GRADE guidance 35: update on rating imprecision for assessing contextualized certainty of evidence and making decisions.

OBJECTIVES: Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance to rate the certainty domain of imprecision is presently not fully operationalized for rating down by two levels and when different baseline risk or uncertainty in these risks are considered. In addition, there are scenarios in which lowering the certainty of evidence by three levels for imprecision is more appropriate than lowering it by two levels. In this article, we conceptualize and operationalize rating down for imprecision by one, two and three levels for imprecision using the contextualized GRADE approaches and making decisions. METHODS: Through iterative discussions and refinement in online meetings and through email communication, we developed draft guidance to rating the certainty of evidence down by up to three levels based on examples. The lead authors revised the approach according to the feedback and the comments received during these meetings and developed GRADE guidance for how to apply it. We presented a summary of the results to all attendees of the GRADE Working Group meeting for feedback in October 2021 (approximately 80 people) where the approach was formally approved. RESULTS: This guidance provides GRADE's novel approach for the considerations about rating down for imprecision by one, two and three levels based on serious, very serious and extremely serious concerns. The approach includes identifying or defining thresholds for health outcomes that correspond to trivial or none, small, moderate or large effects and using them to rate imprecision. It facilitates the use of evidence to decision frameworks and also provides guidance for how to address imprecision about implausible large effects and trivial or no effects using the concept of the 'review information size' and for varying baseline risks. The approach is illustrated using practical examples, an online calculator and graphical displays and can be applied to dichotomous and continuous outcomes. CONCLUSION: In this GRADE guidance article, we provide updated guidance for how to rate imprecision using the partially and fully contextualized GRADE approaches for making recommendations or decisions, considering alternate baseline risks and for both dichotomous and continuous outcomes.

Applying GRADE for diagnosis revealed methodological challenges: an illustrative example for guideline developers.

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

GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions.

OBJECTIVES: Clear communication of systematic review findings will help readers and decision makers. We built on previous work to develop an approach that improves the clarity of statements to convey findings and that draws on Grading of Recommendations Assessment, Development and Evaluation (GRADE). STUDY DESIGN AND SETTING: We conducted workshops including 80 attendants and a survey of 110 producers and users of systematic reviews. We calculated acceptability of statements and revised the wording of those that were unacceptable to ≥40% of participants. RESULTS: Most participants agreed statements should be based on size of effect and certainty of evidence. Statements for low, moderate and high certainty evidence were acceptable to >60%. Key guidance, for example, includes statements for high, moderate and low certainty for a large effect on intervention x as: x results in a large reduction…; x likely results in a large reduction…; x may result in a large reduction…, respectively. CONCLUSIONS: Producers and users of systematic reviews found statements to communicate findings combining size and certainty of an effect acceptable. This article provides GRADE guidance and a wording template to formulate statements in systematic reviews and other decision tools.

Facilitating healthcare decisions by assessing the certainty in the evidence from preclinical animal studies.

Laboratory animal studies are used in a wide range of human health related research areas, such as basic biomedical research, drug research, experimental surgery and environmental health. The results of these studies can be used to inform decisions regarding clinical research in humans, for example the decision to proceed to clinical trials. If the research question relates to potential harms with no expectation of benefit (e.g., toxicology), studies in experimental animals may provide the only relevant or controlled data and directly inform clinical management decisions. Systematic reviews and meta-analyses are important tools to provide robust and informative evidence summaries of these animal studies. Rating how certain we are about the evidence could provide important information about the translational probability of findings in experimental animal studies to clinical practice and probably improve it. Evidence summaries and certainty in the evidence ratings could also be used (1) to support selection of interventions with best therapeutic potential to be tested in clinical trials, (2) to justify a regulatory decision limiting human exposure (to drug or toxin), or to (3) support decisions on the utility of further animal experiments. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach is the most widely used framework to rate the certainty in the evidence and strength of health care recommendations. Here we present how the GRADE approach could be used to rate the certainty in the evidence of preclinical animal studies in the context of therapeutic interventions. We also discuss the methodological challenges that we identified, and for which further work is needed. Examples are defining the importance of consistency within and across animal species and using GRADE's indirectness domain as a tool to predict translation from animal models to humans.

GRADE equity guidelines 1: considering health equity in GRADE guideline development: introduction and rationale.

OBJECTIVES: This article introduces the rationale and methods for explicitly considering health equity in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology for development of clinical, public health, and health system guidelines. STUDY DESIGN AND SETTING: We searched for guideline methodology articles, conceptual articles about health equity, and examples of guidelines that considered health equity explicitly. We held three meetings with GRADE Working Group members and invited comments from the GRADE Working Group listserve. RESULTS: We developed three articles on incorporating equity considerations into the overall approach to guideline development, rating certainty, and assembling the evidence base and evidence to decision and/or recommendation. CONCLUSION: Clinical and public health guidelines have a role to play in promoting health equity by explicitly considering equity in the process of guideline development.

The biological standard of living in Suriname, c. 1870-1975.

The physical stature of Surinamese soldiers is estimated to have increased by more than 3cm between 1870 and 1909. In the subsequent four decades, the increase in adult male and female height amounted to 0.3-0.5cm and 0.9-1.0cm per decade, respectively. This increase in height continued and accelerated during the second half of the twentieth century. Height increase among African and Hindustani Surinamese males and females was similar. Height differences between African and Hindustani Surinamese were therefore fairly constant over time, at 4-5cm. Other indicators of nutritional and health status, such as infant mortality, showed continuous improvement, whereas per capita calorie and protein availability improved in the twentieth century.

