Adjusting trial results for biases in meta-analysis: combining data-based evidence on bias with detailed trial assessment.

Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within-trial biases in meta-analysis include the use of empirical evidence from an external collection of meta-analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta-analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples.

Label-invariant models for the analysis of meta-epidemiological data.

Rich meta-epidemiological data sets have been collected to explore associations between intervention effect estimates and study-level characteristics. Welton et al proposed models for the analysis of meta-epidemiological data, but these models are restrictive because they force heterogeneity among studies with a particular characteristic to be at least as large as that among studies without the characteristic. In this paper we present alternative models that are invariant to the labels defining the 2 categories of studies. To exemplify the methods, we use a collection of meta-analyses in which the Cochrane Risk of Bias tool has been implemented. We first investigate the influence of small trial sample sizes (less than 100 participants), before investigating the influence of multiple methodological flaws (inadequate or unclear sequence generation, allocation concealment, and blinding). We fit both the Welton et al model and our proposed label-invariant model and compare the results. Estimates of mean bias associated with the trial characteristics and of between-trial variances are not very sensitive to the choice of model. Results from fitting a univariable model show that heterogeneity variance is, on average, 88% greater among trials with less than 100 participants. On the basis of a multivariable model, heterogeneity variance is, on average, 25% greater among trials with inadequate/unclear sequence generation, 51% greater among trials with inadequate/unclear blinding, and 23% lower among trials with inadequate/unclear allocation concealment, although the 95% intervals for these ratios are very wide. Our proposed label-invariant models for meta-epidemiological data analysis facilitate investigations of between-study heterogeneity attributable to certain study characteristics.

Control of carbapenemase-producing Enterobacteriaceae outbreaks in acute settings: an evidence review.

BACKGROUND: In recent years, infections with carbapenemase-producing Enterobacteriaceae (CPE) have been increasing globally and present a major public health challenge. AIM: To review the international literature: (i) to describe CPE outbreaks in acute hospital settings globally; and (ii) to identify the control measures used during these outbreaks and report on their effectiveness. METHODS: A systematic search of MEDLINE and EMBASE databases, abstract lists for key conferences and reference lists of key reviews was undertaken, and information on unpublished outbreaks was sought for 2000-2015. Where relevant, risk of bias was assessed using the Newcastle-Ottawa scale. A narrative synthesis of the evidence was conducted. FINDINGS: Ninety-eight outbreaks were eligible. These occurred worldwide, with 53 reports from Europe. The number of cases (CPE infection or colonization) involved in outbreaks varied widely, from two to 803. In the vast majority of outbreaks, multi-component infection control measures were used, commonly including: patient screening; contact precautions (e.g. gowns, gloves); handwashing interventions; staff education or monitoring; enhanced environmental cleaning/decontamination; cohorting of patients and/or staff; and patient isolation. Seven studies were identified as providing the best-available evidence on the effectiveness of control measures. These demonstrated that CPE outbreaks can be controlled successfully using a range of appropriate, commonly used, infection control measures. However, risk of bias was considered relatively high for these studies. CONCLUSION: The findings indicate that CPE outbreaks can be controlled using combinations of existing measures. However, the quality of the evidence base is weak and further high-quality research is needed, particularly on the effectiveness of individual infection control measures.

Systematic review with meta-analysis: the gastrointestinal benefits of COX-2 selective inhibitors with concomitant use of low-dose aspirin.

