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1.  Meta-analyses of Adverse Effects Data Derived from Randomised Controlled Trials as Compared to Observational Studies: Methodological Overview 
PLoS Medicine  2011;8(5):e1001026.
Su Golder and colleagues carry out an overview of meta-analyses to assess whether estimates of the risk of harm outcomes differ between randomized trials and observational studies. They find that, on average, there is no difference in the estimates of risk between overviews of observational studies and overviews of randomized trials.
Background
There is considerable debate as to the relative merits of using randomised controlled trial (RCT) data as opposed to observational data in systematic reviews of adverse effects. This meta-analysis of meta-analyses aimed to assess the level of agreement or disagreement in the estimates of harm derived from meta-analysis of RCTs as compared to meta-analysis of observational studies.
Methods and Findings
Searches were carried out in ten databases in addition to reference checking, contacting experts, citation searches, and hand-searching key journals, conference proceedings, and Web sites. Studies were included where a pooled relative measure of an adverse effect (odds ratio or risk ratio) from RCTs could be directly compared, using the ratio of odds ratios, with the pooled estimate for the same adverse effect arising from observational studies. Nineteen studies, yielding 58 meta-analyses, were identified for inclusion. The pooled ratio of odds ratios of RCTs compared to observational studies was estimated to be 1.03 (95% confidence interval 0.93–1.15). There was less discrepancy with larger studies. The symmetric funnel plot suggests that there is no consistent difference between risk estimates from meta-analysis of RCT data and those from meta-analysis of observational studies. In almost all instances, the estimates of harm from meta-analyses of the different study designs had 95% confidence intervals that overlapped (54/58, 93%). In terms of statistical significance, in nearly two-thirds (37/58, 64%), the results agreed (both studies showing a significant increase or significant decrease or both showing no significant difference). In only one meta-analysis about one adverse effect was there opposing statistical significance.
Conclusions
Empirical evidence from this overview indicates that there is no difference on average in the risk estimate of adverse effects of an intervention derived from meta-analyses of RCTs and meta-analyses of observational studies. This suggests that systematic reviews of adverse effects should not be restricted to specific study types.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Whenever patients consult a doctor, they expect the treatments they receive to be effective and to have minimal adverse effects (side effects). To ensure that this is the case, all treatments now undergo exhaustive clinical research—carefully designed investigations that test new treatments and therapies in people. Clinical investigations fall into two main groups—randomized controlled trials (RCTs) and observational, or non-randomized, studies. In RCTs, groups of patients with a specific disease or condition are randomly assigned to receive the new treatment or a control treatment, and the outcomes (for example, improvements in health and the occurrence of specific adverse effects) of the two groups of patients are compared. Because the patients are randomly chosen, differences in outcomes between the two groups are likely to be treatment-related. In observational studies, patients who are receiving a specific treatment are enrolled and outcomes in this group are compared to those in a similar group of untreated patients. Because the patient groups are not randomly chosen, differences in outcomes between cases and controls may be the result of a hidden shared characteristic among the cases rather than treatment-related (so-called confounding variables).
Why Was This Study Done?
Although data from individual trials and studies are valuable, much more information about a potential new treatment can be obtained by systematically reviewing all the evidence and then doing a meta-analysis (so-called evidence-based medicine). A systematic review uses predefined criteria to identify all the research on a treatment; meta-analysis is a statistical method for combining the results of several studies to yield “pooled estimates” of the treatment effect (the efficacy of a treatment) and the risk of harm. Treatment effect estimates can differ between RCTs and observational studies, but what about adverse effect estimates? Can different study designs provide a consistent picture of the risk of harm, or are the results from different study designs so disparate that it would be meaningless to combine them in a single review? In this methodological overview, which comprises a systematic review and meta-analyses, the researchers assess the level of agreement in the estimates of harm derived from meta-analysis of RCTs with estimates derived from meta-analysis of observational studies.
What Did the Researchers Do and Find?
The researchers searched literature databases and reference lists, consulted experts, and hand-searched various other sources for studies in which the pooled estimate of an adverse effect from RCTs could be directly compared to the pooled estimate for the same adverse effect from observational studies. They identified 19 studies that together covered 58 separate adverse effects. In almost all instances, the estimates of harm obtained from meta-analyses of RCTs and observational studies had overlapping 95% confidence intervals. That is, in statistical terms, the estimates of harm were similar. Moreover, in nearly two-thirds of cases, there was agreement between RCTs and observational studies about whether a treatment caused a significant increase in adverse effects, a significant decrease, or no significant change (a significant change is one unlikely to have occurred by chance). Finally, the researchers used meta-analysis to calculate that the pooled ratio of the odds ratios (a statistical measurement of risk) of RCTs compared to observational studies was 1.03. This figure suggests that there was no consistent difference between risk estimates obtained from meta-analysis of RCT data and those obtained from meta-analysis of observational study data.
What Do These Findings Mean?
The findings of this methodological overview suggest that there is no difference on average in the risk estimate of an intervention's adverse effects obtained from meta-analyses of RCTs and from meta-analyses of observational studies. Although limited by some aspects of its design, this overview has several important implications for the conduct of systematic reviews of adverse effects. In particular, it suggests that, rather than limiting systematic reviews to certain study designs, it might be better to evaluate a broad range of studies. In this way, it might be possible to build a more complete, more generalizable picture of potential harms associated with an intervention, without any loss of validity, than by evaluating a single type of study. Such a picture, in combination with estimates of treatment effects also obtained from systematic reviews and meta-analyses, would help clinicians decide the best treatment for their patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001026.
The US National Institutes of Health provide information on clinical research; the UK National Health Service Choices Web site also has a page on clinical trials and medical research
The Cochrane Collaboration produces and disseminates systematic reviews of health-care interventions
Medline Plus provides links to further information about clinical trials (in English and Spanish)
doi:10.1371/journal.pmed.1001026
PMCID: PMC3086872  PMID: 21559325
2.  Comparative Efficacy of Seven Psychotherapeutic Interventions for Patients with Depression: A Network Meta-Analysis 
PLoS Medicine  2013;10(5):e1001454.
Jürgen Barth and colleagues use network meta-analysis - a novel methodological approach - to reexamine the comparative efficacy of seven psychotherapeutic interventions for adults with depression.
Please see later in the article for the Editors' Summary
Background
Previous meta-analyses comparing the efficacy of psychotherapeutic interventions for depression were clouded by a limited number of within-study treatment comparisons. This study used network meta-analysis, a novel methodological approach that integrates direct and indirect evidence from randomised controlled studies, to re-examine the comparative efficacy of seven psychotherapeutic interventions for adult depression.
Methods and Findings
We conducted systematic literature searches in PubMed, PsycINFO, and Embase up to November 2012, and identified additional studies through earlier meta-analyses and the references of included studies. We identified 198 studies, including 15,118 adult patients with depression, and coded moderator variables. Each of the seven psychotherapeutic interventions was superior to a waitlist control condition with moderate to large effects (range d = −0.62 to d = −0.92). Relative effects of different psychotherapeutic interventions on depressive symptoms were absent to small (range d = 0.01 to d = −0.30). Interpersonal therapy was significantly more effective than supportive therapy (d = −0.30, 95% credibility interval [CrI] [−0.54 to −0.05]). Moderator analysis showed that patient characteristics had no influence on treatment effects, but identified aspects of study quality and sample size as effect modifiers. Smaller effects were found in studies of at least moderate (Δd = 0.29 [−0.01 to 0.58]; p = 0.063) and large size (Δd = 0.33 [0.08 to 0.61]; p = 0.012) and those that had adequate outcome assessment (Δd = 0.38 [−0.06 to 0.87]; p = 0.100). Stepwise restriction of analyses by sample size showed robust effects for cognitive-behavioural therapy, interpersonal therapy, and problem-solving therapy (all d>0.46) compared to waitlist. Empirical evidence from large studies was unavailable or limited for other psychotherapeutic interventions.
Conclusions
Overall our results are consistent with the notion that different psychotherapeutic interventions for depression have comparable benefits. However, the robustness of the evidence varies considerably between different psychotherapeutic treatments.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depression is a very common condition. One in six people will experience depression at some time during their life. People who are depressed have recurrent feelings of sadness and hopelessness and might feel that life is no longer worth living. The condition can last for months and often includes physical symptoms such as headaches, sleeping problems, and weight gain or loss. Treatment of depression can include non-drug treatments (psychotherapy), antidepressant drugs, or a combination of the two. Especially for people with mild or intermediate depression, psychotherapy is often considered the preferred first option. Psychotherapy describes a range of different psychotherapies, and a number of established types of psychotherapies have all shown to work for at least some patients.
Why Was This Study Done?
While it is broadly accepted that psychotherapy can help people with depression, the question of which type of psychotherapy works best for most patients remains controversial. While many scientific studies have compared one psychotherapy with control conditions, there have been few studies that directly compared multiple treatments. Without such direct comparisons, it has been difficult to establish the respective merits of the different types of psychotherapy. Taking advantage of a recently developed method called “network meta-analysis,” the authors re-examine the evidence on seven different types of psychotherapy to see how well they have been shown to work and whether some work better than others.
What Did the Researchers Do and Find?
The researchers looked at seven different types of psychotherapy, which they defined as follows. “Interpersonal psychotherapy” is short and highly structured, using a manual to focus on interpersonal issues in depression. “Behavioral activation” raises the awareness of pleasant activities and seeks to increase positive interactions between the patient and his or her environment. “Cognitive behavioral therapy” focuses on a patient's current negative beliefs, evaluates how they affect current and future behavior, and attempts to restructure the beliefs and change the outlook. “Problem solving therapy” aims to define a patient's problems, propose multiple solutions for each problem, and then select, implement, and evaluate the best solution. “Psychodynamic therapy” focuses on past unresolved conflicts and relationships and the impact they have on a patient's current situation. In “social skills therapy,” patients are taught skills that help to build and maintain healthy relationships based on honesty and respect. “Supportive counseling” is a more general therapy that aims to get patients to talk about their experiences and emotions and to offer empathy without suggesting solutions or teaching new skills.
The researchers started with a systematic search of the medical literature for relevant studies. The search identified 198 articles that reported on such clinical trials. The trials included a total of 15,118 patients and compared one of the seven psychotherapies either with another one or with a common “control intervention”. In most cases, the control (no psychotherapy) was deferral of treatment by “wait-listing” patients or continuing “usual care.” With network meta-analysis they were able to summarize the results of all these trials in a meaningful way. They did this by integrating direct comparisons of several psychotherapies within the same trial (where those were available) with indirect comparisons across all trials (using no psychotherapy as a control intervention).
Based on the combined trial results, all seven psychotherapies tested were better than wait-listing or usual care, and the differences were moderate to large, meaning that the average person in the group that received therapy was better off than about half of the patients in the control group. When comparing the therapies with each other, the researchers saw small or no differences, meaning that none of them really stood out as much better or much worse than the others. They also found that the treatments worked equally well for different patient groups with depression (younger or older patients, or mothers who had depression after having given birth). Similarly, they saw no big differences when comparing individual with group therapy, or person-to-person with internet-based interactions between therapist and patient.
However, they did find that smaller and less rigorous studies generally found larger benefits of psychotherapies, and most of the studies included in the analysis were small. Only 36 of the studies had at least 50 patients who received the same treatment. When they restricted their analysis to those studies, the researchers still saw clear benefits of cognitive-behavioral therapy, interpersonal therapy, and problem-solving therapy, but not for the other four therapies.
