for considering the remaining GRADE domains when rating the certainty in a body of evidence for the relative importance of outcomes. As meta-analyses are not common in this context, inconsistency and imprecision assessments are challenging. Furthermore, confusion exists about inconsistency, imprecision, and true variability in the relative importance of outcomes. To clarify this issue, we suggest that the true variability is neither equivalent to inconsistency nor imprecision. Specifically, inconsistency arises from population, intervention, comparison and outcome and methodological elements that should be explored and, if possible, explained. The width of the confidence interval and sample size inform judgments about imprecision. We also provide suggestions on how to detect publication bias and discuss the domains to rate up the certainty. CONCLUSION We provide guidance and examples for rating inconsistency, imprecision, and other domains for a body of evidence describing the relative importance of outcomes.

Applying GRADE to a network meta-analysis of antidepressants led to more conservative conclusions

OBJECTIVE To explore the impact of applying the Grading of Recommendations and Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of the evidence in a published network meta-analysis (NMA) of antidepressant therapies. STUDY DESIGN AND SETTINGS We applied the GRADE approach to rate the certainty of the evidence for two outcomes, efficacy and acceptability, in each of the 66 paired comparisons within a previously published NMA assessing the relative efficacy and acceptability of 12 new-generation antidepressants. RESULTS For the outcome of efficacy, of the 25 comparisons in which the 95% CrI of OR excluded 1, 18 had certainty of evidence rated high or moderate. For the outcome of acceptability, of the 13 comparisons whose 95% CrI excluded 1, 10 had certainty of evidence rated high or moderate. Of the 11 comparisons involving sertraline, the antidepressants that the authors of the NMA suggested to be best, only 3 demonstrated it to be more effective and only 3 showed better tolerance, based on a 95% CrI excluding 1 and a high or moderate rating of certainty. CONCLUSIONS In this example, application of GRADE highlighted varying evidence certainty, led to more conservative conclusions, and potentially avoided unwarranted strong inferences based on low certainty evidence.

Two alternatives versus the standard Grading of Recommendations Assessment, Development and Evaluation (GRADE) summary of findings (SoF) tables to improve understanding in the presentation of systematic review results: a three-arm, randomised, controlled, non-inferiority trial

Objective Summary of findings (SoF) tables present results of systematic reviews in a concise and explicit format. Adopted by many review groups including the Cochrane Collaboration and the Agency for Healthcare Research and Quality (AHRQ), optimal understanding of SoF table may be influenced by the type of information being conveyed and objectives or preferences of the end user. This study aims to compare three SoF table formats in terms of understanding, accessibility, satisfaction and preference with systematic review users. Methods The primary objective of this three-arm randomised controlled non-inferiority trial is to investigate whether an alternative Grading of Recommendations Assessment, Development and Evaluation (GRADE) SoF table or Evidence-based Practice Center SoF table is non-inferior to the current GRADE SoF table in the understanding of the information presented to systematic review users, particularly for descriptive findings. Researchers, clinical practice guideline developers, policy-makers or knowledge transfer professionals will be recruited. Data will be collected electronically at baseline and after randomisation. Non-inferiority would be declared if the difference in the proportion of participants who understand the information displayed in the alternative SoF table is 10% or less. Ethics and dissemination The Hamilton Integrated Research Ethics Board reviewed this protocol. The findings from this study will be disseminated through a publication in a peer-reviewed journal. Trial registration number NCT02813941.