BACKGROUND: It is uncertain whether concurrent use of low-dose aspirin removes the gastrointestinal benefit displayed by COX-2 selective inhibitors (coxibs) when compared to traditional nonsteroidal anti-inflammatory drugs (NSAIDs). AIM: To evaluate the gastrointestinal risks associated with coxibs and traditional NSAIDs and the interaction with concurrent use of low-dose aspirin. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library through April 2016 to identify randomised trials comparing the gastrointestinal risk between coxibs and traditional NSAIDs in patients taking or not taking low-dose aspirin. Results were combined using random effects meta-analysis. Subgroup analyses by concurrent use of aspirin were undertaken. RESULTS: Eleven trials (84 150 participants) were included. The overall relative risk (RR) of coxibs vs. traditional NSAIDs for complicated gastrointestinal events was 0.54 (95% CI, confidence interval 0.32-0.92), with a significant subgroup difference (P = 0.04) according to concurrent use of aspirin (used: RR = 0.96, 95% CI 0.66-1.24; not used: RR = 0.33, 95% CI 0.14-0.83). The overall RR for clinical gastrointestinal events was 0.59 (95% CI 0.47-0.75), with a significant subgroup difference according to aspirin usage (P = 0.008; used: RR = 0.77, 95% CI 0.62-0.95; not used: RR = 0.50, 95% CI 0.39-0.64). Overall coxibs were associated with significantly lower risk of symptomatic ulcers (RR = 0.60, 95% CI 0.50-0.72) and endoscopic ulcers (RR = 0.29, 95% CI 0.16-0.53) than traditional NSAIDs; a significant subgroup difference was shown for endoscopic ulcers (P = 0.05) but not for symptomatic ulcers (P = 0.27). CONCLUSION: Concomitant use of low-dose aspirin reduces but does not completely eliminate the gastrointestinal benefit of coxibs over traditional NSAIDs.

Applicability and feasibility of systematic review for performing evidence-based risk assessment in food and feed safety.

Food and feed safety risk assessment uses multi-parameter models to evaluate the likelihood of adverse events associated with exposure to hazards in human health, plant health, animal health, animal welfare, and the environment. Systematic review and meta-analysis are established methods for answering questions in health care, and can be implemented to minimize biases in food and feed safety risk assessment. However, no methodological frameworks exist for refining risk assessment multi-parameter models into questions suitable for systematic review, and use of meta-analysis to estimate all parameters required by a risk model may not be always feasible. This paper describes novel approaches for determining question suitability and for prioritizing questions for systematic review in this area. Risk assessment questions that aim to estimate a parameter are likely to be suitable for systematic review. Such questions can be structured by their "key elements" [e.g., for intervention questions, the population(s), intervention(s), comparator(s), and outcome(s)]. Prioritization of questions to be addressed by systematic review relies on the likely impact and related uncertainty of individual parameters in the risk model. This approach to planning and prioritizing systematic review seems to have useful implications for producing evidence-based food and feed safety risk assessment.

Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies.

Meta-analyses that simultaneously compare multiple treatments (usually referred to as network meta-analyses or mixed treatment comparisons) are becoming increasingly common. An important component of a network meta-analysis is an assessment of the extent to which different sources of evidence are compatible, both substantively and statistically. A simple indirect comparison may be confounded if the studies involving one of the treatments of interest are fundamentally different from the studies involving the other treatment of interest. Here, we discuss methods for addressing inconsistency of evidence from comparative studies of different treatments. We define and review basic concepts of heterogeneity and inconsistency, and attempt to introduce a distinction between 'loop inconsistency' and 'design inconsistency'. We then propose that the notion of design-by-treatment interaction provides a useful general framework for investigating inconsistency. In particular, using design-by-treatment interactions successfully addresses complications that arise from the presence of multi-arm trials in an evidence network. We show how the inconsistency model proposed by Lu and Ades is a restricted version of our full design-by-treatment interaction model and that there may be several distinct Lu-Ades models for any particular data set. We introduce novel graphical methods for depicting networks of evidence, clearly depicting multi-arm trials and illustrating where there is potential for inconsistency to arise. We apply various inconsistency models to data from trials of different comparisons among four smoking cessation interventions and show that models seeking to address loop inconsistency alone can run into problems. Copyright © 2012 John Wiley & Sons, Ltd.

Glutathione S-transferase M1 (GSTM1) polymorphisms and lung cancer: a literature-based systematic HuGE review and meta-analysis.

Multiple genes have been studied for potential associations with lung cancer. The gene most frequently associated with increased risk has been glutathione S-transferase M1 (GSTM1). The glutathione S-transferase enzyme family is known to catalyze detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. In this review, the authors summarize the available evidence associating lung cancer with the GSTM1 gene. They describe results from an updated meta-analysis of 98 published genetic association studies investigating the relation between the GSTM1 null variant and lung cancer risk including 19,638 lung cancer cases and 25,266 controls (counting cases and controls in each study only once). All studies considered, the GSTM1 null variant was associated with an increased risk of lung cancer (odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.14, 1.30), but no increase in risk was seen (OR = 1.01, 95% CI: 0.91, 1.12) when only the five largest studies (>500 cases each) were considered. Furthermore, while GSTM1 null status conferred a significantly increased risk of lung cancer to East Asians (OR = 1.38, 95% CI: 1.24, 1.55), such a genotype did not confer increased risk to Caucasians. More data regarding the predictive value of GSTM1 genetic testing are needed before population-based testing may be reasonably considered.

Genetic associations in peripheral joint osteoarthritis and spinal degenerative disease: a systematic review.

UNLABELLED: We conducted a systematic review of genetic association studies for osteoarthritis of the peripheral joints (OA) and spinal degenerative disease (SDD). Electronic searches were carried out for any English language article reporting on a gene association study for either OA or SDD published up until the end of 2006. A team of seven reviewers used a standardised template to extract data in duplicate. In all, 90 studies fulfilled our inclusion criteria, reporting a total of 94 significant associations from 83 different genes. We found relatively few instances in which a specific gene-disease association had been analysed by more than one study, and there were 14 cases in which significant associations were replicated in independent studies (at joints associated with the AGC1, ASPN, COL9A2, COL9A3, COL11A2, ESR1, FZRB, HFE, IL1A, IL1RN, PTGS2 and VDR genes). METHOD: logical and reporting problems were widespread, including failure to report full results, missing population details, multiple testing, and over-reliance on subgroup analysis. In summary, the complex phenotypes of OA and SDD may have made it difficult for researchers to focus their efforts. The field is dominated by isolated analyses of disparate potential associations, a problem that is amplified by the frequent analysis of different polymorphisms within individual genes. Flaws in study methodology and interpretation undoubtedly increase the risk of publication bias. Closer adherence to published recommendations (in particular those produced by HuGENet) will help to ensure that future studies are well-designed and build on current understanding, rather than simply adding to the growing bank of potential associations.

Covariate heterogeneity in meta-analysis: criteria for deciding between meta-regression and individual patient data.

Meta-analyses of clinical trials are increasingly seeking to go beyond estimating the effect of a treatment and may also aim to investigate the effect of other covariates and how they alter treatment effectiveness. This requires the estimation of treatment-covariate interactions. Meta-regression can be used to estimate such interactions using published data, but it is known to lack statistical power, and is prone to bias.The use of individual patient data can improve estimation of such interactions, among other benefits, but it can be difficult and time-consuming to collect and analyse. This paper derives, under certain conditions, the power of meta-regression and IPD methods to detect treatment-covariate interactions. These power formulae are shown to depend on heterogeneity in the covariate distributions across studies. This allows the derivation of simple tests, based on heterogeneity statistics, for comparing the statistical power of the analysis methods.

Cognitive-behavioural interventions for children who have been sexually abused.

BACKGROUND: Despite differences in perceptions of what constitutes child sexual abuse there is a general consensus amongst clinicians and researchers that this is a substantial social problem which affects large numbers of children and young people worldwide. The effects of sexual abuse manifest themselves in a wide range of symptoms, including fear, anxiety, post-traumatic stress disorder and behaviour problems such as externalising or internalising, or inappropriate sexual behaviours. Child sexual abuse is associated with increased risk of psychological problems in adulthood. Knowing what is most likely to benefit children already traumatised by these events is important. OBJECTIVES: The aim of this review was to assess the efficacy of cognitive-behavioural approaches (CBT) in addressing the immediate and longer-term sequelae on children who have been sexually abused. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 5, 2005), MEDLINE (1966-November 2005); EMBASE (1980-November 2005); CINAHL (1982-November 2005), PsycINFO (1897-November 2005); LILACS (1982-November 2005); SIGLE (1980 to November 2005) and the register of the Cochrane Developmental, Psychosocial and Learning Problems Group (November 2005) were searched. SELECTION CRITERIA: Included studies were randomised or quasi-randomised controlled trials investigating the efficacy of cognitive behavioural therapy on children and adolescents up to age 18 years who had experienced sexual abuse. DATA COLLECTION AND ANALYSIS: Titles and abstracts identified in the search were independently assessed for eligibility by two reviewers (GM and PR). Data were extracted and entered into REVMAN (JH and GM), and synthesised and presented in both written and graphical form (forest plots). MAIN RESULTS: Ten trials, including 847 participants, were included in this review. Data suggest that CBT may have a positive impact on the sequelae of child sexual abuse, but most results were statistically non-significant. AUTHORS' CONCLUSIONS: The review confirms CBT's potential as a means of addressing the adverse consequences of child sexual abuse, but highlights the tenuousness of the evidence base and the need for more carefully conducted and better reported trials.

