Using Smalltalk as a Reflective Executable Meta-Language

Object-oriented meta-languages such as MOF or EMOF are often used to specify domain specific languages. However, these meta-languages lack the ability to describe behavior or operational semantics. Several approaches used a subset of Java mixed with OCL as executable meta-languages. In this paper, we report our experience of using Smalltalk as an executable and integrated meta-language. We validated this approach in incrementally building over the last decade, Moose, a meta-described reengineering environment. The reflective capabilities of Smalltalk support a uniform way of letting the base developer focus on his tasks while at the same time allowing him to meta-describe his domain model. The advantage of our this approach is that the developer uses the same tools and environment

Anger, hostility, and posttraumatic stress disorder in trauma-exposed adults: A meta-analysis

This meta-analysis synthesizes the available data on the strength of association between anger and posttraumatic stress disorder (PTSD) and between hostility and PTSD, covering 39 studies with trauma-exposed adults. Effect sizes did not differ for anger and hostility, which could therefore be combined; effect sizes for anger expression variables were analyzed separately. The analyses revealed large effects. The weighted mean effect size (r) was .48 for anger–hostility, .29 for anger out, .53 for anger in, and -.44 for anger control. Moderator analyses were conducted for anger–hostility, showing that effect sizes were substantially larger with increasing time since the event and that effect sizes were larger in samples with military war experience than in samples that had experienced other types of traumatic events.

Efficacy of psychological therapy in schizophrenia: conclusions from meta-analyses

Over the past years, evidence for the efficacy of psychological therapies in schizophrenia has been summarized in a series of meta-analyses. The present contribution aims to provide a descriptive survey of the evidence for the efficacy of psychological therapies as derived from these meta-analyses and to supplement them by selected findings from an own recent meta-analysis. Relevant meta-analyses and randomized controlled trials were identified by searching several electronic databases and by hand searching of reference lists. In order to compare the findings of the existing meta-analyses, the reported effect sizes were extracted and transformed into a uniform effect size measure where possible. For the own meta-analysis, weighted mean effect size differences between comparison groups regarding various types of outcomes were estimated. Their significance was tested by confidence intervals, and heterogeneity tests were applied to examine the consistency of the effects. From the available meta-analyses, social skills training, cognitive remediation, psychoeducational coping-oriented interventions with families and relatives, as well as cognitive behavioral therapy of persistent positive symptoms emerge as effective adjuncts to pharmacotherapy. Social skills training consistently effectuates the acquisition of social skills, cognitive remediation leads to short-term improvements in cognitive functioning, family interventions decrease relapse and hospitalization rates, and cognitive behavioral therapy results in a reduction of positive symptoms. These benefits seem to be accompanied by slight improvements in social functioning. However, open questions remain as to the specific therapeutic ingredients, to the synergistic effects, to the indication, as well as to the generalizability of the findings to routine care.

A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints

Publication bias and related bias in meta-analysis is often examined by visually checking for asymmetry in funnel plots of treatment effect against its standard error. Formal statistical tests of funnel plot asymmetry have been proposed, but when applied to binary outcome data these can give false-positive rates that are higher than the nominal level in some situations (large treatment effects, or few events per trial, or all trials of similar sizes). We develop a modified linear regression test for funnel plot asymmetry based on the efficient score and its variance, Fisher's information. The performance of this test is compared to the other proposed tests in simulation analyses based on the characteristics of published controlled trials. When there is little or no between-trial heterogeneity, this modified test has a false-positive rate close to the nominal level while maintaining similar power to the original linear regression test ('Egger' test). When the degree of between-trial heterogeneity is large, none of the tests that have been proposed has uniformly good properties.