How to generalize efficacy results of randomized trials: recommendations based on a systematic review of possible approaches.

RATIONALE, AIMS AND OBJECTIVES: Randomized controlled trials (RCTs) are the preferred source for evidence for the effect of treatment. However, patients participating in RCTs often manifest important differences from patients seen in practice. Therefore, guideline developers have to decide whether the results are generalizable to the target population not represented in RCTs. METHOD: A systematic review of the literature was undertaken to identify methods to decide whether to generalize the results from RCTs to patients who were not represented in these trials. RESULTS: One approach is to examine the in- and exclusion criteria of trials and infer from these whether the trial population was sufficiently representative. Other authors suggest, because of the inclusion of a broader range of patients, reliance on observational studies if no direct evidence for the target population is available. Another approach is to apply the relative effect of treatment found in trials to patients in practice unless there is a compelling reason to believe the results would differ substantially as a function of particular characteristics of those patients. Although there are exceptions, this approach is supported by empirical evidence that, in general, relative effect of treatment on benefit outcomes seldom differs to an important extent across subgroups of patients. CONCLUSION: We propose this last approach: focusing on RCTs unless there is a compelling reason not to do so. Compelling reasons will most often be found with respect to issues of rare adverse effects, for which observational studies are likely to provide the best estimates.

Dairy products and physical stature: a systematic review and meta-analysis of controlled trials.

The positive relationship between per capita availability of dairy products and average height found in historical studies (for instance in nineteenth century Bavaria, Prussia and France; Baten, 2009) does not necessarily indicate a causal relationship. Historical studies usually apply non-experimental methods that may produce substantial bias. Modern experimental controlled studies may provide high quality evidence supporting a causal relationship between consumption of dairy products and physical growth. This paper provides a systematic review and meta-analysis of controlled trials investigating the effect of supplementing usual diet with dairy products on physical growth. Twelve studies provided sufficient, independent data for meta-analysis. Seven studies were conducted since the 1990s. The other studies were conducted between 1926 and 1980. Studies were conducted in Europe, USA, China, Northern Vietnam, Kenya, Indonesia and India. Many studies had some internal validity problems such as lack of randomisation or dissimilarity of groups at baseline regarding height and age, which affects the quality of evidence. Meta-analysis and sensitivity analysis showed that the most likely effect of dairy products supplementation is 0.4 cm per annum additional growth per ca 245 ml of milk daily. Meta-regression analysis indicated that milk might have more effect on growth than other dairy products while lower height-for-age and being a teenager increased the effect of supplementation. In conclusion, there is moderate quality evidence that dairy products supplementation stimulate linear growth supporting hypotheses that changing levels of consumption of dairy products in the 19th and 20th centuries contributed to trends in height.

[Guideline 'Coeliac disease and dermatitis herpetiformis']. / Richtlijn 'Coeliakie en dermatitis herpetiformis'.

The Dutch evidence-based guideline 'Coeliac disease and dermatitis herpetiformis' contains instructions for detection and treatment of coeliac disease. Coeliac disease has a high prevalence: 0.5 - 1.3%. The disease has a broad spectrum of symptoms, frequently also outside the gastrointestinal tract. Relatives of patients and persons with autoimmune diseases, microscopic colitis, IgA deficiency and syndromes of Down, Turner and Williams have an increased risk of coeliac disease. Detection is carried out by determination of IgA antibodies to tissue transglutaminase and endomysium. Testing for IgA antibodies to gliadin is only recommended in children younger than 2 years. Absence of HLA-DQ2 and DQ8 indicates that coeliac disease is most unlikely. The diagnosis should be confirmed by small bowel biopsy. Single biopsy following gluten ingestion is sufficient for diagnosis at all ages. After the diagnosis, patients should be referred to a dietician. Additionally, a yearly follow-up by a paediatrician or internal medical specialist with appropriate gastroenterology specialisation is recommended.

[Multidisciplinary guidelines for 'Apparent life threatening event' (ALTE)]. / Multidisciplinaire richtlijn 'Apparent life threatening event' (ALTE).

In order to reach a consensus concerning diagnosis, support and follow-up in children with an 'apparent life threatening event' (ALTE) multidisciplinary guidelines have been developed by the Dutch Paediatric Association and the Dutch Institute for Healthcare Improvement (CBO). All children presenting as an emergency with ALTE should undergo inpatient clinical observation for 24-72 h, with at least 24 h of cardio-respiratory monitoring. Observation does not need to be continued once an explanation for the incident has been established. The most common causes of ALTE are: gastro-oesophageal reflux (31%), neurological insult (11%) and lower respiratory tract infection (8%). Results from a targeted case history and from physical and neurological examination serve as a guideline for further investigations and support, in accordance with the formulated flowchart. A complete blood-count, CRP- and glucose concentration determination, blood-gas analysis and exploratory urine analysis should be carried out in all infants admitted with an ALTE, and an acute phase urine sample should be collected and frozen for possible metabolic investigation at a later date. Routine monitoring at home is not recommended following an ALTE.

Observations on the history of Dutch physical stature from the late-Middle Ages to the present.

In the late-Middle Ages and at the onset of the early modern period, the Dutch population was taller than in the first half of the 19th century. This inference is partially based on skeletal evidence, mainly collected by the Dutch physical anthropologist George Maat and his co-workers. A spectacular increase in Dutch heights began in the second half of the 19th century and accelerated in the second half of the 20th century. At the end of the 20th century, the Dutch became tallest in the world.