Systematic review of prevalence studies of autism spectrum disorders.

AIM: To quantitatively examine the influence of study methodology and population characteristics on prevalence estimates of autism spectrum disorders. METHODS: Electronic databases and bibliographies were searched and identified papers evaluated against inclusion criteria. Two groups of studies estimated the prevalence of typical autism and all autism spectrum disorders (ASD). The extent of variation among studies and overall prevalence were estimated using meta-analysis. The influence of methodological factors and population characteristics on estimated prevalence was investigated using meta-regression and summarised as odds ratios (OR). RESULTS: Forty studies met inclusion criteria, of which 37 estimated the prevalence of typical autism, and 23 the prevalence of all ASD. A high degree of heterogeneity among studies was observed. The overall random effects estimate of prevalence across studies of typical autism was 7.1 per 10,000 (95% CI 1.6 to 30.6) and of all ASD was 20.0 per 10,000 (95% CI 4.9 to 82.1). Diagnostic criteria used (ICD-10 or DSM-IV versus other; OR = 3.36, 95% CI 2.07 to 5.46), age of the children screened (OR = 0.91 per year, 95% CI 0.83 to 0.99), and study location (e.g. Japan versus North America; OR = 3.60, 95% CI 1.73 to 7.46) were all significantly associated with prevalence of typical autism. Diagnostic criteria, age of the sample, and urban or rural location were associated with estimated prevalence of all ASD. CONCLUSIONS: Sixty one per cent of the variation in prevalence estimates of typical autism was explained by these models. Diagnostic criteria used, age of children screened, and study location may be acting as proxies for other study characteristics and require further investigation.

The interpretation of random-effects meta-analysis in decision models.

This article shows that the interpretation of the random-effects models used in meta-analysis to summarize heterogeneous treatment effects can have a marked effect on the results from decision models. Sources of variation in meta-analysis include the following: random variation in outcome definition (amounting to a form of measurement error), variation between the patient groups in different trials, variation between protocols, and variation in the way a given protocol is implemented. Each of these alternatives leads to a different model for how the heterogeneity in the effect sizes previously observed might relate to the effect size(s) in a future implementation. Furthermore, these alternative models require different computations and, when the net benefits are nonlinear in the efficacy parameters, result in different expected net benefits. The authors' analysis suggests that the mean treatment effect from a random-effects meta-analysis will only seldom be an appropriate representation of the efficacy expected in a future implementation. Instead, modelers should consider either the predictive distribution of a future treatment effect, or they should assume that the future implementation will result in a distribution of treatment effects. A worked example, in a probabilistic, Bayesian posterior framework, is used to illustrate the alternative computations and to show how parameter uncertainty can be combined with variation between individuals and heterogeneity in meta-analysis.

Interventions for treating hallux valgus (abductovalgus) and bunions.

BACKGROUND: Hallux valgus is classified as an abnormal deviation of the great toe (hallux) towards the midline of the foot. OBJECTIVES: To identify and evaluate the evidence from randomised trials of interventions used to correct hallux valgus. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Injuries Group trials register (2003/1), the Cochrane Central Register of Controlled Trials (The Cochrane Library issue 1, 2003), MEDLINE (January 1966 to March 2003) and EMBASE (1980 to January 2003). No language restrictions were applied. Hand searching of specific foot journals was also undertaken. Date of the most recent search: 31st March 2003. SELECTION CRITERIA: Randomised or quasi-randomised trials of both conservative and surgical treatments of hallux valgus. Excluded were studies comparing areas of surgery not specific to the control of the deformity such as use of anaesthetics or tourniquet placement. DATA COLLECTION AND ANALYSIS: Methodological quality of trials which met the inclusion criteria was independently assessed by two reviewers. Data extraction was undertaken by two reviewers. The trials were grouped according to the interventions being compared, but the dissimilarity in the comparisons prevented pooling of results. MAIN RESULTS: The methodological quality of the 21 included trials was generally poor and trial sizes were small. Three trials involving 332 participants evaluated conservative treatments versus no treatment. There was no evidence of a difference in outcomes between treatment and no treatment. One good quality trial involving 140 participants compared surgery to conservative treatment. Evidence was shown of an improvement in all outcomes in patients receiving chevron osteotomy compared with those receiving orthoses. The same trial also compared surgery to no treatment in 140 participants. Evidence was shown of an improvement in all outcomes in patients receiving chevron osteotomy compared with those receiving no treatment. Two trials involving 133 people with hallux valgus compared Keller's arthroplasty with other surgical techniques. In general, there was no advantage or disadvantage using Keller's over the other techniques. When the distal osteotomy was compared to Keller's arthroplasty, the osteotomy showed evidence of improving the intermetatarsal angle and preserving joint range of motion. The arthroplasty was found to have less of an impact on walking ability compared to the arthrodesis. Six trials involving 309 participants compared chevron (and chevron-type) osteotomy with other techniques. The chevron osteotomy offered no advantages in these trials. For some outcomes, other techniques gave better results. Two of these trials (94 participants) compared a type of proximal osteotomy to a proximal chevron osteotomy and found no evidence of a difference in outcomes between techniques. Three trials involving 157 participants compared outcomes between original operations and surgeon's adaptations. There was no advantage found for any of the adaptations. Three trials involving 71 people with hallux valgus compared new methods of fixation to traditional methods. There was no evidence that the new methods of fixation were detrimental to the outcome of the patients. Four trials involving 162 participants evaluated methods of post-operative rehabilitation. The use of continuous passive motion appeared to give an improved range of motion and earlier recovery following surgery. Early weightbearing or the use of a crepe bandage were not found to be detrimental to final outcome. REVIEWER'S CONCLUSIONS: Only a few studies had considered conservative treatments. The evidence from these suggested that orthoses and night splints did not appear to be any more beneficial in improving outcomes than no treatment. Surgery (chevron osteotomy) was shown to be beneficial compared to orthoses or no treatment, but when compared to other osteotomies, no technique was shown to be superior to any other. Only one trial had compared an osteotomy to an arthroplasty. There was limited evidence to suggest that the osteotomy gat the osteotomy gave the better outcomes. It was notable that the numbers of participants in some trials remaining dissatisfied at follow-up were consistently high (25 to 33%), even when the hallux valgus angle and pain had improved. A few of the more recent trials used assessment scores that combine several aspects of the patients outcomes. These scoring systems are useful to the clinician when comparing techniques but are of dubious relevance to the patient if they do not address their main concern and such scoring systems are frequently unvalidated. Only one study simply asked the patient if they were better than before the treatment. Final outcomes were most frequently measured at one year, with a few trials maintaining follow-up for 3 years. Such time-scales are minimal given that the patients will be on their feet for at least another 20-30 years after treatment. Future research should include patient-focused outcomes, standardised assessment criteria and longer surveillance periods, more usefully in the region of 5-10 years.

One topical fluoride (toothpastes, or mouthrinses, or gels, or varnishes) versus another for preventing dental caries in children and adolescents.