What Do these Findings Mean?
Similar to earlier attempts to summarize and make sense of the many study results, this one finds benefits for all of the seven psychotherapies examined, and none of them stood as being much better than some or all others. The scientific support for being beneficial was stronger for some therapies, mostly because they had been tested more often and in larger studies.
Treatments with proven benefits still do not necessarily work for all patients, and which type of psychotherapy might work best for a particular patient likely depends on that individual. So overall this analysis suggests that patients with depression and their doctors should consider psychotherapies and explore which of the different types might be best suited for a particular patient.
The study also points to the need for further research. Whereas depression affects large numbers of people around the world, all of the trials identified were conducted in rich countries and Western societies. Trials in different settings are essential to inform treatment of patients worldwide. In addition, large high-quality studies should further explore the potential benefits of some of therapies for which less support currently exists. Where possible, future studies should compare psychotherapies with one another, because all of them have benefits, and it would not be ethical to withhold such beneficial treatment from patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001454.
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish); information on psychotherapy includes information on its most common forms
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
The UK nonprofit Mind provides information on depression, including an explanation of the most common psychotherapies in the UK
MedlinePlus provides links to other resources about depression (in English and Spanish)
The UK nonprofit healthtalkonline.org has a unique database of personal and patient experiences on depression
doi:10.1371/journal.pmed.1001454
PMCID: PMC3665892  PMID: 23723742
3.  MCPerm: A Monte Carlo Permutation Method for Accurately Correcting the Multiple Testing in a Meta-Analysis of Genetic Association Studies 
PLoS ONE  2014;9(2):e89212.
Traditional permutation (TradPerm) tests are usually considered the gold standard for multiple testing corrections. However, they can be difficult to complete for the meta-analyses of genetic association studies based on multiple single nucleotide polymorphism loci as they depend on individual-level genotype and phenotype data to perform random shuffles, which are not easy to obtain. Most meta-analyses have therefore been performed using summary statistics from previously published studies. To carry out a permutation using only genotype counts without changing the size of the TradPerm P-value, we developed a Monte Carlo permutation (MCPerm) method. First, for each study included in the meta-analysis, we used a two-step hypergeometric distribution to generate a random number of genotypes in cases and controls. We then carried out a meta-analysis using these random genotype data. Finally, we obtained the corrected permutation P-value of the meta-analysis by repeating the entire process N times. We used five real datasets and five simulation datasets to evaluate the MCPerm method and our results showed the following: (1) MCPerm requires only the summary statistics of the genotype, without the need for individual-level data; (2) Genotype counts generated by our two-step hypergeometric distributions had the same distributions as genotype counts generated by shuffling; (3) MCPerm had almost exactly the same permutation P-values as TradPerm (r = 0.999; P<2.2e-16); (4) The calculation speed of MCPerm is much faster than that of TradPerm. In summary, MCPerm appears to be a viable alternative to TradPerm, and we have developed it as a freely available R package at CRAN: http://cran.r-project.org/web/packages/MCPerm/index.html.
doi:10.1371/journal.pone.0089212
PMCID: PMC3931718  PMID: 24586601
4.  An empirical investigation of the potential impact of selective inclusion of results in systematic reviews of interventions: study protocol 
Systematic Reviews  2013;2:21.
Background
Systematic reviewers may encounter a multiplicity of outcome data in the reports of randomised controlled trials included in the review (for example, multiple measurement instruments measuring the same outcome, multiple time points, and final and change from baseline values). The primary objectives of this study are to investigate in a cohort of systematic reviews of randomised controlled trials of interventions for rheumatoid arthritis, osteoarthritis, depressive disorders and anxiety disorders: (i) how often there is multiplicity of outcome data in trial reports; (ii) the association between selection of trial outcome data included in a meta-analysis and the magnitude and statistical significance of the trial result, and; (iii) the impact of the selection of outcome data on meta-analytic results.
Methods/Design
Forty systematic reviews (20 Cochrane, 20 non-Cochrane) of RCTs published from January 2010 to January 2012 and indexed in the Cochrane Database of Systematic Reviews (CDSR) or PubMed will be randomly sampled. The first meta-analysis of a continuous outcome within each review will be included. From each review protocol (where available) and published review we will extract information regarding which types of outcome data were eligible for inclusion in the meta-analysis (for example, measurement instruments, time points, analyses). From the trial reports we will extract all outcome data that are compatible with the meta-analysis outcome as it is defined in the review and with the outcome data eligibility criteria and hierarchies in the review protocol. The association between selection of trial outcome data included in a meta-analysis and the magnitude and statistical significance of the trial result will be investigated. We will also investigate the impact of the selected trial result on the magnitude of the resulting meta-analytic effect estimates.
Discussion
The strengths of this empirical study are that our objectives and methods are pre-specified and transparent. The results may inform methods guidance for systematic review conduct and reporting, particularly for dealing with multiplicity of randomised controlled trial outcome data.
doi:10.1186/2046-4053-2-21
PMCID: PMC3626625  PMID: 23575367
Systematic review; Randomised controlled trials; Reporting; Bias; Research methodology
5.  A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach 
PLoS Genetics  2014;10(7):e1004469.
Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10−7), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05–1.32); meta-analysis p = 2.6×10−8). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10−15; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
Author Summary
Ischaemic stroke places an enormous burden on global healthcare. However, the disease processes that lead to stroke are not fully understood. Genome-wide association studies have recently established that common genetic variants can increase risk of ischaemic stroke and its subtypes. In this study, we aimed to identify novel genetic associations with ischaemic stroke and its subtypes by addressing the fact that younger onset cases may have a stronger genetic component, and using this information in our analyses. We identify a novel genetic variant on chromosome 11 (rs660599), which is associated with increased risk of large artery stroke. We also show that mRNA expression of the nearest gene (MMP12) is higher in arteries with the disease process underlying large artery stroke (atherosclerosis). Finally, we evaluate our novel analysis approach, and show that our method is likely to identify further associations with ischaemic stroke.
doi:10.1371/journal.pgen.1004469
PMCID: PMC4117446  PMID: 25078452
6.  Bias in meta-analysis detected by a simple, graphical test. 
BMJ : British Medical Journal  1997;315(7109):629-634.
OBJECTIVE: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. DESIGN: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews. MAIN OUTCOME MEASURE: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. RESULTS: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. CONCLUSIONS: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution.
PMCID: PMC2127453  PMID: 9310563
7.  Greater Response to Placebo in Children Than in Adults: A Systematic Review and Meta-Analysis in Drug-Resistant Partial Epilepsy 
PLoS Medicine  2008;5(8):e166.
Background
Despite guidelines establishing the need to perform comprehensive paediatric drug development programs, pivotal trials in children with epilepsy have been completed mostly in Phase IV as a postapproval replication of adult data. However, it has been shown that the treatment response in children can differ from that in adults. It has not been investigated whether differences in drug effect between adults and children might occur in the treatment of drug-resistant partial epilepsy, although such differences may have a substantial impact on the design and results of paediatric randomised controlled trials (RCTs).
Methods and Findings
Three electronic databases were searched for RCTs investigating any antiepileptic drug (AED) in the add-on treatment of drug-resistant partial epilepsy in both children and adults. The treatment effect was compared between the two age groups using the ratio of the relative risk (RR) of the 50% responder rate between active AEDs treatment and placebo groups, as well as meta-regression. Differences in the response to placebo and to active treatment were searched using logistic regression. A comparable approach was used for analysing secondary endpoints, including seizure-free rate, total and adverse events-related withdrawal rates, and withdrawal rate for seizure aggravation. Five AEDs were evaluated in both adults and children with drug-resistant partial epilepsy in 32 RCTs. The treatment effect was significantly lower in children than in adults (RR ratio: 0.67 [95% confidence interval (CI) 0.51–0.89]; p = 0.02 by meta-regression). This difference was related to an age-dependent variation in the response to placebo, with a higher rate in children than in adults (19% versus 9.9%, p < 0.001), whereas no significant difference was observed in the response to active treatment (37.2% versus 30.4%, p = 0.364). The relative risk of the total withdrawal rate was also significantly lower in children than in adults (RR ratio: 0.65 [95% CI 0.43–0.98], p = 0.004 by metaregression), due to higher withdrawal rate for seizure aggravation in children (5.6%) than in adults (0.7%) receiving placebo (p < 0.001). Finally, there was no significant difference in the seizure-free rate between adult and paediatric studies.
Conclusions
Children with drug-resistant partial epilepsy receiving placebo in double-blind RCTs demonstrated significantly greater 50% responder rate than adults, probably reflecting increased placebo and regression to the mean effects. Paediatric clinical trial designs should account for these age-dependent variations of the response to placebo to reduce the risk of an underestimated sample size that could result in falsely negative trials.
In a systematic review of antiepileptic drugs, Philippe Ryvlin and colleagues find that children with drug-resistant partial epilepsy enrolled in trials seem to have a greater response to placebo than adults enrolled in such trials.
Editors' Summary
Background.
Whenever an adult is given a drug to treat a specific condition, that drug will have been tested in “randomized controlled trials” (RCTs). In RCTs, a drug's effects are compared to those of another drug for the same condition (or to a placebo, dummy drug) by giving groups of adult patients the different treatments and measuring how well each drug deals with the condition and whether it has any other effects on the patients' health. However, many drugs given to children have only been tested in adults, the assumption being that children can safely take the same drugs as adults provided the dose is scaled down. This approach to treatment is generally taken in epilepsy, a common brain disorder in children in which disruptions in the electrical activity of part (partial epilepsy) or all (generalized epilepsy) of the brain cause seizures. The symptoms of epilepsy depend on which part of the brain is disrupted and can include abnormal sensations, loss of consciousness, or convulsions. Most but not all patients can be successfully treated with antiepileptic drugs, which reduce or stop the occurrence of seizures.
Why Was This Study Done?
It is increasingly clear that children and adults respond differently to many drugs, including antiepileptic drugs. For example, children often break down drugs differently from adults, so a safe dose for an adult may be fatal to a child even after scaling down for body size, or it may be ineffective because of quicker clearance from the child's body. Consequently, regulatory bodies around the world now require comprehensive drug development programs in children as well as in adults. However, for pediatric trials to yield useful results, the general differences in the treatment response between children and adults must first be determined and then allowed for in the design of pediatric RCTs. In this study, the researchers investigate whether there is any evidence in published RCTs for age-dependent differences in the response to antiepileptic drugs in drug-resistant partial epilepsy.
What Did the Researchers Do and Find?
The researchers searched the literature for reports of RCTs on the effects of antiepileptic drugs in the add-on treatment of drug-resistant partial epilepsy in children and in adults—that is, trials that compared the effects of giving an additional antiepileptic drug with those of giving a placebo by asking what fraction of patients given each treatment had a 50% reduction in seizure frequency during the treatment period compared to a baseline period (the “50% responder rate”). This “systematic review” yielded 32 RCTs, including five pediatric RCTs. The researchers then compared the treatment effect (the ratio of the 50% responder rate in the treatment arm to the placebo arm) in the two age groups using a statistical approach called “meta-analysis” to pool the results of these studies. The treatment effect, they report, was significantly lower in children than in adults. Further analysis indicated that this difference was because more children than adults responded to the placebo. Nearly 1 in 5 children had a 50% reduction in seizure rate when given a placebo compared to only 1 in 10 adults. About a third of both children and adults had a 50% reduction in seizure rate when given antiepileptic drugs.
What Do These Findings Mean?
These findings, although limited by the small number of pediatric trials done so far, suggest that children with drug-resistant partial epilepsy respond more strongly in RCTs to placebo than adults. Although additional studies need to be done to find an explanation for this observation and to discover whether anything similar occurs in other conditions, this difference between children and adults should be taken into account in the design of future pediatric trials on the effects of antiepileptic drugs, and possibly drugs for other conditions. Specifically, to reduce the risk of false-negative results, this finding suggests that it might be necessary to increase the size of future pediatric trials to ensure that the trials have enough power to discover effects of the drugs tested, if they exist.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050166.
This study is further discussed in a PLoS Medicine Perspective by Terry Klassen and colleagues
The European Medicines Agency provides information about the regulation of medicines for children in Europe
The US Food and Drug Administration Office of Pediatric Therapeutics provides similar information for the US
The UK Medicines and Healthcare products Regulatory Agency also provides information on why medicines need to be tested in children
The MedlinePlus encyclopedia has a page on epilepsy (in English and Spanish)
The US National Institute for Neurological Disorders and Stroke and the UK National Health Service Direct health encyclopedia both provide information on epilepsy for patients (in several languages)
Neuroscience for Kids is an educational Web site prepared by Eric Chudler (University of Washington, Seattle, US) that includes information on epilepsy and a list of links to epilepsy organizations (mainly in English but some sections in other languages as well)
doi:10.1371/journal.pmed.0050166
PMCID: PMC2504483  PMID: 18700812
8.  Systematic permutation testing in GWAS pathway analyses: identification of genetic networks in dilated cardiomyopathy and ulcerative colitis 
BMC Genomics  2014;15:622.
Background
Genome wide association studies (GWAS) are applied to identify genetic loci, which are associated with complex traits and human diseases. Analogous to the evolution of gene expression analyses, pathway analyses have emerged as important tools to uncover functional networks of genome-wide association data. Usually, pathway analyses combine statistical methods with a priori available biological knowledge. To determine significance thresholds for associated pathways, correction for multiple testing and over-representation permutation testing is applied.
Results
We systematically investigated the impact of three different permutation test approaches for over-representation analysis to detect false positive pathway candidates and evaluate them on genome-wide association data of Dilated Cardiomyopathy (DCM) and Ulcerative Colitis (UC). Our results provide evidence that the gold standard - permuting the case–control status – effectively improves specificity of GWAS pathway analysis. Although permutation of SNPs does not maintain linkage disequilibrium (LD), these permutations represent an alternative for GWAS data when case–control permutations are not possible. Gene permutations, however, did not add significantly to the specificity. Finally, we provide estimates on the required number of permutations for the investigated approaches.
Conclusions
To discover potential false positive functional pathway candidates and to support the results from standard statistical tests such as the Hypergeometric test, permutation tests of case control data should be carried out. The most reasonable alternative was case–control permutation, if this is not possible, SNP permutations may be carried out. Our study also demonstrates that significance values converge rapidly with an increasing number of permutations. By applying the described statistical framework we were able to discover axon guidance, focal adhesion and calcium signaling as important DCM-related pathways and Intestinal immune network for IgA production as most significant UC pathway.
doi:10.1186/1471-2164-15-622
PMCID: PMC4223581  PMID: 25052024
DCM; UC; GWAS; Permutation tests; Pathway analysis
9.  Can we rely on the best trial? A comparison of individual trials and systematic reviews 
Background
The ideal evidence to answer a question about the effectiveness of treatment is a systematic review. However, for many clinical questions a systematic review will not be available, or may not be up to date. One option could be to use the evidence from an individual trial to answer the question?
Methods
We assessed how often (a) the estimated effect and (b) the p-value in the most precise single trial in a meta-analysis agreed with the whole meta-analysis. For a random sample of 200 completed Cochrane Reviews (January, 2005) we identified a primary outcome and extracted: the number of trials, the statistical weight of the most precise trial, the estimate and confidence interval for both the highest weighted trial and the meta-analysis overall. We calculated the p-value for the most precise trial and meta-analysis.
Results
Of 200 reviews, only 132 provided a meta-analysis of 2 or more trials, with a further 35 effect estimates based on single trials. The average number of trials was 7.3, with the most precise trial contributing, on average, 51% of the statistical weight to the summary estimate from the whole meta-analysis. The estimates of effect from the most precise trial and the overall meta-analyses were highly correlated (rank correlation of 0.90).
There was an 81% agreement in statistical conclusions. Results from the most precise trial were statistically significant in 60 of the 167 evaluable reviews, with 55 of the corresponding systematic reviews also being statistically significant. The five discrepant results were not strikingly different with respect to their estimates of effect, but showed considerable statistical heterogeneity between trials in these meta-analyses. However, among the 101 cases in which the most precise trial was not statistically significant, the corresponding meta-analyses yielded 31 statistically significant results.
Conclusions
Single most precise trials provided similar estimates of effects to those of the meta-analyses to which they contributed, and statistically significant results are generally in agreement. However, "negative" results were less reliable, as may be expected from single underpowered trials. For systematic reviewers we suggest that: (1) key trial(s) in a review deserve greater attention (2) systematic reviewers should check agreement of the most precise trial and the meta analysis. For clinicians using trials we suggest that when a meta-analysis is not available, a focus on the most precise trial is reasonable provided it is adequately powered.
doi:10.1186/1471-2288-10-23
PMCID: PMC2851704  PMID: 20298582
10.  Assessing Differential Expression in Two-Color Microarrays: A Resampling-Based Empirical Bayes Approach 
PLoS ONE  2013;8(11):e80099.
Microarrays are widely used for examining differential gene expression, identifying single nucleotide polymorphisms, and detecting methylation loci. Multiple testing methods in microarray data analysis aim at controlling both Type I and Type II error rates; however, real microarray data do not always fit their distribution assumptions. Smyth's ubiquitous parametric method, for example, inadequately accommodates violations of normality assumptions, resulting in inflated Type I error rates. The Significance Analysis of Microarrays, another widely used microarray data analysis method, is based on a permutation test and is robust to non-normally distributed data; however, the Significance Analysis of Microarrays method fold change criteria are problematic, and can critically alter the conclusion of a study, as a result of compositional changes of the control data set in the analysis. We propose a novel approach, combining resampling with empirical Bayes methods: the Resampling-based empirical Bayes Methods. This approach not only reduces false discovery rates for non-normally distributed microarray data, but it is also impervious to fold change threshold since no control data set selection is needed. Through simulation studies, sensitivities, specificities, total rejections, and false discovery rates are compared across the Smyth's parametric method, the Significance Analysis of Microarrays, and the Resampling-based empirical Bayes Methods. Differences in false discovery rates controls between each approach are illustrated through a preterm delivery methylation study. The results show that the Resampling-based empirical Bayes Methods offer significantly higher specificity and lower false discovery rates compared to Smyth's parametric method when data are not normally distributed. The Resampling-based empirical Bayes Methods also offers higher statistical power than the Significance Analysis of Microarrays method when the proportion of significantly differentially expressed genes is large for both normally and non-normally distributed data. Finally, the Resampling-based empirical Bayes Methods are generalizable to next generation sequencing RNA-seq data analysis.
doi:10.1371/journal.pone.0080099
PMCID: PMC3842292  PMID: 24312198
11.  Chinese Herbal Medicine for Diabetic Peripheral Neuropathy: An Updated Meta-Analysis of 10 High-Quality Randomized Controlled Studies 
PLoS ONE  2013;8(10):e76113.
Background
Diabetic peripheral neuropathy (DPN) is very common in people with diabetes. Chinese herbal medicine (CHM) therapy has been developed for DPN empirically over the years. The aim of this systematic review and meta-analysis was to assess the efficacy and safety of CHMs for patients suffering from DPN.
Methods
We performed a meta-analysis of randomized-controlled clinical trials (RCTs) evaluating the efficacy and safety of CHM on DPN. Six databases were searched up to November 2012. The primary outcome measures were the absolute values or changing of motor or sensory nerve conduction velocity (NCV), and the secondary outcome measurements were clinical symptoms improvements and adverse events. The methodological quality was assessed by Jadad scale and the twelve criteria recommended by the Cochrane Back Review Group.
Results
One hundred and sixty-three studies claimed RCTs. Ten studies with 653 individuals were further identified based on the Jadad score ≥3. These 10 studies were all of high methodological quality with a low risk of bias. Meta-analysis showed the effects of NCV favoring CHMs when compared with western conventional medicines (WCM) (P<0.05 or P<0.01). There is a significant difference in the total efficacy rate between the two groups (P<0.001). Adverse effects were reported in all of the ten included studies, and well tolerated in all patients with DPN.
Conclusion
Despite of the apparently positive findings and low risk of bias, it is premature to conclude the efficacy of CHMs for the treatment of DPN because of the high clinical heterogeneity and small sample sizes of the included studies. However, CHM therapy was safe for DPN. Further standardized preparation, large sample-size and rigorously designed RCTs are required.
doi:10.1371/journal.pone.0076113
PMCID: PMC3797714  PMID: 24146822
12.  Risk of bias: a simulation study of power to detect study-level moderator effects in meta-analysis 
Systematic Reviews  2013;2:107.
Background
There are both theoretical and empirical reasons to believe that design and execution factors are associated with bias in controlled trials. Statistically significant moderator effects, such as the effect of trial quality on treatment effect sizes, are rarely detected in individual meta-analyses, and evidence from meta-epidemiological datasets is inconsistent. The reasons for the disconnect between theory and empirical observation are unclear. The study objective was to explore the power to detect study level moderator effects in meta-analyses.
Methods
We generated meta-analyses using Monte-Carlo simulations and investigated the effect of number of trials, trial sample size, moderator effect size, heterogeneity, and moderator distribution on power to detect moderator effects. The simulations provide a reference guide for investigators to estimate power when planning meta-regressions.
Results
The power to detect moderator effects in meta-analyses, for example, effects of study quality on effect sizes, is largely determined by the degree of residual heterogeneity present in the dataset (noise not explained by the moderator). Larger trial sample sizes increase power only when residual heterogeneity is low. A large number of trials or low residual heterogeneity are necessary to detect effects. When the proportion of the moderator is not equal (for example, 25% ‘high quality’, 75% ‘low quality’ trials), power of 80% was rarely achieved in investigated scenarios. Application to an empirical meta-epidemiological dataset with substantial heterogeneity (I2 = 92%, τ2 = 0.285) estimated >200 trials are needed for a power of 80% to show a statistically significant result, even for a substantial moderator effect (0.2), and the number of trials with the less common feature (for example, few ‘high quality’ studies) affects power extensively.
Conclusions
Although study characteristics, such as trial quality, may explain some proportion of heterogeneity across study results in meta-analyses, residual heterogeneity is a crucial factor in determining when associations between moderator variables and effect sizes can be statistically detected. Detecting moderator effects requires more powerful analyses than are employed in most published investigations; hence negative findings should not be considered evidence of a lack of effect, and investigations are not hypothesis-proving unless power calculations show sufficient ability to detect effects.
doi:10.1186/2046-4053-2-107
PMCID: PMC4219184  PMID: 24286208
Meta-analysis; Power; Heterogeneity; Meta-epidemiological dataset; Randomized controlled trial (RCT)
13.  Effect of Treatment of Obstructive Sleep Apnea on Depressive Symptoms: Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(11):e1001762.
In a meta-analysis of randomized controlled trials, Matthew James and colleagues investigate the effects of continuous positive airway pressure or mandibular advancement devices on depression.
Please see later in the article for the Editors' Summary
Background
Obstructive sleep apnea (OSA) is associated with increased morbidity and mortality, and decreased quality of life. Treatment with continuous positive airway pressure (CPAP) or mandibular advancement devices (MADs) is effective for many symptoms of OSA. However, it remains controversial whether treatment with CPAP or MAD also improves depressive symptoms.
Methods and Findings
We performed a systematic review and meta-analysis of randomized controlled trials that examined the effect of CPAP or MADs on depressive symptoms in patients with OSA. We searched Medline, EMBASE, the Cochrane Central Registry of Controlled Trials, and PsycINFO from the inception of the databases until August 15, 2014, for relevant articles.
In a random effects meta-analysis of 19 identified trials, CPAP treatment resulted in an improvement in depressive symptoms compared to control, but with significant heterogeneity between trials (Q statistic, p<0.001; I2 = 71.3%, 95% CI: 54%, 82%). CPAP treatment resulted in significantly greater improvement in depressive symptoms in the two trials with a higher burden of depression at baseline (meta-regression, p<0.001). The pooled standardized mean difference (SMD) in depressive symptoms with CPAP treatment in these two trial populations with baseline depression was 2.004 (95% CI: 1.387, 2.621), compared to 0.197 (95% CI: 0.059, 0.334) for 15 trials of populations without depression at baseline. Pooled estimates of the treatment effect of CPAP were greater in parallel arm trials than in crossover trials (meta-regression, p = 0.076). Random effects meta-analysis of five trials of MADs showed a significant improvement in depressive symptoms with MADs versus controls: SMD = 0.214 (95% CI: 0.026, 0.401) without significant heterogeneity (I2 = 0%, 95% CI: 0%, 79%). Studies were limited by the use of depressive symptom scales that have not been validated specifically in people with OSA.
Conclusions
CPAP and MADs may be useful components of treatment of depressive symptoms in individuals with OSA and depression. The efficacy of CPAP and MADs compared to standard therapies for depression is unknown.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Obstructive sleep apnea (OSA) is a sleep-related breathing disorder that is particularly common among middle-aged and elderly people, although most are unaware that they have the condition. It is characterized by the occurrence of numerous brief (ten seconds or so) breathing interruptions during sleep. These “apneas” occur when relaxation of the upper airway muscles decreases airflow, which lowers the level of oxygen in the blood. Consequently, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of OSA include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Mild to moderate OSA can also be treated using a mandibular advancement device (MAD), a “splint” that fits inside the mouth and pushes the jaw and tongue forward to increase the space at the back of the throat and reduce airway narrowing. For severe OSA, doctors recommend continuous positive airway pressure (CPAP), in which a machine blows pressurized air into the airway through a facemask to keep it open.
Why Was This Study Done?
OSA is a serious condition that is associated with an increased risk of illness and death. Clinical depression (long-lasting, overwhelming feelings of sadness and hopelessness), for example, is common among people with OSA. The interaction between these frequently co-morbid (co-existing) conditions is complex. The sleep disruption and weight gain that are often associated with depression could cause or worsen OSA. Conversely, OSA could trigger depression by causing sleep disruption and by inducing cognitive changes (changes in thinking) by intermittently starving the brain of oxygen. If the latter scenario is correct, then treating OSA with CPAP or MADs might improve depressive symptoms. Several trials have investigated this possibility, but their results have been equivocal. Here, the researchers undertake a systematic review and meta-analysis of randomized controlled trials that have examined the effect of CPAP or MADs on depressive symptoms in patients with OSA to find out whether treating co-morbid OSA in patients with depression can help to treat depression. A randomized controlled trial compares the outcomes of individuals chosen to receive different interventions through the play of chance, a systematic review uses predefined criteria to identify all the research on a given topic, and meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 22 trials that investigated the effects of CPAP or MAD treatment in patients with OSA and that measured depressive symptoms before and after treatment. Meta-analysis of the results of 19 trials that provided information about the effect of CPAP on depressive symptoms indicated that CPAP improved depressive symptoms compared to the control intervention (usually sham CPAP) but revealed considerable heterogeneity (variability) between trials. Notably, CPAP treatment resulted in a greater improvement in depressive symptoms in trials in which there was a high prevalence of depression at baseline than in trials in which there was a low prevalence of depression at baseline. Moreover, the magnitude of this improvement in depressive symptoms in trials with a high prevalence of depression at baseline was large enough to be clinically relevant. Meta-analysis of five trials that provided information about the effect of MADs on depressive symptoms indicated that MADs also improved depressive symptoms compared to the control intervention (sham MAD).
What Do These Findings Mean?
These findings suggest that both CPAP and MAD treatment for OSA can result in modest improvements in depressive symptoms and that populations with high initial levels of depressive symptoms may reap the greatest benefits of CPAP treatment. These findings give no indication of the efficacy of CPAP and MADs compared to standard treatments for depression such as antidepressant medications. Moreover, their accuracy may be limited by methodological limitations within the trials included in the meta-analyses reported here. For example, the questionnaires used to measure depression in these trials were not validated for use in people with OSA. Further high-quality randomized controlled trials are therefore needed to confirm the findings of this systematic review and meta-analysis. For now, however, these findings suggest that the use of CPAP and MADs may help improve depressive symptoms among people with OSA.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001762.
The US National Heart, Lung, and Blood Institute has information (including several videos) about sleep apnea (in English and Spanish)
The UK National Health Service Choices website provides information and personal stories about obstructive sleep apnea and depression
The not-for-profit American Sleep Apnea Association provides detailed information about sleep apnea for patients and healthcare professionals, including personal stories about the condition
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish)
The Anxiety and Depression Association of America provides information about sleep disorders
The MedlinePlus encyclopedia has a page on obstructive sleep apnea; MedlinePlus provides links to further information and advice about obstructive sleep apnea and about depression (in English and Spanish)
doi:10.1371/journal.pmed.1001762
PMCID: PMC4244041  PMID: 25423175
14.  Intra-Articular Viscosupplementation With Hylan G-F 20 To Treat Osteoarthritis of the Knee 
Executive Summary
Objective
To assess the effectiveness and cost-effectiveness of hylan G-F 20 as a substitute for existing treatments for pain due to osteoarthritis (OA) of the knee, other viscosupplementation devices, and/or as an adjunct to conventional therapy.
Hylan G-F 20 (brand name Synvisc, which is manufactured by Genzyme) is a high molecular weight derivative of hyaluronan, a component of joint synovial fluid. It acts as a lubricant and shock absorber. It is administered by injection into the joint space to treat pain associated with OA of the knee. Although the injection procedure is an insured service in Ontario, the device, hylan G-F 20, is not.
Clinical Need
Osteoarthritis is prevalent in 10% to 12% of Ontario adults, and exceeds 40% in Ontario residents aged 65 years and older. About one-half of these people have mild, moderate, or severe OA of the knee. Conventional treatment involves a combination of nonpharmacological management (e.g., weight loss, exercise, social support, and patient education), drugs, (e.g., acetaminophen, COX-2 inhibitors, nonsteroidal anti-inflammatory drugs with/without misoprostol, intra-articular glucocorticoids, opioids, and topical analgesics) and surgical interventions, such as debridement and total knee replacement, when pharmacological management fails.
The growing burden of OA of the knee in the aging Ontario population combined with recent safety concerns about COX-2 inhibitors and long wait times for total joint replacement is placing pressure on the demand for new, effective technologies to manage the pain of OA.
The Technology
Hylan G-F 20 is derived from rooster comb hyaluronan (HA). At the time of writing, eight viscosupplement hyaluronic products are licensed in Canada. Hylan G-F 20 is distinguished from the other products by its chemical structure (i.e., cross-linked hyaluronan, hence hylan) and relatively higher molecular weight, which may bestow greater therapeutic viscoelastic properties. A complete treatment cycle of hylan G-F 20 involves an intra-articular injection of 2 ml of hylan G-F 20 once a week for 3 weeks. It is licensed for use for patients in all stages of joint pathology, but should not be used in infected or severely inflamed joints, in joints with large effusion, in patients that have skin diseases or infections in the area of the injection site, or in patients with venous stasis. It is also contraindicated in patients with hypersensitivities to avian proteins.
Review Strategy
The Medical Advisory Secretariat used its standard search protocol to review the literature for evidence on the effectiveness of intra-articular hylan G-F 20 compared with placebo, as a substitute for alternate active treatments, or as an adjunct to conventional care for treatment of the pain of OA of the knee. All English-language journal articles and reviews with clearly described designs and methods (i.e., those sufficient to assign a Jadad score to) published or released between 1966 and February 2005 were included. Two more recently published meta-analyses were also included. The databases searched were Ovid MEDLINE, EMBASE, the Cochrane database and leading international organizations for health technology assessments, including the International Network of Agencies for Health Technology Assessments. The search terms were as follows: hyaluronan, hyaluronate adj sodium, hylan, hylan G-F 20 (Synvisc), Synvisc, Hyalgan, Orthovisc, Supartz, Artz, Artzal, BioHY, NASHA, NRD101, viscosupplementation, osteoarthritis, knee, knee joint. The primary outcome of interest was a clinically significant difference, defined as greater than 10 mm on 100 mm visual analogue scale, or a change from baseline of more than 20% in the mean magnitude of pain relief experienced among patients treated with hylan G-F 20 compared with those treated with the control intervention.
One clinical epidemiologist reviewed the full-text reports and extracted data using an extraction form. Key variables included, but were not limited to, the characteristics of the patients, method of randomization, type of control intervention, outcome measures for effectiveness and safety, and length of follow-up. The quality of the studies and level of the evidence was initially scored by one clinical epidemiologist using the Jadad scale and GRADE approach. Level of quality depends on the amount of certainty about the magnitude of effect and is based on study designs, extent of methodological limitations, consistency of results and applicability (i.e. directness) to the Ontario clinical context. The GRADE approach also permits comment on the strength of recommendations resulting from the evidence, based on estimates of the magnitude of effect relative to the magnitude of risk and burden and the level of certainty around these estimates. The quality assessments were subsequently peer-reviewed.
Summary of Findings
The literature search revealed 2 previous health technology assessments, 3 meta-analyses of placebo-controlled trials, 1 Cochrane review and meta-analysis encompassing 18 randomized controlled trials (RCTs) that compared hylan G-F 20 to either placebo or active treatments, 11 RCTs of hylan G-F 20 (all included in the Cochrane review), and 10 observational studies. Given the preponderance of evidence, the Medical Advisory Secretariat’s analysis focused on studies with Level 1 evidence of effectiveness (i.e., the meta-analyses of RCTs and the RCTs). Only safety data from the observational studies were included.
The authors of the 2 health technology assessments concluded that the data were sparse and poor quality. There was some evidence that hylan G-F 20 delivered a small, clinical benefit at 3 to 6 months after treatment on a magnitude comparable to NSAIDs and intra-articular steroids. Hylan G-F 20 appeared to carry a risk of a local adverse reaction of in the range of 3% to 18% per 100 injections, but there was no apparent risk of a severe adverse event, although the data were limited.
Each of the 3 meta-analyses of placebo-controlled trials of intra-articular hyaluronans had only 3 trials involving hylan G-F 20. There results were inconsistent, with one study concluding that intra-articular hyaluronans were efficacious, whereas the 2 other analyses concluded the effect size was small (0.32) and probably not clinically significant. The risk of a minor adverse event ranged from 8% to 19% per 100 injections. Major adverse events were rare.
The authors of the Cochrane review concluded that a pooled analysis supported the efficacy of hyaluronans, including hylan G-F 20. The 5- to 13-week post-injection period showed an improvement from baseline of 11% to 54% for pain and 9% to 15% for function. Comparable efficacy was noted against NSAIDs, and longer-term benefits were noted in against steroids. Few adverse events were noted.
When the Medical Advisory Secretariat applied the criterion of clinical significance to the magnitude of pain relief reported in the RCTs on hylan G-F 20, the following was noted:
There was inconsistent evidence that hylan G-F 20 was clinically superior to placebo at 5 to 26 weeks after treatment.
There was consistent evidence that, in terms of delivering pain relief, hylan G-F 20 was no better or worse than NSAIDs or intra-articular steroids at 5 to 26 weeks after treatment.
There was consistent evidence that hylan G-F 20 was not clinically superior to other hyaluronic products.
There was consistent evidence that hylan G-F 20 delivered a small magnitude of clinical benefit at 12 to 52 weeks post-injection when administered as an adjunct to conventional care.
There were limitations to the methods in many of the RCTs involving hylan G-F 20. When only the results from the higher-quality studies were considered, there was level 2 evidence that hylan G-F 20 was not clinically superior to placebo (or another hyaluronan) at 1 to 26 weeks after treatment in older patients with advanced disease for whom total knee replacement was indicated. There was level 2 evidence that hylan G-F 2- was comparable to NSAIDs at 4 to 13 weeks after treatment, and level 2 evidence that hylan G-F 20 was superior to placebo as an adjunct to conventional care 4 to 26 weeks after treatment.
With respect to safety, overall, hylan G-F 20 carries a risk of a minor, local adverse event rate of about 8% to 19% per 100 injections. Incidents of moderate-severe post-injection inflammatory joint reactions have been reported, but the likelihood appears to be low (0.15% of patients).
Economic Analysis
Case-costing estimates suggest that the annual cost of 2 treatment cycles of hylan G-F 20 (plus analgesics for breakthrough pain) is almost equivalent to the annual cost of taking a NSAID (with a gastroprotective agent) and is more expensive that taking intra-articular corticosteroids (plus analgesics for breakthrough pain). The estimated cost of funding hylan G-F 20 as an adjunct to conventional therapy (i.e., any of analgesics, NSAIDs, intra-articular steroids, physiotherapy, and surgery) is $700 per patient per year. Given the huge burden of mild to moderate OA among adults who seek medical care for it in Ontario (about 300,000), funding hylan G-F 20 as an adjunct to existing treatment could be expensive, depending on its diffusion and uptake. If only 10% to 30% of patients choose this option, then the estimated budget impact would be $21 million to $63 million (Cdn) per year.
Conclusions
When the benefits relative to the risks and costs are considered, NSAIDs and hylan G-F 20 appear comparable, as the table shows. Consequently, there’s little evidence on which to recommend hylan G-F 20 over NSAIDs, except perhaps for patients who cannot tolerate NSAIDs, although this evidence is indirect, since no studies looked specifically at this population.
CC indicates conventional care; IA, intra-articular; NSAID, nonsteroidal anti-inflammatory drug.
Intra-articular steroids appear to deliver the same risks and clinical benefits as hylan G-F 20 at a lower cost; therefore, there’s evidence that intra-articular steroids are the preferred option. Hylan G-F 20 as an adjunct to conventional care appears to deliver some clinical benefit, although funding hylan G-F 20 as an adjunct would have considerable budget impact, so the benefits of this option do not clearly outweigh the costs. There’s some uncertainty about the effect of hylan G-F 20 relative to other hyaluronans, mostly because some of the trials of this comparison were not published.
Many of the studies of hylan G-F 20 have considerable methodological limitations that result in uncertainty about the magnitude of effect. An upcoming review of the evidence by the Osteoarthritis Advisory Panel of clinical experts will likely help to reduce some of this uncertainty.
There is moderate evidence that hylan G-F 20 is no more clinically effective than NSAIDs. The evidence that hylan G-F 20 might be an appropriate option for a person with OA of the knee who cannot tolerate NSAIDs is indirect. The possible benefit of fewer cases of NSAID-induced gastropathy in this population must be weighed against the uncertainty of a severe inflammatory adverse reaction to hylan G-F 20.
Similarly, there is moderate evidence that hylan G-F 20 is no more clinically effective than intra-articular corticosteroids. The lower cost of intra-articular corticosteroids makes them the preferred option.
There is moderate evidence that hylan G-F 20 is effective as an adjunct to conventional care, delivering a small magnitude of temporary relief at 4 to 26 weeks after treatment. The estimated additional cost to the system of providing hylan G-F 20 as an adjunct to conventional care is about $700 (Cdn) per patient annually. The magnitude and duration of clinical benefit of hylan G-F 20 must be weighed against the uncertainty and potential magnitude of the budget impact (about $35 million to $105 million (Cdn) per year) of funding this device given the high burden of OA in Ontario adults.
There is level 2 evidence that hylan G-F 20 is not effective in people with advanced OA for whom total knee replacement is indicated.
PMCID: PMC3382385  PMID: 23074461
15.  ROAST: rotation gene set tests for complex microarray experiments 
Bioinformatics  2010;26(17):2176-2182.
Motivation: A gene set test is a differential expression analysis in which a P-value is assigned to a set of genes as a unit. Gene set tests are valuable for increasing statistical power, organizing and interpreting results and for relating expression patterns across different experiments. Existing methods are based on permutation. Methods that rely on permutation of probes unrealistically assume independence of genes, while those that rely on permutation of sample are suitable only for two-group comparisons with a good number of replicates in each group.
Results: We present ROAST, a statistically rigorous gene set test that allows for gene-wise correlation while being applicable to almost any experimental design. Instead of permutation, ROAST uses rotation, a Monte Carlo technology for multivariate regression. Since the number of rotations does not depend on sample size, ROAST gives useful results even for experiments with minimal replication. ROAST allows for any experimental design that can be expressed as a linear model, and can also incorporate array weights and correlated samples. ROAST can be tuned for situations in which only a subset of the genes in the set are actively involved in the molecular pathway. ROAST can test for uni- or bi-direction regulation. Probes can also be weighted to allow for prior importance. The power and size of the ROAST procedure is demonstrated in a simulation study, and compared to that of a representative permutation method. Finally, ROAST is used to test the degree of transcriptional conservation between human and mouse mammary stems.
Availability: ROAST is implemented as a function in the Bioconductor package limma available from www.bioconductor.org
Contact: smyth@wehi.edu.au
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq401
PMCID: PMC2922896  PMID: 20610611
16.  Types of intraocular lenses for cataract surgery in eyes with uveitis 
Background
Cataract formation often occurs in people with uveitis. It is unclear which intraocular lens (IOL) type is optimal for use in cataract surgery for eyes with uveitis.
Objectives
To summarize the effects of different IOLs on visual acuity, other visual outcomes, and quality of life in people with uveitis.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2013), EMBASE (January 1980 to August 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to August 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 14 August 2013. We also performed forward and backward searching using the Science Citation Index and the reference lists of the included studies, respectively, in August 2013.
Selection criteria
We included randomized controlled trials (RCTs) comparing hydrophobic or hydrophilic acrylic, silicone, or poly(methyl methacrylate) (PMMA) IOLs with or without heparin-surface modification (HSM), with each other, or with no treatment in adults with uveitis, for any indication, undergoing cataract surgery.
Data collection and analysis
We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors screened the search results and for included studies, assessed the risk of bias and extracted data independently. We contacted study investigators for additional information. We did not perform a meta-analysis due to variability in reporting and follow-up intervals for the primary and secondary outcomes of interest.
Main results
We included four RCTs involving 216 participants (range of 2 to 140 participants with uveitic cataract per trial) and comparing up to four types of IOLs. The largest study was an international study with centers in Brazil, Egypt, Finland, France, Japan, the Netherlands, Slovak Republic, Spain, and the USA; two studies were conducted in Germany and one in Saudi Arabia. There was substantial heterogeneity with respect to the ages of participants and etiologies of uveitis within and across studies. The length of follow-up among the studies ranged from 1 to 24 months after cataract surgery. The studies were at low risk of selection bias, but two of the four studies did not employ masking and only one study included all randomized participants in the final analyses. The funding source was disclosed by investigators of the largest study (professional society) and not reported by the other three. Due to heterogeneity in lens types evaluated and outcomes reported among the trials, we did not combine data in a meta-analysis.
In the largest study (140 participants), the study eye of each participant was randomized to receive one of four types of IOLs: hydrophobic acrylic, silicone, HSM PMMA, or unmodified PMMA. Proportions of participants with one or more Snellen lines of visual improvement were similar among the four treatment groups at one year' follow-up: 45 of 48 (94%) in the hydrophobic acrylic IOL group, 39 of 44 (89%) in the silicone IOL group, 18 of 22 (82%) in the HSM PMMA IOL group, and 22 of 26 (85%) in the unmodified PMMA IOL group. When comparing hydrophobic acrylic IOLs with silicone IOLs, the risk ratio (RR) was 1.06 (95% confidence interval (CI) 0.93 to 1.20). At one year' follow-up, fewer eyes randomized to hydrophobic acrylic IOLs developed posterior synechiae when compared with eyes receiving silicone IOLs (RR 0.18, 95% CI 0.04 to 0.79); the effects between these groups were less certain with respect to developing posterior capsule opacification (PCO) (RR 0.74, 95% CI 0.41 to 1.37), corneal edema (RR 0.49, 95% CI 0.22 to 1.12), cystoid macular edema (RR 0.10, 95% CI 0.01 to 1.84), or mild IOL decentration (RR 0.92, 95% CI 0.06 to 14.22).
Two intra-individual studies also compared HSM PMMA IOLs with unmodified PMMA IOLs at three or six months of follow-up. These studies, including a combined total of 16 participants with uveitis, were insufficiently powered to detect differences in outcomes among eyes of people with uveitis randomized to receive HSM PMMA IOLs when compared with fellow eyes receiving unmodified PMMA IOLs.
In the fourth study (60 participants), the study eye of each participant was randomized to receive a hydrophobic or hydrophilic acrylic IOL. At three months, there were no statistical or clinical differences between hydrophobic and hydrophilic acrylic IOL types in the proportions of participants with two or more Snellen lines of visual improvement (RR 1.03, 95% CI 0.87 to 1.22). There were similar rates in the development of PCO between hydrophobic or hydrophilic acrylic IOLs at six months' follow-up (RR 1.00, 95% CI 0.80 to 1.25). The effect of the lenses on posterior synechiae was uncertain at six months' follow-up (RR 0.50, 95% CI 0.05 to 5.22).
None of the included studies reported quality of life outcomes.
Authors' conclusions
Based on the trials identified in this review, there is uncertainty as to which type of IOL provides the best visual and clinical outcomes in people with uveitis undergoing cataract surgery. The studies were small, not all lens materials were compared in all studies, and not all lens materials were available in all study sites. Evidence of a superior effect of hydrophobic acrylic lenses over silicone lenses, specifically for posterior synechiae outcomes comes from a single study at a high risk of performance and detection bias. However, due to small sample sizes and heterogeneity in outcome reporting, we found insufficient information to assess these and other types of IOL materials for cataract surgery for eyes with uveitis.
doi:10.1002/14651858.CD007284.pub2
PMCID: PMC4261623  PMID: 24590672
17.  Activation Likelihood Estimation meta-analysis revisited 
Neuroimage  2011;59(3):2349-2361.
A widely used technique for coordinate-based meta-analysis of neuroimaging data is activation likelihood estimation (ALE), which determines the convergence of foci reported from different experiments. ALE analysis involves modelling these foci as probability distributions whose width is based on empirical estimates of the spatial uncertainty due to the between-subject and between-template variability of neuroimaging data. ALE results are assessed against a null-distribution of random spatial association between experiments, resulting in random-effects inference. In the present revision of this algorithm, we address two remaining drawbacks of the previous algorithm. First, the assessment of spatial association between experiments was based on a highly time-consuming permutation test, which nevertheless entailed the danger of underestimating the right tail of the null-distribution. In this report, we outline how this previous approach may be replaced by a faster and more precise analytical method. Second, the previously applied correction procedure, i.e. controlling the false discovery rate (FDR), is supplemented by new approaches for correcting the family-wise error rate and the cluster-level significance. The different alternatives for drawing inference on meta-analytic results are evaluated on an exemplary dataset on face perception as well as discussed with respect to their methodological limitations and advantages. In summary, we thus replaced the previous permutation algorithm with a faster and more rigorous analytical solution for the null-distribution and comprehensively address the issue of multiple-comparison corrections. The proposed revision of the ALE-algorithm should provide an improved tool for conducting coordinate-based meta-analyses on functional imaging data.
doi:10.1016/j.neuroimage.2011.09.017
PMCID: PMC3254820  PMID: 21963913
fMRI; PET; permutation; inference; cluster-thresholding
18.  Psychosocial Interventions for Perinatal Common Mental Disorders Delivered by Providers Who Are Not Mental Health Specialists in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(10):e1001541.
In a systematic review and meta-analysis, Kelly Clarke and colleagues examine the effect of psychosocial interventions delivered by non–mental health specialists for perinatal common mental disorders in low- and middle-income countries.
Please see later in the article for the Editors' Summary
Background
Perinatal common mental disorders (PCMDs) are a major cause of disability among women. Psychosocial interventions are one approach to reduce the burden of PCMDs. Working with care providers who are not mental health specialists, in the community or in antenatal health care facilities, can expand access to these interventions in low-resource settings. We assessed effects of such interventions compared to usual perinatal care, as well as effects of interventions based on intervention type, delivery method, and timing.
Methods and Findings
We conducted a systematic review, meta-analysis, and meta-regression. We searched databases including Embase and the Global Health Library (up to 7 July 2013) for randomized and non-randomized trials of psychosocial interventions delivered by non-specialist mental health care providers in community settings and antenatal health care facilities in low- and middle-income countries. We pooled outcomes from ten trials for 18,738 participants. Interventions led to an overall reduction in PCMDs compared to usual care when using continuous data for PCMD symptomatology (effect size [ES] −0.34; 95% CI −0.53, −0.16) and binary categorizations for presence or absence of PCMDs (odds ratio 0.59; 95% CI 0.26, 0.92). We found a significantly larger ES for psychological interventions (three studies; ES −0.46; 95% CI −0.58, −0.33) than for health promotion interventions (seven studies; ES −0.15; 95% CI −0.27, −0.02). Both individual (five studies; ES −0.18; 95% CI −0.34, −0.01) and group (three studies; ES −0.48; 95% CI −0.85, −0.11) interventions were effective compared to usual care, though delivery method was not associated with ES (meta-regression β coefficient −0.11; 95% CI −0.36, 0.14). Combined group and individual interventions (based on two studies) had no benefit compared to usual care, nor did interventions restricted to pregnancy (three studies). Intervention timing was not associated with ES (β 0.16; 95% CI −0.16, 0.49). The small number of trials and heterogeneity of interventions limit our findings.
Conclusions
Psychosocial interventions delivered by non-specialists are beneficial for PCMDs, especially psychological interventions. Research is needed on interventions in low-income countries, treatment versus preventive approaches, and cost-effectiveness.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Perinatal common mental health disorders are among the most common health problems in pregnancy and the postpartum period. In low- and middle-income countries, about 16% of women during pregnancy and about 20% of women in the postpartum period will suffer from a perinatal common mental health disorder. These disorders, including depression and anxiety, are a major cause of disability in women and have been linked to young children under their care being underweight and stunted.
Why Was This Study Done?
While research shows that both pharmacological (e.g., antidepressants or anti-anxiety medications) and non-pharmacological (e.g., psychotherapy, education, or health promotion) interventions are effective for preventing and treating perinatal common mental disorders, most of this research took place in high-income countries. These findings may not be applicable in low-resource settings, where there is limited access to mental health care providers such as psychiatrists and psychologists, and to medications. Thus, non-pharmacological interventions delivered by providers who are not mental health specialists may be important as ways to treat perinatal common mental health disorders in these types of settings. In this study the researchers systematically reviewed research estimating the effectiveness of non-pharmacological interventions for perinatal common mental disorders that were delivered by providers who were not mental health specialists (including health workers, lay persons, and doctors or midwives) in low- and middle-income countries. The researchers also used meta-analysis and meta-regression—statistical methods that are used to combine the results from multiple studies—to estimate the relative effects of these interventions on mental health symptoms.
What Did the Researchers Do and Find?
The researchers searched multiple databases using key search terms to identify randomized and non-randomized clinical trials. Using specific criteria, the researchers retrieved and assessed 37 full papers, of which 11 met the criteria for their systematic review. Seven of these studies were from upper middle-income countries (China, South Africa, Columbia, Mexico, Argentina, Cuba, and Brazil), and four trials were from the lower middle-income countries of Pakistan and India, but there were no trials from low-income countries. The researchers assessed the quality of the selected studies, and one study was excluded from meta-analysis because of poor quality.
Combining results from the ten remaining studies, the researchers found that compared to usual perinatal care (which in most cases included no mental health care), interventions delivered by a providers who were not mental health specialists were associated with an overall reduction in mental health symptoms and the likelihood of being diagnosed with a mental health disorder. The researchers then performed additional analyses to assess relative effects by intervention type, timing, and delivery mode. They observed that both psychological interventions, such as psychotherapy and cognitive behavioral therapy, and health promotion interventions that were less focused on mental health led to significant improvement in mental health symptoms, but psychological interventions were associated with greater effects than health promotion interventions. Interventions delivered both during pregnancy and postnatally were associated with significant benefits when compared to usual care; however, when interventions were delivered during pregnancy only, the benefits were not significantly greater than usual care. When investigating mode of delivery, the researchers observed that both group and individual interventions were associated with improvements in symptoms.
What Do These Findings Mean?
These findings indicate that non-pharmacological interventions delivered by providers who are not mental health specialists could be useful for reducing symptoms of perinatal mental health disorders in middle-income countries. However, these findings should be interpreted with caution given that they are based on a small number of studies with a large amount of variation in the study designs, settings, timing, personnel, duration, and whether the intervention was delivered to a group, individually, or both. Furthermore, when the researchers excluded studies of the lowest quality, the observed benefits of these interventions were smaller, indicating that this analysis may overestimate the true effect of interventions. Nevertheless, the findings do provide support for the use of non-pharmacological interventions, delivered by non-specialists, for perinatal mental health disorders. Further studies should be undertaken in low-income countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001541
The World Health Organization provides information about perinatal mental health disorders
The UK Royal College of Psychiatrists has information for professionals and patients about perinatal mental health disorders
doi:10.1371/journal.pmed.1001541
PMCID: PMC3812075  PMID: 24204215
19.  Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis 
PLoS Medicine  2009;6(9):e1000150.
Performing a systematic review of studies evaluating retreatment of tuberculosis or treatment of isoniazid mono-resistant infection, Dick Menzies and colleagues find a paucity of evidence to support the WHO-recommended regimen.
Background
A standardized regimen recommended by the World Health Organization for retreatment of active tuberculosis (TB) is widely used, but treatment outcomes are suspected to be poor. We conducted a systematic review of published evidence of treatment of patients with a history of previous treatment or documented isoniazid mono-resistance.
Methods and Findings
PubMed, EMBASE, and the Cochrane Central database for clinical trials were searched for randomized trials in previously treated patients and/or those with with mono-resistance to isoniazid, published in English, French, or Spanish between 1965 and June 2008. The first two sources were also searched for cohort studies evaluating specifically the current retreatment regimen. In studies selected for inclusion, rifampin-containing regimens were used to treat patients with bacteriologically confirmed pulmonary TB, in whom bacteriologically confirmed failure and/or relapse had been reported. Pooled cumulative incidences and 95% CIs of treatment outcomes were computed with random effects meta-analyses and negative binomial regression. No randomized trials of the currently recommended retreatment regimen were identified. Only six cohort studies were identified, in which failure rates were 18%–44% in those with isoniazid resistance. In nine trials, using very different regimens in previously treated patients with mono-resistance to isoniazid, the combined failure and relapse rates ranged from 0% to over 75%. From pooled analysis of 33 trials in 1,907 patients with mono-resistance to isoniazid, lower failure, relapse, and acquired drug resistance rates were associated with longer duration of rifampin, use of streptomycin, daily therapy initially, and treatment with a greater number of effective drugs.
Conclusions
There are few published studies to support use of the current standardized retreatment regimen. Randomized trials of treatment of persons with isoniazid mono-resistance and/or a history of previous TB treatment are urgently needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, nearly ten million people develop tuberculosis—a contagious infection, usually of the lungs—and about 2 million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with the disease cough or sneeze. Its symptoms include a persistent cough, fever, weight loss, and night sweats. Diagnostic tests for tuberculosis include chest X-rays and sputum slide exams and cultures in which bacteriologists try to grow M. tuberculosis from mucus brought up from the lungs by coughing. The disease can be cured by taking several powerful antibiotics regularly (daily or several times a week) for at least 6 months. However, 10%–20% of patients treated for tuberculosis in low- and middle-income countries need re-treatment because the initial treatment fails to clear M. tuberculosis from their body or because their disease returns after they have apparently been cured (treatment relapse). Patients who need re-treatment are often infected with bacteria that are resistant to one or more of the antibiotics commonly used to treat tuberculosis.
Why Was This Study Done?
As part of its strategy to reduce the global burden of tuberculosis, the World Health Organization (WHO) recommends standardized treatment regimens for tuberculosis. For re-treatment, WHO recommends an 8-month course of isoniazid, rifampin, and ethambutol with pyrazinamide and streptomycin added for the first 3 and 2 months, respectively. All these drugs are given daily (the preferred regimen) or three times a week. Unfortunately, although this regimen is now used to treat about 1 million patients each year, it yields poor results, particularly in regions where drug resistance is common. In this study (which was commissioned by WHO to provide the evidence needed for a revision of its treatment guidelines), the researchers undertake a systematic review (a search using specific criteria to identify relevant research studies, which are then appraised) and a meta-analysis (a statistical approach that pools the results of several studies) of randomized trials and cohort studies (two types of study that investigate the efficacy of medical interventions) of re-treatment regimens in previously treated tuberculosis patients, and in patients with infection that was resistant to isoniazid (“mono-resistance”).
What Did the Researchers Do and Find?
