The selection of appropriate outcomes or domains is crucial when designing clinical trials in order to compare directly the effects of different interventions in ways that minimize bias. If the ...findings are to influence policy and practice then the chosen outcomes need to be relevant and important to key stakeholders including patients and the public, health care professionals and others making decisions about health care. There is a growing recognition that insufficient attention has been paid to the outcomes measured in clinical trials. These issues could be addressed through the development and use of an agreed standardized collection of outcomes, known as a core outcome set, which should be measured and reported, as a minimum, in all trials for a specific clinical area. Accumulating work in this area has identified the need for general guidance on the development of core outcome sets. Key issues to consider in the development of a core outcome set include its scope, the stakeholder groups to involve, choice of consensus method and the achievement of a consensus.
Core outcome sets (COS) can enhance the relevance of research by ensuring that outcomes of importance to health service users and other people making choices about health care in a particular topic ...area are measured routinely. Over 200 COS to date have been developed, but the clarity of these reports is suboptimal. COS studies will not achieve their goal if reports of COS are not complete and transparent.
In recognition of these issues, an international group that included experienced COS developers, methodologists, journal editors, potential users of COS (clinical trialists, systematic reviewers, and clinical guideline developers), and patient representatives developed the Core Outcome Set-STAndards for Reporting (COS-STAR) Statement as a reporting guideline for COS studies. The developmental process consisted of an initial reporting item generation stage and a two-round Delphi survey involving nearly 200 participants representing key stakeholder groups, followed by a consensus meeting. The COS-STAR Statement consists of a checklist of 18 items considered essential for transparent and complete reporting in all COS studies. The checklist items focus on the introduction, methods, results, and discussion section of a manuscript describing the development of a particular COS. A limitation of the COS-STAR Statement is that it was developed without representative views of low- and middle-income countries. COS have equal relevance to studies conducted in these areas, and, subsequently, this guideline may need to evolve over time to encompass any additional challenges from developing COS in these areas.
With many ongoing COS studies underway, the COS-STAR Statement should be a helpful resource to improve the reporting of COS studies for the benefit of all COS users.
Using the example of a diagnostic prediction model using D-Dimer data of patients suspected of having deep venous thrombosis, they emphasize that differences in the distribution of predictor values ...across different studies need to consider both: a) true variation in the characteristics of patients (severity, clinical settings, geographical locations, or time); and b) also the ways that the predictors themselves (e.g., the D-Dimer) were measured. Non randomised studies are beginning to be accepted for demonstrating comparative clinical efficacy by approval agencies, perhaps in part in response to the real world evidence (RWE) movement (and the large recent investments in this by pharma) defined by FDA as the “the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of real world data from observational or longitudinal patient studies”. Turning to cohort studies, Binder et al. provide evidence of the widespread occurrence in top journals of likely bias in cohort studies due to the bias that Binder described in this journal in 2014 3 - For example this occurs when the patient dies before the end of the cohort time period due to the risk factor of interest but the patient is then censored in the analysis. 58 of 125 eligible studies were at risk of this bias, but only 6 addressed this with appropriate sensitivity analyses. The authors reviewed the literature and then worked with a patient panel to develop questionnaire items based on literature review, tested in the target group using a think-aloud procedure, and validated by a cross-sectional study among patients receiving health care at the interface between general practice and hospital care in two regions in the Netherlands.
In cooperation with the Core Outcome Measures in Effectiveness Trials (COMET) initiative, the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) initiative aimed ...to develop a guideline on how to select outcome measurement instruments for outcomes (i.e., constructs or domains) included in a "Core Outcome Set" (COS). A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population.
Informed by a literature review to identify potentially relevant tasks on outcome measurement instrument selection, a Delphi study was performed among a panel of international experts, representing diverse stakeholders. In three consecutive rounds, panelists were asked to rate the importance of different tasks in the selection of outcome measurement instruments, to justify their choices, and to add other relevant tasks. Consensus was defined as being achieved when 70 % or more of the panelists agreed and when fewer than 15 % of the panelists disagreed.
Of the 481 invited experts, 120 agreed to participate of whom 95 (79 %) completed the first Delphi questionnaire. We reached consensus on four main steps in the selection of outcome measurement instruments for COS: Step 1, conceptual considerations; Step 2, finding existing outcome measurement instruments, by means of a systematic review and/or a literature search; Step 3, quality assessment of outcome measurement instruments, by means of the evaluation of the measurement properties and feasibility aspects of outcome measurement instruments; and Step 4, generic recommendations on the selection of outcome measurement instruments for outcomes included in a COS (consensus ranged from 70 to 99 %).
This study resulted in a consensus-based guideline on the methods for selecting outcome measurement instruments for outcomes included in a COS. This guideline can be used by COS developers in defining how to measure core outcomes.
Summary Background Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an ...increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs. Methods We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included “biologics”, “rheumatoid arthritis” and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods. Findings The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1·31, 95% credible interval CrI 1·09–1·58) and high-dose biological drugs (1·90, 1·50–2·39) were associated with an increased risk of serious infections, although low-dose biological drugs (0·93, 0·65–1·33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs. Interpretation Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis. Funding Rheumatology Division at the University of Alabama at Birmingham.