Helicobacter pylori infection and colorectal cancer risk: a meta-analysis

BACKGROUND: Several studies suggested an association between Helicobacter pylori infection and colorectal carcinoma or adenoma risk. However, different authors reported quite varying estimates. We carried out a systematic review and meta-analysis of published studies investigating this association and paid special attention to the possibility of publication bias and sources of heterogeneity between studies. Materials and METHODS: An extensive literature search and cross-referencing were performed to identify all published studies. Summary estimates were obtained using random-effects models. The presence of possible publication bias was assessed using different statistical approaches. RESULTS: In a meta-analysis of the 11 identified human studies, published between 1991 and 2002, a summary odds ratio of 1.4 (95% CI, 1.1-1.8) was estimated for the association between H. pylori infection and colorectal cancer risk. The graphical funnel plot appeared asymmetrical, but the formal statistical evaluations did not provide strong evidence of publication bias. The proportion of variation of study results because of heterogeneity was small (36.5%). CONCLUSIONS: The results of our meta-analysis are consistent with a possible small increase in risk of colorectal cancer because of H. pylori infection. However, the possibility of some publication bias cannot be ruled out, although it could not be statistically confirmed. Larger, better designed and better controlled studies are needed to clarify the situation.

[Effectiveness of Integrated Psychological Therapy for schizophrenia patients : A meta-analysis including 28 independent studies.]

Over the past 24 years, research groups in eight different countries have conducted 28 independent evaluation studies on Integrated Psychological Therapy (IPT) including 1,329 schizophrenia patients. The present study examines the effectiveness of IPT under different treatment conditions by means of a meta-analytic review. The most salient results indicate favourable mean effect sizes for IPT in comparison to control groups (placebo-attention conditions, standard care). Moreover, the superiority of IPT continues to increase during an average catamnestic phase of 8.1 months. The method obtains similarly favourable effects in different functional areas (neurocognition, social behaviour, psychopathology) and different assessment formats (expert ratings, self-reports, psychological tests). The comparison of different settings of IPT and control groups shows the superiority of IPT in any given therapy or site condition. The analysis of subsamples of inpatients, outpatients, and patients in varying rehabilitation phases reveals similarly favourable effects. Comparing only high-quality studies yields comparable results. In summary, the present meta-analysis corroborates evidence that IPT is an 'empirically validated treatment' according to American Psychiatric Association guidelines.

Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis

Whether the two drug-eluting stents approved by the US Food and Drug Administration-a sirolimus-eluting stent and a paclitaxel-eluting stent-are associated with increased risks of death, myocardial infarction, or stent thrombosis compared with bare-metal stents is uncertain. Our aim was to compare the safety and effectiveness of these stents.

Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis

This systematic review assesses the evidence for an association between Mycobacterium avium subspecies paratuberculosis (MAP) and Crohn's disease. We analysed 28 case-control studies comparing MAP in patients with Crohn's disease with individuals free of inflammatory bowel disease (IBD) or patients with ulcerative colitis. Compared with individuals free of IBD, the pooled odds ratio (OR) from studies using PCR in tissue samples was 7.01 (95% CI 3.95-12.4) and was 1.72 (1.02-2.90) in studies using ELISA in serum. ORs were similar for comparisons with ulcerative colitis patients (PCR, 4.13 [1.57-10.9]; ELISA, 1.88 [1.26-2.81]). The association of MAP with Crohn's disease seems to be specific, but its role in the aetiology of Crohn's disease remains to be defined.

Bibliographic study showed improving methodology of meta-analyses published in leading journals 1993-2002

OBJECTIVE: To assess the methodology of meta-analyses published in leading general and specialist medical journals over a 10-year period. STUDY DESIGN AND SETTING: Volumes 1993-2002 of four general medicine journals and four specialist journals were searched by hand for meta-analyses including at least five controlled trials. Characteristics were assessed using a standardized questionnaire. RESULTS: A total of 272 meta-analyses, which included a median of 11 trials (range 5-195), were assessed. Most (81%) were published in general medicine journals. The median (range) number of databases searched increased from 1 (1-9) in 1993/1994 to 3.5 (1-21) in 2001/2002, P<0.0001. The proportion of meta-analyses including searches by hand (10% in 1993/1994, 25% in 2001/2002, P=0.005), searches of the grey literature (29%, 51%, P=0.010 by chi-square test), and of trial registers (10%, 32%, P=0.025) also increased. Assessments of the quality of trials also became more common (45%, 70%, P=0.008), including whether allocation of patients to treatment groups had been concealed (24%, 60%, P=0.001). The methodological and reporting quality was consistently higher in general medicine compared to specialist journals. CONCLUSION: Many meta-analyses published in leading journals have important methodological limitations. The situation has improved in recent years but considerable room for further improvements remains.