The researchers' systematic search for published reports of randomized trials and cohort studies of the currently recommended re-treatment regimen identified no relevant randomized trials and only six cohort studies. In the three cohort studies in which the participants carried M. tuberculosis strains that were sensitive to all the antibiotics in the regimen, failure rates were generally low. However, in the studies in which the participants carried drug-resistant bacteria, failure rates ranged from 9% to 45%. The researchers also identified and analyzed the results of nine trials in which several re-treatment regimens, all of which deviated from the standardized regimen, were used in previously treated patients with isoniazid mono-resistance. In these trials, the combined failure and relapse rates ranged from 0% to more than 75%. Finally, the researchers analyzed the pooled results of 33 trials that investigated the effect of various regimens on nearly 2,000 patients (some receiving their first treatment for tuberculosis, some being re-treated) with isoniazid mono-resistance. This meta-analysis showed that lower relapse, failure, and acquired drug resistance rates were associated with longer duration of rifampicin treatment, use of streptomycin, daily therapy early in the treatment, and regimens that included a greater number of drugs to which the M. tuberculosis carried by the patient were sensitive.
What Do These Findings Mean?
These findings reveal that there is very little published evidence that supports the regimen currently recommended by WHO for the re-treatment of tuberculosis. Furthermore, this limited body of evidence is a patchwork of results gleaned from a few cohort studies and a set of randomized trials not specifically designed to test the efficacy of the standardized regimen. There is an urgent need, therefore, for a concerted international effort to initiate randomized trials of potential treatment regimens in both previously untreated and previously treated patients with all forms of drug-resistant tuberculosis. Because these trials will take some time to complete, the limited findings of the meta-analysis presented here may be used in the meantime to redesign and, hopefully, improve the current standardized re-treatment regimen. In fact, the revised WHO TB treatment guidelines will provide updated recommendations for patients with previously treated TB.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000150.
The results of another WHO-commissioned study into the treatment of tuberculosis are presented in a separate PLoS Medicine Research Article by Menzies et al. (Menzies D, Benedetti A, Paydar A, Martin I, Royce S, et al. (2009) Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis. PLoS Med 6(9): e1000146.)
The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis
The American Thoracic Society, US Centers for Disease Control and Prevention, and Infectious Diseases Society of America offer guidelines on TB treatment
The US Centers for Disease Control and Prevention provide several facts sheets and other information resources about tuberculosis
The 2003 (2004 revision) WHO guidelines for national programs for the treatment of tuberculosis are available; WHO also provides information on efforts to reduce the global burden of tuberculosis (in several languages) and its 2009 annual report on global control of tuberculosis describes the current situation (key points are available in several languages)
The WHO publishes guidelines on TB treatment
For guidelines on drug susceptibility testing (DST) and other information on TB diagnostic tests, the Stop TB Partnership's New Diagnostics Working Group has created a new Web site called Evidence-Based Tuberculosis Diagnosis
doi:10.1371/journal.pmed.1000150
PMCID: PMC2736403  PMID: 20101802
20.  Impact of single centre status on estimates of intervention effects in trials with continuous outcomes: meta-epidemiological study 
Objective To compare estimates of intervention effects between single centre and multicentre randomised controlled trials with continuous outcomes.
Design Meta-epidemiological study.
Data sources 26 meta-analyses totalling 292 randomised controlled trials (177 single centre, 115 multicentre) with continuous outcomes published between January 2007 and January 2010 in the Cochrane database of systematic reviews.
Data extraction Data were extracted on characteristics of trials, single or multicentre status, risk of bias using the risk of bias tool of the Cochrane Collaboration, and results.
Data synthesis The intervention effects were estimated with standardised mean differences. For each meta-analysis, random effects meta-regression was used to estimate the difference in standardised mean differences between single centre and multicentre trials. Differences in standardised mean differences were then pooled across meta-analyses by a random-effects meta-analysis model. A combined difference in standardised mean differences of less than 0 indicated that single centre trials showed larger treatment effects, on average, than did multicentre trials. Because single centre trials may be more prone to publication bias and may have lower methodological quality than multicentre trials, sensitivity analyses were done with adjustment for sample size and domains of the risk of bias tool.
Results Single centre trials showed larger intervention effects than did multicentre trials (combined difference in standardised mean differences −0.09, 95% confidence interval −0.17 to −0.01, P=0.04), with low heterogeneity across individual meta-analyses (I2=0%, between meta-analyses variance τ2=0.00). Adjustment for sample size slightly attenuated the difference (−0.08, −0.17 to 0.01). Adjustment for risk of bias yielded similar estimates with wider confidence intervals, some of them crossing 0 (−0.09, −0.17 to 0.00 for overall risk of bias).
Conclusions On average, single centre clinical trials with continuous outcomes showed slightly larger intervention effects than did multicentre trials. Further research is needed to investigate potential causes of these differences.
doi:10.1136/bmj.e813
PMCID: PMC3279328  PMID: 22334559
21.  Genome Reshuffling for Advanced Intercross Permutation (GRAIP): Simulation and Permutation for Advanced Intercross Population Analysis 
PLoS ONE  2008;3(4):e1977.
Background
Advanced intercross lines (AIL) are segregating populations created using a multi-generation breeding protocol for fine mapping complex trait loci (QTL) in mice and other organisms. Applying QTL mapping methods for intercross and backcross populations, often followed by naïve permutation of individuals and phenotypes, does not account for the effect of AIL family structure in which final generations have been expanded and leads to inappropriately low significance thresholds. The critical problem with naïve mapping approaches in AIL populations is that the individual is not an exchangeable unit.
Methodology/Principal Findings
The effect of family structure has immediate implications for the optimal AIL creation (many crosses, few animals per cross, and population expansion before the final generation) and we discuss these and the utility of AIL populations for QTL fine mapping. We also describe Genome Reshuffling for Advanced Intercross Permutation, (GRAIP) a method for analyzing AIL data that accounts for family structure. GRAIP permutes a more interchangeable unit in the final generation crosses – the parental genome – and simulating regeneration of a permuted AIL population based on exchanged parental identities. GRAIP determines appropriate genome-wide significance thresholds and locus-specific P-values for AILs and other populations with similar family structures. We contrast GRAIP with naïve permutation using a large densely genotyped mouse AIL population (1333 individuals from 32 crosses). A naïve permutation using coat color as a model phenotype demonstrates high false-positive locus identification and uncertain significance levels, which are corrected using GRAIP. GRAIP also detects an established hippocampus weight locus and a new locus, Hipp9a.
Conclusions and Significance
GRAIP determines appropriate genome-wide significance thresholds and locus-specific P-values for AILs and other populations with similar family structures. The effect of family structure has immediate implications for the optimal AIL creation and we discuss these and the utility of AIL populations.
doi:10.1371/journal.pone.0001977
PMCID: PMC2295257  PMID: 18431467
22.  Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis 
PLoS Medicine  2014;11(7):e1001680.
In a systematic review and meta-analysis, Giovanni Musso and colleagues examine the association between non-alcoholic fatty liver disease and chronic kidney disease.
Please see later in the article for the Editors' Summary
Background
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
Methods and Findings
English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.
Conclusion
The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place.
Why Was This Study Done?
CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis.
What Do These Findings Mean?
These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001680.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Digestive Diseases Information Clearinghouse provides information about non-alcoholic liver disease
The US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories, and information on non-alcoholic fatty liver disease
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers
The British Liver Trust, a not-for-profit organization, provides information about non-alcoholic fatty liver disease, including a patient story
doi:10.1371/journal.pmed.1001680
PMCID: PMC4106719  PMID: 25050550
23.  Continuous Subcutaneous Insulin Infusion (CSII) Pumps for Type 1 and Type 2 Adult Diabetic Populations 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics.
Clinical Need and Target Population
Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy.
Type 2, or ‘maturity-onset’ diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy.
CSII Pumps
In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It’s a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes.
Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control.
Part A: Type 1 Diabetic Adults (≥19 years)
An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations.
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?
Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHL
Adults (≥ 19 years)
Type 1 diabetes
Study evaluates CSII vs. MDI
Published between January 1, 2002 – March 24, 2009
Patient currently on intensive insulin therapy
Exclusion Criteria
Studies with <20 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life.
Search Strategy
The literature search strategy employed keywords and subject headings to capture the concepts of:
1) insulin pumps, and
2) type 1 diabetes.
The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies.
Summary of Findings
The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting.
HbA1c
In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant.
Mean Blood Glucose
Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period.
Glucose Variability
All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. also used alternate measures of glucose variability and found that both the Lability index and mean amplitude of glycemic excursions (MAGE) were in concordance with the findings using the standard deviation (SD) values of mean blood glucose, but the average daily risk range (ADRR) showed no difference between the CSII pump and MDI groups.
Hypoglycemic Events
There is conflicting evidence concerning the efficacy of CSII pumps in decreasing both mild and severe hypoglycemic events. For mild hypoglycemic events, DeVries et al. observed a higher number of events per patient week in the CSII pump group than the MDI group, while Hoogma et al. observed a higher number of events per patient year in the MDI group. The remaining two studies found no differences between the two groups in the frequency of mild hypoglycemic events. For severe hypoglycemic events, Hoogma et al. found an increase in events per patient year among MDI patients, however, all of the other RCTs showed no difference between the patient groups in this aspect.
Insulin Requirements and Adverse Events
In all four studies, insulin requirements were significantly lower in patients receiving CSII pump treatment in comparison to MDI. This difference was statistically significant in all studies. Adverse events were reported in three studies. Devries et al. found no difference in ketoacidotic episodes between CSII pump and MDI users. Bruttomesso et al. reported no adverse events during the study. Hanaire-Broutin et al. found that 30 patients experienced 58 serious adverse events (SAEs) during MDI and 23 patients had 33 SAEs during treatment out of a total of 256 patients. Most events were related to severe hypoglycemia and diabetic ketoacidosis.
Quality of Life and Patient Preference
QoL was measured in three studies and patient preference was measured in one. All three studies found an improvement in QoL for CSII users compared to those using MDI, although various instruments were used among the studies and possible reporting bias was evident as non-positive outcomes were not consistently reported. Moreover, there was also conflicting results in two of the studies using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). DeVries et al. reported no difference in treatment satisfaction between CSII pump users and MDI users while Brutomesso et al. reported that treatment satisfaction improved among CSII pump users.
Patient preference for CSII pumps was demonstrated in just one study (Hanaire-Broutin et al. 2000) and there are considerable limitations with interpreting this data as it was gathered through interview and 72% of patients that preferred CSII pumps were previously on CSII pump therapy prior to the study. As all studies were industry sponsored, findings on QoL and patient preference must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low due to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 1) While blinding of patient to intervention/control was not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. Trials reported consistent results for the outcomes HbA1c, mean blood glucose and glucose variability, but the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as most trials used highly motivated populations with fairly good glycemic control. In addition, the populations in each of the studies varied with respect to prior treatment regimens, which may not be generalizable to the population eligible for pumps in Ontario. For the outcome of hypoglycaemic events the evidence was further downgraded to very low since there was conflicting evidence between studies with respect to the frequency of mild and severe hypoglycaemic events in patients using CSII pumps as compared to CSII (see Table 2). The GRADE quality of evidence for the use of CSII in adults with type 1 diabetes is therefore low to very low and any estimate of effect is, therefore, uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c, Mean Blood Glucose, and Glucose Variability for Adults with Type 1 Diabetes
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
HbA1c: 3/4 studies show consistency however magnitude of effect varies greatly; Single study uses insulin glargine instead of NPH; Mean Blood Glucose: 3/4 studies show consistency however magnitude of effect varies between studies; Glucose Variability: All studies show consistency but 1 study only showed a significant effect in the morning
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
GRADE Quality Assessment for CSII pumps vs. MDI on Frequency of Hypoglycemic
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
Conflicting evidence with respect to mild and severe hypoglycemic events reported in studies
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
Economic Analysis
One article was included in the analysis from the economic literature scan. Four other economic evaluations were identified but did not meet our inclusion criteria. Two of these articles did not compare CSII with MDI and the other two articles used summary estimates from a mixed population with Type 1 and 2 diabetes in their economic microsimulation to estimate costs and effects over time. Included were English articles that conducted comparisons between CSII and MDI with the outcome of Quality Adjusted Life Years (QALY) in an adult population with type 1 diabetes.