BACKGROUND: Topical fluorides in the form of toothpaste, mouthrinse, varnish and gel are effective caries preventive measures. However, there is uncertainty about the relative value of these interventions. OBJECTIVES: To compare the effectiveness of one form of topical fluoride intervention with another when used for the prevention of dental caries in children. SEARCH STRATEGY: We searched the Cochrane Oral Health Group's Trials Register (May 2000), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2000), MEDLINE (1966 to January 2000), plus several other databases. We handsearched journals, reference lists of articles and contacted selected authors and manufacturers. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials with blind outcome assessment, comparing fluoride varnish, gel, mouthrinse, or toothpaste with each other in children up to 16 years during at least 1 year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces (D(M)FS). DATA COLLECTION AND ANALYSIS: Inclusion decisions, quality assessment and data extraction were duplicated in a random sample of one third of studies, and consensus achieved by discussion or a third party. Authors were contacted for missing data. The primary measure of effect was the prevented fraction (PF) that is the difference in mean caries increments between the 'experimental' and 'control' groups expressed as a percentage of the mean increment in the control group. Random effects meta-analyses were performed where data could be pooled. MAIN RESULTS: There were 17 studies included, and 15 contributed data for the meta-analyses. Fluoride toothpaste was not significantly different from mouthrinse (pooled DMFS PF 0%; 95% CI, -18% to 19%; p = 0.94), or gel (pooled DMFS PF 0%; 95% CI, -21% to 21%; p = 1), or both gel and mouthrinse (pooled DMFS PF 1%; 95% CI, -13% to 14%; p = 0.94); heterogeneity was substantial. Results from the single trial comparing toothpaste with varnish (in deciduous teeth) were inconclusive (dfs PF 5%; CI not obtainable). The pooled results from the comparisons of fluoride varnish with mouthrinse was a non-significant difference favouring varnish (DMFS PF 10%; 95% CI, -12% to 32%; p = 0.40), but this result was not robust to sensitivity analysis performed, and heterogeneity was considerable. Results from the single trial comparing varnish with gel (14%, 95% CI, -12% to 40%; p = 0.30) and the single trial comparing gel with mouthrinse (-14% DMFS PF; 95% CI, -40% to 12%; p = 0.30) were inconclusive (favoured varnish and mouthrinse respectively). REVIEWER'S CONCLUSIONS: Fluoride toothpastes in comparison to mouthrinses or gels appear to have a similar degree of effectiveness for the prevention of dental caries in children. There is no clear suggestion that fluoride varnish is more effective than mouthrinses and the evidence for the comparative effectiveness of fluoride varnishes and gels, and mouthrinses and gels is inconclusive. No conclusions about adverse effects could be reached, because no data were reported on in the trials. Acceptance is likely to be greater for fluoride toothpaste.

Combinations of topical fluoride (toothpastes, mouthrinses, gels, varnishes) versus single topical fluoride for preventing dental caries in children and adolescents.

BACKGROUND: Topical fluoride therapy (TFT) in the form of toothpastes, mouthrinses, varnishes and gels are effective caries preventive measures. However, there is uncertainty about the relative value of these interventions when used together. OBJECTIVES: To compare the effectiveness of two TFT modalities combined with one of them alone (mainly toothpaste) when used for the prevention of dental caries in children. SEARCH STRATEGY: We searched the Cochrane Oral Health Group's Trials Register (May 2000), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2000), MEDLINE (1966 to January 2000), plus several other databases. We handsearched journals, reference lists of articles and contacted selected authors and manufacturers. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials with blind outcome assessment, comparing fluoride varnish, gel, mouthrinse, or toothpaste in combination with each other in children up to 16 years during at least 1 year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces (D(M)FS). DATA COLLECTION AND ANALYSIS: Inclusion decisions, quality assessment and data extraction were duplicated in a random sample of one third of studies, and consensus achieved by discussion or a third party. Authors were contacted for missing data. The primary measure of effect was the prevented fraction (PF) that is the difference in mean caries increments between the 'treatment' and 'control' groups expressed as a percentage of the mean increment in the control group. Random effects meta-analyses were performed where data could be pooled. MAIN RESULTS: Eleven of the 12 included studies contributed data for the meta-analyses. For the nine trials that provided data for the main meta-analysis on the effect of fluoride mouthrinses, gels or varnishes used in combination with toothpaste (involving 4026 children) the D(M)FS pooled PF was 10% (95% CI, 2% to 17%; p = 0.01) in favour of the combined regimens. Heterogeneity was not substantial in these results (I square = 32%). The separate meta-analyses of fluoride gel or mouthrinse combined with toothpaste versus toothpaste alone favour the combined regimens, but differences were not statistically significant; the significant difference in favour of the combined use of fluoride varnish and toothpaste accrues from a very small trial and appears likely to be a spurious result. Not all other combinations of possible practical value were tested in the included studies. The only other statistically significant result was in favour of the combined use of fluoride gel and mouthrinse in comparison to gel alone (pooled DMFS PF 23%; 95% CI, 4% to 43%; p = 0.02), based on two trials. No other combinations of TFT were consistently superior to a single TFT. REVIEWER'S CONCLUSIONS: Topical fluorides (mouthrinses, gels, or varnishes) used in addition to fluoride toothpaste achieve a modest reduction in caries compared to toothpaste used alone. No conclusions about any adverse effects could be reached, because data were scarcely reported in the trials.

Topical fluoride (toothpastes, mouthrinses, gels or varnishes) for preventing dental caries in children and adolescents.

BACKGROUND: Topical fluoride therapy (TFT) in the form of varnish, gel, mouthrinse or toothpaste has been used extensively as a caries-preventive intervention for over three decades. OBJECTIVES: To determine the effectiveness and safety of fluoride varnishes, gels, mouthrinses, and toothpastes in the prevention of dental caries in children and to examine factors potentially modifying their effect. SEARCH STRATEGY: We searched the Cochrane Oral Health Group's Trials Register (May 2000), CENTRAL (The Cochrane Library Issue 2, 2000), MEDLINE (1966 to January 2000), plus several other databases. We handsearched journals, reference lists of articles and contacted selected authors and manufacturers. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials with blind outcome assessment, comparing fluoride varnish, gel, mouthrinse, or toothpaste with placebo or no treatment in children up to 16 years during at least 1 year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces (D(M)FS). DATA COLLECTION AND ANALYSIS: Inclusion decisions, quality assessment and data extraction were duplicated in a random sample of one third of studies, and consensus achieved by discussion or a third party. Authors were contacted for missing data. The primary measure of effect was the prevented fraction (PF) that is the difference in mean caries increments between the treatment and control groups expressed as a percentage of the mean increment in the control group. Random effects meta-analyses were performed where data could be pooled. Potential sources of heterogeneity were examined in random effects metaregression analyses. MAIN RESULTS: There were 144 studies included. For the 133 that contributed data for meta-analysis (involving 65,169 children) the D(M)FS pooled prevented fraction estimate was 26% (95% CI, 24% to 29%; p < 0.0001). There was substantial heterogeneity, confirmed statistically (p < 0.0001), but the direction of effect was consistent. The effect of topical fluoride varied according to type of control group used, type of TFT used, mode/setting of TFT use, initial caries levels and intensity of TFT application, but was not influenced by exposure to water fluoridation or other fluoride sources. D(M)FS PF was on average 14% (95% CI, 5% to 23%; p = 0.002) higher in non-placebo controlled trials, 14% (95% CI, 2% to 26%; p = 0.25) higher in fluoride varnish trials compared with all others, and 10% (95% CI, -17% to -3%; p = 0.003) lower in trials of unsupervised home use compared with self applied supervised and operator-applied. There was a 0.7% increase in the PF per unit increase in baseline caries (95% CI, 0.2% to 1.2%; p = 0.004). REVIEWER'S CONCLUSIONS: The benefits of topical fluorides have been firmly established on a sizeable body of evidence from randomized controlled trials. While the formal examination of sources of heterogeneity between studies has been important in the overall conclusions reached, these should be interpreted with caution. We were unable to reach definite conclusions about any adverse effects that might result from the use of topical fluorides, because data reported in the trials are scarce.

Lecithin for dementia and cognitive impairment.

BACKGROUND: Alzheimer's disease sufferers have been found to have a lack of the enzyme responsible for converting choline into acetylcholine within the brain. Lecithin is a major dietary source of choline, so extra consumption may reduce the progression of dementia. OBJECTIVES: To determine the efficacy of lecithin in the treatment of dementia or cognitive impairment. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched on 15 May 2002 using the terms lecithin and phosphaditylcholine. This contains records from all major databases and many trials databases. Reference lists and relevant books have been examined. SELECTION CRITERIA: All unconfounded, randomized trials comparing lecithin with placebo in a treatment period longer than one day, in patients with dementia of the Alzheimer type, vascular dementia, mixed vascular and Alzheimer's disease, unclassified or other dementia or unclassified cognitive impairment not fulfilling the criteria for dementia are eligible for inclusion. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers and cross-checked. Meta-analyses were performed when more than one trial provided data on a comparable outcome on sufficiently similar patients. Random effects analyses were performed whenever heterogeneity between results appeared to be present. Standardised differences in mean outcome measures were used due do the use of different scales and periods of treatment. Odds ratios for dichotomous data were pooled using the Mantel-Haenszel or DerSimonian and Laird methods. MAIN RESULTS: Twelve randomized trials have been identified involving patients with Alzheimer's disease (265 patients), Parkinsonian dementia (21 patients) and subjective memory problems (90 patients). No trials reported any clear clinical benefit of lecithin for Alzheimer's disease or Parkinsonian dementia. Few trials contributed data to meta-analyses. The only statistically significant result was in favour of placebo for adverse events, based on one trial, which appears likely to be a spurious result. A dramatic result in favour of lecithin was obtained in a trial of subjects with subjective memory problems. REVIEWER'S CONCLUSIONS: Evidence from randomized trials does not support the use of lecithin in the treatment of patients with dementia. A moderate effect cannot be ruled out, but results from the small trials to date do not indicate priority for a large randomized trial.

Dietary advice given by a dietitian versus other health professional or self-help resources to reduce blood cholesterol.

BACKGROUND: The average level of blood cholesterol is an important determinant of the risk of coronary heart disease. Blood cholesterol can be reduced by dietary means. Although dietitians are trained to provide dietary advice, for practical reasons it is also given by other health professionals and occasionally through the use of self-help resources. OBJECTIVES: To assess the effects of dietary advice given by a dietitian compared with another health professional, or the use of self-help resources, in reducing blood cholesterol in adults. SEARCH STRATEGY: We searched The Cochrane Library (to Issue 3 2002), the EPOC trial register (October 2002), MEDLINE (1966 to September 2002), EMBASE (1980 to September 2002), Cinahl (1982 to August 2002), Human Nutrition (1991 to 1998), Science Citation Index, Social Sciences Citation Index, hand searched conference proceedings on nutrition and heart disease, and contacted experts in the field. SELECTION CRITERIA: Randomised trials of dietary advice given by a dietitian compared with another health professional or self-help resources. The main outcome was difference in blood cholesterol between dietitian groups compared with other intervention groups. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed study quality. MAIN RESULTS: Twelve studies with 13 comparisons were included, involving 727 people receiving advice from dietitians, 515 from other health professionals and 551 people using self-help resources. Four studies compared dietitian with doctor, seven with self-help resources, and only one study was found for each of the dietitian versus nurse and dietitian versus counsellor comparisons. Participants receiving advice from dietitians experienced a greater reduction in blood cholesterol than those receiving advice only from doctors (-0.25 mmol/L (95% CI -0.37, -0.12 mmol/L)). There was no statistically significant difference in change in blood cholesterol between dietitians and self-help resources (-0.10 mmol/L (95% CI -0.22, 0.03 mmol/L)). No statistically significant differences were detected for secondary outcome measures between any of the comparisons with the exception of dietitian versus nurse for HDLc, where the dietitian group showed a greater reduction (-0.06 mmol/L (95% CI -0.11, -0.01)) and dietitian versus counsellor for body weight, where the dietitian group showed a greater reduction (-5.80 kg (95% CI -8.91, -2.69 kg)). No significant heterogeneity between the studies was detected. REVIEWER'S CONCLUSIONS: Dietitians were better than doctors at lowering blood cholesterol in the short to medium term, but there was no evidence that they were better than self-help resources. The results should be interpreted with caution as the studies were not of good quality and the analysis was based on a limited number of trials. More evidence is required to assess whether change can be maintained in the longer term. There was no evidence that dietitians provided better outcomes than nurses.