Grey literature in meta-analyses of randomized trials of health care interventions

BACKGROUND: The inclusion of grey literature (i.e. literature that has not been formally published) in systematic reviews may help to overcome some of the problems of publication bias, which can arise due to the selective availability of data. OBJECTIVES: To review systematically research studies, which have investigated the impact of grey literature in meta-analyses of randomized trials of health care interventions. SEARCH STRATEGY: We searched the Cochrane Methodology Register (The Cochrane Library Issue 3, 2005), MEDLINE (1966 to 20 May 2005), the Science Citation Index (June 2005) and contacted researchers who may have carried out relevant studies. SELECTION CRITERIA: A study was considered eligible for this review if it compared the effect of the inclusion and exclusion of grey literature on the results of a cohort of meta-analyses of randomized trials. DATA COLLECTION AND ANALYSIS: Data were extracted from each report independently by two reviewers. The main outcome measure was an estimate of the impact of trials from the grey literature on the pooled effect estimates of the meta-analyses. Information was also collected on the area of health care, the number of meta-analyses, the number of trials, the number of trial participants, the year of publication of the trials, the language and country of publication of the trials, the number and type of grey and published literature, and methodological quality. MAIN RESULTS: Five studies met the inclusion criteria. All five studies showed that published trials showed an overall greater treatment effect than grey trials. This difference was statistically significant in one of the five studies. Data could be combined for three of the five studies. This showed that, on average, published trials showed a 9% greater treatment effect than grey trials (ratio of odds ratios for grey versus published trials 1.09; 95% CI 1.03-1.16). Overall there were more published trials included in the meta-analyses than grey trials (median 224 (IQR 108-365) versus 45(IQR 40-102)). Published trials had more participants on average. The most common types of grey literature were abstracts (55%) and unpublished data (30%). There is limited evidence to show whether grey trials are of poorer methodological quality than published trials. AUTHORS' CONCLUSIONS: This review shows that published trials tend to be larger and show an overall greater treatment effect than grey trials. This has important implications for reviewers who need to ensure they identify grey trials, in order to minimise the risk of introducing bias into their review.

A unification of models for meta-analysis of diagnostic accuracy studies

Studies of diagnostic accuracy require more sophisticated methods for their meta-analysis than studies of therapeutic interventions. A number of different, and apparently divergent, methods for meta-analysis of diagnostic studies have been proposed, including two alternative approaches that are statistically rigorous and allow for between-study variability: the hierarchical summary receiver operating characteristic (ROC) model (Rutter and Gatsonis, 2001) and bivariate random-effects meta-analysis (van Houwelingen and others, 1993), (van Houwelingen and others, 2002), (Reitsma and others, 2005). We show that these two models are very closely related, and define the circumstances in which they are identical. We discuss the different forms of summary model output suggested by the two approaches, including summary ROC curves, summary points, confidence regions, and prediction regions.

Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis

OBJECTIVE: To compare the effectiveness and safety of intraarticular high-molecular hylan with standard preparations of hyaluronic acids in osteoarthritis of the knee. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials comparing hylan with a hyaluronic acid in patients with knee osteoarthritis. Trials were identified by systematic searches of Central, Medline, EMBase, Cinahl, the Food and Drug Administration, and Science Citation Index supplemented by hand searches of conference proceedings and reference lists (last update November 2006). Literature screening and data extraction were performed in duplicate. Effect sizes were calculated from differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled standard deviation. Trials were combined using random-effects meta-analysis. RESULTS: Thirteen trials with a pooled total of 2,085 patients contributed to the meta-analysis. The pooled effect size was -0.27 (95% confidence interval [95% CI] -0.55, 0.01), favoring hylan, but between-trial heterogeneity was high (I(2) = 88%). Trials with blinded patients, adequate concealment of allocation, and an intent-to-treat analysis had pooled effect sizes near null. The meta-analyses on safety revealed an increased risk associated with hylan for any local adverse events (relative risk [RR] 1.91; 95% CI 1.04, 3.49; I(2) = 28%) and for flares (RR 2.04; 95% CI 1.18, 3.53; I(2) = 0%). CONCLUSION: Given the likely lack of a superior effectiveness of hylan over hyaluronic acids and the increased risk of local adverse events associated with hylan, we discourage the use of intraarticular hylan in patients with knee osteoarthritis in clinical research or practice.