From one study, a subset of the population with type 1 diabetes was identified that may be suitable and benefit from using insulin pumps. There is, however, limited data in the literature addressing the cost-effectiveness of insulin pumps versus MDI in type 1 diabetes. Longer term models are required to estimate the long term costs and effects of pumps compared to MDI in this population.
Conclusions
CSII pumps for the treatment of adults with type 1 diabetes
Based on low-quality evidence, CSII pumps confer a statistically significant but not clinically significant reduction in HbA1c and mean daily blood glucose as compared to MDI in adults with type 1 diabetes (>19 years).
CSII pumps also confer a statistically significant reduction in glucose variability as compared to MDI in adults with type 1 diabetes (>19 years) however the clinical significance is unknown.
There is indirect evidence that the use of newer long-acting insulins (e.g. insulin glargine) in MDI regimens result in less of a difference between MDI and CSII compared to differences between MDI and CSII in which older insulins are used.
There is conflicting evidence regarding both mild and severe hypoglycemic events in this population when using CSII pumps as compared to MDI. These findings are based on very low-quality evidence.
There is an improved quality of life for patients using CSII pumps as compared to MDI however, limitations exist with this evidence.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
All studies used crossover design
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations were highly motivated and half of studies used insulin pens as the mode of delivery for MDI
One short-term study concluded that pumps are cost-effective, although this was based on limited data and longer term models are required to estimate the long-term costs and effects of pumps compared to MDI in adults with type 1 diabetes.
Part B: Type 2 Diabetic Adults
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 2 diabetes?
Are CSII pumps more effective than MDI for improving other outcomes related to diabetes such as quality of life?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, Excerpta Medica Database (EMBASE), Cumulative Index to Nursing & Allied Health Literature (CINAHL)
Any person with type 2 diabetes requiring insulin treatment intensive
Published between January 1, 2000 – August 2008
Exclusion Criteria
Studies with <10 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels. Other outcomes of interest were mean blood glucose level, glucose variability, insulin requirements, frequency of hypoglycemic events, adverse events, and quality of life.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and August 15, 2008. Studies meeting the inclusion criteria were selected from the search results. Data on the study characteristics, patient characteristics, primary and secondary treatment outcomes, and adverse events were abstracted. Reference lists of selected articles were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The database search identified 286 relevant citations published between 1996 and August 2008. Of the 286 abstracts reviewed, four RCTs met the inclusion criteria outlined above. Upon examination, two studies were subsequently excluded from the meta-analysis due to small sample size and missing data (Berthe et al.), as well as outlier status and high drop out rate (Wainstein et al) which is consistent with previously reported meta-analyses on this topic (Jeitler et al 2008, and Fatourechi M et al. 2009).
HbA1c
The primary outcome in this analysis was reduction in HbA1c. Both studies demonstrated that both CSII pumps and MDI reduce HbA1c, but neither treatment modality was found to be superior to the other. The results of a random effects model meta-analysis showed a mean difference in HbA1c of -0.14 (-0.40, 0.13) between the two groups, which was found not to be statistically or clinically significant. There was no statistical heterogeneity observed between the two studies (I2=0%).
Forrest plot of two parallel, RCTs comparing CSII to MDI in type 2 diabetes
Secondary Outcomes
Mean Blood Glucose and Glucose Variability
Mean blood glucose was only used as an efficacy outcome in one study (Raskin et al. 2003). The authors found that the only time point in which there were consistently lower blood glucose values for the CSII group compared to the MDI group was 90 minutes after breakfast. Glucose variability was not examined in either study and the authors reported no difference in weight gain between the CSII pump group and MDI groups at the end of study. Conflicting results were reported regarding injection site reactions between the two studies. Herman et al. reported no difference in the number of subjects experiencing site problems between the two groups, while Raskin et al. reported that there were no injection site reactions in the MDI group but 15 such episodes among 8 participants in the CSII pump group.
Frequency of Hypoglycemic Events and Insulin Requirements
All studies reported that there were no differences in the number of mild hypoglycemic events in patients on CSII pumps versus MDI. Herman et al. also reported no differences in the number of severe hypoglycemic events in patients using CSII pumps compared to those on MDI. Raskin et al. reported that there were no severe hypoglycemic events in either group throughout the study duration. Insulin requirements were only examined in Herman et al., who found that daily insulin requirements were equal between the CSII pump and MDI treatment groups.
Quality of Life
QoL was measured by Herman et al. using the Diabetes Quality of Life Clinical Trial Questionnaire (DQOLCTQ). There were no differences reported between CSII users and MDI users for treatment satisfaction, diabetes impact, and worry-related scores. Patient satisfaction was measured in Raskin et al. using a patient satisfaction questionnaire, whose results indicated that patients in the CSII pump group had significantly greater improvement in overall treatment satisfaction at the end of the study compared to the MDI group. Although patient preference was also reported, it was only examined in the CSII pump group, thus results indicating a greater preference for CSII pumps in this groups (as compared to prior injectable insulin regimens) are biased and must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low according to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 3). While blinding of patient to intervention/control is not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. ITT was not clearly explained in one study and heterogeneity between study populations was evident from participants’ treatment regimens prior to study initiation. Although trials reported consistent results for HbA1c outcomes, the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as trials required patients to adhere to an intense SMBG regimen. This suggests that patients were highly motivated. In addition, since prior treatment regimens varied between participants (no requirement for patients to be on MDI), study findings may not be generalizable to the population eligible for a pump in Ontario. The GRADE quality of evidence for the use of CSII in adults with type 2 diabetes is, therefore, low and any estimate of effect is uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c Adults with Type 2 Diabetes
Inadequate or unknown allocation concealment (all studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; ITT not well explained in 1 of 2 studies
Indirect due to lack of generalizability of findings since participants varied with respect to prior treatment regimens and intensive SMBG suggests highly motivated populations used in trials.
Economic Analysis
An economic analysis of CSII pumps was carried out using the Ontario Diabetes Economic Model (ODEM) and has been previously described in the report entitled “Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario”, part of the diabetes strategy evidence series. Based on the analysis, CSII pumps are not cost-effective for adults with type 2 diabetes, either for the age 65+ sub-group or for all patients in general. Details of the analysis can be found in the full report.
Conclusions
CSII pumps for the treatment of adults with type 2 diabetes
There is low quality evidence demonstrating that the efficacy of CSII pumps is not superior to MDI for adult type 2 diabetics.
There were no differences in the number of mild and severe hypoglycemic events in patients on CSII pumps versus MDI.
There are conflicting findings with respect to an improved quality of life for patients using CSII pumps as compared to MDI.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations may not reflect eligible patient population in Ontario (participants not necessarily on MDI prior to study initiation, pen used in one study and frequency of SMBG required during study was high suggesting highly motivated participants)
Based on ODEM, insulin pumps are not cost-effective for adults with type 2 diabetes either for the age 65+ sub-group or for all patients in general.
PMCID: PMC3377523  PMID: 23074525
24.  Small studies may overestimate the effect sizes in critical care meta-analyses: a meta-epidemiological study 
Critical Care  2013;17(1):R2.
Introduction
Small-study effects refer to the fact that trials with limited sample sizes are more likely to report larger beneficial effects than large trials. However, this has never been investigated in critical care medicine. Thus, the present study aimed to examine the presence and extent of small-study effects in critical care medicine.
Methods
Critical care meta-analyses involving randomized controlled trials and reported mortality as an outcome measure were considered eligible for the study. Component trials were classified as large (≥100 patients per arm) and small (<100 patients per arm) according to their sample sizes. Ratio of odds ratio (ROR) was calculated for each meta-analysis and then RORs were combined using a meta-analytic approach. ROR<1 indicated larger beneficial effect in small trials. Small and large trials were compared in methodological qualities including sequence generating, blinding, allocation concealment, intention to treat and sample size calculation.
Results
A total of 27 critical care meta-analyses involving 317 trials were included. Of them, five meta-analyses showed statistically significant RORs <1, and other meta-analyses did not reach a statistical significance. Overall, the pooled ROR was 0.60 (95% CI: 0.53 to 0.68); the heterogeneity was moderate with an I2 of 50.3% (chi-squared = 52.30; P = 0.002). Large trials showed significantly better reporting quality than small trials in terms of sequence generating, allocation concealment, blinding, intention to treat, sample size calculation and incomplete follow-up data.
Conclusions
Small trials are more likely to report larger beneficial effects than large trials in critical care medicine, which could be partly explained by the lower methodological quality in small trials. Caution should be practiced in the interpretation of meta-analyses involving small trials.
doi:10.1186/cc11919
PMCID: PMC4056100  PMID: 23302257
25.  Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews 
Background Many meta-analyses contain only a small number of studies, which makes it difficult to estimate the extent of between-study heterogeneity. Bayesian meta-analysis allows incorporation of external evidence on heterogeneity, and offers advantages over conventional random-effects meta-analysis. To assist in this, we provide empirical evidence on the likely extent of heterogeneity in particular areas of health care.
Methods Our analyses included 14 886 meta-analyses from the Cochrane Database of Systematic Reviews. We classified each meta-analysis according to the type of outcome, type of intervention comparison and medical specialty. By modelling the study data from all meta-analyses simultaneously, using the log odds ratio scale, we investigated the impact of meta-analysis characteristics on the underlying between-study heterogeneity variance. Predictive distributions were obtained for the heterogeneity expected in future meta-analyses.
Results Between-study heterogeneity variances for meta-analyses in which the outcome was all-cause mortality were found to be on average 17% (95% CI 10–26) of variances for other outcomes. In meta-analyses comparing two active pharmacological interventions, heterogeneity was on average 75% (95% CI 58–95) of variances for non-pharmacological interventions. Meta-analysis size was found to have only a small effect on heterogeneity. Predictive distributions are presented for nine different settings, defined by type of outcome and type of intervention comparison. For example, for a planned meta-analysis comparing a pharmacological intervention against placebo or control with a subjectively measured outcome, the predictive distribution for heterogeneity is a log-normal (−2.13, 1.582) distribution, which has a median value of 0.12. In an example of meta-analysis of six studies, incorporating external evidence led to a smaller heterogeneity estimate and a narrower confidence interval for the combined intervention effect.
Conclusions Meta-analysis characteristics were strongly associated with the degree of between-study heterogeneity, and predictive distributions for heterogeneity differed substantially across settings. The informative priors provided will be very beneficial in future meta-analyses including few studies.
doi:10.1093/ije/dys041
PMCID: PMC3396310  PMID: 22461129
Meta-analysis; heterogeneity; intervention studies; Bayesian analysis

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