Objective
To update the American College of Rheumatology (ACR) 2000 recommendations for hip and knee osteoarthritis (OA) and develop new recommendations for hand OA.
Methods
A list of pharmacologic ...and nonpharmacologic modalities commonly used to manage knee, hip, and hand OA as well as clinical scenarios representing patients with symptomatic hand, hip, and knee OA were generated. Systematic evidence‐based literature reviews were conducted by a working group at the Institute of Population Health, University of Ottawa, and updated by ACR staff to include additions to bibliographic databases through December 31, 2010. The Grading of Recommendations Assessment, Development and Evaluation approach, a formal process to rate scientific evidence and to develop recommendations that are as evidence based as possible, was used by a Technical Expert Panel comprised of various stakeholders to formulate the recommendations for the use of nonpharmacologic and pharmacologic modalities for OA of the hand, hip, and knee.
Results
Both “strong” and “conditional” recommendations were made for OA management. Modalities conditionally recommended for the management of hand OA include instruction in joint protection techniques, provision of assistive devices, use of thermal modalities and trapeziometacarpal joint splints, and use of oral and topical nonsteroidal antiinflammatory drugs (NSAIDs), tramadol, and topical capsaicin. Nonpharmacologic modalities strongly recommended for the management of knee OA were aerobic, aquatic, and/or resistance exercises as well as weight loss for overweight patients. Nonpharmacologic modalities conditionally recommended for knee OA included medial wedge insoles for valgus knee OA, subtalar strapped lateral insoles for varus knee OA, medially directed patellar taping, manual therapy, walking aids, thermal agents, tai chi, self‐management programs, and psychosocial interventions. Pharmacologic modalities conditionally recommended for the initial management of patients with knee OA included acetaminophen, oral and topical NSAIDs, tramadol, and intraarticular corticosteroid injections; intraarticular hyaluronate injections, duloxetine, and opioids were conditionally recommended in patients who had an inadequate response to initial therapy. Opioid analgesics were strongly recommended in patients who were either not willing to undergo or had contraindications for total joint arthroplasty after having failed medical therapy. Recommendations for hip OA were similar to those for the management of knee OA.
Conclusion
These recommendations are based on the consensus judgment of clinical experts from a wide range of disciplines, informed by available evidence, balancing the benefits and harms of both nonpharmacologic and pharmacologic modalities, and incorporating their preferences and values. It is hoped that these recommendations will be utilized by health care providers involved in the management of patients with OA.
Background
Dental caries is a major public health problem in most industrialised countries, affecting 60% to 90% of school children. Community water fluoridation was initiated in the USA in 1945 and ...is currently practised in about 25 countries around the world; health authorities consider it to be a key strategy for preventing dental caries. Given the continued interest in this topic from health professionals, policy makers and the public, it is important to update and maintain a systematic review that reflects contemporary evidence.
Objectives
To evaluate the effects of water fluoridation (artificial or natural) on the prevention of dental caries.
To evaluate the effects of water fluoridation (artificial or natural) on dental fluorosis.
Search methods
We searched the following electronic databases: The Cochrane Oral Health Group's Trials Register (to 19 February 2015); The Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2015); MEDLINE via OVID (1946 to 19 February 2015); EMBASE via OVID (1980 to 19 February 2015); Proquest (to 19 February 2015); Web of Science Conference Proceedings (1990 to 19 February 2015); ZETOC Conference Proceedings (1993 to 19 February 2015). We searched the US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization's WHO International Clinical Trials Registry Platform for ongoing trials. There were no restrictions on language of publication or publication status in the searches of the electronic databases.
Selection criteria
For caries data, we included only prospective studies with a concurrent control that compared at least two populations ‐ one receiving fluoridated water and the other non‐fluoridated water ‐ with outcome(s) evaluated at at least two points in time. For the assessment of fluorosis, we included any type of study design, with concurrent control, that compared populations exposed to different water fluoride concentrations. We included populations of all ages that received fluoridated water (naturally or artificially fluoridated) or non‐fluoridated water.
Data collection and analysis
We used an adaptation of the Cochrane 'Risk of bias' tool to assess risk of bias in the included studies.
We included the following caries indices in the analyses: decayed, missing and filled teeth (dmft (deciduous dentition) and DMFT (permanent dentition)), and proportion caries free in both dentitions. For dmft and DMFT analyses we calculated the difference in mean change scores between the fluoridated and control groups. For the proportion caries free we calculated the difference in the proportion caries free between the fluoridated and control groups.
For fluorosis data we calculated the log odds and presented them as probabilities for interpretation.
Main results
A total of 155 studies met the inclusion criteria; 107 studies provided sufficient data for quantitative synthesis.
The results from the caries severity data indicate that the initiation of water fluoridation results in reductions in dmft of 1.81 (95% CI 1.31 to 2.31; 9 studies at high risk of bias, 44,268 participants) and in DMFT of 1.16 (95% CI 0.72 to 1.61; 10 studies at high risk of bias, 78,764 participants). This translates to a 35% reduction in dmft and a 26% reduction in DMFT compared to the median control group mean values. There were also increases in the percentage of caries free children of 15% (95% CI 11% to 19%; 10 studies, 39,966 participants) in deciduous dentition and 14% (95% CI 5% to 23%; 8 studies, 53,538 participants) in permanent dentition. The majority of studies (71%) were conducted prior to 1975 and the widespread introduction of the use of fluoride toothpaste.
There is insufficient information to determine whether initiation of a water fluoridation programme results in a change in disparities in caries across socioeconomic status (SES) levels.
There is insufficient information to determine the effect of stopping water fluoridation programmes on caries levels.
No studies that aimed to determine the effectiveness of water fluoridation for preventing caries in adults met the review's inclusion criteria.
With regard to dental fluorosis, we estimated that for a fluoride level of 0.7 ppm the percentage of participants with fluorosis of aesthetic concern was approximately 12% (95% CI 8% to 17%; 40 studies, 59,630 participants). This increases to 40% (95% CI 35% to 44%) when considering fluorosis of any level (detected under highly controlled, clinical conditions; 90 studies, 180,530 participants). Over 97% of the studies were at high risk of bias and there was substantial between‐study variation.
Authors' conclusions
There is very little contemporary evidence, meeting the review's inclusion criteria, that has evaluated the effectiveness of water fluoridation for the prevention of caries.
The available data come predominantly from studies conducted prior to 1975, and indicate that water fluoridation is effective at reducing caries levels in both deciduous and permanent dentition in children. Our confidence in the size of the effect estimates is limited by the observational nature of the study designs, the high risk of bias within the studies and, importantly, the applicability of the evidence to current lifestyles. The decision to implement a water fluoridation programme relies upon an understanding of the population's oral health behaviour (e.g. use of fluoride toothpaste), the availability and uptake of other caries prevention strategies, their diet and consumption of tap water and the movement/migration of the population. There is insufficient evidence to determine whether water fluoridation results in a change in disparities in caries levels across SES. We did not identify any evidence, meeting the review's inclusion criteria, to determine the effectiveness of water fluoridation for preventing caries in adults.
There is insufficient information to determine the effect on caries levels of stopping water fluoridation programmes.
There is a significant association between dental fluorosis (of aesthetic concern or all levels of dental fluorosis) and fluoride level. The evidence is limited due to high risk of bias within the studies and substantial between‐study variation.
Abstract Background Lack of standardization of outcome measures limits the usefulness of clinical trial evidence to inform health care decisions. This can be addressed by agreeing on a minimum core ...set of outcome measures per health condition, containing measures relevant to patients and decision makers. Since 1992, the Outcome Measures in Rheumatology (OMERACT) consensus initiative has successfully developed core sets for many rheumatologic conditions, actively involving patients since 2002. Its expanding scope required an explicit formulation of its underlying conceptual framework and process. Methods Literature searches and iterative consensus process (surveys and group meetings) of stakeholders including patients, health professionals, and methodologists within and outside rheumatology. Results To comprehensively sample patient-centered and intervention-specific outcomes, a framework emerged that comprises three core “Areas,” namely Death, Life Impact, and Pathophysiological Manifestations; and one strongly recommended Resource Use. Through literature review and consensus process, core set development for any specific health condition starts by identifying at least one core “Domain” within each of the Areas to formulate the “Core Domain Set.” Next, at least one applicable measurement instrument for each core Domain is identified to formulate a “Core Outcome Measurement Set.” Each instrument must prove to be truthful (valid), discriminative, and feasible. In 2012, 96% of the voting participants ( n = 125) at the OMERACT 11 consensus conference endorsed this model and process. Conclusion The OMERACT Filter 2.0 explicitly describes a comprehensive conceptual framework and a recommended process to develop core outcome measurement sets for rheumatology likely to be useful as a template in other areas of health care.
Our objective was to develop an instrument to assess the methodological quality of systematic reviews, building upon previous tools, empirical evidence and expert consensus.
A 37-item assessment tool ...was formed by combining 1) the enhanced Overview Quality Assessment Questionnaire (OQAQ), 2) a checklist created by Sacks, and 3) three additional items recently judged to be of methodological importance. This tool was applied to 99 paper-based and 52 electronic systematic reviews. Exploratory factor analysis was used to identify underlying components. The results were considered by methodological experts using a nominal group technique aimed at item reduction and design of an assessment tool with face and content validity.
The factor analysis identified 11 components. From each component, one item was selected by the nominal group. The resulting instrument was judged to have face and content validity.
A measurement tool for the 'assessment of multiple systematic reviews' (AMSTAR) was developed. The tool consists of 11 items and has good face and content validity for measuring the methodological quality of systematic reviews. Additional studies are needed with a focus on the reproducibility and construct validity of AMSTAR, before strong recommendations can be made on its use.
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