A meta-analysis of 16 randomized trials of sirolimus-eluting stents versus paclitaxel-eluting stents in patients with coronary artery disease

OBJECTIVES: Our purpose was to make a synthesis of the available evidence on the relative efficacy and safety of 2 drug-eluting stents (DES)--sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES)--in patients with coronary artery disease. BACKGROUND: It is not known whether there are differences in late outcomes between the 2 most commonly used DES: SES and PES. METHODS: Sixteen randomized trials of SES versus PES with a total number of 8,695 patients were included in this meta-analysis. A full set of individual outcome data from 5,562 patients was also available. Mean follow-up period ranged from 9 to 37 months. The primary efficacy end point was the need for reintervention (target lesion revascularization). The primary safety end point was stent thrombosis. Secondary end points were death and recurrent myocardial infarction (MI). RESULTS: No significant heterogeneity was found across trials. Compared with PES, SES significantly reduced the risk of reintervention (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.63 to 0.87, p < 0.001) and stent thrombosis (HR 0.66; 95% CI 0.46 to 0.94, p = 0.02) without significantly impacting on the risk of death (HR 0.92; 95% CI 0.74 to 1.13, p = 0.43) or MI (HR 0.84; 95% CI 0.69 to 1.03, p = 0.10). CONCLUSIONS: Sirolimus-eluting stents are superior to PES in terms of a significant reduction of the risk of reintervention and stent thrombosis. The risk of death was not significantly different between the 2 DES, but there was a trend toward a higher risk of MI with PES, especially after the first year from the procedure.

Meta-analysis: chondroitin for osteoarthritis of the knee or hip

BACKGROUND: Previous meta-analyses described moderate to large benefits of chondroitin in patients with osteoarthritis. However, recent large-scale trials did not find evidence of an effect. PURPOSE: To determine the effects of chondroitin on pain in patients with osteoarthritis. DATA SOURCES: The authors searched the Cochrane Central Register of Controlled Trials (1970 to 2006), MEDLINE (1966 to 2006), EMBASE (1980 to 2006), CINAHL (1970 to 2006), and conference proceedings; checked reference lists; and contacted authors. The last update of searches was performed on 30 November 2006. STUDY SELECTION: Studies were included if they were randomized or quasi-randomized, controlled trials that compared chondroitin with placebo or with no treatment in patients with osteoarthritis of the knee or hip. There were no language restrictions. DATA EXTRACTION: The authors extracted data in duplicate. Effect sizes were calculated from the differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled SD. Trials were combined by using random-effects meta-analysis. DATA SYNTHESIS: 20 trials (3846 patients) contributed to the meta-analysis, which revealed a high degree of heterogeneity among the trials (I2 = 92%). Small trials, trials with unclear concealment of allocation, and trials that were not analyzed according to the intention-to-treat principle showed larger effects in favor of chondroitin than did the remaining trials. When the authors restricted the analysis to the 3 trials with large sample sizes and an intention-to-treat analysis, 40% of patients were included. This resulted in an effect size of -0.03 (95% CI, -0.13 to 0.07; I2 = 0%) and corresponded to a difference of 0.6 mm on a 10-cm visual analogue scale. A meta-analysis of 12 trials showed a pooled relative risk of 0.99 (CI, 0.76 to 1.31) for any adverse event. LIMITATIONS: For 9 trials, the authors had to use approximations to calculate effect sizes. Trial quality was generally low, heterogeneity among the trials made initial interpretation of results difficult, and exploring sources of heterogeneity in meta-regression and stratified analyses may be unreliable. CONCLUSIONS: Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged.